New South Wales Supreme Court CITATION : Denzin & ors v Nutrasweet & ors [1999] NSWSC 106 CURRENT JURISDICTION : Common Law Division FILE NUMBER(S) : 10927/90; 11890/98; 12141/89; 12142/89; 13864/89; 13983/89; 11354/90; 123255/90; 13528/93 HEARING DATE(S) : JUDGMENT DATE : 22 February 1999 Fiona Mary Denzin P1 Margaret Ann Lane P2 Margaret Orders P3 Brenda Southern P4 PARTIES : Sonya Lee Moylan P5 Sharon Gai Robertson P6 Karen Cynthia Tabbah P7 Deborah Lea Gentle P8 Wendy Janene Lee P9 The Nutrasweet Company D1 JUDGMENT OF : Bruce J COUNSEL : SOLICITORS : CATCHWORDS : DECISION : for the defendants THE SUPREME COURT OF NEW SOUTH WALES COMMON LAW DIVISION CORAM: BRUCE J MONDAY 22 FEBRUARY 1999 010927/90 FIONA MARY DENZIN v THE NUTRASWEET COMPANY & 5 ORS. 011890/89 MARGARET ANN LANE v THE NUTRASWEET COMPANY 6 ORS. 012141/89 MARGARET ORDERS v THE NUTRASWEET COMPANY 5 ORS. 012142/89 BRENDA SOUTHERN v THE NUTRASWEET COMPANY & 5 ORS. 013864/89 SONYA LEE MOYLAN v THE NUTRASWEET COMPANY & 5 ORS. 013983/89 SHARON GAI ROBERTSON v THE NUTRASWEET COMPANY & 5 ORS. 011354/90 KAREN CYNTHIA TABBAH v THE NUTRASWEET COMPANY & 5 ORS. 0123255/90 DEBORAH LEA GENTLE v THE NUTRASWEET COMPANY & 5 ORS. 013528/93 WENDY JANENE LEE v THE NUTRASWEET COMPANY & 3 ORS. JUDGMENT TABLE OF CONTENTS Page Summary (i)-(iii) 1. Introduction 1-43 2. Pelvic Inflammatory Disease 44-65 3. Causation 66-98 4. Probability of Causation 99 4.1 Epidemiology 100-207 4.2 Scientific Analysis 208-243 4.3 Clinical Observations 244 5. Warnings 245 6. Conclusion 246-247 Schedule I 248-408 Schedule II 409-410 Schedule III 411-412 SUMMARY The plaintiffs in these proceedings have each suffered considerable physical and emotional injury as a result of contracting pelvic inflammatory disease which has affected their fertility. There is no doubt they have each suffered considerably. They have sued the manufacturer and suppliers of the IUD device they each used essentially on the basis that the manufacturer was negligent in the design of the device and failed to warn them of risks to their health of which they were aware. The litigation was the longest and most complex product liability litigation in Australian legal history. The hearing of evidence commenced on 24 January 1996 and concluded on 13 September 1996. The oral evidence comprised substantially approximately 15 lineal metres of folders of exhibits. The written submissions of the parties comprised approximately 3 lineal metres of folders of submissions and supporting documents. Oral submissions were delivered between 27 October, 1997 and 23 December, 1997. It was common ground that injury of the type sustained by the plaintiffs could be sustained without the use of the defendants' device and that it could also be sustained with the use of the defendants' device. The plaintiffs submitted that if they showed any negligence on the part of the defendants which materially increased the risk to the users of the devices then that was sufficient to establish causation of their injuries so as to entitle them to succeed against the defendants unless the defendants established that the injury was due to some other cause. In my view this is not the law and until it is changed by either a decision of the High Court of Australia or by the Parliament of New South Wales it is necessary for the plaintiffs to establish that their injuries were, on the balance of probability, caused by or materially contributed to by the negligent acts of the defendants. In my view the plaintiffs have not established that the defendants were negligent in any material way nor that the actions of the defendants caused or materially contributed to the injuries to the plaintiffs. Further, in my view, the plaintiffs have not established any breach of any duty to warn the plaintiffs of any matter. There will be judgment for the defendants in each of the cases. 1. INTRODUCTION This litigation involves nine lead cases selected from some two hundred commenced in this Court claiming damages for injury said to arise from the use of an interuterine device known as Copper 7 (Cu-7) or Gravigard or from the use of another interuterine device known as the Mini-Gravigard which was a smaller version of the first device. These devices will be referred to respectively as " Cu-7 " and " Mini ". The devices used fine copper wire carried on a plastic vehicle which is somewhat in the shape of the number 7 for contraceptive purposes. The devices were inserted into the uterus of the user and there was a tail of polypropylene attached to the device which after insertion passed from the device through the cervix of the user into her vagina. The devices were apparently extremely successful in preventing pregnancies occurring while they were in place. The mechanism by which the devices achieved their objective is complex and not known with certainty even by the manufacturer but an understanding of the mechanism is not necessary for the determination of the issues which arise in these cases. The Cu-7 was initially developed by a Chilean doctor, Hime Zipper. A licence agreement was entered into on 13 April 1970 between a corporation with which Dr Zipper was associated and one of the defendants which is a United States corporation. That licence agreement ran until 31 December 1985 when there was an option to purchase the intellectual property associated with the device. By about that time the Cu-7 was no longer marketed in the United States although it continued to be marketed in other countries including Australia until 1990. The Mini was marketed in Australia but not in the United States. This device was apparently regarded as being more appropriate than the Cu-7 for use by women who had never conceived. Each of the nine plaintiffs had one or more Cu-7s inserted in the period between 1974 and 1981. In the selection of the nine lead cases before the Court four plaintiffs were identified as parous, that is they had already borne children at the time they used the Cu-7 devices, namely Moylan, Ottaway, Robertson, Southren and four as nulliparous, that is they had never borne a child, namely Gentle, Lane, Lee and Orders. One of the plaintiffs, Denzin, was nulliparous when she began using the Cu-7 and when she subsequently used the Mini, the first in 1983 and the second in 1985. Four of the plaintiffs, Denzin, Gentle, Lee and Ottaway had documented string retractions, that is the polypropolene string attached to the plastic device retracted from the vagina into the uterus after the device had been inserted. Four of the plaintiffs, Denzin, Orders, Ottaway and Southren had an ectopic pregnancy or ectopic pregnancies. One of the plaintiffs, Gentle, had a septic abortion with her Cu-7 in place. All of the plaintiffs except Gentle suffered either complete infertility or impaired fertility. The defendants are all members of what is now the Monsanto Group of companies. The first defendant carried on all aspects of the business associated with the Cu-7 at all times at least up to 24 May 1978. At that time it was known as G D Searle and Co., but subsequently changed its name to The NutraSweet Company. The second defendant was called Searle Australia Pty Limited at all relevant times and is now known as Monsanto Australia Pty Limited. It carried on the business of distribution, sales, promotion, marketing and provision of information and warnings for health care providers and users within Australia at all relevant times. The third defendant carried on the business associated with the Cu-7 in the period from 24 May 1978 to 1 January 1986 and the fourth defendant carried on that business from 1 January 1986. The fourth defendant changed its name to G D Searle & Co. on 2 January 1986. However, almost all references to "G D Searle & Co." are references to the first defendant. The plaintiffs' case was in essence that use of the devices caused the plaintiffs to contract Pelvic Inflammatory Disease (PID) causing damage to their reproductive organs and thus either permanent or partial infertility and, in some instances, damage to the fallopian tubes resulting in ectopic pregnancies. They submitted that the use of the devices put the users at greater risk of the introduction of infection into the uterine cavity or the fallopian tubes or to the ovaries than was the risk to non-users of the devices. The plaintiffs claimed exemplary damages on the basis that the defendants acted in knowing and contumelious disregard of their rights, health and welfare. The questions to be determined are: 1. Did the plaintiffs contract PID? 2. If so, was use of the defendants' products causally connected with the contraction of PID by the plaintiffs? 3. If so, how were the defendants' products causally connected? 4. Did that connection or connections or any conduct of the defendants or any of them constitute a breach or breaches of the duty of care owed by the defendants to the plaintiffs? 5. If there was a breach, did the defendants or any of them act in knowing and contumelious disregard of the plaintiffs' rights, health and welfare? The hearing of these cases commenced on 29 January, 1996 and the evidence concluded on 13 September, 1996. The addresses concluded on 23 December, 1997. The oral evidence comprised substantially cross-examination of expert witnesses on written statements of evidence tendered by them. The documentary evidence comprised approximately 15 lineal metres of folders of exhibits and included numerous photocopies of medical and scientific papers and publications. A great deal of the exhibits are difficult to read. The quality and complexity of the evidence was such that I clearly informed the parties a number of times during the hearing that the issues which would be determined were:- 1. Those properly raised by the pleadings and in accordance with the particulars provided, and 2. Those which were the explicit subject of submissions by the parties. I also informed the parties that the only evidence which would be considered would be that evidence which was explicitly referred to in the submissions. The submissions of the parties were partly written and partly oral. The written submissions are contained in approximately 3 lineal metres of folders of submissions and supporting documents. The oral submissions were delivered between 27 October, 1997 and 23 December, 1997. In order to bring some order to the vast quantity of material before the Court I have included the following schedules in this judgment: Schedule I A chronological list of relevant facts, documents and publications. The chronology does not include the facts relevant to each individual plaintiff except for the dates of insertion of the defendants' devices. Schedule II Overview of Plaintiffs' Pleadings - Common Law Negligence - Gravigard (Cu-7) prepared by the defendants. Schedule III Overview of Common Law Pleadings: - Design/Manufacture - Clinical Trials - Marketing prepared by the defendants. SUMMARY OF PLAINTIFFS' CASE The two pillars of the plaintiffs' cases (T.7412, l.46) are based on negligence. They are: 1. Failure to warn 2. Defective design 1. Failure to warn The plaintiffs' case on this basis is that 1.1 A woman was placed at greater risk of contracting PID if she used an IUD including a Cu-7. 1.2 That greater risk was known to the defendants. 1.3 The defendants failed to warn: 1.3.1 the plaintiffs; or 1.3.2 the plaintiffs' doctors. The threshold question in determining liability on this count is whether a woman was placed at greater risk of contracting PID if she used a Cu-7. The plaintiffs submitted that the affirmative of this question was established by: 1. Epidemiological evidence. 2. The scientific case as to the role of the IUD and its design defects in increasing the risk of PID. 3. The causes of increased risk of PID as explained from clinical expertise. 2. Defective Design The plaintiffs allege that the Cu-7 had the following defects of which the manufacturer was aware but which it failed to rectify: 2.1 Fraying of the tailstring 2.2 "Memory" of the tailstring which caused it to retract into the uterus 2.3 The inserter tube had the string on the outside of the tube. 2.1 Fraying of the tailstring. This was said to have materially increased the risk of injury from ascending infection by:- (i) fraying creating rough surfaces thereby increasing the area to which bacteria could adhere; (ii) bacteria prefer rough surfaces; (iii) frayed surfaces allowed more bacteria to adhere; (iv) more bacteria could colonise the frayed tailstring; (v) the frayed surface provided a locus for infectious agents which can affect the uterus. The plaintiffs' evidence called to support the case pleaded that the tailstring had a design defect by virtue of being made of polypropylene and subjected to tension in manufacture making it prone to fray. It was not disputed that Cu-7 tailstrings frayed and suffered other morphological (although not chemical) breakdown. This extended to all Cu-7 tailstrings over time. The disputes as to fraying related to how much and where. The plaintiffs tendered a great many documents dating from 1974 (the " dogs breakfast " memorandum - see document 1 dated 17 September 1974 in the fraying bundle attached to Part 5, 'Documentary Case'), including documents from Searle Australia and from the New South Wales Family Planning Association which show that the fraying was readily apparent to the naked eye and a source of real concern. Searle's documents state that " Fraying of some degree exists throughout our production ." (Exhibit P8, Tab 2, page 30). The plaintiffs led evidence to show that Cu-7 tailstrings frayed throughout their length. Professor Fives-Taylor gave evidence as to research performed by her group at the University of Vermont which undertook quantitative scoring of fraying along the length of the tailstrings. She said they found frays along the length of the tailstrings. Dr Piziali gave evidence for the defendants, that a number of new and used tailstrings were examined optically or by scanning electron microscope. These observations were that no or few fibrils appeared on polyethylene or nylon tailstrings whereas polypropylene tailstrings did exhibit fibrillation. However the observations reported by Dr Piziali's team were of fraying on the vaginal portion only of such strings. In this respect Dr Piziali's observations differ from those of Professor Fives-Taylor. They also differ from the observations made by the Australian National Biological Standards laboratory which in February 1980 examined a tailstring and reported to the Commonwealth Department of Health that " numerous fraying parts were evident along the entire length of the filament together with some lengths of split ends protruding from the filament ." (Document No. 134 in Part 5, 'Documentary Case'). There is no dispute between the parties as to the fraying being caused by the way in which the tailstrings were manufactured. Professor Robertson gave evidence that application of tension (or drawing) to the Cu-7 tailstring aligned polymer chains along the length of the tailstring. This had the effect of strengthening the tailstring along its length at the cost of weakening lateral bonds within the tailstring. The result was that the tailstring would withstand a greater pull before breaking but became prone to fray. His evidence applies to the entirety of the length of the tailstring. It was submitted that the evidence of Professor Fives-Taylor and Professor Robertson and the letter from the National Biological Standards Laboratory support the finding that Cu-7 tailstrings, being made of highly drawn polypropylene, frayed throughout their length. I accept that this was so. The defendants argued that fraying by itself was solely an aesthetic problem without medical consequences. The plaintiffs submitted that a frayed tailstring will have a larger and rougher surface area than a non-fraying tailstring and will thereby attract bacterial adhesion and colonisation, increasing the risk of pelvic inflammatory disease. It appears that there is no dispute between the parties as to Professor Fives-Taylor's evidence that the body's primary defence against infection by micro-organisms is desquamation, that is, the defence of flushing out micro-organisms by shedding cells on the outer layer of organs. If a micro-organism has adhered to a surface which does not desquamate, then it is able to stay in the body. Professor Fives-Taylor described adhesion as " the first and most primary virulence factor " for a micro-organism in the body. A Cu-7 or Mini, including its tailstring, cannot desquamate. Any biomedical implant becomes coated with a thin layer of host proteins immediately upon being placed into the body. An IUD is no exception. Micro-organisms can attach to this layer of proteins through specific adhesion. Specific adhesion involves the formation of bonds between the micro-organism and the surface layer on the tailstring. Professor Ellner gave evidence that the initial attachment is due to physical and chemical forces but that within a few hours after attachment micro-organisms which have adhered to an IUD can exude a substance which forms a " slime " layer over the IUD (para 16 of Professor Ellner's first statement, Tab 1, Exhibit P282). This, together with material from the host, forms a biofilm which rapidly covers the whole of the surface of the device. Professor Ellner said micro-organisms can and do colonise the surface and interior of this biofilm. The plaintiffs submitted that because of the fibrillation which causes frayed and rough surfaces, bacteria are better able to adhere to the Cu-7 tailstring than to other tailstrings. This was said to be supported by the evidence of Professor Katz. Professor Katz gave evidence that bacteria are better able to adhere to a rough surface than a smooth surface and that bacteria are more likely to colonise along the frayed areas. (Paragraph 17, Statement of Professor Katz dated 25 August 1995, Tab 1, Exhibit P192). Professor Kaplan agreed that bacteria might be able to adhere better to rough surfaces than smooth. (T5370/L57-5371-L3). Professor Robertson and Professor Fives-Taylor observed that the biofilm preferentially concentrated in the grooves of the tailstring created by fibrillation, frayed areas and areas of pits, crevices and roughness. Professor Fives-Taylor undertook experiments which indicated that up to 10 times as many bacteria adhered to frayed parts of the Cu-7 tailstring as to smooth parts. The defendants accept that bacteria can adhere to IUD tailstrings. Professor Fives-Taylor conducted experiments to measure bacterial adhesion to various tailstrings and polymers. She measured specific adherence of radioactively " tagged " bacteria to unprocessed beads of polyethylene, polypropylene and co-polymer. While some bacterial species adhered better to one material and some to another, there was little or no overall preference shown by various bacterial species for one over another. Six of ten bacterial species tested adhered better to polyethylene and four adhered better to polypropylene. She then measured specific adherence of bacteria to tailstrings of IUDs. The results demonstrated much greater adhesion to the polypropylene tailstring of the Cu-7 over the tailstrings of other devices. This held true across bacterial species. Twelve of the thirteen bacterial species tested adhered better to polypropylene in tailstring form. There was no result for the thirteenth. Professor Fives-Taylor concluded that it was the processing of the material, rather than the choice of polypropylene itself, which accounted for the greater adherence of bacteria to Cu-7 tailstrings over the tailstrings of other materials. The defendants' witness, Professor Kaplan, an expert in microbiology from the University of Texas Medical School, criticised a number of techniques used in Professor Fives-Taylor's bacterial adherence experiments. His evidence was that the use of human saliva rather than oestrus fluid as a medium for coating the tailstrings deprived the results of significance. He criticised the application of the method of counting bacteria and suggested that the experimental technique was sloppy, pointing to the recording in the laboratory notebooks of a number of experiments being spoiled by accidents in the laboratory. Professor Fives-Taylor's group conducted more than a thousand experiments, including replicates and gave evidence that some accidents were to be expected. Professor Kaplan did not point to any scientific literature which suggested that Professor Fives-Taylor's experiments should not be given weight. The plaintiffs submitted that the Cu-7 tailstring has been shown to have certain characteristics resulting from its manufacturing process. The fibrillation and morphological breakdown of the tailstring led to it having a greater surface area and greater surface roughness than tailstrings of the same diameter made of other materials. The plaintiffs submitted that Professor Fives-Taylor's conclusion, that the fraying and degradation of the Cu-7 tailstring promote the adhesion of bacteria should be accepted because: · Professor Fives-Taylor and her group undertook many experiments and replicates so even though some are criticised, the overall weight is convincing. · there are no contrary experiments. · the only experimental work of the defendants about which there is evidence is supportive in that it indicates that E. coli, a recognised PID pathogen, can adhere to the Cu-7 tailstring. · Professor Ellner gave evidence to similar effect including citations of the published science which is itself supportive (Statement 31 July 1995, Exhibit P 282, Tab 1) and Exhibits P 205 (Wilkins et al 1989 IJP 57 1-7) and D347 (Wilkins et al Contraception Vol 39, No 2, p. 205), being two of the footnotes to paragraph 16 of Professor Ellner's statement. · the defendants concede that bacteria adhere to tailstrings so there is nothing unlikely in Professor Fives-Taylor's results. Medical Risks Due To Defects The defendants argued that, even if there are medical risks due to defects, these nevertheless have no clinical implications. Professor Kaplan agreed that microbial adherence based on biofilm is a fundamental and pivotal factor in sepsis involving biomaterials. (T5218/L54-T5219/L5) but was not prepared to extrapolate from this position, which applied to a wide range of other implanted devices, to the case of IUDs. He expressed the view that because the epidemiological data cleared IUDs from involvement in infections, IUDs were necessarily different from other biomedical devices. Professor Kaplan accepted that cells might detach from the biofilm of an IUD in situ and, in a host whose defences are lowered sufficiently, might cause infection. However he suggested that the probability would be that the large numbers of pathogens constantly accessing the upper genital tract would cause PID rather than pathogens detaching from the biofilm- covered IUD. (T5266/L9-41). It was submitted that Professor Kaplan's opinion that pathogens detaching from the biofilm were not likely to cause PID was not based on his expertise in microbiology but rested on his understanding of the epidemiology as exonerating the Cu-7. He agreed that his opinions were not informed by any expertise as an epidemiologist (T5192/L25-332) although he has read the literature and formed opinions. If the epidemiological prop to his argument is removed, it was submitted that his concession as to the microbiological point goes a long way to support the plaintiffs' case. Professor Ellner expressed a quite different view as to the importance of pathogens leaving the biofilm. He expressed the view (as did Professor Katz) that the biofilm protects bacteria from the host immune system and antibiotics, allowing pathogens to survive in the upper genital tract, an area of the body where they would ordinarily be eliminated by the immune system. His evidence was that the biofilm on an IUD can concentrate nutrients, enabling the bacteria to multiply within the biofilm. He stated that the biofilm covered Cu-7 forms a " nidus " or infective reservoir from which micro-organisms can emerge to infect the host. His evidence was that whether the bacterial colonisation of the Cu-7 results in infection or not depends upon many factors involving the state of host defences and the numbers and virulence of the micro-organisms. However the role of the fraying as a design defect was to provide a reservoir of pathogens able to infect the uterus. The danger of frayed strings was said to be given support by Dr Stewart who declared that frayed strings were " medically unacceptable " (Exhibit P 486). A number of Searle documents refer to the dangers of infection from frayed tailstrings. The plaintiffs submitted that the evidence of Professor Ellner, supported by the plaintiffs' and defendants' clinicians, (who agreed that they would remove the Cu-7 in the event of infection), should be preferred to that of Professor Kaplan. Colonisation The plaintiffs alleged in their pleadings that the Cu-7 and Mini tailstring provided a suitable environment for colonisation by bacteria and/or other infectious organisms. There is no issue that the normal uterus is subject to periodic incursions of bacteria which are almost always effectively eliminated by the immune system. There is also no issue that a uterus which has an IUD in it will always have permanent colonies of micro-organisms associated with the biofilm on that IUD. These micro-organisms are protected by the biofilm from the action of the immune system. It is common ground that it is only upon ascension through the cervix into the upper genital tract that micro-organisms, including virulent pathogens such as gonococcus and chlamydia trachomatis, and anaerobes, can cause PID. An issue between the parties was the extent, if any, to which the tailstring of the Cu-7 could assist a potential pathogen to " ascend ". One mechanism pleaded in relation to this is the contamination of the device with bacteria from the vagina or lower cervix upon insertion. There is no dispute that this occurs. Another mechanism pleaded is the retraction of the tailstring into the uterus. Leaving these mechanisms aside, it was submitted that there does not seem to be any dispute that, upon insertion into the body, the Cu-7 rapidly becomes coated by a biofilm which is colonised by bacteria and that some of these bacteria can be pathogenic in the upper genital tract. There was no dispute as to the evidence of Professor Ellner and Professor Fives-Taylor that there are colonies of bacteria in the device biofilm which have bypassed the cervical defences and which enjoy a measure of protection from the immune system whenever an IUD is in situ. These colonies of bacteria are said to be able to exist in the upper genital tract solely by reason of the presence of the device. In this sense it was submitted there is no real argument that the presence of the device has assisted in the establishment of micro-organisms in the upper genital tract. The question is whether they can do any harm. There is consensus that all IUDs (and other biomedical implants) rapidly become covered in biofilm upon insertion into the body. There is debate as to how much of the biofilm is produced by adherent bacteria and how much is host material, an issue which does not need to be decided and which on the evidence cannot be decided. Professor Ellner gave evidence that biofilm confers a substantial number of advantages upon bacteria which permit them to survive permanently in the upper genital tract. Professor Katz supported this evidence as did Professor Fives-Taylor. Professor Kaplan suggested that biofilm might " entomb " bacteria based upon a reference made by Professor Costerton. It was submitted by the plaintiffs that the views of Professors Ellner, Katz, Fives-Taylor, Robertson should be preferred to those of Professor Kaplan. Their views were said to be supported by the published science in the area, including recent work of Professor Costerton. Professor Kaplan put forward no published work other than the older work of Professor Costerton (covered by his disavowal of pre-scanning confocal microscope work), to support it and Professor Kaplan admitted that his use of terms such as " cement " to describe biofilm and " entombed " to describe living bacteria was " theatrical ". (T5394/L1-15). There was disagreement between the parties as to the mechanisms which may allow bacteria to move into the upper genital tract. Professor Ellner identified mechanisms by which he said the Cu-7 and Mini assisted bacterial ascension including: (a) movement of the perimeter of individual colonies, (b) " pollination " from existing colonies on the string, and (c) the establishment of new colonies by planktonic bacteria attaching to the tailstring, whether or not they had emerged from other colonies on the tailstring. Professor Robertson identified a number of mechanisms including the extension of boundaries of a colony by lateral extension driven by multiplication of organisms causing growth of the colony. He also identified " pollination " in which micro-organisms or entire colonies detach from the string and reattach at different places. Professor Katz also identified a tendency of motile organisms to move along the tailstring surface towards a source of nourishment, a process known as chemotaxis. Professor Coughlin demonstrated that micro-organisms can and do grow along Cu-7 tailstrings in the laboratory in preference to random growth. The defendants criticised the laboratory techniques used in the experiments and indeed the applicability of in vitro experiments at all but did not call evidence to the effect that the mechanisms identified by the plaintiffs' scientific experts did not operate. The only evidence as to experiments carried out by the defendants was tendered by the plaintiffs. This related to experiments carried out in 1986/7 which suggested that at least one micro-organism associated with PID, E. coli, was able to attach and to move through mucus in the presence of the tailstring. It was submitted that the evidence of Professors Ellner, Katz, Robertson and Coughlin that the Cu-7 and Mini tailstring can facilitate the transport of micro-organisms into the upper genital tract should be accepted. Design Criteria The plaintiffs pleaded that a number of negligent actions were involved in the design of the tailstring of the Cu-7 and the Mini. An aspect of this is the case the plaintiffs sought to make that the defendants failed to apply applicable design criteria in the decision to use highly drawn polypropylene as the tailstring material. Professor Robertson gave evidence in his reply statement to the effect that criteria are and were applicable, and were routinely applied, to medical devices such as IUDs at the relevant times. He referred to criteria for safety of biomedical implants which were formulated by Hegelyi in an article published in 1971. (Annexure to reply statement of Professor Robertson, Exhibit P.136, Tab 2). These criteria included consideration whether properties of the materials used might exert an effect on the health of the user and whether the biological environment might exert an effect on the material. Dr Piziali's claim said that such criteria only applied to prostheses or materials used to repair or replace organs. (Paragraph 2 of Professor Robertson's reply statement, Exhibit P.136, responding to paragraph 44 of Dr Piziali's statement). Professor Robertson's evidence was that the (primary) principle applicable to the design of biomedical devices was to eliminate risks or, if that could not be achieved, then to reduce them as far as possible and warn of remaining risks. His evidence was that Searle's polypropylene tailstring failed to meet these criteria. He said that at the time the Cu-7 was being designed there was available literature as to the nature of polypropylene and the migration of bacteria and gave a number of references. He was not challenged in cross-examination on this material. It was submitted that Professor Robertson's opinions should be given greater weight because he had direct experience with the design of another IUD in 1970/1, the relevant period. He gave evidence as to the design process for this device. This involved the pharmaceutical manufacturer, Alza, assembling a team of scientific experts to undertake the design. This was said to contrast with the action of Searle in handing device design and development to its in-house Packaging Development group, which according to an internal Searle document, did not have the resources in number or expertise to deal with the issues but accepted the challenge anyway. Dr Piziali gave evidence that an IUD tailstring should be made of a material which resists biodegradation and is biocompatible with the environment to reduce interaction with host tissues. (Paragraph 42 of Dr Piziali's first statement of 19.10.95, Exhibit D.306). This was not challenged by the plaintiffs' experts in biomedical devices, Professor Robertson and Professor Katz. Dr Piziali suggested that Searle had complied with these requirements because polypropylene was more resistant to degradation than other choices, although he appeared to be referring to chemical rather than morphological degradation. Professor Robertson however said that it was all kinds of degradation which could pose a risk to the health of the user which ought be considered. In this regard he was critical of the choice of drawn polypropylene as the polymer used for the Cu-7 tailstring. Professor Katz was also critical of the use of a material which degraded and was unpredictable in its action in the Cu-7/Mini tailstring. It was submitted that the views of Professor Robertson and Professor Katz should be preferred to those of Dr Piziali and it should be found that Searle failed to comply with design criteria applicable and accepted in the early 1970s. 2.2 "Memory" of the tailstring which caused it to retract into the user's uterus. This was said to materially increase the risk of injury from ascending infection by: (i) string retraction into the uterus introducing more potential pathogens than otherwise would be introduced; (ii) string retraction required additional instrumentation of the uterus to remove device the device which instrumentation increased risk of introducing infection; (iii) the defendants admitted that uterine instrumentation increases the risk of introducing infection. Following the successful insertion of a Cu-7 in the uterus, the tailstring ran from the bottom of the Cu-7 in the uterus through the cervix and into the vagina to provide the user or her doctor with an easy method of checking that the device was still in place and to facilitate the removal of the device. The Cu-7 is shaped like a figure 7 with a small rounded cap which fuses the horizontal arm and the curved vertical stem together. Copper wire is wound around the vertical stem. The polypropylene tailstring is attached to the lower end of the vertical stem. When the device is packaged, the Copper 7 stem sits in the inserter tube. The tailstring joins at the base of the stem (inside the inserter tube), and turns to pass up the tube beside the device before emerging from the top of the inserter. It then loops through 180 degrees to run down the outside of the inserter tube. This can be seen clearly in Exhibit P3, a box of packaged Copper 7s. The plaintiffs alleged in each case that in its packaged configuration the tailstring was looped out of the top of the inserter tube rather than run down the inside of the inserter tube, such loop resulting in a string " memory " which caused the tailstring to have a propensity to retract into the uterus resulting in: (A) the tailstring transferring bacteria and/or other infectious organisms from the vagina into the uterus; (B) the need for instrumentation of the uterus; and an increased risk of Pelvic Inflammatory Disease (" PID "). The plaintiffs also pleaded, as particulars of the exemplary damages sought, that Searle was aware that the Copper 7 tailstring had a tendency to retract into the uterus increasing the risk but chose not to remedy the defect. The defendants do not dispute that retraction of the Cu-7 tailstring into the uterus occurs. They say that this retraction phenomenon is unrelated to the design of the Cu-7, and, in any event, does not increase the risk of upper genital tract infection. Dr O'Brien, the Associate Director of Clinical Research of Searle between July 1974 and September 1985, gave evidence for the defendants. His evidence was that Searle received reports of retractions during the clinical trial and following marketing of the Cu-7 and that he became aware of them shortly after they were received. Reports were received from August 1974 through to 5 December 1983. Dr O'Brien explained that the efforts Searle made to find a way to eliminate the string retraction effect were not motivated by any concerns that the retraction of the string might promote infection by the drawing up of micro-organisms into the uterus but rather that these efforts were made for marketing purposes. He went on to say that all IUD tailstrings retract and there was no evidence that the Cu-7 retracted at a rate greater than did the tailstrings of the Lippes Loop. Finally he stated that there was no evidence that retraction promoted infection. The defendants also called Dr Piziali. He is a consultant with a background in mechanical engineering who has experience in the fields of biomechanics and bioengineering. He disclaimed particular expertise in polymer chemistry. His evidence was that while there was a memory effect with the Cu-7 tailstring, it was not of sufficient strength or persistence to account for retraction into the uterus. His evidence included a video of a Cu-7 inside a plastic uterus. While this video showed movement in the tailstring, he was of the opinion that the forces involved would not be sufficient to account for the retractions. He said that although he had given the matter considerable thought, he did not have a theory as to why tailstrings retracted but was confident that it could not be the memory. The defendants relied upon his evidence to counterbalance the exhibits tendered by the plaintiffs many of which are Searle documents referring to the effect that the special characteristic of the polypropylene (the " memory ") used in the tailstring accounted for the retraction phenomenon. These exhibits document reports commencing prior to the period in which all insertions in the lead cases occurred. The defendants' case was that Searle employees believed at the time that there was a memory effect inherent in the polypropylene which accounted for the retractions, but that they were wrong. Searle said that its employees did not have sufficient expertise to know why the tailstrings retracted. The plaintiffs refer to statements to a similar effect from Battelle, expert design engineers employed by Searle to assist in solving the retraction problem. The documents include statements that the alternative polyethylene string Searle proposed for use on the Copper (used on Searle's Tatum T) was a definite improvement in that it had almost no memory. It was submitted that this suggested that Searle employees were right to ascribe the memory problem to the particular characteristics of the highly drawn polypropylene tailstring. Doctors using the Cu-7 reported similar experiences to Searle. For example, Dr Michaelow, described in an internal Searle memo as a " Gravigard devotee " reported that up to 80% of Cu-7 tailstrings retracted in his experience of 2,000 insertions and that the phenomenon was definitely not occurring with other devices. Mr Edmunds of Searle South Africa asked " Why does this not happen with our Tatum-T thread or threads of other devices ?" The plaintiffs have relied on the Searle documents and the evidence of Professor Channing Robertson and Professor David Katz to establish that the polypropylene used by Searle in the tailstring had a propensity to retract. They submitted that unless these documents are ignored or proved to be all wrong on the question, the plaintiffs are entitled to a finding in their favour. Professor Robertson also gave evidence for the plaintiffs. He is a Professor of Chemical Engineering at Stanford University. He is the witness in the case with the greatest expertise in polymer chemistry. Polypropylene is a polymer. It was common ground that the memory effect was a result of the stresses within the polypropylene tailstring deriving from the chemical conformation of polypropylene processed by drawing. Searle designed the packaging so that the tailstring looped above the 7 and then ran down along the outside of the inserter tube. Professor Robertson gave evidence as to the effect of the packaging of the tailstring. His evidence was that by using polypropylene and packaging the Cu-7 with a loop in the tailstring, the result was that the tailstring was prone to resume the shape it had within the packaging. The effect of this was that the tailstring after insertion of the device would have a tendency to withdraw into the uterus, playing a role in the introduction of infection (para 40, Statement dated 28 July 1995, Tab A, Exhibit P 136). Professor David Katz is a Professor in both the Department of Biomedical Engineering and in the Department of Obstetrics and Gynaecology at Duke University, North Carolina. He had previously held a position as a Professor in the Department of Chemical Engineering at the University of California, Davis. He has expertise in polymer chemistry. His evidence was that one of polypropylene's characteristics was to have a memory, in the sense of a tendency to resume a position in which the material had previously been placed, and that this characteristic cannot be removed and cannot be predicted with certainty. It was submitted that the evidence of Professors Robertson and Katz should be accepted and a finding made that the memory characteristic of the polypropylene used in the Cu-7 tailstring caused the tailstring to have a propensity to retract and that this characteristic existed to a markedly greater degree in Cu-7 tailstrings than in the polyethylene alternative which Searle used on its Tatum-T and proposed to use on the Cu-7 and Mini. The second dispute about retraction is whether it increased the risk of PID. Dr O'Brien gave evidence that there was no study which concluded that string retraction played any role in the development of PID. His evidence was that the efforts made to resolve the tailstring retraction problem were made for marketing reasons (i.e. presumably that doctors were reluctant to insert a device that might cause problems) rather than out of concerns about safety of users. Denzin, Gentle, Lee and Ottaway suffered tailstring retractions. It is common ground between the parties that any instrumentation of the uterus increases the risk of contracting, or exacerbating, PID. Each of Denzin, Gentle, Lee and Ottaway required instrumentation of the uterus to remove her Cu-7 because the tailstring had retracted, although in Gentle's case this was associated with treatment of septic abortion. It was submitted that there is no real dispute that the tailstring retractions increased the risk of injury to the plaintiffs by requiring instrumentation. Professor Ellner gave evidence that it was obvious that retraction of the tailstring was a mechanism for contaminating the uterus with bacteria, causing infection. Professors Eschenbach, Robertson and Katz gave evidence to the same effect. In addition, the defendants' expert medical witness, Professor Fraser, confirmed that the retraction of the tailstring might introduce bacteria into the uterus and it would depend upon the type of bacteria and the health of the woman as to whether this would create an infectious process. The plaintiffs submitted that: (a) the evidence of Professors Ellner, Robertson, Katz and Fraser as to the direct contamination of the uterus by string retraction combined with (b) the Searle documents, (c) the consensus as to the risk of instrumentation (necessitated by the retraction in at least three of the lead cases) and (d) the concerns as to the potential of the frayed tailstring to pose a risk of infection independently of fraying to support a finding that the retraction of the tailstring provided a means whereby bacteria could be carried from the vagina into the uterus, thereby increasing the risk of PID for users of the Cu-7. 2.3 The design of the inserter of the Cu-7 had the string on the outside of the inserter tube As a result of this, the string trailed through the bacteria laden parts of the lower genital tract and trans-cervically introduced potential pathogens into the uterus. In the case of each of the nine plaintiffs it was submitted that two or more of the alleged defects increased the risk of injury: 1. Denzin: memory plus fraying plus inserter tube 2. Gentle: memory plus fraying (septic abortion case) 3. Lane: fraying plus inserter tube 4. Lee: memory plus fraying plus inserter tube 5. Moylan: fraying plus inserter tube 6. Orders: fraying plus inserter tube 7. Ottaway: memory plus fraying plus inserter 8. Robertson: fraying plus inserter tube 9. Southren: fraying plus inserter tube The plaintiffs submitted that the general matters which prove liability on the part of the defendants are: (a) the use of the Cu-7 increased the risk of PID and its sequelae; (b) the defendants were aware of the epidemiological data which proved or provided compelling evidence that use of IUDs in general and of the Cu-7 in particular caused an increased risk; (c) the defendants knew or ought to have known that the design defects caused or were likely to cause an increased risk; (d) the defendants, notwithstanding their knowledge as set out in (b) and (c) above, negligently failed (i) to warn of the increased risk; and (ii) to remedy the defects; (e) the plaintiffs suffered injury, namely PID and its sequelae, and for Gentle a septic abortion, as a result of the defects and/or the increased risks; (f) the plaintiffs would not have suffered the injury had each been warned of the increased risks; (g) the plaintiffs were not warned of the increased risks. It was submitted that each of the three alleged design defects dealt with above was a material contribution to the risk of injury and not 'de minimis' because: 1. (i) the defendants' own behaviour revealed its recognition that the problem (ie the added risk) was not de minimis. (ii) contemporary medical opinion: eg Dr Hatcher, Dr Tyrer of the Planned Parenthood Federation of America, the Food and Drug Administration, the Australian National Biological Standards Laboratory was of that view. (iii) epidemiological data showed that users of Cu-7 were at an increased risk of PID and its sequelae. (iv) the foreign body effect potentiates and prolongs the risk of infection from additional bacteria introduced because of design defects. 2. No alternative causes were proved by defendants. The plaintiffs submitted that each of the three defects were negligently incorporated in the design of the Cu7 by the defendants and that independently and jointly they made a material contribution to the risk of injury to each plaintiff. The plaintiffs submitted that each of the plaintiffs suffered tubal damage which is said to be explained by a prior episode of PID. Therefore it was said the task for the medical experts was to identify when the episode was most likely to have occurred, rather than whether it occurred. In the diagnosis of PID, the parties did not disagree as to the fact that the disease could present with severe symptoms ie classic PID, or with less obvious and fewer symptoms ie atypical or unrecognised PID. However on behalf of the plaintiffs Dr Sweet gave evidence that a doctor could identify the signs and symptoms of PID in a woman who had suffered an unrecognised attack if a careful history was subsequently obtained from her. In the case of each plaintiff, it is impossible to identify the pathogen which caused the PID suffered by the plaintiffs. The defendants attempted in all cases except Mrs Denzin to prove that it must have been a sexually transmitted disease (STD), not an IUD, which caused any episode of PID suffered by the plaintiffs. However the plaintiffs submitted that because the IUD plays an independent and additive role in the presence of infection it is irrelevant to enquire whether the pathogen causing the PID was an STD or non-STD micro organism. They also submitted that the attempts by the defendants to establish the occurrence of STD failed because: (i) no identification of an STD pathogen causative of PID was ever made; (ii) the only STD micro-organisms ever identified were "innocent" in the sense that they were not causative of PID eg genital warts or trichomonads; (iii) it was never argued that if a woman had evidence of an "innocent" STD micro-organism she must have also had a "pathogenic" STD capable of causing PID viz. Neisseria gonorrhoea or Chlamydia trachomatis; (iv) the defendants' experts never committed themselves to an opinion that a plaintiff's history and records prior to using a Cu-7 proved an attack of PID; (v) any signs or symptoms of PID identified in association with the hypothetical STD were much less persuasive of PID than the signs and symptoms in association with the use of the Cu-7. The defendants also sought to implicate other occasions in the histories of the individual plaintiffs as establishing an alternative to the IUD as the cause of PID. These included appendectomies, termination of pregnancy, hysterosalpingogram and post-partum infection. The plaintiffs' experts were of the view that in each case the PID occurred during IUD use and not at any other time alleged by the defendants' experts. The plaintiffs' case also included the proposition that the IUDs materially contributed to the PID by reason of their effect on the body's immune system. The plaintiffs submitted that the opinions of the plaintiffs' medical experts as to the occurrence of PID during Cu-7 use (Gravigard and Mini-Gravigard) and the role of the IUD in causing the PID should be preferred to those of the defendants' medical experts who were, it was submitted, not able to offer any convincing alternative explanation for the PID suffered by the plaintiffs. It was also submitted that the expert opinions of the plaintiffs' medical witnesses as to the causal role of the Cu-7 in PID were consistent with and supported by the epidemiological data, the medical principles relating to infections and the foreign body effect, and their own clinical experience. 2…PELVIC INFLAMMATORY DISEASE (PID) 1. The Female Reproductive System The female reproductive system above the vagina consists of: 1.1 The Uterus The uterus is a hollow muscular organ in which the fertilised ovum normally becomes embedded and in which the developing embryo and foetus is nourished. It has a mucous membrane lining known as the endometrium. Its cavity opens into the vagina below and above into two Fallopian Tubes, one on either side of the uterus. At the lower portion of the uterus there is a constricted portion known as the isthmus leading to the cervical canal which is the narrow lower end of the uterus between the isthmus and the opening of the cervix into the vagina. The opening of the cervix into the vagina is known as the cervical os. 1.2 Fallopian Tubes There are two fallopian tubes, one on each side of the uterus. They extend laterally from the uterus and terminate in the peritoneal cavity near each ovary. They serve to convey the ovum from the ovary to the uterus and spermatozoa from the uterus toward the ovary. In the event that an ovum is fertilised by spermatozoa the fertilized ovum is conveyed, in normal cases, to the uterus where it is embedded in the endometrium. 1.3 Ovaries There are two Ovaries, one on each side of the body near the ends of the fallopian tubes. The ovaries are glands which produce the reproductive cells, the ovum, which pass into the fallopian tubes and then to the uterus. 2. PID - Definition The term " pelvic inflammatory disease " is used to describe infections of various parts of the upper reproductive organs covering: 1. endometritis - an infection to the endometrium (the lining of the uterus). In the course of his evidence Eschenbach said that most patients with pelvic inflammatory disease have endometritis, because the infection " starts in the lower genital tract and the lower parts of the uterus and moves up the uterus and into the fallopian tubes and out. So most individuals who have pelvic inflammatory disease would also have endometritis. " (T1664/L25-L30). 2. salpingitis - an infection of the fallopian tubes; 3. oophoritis - an infection of the surface of the ovaries; 4. pelvic peritonitis - in diffuse cases all of the above may be infected together with the pelvic peritoneum. PID may be: 1. Acute 2. Chronic 3. Silent On gynaecological examination tubal scarring or blockage is found and this leads to a retrospective diagnosis of silent PID. 3. The cause of PID The cause of the infections known as PID is usually pathogens which ascend from the vagina to the cervix and then through the cervix into the endometrial cavity where they break the lining of the uterus and group in sufficient numbers to produce an infection. That infection can then move into the fallopiana tubes and to the ovaries, and possibly the abdominal cavity (Eschenbach, Ex. 108 Tab 1, para 12). Eschenbach and Newton's view was that there are two major groups of organisms which, when found in the uterine cavity have been found to lead to PID: (a) exogenous organisms including STD organisms, in particular gonorrhoea and Chlamydia trachomatis; and (b) endogenous bacteria, both aerobic and anaerobic bacteria which are commonly isolated from the vagina and /or vulva and perineum of healthy women. Gonorrhoea and Chlamydia are most commonly, although not exclusively, transmitted to the women's body through sexual contact (Ex. 108 Tab 1, para 14). The presence of gonorrhoea and chlamydial infections in the vagina or cervix may cause localised infections but they will only have serious complications related to a woman's fertility if they are introduced into the upper reproductive tract (Ex.108 Tab 1, para 17). They do not automatically ascend to the uterus and are often prevented by the barrier of the cervix and the body's defence mechanisms. Sweet said that in the absence of a factor such as an IUD, cervical gonorrhoea or chlamydia will cause PID in approximately 10% to 20% of cases (T3070/L38 para 24 as corrected in memorandum of 28 April 1996. Tab 1). Similarly, the vaginal bacteria do not usually ascend into the uterus unless aided in some way (para 25). Sweet said that approximately 65% of women with PID have chlamydia and/or gonorrhoea, and of these about half also displayed evidence of infection with aerobic and/or anaerobic bacteria (Par.26). Approximately 30% of women with PID have only aerobic and/or anaerobic bacteria present. (para 26). Polymicrobial bacteria exist naturally within the vagina, most commonly aerobic and anaerobic bacteria including streptococci, lactobacillus, e. coli, gardnerella, vaginalis, peptostrepococci and acteroides (Ex. 108 Tab 1, para 15). These bacteria are harmless when they form part of the vaginal flora, but if they are introduced into the upper genital tract they can be pathogenic (i.e. they can cause disease) (Ex. 108 Tab 1, para 16). By the 1970s it had become evident, following the widespread development of anaerobic bacteriology, that multiple organisms were often isolated from infected sites, particularly from intra-abdominal abscesses. Polymicrobial infections, consisting of both aerobic and anaerobic bacteria, were commonly identified among women with pelvic inflammatory disease and vaginitis (Ex. P108 Tab 1, para 142). In 1984 Dr Eschenbach presented a paper "Acute pelvic inflammatory disease" at a symposium on sexually transmitted diseases in which he said: (Ex. P108. Tab.12). "Primary pelvic inflammatory disease is usually an acute infection in which organisms ascend into the uterus and fallopian tubes from the cervix. Chronic active infections are unusual except in neglected cases and in actonomyces infection. However, sterile chronic inflammatory adhesions are common residuals of an acute infection." (Tab 12, pp 65-66). As well as sexually transmitted organisms, Dr Eschenbach said that non-sexually transmitted bacteria can also cause pelvic inflammatory disease: "Sexually transmitted organisms, most noticeably Neisseria gonorrhea, Chlamydia trachomatis, and genital mycoplasmas, are recovered from the majority of women who develop pelvic inflammatory disease. However, non-sexually transmitted aerobic and anaerobic endogenous cervicovaginal bacteria also cause pelvic inflammatory disease in a significant number of incidences. The rate with which these micro-organisms have been isolated with pelvic inflammatory disease differs widely in various studies, probably because of the differences between the various populations studies and differences in infection." (Tab 12 p 67 right hand column, paragraph headed 'Microbial Etiology'). The complexity of the infectious position is such that it is possible to: 1. have a sexually transmitted disease in the vagina e.g. gonorrhoea, and not have PID; 2. have a sexually transmitted disease eg gonorrhea, and have PID; 3. not have a sexually transmitted disease and not have PID; 4. not have a sexually transmitted disease and have PID. By 1982, when Eschenbach published " New concepts of obstetric and gynaecological infection " (Ex.P108, Tab 11) research had established that polymicrobial infections of aerobic and anaerobic bacteria had been detected in 20% to 60% of women with PID in the United States (he cited Eschenbach 1975; Sweet et al. 1979 and Monif et al. 1976). Eschenbach concluded: " Although it had become clear that PID is sexually transmitted including by N. gonorrhoea and by C. trachomatis, it is also non-sexually transmitted by polymicrobial infection involving aerobic and anaerobic bacteria " (Tab 1, Par.145). Eschenbach said that N. gonorrhoea and C. trachomatis could be found in anywhere between 50% and 60% of PID cases (T166/L7). However, the actual proportion is very "population dependant" and may be as low as 30% (T1668/L29). In Eschenbach's opinion, he would include in the top category of pathogens causing PID, gonorrhoea, Chlamydia, and commensals such as E. coli and anaerobic bacteria (T1683/L9). Fraser, in para 79 of his first witness statement said that: "Using careful investigations, specific sexually transmissible infection is identifiable in 60% to 80% of cases." The body's defence mechanism Dr Eschenbach said in his first witness statement that the inoculum (i.e. the number of bacteria required to cause infection to a particular organ) varies and depends upon the woman's immunity and other factors (Tab.1 Par. 18;), (T1690/L10-L35). Among the other factors to which he referred is the effect of a foreign body (in this case an intrauterine device) inserted in the uterus. Dr Eschenbach said (second witness statement, Tab 17. Par. 2) that the immune system within the uterus and within other organs is similar for non-pregnant women. The effect of inserting a foreign body in the uterus will be similar to inserting a foreign body elsewhere. "The hypothesis of the uterus as an immunologically-privileged organ only exists during pregnancy, and then, only for a small portion of the intra-uterine contents, the foetal - decidual interface" (Tab.17. Par. 2). It was said that the presence of the IUD modifies the body's normal defence mechanisms, leading in some instances to pelvic infection. Eschenbach reported in March 1976 (Ex. P108. Tab. 5) "Acute pelvic inflammatory disease: aetiology, risk factors and pathogenesis" (NEJM pp.147-169) that the intrauterine device was a risk factor for pelvic inflammatory disease, a major public health problem and that prospective studies of the magnitude of the problem were long overdue (Tab. 5. p.166 at 2). Dr Eschenbach said in that article: "The role of the IUD in the pathogenesis of PID may be similar to that of a foreign body in the presence of bacteria elsewhere in human tissue: it allows colonisation of bacteria on its surface, reducing the effectiveness of normal defence mechanisms. The concentration of anti-body, phagocytes, and other components of the defence mechanism surrounding an IUD is unknown but possibly is inadequate to prevent bacterial colonisation from resulting in infection. Perhaps well-vascularised tissues, without the presence of a foreign body, are more likely to possess defences capable of preventing infection." (Tab. 1 Par.66). It was said that the presence of the intrauterine device, being a foreign body also lowers the inoculum or the amount of bacteria that may be needed to cause an infection. (Tab. 1 Par.21). Dr Eschenbach described a number of ways in which the presence of a Copper 7 adversely affects a woman's defence mechanisms: 1. the string of the Copper 7 acts as a bridge for bacteria which attach to the string and produce a biofilm which protects them from the body's defence mechanism; the biofilm prevents the white cells from destroying the bacteria; and the bacteria can also transfer along the string from the vagina into the uterus. (Tab 1. Par. 22(i)). Elstein had shown in 1967 greater evidence of signs and symptoms suggestive of PID in women using an IUD with a tail. (Ex. D113, first Par.). Dr Eschenbach said with regard to bacterial motility, that bacteria had a capability of using the contiguous spread mechanism as well as the walls of the uterus to ascend to the tubes. (T1997/L5.). 2. the arm of the Copper 7 or its projection can embed in the lining of the uterus giving bacteria access to the basal layers of tissue, creating a more resistant and difficult infection to treat. (Tab 1. Par. 22(ii)). 3. the Copper 7 by increasing the amount of bleeding experienced by the women during and or between menstruation provides nutrients for bacteria to grow within the uterus (Tab. 1. Par. 22(iii)). 4. the Copper 7 affects the uterine environment by lowering the oxygen and permitting preferential growth of anaerobic bacteria, thus increasing the likelihood of uterine infection (Tab. 1. Par. 22(iv); T1907/L45-L55; see also T1984/L5-L20). 5. the device affects the natural barriers in the woman's reproductive system designed to protect the uterus from infection namely the cervix, cervical mucous and epithelial lining; because of the string, the body has no barrier to infection being transmitted between the uterus and the fallopian tubes (Tab 1, Par.23). 6. the retraction of the string associated with the Copper 7 provides another mechanism by which pathogens within the vagina can be transferred to the uterus and cause infection (Tab. 1. Par.24). It was submitted by the plaintiffs that HSG studies reported by Elstein in 1969 (Ex.D113) established an increased incidence of tubal damage and occlusion in women with signs and symptoms of PID which occurred in association with the use of an IUD with a tail (p.279, second last Par.). Effects of PID PID can cause tubal damage leading to a greater risk of impaired fertility, infertility and ectopic pregnancy. PID often takes the form of salpingitis which causes damage to the fallopian tubes in a number of ways: 1. Inflammation or obstruction of the fallopian tube may prevent the egg and the sperm from meeting. 2. The cilia or finger-like projections within the fallopian tube and the secretory cells within the tubes may be damaged, such that the ability of the tubes to keep the egg alive and move the egg and sperm together is destroyed. 3. Adhesions between the tubes and ovaries may be created such that the fallopian tubes cannot move over the ovary during the menstrual cycle to pick up the egg and move it along. Eight per cent of patients who experience infections to the fallopian tube are rendered infertile. 85%-90% of women who develop tubo-ovarian abscesses are rendered infertile (Dr Eschenbach, Ex P108, Tab 1, Paras 27 & 28). There is also the possibility of suffering tubo-ovarian abscesses. Dr Eschenbach said that the most serious form of pelvic inflammatory disease is tubo-ovarian abscesses which are very difficult to treat because the body "walls off the abscess through production of collagen walls, particularly where anaerobic bacteria have been the cause of the abscesses. Given that the collagen walls have no blood vessels within, it is difficult to get the antibiotics to the abscess." (Tab.1 Par.33). Tubo-ovarian abscesses are typically polymicrobial: that is "they are normally produced by infections relating to the bacteria found within the vagina, most normally bacteroides and peptostreptococci. As such, they are not normally associated with STD PID alone, but instead are more commonly associated with the ascension of vaginal bacteria through external means such as through the introduction of an IUD ." (Tab.1 Par.33, 34). Ectopic pregnancies are a further risk. Infections in the fallopian tubes create holes or craters in the tubal area which provide traps for the fertilised egg, or the egg alone, so that the risk of ectopic pregnancies is increased. The seriousness of the health risk from ectopic pregnancy is not in dispute. As Dr Eschenbach said: "The real danger is the rupturing of the ectopic pregnancy which causes great haemorrhaging and can lead to a woman's death." (Ex. P108. Tab 1, paras 29 & 30). Dr Keeping also gave evidence to the effect that PID created an increased rate of ectopic pregnancy (T 6387/L51 - T6388/L12) as did Professor Newton (Ex. D299, para 87). Chronic pain is experienced by approximately 20% of women after contracting pelvic inflammatory disease. Dr Eschenbach summarised the consequences of PID (chronic pain, subsequent episodes of PID, infertility, and ectopic pregnancy) (Ex. P108 Tab 11, p2041) as follows: Consequences Frequency % Chronic pain 15 Subsequent PID 20-25 Infertility* 1 Infection 2 Infections 3 Infections 10-15 25-35 50-75 Ectopic pregnancy (with first subsequent pregnancy) 7 * 8% of patients who experience infections to the fallopian tubes are rendered infertile Infertile Ectopic Pregnancy Intrauterine Pregnancy Category Total Women Number Rate Number Rate Number Rate Control 448 8 2% 6 1% 433 97% PID Patients 1st episode 1,025 112 11% 61 6% 852 83% 2nd episode 198 50 25% 24 12% 124 63% > 3rd episode 69 30 43% 15 22% 24 35% Diagnosis of PID PID may be categorised as: 1. Acute PID This presents with classic symptoms which are usually quite severe. Pelvic inflammatory disease may manifest itself by "classic symptoms" evidenced by inflammation or infection which is accompanied by abdominal tenderness, cervical motion tenderness and adnexal tenderness, but it may also occur without these symptoms. The classic full-blown syndrome of PID includes fever, elevated white count, cervical motion tenderness, adnexal tenderness. 2. Atypical PID This may be: 2.1 subacute; or 2.2 chronic Each of these subcategories presents with lesser signs and symptoms. They are usually characterised by inter-menstrual bleeding and pain. It is often termed ' asymptomatic ' though it is probably more accurately a case of ' unrecognised ' pelvic inflammatory disease. Atypical PID has also been called "silent" PID. This suggests that there are no recognisable symptoms, but Dr Sweet gave evidence to the effect that a survey of histories of patients with "silent" PID would reveal episodes from which a retrospective identification of the presence of PID can be made (T 3055/L33-35, Ex. P247, p3163). The damage which might be suffered by a woman who suffers from atypical PID may not be any less than that suffered by a woman with acute PID, including severe tubal damage (Dr Keeping, T6153/L10; Dr Sweet, T 3054-7). Dr Sweet said that a person can have acute pelvic inflammatory disease that is unrecognised and "we are beginning to understand that probably the majority of pelvic inflammatory disease is actually of the unrecognised or atypical which physicians have not been attuned to addressing. It is very similar to the point I tried to make to the FDA back in 1977, that we needed to be aware that these patients with abnormal bleeding, with pain who did not have fever did indeed have pelvic inflammatory disease." (T3054/L49-T3055/L2). PID may be acute, involving infection of the fallopian tubes, but not manifested by significant severe pain or fever, presenting as Dr Sweet said a more subtle picture (T3055/L15-L20). In the case of atypical PID, a woman may not even elicit tenderness on bimanual examination: "That can happen, we now recognise that women may have endometritis and have low grade infection, may have some bleeding, spotting, pain, but may not actually have the tenderness." (T3066/L10). In the case of unrecognised PID, Dr Sweet said that the doctor typically sees things such as "abnormal bleeding, complaints of abdominal or pelvic discomfort, you may get discharge, maybe discomfort with sexual intercourse, those types of things" (T3066/L35). The degree of bleeding may be heavy which the patient would notice, or simply something that the doctor might notice at the time of a speculum examination (T3067/L24) or it may simply be spotting which may not occur on the days the patient sees the doctor (T3067/L29). The pelvic discomfort may be cramps or aches, commonly symptoms reported by menstruating women (T3068/L39), but the patients usually know the pattern of their own menstruation established over time and are aware of differences (T3069/L5). In the case of vaginal discharge, particularly with bacterial vaginosis, 40% of those women "have histologic and microbiologic evidence of endometritis" with bacterial vaginosis being present (T3069/L30). The presence of dyspareunia is something which the patient may describe. (T3070/L5). Dr Sweet said that the studies by Wolner-Hanssen showed that "....If you went back and took a careful history from the women, asked questions about pain, discomfort, that the overwhelming majority of women had had those types of symptoms that had not been diagnosed as PID because physicians were relying on the classis criterion. When you questioned the patients closely they could have symptoms, that is why its has moved to be unrecognised or atypical" (T3055/L40-L45) Dr Sweet said that the mild clinical PID can have the same outcome for the patient as full-blown PID (T3057/L55). A question to be determined in each of the nine cases is whether the plaintiffs suffered PID in association with Cu-7 use. The plaintiffs submitted that in eight of the cases (Denzin, Lane, Lee, Moylan, Orders, Ottaway, Robertson and Southren) the existence of PID has been confirmed by objective tests so that the task of the expert witnesses was to identify whether or not there were signs or symptoms of PID in association with Cu-7 use. They submit that the presence of tubal damage in the absence of any alternative cause supports the finding that it was caused by PID. 3. CAUSATION The evidence established that women who have not used the Cu-7 device both do and do not contract PID and that women who do use the Cu-7 device both do and do not contract PID. Thus if a woman uses a Cu-7 and contracts PID the question to be determined is whether the Cu-7 was causative of the PID in the particular case. The plaintiffs stated the legal principle upon which their case is based as follows (in the Summary of Plaintiffs' Case B.1.): "The defendant is liable for negligent defects which result in injury where those defects materially increase the risk of injury, i.e. other than de minimis, unless the defendant proves that the injury was in fact caused by some other cause unrelated to its negligent act." This statement appears to me to beg the question and should be stated properly to reflect their position as follows: "The defendant is liable for injury to the plaintiffs where there are negligent defects which materially increase the risk of injury, i.e. other than de minimus, unless the defendant proves that the injury was in fact caused by some other cause unrelated to its negligent act." Their proposition was stated orally by their counsel at T.7435-6: "If you use a Copper 7, you are more likely to get PID than if you don't, and that is our client's case. That is to say, applying the reasoning, for example, in Bonnington Castings and in McLean if there is negligence on the part of the defendant that places the woman at an increased risk of contracting PID, then if the injury is suffered, that will be sufficient to establish legal causation. ……it is always open to the defendant to attempt to prove that irrespective of the increased risk of using the IUD, the injury was suffered because of some other entirely different event. For instance, if there was a case of a ruptured appendix as a young woman and if it was shown of course that damage was suffered and caused by a ruptured appendix….the plaintiff cannot succeed because the injury would have been suffered irrespective of the IUD… If the defendant wants to prove an alternative cause, then it must do so according to the laws of proof. It must satisfy the Court that there is another cause…." The first proposition that if you use a Copper 7 " you are more likely to get PID than if you don't " is a factual question to which I shall come later. The next proposition is that if the first proposition is established and the woman has suffered PID, that in itself (subject to the third proposition) is enough to establish causation in the legal sense. The third proposition was that it is open to the defendant to attempt to prove that irrespective of the increased risk of using the IUD, the injury was suffered because of some other entirely different event. In Bonnington Castings Ltd v Wardlaw (1956) AC 613 an employee was exposed to silica dust by his employer from two sources. One source of exposure did not render the employer legally liable but the other source did. Lord Reid said (p.622): "I think that the position can be shortly stated in this way. It may be that, of the noxious dust in the general atmosphere of the shop, more came from the pneumatic hammers than from the swing grinders, but I think it is sufficiently proved that the dust from the grinders made a substantial contribution. The respondent, however, did not only inhale the general atmosphere of the shop; when he was working his hammer his face was directly over it and it must often have happened that dust from his hammer substantially increased the concentration of noxious dust in the air which he inhaled. It is therefore probable that much the greater proportion of the noxious dust which he inhaled over the whole period came from the hammers. But, on the other hand, some certainly came from the swing grinders, and I cannot avoid the conclusion that the proportion which came from the swing grinders was not negligible. He was inhaling the general atmosphere all the time, and there is no evidence to show that his hammer gave off noxious dust so frequently or that the concentration of noxious dust above it when it was producing dust was so much greater than the concentration in the general atmosphere, that that special concentration of dust could be said to be substantially the sole cause of his disease." At p.623 his Lordship said: "No doubt the total amount from both sources in the atmosphere was small at any one time, but the combined effect over a period of eight years was to cause the respondent's disease. The importance of evidence of the fellow-workmen is that it shows that the visible dust and therefore also the invisible dust from the swing grinders was not immediately dispersed, and therefore that the respondent was bound to inhale some of the invisible noxious dust from the swing grinders. On this matter Lord Carmont said: "Even if the majority of the pursuer's inhalations took place near the source where the silica dust was produced, i.e., at his hammer, a minority of inhalations from the general atmosphere of the shop needlessly contaminated owing to the breakdown of the extracting hood, duct and fan at the swing grinders may well have contributed a quota of silica dust to the pursuer's lungs and so helped to produce the disease." On his view of the onus of proof Lord Carmont did not require to go farther than that. In my opinion, it is proved not only that the swing grinders may well have contributed but that they did in fact contribute a quota of silica dust which was not negligible to the pursuer's lungs and therefore did help to produce the disease. That is sufficient to establish liability against the appellants, and I am therefore of opinion that this appeal should be dismissed." This decision turned on a factual finding that the exposure of the employee to silica dust negligently by his employer did in fact materially contribute to the onset of the disease from which he suffered. The plaintiffs accepted that the onus of proving that the defendant's negligent conduct caused the plaintiffs' injury remains on them but submitted that the onus is discharged by proving exposure to increased risk that could materially contribute to the injury. They submitted that establishing increased exposure to risk caused by the negligence of the defendant prima facie establishes causation (T.7438). The determination of causation is governed by March v E & MH Stramare PtyLtd (1991) 171 CLR 506. It is essentially a question of fact to be answered by reference to commonsense and experience and one into which considerations of policy and value judgments necessarily enter. The plaintiffs referred to authorities cited by Mason CJ at page 514 of Stramare in support of the statement: "Nonetheless, the law's recognition that concurrent or successive tortious acts may each amount to a cause of the injuries sustained by a plaintiff is reflected in the proposition that it is for the plaintiff to establish his or her injuries are ' caused or materially contributed to ' by the defendant's wrongful conduct." Those authorities were: 1. Bonnington Castings Ltd v Wardlaw (1956) AC 613. 2. McGhee v National Coal Board (1973) 1 WLR1. In McGhee , Lord Reid referred to Bonnington Castings . He said at p.4D: "It has always been the law that a pursuer succeeds if he can show that fault of the defendant caused or materially contributed to his injury. There may have been two separate causes but it is enough if one of the causes arose from fault of the defendant. The pursuer does not have to prove that this cause would of itself have been enough to cause his injury. That is well illustrated by decision of this House in Bonnington Castings …." The medical evidence in that case could not explain why it was that the employee's cycling home caked in grime and sweat had added to the risk that the disease might develop. Lord Reid said: "It does not and could not explain why this is so. But experience shows that it is so. Plainly that must be because what happens while the man remains unwashed can have a causative effect, though just how the cause operates is uncertain…. From a broad and practical viewpoint I can see no substantial difference between saying what the defendant did materially increased the risk of injury to the pursuer and saying that what the defendant did made a material contribution to his injury." 3. Duyvelsheff v Cathcart & Ritchie Ltd (1973) 47 ALJR 410. At 417 Gibbs J said: "The plaintiff had to prove that the defendant's breach of duty caused or materially contributed to the injury. It was sufficient where there was a breach and an injury of the kind that might thereby be caused to justify the drawing of an inference, in the absence of any sufficient reason to the contrary, that in fact the injury did occur because of the breach." 4. Tubemakers of Australia Ltd v Fernandez (1976) 50 ALJR 720. Mason J said (p.724E) that where the issue of causation is not within the realm of common knowledge and experience and " fails to be determined by reference to expert medical evidence " , if the expert evidence provided a sufficient basis for the inference that on the probabilities a particular act or event caused or materially contributed to the occurrence of the medical condition, then liability is established. It was submitted that the following conclusions arise from these authorities: 1. Where medical evidence does not explain a causative effect, nevertheless such an effect will be found where clinical experience or observation confirms the causal link. 2. Where the injury may be caused by more than one factor, if the defendant's conduct materially contributed to the injury in the sense that it is not de minimis, then the defendant will be liable. 3. Conduct of the defendant which materially increased the risk of injury will be found to have materially contributed to the injury. The plaintiffs also relied on Commonwealth of Australia v McLean (1997) 41 NSWLR 389. The plaintiff in that case suffered post-traumatic stress disorder and, as a result, over the next thirty years and more he drank alcohol and smoked tobacco, both to excess, which caused him to develop throat cancer. Handley JA and Beazley JA referred inter alia to Bonnington Castings Limited and McGhee and said (p.409A): "These cases decide that where medical science does not permit a clear answer, the court can find that a disease was caused by a breach of duty which materially increased the risk of contracting it: see also Duyvelshaff v Cathcart & Ritchie Ltd (1973) 47 ALJR 410 at 417, per Gibbs J." Their Honours then referred to Wilsher v Essex Area Health Authority (1980) AC 1074. This was a medical negligence case where there were five possible causes of the blindness suffered by the plaintiff only one of which arose from the negligence of the defendant. The English Court of Appeal followed McGhee and the plaintiff was successful. In the House of Lords, Lord Bridge said that in McGhee the House had done no more than adopt a robust and pragmatic approach to the drawing of an inference of causation, but the decision did not assist a plaintiff where there were four other possible causes. Causation is a question of fact to be resolved as a matter of commonsense. Their Honours said (p.410B): "Some of the plaintiff's consumption was not caused by the tort because the ' but for' test was not satisfied. However on the jury's findings a significant part of his total consumption would not have occurred 'but for' the tort seems to us that the rule in Bonnington Castings v Wardlaw and the related cases applies and that the nature of the duty and the chain of causation under consideration were not fundamental to those decisions. They supply a principle for deciding responsibility where injury results from a noxious substance situation where only some of the exposure was caused by the tort. Those cases do not stand alone. A tribunal of fact is entitled to find causation as a matter of commonsense from the sequence of events, although medical science does not support an affirmative answer, provided it does not exclude such a finding: see Adelaide Stevedoring Co Ltd v Forst (1940) 64 CLR 535 at 563-564, 569 and Tubemakers of Australia Ltd v Fernandez (1976) 50 ALR 720. The principle established in Purkess v Crittenden (1965) 114 CLR 164 is also relevant. The majority there said (at 168): "….where a plaintiff has….made out a prima facie case that incapacity has resulted from the defendant's negligence, the onus of adducing evidence that his incapacity is wholly or partly the result of some pre-existing condition or that incapacity, either total or partial, would, in any event, have resulted from a pre-existing condition, rests upon the defendant." The plaintiff's pre-collision smoking and drinking habits were not literally a ' pre-existing condition'. However the defendant's case that the throat cancer would ' in any event' have resulted from those habits is equivalent to the situations referred to in this passage. The later reasoning of the majority (at 168) therefore applies: "…it is not enough for the defendant merely to suggest the existence of a progressive pre-existing condition in the plaintiff or a relationship between any such condition and the plaintiff's present incapacity. On the contrary…both the pre-existing condition and its future probable effects or its actual relationship to that incapacity must be the subject of evidence which, if accepted, would establish with some reasonable measure of precision what the pre-existing condition was and what its future effects both as to their nature and their future development and progress, were likely to be. That being done, it is for the plaintiff upon the whole of the evidence to satisfy the tribunal of fact of the extent of the injury caused by the defendant's negligence." The defendant's evidence did not satisfy these tests. The defendant did no more than ' suggest' that the plaintiff's consumption of alcohol and tobacco, without any increase due to the tort, could have caused the cancer in any event. In our judgment the direction to the jury that they were entitled to award damages for the cancer if they found that the increase in consumption caused by the tort was significant was correct. The issue was causation in fact of an actual event, and not causation of an hypothetical event where the court allows for the probability that the event would or would not have occurred: see Malec v J C Hutton Pty Ltd (1990) 169 CLR 638. Causation in fact of an actual event is an all or nothing issue. The plaintiff was not entitled to recover anything for his throat cancer unless he established, on the balance of probabilities, that it had been caused by the tort. Once the plaintiff succeeded on that issue the defendant was not entitled to any deduction for the chance that the plaintiff might have contracted throat cancer in any event: see Hotson v East Berkshire Health Authority (1987) AC 750 at 783." The question was again dealt with by the Court of Appeal (Mason P, Beazley JA and Stein JA) in Bendix-Mintex Pty Ltd & Ors v Barnes (1997) 42 NSWLR 307. The learned President said (p.311D): "It is sufficient for a plaintiff to establish that his or her injuries were " caused or materially contributed to" by the defendant's wrongful conduct: March v E & MH Stramare Pty Ltd (1991) 171 CLR 506 at 514. The basal principle does not change when the plaintiff sues more than one defendant. The test must be satisfied as against each defendant from whom the plaintiff seeks a verdict before such a verdict will be entered. Hope JA summed-up the principle in Kilgannon v Sharpe Bros Pty Ltd (1986) 4 NSWLR 600 at 628 when he said that cases such as Nesterczuk v Mortimore (1965) 115 CLR 140 and Host v Bassett (1983) 57 ALJR 681; 48 ALR 404: "…require a plaintiff to be able to point, on a balance of probabilities, to the particular defendant or defendants who was or were negligent; it is not enough that he can say that one of them must have been and all of them may have been negligent." The law might, and in some jurisdictions does, distinguish between proof of unreasonable want of care and causation of damage. But it does not do so in Australia, on my understanding. While the law is prepared to adopt " a robust and pragmatic approach" (Wilsher v Essex Area Health Authority) (1988) AC 1074 at 1090, per Lord (Bridge) to proof of causation in fact, the principles I have referred to extend to proof of damage as I shall endeavour to demonstrate. In this sense, where only one of two events could have caused or materially contributed to an injury, there is no difference in principle between a plaintiff who is in doubt as to which of several defendants is liable and a plaintiff who is in doubt as to which event (one innocent, the other negligent) touching a single defendant was the cause of compensable injury." At page 312A he said: "The sufficiency of material contribution is well attested: March v E & MH Stramare (at 514); Bennett v Minister of Community Welfare (1992) 176 CLR 408 at 420. However, introduction of the notion of increased risk involves a different universe of discourse, albeit one which is not unhelpful, provided that the plaintiff's ultimate onus of proof is not displaced." At page 312B he said: "Before the House of Lords decided Wilsher v Essex Area Health Authority, English courts had moved to the idea that a plaintiff who was unable to weigh the scales down in favour of one of several competing but independent causative events could still succeed if the defendant(s) owed a duty of care and was/were engaged in conduct that created the risk of the injury which occurred, even though the plaintiff was unable to ascertain the existence or extent of the contribution made by the breach(es) to the injury suffered. The trend reached its final and highest exposition in the judgment of Mustill LJ in the Court of Appeal in Wilsher v Essex Area Health Authority (1987) QB 730 at 771-772, where he said: "There is, however, one problem which must be tackled. I had at one time believed that the present case is on all fours with the McGhee case (1973) 1 WLR 1 and that any apparent difference between the two simply stemmed from the way in which the problem happened to be expressed. I am now persuaded that this is not so, and that the two situations really are different. In the McGhee case there was only one risk operating, namely that contact of a sweaty skin with brick dust would lead to dermatitis. The fact that such contact did cause the injury was not in dispute. Just as in Bonnington Castings Ltd v Wardlaw (1956) AC 613 the defenders' fault lay in not taking proper steps to reduce that single risk. The uncertainty was whether the fault had tipped the scale. In the present case there is a greater uncertainty. Instead of a single risk factor known to have caused the injury there is a list of factors, which cannot be fully enumerated in the current state of medical science, any one of which might have caused the injury. What the defendants did was not to enhance the risk that the known factor would lead to injury, but to add to the list of factors which might do so. I acknowledge that this is much further from the fact of Bonnington Castings Ltd v Wardlaw, which was the springboard for the McGhee case than were the facts of the McGhee case itself. The question is whether this makes a crucial difference. The root of the problem lies in the fact that, for reasons of policy their Lordships' House mitigated the rigour of the rule that the plaintiff must prove that the breach caused the loss, in the interests of achieving a result which was considered to be just. Given that this was a decision based on policy, rather than a chain of direct reasoning, the difficulty is to know whether a similar approach can properly be adopted in the different circumstances of the present case. After much hesitation I have come to the conclusion that it can. Reading all the speeches together, the principle applied by the House seems to me to amount to this. If it is an established fact that conduct of a particular kind creates a risk that injury will be caused to another or increases an existing risk that injury will ensue; and if the two parties stand in such a relationship that the one party owes a duty not to conduct himself in that way; and if the first party does conduct himself in that way; and if the other party does suffer injury of the kind to which the risk related; then the first party is taken to have caused the injury by his breach of duty, even though the existence and extent of the contribution made by the breach cannot be ascertained." Expressed in such terms, an onus was placed on the defendant to whom the principle applied to prove that he or she was not in fact responsible for the injury suffered: see also McGhee v National Coal Board (1973) 3 All ER 1008 at 1012-1013, per Lord Wilberforce. This beneficial approach to proof of causation by plaintiffs was applied to a single defendant where it was uncertain whether a negligent or innocent act was the cause of injury ( McGhee v National Coal Board) as understood before Wilsher v Essex Area Health Authority ; and Wilsher v Essex Area Health Authority in the Court of Appeal) and to multiple defendants ( Fitzgerald v Lane (1987) QB 781; reversed on other grounds (1989) AC 328). And it was seen to offer a just solution to plaintiffs facing difficulties of proving causation due to the absence of factual evidence of which lay persons might attest ( Fitzgerald v Lane ) or due to the imperfect state of medical knowledge of which expert testimony was required ( Wilsher v Essex Area Health Authority (at 766E-F, 771B-C, 776E); Fitzgerald v Lane (at 799F-G). Fitzgerald v Lane was an example of the former and Wilsher v Essex Area Health Authority (in the English Court of Appeal) an example of the latter. In Fitzgerald v Lane , there were three possibilities touching a complicated motor accident (two affecting one defendant and the third affecting the other defendant) that could account for the plaintiff's tetraplegia. The trial judge held that each of the three possibilities was equally probable and that he was unable to distinguish between them. The Court of Appeal recognised that this did not mean that all three combined to produce the injury by cumulative effect: see at 795D. Nevertheless each defendant was held liable. In Wilsher v Essex Area Health Authority , the plaintiff's blindness could have been caused either by one of four medical conditions associated with the plaintiff's premature birth, or by the negligent saturation of oxygen by medical staff. Medical science was unable to identify the causal culprit. Since, however, the administration of excess oxygen increased the risk statistically in the sense of doubling the " contingency" (19887) 1 QB at 771) a causal connection was " presumed" (at 771) by the majority of the English Court of Appeal. Sir Nicolas Browne-Wilkinson V-C dissented. This approach put English law in line with that then prevailing in North America with respect to what Prosser and Keeton describe as " clearly established double fault and alternative liability ": Prosser and Keeton on Torts, 5th ed (1984) at 271. The classic example is where two defendants negligently shoot but the plaintiff is struck by one bullet which might have been fired from either gun. As the matter stood in 1984, the North American case law took the position that, where negligence on the part of both defendants was clear, and it was only the issue of causation which was in doubt, the onus shifted to each defendant to displace that burden. If it could not be displaced, then a verdict should be entered against each defendant with equal contribution towards satisfying the verdict: Summers v Tice 199 P 2d 1 (1948); Cook v Lewis (1952) ` DLR 1. (The two cases are criticised by T B Hogan in " Cook v Lewis Re-examined " (1961) 24 Mod LR 331). A similar principle has been applied to products liability cases where a number of manufacturers were negligent in the preparation of a common drug but where the plaintiff was unable to identify the manufacturer of the precise product which led to his or her injuries. However, in that case each manufacturer's liability was limited to its market share: Sindell v Abbott Laboratories 607 P 2d 924 (1980) (cert denied 449 US 912). However, the Court of Appeal (majority) decision in Wilsher v Essex Area Health Authority was overturned in the House of Lords. The proceedings were remitted for a re-trial on the issue of causation. Significantly, the House of Lords adopted the dissenting judgment in the Court of Appeal (that of the Vice-Chancellor) who had said (1987) 1 QB at 779) that: "….A failure to take preventative measures against one out of five possible causes is no evidence as to which of those five caused the injury." (see (1988) AC at 1091). In Wilsher v Essex Area Health Authority , Lord Wilberforce's speech in McGhee v National Coal Board was identified as adopting a minority position which should be rejected: see Wilsher v Essex Area Health Authority (at 1087). Nevertheless the conclusion was affirmed, McGhee v National Coal Board being explained as promoting a robust and pragmatic approach to the particular facts which allowed an inference of negligence to be drawn even though medical or scientific expertise could not arrive at a definite or more probable conclusion. This was because the risk of contracting the particular disease in McGhee v National Coal Board (dermatitis) was increased the longer the brick dust remained on the body. In those circumstances, the trier of fact was able to infer that a failure to provide washing facilities materially contributed to the disease by materially increasing the risk. The Supreme Court of Canada followed Wilsher v Essex Area Health Authority in Snell v Farrell (1990) 72 DLR (4th) 289, holding that the onus of proof does not shift in medical malpractice cases. In doing so, the Court explained that causation need not be determined by scientific precision; and that the common situation where the facts lie particularly within the knowledge of the defendant in malpractice cases means that very little affirmative evidence on the part of the plaintiff would justify the drawing of an inference of causation in the absence of evidence to the contrary: see at 299-301. Nevertheless, the reasoning was confined to medical malpractice cases, and Cook v Lewis was inferentially re-affirmed (at 299) on the basis that: "…Reversing the burden of proof may be justified where two defendants negligently fire in the direction of the plaintiff and then by their tortious conduct destroy the means of proof at his disposal. In such a case it is clear that the injury was not caused by neutral conduct. It is quite a different matter to compensate a plaintiff by reversing the burden of proof for an injury that may very well be due to factors unconnected to the defendant and not the fault of anyone." See also Hollis v Dow Corning Corporation (1996) 129 CLR (4th) 609 at 639. In Snell v Farrell , a robust factual approach to causation issues was compared to the theoretical reversal of onus of proof suggested by Lord Wilberforce in McGhee v National Coal Board . The Supreme Court endorsed Lord Bridge's speech in Wilsher v Essex Area Health Authority (1988) AC at 1088 where he explained McGhee v National Coal Board in the following terms: "…..where the layman is told by the doctors that the longer the brick dust remains on the body, the greater the risk of dermatitis, although the doctors cannot identify the process of causation scientifically, there seems to be nothing irrational in drawing the inference, as a matter of common sense, that the consecutive periods when brick dust remained on the body contributed cumulatively to the causation of the dermatitis. I believe that a process of inferential reasoning on these general lines underlies the decision of the majority in McGhee's case." In Bennett v Minister for Community Welfare (at 421), Gaudron J notes that the debate in Canada on a possible shift in the onus of proof is seemingly resolved in the manner indicated by Lord Bridge in Wilsher v Essex Area Health Authority. Where stands the current law in Australia? I am not aware of rejection of Wilsher's reassessment of McGhee v National Coal Board . In March v E & MH Stramare (at 524), Mason J cites various passages in McGhee v National Coal Board , including a passage from the speech of Lord Wilberforce. It is significant, however, that he does so in support of the uncontroversial proposition that the plaintiff must prove that his or her injuries are " caused or materially contributed to" by the defendant's wrongful conduct. In St George Club Ltd v Hines (1961) 35 ALJR 106 at 107; (1962) ALR 30 at 41, the High Court, in a joint judgment of five justices, said: "In an action of law a plaintiff does not prove his case merely by showing that it was possible that his injury was caused by the defendant's default, Bonnington Castings Ltd v Wardlaw (1956) AC 613; nor does proof of default followed by injury show that the default caused the injury, for as Viscount Simonds said in Quinn v Cameron & Robertson Ltd (1958) AC 9 at 23, "' Post hoc, ergo propter hoc '" is a fallacy in respect of a breach of a statutory regulation as it is in respect of any other event in life'. Similar principles apply to a claim for compensation where it is necessary to show that the employment contributed to the injury." See also Australian Iron & Steel Ltd v Connell (1959) 102 CLR 522 at 531-532; EMI (Australia) Ltd v Bes (1970) 2 NSWR 238; Duyvelshaff v Cathcart & Ritchie Ltd (1973) 47 ALJR 410 at 417; 1 ALR 125 at 138; Tubemakers of Australia Ltd v Fernandez (1976) 50 ALJR 720 at 724; 10 ALR 303 at 310; Wintle v Conaust (Vic) Pty Ltd (1989) VR 951 (discussed below); Western Australia v Watson (1990) WAR 248 at 286; Chance v Alcoa of Australia Ltd (190) Aust Torts Rep 67, 719." At page 316E he stated: "In the end I do not think it open to an immediate court of appeal to take this path, in the light of the many Australian authorities starting with St. George Club Ltd v Hines which I have cited above; and the more recent developments in England and Canada. In Pibworth v Bevan M Roberts Pty Ltd (1994) 176 LSJS 39 (otherwise unreported, Supreme Court of South Australia, Full Court, 15 April 1994) the Full Court of the Supreme Court of South Australia followed Wilsher v Essex Area Health Authority and adopted the summary of what the case stands for offered by Andrew Grubb in the case note (" Causation and Medical Negligence") in (1988) Cam LJ 350. That summary states, as its third proposition (at 350-351): "The law does not equate the situation where the defendant had materially increased the risk of injury with one where he had materially contributed to the injury." I respectfully agree. Only parliament or the High Court may change this. The difficulties which these principles place in the way of a plaintiff can be very considerable. To say that they are the logical outcome of a legal system that requires proof of fault before damages flow against a particular defendant does not remove a lingering sense of injustice, particularly in the case of multiple defendants where each has been shown to have negligently exposed a plaintiff to a risk of injury. Nevertheless our law remains wedded to the principle that if the risk does not come home in a way that is causally linked to the particular defendant's negligence, then it is the plaintiff who must bear the loss: see Rhesa Shipping Co SA v Edmunds, The "Popi M" (1985) 2 Lloyd's Rep 1 at 5. These principles have been reversed by legislation in several jurisdictions, including Ireland, Germany and the Netherlands: Civil Liabilities Act 1961 (Eire), s 11(3); J G Fleming, " Probabilistic Causation in Tort Law" (1989) 68 Can Bar Rev 661 at 671; M Vranken, " The first decennium of the European Product Liability Directive: a cause for celebration?" (1996) 4 Torts LJ 225 at 236-238. In Kilgannon v Sharpe Bros Pty Ltd, Kirby P suggests that the principles of res ipsa loquitur may bring about a similar result in some circumstances involving multiple defendants all having " control" of the relevant situation: see at 6140619. However, this view was rejected by the majority of the Court (Hope JA and Priestley JA). More importantly for present purposes, Kirby P recognised that it would be unreasonable and possibly unjust to apply the principle he espoused where " there is a possible explanation, in an extraneous cause, originating in a party who is not before the Court" (at 617D; see also at 618B). The absence of the Royal Navy as a defendant in the present case is therefore critical, even on Kirby P's approach. It can be demonstrated that the common law is not unsympathetic to the plight of plaintiffs who are faced with multiple defendants yet uncertain as to which of them was legally responsible, where it appears that not all of them were…….." At page 318A he said: "But none of these procedural or adjectival concessions in favour of an uncertain plaintiff support the principle that a party who negligently exposes a plaintiff to a risk of injury will be liable unless the plaintiff can persuade the trier of fact that it was probable that the risk came home. The basal principle remains that: " The law never gives judgment in favour of a plaintiff when the only finding is equally consistent with liability and non-liability." (Moriarty v Evans Medical Supplies (1958) 1 WLR 66 at 91, per Lord Denning.) At page 319C he said: "I agree with Beazley JA on the issue of causation. My view may be summarized as follows: 1. ……… 2. The ultimate issue, in the light of the principles which I have endeavoured to summarise, is which (if any) of the persons sued by the respondent were shown, on the balance of probabilities, to have caused or materially contributed to Mr Barnes' mesothelioma. 3. Expert evidence, which the trier of fact is entitled to accept despite the weight of evidence to the contrary, established that the appellants might have caused or materially contributed to Mr Barnes' fatal illness.. (I refer to the evidence of Dr Burns and Dr Joseph.) 4. Nevertheless, the evidence as to the type of fibre to which the respondent was exposed in the Royal Navy (crocidolite), the dose to which he was then exposed and the lag time involved all pointed strongly in the direction of the Royal Navy. Although that evidence, in the final analysis, merely supported the greater risk of the fatal disease having been contracted by the respondent during this period of his working life, that evidence (taken cumulatively) can, and in my mind does, support the finding that this was the employer more probably than not whose act or omission caused the fatal disease. As against the Ministry of Defence (UK) it is a situation where an inference of causation is warranted in that there is no practical difference between materially contributing to the risk of harm and materially contributing to the harm itself: cf Snell v Farrell (at 296G). Another way of addressing the issue is to hold that, were the Ministry of Defence (UK) the sole defendant, then a verdict against that defendant would be clearly open on the evidence. Judge Maguire reached a similar conclusion in the passage quoted early in this judgment. 5. None of this precludes a verdict against one or more of the appellants each of whom have been shown to have negligently exposed Mr Barnes to a risk of contracting the fatal disease. But that is not enough. Has it been shown to be probable that the risk they or any of them created actually caused injury? It will be sufficient if their several acts caused or contributed materially to the onset of mesothelioma. 6. As Beazley JA demonstrates, the evidence of the respondent's principal expert witnesses (Dr Burn and Dr Joseph) does not rise higher than demonstrating that the chrysotile in the brake linings was a potential contributor to Mr Barnes' mesothelioma. Unlike the appellants' expert witnesses, Dr Burns considered that chrysotile was "just as likely to be harmful as any other asbestos." This, if accepted, provided the evidentiary basis upon which the trier of fact might conclude that the appellant were responsible in fact and law for the fatal disease. But it does not compel that conclusion. I read the evidence about repeated stimuli increasing the chances of getting mesothelioma in the same sense. The effect of the evidence of Mr Barnes' exposure to greater quantities of the more risky crocidolite at a more likely time cannot be ignored. Nor can one ignore the evidence of lighter exposure to the less lethal cyrysotile in the more recent periods involving the appellants. The evidence of Dr Burns and Dr Joseph simply fails to offer a scientific or indeed a rational basis for preferring the chrysotile of the appellants over the crocidolite of the Royal Navy; or for concluding that the later exposure had a harmful cumulative effect, like the brick dust in McGhee v National Coal Board on prolonged exposure to noise. The essence of this view is that the scales remain equipoised because medical science cannot say which exposure was significant. If the Royal Navy exposure had not occurred, the trier of fact (and, one infers, even the appellants' experts) would have found it probable that the appellants were liable. But the presence of the Royal Navy cannot be ignored, especially since the evidence points strongly to it in the sense that it, more than any other person, materially increased the risk of contracting mesothelioma. 7. It would be speculation, not inference, to conclude that it was more probable than not that the appellants or any of them materially contributed to the respondent's disease. The highest that the respondent's case can be put is that the appellants' involvement increased the statistical contingency that their acts or omissions may have caused or materially contributed to the mesothelioma. The inability of medical science to identify the aetiology of the disease or to establish a likelihood let alone probability that the appellants' asbestos contributed to the disease, means that the respondent has not established against any party from whom he seeks a verdict that that party is liable in the tort of negligence. Beazley JA also dealt with causation, reaching the same conclusion as the learned President. At page 335 her Honour said: "Causation is a question of fact to be determined by the application of commonsense to the facts of each case: March v E & MH Stramare Pty Ltd (1991) 171 CLR 506 at 515, per Mason CJ; Bennett v Minister of Community Welfare (1992) 176 CLR 408. Notwithstanding this exceedingly simple formulation of principle, its application in a case of this sort is not easy of resolution. Mesothelioma is a condition of uncertain aetiology and Mr Barnes was serially exposed to asbestos which the evidence indicated possibly had different degrees of toxicity depending upon the particular fibre, the first exposure being to crocidolite, which is considered to be a more virulent causative agent of mesothelioma than chrysotile, to which Mr Barnes was later exposed. The factual question which calls for resolution in the first instance is whether, on the balance of probabilities, the exposure to chrysotile during the period 1962 to 1985 or any relevant part of this period, caused or materially contributed to Mr Barnes' contraction of mesothelioma: Bonnington Castings Ltd v Wardlaw (1956) AC 613. In Bonnington Castings Ltd v Wardlaw , a steel dresser was exposed to silica dust from two sources in the course of his employment: a pneumatic hammer and swing grinders. There was no dust extraction plant known or practicable for use with the hammer. Although the swing grinders were fitted with such equipment, they were not kept free from obstruction. The employer conceded it was thereby in breach of relevant regulations which governed its operations. The steel dresser contracted pneumoconiosis. The question which arose was whether the worker had established that the cause of his pneumoconiosis was due to the breach of statutory duty. Lord Reid stated (at 620-621): "…In my judgment, the employee must in all cases prove his case by the ordinary standard of proof in civil actions: he must make it appear at least that on balance of probabilities the breach of duty caused or materially contributed to his injury…. ….I am in agreement with much of the Lord President's opinion in this case, but I cannot agree that the question is: which was the most probable source of the respondent's disease, the dust from the pneumatic hammers or the dust from the swing grinders? It appears to me that the source of his disease was the dust from both sources, and the real question is whether the dust from the swing grinders materially contributed to the disease. What is a material contribution must be a question of degree. A contribution which comes within the exception de minimis non curat lex is not material, but I think that any contribution which does not fall within that exception must be material. I do not see how there can be something too large to come within the de minimis principle but yet too small to be material…." Dealing with the particular facts in the case, Lord Reid stated (at 622): "I think that the position can be shortly stated in this way. It may be that, of the noxious dust in the general atmosphere of the shop, more came from the pneumatic hammers than from the swing grinders, but I think it is sufficiently proved that the dust from the grinders made a substantial contribution. The respondent, however, did not only inhale the general atmosphere of the shop: when he was working his hammer his face was directly over it and it must often have happened that dust from his hammer substantially increased the concentration of noxious dust in the air which he inhaled. It is therefore probable that much the greater proportion of the noxious dust which he inhaled over the whole period came from the hammers. But, on the other hand, some certainly came from the swing grinders, and I cannot avoid the conclusion that the proportion which came from the swing grinders was not negligible." Lord Reid reiterated the principle he had formulated in Bonnington Castings Ltd v Wardlaw in McGhee v National Coal Board (1973) 1 WLR 1 at 4; (1972) 3 All ER 1008 at 1010, stating: "It has always been the law that a pursuer succeeds if he can show that fault of the defender caused or materially contributed to his injury. There may have been two separate causes but it is enough if one of the causes arose from fault of the defnder. The pursuer does not have to prove that this cause would of itself have been enough to cause him injury. That is well illustrated by the decision of this House in Bonnington Castings Ltd v Wardlaw (1956) AC 613." The causation issue in McGhee v National Coal Board was slightly different to the problem encountered in Bonnington Castings Ltd v Wardlaw . McGhee had been a long time employee in brickworks and during the course of his daily employment would become covered in brick dust. The respondent failed to provide him with showering facilities so that at the end of the work day, he would cycle home still covered in the brick dust. He contracted dermatitis. Lord Reid noted that the evidence did not establish how dermatitis of the type suffered by the worker was contracted. Two possible theories were advanced, one to the effect that there had t be multiple tiny abrasions to the horny layer of the skin before the dermatitis developed, the other to the effect that a single abrasion was sufficient, the effect of multiple abrasions being to increase the possible sites where the disease could start. Lord Reid considered that the evidence tendered to the former view. However, the lack of certainty as to the precise cause of the disease did not mean that a plaintiff could not establish causation. As Lord Reid further stated (at 4; 1011): "…in a field where so little appears to be known with certainty I could not say that that is proved. If it were, then this case would be indistinguishable from Wardlaw's case. But I think that in cases like this we must take a broader view of causation. The medical evidence is to the effect that the fact that the man had to cycle home caked with grime and sweat added materially to the risk that this disease might develop. It does not and could not explain just why that is so. But experience shows that it is so." See also Lord Simon (at 8), Lord Kibrandon (at 10) and Lord Salmon (at 12). Lord Reid added that he saw no distinction between " materially increasing the risk that the disease will occur and making a material contribution to its occurrence." Bonnington Castings Ltd v Wardlaw and McGhee v National Coal Board were explained in Wilsher v Essex Area Health Authority (1988) AC 1074 at 1087, by Lord Bridge of Harwich in there terms: "A distinction is, of course, apparent between the fact of Bonnington Castings Ltd v Wardlaw , where the ' innocent' and guilty' silica dust particles which together caused the pursuer's lung disease were inhaled concurrently and the fact of McGhee v National Coal Board (1973) 1 WLR 1 where the 'innocent' and ' guilty' brick dust was present on the pursuer's body for consecutive periods. In the one case the concurrent inhalation of ' innocent' and ' guilty' dust must both have contributed to the cause of the disease. In the other case the consecutive periods when ' innocent' and ' guilty' brick dust was present on the pursuer's body may both have contributed to the cause of the disease or, theoretically at least, one or the other may have been the sole cause. But where the layman is told by the doctors that the longer the brick dust remains on the body, the greater the risk of dermatitis, although the doctors cannot identify the process of causation scientifically, there seems to be nothing irrational in drawing the inference, as a matter of common sense, that the consecutive periods when brick dust remained on the body probably contributed cumulatively to the causation of the dermatitis. I believe that a process of inferential reasoning on these general lines underlies the decision of the majority in McGhee's case." Lord Bridge further stated (at 1090): "The conclusion I draw from these passages is that McGhee v National Coal Board (1973) 1 WLR 1 laid down no new principle of law whatever. On the contrary, it affirmed the principle that the onus of proving causation lies on the pursuer or plaintiff. Adopting a robust and pragmatic approach to the undisputed primary facts of the case, the majority concluded that it was a legitimate inference of fact that the defenders' negligence had materially contributed to the pursuer's injury. The decision, in my opinion, is of no greater significance than that and to attempt to extract from it some esoteric principle which in some way modifies, as a matter of law, the nature of the burden of proof of causation which the plaintiff or pursuer must discharge once he has established a relevant breach of duty is a fruitless one." In Wilsher v Essex Area Health Authority, the defendant's staff negligently allowed the plaintiff to be exposed to excess oxygen which could have caused his blindness. During the same period he suffered from four other conditions which could also have caused his blindness. The Court of Appeal, purporting to apply McGhee v National Coal Board held that the breach of duty established a presumptive inference that the exposure to the oxygen was the cause of the blindness. However, the House of Lords rejected the proposition that there was any reversal of onus in such a case such that the defendant had to prove that its breach had not materially contributed to the plaintiff's injury. They endorsed the dissenting view of Browne-Wilkinson V-C (at 1091) that: "A failure to take preventative measures against one out of five possible causes is no evidence as to which of those five caused the injury." The principle established by Bonnington Castings Ltd v Wardlaw and McGhee v National Coal Board has been consistently applied in England and Australia. In March v E & MH Stramare , Mason CJ stated (at 514): "….the law's recognition that concurrent or successive tortious acts may each amount to a cause of the injuries sustained by a plaintiff is reflected in the proposition that it is for the plaintiff to establish that his or her injuries are ' caused or materially contributed to' by the defendant's wrongful conduct: Duyvelshaff v Cathcart & Ritchie Ltd (1973) 47 ALJR 410 at 417; 1 ALR 125 at 138, per Gibbs J; Tubemakers of Australia Ltd v Fernandez (1976) 50 ALJR 720 at 724; 10 ALR 303 at 310, per Mason J: Bonnington Castings Ltd v Wardlaw (1956) AC 613 at 620; per Lord Reid; McGhee v National Coal Board (1973) 1 WLR 1 at 4,6,8 and 12. Generally speaking, that causal connexion is established if it appears that the plaintiff would not have sustained his or her injuries had the defendant not been negligent: see ICIANZ Ltd v Murphy (1973) 47 ALJR 122 at 127-128. But, as the decision in that case illustrates, it is often extremely difficult to demonstrate what would have happened in the absence of the defendant's negligent conduct." See also Bennett v Minister of Community Welfare; Commonwealth v McLean; Birkholtz v R J Gilbertson Pty Ltd (1985) 38 SASR 121; Seltsam Ltd v Minahan. Wintle v Conaust (Vic) Pty Ltd (1989) VR 951 was a mesothelioma case in which the applicant sought an extension of time within which to commence proceedings. Crockett J and Gray J dismissed an appeal from the trial judge's refusal of the application, stating (at 953): "The difficulty simply is - as the judge pointed out - that the evidence does not disclose for how long (constantly or intermittently) a person must be exposed to asbestos dust before it can be said that a subsequently contracted mesothelioma was as a matter of probability caused by that exposure." Their Honours added: "In cases such as that with which the court is now concerned the burden of proof of actionable negligence against any defendant remains firmly with the plaintiff. Despite this court's rejection of the hearsay in Pastras v The Commonwealth (1967) VR 161, there have remained suggestions that a defendant carried the burden of disproof if it were shown that he was one of a number any one or more of whom must have been negligent. These have now been firmly rejected by the House of Lords: Wilsher v Essex Area Health Authority (1988) 2 WLR 557." The clear effect of these cases is that the onus remains on the plaintiff to prove causation on the balance of probabilities. The onus is not discharged by establishing that a particular matter cannot be excluded as a cause of the injury: see Sydney County Council v Furner (1991) 7 NSWCCR 210, where Hope A-JA said (at 214): "…To find that a particular cause cannot be excluded as the cause of the relevant injury does not establish that on the probabilities it was the cause of that injury; it may have been ' the' or ' a' cause. In other words, to establish that medical evidence supports a conclusion that the cause could not be excluded as a cause of an injury does not establish, without more, that particular cause in fact resulted in or caused the injury." Subsequently the Court of Appeal decided ICI Operations Pty Limited v Watel & Ors . (Unreported 3 October, 1997). The bench consisted of the President and Justices Handley and Meagher. The learned President shortly restated his views as expressed in Bendix. Handley JA (one of the members of the Court in McLean ) agreed with the views of the President. In my view the law of New South Wales is as was stated by the learned President in Bendix. It is not, as he says, for an intermediate Court of Appeal to change it let alone for a trial judge such as myself. Whatever may be one's views of the social desirability of the High Court and Parliament of changing the law to in effect shift the burden of proof to a defendant of showing that his negligent actions did not cause injury to the plaintiff where the plaintiff has shown that the actions of the defendant increased the risk of the plaintiff sustaining the injury which was sustained, it is not open to me to decide this case on that basis. Simply establishing that a causal connection between the actions of the defendant and the injury to the plaintiff is possible does not justify a finding of causation unless the evidence justifies an inference of probable connection. Accordingly I do not accept the submission on behalf of the plaintiffs in respect to the proof of causation. In order to succeed the plaintiffs must, according to the law of New South Wales, establish that the or a probable cause of their injury was the negligence of the defendants. 4. PROBABILITY OF CAUSATION The evidence of causation relied on by the plaintiffs as pointing to the conclusion that Cu-7 use caused or materially contributed to the acquisition of PID and its sequelae and to septic abortion was as follows: 4.1 Epidemiology 4.2 Scientific analysis 4.3 Clinical observation The plaintiffs' case is that use of IUDs "enhanced" or "materially contributed " to PID. 4.1 EPIDEMIOLOGY The threshold question is whether a user of a Cu-7 was placed at a greater risk of PID than if she had not used a device. The parties were diametrically opposed on the answer to this question. The plaintiffs assert that there was an increased risk. The defendants assert that the only increased risk involved was a risk associated with the process of insertion of the device into the uterus (an iatrogenic risk). The plaintiffs seek to establish the existence of an increased risk by the use of epidemiological evidence. They submitted that throughout the decade from 1975 when the first insertion of an IUD relevant to these proceedings occurred " there was a drum beat of concern in the medical literature about the increased risk from IUD use, PID and its sequelae." The defendants conceded that virtually all of the numerous case studies published reported a statistical association between PID and the use of an IUD but submitted that there are " cogent reasons why these studies, when properly interpreted, cannot establish a causal link between the use of the Gravigard/Mini and PID with its sequelae. " Epidemiology is the statistical study of disease in relation to such things as prevalence or factors associated with suffers of the disease which may be causative of it. One method of statistically determining cause is by conducting what is known as an observational cohort study. An example of this is given by the defendants in Chapter 7 Volume 1 Page 6 of their submissions. That example is that if an investigator suspects that tea drinking causes renal stones, a group of four thousand tea drinkers and a group of four thousand non-tea drinkers are assembled. They are then followed for ten years and results of their renal stone incidents are tabulated. If there are fewer renal stone incidents among non-tea drinkers than there are among tea-drinkers then that may suggest that tea drinking may cause renal stones. The difference in the number of incidents will indicate the seriousness of the hazard. An alternative method of determining cause is a case control study which follows a reverse direction. The investigator studies people who already have the disease and a control group is assembled comprising people in whom the disease has not been noted. The two groups are then followed in a backward direction with enquiries aimed at determining each member's antecedent exposure to the alleged aetiological agent or cause of the disease. The defendants submitted that one can conclude that any difference which appears in the results of a case control study only reflects some causal link if it is possible to exclude all other plausible explanations for the difference. They refer to " non-causal" explanations which they submit must be excluded as: (a) Selection bias: This is said to mean that there is some fundamental difference between the members of the two groups " rather than the tea drinking having any effect. " In support of this proposition the defendants refer to an article by Grimes " Biases: the Saboteurs of Silence ". (Exhibit D384 Tab 10). In that article Grimes refers to an example of methological weaknesses in cohort studies as examples, which methological weaknesses may have damaged a study's validity. The first he refers to is selection bias where he opines that " selection bias implies that subjects in one study group are different from those in another in some feature other than the exposure of interest. If this feature is not measured it cannot be controlled for in the analysis and thus may bias the results. " He concluded: " In a cohort study, both groups should be comparable in all respects, except for the exposure of interest (here hormone therapy) ". Grimes is referring to cohort studies in the article referred to but it is difficult to see why there should be any difference in principle in this aspect between cohort studies and case control studies. (b) Assessment or data bias: The diagnosis is not assessed in identical ways in the two groups that are being studied. (c) Chance: Despite there being no " real" difference sampling error or random variation has resulted in difference in the study data. The studies referred to in these proceedings are essentially case control studies. They are " retrospective studies. " They compare women who had the problem under investigation and " controls ", women who did not have the same problem. Professor Newton said that the disadvantage of this type of investigation is that " bias is inherent and difficult to control." (Exhibit D299 para 105(b)). Another difficulty with case control studies are what are known as confounders. The most common confounder in medical studies is the age of the persons studied. In a comparison there should be an adjustment for age so that the comparison is between people of the same age. Professor Daling who gave evidence on behalf of the plaintiffs said (T2770) that it is not possible to entirely remove bias but " I mean we do the best we can to remove all possible bias. " At T2773 Professor Daling said, when referring to the elimination of the effect of other factors relating to a disease, " you have taken all those steps made possible by your data collection and your statistical tools to reduce as much as possible. " Studies may suffer from bias for various reasons and the effect of that is that you may get an estimate of the risk which is not the true estimate of the risk. (Daling, T2768). The defendants in their submissions dealt simply with the definition of a number of relevant epidemiological terms and it is convenient to deal with those definitions at this stage. They were illustrated by the following example. 5,000 men and 5,000 women crossed Elizabeth Street and the number of each group who stumbled were counted. Of the 5,000 men 100 or 2% stumbled. Of the 5,000 women 150 or 3% stumbled. Those percentages are both incidence rates or simply the likelihood of stumbling. From the figures appearing in this example it would be correct to say that women have an increased incidence rate of stumbling compared to men. The relative risk is 3%/2% or 1.5 which means that women are 1.5 times more likely to stumble while crossing Elizabeth Street as men. One can then say that women have an increased risk of stumbling compared to men. A case control study does not obtain data which enables incidence rates to be calculated so what is known as an " odds ratio " is used to estimate the relative risk and adding a confidence interval. If it is sought to use data from a case study to estimate relative risk one assumes that the larger study is the more accurate will be the estimate. A confidence interval is calculated. This is an interval within which the true relative risk probably falls. In simple terms, it is likely that the larger the data set the greater is the confidence interval. A 95% confidence interval is used to indicate that the true odds ratio or relative risk is 95% likely to be at the figure or band determined. If the relative risk was 1.5 a 95% confidence interval means that if repeated samples of the same size were taken from the population study and studied, ninety-five times out of one hundred the relative risk calculated would fall within the confidence limit. The defendants submitted that it is not possible to come to a conclusion regarding causation from statistical results obtained in observational epidemiology or at least coming to a conclusion is fraught with difficulty. The defendants refer to Feinstien and Horwitz (Exhibit D291) where the author attacked the scientific methods used by epidemiologists. Keeping gave evidence in relation to the use of epidemiology at some length and concluded that the procedures and processes " still falls short of the only true method, which would be a control trial." There have been two significant reviews of the literature relevant to the issue of causal connection between IUD use and PID and its sequelae including ectopic pregnancy.. First was Senanayke and Kramer 1980 and second was the WHO Technical Group Report 1987 . The conclusion reached by Senanayke and Kramer was: "Taken together, the reported studies on the IUD and PID deal with most of biases that could explain the apparent increases in risk with the IUD. Results of the studies are consistent in direction despite varying study designs, researchers, and locations, and they generally point to an increased risk of 150% to 400% for IUD users when compared with all non-users of contraceptives." (p.857, LHC, last para). Review Articles are articles which overview the relevant medical literature and attempt to synthesise the state of knowledge researched at the time of writing. Professor Daling gave evidence that one criterion to be looked at is what is known as " consistencies across the studies ", namely a pattern mostly in one direction or the other across different study populations observed by different researchers. Senanayke and Kramer 1980 referred to above, canvassed sixteen studies. They are set out in Attachment 2 which forms part of the review. The WHO Technical Group Report 1987 canvassed those sixteen studies together with nine others. In all sixteen studies reported on by Senanayke and Kramer that there was an increased risk of PID from IUD use whether the comparison was made with women using other forms of contraception (the results show an increased risk varying from 1.9 to 9.3) or using no contraception at all (the results show an increased risk varying from 1.5 to 7.3). The nine further studies dealt with by the WHO Report show on their face an increased risk for IUD users varying between 2.1 and 10.5 compared to women using other forms of contraception and between 1.5 and 11.5 compared to women using no contraception. The conclusion reached by the WHO Technical Group was: "Since 1980, when 16 reports were reviewed by Senanayke and Kramer, 9 additional reports of significantly increased risk of pelvic inflammatory disease or tubal infertility among IUD users have been published. These 25 studies, conducted in many different countries by different investigators, albeit with different diagnostic criteria, have all found an increased risk of the disease or its sequelae among IUD users, which argue strongly for a causal relationship" (WHO Report p.38, LHC, para 7.4). Eschenbach gave evidence (T1822, L46-57) that the three studies of Wright and Laemmle 1968, Noonan and Adams 1974 and Targum and Wright 1974 were enough to lead to the conclusion that that there was an increased risk of PID from IUD use. Ory said of the six epidemiological studies he reviewed: "In summary, then, I think that these six studies point in the same direction, that IUD use is associated with the increased risk of acute PID. The best estimate suggests that IUD users have from three to five times the risk of developing PID compared to non-users, that teenagers appear as likely to be affected as older women, that copper IUD's do not offer any protection from gonococcal PID, and finally, there is the intriguing but as yet unconfirmed suggestion that nulliparous IUD users are more likely to develop acute PID than are multi-parous users. As an epidemiologist, I kind of look at these six studies, you know, done by five different investigators at three different countries, all showing the same results, and that, to me, provides some evidence that the association is one of cause and effect. Each study had its strengths and its weaknesses. However, all together, they rule out virtually every major source of bias as a possible reason for observing this association. In addition, when you couple it with Dick Soderstrom's recent report of the histologic changes and the possibility that this is altering tubal defense mechanisms; also if you couple it with the fact that previously rare syndromes, or so they are said to be in the literature, such as unilateral tubo-ovarian abscess and infective agents like Actinomycoses are now being reported in association with IUD use, I think biologic plausibility is added to a causal interpretation of these six studies." (Ex. P228, Tab 13, pp.72-73). The plaintiffs sought a finding that at the time of each IUD insertion relied upon by the plaintiffs, Searle was in possession of strong evidence from epidemiological studies which pointed to a causal association between IUD use and PID. The association, as revealed by the studies referred to above, was so strong and consistent that Searle was under a legal obligation to act on the basis of that causal association. The plaintiffs submitted that if this finding is made and if subsequent scientific research has not reviewed the conclusion in so far as it applies to Cu-7 then their case relating to a failure to warn is made out. The defendants submitted that later epidemiology was able to isolate the risk associated with Cu-7 itself and established that there was no increased rate of PID associated with Cu-7 use. The defendants further submitted that there was no increased risk among women in stable monogamous relationships. The defendants dealt with the papers referred to in the two overview papers to attempt to demonstrate that they could not be relied upon to support the conclusion contended for by the plaintiffs. I shall deal with each of the papers in the order in which they appear in the reports. Wright & Laemmle 1968 This is one of the first studies which attempted to look at the aetiology and epidemiology of PID within a large family planning program: The study was carried out in 1965 at the Grady Memorial Hospital, Atlanta, Georgia amongst a population of black indigent women. The methodology was that 902 first episode cases of acute PID were obtained from the Hospital records. The denominator used was the estimated total population of indigent women aged between 15 to 44 years in the 2 counties surrounding the hospital. A rounded-up figure of 50,000 was used to calculate the rates. A definite diagnosis of acute PID was made if a patient presented with a fever plus 2 or more of the following: · lower abdominal tenderness with or without guarding; · cervical motion tenderness; · uni- or bi-lateral adnexal tenderness with or without masses. An exception was made if there was actual visualization of PID at laparotomy. The authors looked at different factors which might have been relevant to the incidence of PID including age and marital status. They also looked at attack rates of acute PID among women according to the type of contraceptive method that was currently being used. The results of an analysis of 108 subjects with PID appear in Table VIII on page 985 of the paper. A summary of the table prepared by the defendants appears below: % Selecting Method Woman Years PID PID Per 1000 Woman Years IUD 43 1238 82 66.2 OC 44 1267 17 13.4 Vaginal Foam 11 317 8 25.2 Other <2 58 1 Total 100 2880 108 37.5 (Average) The summary table shows a significantly higher incidence of PID among IUD users than among the other types of contraceptors reported on. The defendants point to the following alleged shortcomings: 1. No information is given in the paper as to the type of IUD used by the subjects in this study but they would not have included Cu-7s. (It was not on the market then). 2. There is no information in the paper as to the duration of use and the incidence of PID among cases. 3. No relative risk estimates were reported by the authors. 4. The authors state that the study findings should be considered as being tentative. 5. It appears that most of the IUD-associated attacks of PID referred to in the paper were mild and were treated with the device in place. Given the above matters the defendants submitted that extrapolation from the results of the study is " fraught with difficulty ". Noonan & Adams 1974 The aim of this study was to determine the relationship between the prevalence of gonorrhoea and the presence of symptoms and the use of various contraceptive methods. This study was also carried out in the Family Planning Clinic of Grady Memorial Hospital in Atlanta, Georgia amongst a population of black indigent women. 1,706 women were selected from the clinic being every third non-post partum patient presenting at the clinic. They were screened for cervical gonorrhoea and questioned for a history of PID symptoms. A non-specific definition of PID was used. Subjects were classified as being symptomatic if: (a) they complained of pelvic pain or cramping abdominal pain at times other than during menstruation; or (b) if the examining physician elicited pelvic tenderness that the reviewer felt was pathological. Dyspareunia alone was not considered a symptom. Among women with symptoms of PID, 20.6% used oral contraceptives, 33.3% used IUDs and 16.2% used other methods of contraception. Among women diagnosed with gonococcal PID, 0.7% used oral contraceptives, 3.1% used IUDs and 0.2% used other methods of contraception. There were no relative risk estimates reported. However it was subsequently reported in Senanayake & Kramer 1980 that women with IUDs had symptoms of PID 2.5 times more frequently than women not using any contraception and 1.8 times more frequently than women using all other methods of contraception combined (Ex. P124 page 854). No information was given as to the type of IUDs being used by subjects in this study but Cu-7s were not used. The authors stated that the prevalence rate of gonorrhoea was essentially the same for IUD and other contraceptive users. They concluded (page 704) that none of the methods of contraception (including IUDs) seemed to be associated with an increase in the prevalence of gonorrhoeal infection. The increased prevalence of symptoms of PID in IUD users was a comparative observation to those women who were using methods of contraception which provided a chemical or physical barrier against the ascension of bacteria from the vagina. The authors hypothesized that the protective effect of other types of contraceptors may have given rise to the differing prevalence rates of PID. Targum & Wright 1974 This was a case-control study which examined first-episode acute PID in 50 disadvantaged black and Hispanic patients in a major New York hospital: For a diagnosis of PID there needed to be a temperature in excess of 37.7 o C and 2 of the following 3 findings: · lower abdominal pain and tenderness; · cervical motion tenderness; · adnexal tenderness. Two sets of controls were chosen, one from women attending the general medical clinic and the other from women appearing with sick children in the paediatric emergency room. 100 controls were selected and their current contraceptive practises were as follows: · 9% IUDs; · 50% OCs; · 41% no contraception. The current contraceptive practises of the 50 cases were: · 48% IUDs · 22% OCs · 36% no contraception. Of the 24 cases using an IUD, 11 women had Lippes Loops, 8 had the Majzlin Springs (ultimately recalled by the FDA) and 4 were using the Saf-T-Coil. One women did not know which IUD she was wearing. The relative risk estimate for IUD users versus non-users was 9.3 (4.2 - 20.9). The relative risk for IUD users versus non-contraceptors was 7.3 (2.9 - 18.4): The relative risk estimates for IUD users in this study is one of the highest reported in any of the studies and may have been due in part to the fact that of the 50 subjects 40 had been hospitalised. Of the 50 PID cases, there were 24 IUD users. Of the 100 controls, there were 9 IUD users. There were no copper devices in the study. The relative risk estimates were accompanied by very wide confidence intervals. Eschenbach said, as I have stated above that in his view those three studies were enough to lead to the conclusion that there was an increased risk of PID from IUD use. Lippes 1975 This study was a preliminary report to answer the question " Does the IUD increase the incidence of pelvic infection? " It was prepared by Dr Jack Lippes and presented to the FDA at its hearing on IUDs in August 1974. To prepare for his testimony (and therefore the study) the medical record library of the Buffalo General Hospital was asked to review all cases carrying a discharge diagnosis of PID, salpingitis or endometritis for the year 1973. 91 patients were identified as a result. The diagnosis of PID was based on acceptance of a discharge diagnosis of PID, salpingitis or endometritis but was otherwise not specified. Controls were identified by a review of the charts of all women of reproductive age with a diagnosis of acute appendicitis for the years 1972 and 1973. 38 controls were identified. Among the cases identified, 13 of the 91 (14%) were wearing an IUD. Among controls, 3 of 38 (8%) were wearing an IUD. The difference on these very small numbers is not statistically significant. One Dalkon Shield associated with a serious bacterial septicaemia was specifically identified, but otherwise, individual devices were not specified. The relative risk estimate for IUD users versus non-users was 1.9 (0.5-7.2). The relative risk estimate for IUD users versus non-contraceptors was not ascertained. Dr Lippes concluded from the data collected that the incidence of PID was no higher in women wearing an IUD than in women who did not. However, he acknowledged that there was a potential for hospital bias as the PID cases who were admitted to the hospital were the more seriously ill patients with PID. Phaosavasdi et al 1975 This was a retrospective case series in which evidence of PID was observed during 200 transvaginal tubal sterilisations carried out at the Chulalongkorn Hospital, Bangkok between October 1972 and June 1973. 200 patients selected from the Family Planning Unit at the hospital underwent transvaginal tubal sterilisation. Among the cases, 101 patients were immediate past users of the Lippes Loop (the only device in the study), 73 were past users of other contraceptives and 26 were non-contraceptors. The authors state that no prostitutes or other unspecified categories particularly prone to PID were included among the cases. PID was diagnosed if at least one of the following were present: · adhesions · congestion · tubal occlusion with clubbing or oozing of pus from the fimbria. No hysterological examination was performed. There were 33 patients with evidence of pelvic inflammatory change. Among those 28 (of 101) were Lippes Loop users, 3 (of 73) were other contraceptive users and 0 (of 26) were non-contraceptors. This calculated that 84% of those with evidence of pelvic inflammatory diseases were Lippes Loop users, 9% were other contraceptors and 0% were non-contraceptors. The relative risk estimate for IUD users versus non-users was 9.2 (3.7 - 22.5) ( Senanayake & Kramer 1980 ) : The relative risk estimate for IUD users versus non-contraceptors was not reported. The authors stated that the observations contained in this study were very preliminary and there was a need for further studies on larger groups of women. Senanayake & Kramer 1980 noted that this retrospective (self-selected) cohort involved a non-specific definition of previous or current PID which was diagnosed visually at sterilization. There was a reported prevalence rate of 15% of PID in the cohort whose method of selection (other than being sterilization patients) was not clear: Combined Bangkok Hospital Group 1975 This study involved an examination of unsuspected pelvic infection in 1583 healthy, previously fertile Thai women undergoing interval sterilization over a 5 month period in 1974 at 4 Bangkok hospitals: Cases were taken consecutively. The diagnosis of PID depended on surgical putative evidence of past PID including adhesions, hydrosalpinx, adnexitis, uterine adhesions or enlarged ovaries. Post-partum sterilization cases were excluded to ensure adequate visualization. The pathological examination of tissue was only undertaken in a minority of cases and there were no pre-operative cervical smears. Associated demographic information was collected but no information about prior pelvic infection or sexual history, other than contraceptive use, was obtained nor was there any differentiation between the types of devices used. 60% of subjects were sterilized by laparoscopy, 19% by laparotomy and 16% by culdoscopy. Among the 1583 subjects, 86.5% had used contraception and 71% were current contraceptors, 13.5% had never used any form of contraception and 29% were non-current contraceptors. At sterilization, 10% had putative evidence of unsuspected past PID. The authors then focussed on the largest group with putative evidence, namely, 120 cases involving tubal adhesions. Despite absence of detail in the report, Edelman 1980 concluded that 8.9% of cases with tubal adhesions had never used a contraceptive method, 12.3% had used the IUD only and 4.9% had used the pill only. The relative risk estimate for IUDs versus non-users was 2.1 (1.3-3.3). The relative risk estimate for IUD users versus non-contraceptors was 1.4 (0.8-2.5) ( Senanayake & Kramer 1980 ) : The authors proposed a risk gradient which showed that IUD only users had the highest chance of tubal adhesion, pill only users had the lowest chance and users of both methods had an intermediate level of chance of tubal adhesion. The authors suggested that there was a high risk of developing adhesions or hydrosalpinx among women who did not wear or had not worn the IUDs very long flattening out to a low and reasonably constant risk over longer wearing periods. The authors urged caution in relation to the results from this self-selected population because of the perceived difference between women seeking sterilization and women abandoning a non-permanent method. The reasons for their discontinuances were not dealt with. The authors also noted that, given the population would never again test their fecundity, it was not possible to say whether the lesions would have compromised their ability to become pregnant. Faulkner & Ory 1976 This was a case-control study which was designed to investigate the relationship between PID and IUDs. Following Wright & Laemmle 1968 and Noonan & Adams 1974 , this study was also conducted at Grady Memorial Hospital, Atlanta, Georgia amongst a population of substantially black women. Cases were selected from women seen in the emergency room of the Hospital. 50 febrile PID cases were identified. These were women who: (a) were seen in the emergency room with a complaint of abdominal pain for discomfort; (b) were confirmed to have an oral temperature of 38C or more; (c) had uterine or adnexal tenderness on pelvic examination; and (d) had no diagnosis other than PID to explain this illness either at the time of the initial visit or within one month. 100 cases of afebrile PID were also identified. These women did not have confirmed oral temperatures as high as 38C. 200 women were selected as controls from women who: (a) were seen in the same emergency area; (b) had an initial complaint other than abdominal pain or discomfort; and (c) did not have this complaint diagnosed as a gynaecologic problem either at the time of the initial examination or within 1 month. Distribution of IUDs among cases and controls appear by type in Table 4 of the article. Only 1 Gravigard was used by 1 control. The balance of the IUDs were primarily Lippes Loops and Dalkon Shields. The Dalkon Shield was found in a higher proportion of febrile cases than the controls. The relative risk estimates for IUD users versus non users was 5.1 (2.5 - 10.5). The relative risk estimate for IUD users versus non contraceptors was 3.7 (1.7 - 8.2). The authors concluded that there was no association between the length of IUD use and the risk of developing PID or febrile or afebrile cases. The numbers in this study are comparatively small. Among the 50 febrile PID cases, 19 women were using an IUD. This can be compares with 17 women who were using no method of contraception and 10 women who were using an oral contraceptive. Among the 100 afebrile PID cases, 24 women were using an IUD. This compares with 48 women who were using no method of contraception and 23 women who were using an oral contraceptive. Westrom et al 1976 This was a case-control study which examined the frequency of IUD use among women with acute salpingitis who had been laparoscopically verified against the frequency of age matched controls selected from patients seen in the University Hospital, Lund, Sweden between January 1971 and June 1975: In the study period, 515 cases of acute salpingitis which had been laparoscopically verified were treated in the Department of Obstetrics and Gynaecology at the University Hospital. 1545 potential controls were matched for age from the Lund regional register and contacted by postal questionnaire. Currently pregnant and women using no contraception were excluded leaving 741 contracepting controls. The authors reported that in the period up to August 1972, IUDs available in Sweden consisted of Lippes Loops and Saf-T-Coils. After August 1972, the Copper-T 200 and Gravigard were used almost exclusively. There was no precise analysis of cases and controls by reference to the type of device used. The authors state that there had been a significant increase in the frequency of IUD use per se both among patients and controls in the period 1971 to 1975. 125 of the 515 patients were IUD users compared with 72 of 741 controls. The higher rate of usage of IUDs was most pronounced in women who were less than 20 years of age and who had never been pregnant. The authors concluded that if the relative risk of acute salpingitis in women not using IUDs (but still contracepting) is 1, then the relative risk for IUD users was 3.1 for all women, 6.9 for those who had never been pregnant and 1.7 for those women who had previously been pregnant. Senanayake & Kramer 1980 , calculated the relative risk estimate in IUD users versus all other contraceptors as 2.9 (2.1-4.0): The relative risk estimate in IUD users versus non-contraceptors was not ascertained. The authors considered that a higher proportion of sexually promiscuous women amongst the cases than among the controls could possibly explain the differences shown but there was no basis reported for asserting that there was in fact any such difference between the two groups. Vessey et al 1976 This was the Interim Report of a long term follow-up prospective study of British women using different methods of contraception seen by the Oxford Family Planning Association which commenced in 1968: To be eligible for admission to the study a woman had to be married, aged 25-39, a white British subject, willing to participate, and either a current user of oral contraceptives of at least 5 months standing or a current user of the diaphragm or an IUD of at least 5 months standing without prior exposure to oral contraceptives. By the end of July 1974, when recruiting ended, 17,032 subjects had been admitted. 56.6% were oral contraceptive users, 24.8% were diaphragm users and 18.6% were IUD users. Cases of PID were classified as acute (surgically confirmed) definite but not acute (not surgically confirmed) and other (inconclusive clinical diagnosis without confirmation). On admission to the study 0.28% of women reported a past occurrence of salpingitis or oophoritis. There were no statistically significant differences between oral, diaphragm and IUD users in this group. The report included almost 10,000 woman-years observation of IUD users. 58% used the Lippes Loop; 29% used the Saf-T-Coil and 13% used an unknown IUD. Table 19 in the Interim Report records results for salpingitis, PID and endometritis as a standardized first event rate (per 1000 woman-years) according to method of contraception actually used during follow-up among subjects with no past history of salpingitis on admission. The relative risk estimate for IUD users versus all other contraceptors was 3.5 (2.1-6.1) ( Senanayake & Kramer 1980 p.855 ) : The study did not include non-contraceptors. There was no relative risk estimate in IUD users versus non-contraceptors reported. Further analysis of the Oxford Family Planning Study resulted in papers by Vessey et al in 1981 (not tendered) and a reanalysis by Buchan et al 1990 . Kessel 1989 reported that the 1981 paper by Vessey et al summarized the findings of the Oxford Family Planning Study up to 1979. By that time data from 20,482 woman years of use for all devices had been obtained and the rate was 1.51 per 1000 woman-years. The data revealed a PID rate of 1.15 per 1000 woman-years in Lippes Loop users, 2.09 per 1000 women years in Saf-T-Coil users, 8.09 per women years in Dalkon Shield users and 0.90 per women years in Cu-7 users. Although the Dalkon Shield results were significantly higher, this outcome was based on only 3 cases in a study where all non-users were current contraceptors. The reanalysis by Buchan et al 1990 was published 14 years after the Interim Report. The authors noted the influence of the WHO Scientific Group Technical Report ( WHO 1987 ) which had identified a number of what were said to be significant epidemiological flaws in earlier studies, including previous reports from the Oxford Family Planning Study: Using multiple regression analysis the authors subjected the data to control for age, parity, social class, cigarette smoking and age at first marriage. Parity was excluded (there were no nullips). Having examined the remaining associations without reference to the influence of contraceptive methods, it was decided to allow for the influence of age, social class, cigarette smoking and age at first marriage. These results are reported in Tables I to IV of the study. First hospital referral rates for acute, definite and other pelvic inflammatory disease in relation to current use of various contraceptive methods are given in Tables V-VII. IUD users were divided into non-medicated devices (Lippes Loop, Saf-T-Coils and Dalkon Shields) versus the more modern medicated devices (Cu-7s and Copper-Ts). The reference group was taken as women who used any other method of contraception. This would have included a large number of oral contraceptive users. Table VIII records the first hospital referral rates per 1000 woman years for all pelvic inflammatory disease by contraceptive method. Non-medicated IUDs gave rise to a relative risk versus non-users of 3.3 (2.3-5.0). Medicated IUD users had a relative risk estimate versus non-users of 1.8 (0.8-4.0), which was said to be not statistically significant. Table VIII also confirmed that the protective effect of oral contraceptives is statistically significant. The authors indicated that there was then considerable evidence that barrier methods and female sterilisation are also protective. Among current users of an IUD who have had previous exposure to a Dalkon Shield, the relative risk of hospital referral for PID was estimated as 4.7 (2.1-9.0) compared to current users of IUDs who had had no exposure to a Dalkon Shield. Use of the Dalkon Shield appeared to be a greater risk than other inert and medicated devices. The authors aligned their finding in relation to the relatively lower rate of referral for PID in users of modern medicated devices by comparison with older inert devices with the results of the two leading studies on tubal infertility which had reported lower risks of tubal occlusion in users of copper containing devices than in users of unmedicated devices ( Daling et al 1985, Cramer et al 1985 ). It was submitted on behalf of the defendants that the data set did not allow an effective study of the relationship between the onset of PID and the duration and use of IUDs as was possible in the other significant data set, the Women's Health Study. Eschenbach et al 1977 This study involved the case-control matching of patients with gonococcal and non-gonococcal PID against control subjects without PID who had uncomplicated gonorrhoea or no gonorrhoea in order to elucidate risk factors which contribute to infection of the Fallopian tubes and pelvic peritoneum by bacteria which normally remain confined to the cervix and vagina. 204 women with a diagnosis of acute PID were recruited between July 1972 and February 1973 (102 consecutive women) and between January 1974 and July 1974 (102 consecutive women) at University of Washington affiliated hospitals, were matched against 308 consecutive sexually active women without PID who had entered a Seattle VD clinic between February 1972 and December 1972 and 399 consecutive sexually active women without PID or contraceptive related complaints who had attended the gynaecology clinics at the University of Washington Hospital and Harbourview Medical Centre between February 1973 and July 1974. The clinical diagnosis of acute PID required the patient to have had: · pain in the lower abdomen for less than or equal to 3 weeks duration, · abdominal tenderness and, · on pelvic examination, moderate to severe tenderness maximally localized to one or both adnexal areas with involuntary guarding proportional to the degree of tenderness. Diagnosis of PID was only laparoscopically confirmed in 80 of 204 cases. Of these 80, salpingitis was diagnosed in 18 of 20 women who subsequently underwent laparoscopy or laparotomy because they presented with a clinical course which was atypical. Each PID patient was matched with a patient in the concurrent comparison group by age, race, marital status, presence or absence of gonococcal infection, parity and number of sex partners within the past 6 months. Among the cases (204 patients), 30% were using an IUD; 23% were using oral contraceptives; 4% were using mechanical (barrier) methods; 1.5% had undergone tubal ligation; 0.5% were using the rhythm method and 41% were non-contraceptors. Among the combined controls (707 patients) 15% were using an IUD; 39% were using oral contraceptives; 8% were using mechanical (barrier) methods; 5% had undergone tubal ligation; 1% had had a hysterectomy; 1% were using the rhythm method and 30% were non-contraceptors. Case-control matching for the analysis of contraceptive methods produced 173 matched pairs (Table II). In these pairs, 29% of cases versus 11% of controls used an IUD. Oral contraceptive use was lower amongst PID patients (24%) than among the matched controls (42%). In these 173 matched pairs, there were 40 pairs in which the PID patient was using an IUD but the control was not. In 9 pairs, the PID patient was not using an IUD but the control was. This ratio, expressed as a relative risk, of 4.44 was statistically significant. The analysis was then further limited by exclusion of women who had undergone tubal ligation or hysterectomy and all non-contraceptors. Among the balance, 50 of 99 PID patients (50%) and 19 of 114 controls (17%) were using IUDs. At 95% confidence, the relative risk estimate for IUD users versus non-users was calculated at 4.4 (3.0-6.9). The authors concluded that PID was attributable to use of an IUD in the case of 77% of IUD users. The relative risk estimate for IUD users versus non-contraceptors calculated by Senanayake & Kramer 1980 as 4.0. (No confidence interval was available.) P124 page 855. Among IUD users, 70% used Dalkon Shields, 18% used Lippes Loops, 11% used the Saf-T-Coil and there was only one case who used the Cu-7. No type of IUD was specifically associated with a disproportionate risk of PID, although the number of IUDs other than the Dalkon Shield were probably too small to permit a statistical comparison. It was submitted on behalf of the defendants that this paper is significantly at odds with other studies for the following reasons: (a) The study included a disproportionate number of Dalkon Shield users by comparison with only one identified Cu-7. (b) The authors found no increased risk of PID with an increased frequency of intercourse or number of sexual partners. (c) The highest relative risk was in the higher socio-economic group, the lowest relative risk was in the lower socio-economic group. (d) The IUD was usually in place several months before the development of PID. (e) Fever was less common in IUD cases. Thaler 1978 Edelman 1980, Senanayake & Kramer 1980 and Kessel 1989 all refer to a paper by Thaler et al entitled " Intrauterine device and pelvic inflammatory disease " published in the International Journal of Fertility in 1978 (not tendered). Kessel 1989 indicates that the Thaler study took place in Haifa, Israel, between 1969 and 1970: Edelman 1980 stated that the Thaler study was a case-control study in which 101 cases, not including women with recurrent PID, were matched against 101 controls for age, current marital status and interval since last pregnancy termination but that the type of IUDs were not stated. The study was said to have reported a relative risk estimate for IUD users versus non-users of 2.3 (0.9-5.9). Senanayake & Kramer 1980 point out that the population from which the controls for the study were drawn was unspecified and that the study was limited to first event acute PID only. Flesh et al 1979 This was a case-control study conducted in a hospital clinic serving an indigent population in Central and East Los Angeles. The authors asserted that recent studies had used inappropriate control groups, (ie women using methods of contraception which reduced the risk of developing acute salpingitis). They asserted that it was therefore not known whether IUDs increase the chance of developing acute salpingitis compared to non contraception. However, they did not take any alleged protection effect of using certain contraceptors into account in their analysis. The study initially involved 163 consecutive cases who were women hospitalized with a clinical admission diagnosis of acute salpingitis. These were ultimately reduced to 146. There was no written diagnostic criteria for hospitalising patients with salpingitis but those hospitalised were generally those with physical signs of acute pelvic peritonitis. All of the study group had uterine or adnexal tenderness and a temperature greater than 99.8 on admission. There were 222 controls who were ultimately reduced to 199. They were women presenting to the minor trauma section of the emergency room for treatment for minor lacerations, burns, fractures and other injuries.. Four variables were analysed: · black versus non black; · IUD versus no IUD; · multiple sex partners versus one sex partner; and · previous salpingitis versus no previous salpingitis. The authors indicated that the control group in the study was not perfect but concluded that their results demonstrated that the number of sexual partners in the previous 12 months was a major risk factor for PID. They also warned against women using IUDs who are from a low socio-economic status, who are black or who have had previous salpingitis on the basis that the study only dealt with women from a low socio-economic population and the author did not know what the results would be in other socio-economic populations. There was no information given as to the type of IUDs used nor as to the duration of use. Relative risk estimates were not calculated in the paper but Senanayake & Kramer 1980 estimated the relative risk of IUDs versus non users in this study to be 2.2 (1.3 - 3.9): Maqueo et al 1979 This is the report of a study of the histology of the fallopian tubes in asymptomatic women who had used an IUD for at least one and usually two years by comparison with asymptomatic post-partum women and normally menstruating women scheduled for surgical sterilisation. Among 225 patients, 75 had had an inert IUD in place for at least one year, 75 underwent a salpingectomy 2-3 days post-partum and 75 were normally menstruating women (controls) who had an elective salpingectomy at various stages of their cycles. On histological examination, there was no difference in the frequency of oedema and congestion in the tissue of control subjects versus those using an IUD whereas there was a higher frequency of this alteration in post partum subjects which was statistically significant. An analysis of the intensity of acute inflammatory infiltrate (patchy/moderate/marked) does not indicate any statistically significant difference between the distribution in control patients (non-contraceptors) and that observed in IUD or post-partum subjects. The authors refer to the histological observation reported by the Combined Bangkok Hospital Group (1975 ) where only one of 39 subjects with external adhesive disease showed histological evidence of salpingitis. The authors also refute the proposition by Smith and Soderstrom that salpingitis " similar to that found in the endometrium " and, by inference, possibly an extension thereof, is a concomitant of IUD use. The IUD device types were inert but were not otherwise specified. Senanayake & Kramer 1980 calculated a relative risk estimate for IUD users versus non-contraceptors of 1.5 (0.8-2.8). Senanayake & Kramer stated that the small number of subjects, the absence of any IUD users with a recently inserted device and a non-specific case definition for PID limited the use of this study: Ryden et al 1979 This study involved an analysis of the influence of different contraceptive techniques on the incidence of PID in 672 female patients with gonorrhoea: The lowest frequency of PID was found in patients using hormonal contraceptors (8.8%). This compared with 23.5% of patients using IUDs and 15.1% of patients using neither technique. Between 1973 and 1977, 744 women were treated for uro-genital gonorrhoea at the University Hospital in Linköping, Sweden. 72 women were excluded due to pregnancy, sterilisation, being post-menopausal, as non- contraceptors or because of doubtful diagnosis of PID. Among the remaining 672 patients, PID was diagnosed in 87 (12.9%). PID was confirmed by laparoscopy. In all cases the diagnosis required a reddened serosa of the tubes, oedema of the tubal wall or purulent discharge from the abdominal orifice of the tube. Each case was then matched against 2 uncomplicated gonorrhoea patients. All of the IUD users had used copper devices with the exception of some isolated instances of use of plastic devices. The authors determined that it was not possible to evaluate any difference in risk of PID in patients using copper or plastic devices due to the small number of plastic devices. Among the PID cases, 30 used hormonal contraceptives, 20 used IUDs and 37 used neither hormonal contraception nor an IUD. Among the controls, 90 used hormonal contraceptives, 20 used IUDs and 64 used neither. Each group was examined by age, marital status and the number of sexual contacts (1, 2, 3, 4 or more). By using multiple regression analysis, the authors concluded that, apart from birth control methods, no other parameter (age, marital status, number of sexual contacts) influenced the incidence of PID in the patients. The relative risk estimate for IUD users versus non-users was calculated by Senanayake & Kramer 1980 at 2.3 (1.2-4.6) which difference is said by the authors to be statistically significant: The relative risk for IUD users versus non-contraceptors was 1.7 (0.8-3.6). The authors found that a statistical analysis demonstrated a significantly lower incidence of PID amongst hormonal contraceptive users than IUD users and users of neither method. However, it was said there was no significant difference found between IUD users and patients using neither hormonal contraceptives nor IUDs. Cervical gonorrhoea was also more common in women with PID than in women with uncomplicated gonorrhoea. The authors considered that the results obtained in the present study, with a higher incidence of PID in the IUD group; and a lower incidence in the hormonal contraceptive group compared to patients using neither method, were related to the contraceptive method per se. Kaufman et al 1980 This was a hospital-based case-control study of the relationship between IUD use and first episodes of PID amongst sexually active women. The effects of duration of use of particular IUDs were also investigated. There were 44 patients and 259 hospital control subjects. All of the women used IUDs or oral contraceptives. The age adjusted relative risk for those using IUDs at the time of admission was 6.5 (95% confidence material 3.2 to 13.0). The records of 185 pre-menopausal women with a discharge diagnosis of PID, salpingitis or pelvic abscess at hospitals in 7 metropolitan areas in the United States, one hospital in Canada and two in Israel were reviewed to identify cases adjudged to be first episodes of PID. 120 such cases were identified. From 4891 pre-menopausal women available as potential controls, 2058 were selected as suitable on the basis of having a first diagnosis judged not to be related to contraceptive use. Women with gynaecological disorders were excluded as were women who had recently undergone an abortion or suffered an ectopic pregnancy. The analysis was then confined to women who were presumed to be sexually active, by virtue of their use of IUDs or other contraceptives. All cases and controls were less than 45 years of age. The study reported on a final analysis of 44 subjects and 259 control subjects. Among the subjects, half of all diagnoses were based on laparotomy, laparoscopy or observation of pus emerging from the cervix. The balance were diagnosed on the basis of clinical evidence such as fever and adnexal tenderness. Table IV of the report sets out the relative risk of PID amongst IUD users by reference to specific devices. The referent group were oral contraceptive users rather than non-contraceptors. The relative risk estimate for Cu-7 users versus non-users was 3.8 (9 of 44 cases versus 29 of 259 controls). The relative risk for Dalkon Shield users was 12.3 (5 of 11 versus 5 of 259). Lippes Loop users had a relative risk of 7.9 (11 of 44 versus 17 of 259). For users of the Saf-T-Coil, the relative risk was 9.2 (3 of 44 versus 4 of 259). The referent group consisted of 14 of 44 cases versus 172 of 259 controls. Senanayake & Kramer 1980 calculated an overall relative risk estimate for IUD users versus non-users of 7.9 (3.7-16.9) and expressed their view that the limitation of the study population to only sexually active women who used either IUDs or oral contraceptives meant that no other comparison group was included, producing a spuriously low relative risk for oral contraceptive users and a spuriously elevated risk for IUD users. In 1983 Kaufman et al published a further report (not tendered). According to Kessel 1989 , this further report updated the study period to March 1981 with a total subject population of 460. The relative risk for IUD users versus non-users reported was said to be 4.7 (3.1-7.1) which, when adjusted for the use of oral contraceptives, was 3.2 (1.6-6.6). However, the relative risk for users of the Dalkon Shield versus non-users was 78.7 (22.7-272). Osser et al 1980 This was a study conducted in Malmo, Sweden to investigate whether PID was more common amongst IUD users than in a sexually active age matched control group and, if so, whether it is more common amongst those who have not previously been pregnant: The authors concluded that the risk of PID was raised twofold by IUD use and that there was no significant difference between women who had never been pregnant and those who had been pregnant. The records of 720 patients admitted to the Department of Obstetrics and Gynaecology at the General Hospital in Malmo between 1973 and 1975 were traced and all relevant gynaecological and obstetric notes were extracted. Age matched controls were then selected by questionnaire in relation to the month that the matched case was in hospital for PID. Apart from questions concerning pregnancy and health, each potential control was queried about her use of any method of contraception in that month, the number of sexual partners she had had and how often she had had intercourse during that month. Women who were not apparently sexually active were excluded. By this method, 690 of the 720 patients were matched with one control each and were included in the study.. A diagnosis of PID was confirmed by laparoscopy in 86.1% of cases. The authors asserted that a complete statistical analysis of the frequency and distribution of PID in the balance of patients gave the same frequency of IUD use and the same risks in the different groups. Among the patients, 31.9% were IUD users, 23.0% were users of oral contraceptives and 45.1% used other methods or none. Among the controls, 16.5% were IUD users, 47.1% used oral contraceptives and 36.5% used other or none. The relative risk estimate for IUD users versus non-users was said to be 2.1 (1.6-2.7). Senanayake & Kramer 1980 calculated a slightly different risk of 2.0 (1.6-2.6). The type of IUDs included in the study were not specified. These authors found a relative risk of PID for parous women of 2.6 compared with that for nulliparous women of 1.6. This difference between parous and nulliparous women contrasts with results reported in earlier studies but it does not appear to be statistically significant. The authors suggested that whereas Professor Westrom had considered the mere use of a contraceptive as proof of sexual activity and excluded women not using contraceptives, this study had made greater efforts to ensure that all controls were sexually active. As in Westrom et al 1976 , this study reported more oral contracepting controls than patients and that there appeared to be a significant protective effect which reduced the relative risk of PID by two thirds. In reviewing this paper, Senanayake and Kramer 1980 calculated the relative risk for IUD use compared to no contraceptive use as 1.6 (1.2-2.1), which is the lowest statistically significant increase in risk shown in any of the studies reviewed by them. Paavonen & Vesterinen 1980 This study sought to evaluate the contraceptive practices of hospitalized patients with clinically verified acute salpingitis, in particular the frequency of IUD use, compared with that of controls for asymptomatic partners of men suffering from non-gonococcal urethritis. The control group was chosen by the authors because of their concern that prior studies (cited in Table I of the study) may have included sexual exposure differences between cases and controls making it difficult to define the actual risk of salpingitis in IUD users. The patient series consisted of 144 women treated for symptoms of acute PID at the University Central Hospital in Helsinki, Finland between October 1977 and August 1978. Clinical diagnosis of acute salpingitis was based on: · pelvic pain of short duration, · increased vaginal discharge, · tender adnexal masses, · increased ESR (greater than 15) and usually fever. All patients were hospitalized because of severe symptoms. The control group consisted of 240 consecutive women below 50 years of age who were examined at the same outpatient clinic during the same period of time and was limited to women whose partners were suffering from non-gonococcal urethritis diagnosed within the same hospital. Following the exclusion of pregnant women, 229 of these 240 women were included in the study. The patients provided a contraceptive history by answering a standard questionnaire. They were divided between IUD use, oral contraceptive use and use of other methods or none at all. The third category was selected to represent the basal level of disease when calculating relative risks for salpingitis. The types of IUD in the study were not specified however copper devices were included. Among these patients, 58% were IUD users, 11% were oral contraceptive users and 31% used other methods or none at all. Among the controls, 32% were IUD users, 30% were oral contraceptive users and 38% used other methods or none at all. The authors estimated the relative risk for salpingitis in IUD users versus the referent group, other methods or none at all was 2.06 (1.23-3.46). This appears to be attributable mainly to a higher relative risk 2.20, (1.09-4.43) in nulliparous women. Oral contraceptives were significantly protective with a relative risk of 0.37 (0.19 - 0.73). Table IV of the article shows the relative risk in parous women as 1.92 but the confidence interval crossed unity. In nulliparous women, the relative risk was statistically significant but the lower confidence interval was only just above unity. The referent group (other method or none at all) included users of barrier methods of contraception which, themselves, are protective against the transmission of STDs. Burkman et al 1981 This is the first of 3 papers (Burkman et al 1981, Lee et al 1981 and Lee et al 1988 ) which analysed data collected through the Women's Health Study. This was a concurrent case-control study conducted at 16 hospitals in 9 cities throughout the United States. It was designed to examine the relationship between the use of an IUD and PID severe enough to require hospitalization: Data collection for the study commenced in October 1976 and concluded in 1978. In attempting to detect whether the use of an IUD resulted in serious complications which required hospitalisation, the Women's Health Study examined uterine perforation, PID, vaginal haemorrhage, ectopic pregnancy, foetal loss, abruptio placentae and placenta previa. Burkman et al 1981 and the subsequent reports examined the findings of the Women's Health Study regarding PID. Subjects in the study were between 18 and 44 years of age, sexually active, not surgically sterile (and the partner not surgically sterile) and menstruating within the last year. Women who had been pregnant in the previous 6 weeks were excluded. In addition, women with a hospital discharge diagnosis of epilepsy, thromboembolism, cerebrovascular disease or cancer were excluded. Cases were confined to patients who required hospitalization with a diagnosis of PID which diagnosis had been confirmed on discharge. Patients were presumed to have an infection of the upper genital tract if they had: · low abdominal pain, fever · adnexal pain on examination · adnexal masses and · vaginal discharge. PID cases were then sub-categorized as: · certain (visualization of the adnexa or the draining of an abscessed cavity) · moderately certain (hospitalization with acute symptoms but no surgery), and · less certain (discharge diagnosis of PID without surgery and not acute). From 2761 potential PID cases, 1447 patients were finally classified as having PID and were included in the study. Controls were drawn from women admitted to the same hospital during the same period but excluding women admitted for several diseases that might influence contraceptive practice. Both surgical and medical controls were admitted. However, in the absence of any discernible difference, the two groups were combined in the analysis. While controls were not matched to cases, they were parallelled by hospital and time of admission. From 7199 potential controls, 3453 women were included in the study as controls. Age, race, gravidity, parity, sexual activity and number of sexual partners were all considered potentially confounding factors and were analysed using a multi-variate analysis to determine whether IUD use had any effect in the presence of other risk factors. In order to determine contraceptive method women who had used a method during the 30 days prior to hospital admission or, for IUD users, had the IUD present at the time of admission or had had it removed within 30 days prior to admission were all included as current users of the various contraceptive methods. An analysis of past users and women who had never used contraception produced little discernible difference and accordingly those two groups were combined and labelled as non-users. The study was designed to ensure that the non-contracepting group did not include women who very recently ceased using methods known to be relatively protective against PID, such as oral contraceptives. Among cases, 22% were IUD users, 15% oral contraceptive users, 8% barrier users, 5% used other methods and 50% were non-contraceptors. Among controls, 15% were IUD users, 29% were oral contraceptive users, 13% were barrier users, 15% used other methods and 28% were non-contraceptors. 27% of cases versus 16% of controls had had more than one sex partner in the last six months. The relative risk estimate for IUD users versus non-users was 1.6 (1.4-1.9). In patients with a PID history, this relative risk was 1.2 (1.0-1.6) whereas patients without a history of PID had a higher relative risk of 2.1 (1.8-2.5). It was submitted that this report of an increased relative risk for patients without a history of PID was anomalous given earlier findings and argues against the proposition that previous PID compromises the host tissue against the threat of future episodes. Table VI on page 274 of the article provides a ranking of selected risk factors for PID among women without a prior PID history. The highest relative risks were associated with a woman's number of sexual partners and potential for exposure to STDs. Other significant relevant risk factors included women who were black and under the age of 25. These relative risks were all greater than current use of an IUD. There were no major differences between nulligravid and gravid women with or without adjustment for age, race, sexual activity and number of partners. Lee et al 1983 In this analysis 657 cases and 2566 controls were identified in the Women's Health Study and data was analysed to attempt to determine the PID risks associated with individual IUD types. The risk of PID by different contraceptive methods compared with women who used no contraceptive method was analysed. The results appear in Table 1 of the article. Oral contraceptives and barrier methods were found to be protective against PID whereas IUDs were found to have a relative risk of 1.9. The next matter analysed was the risk of PID associated with the various types of IUDs. This had not been done before. The results are set out in Table 2 of the article. Compared with users of other types of IUDs, Dalkon Shield users had 5 times the risk of pelvic inflammatory disease. Cu-7 users had a relative risk of 1.9. The analysis continued by excluding the Dalkon Shield users. It was then found that the increased risk of PID was greater in the first four months after insertion than after that time. The highest PID risk was within the first month, a point estimate of 3.8. However, after the first four months, the relative risk was 1.1. These results are set out in Table 4 of the article. The study then further analysed the effect of duration of use by specific IUD types. The relative risk for Cu-7 users in the first four months after insertion was 3.3 and after four months was 1.3. Both these figures are higher than for the Lippes Loop whose figures were 2.5 and 1.0. The defendants submitted that the main finding of Dr Lee's 1983 analysis is that the risk of PID from all IUDs was double that of using no contraception. However, part of this risk is due to the Dalkon Shield because it had five times greater risk than other IUD types. Once the Dalkon Shield users were excluded from the analysis, it was submitted the increased risk was confined to the first four months after insertion. This submission must be considered in the light of the figures set out above. It was submitted that the duration of use results reported by this study represented a significant advance in state-of-art knowledge about iatrogenic PID. There had been previous reports of PID incidence rates over duration of use, but they had provided only limited information. Witoonpanich et al 1984 This was the report of a multinational case-control study of PID in relation to contraceptive use initiated through the World Health Organisation Special Program of Research Development and Research Training in Human Reproduction and conducted concurrently in 12 centres located in 10 developed and developing countries worldwide. The objective was to compare characteristics of patients with acute febrile episodes of moderate or severe PID with the characteristics of controls and, in doing so, to take into account the extent of PID associated with contraception in developing countries: Cases included women aged 15-44 with acute PID treated as inpatients or outpatients between March 1978 and December 1979. A definitive diagnosis of PID required: · a temperature of 38C or higher within 24 hours of presentation suprapubic tenderness with guarding on physical examination and, · in addition to these mandatory signs, on vaginal examination there should have been at least tenderness on movement of the cervix. · adnexal tenderness or a palpable adnexal mass. · Operative diagnosis was acceptable and, where possible, bacteriology and histopathology was performed. Controls were selected from non-gynaecological non-obstetrical hospital admissions or outpatients in a six month period before or after the identification of each case. Controls were then individually matched (2 for 1) by age band, parity, marital status and by in or out patient status. Controls were also matched by post-abortal or post-partum status. Subjects were questioned as to this relevant medical history and use of current and previous contraceptive types. However, due to cultural sensitivity in some centres, the study did not obtain a history of sexual activity and matching for marital status was used as a proxy. It was submitted that in light of the findings from the Women's Health Study, the use of this proxy introduced a problematic bias. There were 968 cases and 1936 controls identified. From this, 862 initial case-control sets included 608 sets of women who were either nulliparous or had a pregnancy which terminated more than 6 weeks prior to interview were studied. Types of devices were not differentiated in the study. The relative risk estimate of the first episode of PID in IUD users compared with non-contraceptors reported ranged from 11.5 (3.6-36.2) in current nulliparous IUD users in developed countries to 4.1 (1.1-15.1) in current parous users in developed countries. When differentiating between first episodes and recurrent PID and between nulliparous and parous women, the study produced increased relative risks associated with IUD use ranging between low and statistically insignificant risks to high risks with very wide confidence intervals. The authors stated that the inability to properly assess sexual activity would introduce serious bias if a higher proportion of cases were generally active compared with the controls. Cramer et al 1985 The study was directed by Dr Cramer of Harvard University. It was a case-control study conducted at 7 different centres across the North American continent designed to investigate tubal infertility and IUD use. Data was collected between 1981 and 1983. Over 2,000 potential cases were interviewed and over 4,000 controls were identified. Eventually 388 women with tubal disease confirmed by HSG or laparoscopy were identified and used in the analysis. The profiles of the cases and controls are set out in Table 1 of the article. The study concluded inter alia: 1. The adjusted risk of primary tubal infertility associated with any IUD use before a first time birth was 2.0 (95% confidence limits 1.5 to 2.6) relative to non-use. 2. Users of copper IUDs had a risk of 1.6 (1.1 to 2.4). 3. Women who reported having only one sexual partner had no increased rate of primary tubal infertility associated with IUD use. 4. Tubal infertility is associated with IUD use but less so with copper IUDs. Cramer stated: "In general, the use of an IUD by women with a history of a genital or pelvic infection doubled their baseline risk. As important, even women without a history of infection at the time of IUD insertion had a significantly increased risk of tubal infertility from the IUD. Thus, absence of prior infection cannot be used as an indicator that the use of an IUD by a nulliparous woman will be safe." (p.946, RHC, middle para). The plaintiffs submitted that the duration of IUD use (Table 3 of the article) showed an elevated risk for the first 3 months and a more gradual increase thereafter. They also submitted that these results are contrary to the defendants' submission that the increased risk of PID is limited to iatrogenic risk. The defendants submit that the plaintiffs' submission is erroneous for the following reasons: First, the duration of use estimates are for all IUDs including the Dalkon Shield which the authors acknowledge artificially elevated the relative risk estimates. Second, the study was designed to look at tubal infertility as opposed to episodes of PID. Accordingly, duration of use data cannot provide any insight concerning the impact of iatrogenic risk. The cases in this study were all women who were presenting for tubal infertility. Causal factors for their infertility had all occurred at some unknown time in their past. No data were collected on past episodes of PID or when it had occurred in relation to contraceptive use. Therefore, it was submitted the duration of use results in Table 3 of the article demonstrate something in the nature of cumulative incidence rates of tubal infertility. It was submitted that tubal infertility is not PID and they are not the same as the relative risk estimates for PID of the kind presented in the Women's Health Study ( Lee et al 1983 Table 5): It was submitted that if results for IUD users for less than 3 months are reported as opposed to IUD users of more than 3 years, it is inevitable that additional risk factors will be incorporated and additional cases of tubal infertility will be identified. More events happen as more time elapses. Multi-variate analysis attempts to control for some of these known confounding variables but it cannot control for all of them so it was submitted that there was a cumulative incidence effect. In Table 4 of the article the authors set out their findings of the influence of certain subject characteristics on the risk of primary tubal infertility. They reported that women who had never used an IUD but reported having more than one sexual partner had a higher relative risk of tubal infertility than women who had only one partner and did not use IUDs. Further they reported women who had used a copper IUD and reported having only one sexual partner had no increased risk of tubal infertility. Finally women who reported suffering a minor infection in the past (genital herpes, venereal warts, trichomonas infection or vaginitis other than due to yeast) had an increased relative risk of tubal infertility even if they had not used an IUD. The relative risk estimates and confidence intervals are set out in the table below: Relative Risk Confidence Interval Never used IUD but more than 1 partner 1.5 1.1 - 2.1 Copper IUD and 1 partner 1.1 0.5 - 2.7 Copper IUD and more than 1 partner 2.8 1.7 - 4.5 No IUD use but suffered minor infection in past 1.5 1.0 - 2.3 In Table 3 of the article the relative risk of primary tubal infertility for women using a copper device only was 1.6 (1.1 - 2.4). Such an estimate is similar to the relative risk of primary tubal infertility for women who had never used an IUD before but had either more than one partner or suffered an episode of a minor infection in the past. The defendants submitted that when the relative risk estimate for copper IUD users with one partner (1.1) is compared to those other figures (1.5), the results of the study do not support the plaintiffs' submissions. The authors concluded that the risk of tubal infertility does not apply to women with a single partner at low risk for sexually transmitted diseases and that for women who have had one child copper IUDs may offer a relatively safe, if not risk-free, alternative to other methods. In relation to the number of sexual partners which a woman had Cramer made the following observation: "The risk of tubal infertility associated with IUD use was confined to women with more than one sexual partner. The usefulness of the number of partners as a predictor variable as defined by this study should not be overstated, however, because it is based on the life-time number of partners reported at interview, rather than on the number of partners by the time of the first use of an IUD. Furthermore, not only the number of partners, but obviously their likelihood of having sexually transmitted diseases, is important." (p.946, RHC, middle para). Daling et al 1985 Daling et al 1985 follows Cramer et al 1985 in the same edition of the New England Journal of Medicine. In their introductory remarks, the authors offered a summary of the state of the literature as at 1985 in relation to the increased risk of infertility for IUD users as a result of PID. They said that it was likely that users of an IUD had an increased risk of subsequent involuntary infertility (through their susceptibility to salpingitis) although the data fell short of being conclusive. In her evidence, Professor Daling said that this state-of-art conclusion related not only to the 12 references footnoted in her paper but was an accepted part of general knowledge at the time. ( T2889 line 53 - T2890 line 6). Daling dealt with Cramer in Ex. P209, Tab 2, para 20: "The selection out of one non-significant finding among monogamous women does not accurately depict this study's conclusions. Cramer found a significant increase in risk of infertility among women who use the Copper IUD, RR=1.9." Cramer dealt with criticism of his study in a letter to the New England Journal of Medicine on 5 September, 1985 when he said: "Dr Hasson's primary arguments may perhaps be paraphrased as follows: There is only one cause of tubal infertility, and that cause is infection with sexually transmitted diseases; therefore, IUDs cannot be a cause of tubal infertility. Even if one assumes that the majority of cases of tubal infertility are preceded by infection, this does not negate a role for the IUD in potentiating the damage from those infections. This is clearly illustrated in Table 4 of our original report, which demonstrated that women who had minor genital or major pelvic infections and who had used an IUD had greater relative risks of infertility than women who had had these infections but had not used the IUD". (p.637, LHC, second last para). Daling gave evidence consistent with Cramer's view as to the potentiating effects of IUD use on infections. (T3034, L5-25): "…A woman who uses an IUD, if she is exposed to those pathogens it is more likely to exhibit an infection of the magnitude that rises up into the tube. It is an effect modifier. Given a woman is exposed, her chance of getting an infection that leads to disease who wears an IUD is different than a woman who does not. It is clear from our data, clear from other people's data, that is truly the case. We call that an effect modifier; something that modifies the effect of an exposure." Senanayake and Kramer 1980 made similar observations. (p.859, Ex. P124). The study was a case-control study with data being collected between 1979 and 1981. It was not a multi-centre study and 159 matched pairs were identified and used in the analysis. Like Cramer et al 1985 , this report looked at the characteristics of women with primary tubal infertility and matched controls. The results were similar to the Women's Health Study. More cases reported having 5 or more sexual partners. More cases were smokers and were married more often. The Dalkon Shield was associated with the highest relative risk for primary tubal infertility and the duration of use figures indicated a higher relative risk for the shortest period of use tabulated. ( P130 pages 939, 940). The authors also reported that for those women who had only used a copper IUD the relative risk was 1.3 (0.6 - 3.0). That is not a statistically significant result. The authors reported that women who had used a copper IUD had very little excess risk and said that they regarded the result as reassuring. Daling reported that use of any IUD in the past increased the risk of primary tubal infertility to 2-6 (confidence 95% CL 1.3 - 5.2). She found that the risk for women who had only used copper IUDs was 3.1 (95% CL 1.5 - 6.5) when she reanalysed her data in 1992. Westrom 1980 This was in the nature of a review article which also incorporated a report of original data. Professor Westrom was continuing his original research which is referred to in his earlier papers. This paper attempted an analysis of the incidence, prevalence and trends of acute PID in a range of industrialized countries. Professor Westrom stated that, in the vast majority of cases, salpingitis is caused by STD infections which ascend from the lower to the upper genital tract. He added that, from a public health perspective, any attempt to decrease the incidence of PID must start with attempts to decrease the incidence of STD in general. The relationship between IUDs and PID was referred to on a number of occasions within this review. Professor Westrom referred to iatrogenic PID and identified IUD insertion as being one of a number of different procedures which involve instrumentation of the uterus with consequent risk of infection. Professor Westrom stated that, as at 1980, epidemiological studies had revealed that IUDs were used significantly more often by women with PID than by control women. He also noted that age, race, socio-economic status and sexual activity were of importance in differences in the risks of PID in IUD users versus non-users. Westrom 1980 also included original data from a study population of women in Lund [see Table II of the article]. Professor Westrom noted that this data appeared to show that the use of an IUD increased the risk of acute salpingitis. However, as he noted in his 1976 study, there appeared to be a protective effect provided by oral contraceptives and barrier methods. In Professor Westrom's view, sexually active women who use no contraceptive method constitute the correct reference group to be used when studying the epidemiology of genital tract infections but he did not perform a further statistical analysis to take this into account. The plaintiffs had IUDs inserted on the following dates: (a) Mrs Lee 19 May 1975 (b) Mrs Orders 20 April 1977 (c) Mrs Robertson 1 August 1977 (d) Ms Ottaway 13 September 1977 (e) Mrs Southren 14 February 1978 (f) Mrs Moylan 10 July 1978 (g) Mrs Gentle 3 November 1978 (h) Mrs Denzin November 1978 December 1978 June 1980 November 1981 June 1983 June 1985 (i) Mrs Lane 22 August 1980 The plaintiffs sought the following finding of facts: "At the time of each of the above insertions Searle was in possession of strong evidence from epidemiological studies which pointed to a causal association between IUD use and PID." The plaintiffs sought the following finding of fact and law: "The association, as revealed in these studies was under a legal obligation to act on the basis of that causal association." With regard to the state-of-knowledge at that time, Dr Eschenbach said during his oral evidence (T1822, L46-57) that the three studies namely Wright and Laemmle 1968 , Noonan and Adams 1974 , and Targum and Wright 1974 were enough to lead to the conclusion that there was an increased risk of PID from IUD use. Dr Ory from the Centre for Disease Control said of the six epidemiological studies he reviewed (viz Wright and Laemmle 1968 , Targum and Wright 1974 , Lippes 1975 , Faulkner and Ory 1976 , Westrom et al 1976 , and Vessey 1976 ): "In summary, then, I think that these six studies point in the same direction, that IUD use is associated with the increased risk of acute PID. The best estimate suggests that IUD users have from three to five times the risk of developing PID compared to non-users, that teenagers appear as likely to be affected as older women, that copper IUDs do not offer any protection from gonococcal PID, and finally, there is the intriguing but as yet unconfirmed suggestion that nulliparous IUD users are more likely to develop acute PID than are multi-parous users. As an epidemiologist, I kind of look at these six studies, you know, done by five different investigators at three different countries, all showing the same results, and that, to me, provides some evidence that the association is one of cause and effect. Each study had its strengths and its weaknesses. However, all together, they rule out virtually every major source of bias as a possible reason for observing this association. In addition, when you couple it with Dick Soderstrom's recent report of the histologic changes and the possibility that this is altering tubal defense mechanisms; also if you couple it with the fact that previously rare syndromes, or so they are said to be in the literature, such as unilateral tubo-ovarian abscess and infective agents like Actinomycoses are now being reported in association with IUD use, I think biologic plausibility is added to a causal interpretation of these six studies" (Exhibit P228, Tab 13, pp. 72-73). Before the second insertion (Mrs Orders 20 April 1977) there was a documented recognition of the risk within Searle itself. On 25 February 1977 Mr Peddie from Searle Australia sought from Dr Inglis in the US Searle's "official position" on the risk of PID and ectopic pregnancy associated with IUD use. Mr Peddie drew attention to then current literature which supported that causal association. Before the third insertion (1 August 1977 Mrs Robertson) the FDA Panel proceedings took place. Dr O'Brien was the Searle US employee who had answered Mr Peddie's memorandum referred to above. There is no evidence of any corrective measures being taken to inform Mr Peddie of the information from the FDA Panel proceedings. During the course of the FDA Panel proceedings, there was recognition among the participants that strong evidence supported a 3-5 fold increased risk of PID and its sequelae among IUD users. At several points during these proceedings, specific reference was made to copper devices (mainly the Cu-7) as being implicated. Dr Tyrer represented the Planned Parenthood Federation of America which was described during the proceedings as "undoubtedly the leader in the United States in family planning" (Exhibit P228, Tab 13, p. 60, line 23 ff) with the largest number of clients. She said the Cu-7 was by far the IUD of choice. She said there was sufficient data to document a definite decrease in fecundability after IUD use and the PPFA had prepared a memorandum "that there is a 3-5 fold increase risk of infection among IUD users" (ibid p. 5943, p. 61, L17). These remarks related to all IUD use but in context her remarks clearly implicated the Cu-7 because she wanted the Drug Panel (which was formally concerned with the copper devices) to issue the same warning (ibid p. 178, L12-17). In the period after the FDA Panel proceedings, all of the plaintiffs except Mrs Lee and Mrs Orders had a Copper 7 inserted. In the period between the FDA Panel meeting on 6 June 1977 and Mrs Lane's insertion on 22 August 1980, Table 1 from Senanayake and Kramer shows publications by Eschenbach 1977 , Thaler 1978 , Flesh , Maqueo and Ryden 1979 , and Kaufman, and Osser 1980 . This period of time covers all IUD insertions among those seven remaining plaintiffs except for Mrs Denzin's fourth, fifth and sixth insertions in November 1981, June 1983 and June 1985. The plaintiffs sought a finding that the epidemiological studies showed that an IUD placed a woman at greater risk of PID. The plaintiffs submitted that the studies referred to and the evidence of Professor Daling lead to the conclusion that the broad sweep of epidemiological evidence leads to the conclusion that use of the Cu-7 increases the risk of PID to the users. The epidemiological material relied upon included many studies which do not include the Cu-7 and which relate to populations which are significantly different in a sociological sense to any of the plaintiffs. The plaintiffs seek to draw a conclusion from this disparate material that use of the Cu-7 by the plaintiffs in these proceedings increased the risk of their contracting PID leading to a conclusion of probable causation of the injuries which they sustained. The defendants on the other hand submitted that it was proper to analyse each study and to ascertain how they fitted into the pattern of knowledge after proper allowance was made for weaknesses which appeared in their methodology. In my view this is the correct approach. In particular the defendants criticised studies on the bases that they: (a) include Dalkon Shield users; (b) the duration of use is not obtained so as to indicate iatrogenic risk from any longer term risk; (c) the control group contained women who used a method of contraception which was protective against PID (e.g. barrier methods, oral contraceptives); (d) compounding factors for PID such as age, number of sexual partners, marital and socio-economic status are not identified and controlled using multivariate analysis; (e) biases are not adequately addressed. These factors may, either individually or taken with others, elevate the relative risks for IUD users. The defendants also submitted that the analyses of the material shows that women in the category of the plaintiffs do not have any statistically significantly higher risk of contracting PID when using copper IUDs. In addition to lengthy analysis and criticism of the twenty-five publications referred to earlier the defendants relied upon extensive state-of-the-art literature supporting the use of IUDs. I accept the evidence of Professor Roy as to the risk of infection based on his own experience and on the WHO Report ( Farley 1992 ) that the risk was greatest for the first twenty days after insertion and that thereafter the rate of infection closely paralleled the background rate of sexually transmitted organisms of the population under study. (Ex. D.301, para 41). Professor Roy also drew attention to the 1983 Women's Health Study which analysed different degrees of risk of PID witih specific types of IUDs ( Lee et al, 1983) and concluded that there were differences. Professor Roy also pointed out that earlier studies had compared IUD users with women who used contraceptives which protected against PID and that this comparison falsely elevated the risk or PID for IUD users. Also earlier studies had in many cases included users of Dalkon Shield IUDs which increased the rate of infection shown. I do not accept Professor Daling's 1992 recalculation of her 1985 report as displacing the opinions of Professor Roy which I accept. It follows that with all its manifest imperfection the epidemiological evidence does not establish in my view that there is any statistically significant increase in risk of contracting PID for users of the Cu-7 although there is an increased risk in the first twenty days after insertion which risk is associated with the insertion procedure. In the light of this finding the findings sought by the plaintiffs on pages 181 and 182 are not relevant as the information which was then available was not in my view reflective of the true situation. ECTOPIC PREGNANCY There does not appear to be any issue between the parties as to the existence of a relationship between pelvic inflammatory disease and ectopic pregnancy. There is a dispute however between the parties as to the role of the IUD in this relationship. An ectopic pregnancy is a pregnancy which occurs at a site outside the uterus. Although they may occur elsewhere the vast majority of ectopic pregnancies occur in the fallopian tubes. The plaintiffs tendered an editorial published by Dr Eschenbach and Dr Daling in the April 1983 edition of the Journal of the American Medical Association (Ex. 209, Tab C) in the following terms: "The most widely held mechanism has been a partial failure of the ovum to pass down the fallopian tube in the carefully timed sequence that would allow proper uterine implantation. Partial tubal obstruction after tubal infection stands out as one of the most important known causes of ectopic pregnancy. Women with documented acute salpingitis have an ectopic pregnancy rate that is increased 7 fold over women who have had no known salpingitis. Seven percent of the first pregnancies that occur after salpingitis are ectopic. Evidence of prior salpingitis is demonstrated in one third of the women with an ectopic pregnancy at the time of operation" (Exhibit P209, Tab C). Dr Keeping gave the following evidence on behalf of the defendants. He said: "Q. I am asking doctor about former IUD use? A. Former now, now moving on to former IUD use and ectopic, whatever the literature says, there would have to be an increase in PID in a population that has had an IUD before. I have acknowledged that there is an insertion risk of PID and I think we got down to a figure that once the IUD is in, there might be a relative risk ratio of one point something to 1 for people who have an IUD in... Having said that, I have acknowledged that there will be some people that will get PID as a result of their IUD, particularly around, mainly around the insertion period. As such, that population must be more at risk of ectopics, so there is - there has to be an increased risk of ectopics in previous IUD users" (T6387 L51 - T6388 L9). The plaintiffs submitted that I should conclude that if an IUD use puts a woman at greater risk of PID, it will put her at greater risk of an ectopic pregnancy. It was put that where an increased risk of ectopic pregnancy occurs among women who have used an IUD, it follows that they have been at a greater risk of contracting PID from IUD use. Similarly it was put that the tubal infertility studies were used as independent and objective confirmation of past PID, so the ectopic pregnancy studies operate in the same way. Dr Daling's evidence was that the studies of tubal infertility and ectopic pregnancy both avoid referral bias and diagnostic bias in the studies of clinical PID. The WHO Report 1987 makes the same point. There have been a large number of studies referred to relating to the relationship between IUD use and ectopic pregnancies which included review articles which summarise the results of studies over the years. In 1995, the medical journal Contraception published two such studies, Mol et al "Contraception and the risk of ectopic pregnancy: a meta-analysis" (Ex. P426) and Xiong et al "IUD use and the risk of ectopic pregnancy: A meta-analysis of case control studies" (Ex. P209, Tab 2, Annexure B). The first meta-analysis by Mol et al reported the relationship between past IUD use and the increased risk of ectopic pregnancy in Table 1 of that review an extract from which is set out below: TABLE 1: Detected studies and common odds ratios Study (reference) Control* OR† 95% CI‡ IUCD (past use) Ory (15) NP 1.6 1.3.2.0 Basuki (16) NP 1.7 1.3-2.4 Holt (8) NP 1.8 1.3-2.5 Chow (9) P 1.4 1.0-2.1 Chow (19) D 1.9 1.3-2.8 COR 1.6 1.4-1.8 0.1 1 - - Odds Radio and 95% CI *Control definition: NP = non-pregnant: P = pregnant: D = recently delivered: COR - Common Odds Ratio †:Odds ratio: ‡:95% confidence intervals §Breslow Day Test Statistic Co homogeneity The plaintiffs submitted that these results show that from 1981 five studies ( Ory 1981 , data from the Women's Health Study; Chow, Daling & Ors 1986 ; Chow et al 1990 ; Hoult , Chu , Daling & Ors 1991 ; Basuki , Rossing and Daling 1994 ) demonstrated an increased risk of ectopic pregnancy among past IUD users using pregnant, non-pregnant and recently delivered controls. Pooling the data, the common odds ratio was 1.6. For practical purposes it was submitted this is equivalent to a relative risk. Mol et al concluded: "……After disontinuance of an ICDU, however, the risk continues to be increased, suggesting a relation between ICDU use and subsequent tubal damage." In the same volume of Contraception in 1995, Xiong and others published their own meta analysis which reviewed the published literature from 1977 to 1994. In the Xiong meta analysis, the pooled risk of ectopic pregnancy associated with past IUD use from 19 studies between 1977 and 1994 was 1.4. Past IUD use and the risk of ectopic pregnancy Duration of IUD Use Study OR 95%CI Time (Year) OR 95% CI Quality Score Pregnant controls: Savolainen et al Levin et al WHO Chow et al 0.33† 1.4 0.7 1.7 0.09-1.13 0.7-2.5 0.4-1.2 1.1-2.6 <1 >1-3 >3 1.2 5.4 2.9 0.3-4.8§ 1.5-19.9 0.8-11.5 0.63 0.67 0.90 0.90 Marchbanks et al Chow et al Coste et al Kalandidi et al Pooled result: 1.2 1.5 1.6 3.89 1.33 0.6-2.6 1.0-2.2 0.9-2.9 0.72-21.02 1.08-1.63 >2 6.19 not avail 0.93 0.73 0.87 0.73 Non-pregnant controls: Savalainen et al Ory et al WHO Zhang et al Rossing et al Basuki et al Total pooled result: 1.45‡ 1.4 0.7 0.25* 0.33** 1.6 1.7 1.42# 0.3-7.05 1.1-1.7 0.1-3.9 0.03-1.87 0.02-1.92 1.1-2.2 1.1-2.5 1.25-1.62# <2 >2 <1 1-3 >3 <1 1-3 <3 <1 1-3 >3 1.0 3.9 1.1 1.4 2.5 0.9 1.6 1.8 1.6 1.1 2.3 referent 1.1-14.4 0.7-1.9 0.8-2.6 1.5-4.3 0.5-7.0§ 0.8-3.4 0.9-3.5 0.9-2.9 0.5-2.2 1.3-4.0 0.63 0.87 0.90 0.73 0.73 0.93 0.83 *Hospital control; **Neighborhood control; †Unadjusted OR; ‡Unadjusted OR and legal abortion control; §Dalkon Shield users; #Only including adjusted OR This table is adapted from Xiong. The authors concluded: "Past IUD use could slightly increase the risk of ectopic pregnancy (Pooled O.R.:1.40, 95% C.I..:1.23-1.59). This result challenges currently held opinions about the absence of risk associated with past IUD use. Although this Pooled O.R. is weak, it is firmly confirmed by: 1) consistent results (independent of choice of control group; 2) no indication of compounding (O.R.'s with or without adjusted studies are similar); 3) no effect of quality of study (Table 5); and 4) no indication of publication bias (Figure 3). Furthermore, five studies explored the relationship between the duration of past IUD use and the risk of ectopic pregnancy showing that the risk of ectopic pregnancy increased with the duration of past IUD use." Dr Daling gave evidence that "the overall estimate is significantly elevated" (third witness statement para 2). The authors themselves, referring to the 40% increase in risk, said: "Past IUD use could slightly increase the risk of ectopic pregnancy." The plaintiffs also submitted that recent studies have shown that the risk of ectopic pregnancy increases with duration of use of the IUD Parazzini et al . (Ex. P209, Tab 3, para 1 which refers to Parazzini et al " Past Contraceptive Method Use and Risk of Ectopic Pregnancy" Contraception 1995 , and Tab 2, para 29 Rossing et al 1993 , para 32, Basuki et al 1994.) Dr Daling gave evidence of her own findings that amongst long-term users of an IUD, an elevated risk of tubal pregnancy was apparent for at least seven years after discontinuance of use. ((Ex. P209, Tab 1, para 10.) The defendants criticise reliance upon these studies of the epidemiology of ectopic pregnancy on the basis that they do not break out the data for copper IUD users to permit findings of increased risk associated with Cu- 7 use. They also submitted that a paper by Sivin published in 1983 shows Dalkon Shield use explains the reported increase risk in studies to that time. However, one of the studies Dr Daling relied upon, namely Rossing et al 1993 , reported that for women who had used IUDs in the past, compared with women who had never used IUDs, there was a relative risk of 1.7 of an ectopic pregnancy after cessation of IUD use. For Copper-T and Cu-7 users, the risk was 2.2. Moreover, Rossing et al 1993 stated: "Although there was no evidence of increased risk of tubal pregnancy associated with up to one year of past IUD use, the risk rose steadily with increasing duration of use beyond one year. For women with three or more yeas of past IUD use, the risk relative to women who had never used an IUD was 2.5 whether for IUD use in general or copper IUD use only" (P247, RHC, first para). Second, there was no Dalkon Shield use to affect the results of later research ( Basuki et al 1994 ). It was submitted that these support a finding that the epidemiological evidence suggests past IUD use in general and past Cu-7 use in particular puts a woman at greater risk of an ectopic pregnancy. The duration of use for the various plaintiffs in these proceedings is as follows (the number of months being rounded up): 1. Mrs Lee 14 May 1975 to 28 Jun 1977 25 months 2. Mrs Southren 5 Apr 1976 to 14 Feb 1978 14 Feb 1978 to 6 Jul 1991 22 months 41 months (ie continuous use for 63 months) 3. Ms Ottaway 16 Jul 1974 to late 1976 13 Sep 1977 to 8 Dec 1977 24-28 months approx. 3 months 4. Mrs Moylan 10 Jul 1978 to 19 Feb 1980 19 Feb 1980 to 16 Apr 1980 19 Feb 1981 to 2 Feb 1982 13 Apr 1984 to 14 Sep 1984 19 months 2 months adding up to 21 months of continual use 12 months 5 months. (In total approximately 38 months of use) 5. Mrs Lane 1975 to 1977 1977 to 2 Apr 1980 22 August 1980 to 13 December 1983 approx. 24 months approx. 36 months 40 months A total of approx. 100 months 6. Mrs Robertson 1 Aug 1977 to 23 Aug 1977 less than one month 7. Mrs Orders 20 Apr 1977 to 9 Jun 1977 less than two months 8. Mrs Denzin #1 Nov 1978 #2 Dec 1978 to Jun 1980 #3 Jun 1980 to Nov 1981 #4 Nov 1981 to Jun 1983 #5 Jun 1983 to May 1985 #6 June 1985 to Sep 1986 1 month 18 months 19 months 19 months 23 months 15 months A total of approx. 93 months of use. Among these plaintiffs, ectopic pregnancies were experienced by Denzin, Lane, Orders, Ottaway and Southren, after discontinuing IUD use. On behalf of these five plaintiffs it was submitted that the use of the IUD placed them at greater risk of ectopic pregnancy after cessation of IUD use and that they were not warned of this risk by the defendants. The defendants submitted that there were other risk factors involved in the results for the plaintiffs. Orders, Ottaway and Lane were " maternal smokers ". The defendants submitted that by smoking they were exposed to the risk of tubal pregnancy. The relative risks for past smokers was 1.3 (CI 1.0-1.8) and smokers at conception was 1.4 (CI 1.0 to 2.0). On 25 February 1977 Mr Peddie from Searle Australia wrote a memorandum seeking advice as to Searle's official position with regard to the risks of PID and ectopic pregnancy associated with Cu-7 use. In that memorandum, Mr Peddie drew particular attention to the publication by Dr Hallatt of 15 July 1976. In that publication Dr Hallatt made the following observations about the association between IUD use and ectopic pregnancy: "This is the crux of the whole question: Does the IUD cause PID? If it does, then it increases the incidence of ectopic pregnancy and I think the message for us is that PID is actually a contraindication to the use of the intrauterine device" (p. 758, LHC, last para). It was submitted that this analysis by Dr Hallatt was in accord with the evidence given by Dr Keeping that IUD use increases the risk of ectopic pregnancy. During the 6 June 1977 FDA Panel proceedings Dr Tyrer made a similar warning of a higher than normal incidence of ectopic pregnancy among women who became pregnant following IUD removal (see Reply to Chapter VII p. 53, para 58.9). Searle's own documents show it was aware of this: (see Reply to Chapter VIII, para 19.3, 19.4). It was submitted on behalf of the plaintiffs that I should find that from February 1977, when the Peddie memorandum was written, Searle was on notice of the causal association between past IUD use and ectopic pregnancy. It was submitted that the association between past IUD use and ectopic pregnancy was related to the proposition that IUD use increases the risk of PID and thus tubal damage which inevitably increases the risk of ectopic pregnancy and this risk continues after IUD use has ceased. The literature which Professor Daling referred to in support of her conclusions was in all but two cases published after the distribution of the defendants' product ceased in Australia. The defendants reviewed an extensive range of medical literature: 1. Hallatt 1976 This case series compared 70 patients who had used an IUD and suffered an ectopic pregnancy against 1,428 consecutive ectopic pregnancy patients who had not used an IUD. (Ex. D477). Dr Hallatt concluded that any causal link between IUD use and ectopic pregnancy had not been established and was doubtful. The author commented on the then increasing incidence of ectopic pregnancies as reflecting the increasing incidence of PID. 2. Snowden 1977 Snowden concluded that there was no certainty that the Progestasert had a causal role in ectopic pregnancy and a detailed evaluation was necessary. 3. Eschenbach and Daling 1983 (Ex. P.209, Tab C) The defendants summarized the effect of this paper, in my view correctly, as follows: (a) As at 1983 there had been a dramatic increase in the number of ectopic pregnancies over the previous 2 decades. (b) The pathological cause of ectopic pregnancy is tubal obstruction most often the result of previous infection, particularly salpingitis. (c) The mechanics of ectopic pregnancy were then, as now, not properly understood. (d) There are a myriad of risk factors for ectopic pregnancy, among which the method of contraception is but one possible factor. Prof Daling's extensive work with the population of the Puget Sound in relation to other risk factors for ectopic pregnancy is dealt with elsewhere. (e) These risk factors are inter-related and constantly changing. (f) Among the 4 cited controlled studies published prior to 1983, the authors note only 1 ( Ory et al 1981 ) which analysed IUD use but yet concluded that, in aggregate, women who had used an IUD had the same risk of ectopic pregnancy as women who had never used one. (g) Clearly, the high prevalence of STDs (gonorrhea and chlamydia) was causing tubal obstruction (and continues to do so). (h) Oral contraceptives appear to be protective against the risk of ectopic pregnancy. (i) However, only well designed studies using proper controls and multivariate techniques would, in Profs Eschenbach's and Daling's opinions be able to clarify the cause and risk factors for ectopic pregnancies. 4. Sivin 1983 (Ex. D.384, Tab 24) Dr Sivin concluded that when past and present IUD users are compared with women who have never used an IUD the risk was not statistically different from unity. He also concluded: (a) A large part of the engine driving the ectopic pregnancy rate up was the increase in PID, although that was not a complete explanation. (b) Oral contraceptives and barrier methods are protective against the risk of ectopic pregnancy. (c) However, contrary to the tentative queries raised by Beral and Tatum, there was no indication of a causal relationship between copper bearing IUDs and ectopic pregnancies. 5. WHO 1985 (Ex. D.437, pages 131-141). The effect of this study of 1,108 cases effectively concluded that there was no increased risk of ectopic pregnancy for past IUD users but that there were other risk factors such as smoking which could affect incidence rates. 6. Chow et al 1986 (Ex. D.209, Tab E) Professor Daling was one of the authors. The results of this study showed that once the Dalkon Shield was excluded there was no material association between ectopic pregnancy and use of other IUD's. 7. Edelman & Porter 1986 (Ex. D.384, Tab 6, pages 55-62). This report showed that there was no statistically significant result showing any increase in ectopic pregnancies from the use of Cu-7s. 8. Chow et al 1987 (Ex. P.209, Tab M, pages 70-88). Again Professor Daling was one of the authors. The effect of that review of the epidemiology of ectopic pregnancy was that no IUCD other than the Dalkon Shield gave statistically significant increase in risk. 9. Rossing et al 1993 (Ex. P.132). This study referred to a small number of Cu-7 users and did not differentiate between devices. It produced results at the bottom of the statistically significant range indicating some risk. The degree of risk varied to some extent depending on time. The study concluded that there may be increased risk. These factors have varying degrees of impact on the rates of ectopic pregnancies. It is not necessary to deal with the other to indicate that they may be factors which increase the apparent rate in association with IUDs. Experts called on behalf of the defendants expressed the opinion that past use of a Cu-7 did not result in an increased risk of ectopic pregnancy. Professor Grimes T.5884-5 Professor Roy T6099-6101 Dr Keeping T6389-6390 Professor Newton T6643-6645 Professor Fraser T6750-6751 and 7691-6794 10. Basuki et al 1994 (Ex. P209, Tab 1). This study showed a statistically significant increased risk for women with 36 or more months use. Any shorter duration of use did not produce a statistically significant result. The study did not determine the type of IUD used. There was also a very small number of relevant articles which gives an extremely wide confidence interval. In my view the material relied upon by the plaintiffs and the evidence by Professor Daling as to the effect of past use of Cu-7 on ectopic pregnancies does not establish that there was in fact any statistically significant increase in the risk of ectopic pregnancies as a result of past use of a Cu-7. An analysis of the literature not show any support basis for the proposition propounded by the defendants. I accept the evidence of Grimes, Roy, Keeping, Newton and Fraser referred to above and find that there was no increase in ectopic pregnancies as alleged by the plaintiffs. I found Professor Daling's selective assessments throughout her evidence unfairly pointing to IUD associated risk unsatisfactory and her general approach to the giving of her evidence is not to be ignored in the conclusions which I arrive at. Further, in my view none of the material referred to led to the conclusion that the state-of-the-art while the Cu-7 was sold showed a view that use of a Cu-7 would increase the risk as alleged. Nor is there any basis for concluding that the defendants were aware of such an increase. The so-called Peddie Memorandum does not in my view disclose any such knowledge. The plaintiffs also relied upon three 1995 publications. 1. Parazzini This study involved a small number of IUD users and there was no indication of the types of devices used. The authors concluded that there may be an increased risk of ectopic pregnancy which increased with prolonged direction of use but that the study does not confirm that. 2. Mol et al 1995 (Ex. P426, pages 337-340) This paper relied upon the papers referred to above and one other paper. 3. Ziong et al 1995 (Ex. P.209, Tab 3, pages 23-32) This paper pooled existing material calculated a relative risk of 1.4 (1.23 - 1.59) which the authors described as a mild or slight increase. The result was obtained without differentiating the Dalkon Shield results. In my view these three recent publications, when properly analysed, do not alter the conclusion which I have expressed above. The Mol and Xiong papers analyse previous data without what, in my view is necessary, namely excluding Dalkon Shield results and differentiating between types of IUDs. Parazzini is a small and inconclusive study. The defendants drew attention to other risk factors for ectopic pregnancies including prior induced abortions, previous abdominal surgery including appendectomy, vaginal douching and maternal smoking. 4.2 THE SCIENTIFIC ANALYSIS This topic was dealt with in detail in Part 3 of the plaintiffs' submissions. It was an attempt to demonstrate ways in which the IUD could be shown scientifically to cause the introduction of pathogens. The matters dealt with under this heading are: 1. Tailstring It was said that bacteria which are pathogenic if introduced into the upper genital tract are able to adhere to the polymer of which the Cu-7 tailstring was made and that as that polymer was prone to fray more bacteria could adhere to it than would otherwise be the case so that in the event that the tailstring retracted into the uterus pathogens were introduced. Secondly it was said that bacteria could adhere to the tailstring and colonise it. The bacteria could then spread along the tailstring thereby finding a means of entry into the upper genital tract. In summary it was submitted that the Cu-7 may " cause" the ingress of PID bacteria by (a) retraction of the tailstring (b) " ascension" of the bacteria up the tailstring (c) carriage upon insertion. The defendants submitted that neither (a) nor (b) have been shown to increase the chance of upper genital tract infection. The defendants admitted that (c) was a possibility but submitted that in relation to Lee, Moylan, Orders, Ottaway and Robertson whose cases were opened as cases of insertion infection they did not suffer PID as a result of the insertion of their Cu-7s. They further submitted that insertion infection was a matter of which all doctors were aware and was not a risk which rendered the Cu-7 defective so that there was no causal link rendering Searle liable for insertion infection. Further it was submitted that there was no evidence of facts which elevated mere possibility to the requisite level of more likely than not. 2. Foreign body effect It was said that the amount of bacteria required to cause infection in the upper genital tract varies depending upon such things as the virulence of the organism, the access it may have to vulnerable tissue liable to be infected and the immune system of the patient which may be affected by the woman's health at the time. It was also said that the presence of a plastic and copper device inside the uterus causes a reaction called the foreign body effect which dramatically reduces the amount of bacteria necessary to cause infection. The defendants submitted that this did not achieve the status of an accepted hypothesis and should be rejected as inadequate to show or assist in showing a causal link. Tailstring As indicated in the introductory passage above the plaintiffs allege that PID bacteria may enter the uterus of a user of a Cu-7 by (a) retraction of the tailstring (b) " ascension" up the tailstring (c) by carriage on insertion (a) Retraction of Tailstring It was said that there was a tendency of polypropylene to resume its earlier configuration as string memory and when it happened it would draw the string up into the uterus introducing the likelihood of contamination by pathogens. This allegation relates to Denzin, Gentle, Lee and Ottaway. The plaintiffs summarised their case on this point as follows: "(i) string retraction into uterus introduces more potential pathogens than otherwise; (ii) string retraction requires additional instrumentations of uterus to remove device which uterine instrumentation increases risk of introducing infection; (iii) the defendants admit that uterine instrumentations increased the risk of introducing infection." The plaintiffs sought to establish the above in the following ways: 1. Following the successful insertion of a Cu-7 in the uterus, the tailstring ran from the bottom of the Cu-7 in the uterus through the cervix and into the vagina to provide the user or her doctor with an easy method of checking that the device was still in place and to facilitate the removal of the device. 2. The Cu-7 was shaped like a figure 7 with a small rounded cap which fuses the horizontal arm and the curved vertical stem together. Copper wire was wound around the vertical stem. The polypropylene tailstring was attached to the lower end of the vertical stem. When the device was packaged, the Cu-7 stem sat in the inserter tube. The tailstring joined at the base of the stem (inside the inserter tube), and turned to pass up the tube beside the device before emerging from the top of the inserter. It then looped through 180 degrees to run down the outside of the inserter tube. This can be seen clearly in Exhibit P3, a box of packaged Copper 7s. 3. The plaintiffs alleged in each case that in its packaged configuration "the tailstring was looped out of the top of the inserter tube rather than run down the inside of the inserter tube, such loop resulting in a string " memory " which caused the tailstring to have a propensity to retract into the uterus resulting in: (A) the tailstring transferring bacteria and/or other infectious organisms from the vagina into the uterus; (B) the need for instrumentation of the uterus; and an increased risk of Pelvic Inflammatory Disease ("PID")." The plaintiffs also pleaded, as particulars of the exemplary damages sought, that Searle was aware that the Cu-7 tailstring had a tendency to retract into the uterus increasing the risk but chose not to remedy the defect. 4. The defendants do not dispute that retraction of the Cu-7 tailstring into the uterus occurs. They say that this retraction phenomenon is unrelated to the design of the Cu-7, and, in any event, doers not increase the risk of upper genital tract infection. (a) Polypropylene Tailstring's Propensity To Retract 5. Dr O'Brien, the Associate Director of Clinical Research of Searle between July 1974 and September 1985, gave evidence for the defendants. His evidence was that Searle received reports of retractions during the clinical trial and following marketing of the Cu-7 and that he became aware of them shortly after they were received. Searle's documents confirm this statement as to receipt of reports from August 1974 through to 5 December 1983. Dr O'Brien said that the efforts Searle made to find a way to eliminate the string retraction effect were not motivated by any concerns that the retraction of the string might promote infection by the drawing up of micro-organisms into the uterus but rather that these efforts were made for marketing purposes. He said that all IUD tailstrings retract and there was no evidence that the Cu-7 retracted at a rate greater than did the tailstrings of the Lippes Loop. Finally he stated that there was no evidence that retraction promoted infection. 6. The defendants also called Dr Piziali. He was a consultant with a background in mechanical engineering who has experience in the fields of biomechanics and bioengineering. He disclaimed expertise in polymer chemistry. His evidence was that while there was a memory effect with the Cu-7 tailstring, it was not of sufficient strength or persistence to account for retraction into the uterus. His evidence included a video of a Copper 7 inside a plastic uterus. While this video showed movement in the tailstring, he explained that the forces involved would not be sufficient to account for the retractions. He explained that although he had given the matter considerable thought, he did not have a theory as to why tailstrings retracted but was confident that it could not be the memory. 7. The plaintiffs tendered more than fifty exhibits which are described at Tab " Memory" in Part 5 of the plaintiffs' written submissions. Many are Searle documents containing statements to the effect that the special characteristic of the polypropylene (the "memory") used in the tailstring accounted for the retraction phenomenon. These exhibits document reports commencing prior to the first Cu-7 insertion of which the plaintiffs complain and extend over the period in which all insertions in the lead cases occurred. The defendants seek to explain these by saying that Searle employees believed at the time that there was a memory effect inherent in the polypropylene which accounted for the retractions, but that they were wrong. Searle claims that its employees did not have sufficient expertise to know why the tailstrings retracted. However the documents include statements to similar effect from Battelle, expert design engineers employed by Searle to assist in solving the retraction problem. Further, the documents include statements that the alternative polyethylene string Searle proposed for use on the Copper (used on Searle's Tatum T) was a definite improvement in that it had almost no memory, strongly suggesting that Searle employees were right to ascribe the memory problem to the particular characteristics of the highly drawn polypropylene tailstring. Doctors using the Cu-7 reported similar experiences to Searle. For example, Dr Michaelow, described in an internal Searle memo as a " Gravigard devotee" reported that up to 80% of Cu-7 tailstrings retracted in his experience of 2,000 insertions and that the phenomenon was definitely not occurring with other devices. Mr Edmunds of Searle South Africa asked " Why does this not happen with our Tatum-T thread or threads of other devices? " 8. The plaintiffs have relied on the Searle documents and the evidence of Professor Channing Robertson and Professor David Katz to establish that the polypropylene used by Searle in the tailstring had a propensity to retract. Unless these documents are ignored or proved to be all wrong on the question, it was submitted that the plaintiffs are entitled to a finding in their favour. 9. This propensity to retract was supported by the evidence of Professor Robertson who gave evidence for the plaintiffs. He is a Professor of Chemical Engineering at Stanford University. He is the witness in the case with by far the greatest expertise in polymer chemistry. Polypropylene is a polymer. It was common ground that the memory effect was a result of the stresses within the polypropylene tailstring deriving from the chemical conformation of polypropylene processed by drawing. Searle designed the packaging so that the tailstring looped above the 7 and then ran down along the outside of the inserter tube. Professor Robertson gave evidence as to the effect of the packaging of the tailstring. His evidence was that by using polypropylene and packaging the Copper 7 with a loop in the tailstring, the result was that the tailstring was prone to resume the shape it had within the packaging. The effect of this was that the tailstring after insertion of the device would have a tendency to withdraw into the uterus, playing a role in the introduction of infection (para 40, Statement dated 28 July 1995, Tab A, Exhibit P 136). 10. Professor Katz is a Professor in both the Department of Biomedical Engineering and in the Department of Obstetrics and Gynaecology at Duke University, North Carolina. He had previously held a position as a Professor in the Department of Chemical Engineering at the University of California, Davis. He has expertise in polymer chemistry. His evidence was that one of polypropylene's characteristics was to have a memory, in the sense of a tendency to resume a position in which the material had previously been placed, and that this characteristic can not be removed and cannot be predicted with certainty. However Professor Katz had not taken any steps to ascertain the degree of memory needed for retraction either by theoretical or observational means. 11. The plaintiffs submit that the evidence of Professors Roberts and Katz should be accepted and there be a finding that the memory characteristic of the polypropylene used in the Cu-7 tailstring caused the tailstring to have a propensity to retract and that this characteristic existed to a markedly greater degree in Cu-7 tailstrings than in the polyethylene alternative which Searle used on its Tatum-T and proposed to use on the Cu-7 and Mini. The defendants do not dispute that retraction occurs but say that it is not due to any design defect or " memory ". (Dr. Piziali, Ex. D.306 at para 112). Dr Piziali also demonstrated on a video the deformation of a Cu-7 tailstring. He expressed the view that it was impossible for the tailstring to retract because of memory. I accept the evidence of Dr Piziali. In my view the plaintiffs have not established that retraction occurs because of " memory " or any other design fault in the Cu-7. Retraction does however occur as it does apparently with all tailed IUDs. (b) Increasing The risk of PID 12. The second dispute about retraction is whether retraction increases the risk of PID. Dr O'Brien gave evidence that there was no study which concluded that string retraction played any role in the development of PID. His evidence was that the efforts made to resolve the tailstring retraction problem were made for marketing reasons (i.e. presumably that doctors were reluctant to insert a device that might cause problems) rather than out of concerns about safety of users. It was submitted that Searle documents make this an unlikely explanation. For example, the FDA were unlikely to be concerned about Searle's marketing choices when prompting Searle to fix the problem. 13. Denzin, Gentle, Lee and Ottaway suffered tailstring retractions. It is common ground between the parties that any instrumentation of the uterus increases the risk of contracting, or exacerbating, PID. Each of these plaintiffs required instrumentation of the uterus to remove her Cu-7 because the tailstring had retracted, although in Gentle's case this was associated with treatment of septic abortion. It was submitted that there is no real dispute that the tailstring retractions increased the risk of injury to the plaintiffs by requiring instrumentation. 14. Professor Ellner gave evidence that it was obvious that retraction of the tailstring was a mechanism for contaminating the uterus with bacteria, causing infection. Professors Eschenbach, Robertson and Katz gave evidence to the same effect. In addition, the defendants' expert medical witness, Professor Fraser, confirmed that the retraction of the tailstring might introduce bacteria into the uterus and it would depend upon the type of bacteria and the health of the woman as to whether this would create an infectious process. The plaintiffs submitted that (a) the evidence of Professors Ellner, Robertson, Katz and Fraser as to the direct contamination of the uterus by string retraction combines with (b) the Searle documents, (c) the consensus as to the risk which instrumentation (necessitated by the retraction in at least three of the lead cases), and (d) the concerns as to the potential of the frayed tailstring to pose a risk of infection independently of fraying support a finding that the retraction of the tailstring provided a means whereby bacteria could be carried from the vagina into the uterus and thereby increased the risk of PID for users of the Cu-7. The defendants position is that tailstrings are a common element in IUD design to aid in location and removal. The defendants submitted that irrespective of the propositions put forward on behalf of the plaintiffs there was no evidence that users of tailed IUDs suffered a higher incidence of PID than did users of tail-less IUDs and relied on the following evidence: Statement of Professor Newton; Ex. D299 at paras 141-153. Statement of Dr Piziali; Ex. D306 at paras 24-41. Statement of Professor Grimes; Ex. D300 at paras 97-103. The plaintiffs did not tender any published literature showing any difference in the incidence of PID between tailed and tail-less IUDs. Indeed the published science is to the contrary (e.g. Rivera 1993 , Ex. D321 at page 177). Further the defendants submitted that there was no evidence that the tailstring on the Cu-7 retracted at any greater frequency than tailstrings on other IUDs. A survey of the literature by Drs. Ebi and Piziali (Ex. D362) showed that the Cu-7 retractions were less than for the other two makes of IUDs reported on. In my view the evidence establishes that: (1) Tailstrings of the Cu-7 did retract and assume their pre-insertion shape. (2) There were many complaints of the retractions to the defendants. (3) The defendants believed that the cause of the retractions was the "memory" of the string. (4) The defendants set about changing the tailstring for what was described as " safer" polyethylene . (5) The change was not implemented. (6) The non-implementation was most probably because Searle was subject to law suits in the United States and did not wish to provide a " new and improved" product design so as to affect prospects of that litigation. (7) The rate of retraction was not out of the ordinary in relation to other IUDs in respect of which data is available. (8) Retraction theoretically can increase the risk of transferring pathogens from the vagina to the uterus. (9) The evidence does not establish that the fact of retraction and the rate of retraction increases the rate of PID on epidemiological evidence.. (10) There is no evidence of any difference in the incidence of PID where the strings of IUDs are made of different materials (except for Dalkon Shield). (c) Fraying: The plaintiffs summarised their case in the following way: (a) Fraying As A Property Of Highly Drawn Polypropylene 1. It was not disputed that Cu-7 tailstrings frayed or fibrillate and suffered other morphological (although not chemical) breakdown. This extended to all Cu-7 tailstrings over time. The disputes as to fraying related only to how much and where. 2. The plaintiffs have tendered a great many documents dating from 1974 including documents from Searle Australia and from the New South Wales Family Planning Association which show that the fraying was readily apparent to the naked eye and a source of real concern. Searle's documents state that " Fraying of some degree exists throughout our production. " (Ex. P8, Tab 2, page 30). 3. The plaintiffs led evidence to show that Cu-7 tailstrings frayed throughout their length. Professor Fives-Taylor gave evidence as to research performed by her group at the University of Vermont which undertook quantitative scoring of fraying along the length of the tailstrings. They found frays along the length of the tailstrings. 4. For the defendants, Dr Piziali gave evidence that a number of new and used tailstrings were examined optically or by scanning electron microscope. These observations were that no or few fibrils appeared on polyethylene or nylon tailstrings whereas polypropylene tailstrings did exhibit fibrillation. However the observations reported by Dr Piziali's team were of fraying on the vaginal portion only of such strings. In this respect Dr Piziali's observations differ from those of Professor Fives-Taylor. They also differ from the observations made by the Australian National Biological Standards laboratory which in February 1980 examined a tailstring and reported to the Commonwealth Department of Health that " numerous fraying parts were evident along the entire length of the filament together with some lengths of split ends protruding from the filament ." (Document #134 in Part 5, 'Documentary Case'.) 5. There is no dispute between the parties as to the fraying being caused by the way in which the tailstrings were manufactured. Professor Robertson gave evidence that application of tension (or drawing) to the Cu-7 tailstring aligned polymer chains along the length of the tailstring. This had the effect of strengthening the tailstring along its length at the cost of weakening lateral bonds within the tailstring. The result was that the tailstring would withstand a greater pull before breaking but became prone to fray. His evidence applies to the entirety of the length of the tailstring. It was submitted that the evidence of Professor Fives-Taylor and Professor Robertson and the letter from the National Biological Standards Laboratory support the finding that Cu-7 tailstrings, being made of highly drawn polypropylene, frayed throughout their length. (b) Significance Of Fraying (i) Rougher and Larger Surface 6. The defendants argued that fraying by itself was solely an aesthetic problem without medical consequences. The plaintiffs said that a frayed tailstring will have a larger and rougher surface area than a non-fraying tailstring and will thereby attract bacterial adhesion and colonisation, increasing the risk of pelvic inflammatory disease. 7. It appears that there is no dispute between the parties as to Professor Fives-Taylor's evidence that the body's primary defence against infection by micro-organisms is desquamation, that is, the defence of flushing out micro-organisms by shedding cells on the outer layer of organs. If a micro-organism has adhered to a surface which does not desquamate, then it is able to stay in the body. Professor Fives-Taylor described adhesion as " the first and most primary virulence factor " for a micro-organism in the body. 8. A Cu-7 or Mini, including its tailstring, can not desquamate. Any biomedical implant becomes coated with a thin layer of host proteins immediately upon being placed into the body. An IUD is no exception. Micro-organisms can attach to this layer of proteins through specific adhesion. Specific adhesion involves the formation of bonds between the micro-organism and the surface layer on the tailstring. Professor Ellner gave evidence that the initial attachment is due to physical and chemical forces but that within a few hours after attachment micro-organisms which have adhered to an IUD can exude a substance which forms a " slime " layer over the IUD. (Para 16 of Professor Ellner's first statement, Tab 1, Ex. P282). This, together with material from the host, forms a biofilm which rapidly covers the whole of the surface of the device. Professor Ellner said micro-organisms can and do colonise the surface and interior of this biofilm. 9. The plaintiffs say that because of the fibrillation which causes frayed and rough surfaces, bacteria are better able to adhere to the Cu-7 tailstring than to other tailstrings. 10. Professor Katz gave evidence that bacteria are better able to adhere to a rough surface than a smooth one and that bacteria are more likely to colonise along the frayed areas. (paragraph 17, Statement of Professor Katz dated 25 August 1995, Tab 1, Ex. P192). Professor Kaplan agreed that bacteria might be able to adhere better to rough surfaces than smooth. (T.5370/L57-5371/L3). Professor Robertson and Professor Fives-Taylor observed that the biofilm preferentially concentrated in the grooves of the tailstring created by fibrillation, frayed areas and areas of pits, crevices and roughness. Professor Fives-Taylor undertook experiments which indicated that up to 10 times as many bacteria adhered to frayed parts of the Copper 7 tailstring as to smooth parts. The defendants accept that bacteria can adhere to IUD tailstrings. (ii) Bacterial Adhesion Greater In Polypropylene Tailstrings 11. Professor Fives-Taylor conducted experiments to measure bacterial adhesion to various tailstrings and polymers. She measured specific adherence of radioactively " tagged " bacteria to unprocessed beads of polyethylene, polypropylene and co-polymer. While some bacterial species adhered better to one material and some to another, there was little or no overall preference shown by various bacterial species for one over another. Six of ten bacterial species tested adhered better to polyethylene and four adhered better to polypropylene. 12. She then measured specific adherence of bacteria to tailstrings of IUDs. The results demonstrated much greater adhesion to the polypropylene tailstring of the Cu-7 over the tailstrings of other devices. This held true across bacterial species. Twelve of the thirteen bacterial species tested adhered better to polypropylene in tailstring form. There was no result for the thirteenth. 13. Professor Fives-Taylor concluded that it was the processing of the material, rather than the choice of polypropylene itself, which accounted for the greater adherence of bacteria to Copper 7 tailstrings over the tailstrings of other materials. 14. The defendants' witness, Professor Kaplan, an expert in microbiology from the University of Texas Medical School, criticised a number of techniques used in Professor Fives-Taylor's bacterial adherence experiments. His evidence was that the use of human saliva rather than oestrus fluid as a medium for coating the tailstrings deprived the results of significance. He criticised the application of the method of counting bacteria and suggested that the experimental technique was sloppy, pointing to the recording in the laboratory notebooks of a number of experiments being spoiled by accidents in the laboratory. Professor Fives-Taylor's group conducted more than a thousand experiments, including replicates and gave evidence that some accidents were to be expected. Professor Kaplan has not however pointed to any scientific literature which suggests that Professor Fives-Taylor's experiments should not be given weight. 15. The Cu-7 tailstring has been shown to have certain characteristics resulting from its manufacturing process. The fibrillation and morphological breakdown of the tailstring led to it having a greater surface area and greater surface roughness than tailstrings made of other materials. The plaintiffs submitted that Professor Fives-Taylor's conclusion that the fraying and degradation of the Copper 7 tailstring promote the adhesion of bacteria should be accepted because: · Professor Fives-Taylor and her group undertook many experiments and replicates so even though some are criticised, the overall weight is convincing. · there are no contrary experiments. · the only experimental work of the defendants about which there is evidence is supportive in that it indicates that E. coli, a recognised PID pathogen, can adhere to the Cu-7 tailstring. · Professor Ellner gave evidence to similar effect including citations of the published science which is itself supportive. See paragraph 16 of Professor Ellner's statement of 31 July 1995 (Exhibit P 282, Tab 1) and Exhibits P 205 (Wilkins et al 1989 IJP 57 1-7) and D347 (Wilkins et al Contraception Vol 39, No 2, p. 205), being 2 of the footnotes to Professor Ellner's paragraph 16. · the defendants concede that bacteria adhere to tailstrings so there is nothing unlikely in her results. (iii) Medical Risks Due To Defects 16. The defendants submitted that, even if this is so, it nevertheless has no clinical implications. Professor Kaplan agreed that microbial adherence based on biofilm is a fundamental and pivotal factor in sepsis involving biomaterials. (T.5218/L54- T5219/L5). However he was not prepared to extrapolate from this position,which applied to a wide range of other implanted devices, to the case of IUDs. He expressed the view that because the epidemiological data cleared IUDs from involvement in infections, IUDs were necessarily different from other biomedical devices. 17. Professor Kaplan accepted that cells might detach from the biofilm of an IUD in situ and, in a host whose defences are lowered sufficiently, might cause infection. However he suggested that the probability would be that the large numbers of pathogens constantly accessing the upper genital tract would cause PID rather than pathogens detaching from the biofilm covered IUD. (T5266/L9-41). 18. Professor Kaplan's opinion that pathogens detaching from the biofilm were not likely to cause PID was not based on his expertise in microbiology but rested on his understanding of the epidemiology as exonerating the Cu-7. He agreed that his opinions were not informed by any expertise as an epidemiologist. (T5192/L25-32). although he has read the literature and formed opinions. It was submitted that if the epidemiological prop to his argument is removed, it would appear that his concession as to the microbiological point goes a long way to support the plaintiffs' case. 19. Professor Ellner expressed a quite different view as to the importance of pathogens leaving the biofilm. He expressed the view (as did Professor Katz) that the biofilm protects bacteria from the host immune system and antibiotics, allowing pathogens to survive in the upper genital tract, an area of the body where they would ordinarily be eliminated by the immune system. His evidence was that the biofilm on an IUD can concentrate nutrients, enabling the bacteria to multiply within the biofilm. He stated that the biofilm covered Cu-7 forms a " nidus " or infective reservoir from which micro-organisms can emerge to infect the host. His evidence was that whether the bacterial colonisation of the Cu-7 results in infection or not depends upon many factors involving the state of host defences and the numbers and virulence of the micro-organisms. However the role of the fraying as a design defect was to provide a reservoir of pathogens able to infect the uterus. 20. The danger of frayed strings was given support by Dr Stewart who declared that frayed strings were " medically unacceptable ". (Ex. P486). It submitted that the Searle documents provide further support in that they contain many references to the dangers of infection from frayed tailstrings. The plaintiffs submitted that the evidence of Professor Ellner, supported by the plaintiffs' and defendants' clinicians, (who agreed that they would remove the Cu-7 in the event of infection), over that of Professor Kaplan. The defendants submitted that: (1) No adverse medical conditions has ever been associated with a frayed or fibrillated tailstring. (2) No medical practitioner, including those who took the matter up with Searle, ever reported an infection associated with a frayed tailstring. (3) No government or regulatory agency ever complained of, or otherwise draw Searle's attention to, an infection, or other adverse medical outcome, associated with a frayed tailstring, as distinct from the fact that fraying had been observed. The experts, Professors Coughlin, Fives-Taylor and Robertson speculated that in their view that there was preferential attachment to the crevices and grooves. Professor Wachtel, an SEM expert retained by Professor Coughlin to assist him in his research, reported from actual observation that the bacteria were not propentially attached to grooves and crevices. (Ex. P.245, page 2). The essence of the plaintiffs' case on this aspect is that Searle was negligent in using polypropylene probably rather than polyethylene. There was no evidence on behalf of the plaintiffs that polyethylene was " safer ". The epidemiological evidence established that there is no difference in the performance of IUDs using either polypropylene or polyethylene. Professor Robertson conducted no comparative studies. Professor Coughlin had obtained data which showed the performance was similar. (Ex. D.305 at para 119). This data was omitted from Coughlin et al 1992 by Professor Coughlin at a time when he was retained by plaintiffs' lawyers and was aware that the lawyers thought Searle should have used polyethylene. Dr Piziali (Ex. D.396, paras 45-54, 95-99) gave evidence that polypropylene had certain advantages over polyethylene in (i) the manner of attachment to the IUD; (ii) the surface area of the tailstring. Dr Piziali calculated that the overall area of the fibrillated polypropylene was less than the alternative polyethylene. It is clear from the evidence of Dr Piziali that drawing the tailstring material to produce higher tensile strength is a trade-off for fibrillation. (b) "Ascension" up the tailstring The plaintiffs' case is as follows: 1. The plaintiffs alleged in their pleadings that the Cu-7 and Mini tailstring provided a suitable environment for colonisation by bacteria and/or other infectious organisms. (See e.g. Paras 14(A)(i), (ii), (iii) and (iv) of the Amended Statement of Claim) 2. There is no issue that the normal uterus is subject to periodic incursions of bacteria which are almost always effectively eliminated by the immune system. There is also no issue that a uterus which has an IUD in it will always have permanent colonies of micro-organisms associated with the biofilm on that IUD. These micro-organisms are protected by the biofilm from the action of the immune system. 3. It is common ground that it is only upon ascension through the cervix into the upper genital tract that micro-organisms, including virulent pathogens such as gonococcus and chlamydia trachomatis, and anaerobes can cause PID. An issue between the parties was the extent, if any, to which the tailstring of the Cu-7 could assist a potential pathogen to " ascend " . 4. There does not seem to be any dispute that, upon insertion into the body, the Cu-7 rapidly becomes coated by a biofilm which is colonised by bacteria and that some of these bacteria can be pathogenic in the upper genital tract. There was no dispute as to the evidence of Professor Ellner and Professor Fives-Taylor that there are colonies of bacteria in the device biofilm which have bypassed the cervical defences and which enjoy a measure of protection from the immune system whenever an IUD is in situ. These colonies of bacteria are able to exist in the upper genital tract solely by reason of the presence of the device. In this sense there was no real argument that the presence of the device has assisted in the establishment of micro-organisms in the upper genital tract. the question is whether they can do any harm. 5. There is consensus that all IUDs (and other biomedical implants) rapidly become covered in biofilm upon insertion into the body. There is debate as to how much of the biofilm is produced by adherent bacteria and how much is host material, an issue which does not need to be decided. Biofilm is a bacterial adaptation which has the effect of promoting the survival and proliferation of bacteria. Bacteria associated with biofilm can survive in environments where bacteria in their planktonic form would not be able to survive. Bacteria are able to adhere to and leave the biofilm. Professor Ellner gave evidence that biofilm confers a substantial number of advantages upon bacteria which permit them to survive permanently in the upper genital tract. Professor Katz supported this evidence as did Professor Fives-Taylor. Professor Kaplan suggested that biofilm might " entomb " bacteria based upon a reference made by Professor Costerton many years ago. It is submitted that the views of Professors Ellner, Katz, Fives-Taylor, Robertson should be preferred to those of Professor Kaplan. Their views were said to be supported by supported by the published science in the area, including recent work of Professor Costerton. Professor Kaplan put forward no published work other than the older work of Professor Costerton (covered by his disavowal of pre-scanning confocal microscope work), to support it and Professor Kaplan said that his use of terms such as " cement " to describe biofilm and " entombed " to describe living bacteria was " theatrical ." (T5394/L1-15). 6. The parties disagreed as to the mechanisms which allow bacteria to move into the upper genital tract. Professor Ellner identified mechanisms by which the Cu-7 and Mini assisted bacterial ascension including: (a) movement of the perimeter of individual colonies, (b) " pollination " from existing colonies on the string, and (c) the establishment of new colonies by planktonic bacteria attaching to the tailstring, whether or not they had emerged from other colonies on the tailstring. 7. Professor Robertson identified a number of mechanisms including the extension of boundaries of a colony by lateral extension driven by multiplication of organisms causing growth of the colony. He also identified " pollination "in which micro-organisms or entire colonies detach from the string and reattach at different places. 8. Professor Katz, an expert in how micro-organisms move, also identified a tendency of motile organisms to move along the tailstring surface towards a source of nourishment, a process known as chemotaxis. 9. Professor Coughlin demonstrated that micro-organisms can and do grow along Cu-7 tailstrings in the laboratory in preference to random growth. The defendants criticised the laboratory techniques used in the experiments and indeed the applicability of in vitro experiments at all but did not call evidence to the effect that the mechanisms identified by the plaintiffs' scientific experts did not operate. 10. The only evidence as to experiments carried out by the defendants was tendered by the plaintiffs. This related to experiments carried out in 1986/7 which suggested that at least one micro-organism associated with PID, E. coli, was able to attach and to move through mucus in the presence of the tailstring. 11. The plaintiffs submitted that the evidence of Professors Ellner, Katz, Robertson and Coughlin that the Cu-7 and Mini tailstring can facilitate the transport of micro-organisms into the upper genital tract should be accepted. The defendants dispute that there is evidence as demonstrated of movement of bacteria along the tailstring. Professor Robertson on behalf of the plaintiffs suggested three mechanisms by which bacteria might migrate along the tailstring: (a) direct migration (b) sheer forces (c) locomotion of the bacteria guided by chemotaxis. Professors Robertson and Fives-Taylor reported in Warner et al 1991 on the only two cases of bacaterial colonisation they found. Both were on the portion of the tailstring which was in the user's vagina. Apparently Professor Robertson did not find any bacteria at the uterus end of the string using TEM. The only bacteria found on any used IUD tailstrings was found encapsulated in biofilm. Professor Kaplan expressed the view that when bacteria are encapsulated in biofilm they remain so. (Ex. D.305, paras. 29, 31 & 34). There is no evidence of continuous or semi-continuous bacteria which casts considerable doubt on (a) and (b) above. In respect to attraction of bacteria by chemotaxis there was nothing to suggest that the presence of an IUD played any part in such movement if it occurred. In relation to the dispute between the parties Professor Ellner who gave evidence on behalf of the plaintiffs indicated the importance of the number of bacteria entering the uterus in determining the risk of infection. Professor Ellner also gave evidence in relation to a number of in vitro experiments carried out by Professor Fives-Taylor and others in relation to the ascension of bacteria. He was of the view essentially that they were of limited value because they did not mimic the in vivo conditions. There was a vast amount of evidence given by Professors Fives-Taylor, Coughlin, Ellner and Katz on behalf of the plaintiffs and Dr Piziali and Professor Kaplin on behalf of the defendants relating to tailstrings and their characteristics. That evidence encompassed evidence of experiments and technical criticisms of those experiments and of opinions and counter opinions. In my view the extraordinary complexity of these issues may be disposed of by determining the effect, if any, of the matters alleged by the plaintiffs on the health of users of Cu-7 device. The matters raised are in my view advanced as possible causes of infection of users of Cu-7 devices. As I indicated above in my view the evidence does not indicate any statistically significant increase in the rate of infection and in my view there is no evidence that these issues had any effect on the health of users of Cu-7 devices. 4.3 CLINICAL OBSERVATIONS The plaintiffs sought to establish a causal connection between use of the Cu-7 device and the contracting of PID by the observation of treating doctors of the fact of the contracting of PID by users of Cu-7 and other devices. In my view this submission has no substance whatsoever. There was no basis put forward for concluding that the mere observation of a condition which may occur with or without the use of an IUD in a person who uses an IUD is probative in any way of any causal connections between the use of an IUD and the contracting of PID. The three areas of proof propounded by the plaintiffs, Epidemiology, the Scientific Analysis and Clinical Observations, do not either individually or together establish any causal association between the use of the Cu-7 devices and the incidence of PID. 5. WARNINGS In my view the defendants did not fail to warn the plaintiffs of any matter of which they were required to warn. The evidence does not establish that perhaps, despite the then current views, the devices increased the risk to users of the devices except as a result of the insertion procedure. Counsel for the plaintiffs acknowledged that in the absence of an appropriate increased risk there was no duty to warn and the defendants had not breached any such duty. The insertion procedure carried with it an element of risk which was known to all inserting doctors and of which they were all aware at the time of carrying out the relevant insertion. In my view there was no requirement to warn medical practitioners of such an elementary matter nor was there any obligation to warn users of such a risk when they could only obtain access to use of the devices with the service of a doctor. 6. CONCLUSION In my view the plaintiffs have not established that: (1) Use of the Cu-7 IUD increased the risk of the user contracting PID by any statistically significant degree. (2) There was not any negligence on the part of the defendants in the design and/or manufacture of the Cu-7 or Mini devices. It is true that employees of the defendants expressed contrary views in relation to the tailstring of the device which indicated that there were defects in the devices but in the light of the evidence before me I am of the view that those views did not reflect correctly the effect of the matters referred to on the well-being of users of the devices. A considerable amount of evidence was given as to the possible causes of the injuries which the plaintiffs each suffered. In my view the cause of the infection is not relevant to the determination of the liability of the defendants in the light of my conclusions. It is clear that injury of the type sustained by each of the plaintiffs could have been sustained even if the devices had not been used and in my view the evidence does not establish as is required by the law of New South Wales that on the balance of probability the injury to the plaintiffs was caused or materially contributed to by the use of the devices. SCHEDULE I Chronology of Relevant Events and Publications. 9 August Elek & Conen " Virulence of Staphylococci for 1957 Man " (Ex D352). This article demonstrated the effect of a foreign body in lowering the bacterial inoculum. 1961 The above work was accepted (see James and MacLeod: " Induction of Staphylococcal Infections in Mice with Small Inocula Introduced on Sutures ", British J Experimental Pathology 1961 Vol XLII, No 3, pp 266-277 at 276). (Ex. P297, P2032). 1961 Townsend: " Gynaecology for Students." (Ex. D78). 1962 Jack Lippes, "A Study of Intra-Uterine Contraception: Development of a Plastic Loop" (Ex. D420 tab 25). 1962 Reid: "Septic Abortion: Abortion & Premature Labour." Obstetrics. (Ex. P387). 30 April Intrauterine contraceptive devices: "Proceedings of the 1962 conference of April 30-May 1, 1962, New York City. Excerpta Medica Foundation International Conquest Series, No. 54, New York." (Ex. D488 at D152). 30 April Tietze: " Intrauterine contraceptive rings: History & 1962 to 1 May Statistical Appraisal." Intrauterine contraceptive 1962 Devices Proceedings of the Conference, New York. (Ex. D473). 2 October "Intrauterine contraception". Proceedings of the Second 1964 International Conference, October, 2-3, 1964, New York City, sponsored by the Population Council. (Ex. D488 at D169). November Willson, Bollinger and Ledger, "The effect of an intrauterine 1964 contraceptive device on the bacterial flora of the endometrial cavity" Amer J Obstet Gynec, vol 90 (Ex. D420 tab 53). 15 November Willson, Ledger and Andros "The Effect of an 1965 Intrauterine Contraceptive Device on the Histologic Pattern of the Endometrium ", Am J Obstet Gynaecol Vol 93, No 6, pp 802-811 (Ex P297, p2319) commented that further research was needed. 1966 Lehfeldt, Hans MD, " Intrauterine Contraception: Tailed vs Tailless Devices". New York study. 1966 World Health Organisation Report, " Basic & Clinical Aspects of Intrauterine Devices." (Ex. D420, tab 55). 1967 Elstein, " Pelvic Inflammation and the Intrauterine Contraceptive Device " Proc R Soc Med 397 (Ex P5, Tab 3). This article concluded by stating: "We feel that the IUD should not be used in women who are unaware of this risk and who would like to be sure of retaining their fertility." The plaintiffs submitted that this article recognised: (i) that the diagnosis of pelvic inflammation was not a simple matter and that there were a number of symptoms, including backache, or simply feeling off colour, or pelvic discomfort that could point to pelvic inflammation. (ii) that bacteria may gain entry into the upper genital tract up the thread through the cervix. (iii) that pelvic inflammation does occur in women with an IUD. (iv) that the IUD should not be used in women who are unaware of the risk of pelvic inflammation and who would like to be sure of retaining their fertility. They further submitted that the article placed manufacturers on notice of the risk of introducing infection with the IUD string and of the risk of future infertility. 1967 Jeffcoate: " Principles of Gynaecology". (Ex. D32, D44 ). 27 February American Medical Association's Committee on Human 1967 Reproduction's report on IUDs , JAMA (Ex. D420, tab 9). 1968 World Health Organisation Technical Reports, Series No. 397: "Intrauterine devices: Physiological and clinical aspects." (Ex. D488 at D204). January Report on Intrauterine Contraception Devices by the 1968 FDA's Advisory Committee on Obstetrics and Gynaecology (Ex. P297, P1757) which stated: 1. PID and death were serious complications of IUD use. 2. The incidence of pelvic infection was higher in women wearing IUDs than in a control population without the devices. 3. Further studies with control populations are necessary before any definite conclusions can be reached. March Scott: " Critical Illnesses and Deaths associated with 1968 Intrauterine devices." (Ex. D101). "In May 1967 the Sub-Committee on Inflammation reported knowledge of 3 deaths from overwhelming infection (without uterine perforation) in association with the use of the IUD and recommended that a national survey be conducted to ascertain the magnitude of this problem. This recommendation was accepted and expanded to include critical illnesses as well as deaths from pelvic inflammatory disease and complications of uterine perforations in association with the use of an IUD." 20 May Proceedings of the 6th World Congress on Fertility and 1968 Sterility, 20-27 May, 1968. (Ex. D488 at D220). 1 August Wright and Laemmle "Acute PID in an Indigent 1968 Population " AM J Obs Gyn p 979-990 (Ex P5 Tab 4, Ex. 111). The Article reported finding that PID was five times higher in IUD users than in non-users. September Author unknown. "Side effects." American College 1968 of Obstetrics & Gynaecology Technical Bulletin on IUDs. (Ex. D474). December Ober et al, " Endometrial Morphology and Polyethylene 1968 Intrauterine Devices" , Obstetrics & Gynaecology Vol.32, No. 6 December 1968 (Ex. P297, P.2121) commented that further research was needed. March Mishell & Moyer " Association of Pelvic Inflammatory 1969 Disease with the Intrauterine Device ", Clinical Obstetrics and Gynaecology, March 1969 pp169-197 (Ex. D439 p179). The Article reported that from the time of Dr Grafenberg (in the 1920s) the " vast majority " of gynaecologists " strongly condemned " intrauterine contraception. It said " one of the reasons for this new universal condemnation was the reports of severe pelvic inflammatory disease associated with the use of intrauterine rings." 18 September Patent Application filed by Dr Zipper (Ex. P297, P.0816). 1969 The abstract described the invention as follows: "A method of contraception is disclosed characterized by providing for the presence of elemental copper or zinc in the uterine cavity. This invention is preferably practiced by wrapping a small amount of wire or foil or by placing a sleeve around a conventional intra- uterine device prior to implantation. In a modification of this method, two different metals are employed to provide improved effectiveness." October - Elstein, " The Effects of Pelvic Inflammation December 1969 Associated with the IUD, a Salpingographic Study ", Int J of Fertility, Vol 14 No 4 pp275-279 (Ex P5 Tab 5, p5; Ex. 113; Ex. P5 at P1945). This report concluded: "An increased incidence of tubal damage and occlusion has been demonstrated in women who have had symptoms and signs of pelvic inflammation treated, which occurred in association with the use of an IUD with a cervical appendage. In view of this, a plea is made that the IUD be reserved for parous women for whom the retention of their fertility potential is not vital." 1 December Jacobson & Westrom et al : "Objectivised diagnosis of 1969 acute pelvic inflammatory disease, diagnostic & prognostic value of routine laparoscopy ". American Journal of Obstetrics & Gynaecology, Vol 105, No. 7, (Ex. P227). 1970 Fox et al: "Measurement of intravaginal and intrauterine pressures during human coitus by radio-telemetry" Journal of Reproductive Fertility, 22: 243-251, 1970. (Ex. D329). 1970 Websters New 20th Century Dictionary (unabridged) 2nd Ed; Definition of "co-habit". (Ex. P390). 7 January Memorandum from Drill to Saunders (Ex P297, P0797) 1970 " Another Rush Project has developed, namely, the development of an IUD with copper". April Buchman: " A Study of the intrauterine contraceptive 1970 device with and without an extra cervical appendage or tail." Fertility & Sterility, Vol. 21, No. 4, April, 1970. (Ex. D112). 13 April Searle acquired the rights to the patents and technology 1970 relating to the use of copper in contraceptives which allowed it to market the Cu-7 from Technology Associates Inc. which had itself acquired that property from Dr. Zipper (Ex. 5, Tab 6). 11 May Memorandum from Stewart to Winter. 1970 (Ex. D447 at D254). 21 May Letter to Mr J K Butler (Searle UK) regarding the 1970 development of what was to become known as the "Mini- Gravigard" - an IUD device small enough to be suitable for nulliparous women. (Ex. D482 at D3805). July Tietze & Lewit " Studies in Family Planning, A 1970 Publication of the Population Council, Number Fifty-five. Evaluation of Intrauterine Devices: Ninth Progress Report of the Cooperative Statistical Program". (Ex D322). This report stated: "Of the 1,170 removals for medical reasons other than bleeding or pain, 340 or 72 per cent were not followed by reinsertion, and 28 per cent were followed by reinsertion of the same or another type of IUD. All of the 61 cases of carcinoma of the cervix were closed for that reason, as well as 80-90 per cent of the reported cases of removal for pelvic inflammatory disease (PID), perforation of the uterus, and various pathological conditions involving the pelvic organs. About one-third of the 840 closures were cases of PID (277 cases), and an additional one-third involved diagnoses such as vaginitis, ovarian cyst, fibromyomata, cystocele, and other genital pathology (268 cases). Except for the spirals, PID was the most frequent reason for removal for other medical reasons. The event rates for this cause, ranging from 1.3 per 100 users for the steel ring to 2.5 per 100 with the double coil, were not significantly different by device. In addition to the 329 cases of PID involving removal of the device, there were 437 cases of PID treated with the device remaining in situ, making a total of 766 cases of PID among women wearing intrauterine devices (see upper panel of Table 26). Differences between the net cumulative rates based on 766 cases of PID, by type of IUD, were also not significant. When PID rates were computed per 100 woman-years of use, according to the date the diagnosis was made, the rate for the first month was substantially higher than the rates for later months. When the first month was divided into two equal periods, the rate for the first half of the month was significantly higher than rates for any subsequent periods. Table 27 shows a steady decline in PID rates from the first half-month through six years of use." September Zipper's Report, " Contraception with use of intrauterine 1970 metals." (Ex. D489). 22 September Letter from Zipper to Dr Harry W. Rudel. 1970 (Ex. D447 at D264). 16 October Letter from Johnson, Battelle North West to Gibor. 1970 (Ex. D447 at D265). C October Dear Doctor letter from Searle asking doctors to 1970 participate in the Cu-7 IUCD study commencing 1 December, 1970. (Ex. P5, P796, P0796). 4 November Meeting of G D Searle's Copper 7 Sub-Committee. 1970 (Ex P297, P.0807). Stewart presented the form which was used to gather data for the Population Council Report (Ex D322) and suggested that it be used in the Searle clinical trial. This form contained an item relating to PID (Ex P297, P087 & P0807). 6 November Memorandum from St John to all Clinical Research 1970 Associates " Re: Crash Program Studies on the Cu-7 IUD ". (Ex. P5 Tab 7, P0808). 9 November Memorandum from Jenkins to Product Introduction 1970 Committee Managers, (Ex. P5 at P0810) Searle US stated: "Based on updated efficacy data recently received, Dr. Winter has concluded that, pending the successful completion of a short preliminary trial (to begin in December) and pending the continued success now being observed with the Copper Intrauterine Insert, the Medical Department will be ready, by April 1st, to recommend the commercial introduction of this produce. I've asked Dr. Winter to outline the data supportable claims which we will be able to make for this product at that time." 17 November Letter from Zipper to Stewart. 1970 (Ex. D447 at D269). 25 November Searle's Product Introductory Committee Meeting 1970 Minutes record as follows: "11/25/70 - Copper 7: Since our last meeting, the Medical Department has concluded that efficacy and safety data to date are adequate for medical release for marketing. We will run two short studies under our own monitorship, as fast as they can be started, and data are to be called in so that a final medical conclusion can be reached by April 1, 1971. Based on the good efficacy data presently in hand and on a prediction that the safety data we expect to derive from the short trials will permit a favorable medical conclusion, DPD is making arrangements to introduce this product by April 1, 1971. A network for product introduction is now being constructed and should be available by December 20th." December Population Report, "Intrauterine Devices: Copper IUDs: 1970 Performance to Date" . (Ex. D420 tab 34). 1 December Searle PIC Minutes. (Ex. P5, P0811). 1970 1970 "Fundamentals of Obstetrics & Gynaecology," Derek Llewellyn-Jones. (Ex. P24). Late Letter from Gibor to Doctors relating to Cu-7 1970 Clinical Trials. (Ex. P297, P0796). 15 December Drs Sedlis and Reyniak concluded that, as things then 1970 stood, observed inflammatory reaction was not to be regarded as a demonstrated disease - Amer. J. Obstetr. Gynec . (Ex. D420 tab 41). 1971 Report - " Statistics Relating to 226 Patients Reports with Symptoms of PID ". (Ex. P5, Tab 2B) 1971 Green: "Essentials of Clinical Practice." Gynaecology. (Ex. P297, P1997). 6 January Letter from Dr. W.W. Taylor to Baddeley. 1971 Taylor was a medical practitioner participating in Searle's trials. He wrote saying: (Ex. P.5, Tab 16) "The procedure and protocol will provide a minimum of information rather than a maximum of information. My assessment at the moment is that this study is not going to prove worthwhile from the standpoint of time, money and research results obtained…. The disappointment I am expressing involves only the schizophrenic approach to the present clinical testing program". 12 January Letter from Stewart to Zipper re distribution to date of Cu-7 1971 devices. (Ex. D447 at D281). 16 January Patent granted (Ex. P297, P.0816). 1971 18 January "Copper contraception - a summary of existing programs 1971 and recommendations for future studies." (Ex. D447 at D283). 26 January Memorandum from Rowe to Robertson. 1971 (Ex. P5, P0815). 10 February Memorandum from Gibor to Gwinn. 1971 (Ex. D447 at D286). 1 March Zipper et al: "Contraception through the use of 1971 intrauterine metals, I Copper as an adjunct to the T device". American Journal of Obstetrics & Gynaecology, Vol. 109. (Ex. D489). 5 March Memorandum McGowan to Jenkins (Ex. P.297, P.0817). 1971 22 March Memorandum from Helling to Buzard & Carney. 1971 (Ex. P297, P0819, D447 at D294). 23 March Press Release from Searle about launch of Cu-7 stating: 1971 "The new product is considered by Searle to be a breakthrough in intrauterine contraception." The press release also stated: "The effect of the Cu-7 is localized in the uterus, and that the contraceptive action is quickly reversible once the copper is removed." " Re: Cu-7 Breakthrough in Intrauterine Contraception ". (Ex. P.5, Tab 12).) 31 March Memorandum from Helling to Stewart et al, regarding the 1971 regulation of the Cu-7. (Ex. D447 at D298). 31 March Memorandum from Helling to O'Bleness Re: Meeting 1971 with FDA regarding preclinical (animal testing) and clinical (human testing) studies. (Ex P297, P.0820) stated: "First of all, as we expected, the decision to classify the Cu-7 as a new drug is a firm decision and not subject to appeal. However, having classified the Cu-7 as a new drug, the FDA people are in considerable discomfort having to regulate an area with which they have no experience and being threatened with the prospect of having to choke off all existing studies if regulations are to be followed to the letter. As a result, both in the preclinical and clinical areas, the FDA seems to be fairly flexible and interested in getting themselves (and us) off of a hook. Accordingly, we plan to file an IND at the earliest possible date, although this IND will probably be a fairly skimpy document and we may not have on hand all of the data needed for an IND as we normally would file one. This submission will be followed by periodic updating submissions until such time as we are ready to file a New Drug Application. Hopefully by this time, most of the data will have been submitted to the FDA in the three primary areas of concern, namely clinical, preclinical and manufacturing and control. It is my hope that if this can be successfully carried out, the NDA could be fairly rapidly approved. However, before we start counting chickens, it will be necessary for us to pay very close attention to several points. First, in order to solidify the FDA position, we would be wise to provide the FDA with every conceivable piece of data which we can beg, borrow or steal. The published literature should be freely used. Second, any submission which we make must very carefully distinguish as to the type and size of device to which the data may apply. Third, our protocols for long-term animal and human studies must be complete and precise. The co-operative approach of the FDA must not be taken as an excuse to provide the Agency with a second rate submission. In summation, it is my impression that the FDA attitude was generally one of co-operation and at this point in time I do believe that our prospects for compiling an approvable New Drug Application are quite good." 5 April Memorandum O'Bleness to Carney. (Ex. P297, P0823). 1971 6 April Memorandum from Biological Research Department 1971 to Carney. (Ex. D447 at D304). 8 April Letter from Penfold to the Department of Health. 1971 (Ex P297, P.0003) enquiring as to the Department of Health's attitude to marketing an IUD wound with copper wire. It was submitted that this document establishes that Searle was seeking to sell Cu-7s outside the United States without waiting for the results of the testing being carried out. 20 April Memorandum from Gibor to Carney, Re: Cu-7 copper 1971 blood levels. (Ex P297 P0828). This memorandum stated: "It is our understanding that the ultimate objective is to file the NDA by August 1, 1971, even if this will mean sacrificing some of the medical and scientific aspects of our studies." 1 May First Progress Report on Clinical Studies of Cu-7 1971 intrauterine device. (Ex. D447 at D311). May 1971 Quantitative composition. (Ex. D482 at D3812). May 1971 Investigator's Manual for the Cu-7 device for intrauterine contraception. (Ex. D482 at D3813). 1 May Helling to FDA. 1971 (Ex. D482 at D3811). 10 May Memorandum from Gibor to Gwinn, Re: 1971 International Marketing of the Cu-7. (Ex. P5, P0830), The memorandum set out the issues for early introduction on the international market as follows: "1. To beat the possible competition of the Copper T in a market unprotected with our US patent. 2. Association of the international introduction with the NDA may cause some concern in foreign legislation bodies as they would like to wait for the FDA decision before acceptance of the Cu-7. While our present data can support eh Cu-7 introduction scientifically, we may face some problems created by the FDA as far as foreign data are concerned. 3. A wide acceptance of the Cu-7 internationally may influence the FDA to look at it more favorably. 4. Last, but not least, it is time to see some profits on our investments in this project." The international market date was set at " no later than mid- October, 1971". 1 June Second Progress Report on Clinical Studies of Cu-7 1971 Intrauterine device. (Ex. D447 at D318). 10 June Letter from Louis Wienholt, Acting Director-General of 1971 Health, to the Managing Director, G.D. Searle (Australia) Pty Limited, regarding the marketing of Cu-7 in Australia. (Ex. P297, P0004). 10 June Handwritten memorandum from Reich to Gibor, H. St. John. 1971 (Ex. D447 at D319). Handwritten memorandum from Reich to Gibor, H. St. John. (Ex. D447 at D320). Handwritten memorandum from Reich to Gibor, H. St. John. (Ex. D447 at D321). Handwritten memorandum from Reich to Gibor, H. St. John. (Ex. D447 at D322). 11 June Handwritten memorandum from Reich to Gibor, H. St. John. 1971 (Ex. D447 at D323). 12 June Handwritten memorandum from Reich to Gibor, H. St. John. 1971 (Ex. D447 at D324). 14 July Battelle, "Volume and Copper concentration of menstrual 1971 discharge from women employed in Cu-7 and other types of contraceptives." Population Studies Center Program. (Ex. D482 at D329). 16 June Memorandum from Stewart to Winter. 1971 (Ex. D447 at D325). 26 July Memorandum from Helling to Carney. 1971 (Ex. P297, P0834). August New drug application for Cu-7 intrauterine device. 1971 (Ex. D488 at D3829, D3830, D3832 & D3833). 10 August Letter from Andrews to Department of Health. 1971 (Ex. D488 at D331). 27 August Letter Helling to FDA. 1971 (Ex. D482 at D3815). 2 September Memorandum from Stewart to Gwinn. 1971 (Ex. D447 at D334). 13 October Searle executives met with FDA. 1971 14 October Searle document being a " Rough Draft " of a memorandum 1971 relating to the meeting of 13 October 1971. (Ex. P297, P0838). This rough draft of a memo regarding the FDA rejection notes in its draft form: "The FDA position was not totally unexpected, but is rigid will remain in force unless until we are able to get it changed from top side FDA. Dr Berliner refused to exercise any kind of discretion and retreated to the regulations to solve every problem that than (sic) came up". Under " Proposed Actions " it is noted: "Explore possibilities of using the pressure from Congress or other Federal Agencies to reduce the FDA's position so that the NDA can be approved in its present form." It is also noted: "Dr Bennett indicated considerable concern about the fact that the bulk of our clinical data had been gathered…on the device which we do not intend to market, and which he maintained was different from the device which we wish to market." The final version of this document appears at P0839 without reference to any use of pressure from Congress or " Top side FDA ". 15 October Finished memorandum from Helling to O'Brien. 1971 (Ex. P297, P0839). It stated: " The FDA position was not totally unexpected, and should not be accepted as final ." 19 November Letter from Department of Health to Searle. 1971 (Ex. D488 at D336). 1972 Stewart, Gibor, Deysach & Nissen in Clinical proceedings IPPF South-East Asia and Oceania Congress. " Clinical Studies with Cu-7: a Comparison of Results in Parous and Nulliparous Women ". Australian New Zealand Obstetric & Gynaecological Journal. (Ex. P5, Tab 20, P109, P2215). 19 January Letter from Kennedy to Department of Health. 1972 (Ex. D488 at D349). 28 January Memorandum from Stewart, Gibor & Deysach to Winter. 1972 (Ex. D447 at D350). 1 April Howard J Tatum MD, PhD, "Intrauterine Contraception" 1972 New York. (Ex. D420 tab 45). 1 April Michael Burnhill: "Syndrome of progressive 1972 endometritis associated with intrauterine contraceptive devices." (Ex. P297, P1794). 20 April Memorandum from Helling to Carney: Re: Status 1972 Report of Cu-7 Project. (Ex. P297, P827). 9 June National Biological Standards Laboratory to Department 1972 of Health. (Ex. D488 at D360). 26 June Letter from Kennedy to Walsh, Commonwealth Department 1972 of Health enclosing studies in relation to Cu-7 device. (Ex. D447 at D362). Mid 1972 Cu-7 intrauterine device - Fourth Progress Report. (Ex. D447 at D363). 11 July Preliminary Report on Cu-7 IUD trial. 1972 (Ex. D447 at D365). August Bernstein et al, "Clinical Experience with the Cu-7 1972 Intrauterine Device" Contraception, Vol. 6, no.2. (Ex. D384 tab 2). 10 August Letter from Kennedy to Walsh, Department of Health. 1972 (Ex. D447 at D375). 24 August Memorandum from Thies to Buzard. 1972 (Ex. P297, P0844). 28 August Letter from A.J. Leslie, Pharmacological Section, 1972 to Assistant Director-General, Therapeutic Substances Branch, Department of Health. (Ex. D488 at D381). 11 September Letter from Tietze to Stewart " Re: Records of Study Case 1972 No. 201 attached." (Ex. P297, P0847). The Population Council provided Stewart with a copy of a follow-up form for one of the patients in their double blind study of the Cu-7 and Copper T. The Population Council was in fact using the form suggested by Stewart which was coded for PID. 20 September Battelle: "Progress Report on a scanning electron 1972 microscope study of the effects of the Cu-7 IUD on human endometrium". Population Study, Center Program. (Ex. D447 at D389). 4 October Battelle: "Corrosion phenomena on Copper wound IUDs 1972 exposed in human subjects." Population Studies Center Program. (Ex. D482 at D392). 20 October Memorandum from Geral to Attwater & Ors. 1972 (Ex. D488 at D397). 10 November Letter from Kennedy to Director-General of Health. 1972 (Ex. D447 at D404). 16 November Letter from Kennedy to Dr Walshe, Department of Health. 1972 (Ex. D447 at D406). 30 November Letter from Kennedy to Walshe regarding promotional 1972 material for Gravigard. (Ex. P8 at P1654, also D447 at D407). 6 December Recommendation by Australian Drug Evaluation Committee. 1972 (Ex. P14, Tab 2). 27 December Letter Gibor to Dahl. (Ex. P5, Tab 24). 1972 28 December Zipper to Stewart. 1972 (Ex. D447 at D414). 29 December " Cu-7 Clinical trial usage data." Table of data 1972 published in package inserts submitted to FDA, US and distributed with the device. (Ex. D472). 29 December New drug application for Cu-7 intrauterine device. 1972 (Ex. D488 at D3829, D3830, D3832 & D3833). 29 December New Drug Application with a letter from Helling to 1972 Ortiz, Re: New Drug Application for Cu-7 plus attachments. (Ex. P297, P0742). Searle stated (p.108): "(i) that pelvic inflammatory disease (PID) seemed to be second only to excessive bleeding and/or cramps as the most common disorder associated with wearing an IUD." Searle further stated (p.108, paragraph 2): "the overall incidence of symptoms suggestive of PID in the Cu-7 Study Population is 1.84%. The incidence of PID in the Cu-7 Studies is between reported incidences of PID in clinic vs private patients. This is realistic since the Cu-7 population is evenly divided into clinic and patients. Three of the investigators had extremely high incidences of PID in their studies: - from Dr. Kohl's Clinic came 41.5% of the PID cases. This clinic supplied on 2.5% of the Cu-7 population. 25 patients came from the clinics of Dr Tricomi and Dr Goldsmith in which 229 Cu-7 were studied. This suggests that clinic conditions, or living conditions of the patients visiting these clinics, contributed more to the etiology of PID than did C-7." Searle stated (p. 109 (ii): "a variety of gynaecological changes were reported by Cu-7 patients. It is not felt that any of these are attributable to the device. Approximately 1.0% of the Cu-7 wearers complain of backaches, frequently accompanied by pain or cramps in the legs especially the thighs." At p. 95: "as reported in the New Drug Application for the Cu-7, nulliparous women had significantly more complaints than multiparous women in every category except bleeding where no significant difference occurred." At p. 165 under the heading " Continuing Clinical Studies ": "….(d) patients who drop from the study to become pregnant will be followed to document the rates of fertility after removal of the Cu-7. Patients who do not become pregnant will be followed in an attempt to determine the cause of their infertility." C 1972 STIP Documents: Studies of women in which Cu-7 removed for reasons other than expulsion." NDA, Vol. 1.6 of Searle. (Ex. D470). C 1972 Typed note: "Description of the copper device." (Ex. D478). C 1972 Reports stating number of IUD patients who had symptoms that could be related to PID. (Ex. P5,P750). 1973 Golditch & Huston: "Serious pelvic infections associated with the intrauterine contraceptive device." Int. J. Fertil, 18: 156-160, 1973. (Ex. P297, P1992). 1973 Tietze & Lewit: "Recommended procedures for statistical evaluation of intrauterine contraception." (Ex. P406). January Memo from Gibor concerning Prangley, Re: Modification 1973 of Cu-7 Design to Smaller Unit. (Ex. P5, Tab 17). 1. The medical investigator complained about the " over- simplistic and superficial questionnaire" sent to him initially for the early study of this new Cu-7. 2. Gibor stated that the current design of the Cu-7 IUD " leaves much to be desired" (P.1, para.2) and it was "impractical to change to different and more detailed forms for the new studies". 3. The investigator was concerned about the dimensions of the device. He was also concerned about the string being on the outside of the inserter tube. 1 January Department of Health internal document. 1973 (Ex. D488 at D426). 3 January Searle inter-office memorandum from Kennedy to Inglis 1973 regarding classification of the Cu-7. (Ex. P297, P0021). 23 January Letter from Shearman to Dr Walsh regarding results of Cu-7 1973 clinical trials. (Ex. P5, P0297 at P0033). 7 February Extract from Minutes of 51st meeting of ADEC meeting. 1973 "Possible toxicity of the Gravigard." (Ex. P14, P1655). 9 March Letter from Soutter to Verge, Re: Copper 7 trials. 1973 (Ex. P297, P0029). This letter stated: "As you may know, we have been performing extensive clinical trials with this device in Australia and are at present collating the results obtained. The Copper-7 intrauterine device is suitable not only for multiparous but also for nulliparous patients." As at the 8 January, 1973 a total of 970 insertions had occurred with 3,020 cycles making an equivalent of 1 year of use for 251 women. 29 March Memorandum from Helling to Gibor. 1973 (Ex. D447 at D355). 2 April Memorandum from Gibor to Rees. 1973 (Ex. D447 at D450). 2 April Department of Health to Searle Australia. 1973 (Ex. D488 at D449). 10 April Letter from Helling to FDA. 1973 (Ex. D447 at D453). 17 April Letter from Soutter to Dr Lim of Balgowlah Heights 1973 Re: Gravigard (Ex. P297, P0036) stating that Gravigard has an efficacy approaching that oral contraceptives and is suitable for both nulliparous and multiparous patients. 30 April Letter from Gibor to Dr Ortiz, FDA. 1973 (Ex. D447 at D455). 1 May Memorandum from Dr Prangley, a clinical investigator 1973 (Ex. P5, P0862) complained that: "a great deal of valuable information was not obtained in the Cu-7 study due to an over-simplistic and superficial questionnaire." Gibor responded stating that "the original monitor assigned to the study insisted on minimal information (no more than a postcard) and the agony I experienced merely to include each of the questions in the present forms…as anything beyond patient I.D., dates of insertion and drop outs were considered unnecessary". (Ex. P.5, Tab 17). 22 May "Section B1 Gravigard (Cu-7)" - Searle submission on 1973 Gravigard requested by DOH; contained detailed material on Gravigard's manufacture and composition, including information on tailstrings. (Ex. P297 at P37). 31 May Letter from Kennedy to Dr Walsh, Department of Health. 1973 (Ex. D447 at D463). June Foreman: "Copper 7 intrauterine device, clinical 1973 experience." Minnesota Medicine, June 1973. (Ex D488 at D3822). 1 July The line extension proposal for the Cu-7 small. 1973 (Ex. P12, Tab 0). 5 July Letter from Ortiz, FDA to Searle. 1973 (Ex. D447 at D472). 1 August Letter from Refshauge, Department of Health to 1973 Managing Director, Searle Australia. (Ex. P297, P0041). 4 September H M Hasson, MD, Facog, "Differential Uterine 1973 Measurements Recorded In Vivo" J Obstetrics and Gynecology (Ex. D420 tab 16). 6 September Letter from John Middleton to Dr Walsh, Department of 1973 Health enclosing requested data. (Ex. D447 at D492). 14 September Memorandum from King to Agre & Ors. 1973 (Ex. P12, Tab 2). November Gibor, Deysach & Nissen: " A prognostic indicator for the 1973 successful use of the Cu-7 Intrauterine device." The Journal of Reproduction Medicine, Vol 11, No. 5, November, 1973. (Ex. P109, P1987). December Goldman: "Infected ovarian cysts and the IUD." 1973 Contraception, December 1973, Vol, 8, No. 6. (Ex. P297, P1993). 1974 Targum and Wright. (Ex. P297 at P734). 9 January Memorandum from O'Brien to Gaspar. 1974 (Ex. P8, P0884). 15 January FDA Summary of basis of approval. 1974 (Ex. P297, P0805). 29 January National Biological Standards Laboratory to 1974 Department of Health. (Ex. D488 at D551). 25 February Letter from J. Richard Craut, Director, Bureau of 1974 Drugs, FDA to G.D. Searle & Co. (Helling). (Ex. P297, P0888, D447 at D555). 1 March Tietze and Lewit, "Statistical Evaluation of Contraceptive 1974 Methods" (report testing effectiveness and acceptability of two types of contraception: IUDs and oral contraceptives), J Clinical Obstetrics and Gynaecology. (Ex. D420 tab 49). 14 March National Biological Standards laboratory to Department 1974 of Health. (Ex. D488 at D560). 18 March Letter from Middleton to Andrews. 1974 (Ex. D447 at D562). 19 March Letter from Middleton to Australian Drug Evaluation 1974 Committee. (Ex. D447 at D563). 20 March Draft advertising copy for Cu-7 (Ex. P297, P0045) stating: 1974 The Copper-7 " has no residual effect on fertility". Under "Major Benefits" it is noted that the Gravigard is "suitable for nulliparous and multiparous patients." 5 April Minutes of resolution of Australian Drug Evaluation 1974 Committee. (Ex. D447 at D569). 23 April Letter from Kennedy to Ashley, Department of Health. 1974 (Ex. D488 at D573, D447 at D574). 24 April Memorandum from Kennedy to Ferguson. 1974 (Ex. D447 at D575). 15 May Memorandum from Van de Water to Goss. 1974 (Ex. P8, P0288). 17 May National Biological Standards Laboratory to 1974 Department of Health. (Ex. D488 at D582). 20 May Memo from Charles to Helling. 1974 (Ex. P297, P0895). 23 May Letter Stewart to Mann. (Ex. P5, Tab 22). 1974 23 May Letter to Mann from Stewart. Comments on Polymer 1974 Change from Polypropylene to Polyethylene and Diameter Change to Tube. This document states that the diameter of the inserter tube was " near the limit which would be tolerated by the nulliparous cervix". (P.2). "I have a firm consensus among the users I have talked to that we must not increase the diameter of the tube. They believe that we are near the limit that will be tolerated by the nulliparous cervix and state that we would be running the risk of wiping out our main advantage over other devices by increasing the size of the tube." 28 May First Quarterly Surveillance Report. 1974 (Ex. D488 at D3837). 24 June Memo from Stewart to Jenkins Re: Proposals from 1974 Dr Rudel, Technology Associates. (Ex. P297, P0903). "Since we do not know whether the present Copper 7 model is the correct size and since it appears likely that it is not the ideal size for the small nulligravid uterus we must investigate the concept of a smaller device and possibility market two sizes." 28 June Letter from (only visible signature G H M-PS) to Loncin. 1974 Re: Gap in correlation of the activities WWPD/CMO (Ex. P297, P0904) proposals stating that: "Zipper and Mann are concerned at the possible unsuitability of the present dimensions of Cu- 7 for the never pregnant uterine cavity which is much smaller and into which it is more difficult for the long horizontal armed 7 frame to open out correctly. In view of the particular suitability of the 7 frame IUD for the nulliparous, it is obviously important to study this outlet in greater depth." July Noonan & Adams: " Gonorrhoea screening in an urban 1974 hospital family planning program." AJPH, July 1974, Vol. 64, No. 7. (Ex. D110). 16 July Memorandum from Stewart to Smith. 1974 (Ex. D482 at D595). 18 July Letter from Mann to Stewart. 1974 (Ex. D447 at D597). 23 July Letter from Battelle to Stewart. 1974 (Ex. D447 at D598). 31 July Letter from Kennedy to Australian Drug Evaluation 1974 Committee. (Ex. P297, P1658). 9 August Letter from Dr Peterson of Lancaster County to 1974 Medical Director of Searle US re retraction of string. (Ex. P8 Tab 1 at P906). A complaint from a US physician that strings from Cu-7 pulled back into the uterus and that composition of string may be the culprit. 19 August Letter from Stewart to Battelle. 1974 (Ex. D447 at D606). 19 August Letter from O'Brien to Peterson Re: letter of 1974 complaint dated 9/8/74. (Ex. P8 Tab 1 at P906). The letter of reply confirmed that other physicians had brought the problem of string retraction of the Cu-7 IUD to the notice of Searle. 21 August Letter from Stewart to Anatole Schweiger. 1974 (Ex. D447 at D608). 22 August Dr Ritman's evaluation of clinical trials of Cu-7. (Ex. D447 1974 at D609). 26 August Memorandum from O'Brien to Loncin. 1974 (Ex. D447 at D612). 29 August Critique of paper by Dr Perlmutter on the Dalkon Shield (Ex. 1974 P526). September ACOG Technical Bulletin, No. 10: " Intrauterine 1974 Device." (Ex. D476). 12 September Memo from Polli to Deysach. 1974 (Ex. P297, P0910, D447 at D618). 13 September Memorandum from O'Brien to Smith. 1974 (Ex. D447 at D620). 17 September Letter fromVance to Loncin Re: SEMS. (Ex. P8 Tab 2 at 1974 P912). 18 September Memo from Bonnie to D'Agastino Re: General 1974 Status Reports of Cu-7. (Ex. P297, P0913) In this document there is a discussion of the problems encountered with the Cu 7 Study in relation to the collection of data. It states: "The follow-up information and the drop-out information is the same physical form. This is creating confusion and I am in the process of re-doing these forms to separate the two. The drop-out form is very crammed in lay-out and contains a considerable number of redundant questions, this is confusing; this has generated much conflicting, missing and invalid data." Under " Miscellaneous Problems" it states: "One of the biggest problems is that patients move and change their names. We have had difficulty identifying the patient if she has changed her name or moved. In addition, we have seen a number of follow-up forms without the doctor's name on it…Follow-up on patients lost TO (sic) follow-ups; two problems are occurring: patient who is considered lost to follow-up, - then at some later date reappears and patient who never returns after insertion. The former will be rectified during the audit, but the latter can only be rectified by establishing a rule as to when a patient is considered LTF. This then requires some sort of document should be created to certify that the patient is actually LTF. Meanwhile, the patient is concerned active which does affect the life table numbers". Under the heading " Summary " it states: "Most of these problems have been uncovered in the last month. The Patients Status Reports gave us a look at the data in a different light but opened the proverbial, ' can of worms '. A number of problems have been solved; more surface all the time and it is taking a considerable amount of time and effort to bring the Cu-7 project into good order…" C September Snowden: "Pelvic inflammation, perforation and 1974 pregnancy outcome associated with the use of IUDs". (Ex. P297 at P2202). 26 September Letter from G.C. Liggins, Post-Graduate School of 1974 Obstetrics & Gynaecology, National Women's Hospital, Auckland to Coy. (Ex. D447 at D623). 27 September Australian Drug Evaluation Resolutions. 1974 60th Meeting Re: Cu-7 Gravigard intrauterine contraceptive device. (Ex. D447 at D3779, D626). 27 September Statement for Agenda papers for the 60th meeting of the 1974 A.D.E.C. re new drug application. (Ex. D447 at D628). 27 September Searle inter-office memo from Coy to Kennedy. 1974 (Ex. P297, P0051). 8 October Letter from Kennedy to Australian Drug Evaluation 1974 Committee. (Ex. D447 at D637). 12 October Memorandum from O'Brien to Loncin. 1974 (Ex. D447 at D640). 15 October Letter from Therapeutic Goods Branch, Department of 1974 Health to Searle Laboratories. (Ex. D447 at D643). 16 October Letter from O'Brien to Vance. 1974 (Ex. D447 at D644). 17 October Letter from Stewart to Butler. 1974 (Ex. D447 at D645). 25 October Letter from The Population Council to FDA. 1974 (Ex. D447 at D647). November US patient brochure for Cu-7. 1974 11 November Letter from Battelle to Stewart. 1974 (Ex. D447 at D654). 11 November Memo from Battelle to Berg & others including O'Brien. 1974 (Ex. P5, P0918). Consultant Visits of Drs Caldwell and Speroff (Yale Medical School). (Ex. P5, Tab 27). It was then stated that (P.8) long-term studies were needed to prove safety and efficacy. Speroff stated (P.8) that IUDs could not be recommended for patients who had not had children. 11 November Letter to Stewart (Director of Clinical Research in 1974 Obstetrics & Gynaecology, Searle) from Wheeler (Project Director, Population Studies) re report completed with goal of identifying and correcting potential IUD problems " before they grow". (Ex. D447 at D655). 15 November Memo from O'Brien to Loncin re: Cu-7 Foreign 1974 follow-up study 123. (Ex. P297, P0920). "Please note that the majority of patients have not been seen (reported on) since 1971-1972. In order to handle the unreliable data generated by such irresponsibility, we have had to go through significant expense to adjust our computer programs for these forgotten 'active' patients. More important, since these investigators signed 15 73's, they have failed to comply with the protocol. This might put any of their data in jeopardy of being rejected by the FDA. Since these patients represent 38% of long term active patients any 36 month claims for the Cu-7 efficacy and safety might be delayed for a year while acceptable data is gathered." The attached list of investigators includes a listing for Dr Newton who had 33 active patients and 10 inactive patients. 18 November Emmett to Department of Health. 1974 (Ex. D447 at D657). 20 November Letter from Emmett to Director-General of Health 1974 regarding amended Gravigard package insert. (Ex. P297 at P56). 27 November Third Quarterly Report. 1974 (Ex. D488 at D3839). December FDA Drug Bulletin. 1974 (Ex. P297, P0923). 2 December Memorandum from Kaufman to Hollis. 1974 (Ex. D447 at D664). 6 December Letter from Middleton to Dr Ashley, Department of 1974 Health. (Ex. D447 at D668). 9 December Letter from Middleton to Department of Health. 1974 (Ex. D447 at D669). 12 December Ritman: Handwritten note headed "Gravigard". 1974 (Ex. D447 at D3780). 16 December Emmett to Department of Health. 1974 (Ex. D447 at D672). 17 December Letter from Director-General of Health to Searle 1974 Australia Pty Limited. (Ex. P297, P1663). 17 December Letter from Howells to Managing Director, Searle. 1974 Re: Australian Drug Evaluation Committee's consideration of the application for approval for importation and general marketing of Gravigard- Cu-7 device. (Ex. D447 at D675). 23 December Letter from Emmett to Director-General of Health. 1974 Re: Enclosure of further promotional pieces for the Gravigard IUD and for the Department's approval. (Ex. D447 at D676, D674). 1974 Targum & Wright: "Association of intrauterine device and pelvic inflammatory disease: A retrospective pilot study." American Journal of Epidemiology (Ex. D114). 27 December Memorandum from Stewart to Smith. 1974 (Ex. D447 at D677). 30 December Memorandum from Kaufman to Sales Representatives. 1974 (Ex. D447 at D679). 1975 Combined Bangkok Hospital Group & Wright, Population Council, Bangkok. " Unsuspected pelvic infection discovered at tubal ligation: relationship to use of intrauterine contraception." (Ex. P483). 1975 Lippes. (Ex. P5 at P927). 1975 Eschenbach & Holmes: "Acute Pelvic Inflammatory Disease: Current concepts of pathogenesis, aetiology, and management." Clinical Obstetrics & Gynaecology, Vol. 18, No. 1, March 1975. (Ex. P108, Tab 3). 1975 H. Zuckerman & Ors. " Anti-bacterial activity of human cervical mucus." Gynecol. Invest. Vol. 6, 1975 (Ex. D193). 1975 Phaosavasdi & Ors: "Pelvic Inflammatory Disease in contraceptive acceptors disclosed at transvaginal tubal sterilisation." (Ex. P297, P2141). 1975 Jain: "Comparative performance of three types of IUDs in the United States..: (Ex. D447 at D689). 1975 Worldwide: Gravigard Marketing Profile - 1975 by Donahue. This document provides a useful history to the development and marketing of the Gravigard. The product was sold outside the USA through pharmaceutical wholesalers to physicians. It stated (p.15) that the promotional material used the "creative" concept to create an image Cu-7 as a contraceptive device rather than the "usual highly suspect stereotyped IUD". It stated that the nulliparous marketing aspect of Searle's promotion was in place by at least 1974 (p 16) and that the Cu-7 was second only to the pill in its efficacy (p 18). It stated Searle targeted a small group of "IUD supporter" physicians (usually gynaecologists) and used them as an existing base to key the initial promotion. Searle advised its sales staff to use this "key" concept to overcome any resistance by inexperienced physicians to using Cu-7. Searle's strategy was to promote Cu-7 for all women of child-bearing age including nulliparous (p.23), and it decided to "stress nullip use" in its 1975 tactics (p.24). January Huber et al, "IUDs Reassessed - A Decade of Experience" , 1975 Population Reports - Intrauterine Devices. (Ex. D420 tab 17). 1 January Australian Gravigard A1 product insert distribution starts 1975 1 January Report titled Searle Laboratories Marketing Plan 1975 1975 Australia. (Ex. P5, Tab 36). Under " Promotional Methods" it noted the "increased demand for continuous medical education". Under qualitative objectives it noted: "(a) to gain maximum doctor awareness of Cu-7 as a new and unique concept in contraception and enhance the image of Searle as a research company." Under " Medical/Marketing Action Plans" it noted: "by holding a half/day symposia to be published as a supplement to the Medical Journal of Australia we will ensure published local clinical data on Gravigard is disseminated to the medical profession. ($5,500 allocated in medical budget)". Further it noted under " Action Plan" by continuing current Cu-7 Trials. ($500 allocated in medical budget). Searle have said that: "Appropriate and proper information and adequate warnings were available to the plaintiffs' medical care providers." In response to particulars the defendants stated "Information concerning the safety and efficacy of intrauterine contraception as acquired by the medical care providers in the course of their studies, clinical practise, their review of medical and scientific journals, attendances of conferences, symposia and discussions with other medical care providers." 3 January Letter from Emmett to Hodge, Re: Gravigard string is a 1975 monofilament cord. (Ex. P8 Tab 2 atP66; D477 at D712). Hodge confirmed that the cord or string used in the Gravigard was a monofilament cord. 13 January Letter from Emmett to Department of Health. 1975 (Ex. D447 at D716). 17 January Memo from Ericson to " Those Present " including O'Brien. 1975 (Ex. P8, Tab 1). A group meeting of Searle's employees to exchange information on Cu-7 string breakage and disappearance notes that the string used in the investigation was different to the string used in production. 16 January Letter from Ericson to FDA. 1975 (Ex. D447 at D719). 28 January Handwritten note describing promotional material 1975 and booklets. (Ex. D447 at D3781). 30 January Letter from Middleton to Ashley, Department of Health. 1975 (Ex. D447 at D725). 1 February " The intrauterine device as a cause of septic abortion ." 1975 (Ex. D33). 6 February Dr Truman W. Grauel, Women's Clinic, PA to Paullin. 1975 (Ex. P8, P0931). 7 February Article/Lecture " Development of Copper IUDs " by O'Brien. 1975 (Ex. P.297 at P933). 13 February Letter from Altman to Department to Health. 1975 (Ex. D447 at D732). 17 February Tatum et al: "Dalkon Shield controversy, structural 1975 and bacteriological studies of IUD tails." JAMA, February 17, 1975, Vol. T231, No. 7. (Ex. D488 at D733). 20 February Letter from Emco, Engineered Monofilm Corporation 1975 to Cribb. (Ex. D447 at D735). 21 February O'Brien to Dr Grauel MD (Women's Clinic, Kansas), 1975 concerning recoiling of Cu-7 string. (Ex. P8, P0934). 25 February Fourth Quarterly Report. 1975 (Ex. D488 at D3840). 4 March Letter from Searle to FDA. 1975 (Ex. D447 at D744). 13 March Letter from Emco to Cribb. 1975 (Ex. D447 at D747). 13 March Memorandum from Stewart to Cribb. 1975 (Ex. D447 at D748). 18 March Memorandum from Cribb to Charles & Ors. 1975 (Ex. D447 at D749). 19 March Letter from Altman to Department of Health. 1975 (Ex. D447 at D750). 21 March O'Brien to Dr H. K. Moore. 1975 (Ex. P8, P0936). 26 March Memo from O'Brien to Stewart. Re: Telephone 1975 conversation with Dr Freeman - Memory. (Ex. P8, Tab 1; P8, P0937). Freeman was a Cu-7 Investigator, who studied the phenomenon of disappearing IUD strings with a hysteroscope. He noted that the IUD string assumed the shape of the string as it is packaged. The explanation for "memory" by Freeman was to be published in Contraception and presented to the Planned Parenthood Physicians in Los Angeles. 9 April Memorandum from Ericson to Charles & Head. 1975 (Ex. D447 at D762). 10 April Memorandum from Klimstra to McConnell relating to 1975 liability and responsibility for safety data. (Ex. P5, P0939). 14 April Memorandum from Charles to Ericson. 1975 (Ex. D447 at D763). 15 April Memo from Donahoe to Aquirre & others; Re: 1975 Gravigard Marketing Profile 1975. (Ex. P297, P0940). This Cu-7 Marketing Profile was distributed world-wide including to three recipients in Australia. It states in part: "Cu-7 continues to offer significant advantages over the Copper-T with its smaller insertion tube providing ease of insertion particularly for nullips. A low incidence of removal and excellent efficacy rates are strong factors for the growth of the product…. We continue to support the marketing strategy promoting the Cu-7 as a contraceptive rather than an IUD. Most markets report this approach has helped to establish the Cu-7 as a contraceptive apart from the IUD image and has allowed for a more unbiased introduction for the product." 16 April Memorandum from Emco to Cribb. 1975 (Ex. D447 at D765). 21 April Memo from Deysach to Rees, Re: Uterine Length and Side 1975 Effect Incidence + Attached Cu-7 Admission & Follow-up Forms. (Ex. P5, Tab 18, P0941). 1. This document stated that "little side effect information is asked for" in the admission and follow-up forms used in the International Copper-7 IUCD Study. 2. The follow-up forms for the clinical trial did not provide that PID be coded as an item by the investigators. 1 May Letter from Emco to Cribb. 1975 (Ex. D447 at D772). 12 May Letter from O'Brien to Coy. 1975 (Ex. D447 at D776). 16 May Letter from All States Design & Development Co. 1975 to Cribb. (Ex. D447 at D778). 19 May Insertion for Ms Lee. 1975 20 May Letter from Head to FDA. 1975 (Ex. D447 at D779). 4 June Letter from Emmett to Department of Health. 1975 (Ex. D447 at D789). 19 June Memo from Blake to Donahue. (Ex. P5, Tab 31). 1975 cc. Dr. O'Brien. (Ex. P297, P0946). "Doctors here have an interest in fitting nullip patients. Our market research data shows that approximately 20-25% of fittings of the current Gravigard are in nullips. Opinions on PID vary widely. A recent report described the incidence of PID in nullips as 'alarmingly high' (FPA Newsletter No. 55) with Gravigard, but most doctors probably consider PID to be unrelated to IUD usage. The diversity is confirmed by the fact that some doctors fit Gravigard exclusively in nullips whereas others fit only multips. If the new special device performed better in nullips than the present device it would largely supplant the present device in this segment of the market." 19 June Letter from Blake to Mr Martin Re: Gravigard 1975 Special Device Doctors have interest in fitting nullips. Reviewed by O'Brien. (Ex. P297, P0946). "Doctors here have an interest in fitting nullip patients. Our market research data shows that approximately 20-25% of fittings of the current Gravigard are in nullips. Opinions on PID vary widely. A recent report described the incidence of PID in nullips as 'alarmingly high' (FPA Newsletter No. 55) with Gravigard, but most doctors probably consider PID to be unrelated to IUD usage." 23 June Handwritten note on Gravigard Product Kit. 1975 (Ex. D447 at D3782). 30 June Letter from Department of Health to Searle. 1975 (Ex. D447 at D797). July Lippes: "Infection and the IUD: a preliminary report." 1975 Contraception, July 1975, Vol. 12, No. 1. (Ex. D488 at D3823). July 1975 FDA Report on rationales for Cu-7. (Ex. P12, P0948). 24 July Eschenbach et al, "Cultures and Serologic Tests" The New 1975 England Journal of Medicine, Vol.293 (Ex. D108 tab 4, p170). 28 July Memorandum from Mann to Area Medical Directors. 1975 (Ex. P297, P0955). 31 July Letter from Mann to Cohen, Re: Cu-7/Gravigard - 1975 FPA/Exeter Trial. (Ex. P297, P0956). "If and when we proceed with a nulliparous Cu-7, we are going to have a difficult enough job overcoming resistance to insertion in the nullip due to fears of infection/infertility, and reports such as the Exeter study: The FPA/Exeter trial by emphasising the double infection rate of nullip against multip, will in no way be helpful particularly….the difference includes incidence rates PID between the parous and nulliparous women…the Exeter report does not even approach statistical significance." Under the heading " Points for Clarification" the author notes: "'Field Trial' - the implication here is that this trial is so much more worthwhile than the pharmaceutical company base trails…in that the admission criteria applied had been much wider and more representative of normal clinical practise. Very largely, the criteria will have had to be the same, …and this leaves out a few such as menorrhagia, particularly when using other devices, patients who have already rejected an IUD and the point they have about not cohabiting at the time of admission to the study." "I am always conscious that we are dealing with a sociologist with medical aspirations, and not with a doctor. I'm also conscious that this trial is essentially [worked] by FPA doctors and it is only the statistical correlation and the odd spot of useless guff about patient types and social class that justifies a sociologist's interest." August Review and analysis of the scientific and clinical data on 1975 the safety, efficacy, adverse reactions, biological action, utilisation and design of intrauterine devices -- Battelle - North West prepared for FDA. (Ex. P297, P0957). 11 August Review and analysis of scientific & clinical data on the 1975 safety, efficacy, adverse reactions, biological action, utilisation and design of intrauterine devices. Battelle Memorial Institute. (Ex. D447 at D819). 14 August Letter from Department of Health to Searle. 1975 (Ex. D447 at D822). 26 August Letter from Dr Ortiz, Bureau of Drugs to Searle. 1975 (Ex. D447 at D824). 17 September First semi-annual Surveillance Report (partial) to be 1975 provided. (Ex. D447 at D829, D488 at D3841). 22 September Memorandum from Agre to Mann. 1975 (Ex. D447 at D831). 23 September Letter from Altman to Department of Health. 1975 (Ex. D447 at D832). 8 October Memo from Stewart to Inglis, Memo: Proposed 1975 Comparative IUD Trial in Kuala Lumpur. (Ex. P5, Tab 37, P0963). Stewart stated that Searle's products seem to "come out second best in such trials through no fault of the device." 9 October Letter from O'Brien to Dr Winkelbauer of Brunswick 1975 (Ex. P297, P0964) Re: Inquiry about Cu-7s for nulliparous patients. "On my travels throughout the country I have been repeatedly told that the Cu-7 is a nulliparous device. I do realise that a small segment of the nulliparous population requires an even smaller device." 15 October Memo from Mann to Inglis Re: Copper-7 Comparative 1975 IUD trials. (Ex. P5, Tab 30, P0966). 16 October Memorandum from Vance to O'Brien. 1975 (Ex. P297, P0968). 22 October Memorandum from O'Brien to Vance. 1975 (Ex. P297, P0972). 23 October Memorandum from Cribb to Bladen. 1975 (Ex. D447 at D848). 28 October Letter from O'Brien to Hewell S Brown of Texas, (Ex. P247, P.0974). 1975 Re: Brown 3/10/75 Report. O'Brien stated: "The subject of PID is a complex one…. Two physicians will make the same diagnosis in patients with completely different findings. For example, one physician might limit the diagnosis to people with pelvic tenderness, pelvic masses and fever while another will label any patient who complains of pain on pelvic examination as PID. Since physicians do not always define what they mean by PID, it is difficult to collect information. While Dr Eschenbach's suggestion is well taken, it would be hard to implement. His opinion that all IUDs cause PID is shared by others…" 3 November Letter from Vance to Inglis, Re: 100% incidence in 1975 salpingitis in women with IUDs in utero. (Ex. P297, P0975). Inglis is advised that a paper will soon be published in the USA: "The paper is apparently from an obstetrician at the University of Washington in Seattle. ….However, the author, in tubal biopsies, has apparently found a 100% incidence of salpingitis in women with IUDs in uteri." 6 November Amended Gravigard booklet. 1975 (Ex. D447 at D833). 7 November Memo from O'Brien to Altman, Re: Gravigard Trial 1975 Report of 3 November, 1975. (Ex. P297, P.0976). With regard to the reporting of information from the Searle International Clinical Trial O'Brien stated: "…However, because of bad writing, misspelling and local acronyms we cannot use these comments as a basis for retrieval of specific items such as infection. No one at Searle who is currently working on the Gravigard Project was associated with the original design of the code sheet, so I cannot offer Dr Mather an intelligent answer to the question of coding infections as a specific item… We are in the process of analysing our infections. This is done by listing all the comments and then doing a hand tally… Previous analysis of the data for infection has indicated an incidence of less than 1%." 11 November From Vincent to Judy Chock, Mt. Sinai Hospital. 1975 (Ex. P297, P0977). 13 November Letter form Altman to Department of Health. 1975 (Ex. D488 at D854). 1 December Letter from Darragh to Dear Doctor, (Ex. P297, P.0081). 1975 This is an example of statements made to doctors by way of bulk mailing of " Dear Doctor " letters. This letter stated: " It is suitable for both nulliparous and multiparous patients." 3 December Promotional Material entitled " Gravigard Interview Aid ". 1975 (Ex. P297, P.0082). advertising copy. This copy for a Gravigard Visual Aid notes " Suitable for both Parous and Nulliparous Patients :- Nulliparous patients have traditionally been regarded as unsuitable for IUD contraception. Gravigard has proven of benefit to these patients, providing effective contraception and a low rate of side-effects - the small size of Gravigard also aids easy insertion in these patients." 5 December Memo from O'Brien to Agre, Re: Small Cu-7 line 1975 extension proposal. (Ex. P197, P.0297). "1. The Cu-7 is considered at the present time by physicians as a nulliparous device. 2. As indicated in the proposal there are many white female nullipara with a uterine cavity that is too small to accept the Cu-7. 3. Clinically, physicians feel that a total cervical fundal length of 6.5cm is the minimum for successful insertion. 4. A comparative clinical trial on a large random sample…would take about 12,000 patients and cost over $2 million". 9 December Memo from Smith to Ramseier, Re: Small Cu-7. 1975 (Ex. P297, P0981). With regard to the proposed small Cu-7 Smith wrote: "…We agree in principle to a smaller Cu-7 for the nulliparous female with a small uterine cavity… I would think the time and expense of carrying out the necessary study would be the deciding factor." 10 December Letter from Emmett to Director-General of Health, 1975 Commonwealth Department of Health. Re: Reply to letter regarding approval to market Gravigard IUD. (Ex. D447 at D3783). 11 December Memo from McConnell to D. Searle, Chairman & 1975 C.E.O. of Board Re: Request for additional relevant information regarding the Searle laboratories operation be provided to the FDA. (Ex. P297, P0982). This memo notes in relation to competing demands for the path/tox resources: "…Where the senior personnel resources [have] available for marketed product support projects only by 'stretch performance in response to crisis-type situations'…. My most assertive request for higher priorities for marketed product support activity is evidenced in the six page memo (attached) submitted to P. Klimstra, Director of Pre-Clinical R&D, dated 26 April 1974. This inventory of the animal safety study status of each marketed drug product was requested by Dr Klimstra… The memo continues to address each Searle drug product and indicate the relative amount and utility of animal safety data on each. …The only response which I received to this memo was from SLEC via Dr Klimstra, - an oral request to - destroy your copy of this memo. ...Now I insist that the 'when' be related to the FDA in its full and proper perspective within the Searle Laboratories Organisation. This matter should be communicated to Mr Brodsky, FDA by Drs Moe and Klimstra and I insist on being present throughout the entire meeting." 17 December Letter from Hardin E. Olson, MD to Medical Director, 1975 Searle Laboratories. (Ex. P297, P0984). 18 December Handwritten file note. Gravigard Re: Package 1975 inserts and Dear Doctor letter. (Ex. D447 at D3784). 1976 Vessey et al: "A long term follow-up study of women using different methods of contraception - an interim report." Journal J. Biosoc Sci. (1976) 8, 373-427. (Ex. P297, P2287). 9 January Letter from O'Brien to Olson. 1976 (Ex. P297, P0985). 19 February Letter from O'Brien to Foreman, (Ex. P5, Tab 48). 1976 Re: physician making adverse statements concerning Cu-7 and high infection rates and inadequate size relative to uterus. Searle stated (P.1, para 2) that its PID rate was less than 1% and that there had been no reports of proven septic abortion among 16,000 patients. 22 January Letter from Altman to Department of Health. 1976 (Ex. D447 at D911). 28 January Memorandum from Altman to Jarratt. 1976 (Ex. D447 at D915). 13 February Letter from Willson, Department of Health to Searle. 1976 (Ex. D447 at D919). March B Simcock, "The Role of the Intrauterine Device in 1976 Contraceptive Practice", Australian Family Physician, vol 5 (Ex. D34). March Eschenbach: Acute pelvic inflammatory disease: 1976 aetiology, risk factors, pathogenesis." Clinical Obstetrics & Gynaecology, Vol. 19, No. 1, March 1976. (Ex. P108, Tab 5). 9 March Letter from O'Brien to Brown. 1976 (Ex. D447 at D931). 15 March Memorandum from O'Brien to Kaufman. 1976 (D447 at D940). 15 March Handwritten note stating in general that there are no 1976 objections to the alterations proposed by Department of Health to promotional material. (Ex. D447 at D3785). 17 March Memo from O'Brien to Altman, Re: Dr Simcock's 1976 Loss to Follow-up Patients. (Ex. P297, P3307; Ex. P464). "The life table computes the rates on the cycles on which the patient is declared loss to follow-up rather than on the cycle on which they were last seen (or close to that cycle). These low rates for three years reflect that the fact that many of the lost to follow-up patients were not declared lost to follow-up until after three years (i.e. in cycles 36 or higher)." 18 March Memo from O'Brien to Stewart (Ex. P297, P.0991), 1976 Re: Trip Report of March 14-16, 1976 Washington DC. This memo relates to a meeting between various representatives of other intrauterine device manufacturers. "The purpose of this meeting was to see if a consensus existed considering the proposed product development protocol for IUDs. The chief difference was Searle's objection to the requirement for comparative trials." The memo also reported on a meeting at the FDA on March 15 and 16, 1976: "Dr. Bennett from the Bureau of Drugs…emphasised that the Bureau was most interested in estimating how the drug would work in the real world rather than just within the confines of a highly controlled clinical trial done by super specialist. Mr Sivin of the World Population Council stressed the importance of non-observation, ie, lost to follow-up patients and the bias they introduce into a study". 19 March Letter from O'Brien to Jerome H. Blumen. 1976 (Ex. P297, P0992). March Simcock: "The role of the intrauterine device in 1976 contraceptive practise ." Australian Family Physician , Vol. 5, March, 1976. (Ex. D34 ) April Smith & Soderstrom: "Salpingitis: A frequent response 1976 to intrauterine contraception." Journal of Reproductive Medicine, Vol. 16, No. 4, April 1976. (Ex. P297, P2200). 6 April 1st insertion for Mrs Southren 1976 12 April Inter-office memo from Coy of G.D. Searle to O'Brien 1976 "Malaysian Gravigard Study." (Ex. P448). 12 April Letter from Emmett, Searle to Director-General of 1976 Health. "Gravigard trial drop-out rate per 100 women for the first year." (Ex. P14, P97). 14 April Letter from Department of Health to Searle. 1976 (Ex. D447 at D972). 14 April File Note re Cu-7 package insert. 1976 (Ex. D447 at D973). 23 April Letter from Altman to Department of Health. 1976 (Ex. D447 at D978). 26 April Faulkner & Ory: " Intrauterine devices and acute 1976 pelvic inflammatory disease ." JAMA, April 26, 1976, Vol. 235, No. 17. (Ex. D115). 27 April Statement of Dr Ritman to ADEC, regarding efficacy status 1976 of the Gravigard. (Ex D447 at D3786). 27 April Ritman: Confidential document. Gravigard Cu-7 IUD. 1976 (Ex. D447 at D3787). 1 May Mead, Beecham & Maeck: "Incidence of infections 1976 associated with the intrauterine contraceptive device in an isolated community". American Journal of Obstetrics & Gynaecology, Vol. 125, No. 1, P79. (Ex. P297, P2098). 21 May Letter from Assistant Director-General, Therapeutic 1976 Goods Branch to Managing Director, Searle Laboratories Re: Telephone conversation with Atkinson re revised package insert for the Gravigard. (Ex. D447 at D3787). June " Intrauterine Devices". ACOG Technical Bulletin, 1976 No. 40. (Ex. P395). 9 June Searle Laboratories QC No. D-1186 Sheet - some 1976 strings are fibrous 2-5, 11-17, 19-24. (Ex. P297, P3303). This is a quality control department document and stated: "Because 19 spools out of the 24 showed surface fibres, I would suspect that portions of the other spool might also be unsatisfactory even though the piece the lab got is OK." 28 June Memorandum from Robin to Gerel. 1976 (Ex. D447 at D1020). July Propper & Moore, " Association of E. coli sepsis 1976 in Pregnancy with a Cu-7 intrauterine device in place." Obstetrics & Gynaecology, Vol. 48, No. 1 ( July 1976). (Ex. P297, Vol. 17A). 12 July Memo from Darragh to Jarratt; 1976 Re: Gravigard Film Introduction. (Ex. P297, P0112). This was an internal memo which discussed the Gravigard film and Barbara's (presumably Dr Simcock's) commentary on it. The plaintiffs submitted that Searle sought to influence Dr Simcock to make statements about safety of the Cu-7. 15 July Hallatt: " Ectopic pregnancy associated with intrauterine 1976 device: A study of 70 cases." American Journal of Obstetrics & Gynaecology, Vol. 125, No. 6. (Ex. D477). 15 July Letter from Altman to Department of Health. 1976 (Ex. D447 at D1029). 16 July Confidential handwritten file note: Cu-7 Product 1976 Information re amendment to package inserts. (Ex. D447 at D3789). 28 July Letter from Lynch to FDA. 1976 (Ex. D447 at D1058). 31 July Westrom & Ors. " The risk of pelvic inflammatory 1976 " Disease in women using intrauterine contraceptive Devices as compared to non-users." The Lancet, July 31, 1976. (Ex. D46). 1976 Insertion for Ms Lane (?) 2 August " IUD in utero can cause abortion in second trimester". 1976 Modern Medicine in Australia, April, 1977. (Ex. D36). 21 August The Medical Journal of Australia, August 21, 1976, p297. 1976 A Three-Year Trial of the Gravigard (Cu-7) Intrauterine Device. Barbara W.Simcock. (Ex. D20). "One of the most noteworthy features of this new IUCD is the extreme ease of its insertion in both nulliparous and multiparous patients." 21 August Kemp: " Four years experience with Gravigard in 1976 nulliparous women." Medical Journal of Australia, August, 21, 1976, p.295. (Ex. D21). 24 August Searle Laboratories AC No. D-1331 Sheet 1976 (Ex. P297, P3302) Re: All strings are smooth except Nos. 31, 34, 43, 45 and 47. This quality control department document notes that: "All strings are SMO (presumably smooth) except Nos. 31, 34, 43, 45 and 47 which are fibrous." 25 August Memorandum from Kaufman to all US Searle 1976 Representatives, all US District Sales Managers, all US Regional Sales Directors. (Ex. P297, P1004). 30 August Letter from Altman to Dr G. Wright regarding infromation on 1976 Gravigard and ectopic pregnancies and infection (Ex. P297 at P0125; also D447 at D1085). 2 September Letter from Department of Health to Searle. 1976 (Ex. D447 at D1094). 9 September Letter from Dr Ortiz, FDA to Searle. 1976 (Ex. D447 at D1100). 28 September Guidelines for Evaluation of Non-Drug IUDs adopted 1976 by Ob-Gyn Device Classification Panel. (Ex. P297, P3318). These objectives stated: "The objective of pre-clinical and clinical investigations is to assess the relative safety of the new IUD. Its effectiveness in preventing pregnancy, its risks or undesirable effects and the relative relationship of these assessments." At P.9 it is stated: "Data needed to record and analyse for evaluation of safety and effectiveness:…4. The infection rate (estimated to be 2.5-5% for marketed non-drug IUDs)." At P.11: "The new device must be compared in patients of equal age, parity and marital status and randomized studies to a non-drug IUD that is currently available on the market, appropriate to the type of patient for whom the new IUD is intended (eg nulligravida or multipara)…The analysis of this study should be done by life table method with a minimal number of patients lost to follow-up not to exceed approximately 10%". At P.12: "Post-marketing surveillance is needed for a newly marketed IUD for the following reasons… b. the need to know numerator and denominator use data on all marketed IUDs. c. the need to survey the following: 1. infection." 29 October Australian Gravigard A3/A4 product insert distribution starts. 1976 3 November Letter Altman to Department of Health. 1976 (Ex. D447 at D1123). December Gupta et al, "A Statistical Study of the Copper T and 1976 Copper 7 Intrauterine Devices" Contraception, Vol. 14 no.6 (Ex. D420 tab 15). 6 December Letter from Nils Asmussen to Loncin, cc: Inglis, 1976 encl. Westrom's doctor's thesis. (Ex. P297, P1015). This letter stated that Searle was aware of published literature regarding the increased risk for nullipara of contracting salpingitis with IUDs. 1976 Patient information pamphlet compiled by Royal College of Obstetricians & Gynaecologists and Royal Australian College of General Practitioners. (Ex. D55). 1977 Eschenbach et al. 1 January Snowden, Williams & Hawkins: Brochure for "The IUD: A 1977 Practical Guide" (Ex. P297 at P0133). 11 January From Ballantyne to Mrs Rosemary Stevens. 1977 (Ex. P297, P1019). 27 January Letter from Jarratt to Department of Health. 1977 (Ex. D447 at D1183). 18 January Australian Department of Health Evaluation Cu-7. 1977 Report on post-marketing studies. (Ex. D447 at D1176). February Larsson & Wennergren: "Investigation of a copper 1977 intrauterine device (Cu-IUD), the possible effect on frequency and healing of pelvic inflammatory disease." Contraception, 1977, Vol. 15, No. 2. (Ex. D488 at D1185). 25 February Memo from Peddie to Inglis dated 25 February, 1977. 1977 "PID & ectopic pregnancies with Gravigard" (Ex. P5, Tab 40), "Our marketing group is receiving an increasing number of enquiries in relation to the above topics. Our response to doctors has usually been to reassure them that there is no increased incidence of PID with Gravigard and no increased occurrence of ectopic pregnancies. However, we have never supported the statements with any published data. Recent publications have made our response to these enquiries more difficult and I will appreciate comment from you as to our official position on this topic. It would seem from the results from Westrom et al (1976) that in general clinical use, Gravigard may be associated with an increased incidence of PID. Taking the argument further and relying on the results of Hallett (1976) we may also expect a slightly increased incidence of ectopic pregnancies. Can we quote the figures used by Burke (1977) or should we quote results from our own international study where ectopic pregnancies occurred at a rate of 3.8% of total pregnancies. I have not seen the report by Beral, in British Journal of Obstetrics & Gynaecology (1975) vol. 82 p.775, but he apparently singles out the Gravigard IUD as possibly causing a greater increase in ectopic pregnancies than other 'coils'. We certainly require a carefully prepared response to this type of enquiry in future and I look forward to any assistance you may be able to give." 2 March Memo from O'Brien to Peddie, Re: Your memo of 1977 25 February 1977 - Process Dr Black's unofficial data, ectopics, diagnosis of PID. (Ex. P5 at P1023; P297 at P145; D447 at D1213). March Modern Medicine in Australia. (Ex. D47). 1977 7 March Annual Surveillance Report. 1977 (Ex. D488 at D3843). April Memo from Donahue to Gravigard List, (Ex. P297, P1027). 1977 Re: Concerning the 1977 Gravigard Marketing overview plus Gravigard International product overview. The 1977 Gravigard marketing overview stated: "Gravigard has unique design, permits small size for nullips." Under " Opportunities " it is noted at page 103553. "Gravigard is only acceptable IUD for nullips." 1 April Market plan for Cu-7/Gravigard titled Gravigard International 1977 Product Overview by E J Donahoe. (Ex. P297, P0147). This document set out the promotional objectives for Searle marketing world-wide. The copy points noted on P.20 include " only really satisfactory contraceptive device for the nullipara, low incidence of removal for medical reasons and top efficiency." 7 April Letter from Dr Hardin E. Olson to O'Brien. 1977 (Ex. P8, P1028). 15 April Letter from O'Brien to Dr Hardin Olson of Minneapolis 1977 regarding string memory of Cu-7. (Ex. P8 Tab 1 at P1030). "The memory of our string has been well documented by hysteroscopy studies. This is a characteristic of the material used." 18 April Protocol Aus G1/77 for Mini Clinical Trials. 1977 (Ex. P297, P0148; Ex. P15 tab 1). 20 April Insertion for Ms Orders. 1977 6 June "Obstetrical-Gynaecological device classification". 1977 (Ex. P228, Tab 13). 6 June FDA Advisory Committee on Obstetrics & Gynaecology 1977 meeting. O'Brien attended. This meeting was held to analyse data which had already appeared in medical literature relating to IUDs, PID and infertility. O'Brien reported the proceedings to his colleague by a memorandum dated 7 June, 1977 (Ex. P5, Tab 42). O'Brien reported in effect that each speaker addressed the link between IUDs and PID and PIDs adverse effect on future fertility and stated: "I have reached the conclusion that the FDA will consider the IUD to be a cause of salpingitis with possible adverse effects on the future fertility of the wearer and I suggest that we have a meeting of legal, regulatory, clinical and marketing to determine if we should take any action now about our labelling. We might be at a medico-legal disadvantage if we do not make a stronger warning. The group considered highest risk for infection and subsequent loss of fertility is that consisting of nulligravida, under 26, with multiple sex partners. It seems to be that the identification of such a group by the FDA, mishandled by the lay press, might have an impact on our marketing strategy." The committee had substantial evidence that a problem existed and concluded that 1. It was important that steps be taken to protect users by 1.1 warning patients and the medical profession that a problem does exist and instructing them in recognising the problem early enough so that it may be treated. 1.2 avoiding use of IUDs where possible in women most susceptible to PID, the young, the nullipara and those with multiple sexual partners. 2. There should be additional research aimed at: 2.1 Discovering the incidence of infertility in women who have discontinued IUDs for medical reasons. 2.2 Finding better methods for prevention or treatment of those conditions. 16 June Compliance Committee submissions Form. 1977 (Ex. P297, P1051). Re: Revised Cu-7 full disclosure. Labelling changes were proposed within Searle to take into account the increased risk of PID associated with the use of IUDs as well as the higher risk to nulliparous women. (Ex. P297, P.1051). The proposed labelling changes were ' watered down ' by Searle's Compliance Committee. Searle continued to aggressively market Cu-7s and later the Minis to young nulliparous women. (Ex. P297, P.1076). The changes which were made in the product literature were given to physicians and patients in the USA but the position did not change in Australia. 20 June Letter from Lynch to Sobell, Re: Dr Baxter's 1977 complaint of string retraction in patients. (Ex. P8 Tab 1 at P1053). Searle stated that only 2 cases of string " memory" problems were to be found in their files and denied that there were any design or packaging problems with the Cu-7 IUD (Para 2). 23 June Memorandum from D'Agostino to Brown, 1977 (Ex. P297, P1055). 27 June Gravigard package insert. 1977 (Ex. D447 at D1291). 29 June Letter from Emco to Krzeminski. 1977 (Ex. D447 at D1263). 30 June Letter from Altman to Crawford, Department of Health, 1973 Re: Gravigard-P Clinical Trial application. (Ex. D262). June Amendment to US package insert 1977 July Modern Medicine in Australia. (Ex. D37). 1977 1 July Letter from Jarratt to Department of Health. 1977 (Ex. D447 at D1269). 6 July Letter from Altman to Director-General, Department 1977 of Health: " Second Annual Gravigard post-marketing Report, No. 74-8438". (Ex. D488 at D1272). 21 July Letter to O'Brien from Goldstuck (Medical Adviser) (Ex. 1977 D447 at D1277), reporting the large number of complaints from doctors that the Gravigard thread was too thick, resulting in discomfort to their patients. 25 July Letter from O'Brien to Goldstuck. 1977 (Ex. D447 at D1277). 1 August Insertion for Ms Robertson 1977 2 August Letter from Department of Health to Searle replying to 1977 letter of 1 July, 1977. (Ex. D447 at D1283). 3 August Letter to Managing Director (Searle) from Assistant Director- 1977 General, Department of Health, concerning the former's requests for approval to undertake a Gravigard P multicentre clinical trial. (Ex. P297 at P156). 15 August Eschenbach, Harnisch & Holmes: " Pathogenesis of acute 1977 pelvic inflammatory disease: Oral contraception and other risk factors." AMJ Obstet. Gynaecol., Vol. 128, No. 8, p.838. (Ex. P108, Tab 6). 20 August A new patient brochure arising out of the meeting of 1977 6 June, 1977 was begun to be distributed in the USA. (Ex. 9, Tab 8). It was not distributed in Australia. 30 August Letter from Department of Health to Searle Laboratories. 1977 (D488 at D1299). 7 September Telex from Emmett to Winters indicating that Emmett 1977 anticipated no problems with the Department of Health in changing to natural polyethylene string. ( Ex. P297, P0159). 13 September Insertion for Ms Ottaway. 1977 18 November Memo from Lewis to all US District Sales Managers 1977 Re: Verification of destruction of Cu-7 booklets. (Ex. P297, P1069). This memo gives instructions to the sales representatives in the US to destroy their old Cu-7 booklets. 5 December Letter from Department of Health to Searle Laboratories. 1977 (Ex. D488 at D1329). 17 December British Medical Journal. (Ex. D100). 1977 1977-78 2nd insertion for Mrs Lane. 1978 "Fertility IUDs" , G D Searle & Co Worldwide Pharmaceutical/Consumer Products Group - 1978 Planning Process. (Ex. P297, P1076). The G D Searle & Co Worldwide Pharmaceutical/Consumer Products Group 1978 Plan noted at P.4 that it was to launch the Cu-7(s) in late 1979 to expand usage among nulliparous patients. 1978 Costerton, Geesey & Cheng: "How bacteria stick." (Ex. P297, P3019). 1978 Thaler et al. 1978 Thiery et al: "Three years experience with the MLCU-250 a new copper wired intrauterine contraceptive device." Advances in Planned Parenthood. Vol. 8, Nos. 3&4. (Ex. D264). 1978 Bouchert, Albert and Carskus, "A Study of the Cu-7 Device at the Family Planning Clinic, Edmundstein, New Brunswick". (Ex. D384 tab 4). 5 January Memorandum from Branning to Bryant & Ors. 1978 (Ex. D447 at D1365). 31 January Gravigard package insert. 1978 (Ex. D447 at D1372). 1 February Grossman, Adams, Hierholzer and Andriole, "Endometrial 1978 and vaginal cuff bacteria recovered at elective hysterectomy during a trial of antibiotic prophylaxis" , Amer J Obstet Gynec, vol 130 (Ex. D420 tab 13). 14 February 2nd insertion for Ms Southren. 1978 15 February Memorandum from Stewart to Agre. 1978 (Ex. 8, P1081). March Modern Medicine in Australia. (Ex. D38). 1978 23 March Letter from Altman to Department of Health. 1978 (Ex. D447 at D1392). April Modern Medicine in Australia. (Ex. D39). 1978 20 April Telex from Altman to Winters. 1978 (Ex. D447 at D1406). 21 April Letter from Donald Baieroski (Newton Filaments, Inc) to 1978 Krzeminski. (Ex. D447 at D1409). 21 April Telex from Altman to Winters. 1978 (Ex. D447 at D1410). May- FDA Drug Bulletin 1978: " Information of importance to July physicians and other health professionals" , Vol. 8, no.3. 1978 (Ex. P228 tab 7). May Wood: " Infertility in the damaged tube - what are 1978 the prospects ?" (Ex. D58). 8 May Memorandum from Graham to Rees. 1973 (Ex. D447 at D1419). 24 May T hird defendant begins to carry on Cu-7 business. 1978 31 May Letter from Van De Water to Needle, Re: Fertility 1978 upon IUD removal. (Ex. P297, P0186) Van de Water wrote to Needle stating: "…as far as I am aware, the contraceptive protection offered by an IUCD is rapidly reversed when the device is removed and the level of fertility returns to the level that it would have been at, had the woman not been using the device." He quoted the Searle worldwide study of more than 16,000 women and said: "Of 305 women who had the device removed to become pregnant 95 made themselves 'available for follow-up.' Of these 95 women 15 had not conceived 1 to 16 months after removal." 2 June Letter from Altman to Department of Health. (Ex. P297 at 1978 P194; P297 at P1673; D447 at D1440). Third Annual Gravigard Post-Marketing Report 74/8438. (Ex. P297, P0194). 16 June Letter from Department of Health to Searle. 1978 (Ex. D447 at D1449). July Cosmopolitan: " The Pill Predicament." 1978 (Ex. D29). 10 July Insertion for Ms Moylan. 1978 17 July Letter from Altman to Department of Health. 1978 (Ex. D447 at D1469). 18 July Letter to FDA from Searle: "Resolving to withdraw 1978 its application for marketing approval of the Mini." (Ex. P297, P218). 22 July British Medical Journal 1978 (Ex. P297, P1785). 4 August Form letter from Gwinn to Joseph Varallo. 1978 (Ex. P297, P1095). 7 August Letter from Assistant Director-General, Therapeutic Goods 1978 Branch to Managing Director, Searle Australia, regarding post-marketing reports for Gravigard Copper & IUD. (Ex D447 at D1488). 9 August Letter from Altman to Ashley. (Ex. P8, Tab 3; P8, P0225) 1978 re: Gravigard retrieval thread Ref 77/3814. Searle Australia requested approval for polyethylene which is " softer filament thread " and has " less memory " and is therefore expected to have a reduced propensity for retraction into the uterus. 11 August Letter from Altman to Ashley Re: Revised Gravigard 1978 Package Insert. (Ex. D447 at D1495). 14 August Letter to Lynch (Searle Illinois) from James M Bilstad 1978 (Bureau of Drugs) re application for a polyethylene retrieval thread as replacement for the existing polypropolene thread. (Ex. D447 at D1497). 25 August Letter fro DOH to Managing Director, Searle Australia, 1978 regarding amendment to revised package insert for Gravigard Cu-7. (Ex. D447 at D1502). 31 August Letter from Altman to Ritchie, Re: Gravigard Enquiry. 1978 (Ex. P.297, P0237). Searle Australia wrote to Ritchie in response to an enquiry from a Searle Medical Representative and stated: "To the best of my knowledge, no data has been published, which shows nulliparous patients to have a lesser or greater incidence of pelvic infection compared to IUD users as a whole." Altman also stated: "During the 1960s infection following IUD insertion was not uncommon. However, the incidence of infection associated with modern IUDs has been greatly reduced by the use of sterile pre-packaged devices, aseptic insertion procedures and screening patients with existing pelvic inflammatory disease." 11 September Letter to Director-General, DOH from Dr L Graham 1978 (Medical Director) containing response to Department's suggestions for amendment of Gravigard Copper 7 IUD package insert. (Ex. D447 at D1517). 12 September Memo from Grigg to Krzeminski, (P297, P1097). 1978 Re: Price increase of Cu-7 because of change to polyethylene string. Searle stated that a 78% price increase was created because of the change from polypropylene to a polyethylene retrieval string. 22 September Memo from O'Brien to Hutton, 1978 (Ex. P8, Tab 3; P8, P1098). ( Re: Tensile strings, the Cu-7 string) stating that the polyethylene string has adequate tensile strength. It is softer and has minimal memory compared to the polypropylene. 23 October Telex from Hall to Myles. 1978 (Ex. D447 at D1527). 27 October Memorandum from Cabano to Azarnoff & Ors. 1978 (Ex. D447 at D1529). 27 October Memorandum from Charles to Gray & Ors. 1978 (Ex. D447 at D1531). November Nebel, Currie and Lassiter, "Clinical Experience with the 1978 Copper 7 Intrauterine Device" Fertility and Sterility, Vol. 30, no.5. (Ex. D384 tab 22). 1 November First insertion for Ms Denzin. 1978 11 November Compliance Committee Submission Form No. 2328 Re: 1978 press release entitled, " OC's combined: Physician Services Item - The pill & IUD danger signals " + memo of 19.01.78. (Ex. P297, P1104). A physician service item (the pill and IUD danger signals) which was proposed to be used in clinics to minimise the risk of major pelvic and IUD complications was not approved by the Compliance Committee. The IUD warning card proposed was to include the following: "Early IUD danger signals abdominal pain, unusual vaginal bleeding, fever or chills, bad vaginal discharge. See your doctor right away." 2 November Memorandum from Johnson to Branning & Charles. 1978 (Ex. D447 at D1538). 3 November Insertion for Ms Gentle 1978 November "CHECK Program of Self Reassessment ". 1978 Royal Australian College of Practitioners. (Ex. D79). 4 November Handwritten letter from James, Searle to Boyd seeking 1978 advice on the use of clear thread for the Gravigard. (Ex. P297, P251, P0251). 6 November Woman's Day. (Ex. D28). 1978 11 November Gravigard-P Status Reports. 1978 to 7 February 1980 4 November Handwritten Memorandum. 1978 (Ex. P297 at P0251). 15 November Memorandum from O'Brien to Krzeminski. 1978 (Ex. P297, P1106). 20 November Memorandum from Kistler to Krzeminski. 1978 (Ex. P297, P1107). 23 November Letter from Department of Health to Searle Laboratories. 1978 (Ex. D447 at D1554). 29 November Letter from Dodson, Director of the National 1978 Biological Standards Laboratory to the Assistant Director of Health, Therapeutic Goods Department, ACT. (Ex. P8, Tab 3; P8, P1678). 30 November Letter from Altman to Department of Health. 1978 (Ex. D447 at D1560). December Second insertion for Ms Denzin. 1978 December Second Report on intrauterine contraceptive devices. 1978 (Ex. P297, P2099). 19 December Letter from Van de Water to Department of Health. 1978 (Ex. D447 at D1573). 20 December Memorandum from Johnson to Branning & Ors. 1978 (Ex. D447 at D1574). 22 December Letter from Altman to Department of Health. 1978 (Ex. D488 at D1576). 1979 Flesh et al: " The Intrauterine contraceptive device & acute salpingitis: A multi-factor analysis." American Journal of Obstetrics & Gynaecology, Vol. 135, No. 3, (Ex. D116). 1979 Goldzieher: " Interpretation of Data by the clinician." (Ex. D97). 1979 Maqueo et al. 1979 B.G.A. Purrier & Ors: " Invitro study of the possible role of the intrauterine contraceptive device tail in ascending infection of the genital tract:" Diagram depicting string without mucus, mucus without string and string with mucus. British Journal of Obstetrics & Gynaecology, 1979. (Ex. D190). 1979 Purrier & Ors. Handwritten notes on what study showed. British Journal of Obstetrics & Gynaecology, No. 86, 1979. (Ex. D203). 1979 Fertility Product/Market Segment Plan for 1979 onwards. This is an internal memo which set out the Cu-7 product redesign with the description " Redesign Copper 7 to allow for placement of filament inside insertion tube" The objective as stated was " regulatory/eliminate concern of microbial contamination and filament withdrawal." There was a 13 point activity schedule to accomplish the task, with an estimated completion date in early 1983. The process was never implemented (P297, P0775; D447 at D2238). 1979 Product Information of Gyne-T IUCD by Ethnor Pty Ltd & advertisement - "An IUD that will fit your patients to a T." (Ex. P297 at P3301). This product information regarding the Gyne-T was provided by Ortho Pharmaceutical Division of Ethnor Pty Limited Sydney. It is dated 1979. It noted as follows under the heading " Pelvic Infection". "Pelvic infection is 3-5 times more likely in users of IUDs than non-users. It may result in the development of tubo-ovarian abscesses or general peritonitis which may interfere with future fertility. Those most likely to develop pelvic infection are nulliparous women under 25 years of age, those with a previous history of pelvic infection and those who have more than one sexual partner or who frequently change…". Under " Precautions" and the heading "Patient Counselling" it stated: "Nulligravida or women desiring further pregnancies should be made particularly aware of the increased risk of pelvic inflammatory disease and its possible interference with future fertility. Because of this risk, women using intrauterine devices should be told to be on the alert of the following symptoms: - new development of menstrual disorders, menorrhagia, abnormal vaginal discharge, fever, abdominal or pelvic pain and dyspareunia." 2January Memorandum Stagnaro to Cole & Ors; Subject: "IUD 1979 String Situation" (Ex. P297 at P261). 4 January Memo from Johnson to Branning; Re: Polypropylene IUD 1979 (Ex. P297, P0262) withdrawal string stated: "Inherent Characteristics of Material Although considered a monofilament, as distinct from a braided or twisted multifilament strand, polypropylene consists of a bundle of fused microfilaments. If the strand surface is damaged or abraded a microfilament may break loose. If this happens, it is sometimes possible to detach a microfilament that is several inches long." 8 January Memorandum from Cabano to Bryant & Ors. 1979 (Ex. D447 at D1602). 19 January Letter from Houghton to Goss; Re: Gravigard 1979 Batch No. 878813 stated: (Ex. P297, P0265). "I understand, in fact, that Gravigard string, although cord or monofilament by virtue its formation, is likely to undergo a 'flaking' process. Therefore, the elimination of this depends upon modification of the thread forming process. …..As I said in my memo of 6 December 1978….this matter should be investigated and followed up in the US…". 2 February Letter from Graham to Department of Health. 1979 (Ex. D447 at D1618). 14 February Letters and QC Report of 9/11/79 & 27/2/79 concerning 1979 Gravigard string from Pre-term Foundation & Searle Australia. (Ex. P297, P0269). There was a Complaint report of a frayed retrieval string and the attached QC results stated: "Thread has two areas where there are so many fine filaments they formed sort of a ball." 22 February Letter from Goss to Cabano dated 22/02/79. 1979 (Ex. P297, P0274). "On examining Gravigard ex UK we find Batch 1078889-7 out of 20 have frayed retrieval threads." 28 February Telex from Johnson to Goss; Re: String is a bundle 1979 of microfilaments. (Ex. P297, P0277). "Regarding polypropylene monofilament fraying… This is a normal inherent characteristic of extruded, stress, tempered polypropylene monofilament." February Modern Medicine in Australia. (Ex. D59). 1979 6 February Letter from Department of Health to Searle Laboratories. 1979 (Ex. D488 at D1619). 1 March Telex from Johnson (US) to Goss. 1979 (Ex. P8, P0281). 2 March Telex from Mathews to Cabano, (Ex. P8, Tab 2). 1979 Re: Telex reject rates of Copper-7 threads. Australian Searle Executives complain that 25% of the finished goods received from the UK were being rejected because of fraying as well as kinking (para 1). This document confirms that the problem was first identified in November 28 1978 (para. 3). This problem also occurred in other countries including in Milan, Italy. "There was some wonderment here on how a monofilament thread could fray but received telex from R J Johnson February 28 indicating monofilament composed of microfilament fibres and fibrils could occur under adverse conditions… Apart from this, believe problem is not just quality assurance but medical is also involved as there could be construed to be some implications in this area. This means there is reasonable possibility of product recall being necessary with resultant repercussions outside region. Believe the matter requires urgent attention." 5 March Memo of reply from Cabano to Mathews, Re: Defects in 1979 string. (Ex. P8, Tab 2, P1117, D1643). "1. Small visible fibrils up until now have not been considered defect by North American QC. 2. There is no specification covering this characteristic. 3. Complaint history in US is not indicative of problem. 4. All existing product in Skokie and Morpeth is made to current specification. 5. Currently there is no examination by magnification. 6. Do not believe product recall is warranted at this stage unless fibrils are causing weakening of the string. To date there are no data to support this contention. 7. Should Australia require a level of quality with complete absence of fibrils by examination under magnification it will be necessary to revise specification and obtain agreement from manufacturing units that they will be able to supply material meeting your specification. With respect to defect you term " kinks " normal thread when pulled between thumb and forefinger feels bumpy. Subject was discussed with Goss today. In your estimation should you feel the market in Australia requires the current level of inspection then it is your decision to continue. At this stage there would be no replacement material available meeting your demands. Therefore suggest you re-evaluate need for examination under magnification." 7 March Telex from Goss to Johnson, Re: Rejecting any thread 1979 that is frayed. (Ex. P8, Tab 4; P8, P0282). This document deals with the question of bacterial colonisation and whether there was a medical problem associated with the tail string. It stated that doctors are worried about infection as a consequence of frayed strings because of the parallels with Dalkon Shields. 8 March Telex from Stairs, Searle to Hailwood. Complaints 1979 concerning fraying of string. (Ex. P8, P1119). 13 March Telex from Cabano to Goss, Re: Prepare summary of 1979 all documented complaints. (Ex. P297, P0283) "Regarding Gravigard String Defect…." 13 March Memorandum from Johnson to Krzeminski. 1979 (Ex. D447 at D1651). 15 March Memo from Johnson to Bryant. Review of 1979 available data on fraying of string. (Ex. P8, P1125). 21 March Memo to File from Cabano, Re: Gravigard complaints, 1979 fraying of strings. (Ex. P8 Tab 4 at P1126). This document deals with the question as to medical consequences if such a defect of fraying were to go unnoticed. Inglis felt that there was no patient hazard as he didn't believe that there was any wicking effect. (para 2). 22 March Memorandum from Johnson to Cabano. 1979 (Ex. P9, P1128). 22 March Teletype from Cabano to Houghton. 1979 (Ex. D447 at D1656). 28 March Memo from Sprod to Boyle, Re: Rejection rate varies 1979 between 18-40%. (Ex. P297, P0284). This was an internal memo which stated that Searle will utilise the clear string just for export and arrange a quantity with blue strings to be imported by air freight. The clear string which was the subject of doctors complaints because of the difficulty of seeing it and therefore knowing whether the Gravigard was in fact still in place (for example see the letter regarding Dr Chapman's complaint at Exhibit P297, P0251). 29 March Memo from Goss to Barry, Re: Reject batches. 1979 (Ex. P297, P0285). Mrs Goss stated that 200 units have been rejected from 16 batches of Gravigard. 30 March Memorandum from Johnson to Cabano. Visit to 1979 Engineered Monofilaments. (Ex. P365). 13 April Gwinn to Dr As-Sanie. 1979 (Ex. P297, P1133). 24 April Memo from O'Brien to Agre, Re: Canadian report - 1979 " Initial Two Years' Experience with the Copper-7 IUD in Canada." (Ex. P297, P1137). O'Brien having reviewed the Canadian initial two year experience with the Copper-7 stated: "I have attached our table comparing US and Canadian rates. As noted in the report, the removal rate for pain/bleeding is high. What is not mentioned in the report is an extremely high lost to follow up rate which occurred primarily due to losses during the first 12 months of the study. A rate in excess of 10% is considered unacceptable by some authorities." May G.B.A. Purrier & Ors: "Invitro study of the possible 1979 role of the intrauterine contraceptive device tail in ascending infection of the genital tract." British Journal of Obstetrics & Gynaecology, Vol. 86. (Ex. D186). 28 May A ustralian Gravigard A6 product insert distributed from this 1979 date. 31 May Memorandum from Stairs to Cabano & Ors. 1979 (Ex D447 at D1686). 4 June Memorandum from Gwinn to all US Searle Representatives, 1979 all US District Sales Manager, all US Regional Sales Directors. (Ex. P297, P1142). 5 June Memo to Coy from Goss, Re: 3 doubtful samples of 1979 Gravigard. (Ex. P297, P0291). "Enclosed please find three doubtful samples of Gravigard… Would you please advise me if these look medically acceptable, with special reference to the retrieval thread. I am trying to avoid the expense and trouble of looking at each device before sending it overseas." 6 June Searle Inter-Office Memorandum to Goss from Coy (Ex. 1979 P297 at P292). The memo concluded with Coy's assertion that the retrieval thread was medically acceptable, he having failed to detect any abnormality with it on an inspection of the Gravigard. 8 June Letter from Van de Water to Department of Health. 1979 (Ex. D488 at D3821). 14 June Letter from Department of Health to Searle Laboratories. 1979 (Ex. D488 at D1703). 2 July Deysach: Scientific Evaluation Project No. MI006: 1979 Searle Research. " Statistical analysis of a clinical trial of the Gravigard-P as a contraceptive intrauterine device." (Ex. D273). 7 July Report Ashley, Overview: " Intrauterine progesterone 1979 contraceptive system". May & Baker. (Ex. D263). 9 July Note from D'Agostino to Azarnoff, 1979 (Ex. P5, Tab 44; P297, P1148). Re: Legal semantic issues with statistical report and Clinical Research Report on Gravigard - P…Both the Clinical Research Report on Gravigard-P and the Statistical Report were revised for " legal semantic issues." The plaintiffs submitted that the documents were of a scientific nature but Mr D'Agostino felt it was absolutely essential to ' sanitize' these reports to make them acceptable to Searle's company policy. 11 July Azarnoff approved the marketing of the Mini outside 1979 North America for use in nulliparous women. (Ex. P297, P.0296). 20 July Memo from Azarnoff to LaBrosse, 1979 (Ex. P5, Tab 43; P297, P1151), Cu-7 Consumer Advertising Re: Changes to A2, B2-Septic Abortion and against company policy to state PID is a side effect of IUDs. 27 July Memo from Rees to P. Brown, Re: Gravigard-P. 1979 (Ex. P297, P0296). Internal Searle memo advising that Azarnoff has issued a memo stating: "I have reviewed the International Clinical Trial results of the small Gravigard. The results are satisfactory and approval for marketing outside North America is granted for the use in nulliparous women." August Ryden & Ors: "Do contraceptives influence the incidence 1979 of acute pelvic inflammatory disease in women with gonorrhoea"? Contraception, Vol. 20, No. 2, August, 1979. (Ex. P297, P2162). 3 August Memo from Boyd to Goss, Re: 8 Gravigard returned 1979 from FPA because of frayed strings. (Ex. P297, P0299). The Family Planning Association of New South Wales returned eight Gravigards because of frayed strings (7 with clear strings and 1 with the new blue string). 22 August Memorandum from Goss to Ferguson. 1979 (Ex. P297, P0305). 29 August Memorandum from Martz to Krzeminski 1979 (Ex. D447 at D1729). 6 September Memorandum from Mathews to Cole. 1979 (Ex. D447 at D1736). 6 September Memorandum from Ferguson to Goss. 1979 (Ex. D447 at D1737). 10 September Letter from Barry to Goss. (Ex. P8, Tab 2). 1979 13 September Clinical Research Report "Gravigard-P" prepared 1979 by Rees. (Ex. P258, pp117-119, 124-125). 14 September Memorandum from Kassel to La Brosse. 1979 (Ex. P8, P1155). 24 September Memorandum from Ferguson to Inglis. 1979 (Ex. P8, tab 2). 4 October Memorandum from Ferguson to Mathews. 1979 (Ex. P297, P0316). 12 October Letter from Emco to Searle Laboratories. 1979 (Ex. D447 at D1753). 23 October Letter from Van de Water to Assistant Director-General 1979 Department of Health regarding Gravigard Retrieval Thread. (Ex. P297, P0257). 9 November Memo from Boyd to Ferguson, 1979 (Ex, P8, Tab 2; P297, P0319; D447 at D1758). Re: Gravigard & FPA concerned with fraying. Searle was advised by the FPA of New South Wales that the FPA had concerns there was a danger of frayed string introducing infection into the uterus. 15 December Sedlis and Reyniak, "Endometrial leukocytes in patients 1979 using IUDs" , Amer J Obstet. Gynec. (Ex. D420 tab 41). 1980 Cole and Edelman, "A Comparison of the Lippes Loop and Two Copper-Bearing Intrauterine Devices" Am J Gynec and Obstet, Vol. 18 (Ex. D420 tab 8). 1980 Osser et al. 1980 Paavonen and Vesterinen 1980 Westrom 1980 Edelman: " Pelvic Inflammatory Disease and the Intrauterine device: A causal relationship.?" International Forum. (Ex. D102). 4 January Morbidity & Mortality Weekly Report. 1980 (Ex. D447 at D1813). 15 January Kaufman & Ors: "Intrauterine contraceptive device use 1980 and pelvic inflammatory disease." American Journal of Obstetrics & Gynaecology, Vol. 136, No. 2, 1-15-80. (Ex. P297 at P2051). February Modern Medicine in Australia. (Ex. D60). 1980 February Letter from Dodson to Atkinson, Re: Complaint T.G.B. 1980 Gravigard intrauterine device fraying. (Ex. P8, Tab 2). This letter referred to the high incidence of fraying before and after insertion of the Cu-7 device. One complainant alleged that a danger of infection could result from fraying of the filament. The NBSL confirmed that the fraying was evident along the tail length of the filament. The NBSL indicated that the polypropylene was of poor quality as normal commercial quality polypropylene filament is smooth on the surface and free from the above defects. 5 February Letter from Dodson to Assistant Director-General, 1980 Department of Health. Fraying of Cu-7 string. (Ex. P8, P1683). 14 February Letter from Skene to Managing Director, Searle Australia 1980 Re: High incidence of fraying complaints. (Ex. P297, P0325). The Department of Health notified Searle Laboratories at North Sydney that the examination of the sample of Gravigard retrieval string submitted to the National Biological Standards Laboratory showed that: "The filament was of poor quality and when examined under the microscope numerous fraying parts were evidence along the entire length…together with some lengths of split ends protruding from the filament." 19 February 2nd insertion for Ms Moylan. 1980 22 February Letter from Ferguson to Department of Health. 1980 (Ex. D447 at D1841). 25 February Memo from Ferguson to Cafano, Re: Gravigard rejection 1980 and handling of thread. (Ex. P297, P0324). This was an internal memo which stated: "I know remedial action has been taken with the thread, the way the thread is drawn and also the way the thread is handled during assembly at Morpeth. Despite this I firmly believe we need a clear statement from somebody in answer to the Department's letter." (The letter referred to is at P0325). 26 February Letter from Van de Water to Dr J H Passehl, 1980 Re: Increase in rates of pregnancy and PID. (Ex. P297, P0328). Van de Water responded to a request passed to him by their Medical Representative by Dr Passehl and stated that: "I understand that you have recently found an increase both in pregnancy rate and pelvic inflammatory disease, associated with Gravigard. I cannot offer you a rational explanation as to why this may be occurring. The only change which has taken place has been the change in dye in the retrieval string. This has not been associated with an increase in either pregnancy or PID…." 29 February Cu-7 Annual Surveillance Report. 1980 (Ex. P297, P0329). 29 February Annual Surveillance Report. 1980 (Ex. D488 at D3845). 15 March Cu-7 Existing problems and proposed remedies. 1980 (Ex. D447 at D1856). 24 March Ritman: " Evaluation of the intrauterine contraceptive 1980 device ". MLCu. 250 (Multiload). (Ex. D264). 26 March Memorandum from Matthew to Tomalin. 1980 (Ex. P297, P1176; P8, Tab 3; D447 at D1860). 31 March Memo from Stewart to Agre and Inglis, 1980 re: Dr Chen's proposed IUD study. (Ex. P297, P1177). There was a proposal by Dr Chen to conduct a comparative trial which included the Cu-7: "Probably a good deal of good publicity could be generated in some areas of the world if the numbers turned out right, i.e. if the Cu-7 had a lower failure rate whether by some superiority or by chance. It is equally likely that the Cu-7 would perform worse in the study." 1 April Dr Rebecca Donohue, Medical Reports, UA28. 1980 (Ex. D180). 8 April Memorandum from Cafano to Ferguson. 1980 (Ex. P297, P1197; D447 at D1867). 24 April Memorandum from K.R. to Steve, confirming Australia's 1980 receipt of credit for 11,700 units from Morpeth. (Ex. D447 at D1875). 29 April Letter to Managing Director of Searle from Assistant 1980 Director-General, Department of Health, informing the former there was no governmental objection to distribution of Gravigard with blue polypropolene thread. (Ex. P297 at P1686). May Eschenbach, "Epidemiology and diagnosis of acute 1980 pelvic inflammatory disease." Obstetrics & Gynaecology, Vol. 44, No. 5 (supplement), May 1980, p. 142s. (Ex. P108, Tab 8.) 9 May Memorandum from Rees to Whitehead. 1980 (Ex. D447 at D1881). Memorandum from Whitehead to Beers & Ors. (Ex. D447 at D1882). 14 May Letter from Alberti to Dr K. Klinges of Eaglewood, New 1980 Jersey: Expression of considerable concern relating to PID in association with IUDs. (Ex. P5 tab 5(b); Ex. P297 at P1186). "The total incidence of post-insertion pelvic infection was 0.7% in the experimental group. The 0.7% figure was derived from Searle sponsored clinical trials and represents a group of physicians expert in gynaecological procedures…. Our marketing experience now involves about a million women, and we are confident that very few pelvic infections have occurred which have not been reported. The incidence in general usage is slightly higher than in the more expert group, but still is less than 1%. The difference may be partly related to sterile technique in the insertion process." 14 May Dr D.R.L. Elam to a Medical Director, Searle Laboratories. 1980 (Ex. P8, P0357). 14 May Memo from Alberti to Brill, 1980 Re: Letter of reply to Dr Klinges. (Ex. P5, Tab 58). "All the studies with which I am familiar conclude that all IUDs enhance the potential for PID and to a greater degree in nulliparous than in multiparous. However the magnitude of this increased risk does not appear to be so great as to markedly limit the rational use of IUDs." 16 May Memo from Huff to Azarnoff, 1980 Re: Statement for response to press inquiries article on PID and IUDs. (Ex. P297, P.1187). "Please review the attached statement for response to press enquiries from a recent article on PID and IUDs. This was prepared with medical and also reviewed by legal, regulatory affairs and marketing. Q: What is Searle's reaction to the recent article on IUDs in New West? A: A warning of an increased risk of pelvic inflammatory disease (PID) associated with IUDs is included in Searle's labelling for the Copper-7 and Copper-T, and is included in a booklet given to all patients prior to receiving the products. Although studies have shown a higher incidence of PID in women using IUDs in general compared to women not using IUDs, clinical studies have suggested a low incidence of PID in women using copper-bearing IUDs. While methods of contraception other than IUDs are less associated with PID, they in turn pose other risks." 21 May Memo from J Beers to: 1980 All US Searle Sales Representatives; All US Searle Regional Sales Directors; All US Searle District Sales Managers Re: PID in proper perspective. (Ex. P297, P1188). This memorandum discussed the then current literature for the purpose of putting " PID in proper prospective." The memo stated: "We do not have the data to make a claim that the Cu-7/Tatum-T reduces the risk of contracting gonorrhoea. But we do have data to show an incidence of PID (30%-60% on which is said to be gonorrhoea) with the Cu-7 to be 0.7%". 30 May Confidential letter from Lykke, University of NSW, to 1980 Haining, Department of Health re study of data obtained on effects of the Cu-7 IUD. (Ex. D447 at D3792). 30 May Letter from Alberti to John Glasser, MD 1980 Re: PID in nulliparous women with IUDs. (Ex. P297, P1189) In response to a question regarding the incidence of pelvic inflammatory disease associated with the Cu-7 particularly when it is utilised for nulliparous women Searle stated: "…the total incidence of post-insertion pelvic infection was 0.7% in the experimental group… The incidence and general usage is slightly higher than in the more expert group, but still is less than 1%." June Third insertion for Ms Denzin. 1980 June Modern Medicine in Australia. (Ex. D62). 1980 June Ashley: "Overview of the Multi-load Copper 250 1980 Intrauterine device." (Ex. D264). 21 July Letter from Alberti to Dr Miller of Ohio. 1980 (Ex. P297, P1194). 31 July Letter from Associate Professor, Robert Hatcher to FDA 1980 relating to serious problems said to be associated with the Cu-7 insertion mechanism. (Ex. P297, P1196). August Paavonen et al: " Intrauterine contraceptive device use 1980 in patients with acute salpingitis". Contraception, 7,1980. (Ex. P229). 1 August Memorandum from Agostinelli to Stewart & Whitehead. 1980 (Ex. D447 at D1904). 7 August Gravigard: Carcinogenicity Studies. 1980 (Ex. D447 at D1905). 18 August Product Development Proposal re copper IUD string changes. 1980 (Ex. D447 at D1908). 20 August Memo from O'Brien to Azarnoff. (Ex. P5, Tab 46). 1980 "Confidential" "It is generally agreed that the incidence of PID of all kinds is higher in IUD users than non-IUD users. We have not collected accurate statistics on the Cu-7 because it was not entered into the data base as a coded item. My estimates are based on reading comments for statements suggesting PID as a diagnosis and then doing manual tabulations. I do know that for some period of time before I came to Searle much of the comments and data was not entered into the computer so that my estimates are low. However, there is no evidence in our own files or in the literature in general to suggest that the incidence of PID is any higher with the Cu-7 than with any other IUD. The speculation that this " PID " will cause infertility has never been substantiated in short term studies (2-3 years) because the return to fertility has been normal. Our incidence of PID is about .8% per year." 22 August 3rd insertion for Mrs Lane. 1980 25 August Manufacturing-related document titled Searle Laboratories 1980 Complaint Report No. 12/80 Re: Frayed retrieval string. (Ex. P8, Tab 2). The quality control report comments with regard to the frayed retrieval string complaint from the Family Planning Association. "These filaments can only be seen against a dark background and would be impossible for inspectors to pick up against the white cardboard. There is no way that we can guarantee that this will not happen again, in spite of a 100% inspection of all Gravigards sent to the Family Planning." 25 August Complaint Report No. 12/80 from John Boyd, Re: 1980 Frayed Retrieval Threads. (Ex. P8, Tab 2). Searle informed the FDA verbally that fine filaments were present but, that they didn't appear to be of a major concern. Searle was not prepared to guarantee that this wouldn't happen again. 4 September Letter from Mathews to FDA, 1980 Re: Review of Dr Hatcher's comments regarding the Cu-7 insertion technique as cited in ' Contraceptive Technology' , 1980-81. (Ex. P297, P1207; D447 at D1918). In respect to Dr Hacher's complaint to the FDA, Searle responded: "An increased incidence of infection has not been manifested either in our clinical trials or during commercial usage of the Cu-7. We have not seen any data to substantiate this opinion of Dr Hatcher." 8 September Agostinelli to Mathews. 1980 (Ex. D447 at D1919). 22 September Medical Information Request from John Tepper 1980 Re: Response to Dr J. Siegel of New Jersey - string retraction problems. (Ex. P297, P3306). The Department of Medical Communications was advised: "Dr Siegel has inserted several hundred Cu-7's. He complained to me that Cu-7 strings seem to retract into the uterus between periods, but are pushed back down during periods and are reachable by the patient for a short time of this period." 30 September Memo from Whitehead to Beers and others of Searle, 1980 Re: IUD string change - Current Status + attachment. (Ex. P297, P1213). This memo stated that the Battelle proposal regarding redesigning the Cu-7 string has been received, a contract signed and development work started. It stated that the modifications were expected to be completed by mid-1981 and that a new string should be available for marketing by December 1981. The executive summary statement stated in part: "…The particular characteristics and properties of the polypropylene have caused several medical problems… It's memory has on occasions, caused the string to retract from the vagina into the cervix and uterus making it impossible to detect in situ. In addition, polypropylene has a tendency to fray giving the string a low quality appearance and perhaps increasingly likelihood of uterine infection." 30 September Memo from Whitehead to Beers and Ors (Ex. P8, P1213). 1980 Re: IUD string changes other status. October Telex from Van de Water to Rees, Searle. 1980 requesting copy of some Status Reports. (Ex. D447 at D3795). 16 October Memorandum from Van de Water to Graham. 1980 (Ex. D447 at D1953). 10 November Letter from Strathman to Planned Parenthood of 1980 North West Indiana, Re: Reply to Inquiry with regard to fraying of Copper-7 string. (Ex. P297, P1221; P8, Tab 2; D447 at D1961). Draft letter: "Fraying is due to an inherent tendency of polypropylene string to fray when abraded. The Medical Department does not believe that it poses any health hazard." This letter included a description of the string as composed of " thousands of roughly parallel microfilaments." This letter was shown to Dr "O'Brien who " felt the term 'microfilaments' might be misunderstood." 10 November Letter from Levy to Strathman, 1980 Re: Cu-7 (Frayed string), Ann McFarren CICS 80-0857. (Ex. P297, P1219; P8 Tab 2 at P1211). With regard to P1219 the memo stated that the statement that: "Our Medical Department does not believe it poses a medical problem was cleared with Dr O'Brien". The memo went on to say: "This letter was shown to Dr F. O'Brien who felt that the term ' microfilaments ' might be misunderstood when used to explain the composition of a ' monofilament ', and asked me to clear the terminology with M. Krzeminski. M. Krzeminski advised describing the fraying as an abrasion of the monofilament, causing the string to fibrillate or break down into small fibres." 10 November Letter from Strathman to McFarren, following up latter's 1980 inquiry about the fraying of the Cu-7 tailstring. (Ex. D447 at D1957). 10 November Letter from Levy to McFarren. 1980 A draft response was prepared as follows: "This is a response to your report of finding Cu-7s with frayed strings. Fraying is due to an inherent tendency of polypropylene string to fray when abraided. The Medical Department does not believe that it poses any health hazard. The monofilament is composed of thousands of roughly parallel microfilaments, and the fraying results as abrasions lodges a microfilament from the bundle." 13 November Letter from Department of Health to Searle Laboratories. 1980 (Ex. D447 at D1961). 14 November Memorandum Stewart to Agre. 1980 (Ex. P297, P1223). 19 November Letter from Alberti to Dr Foote of Tennessee, 1980 Re: Lawsuits against doctors inserting IUDs into nulliparous women and women who do not completely understand the danger of PID + attachment. (Ex. P297, P1228). In response to some expressed concern relating to insertion of a Cu-7 in a nulliparous woman the Director of Medical Communications wrote: "I am somewhat at a loss to respond to your first concern, since there exists no contraindication to the use of a Cu-7 or any presently marketed IUD by nulliparous women. As a matter of fact, the scientific data which report a definite relationship between the occurrence of PID and the use of an intrauterine device remain quite confusing and often conflicting. Obviously, a physician would be ill advised to insert an IUD into a woman, whether nulliparous or multiparous, who had a previous history of venereal disease, who was known to be sexually promiscuous, or who entertained a multiplicity of sexual partners." 19 November Letter from Tyrer to Stewart, Re Dr Hatcher and his 1980 concerns in relation to the insertion mechanism of the Cu-7 IUD. (Ex. P8, Tab 5; Ex. P8, P1226). Dr Hatcher and the Family Planning Federation requested that Searle review the insertion mechanism of the Cu-7 in 1980. Dr Hatcher was also concerned that bacteria would enter the uterus from the vagina during insertion because of the presence of the Cu-7 thread on the outside of the inserter barrel. Other concerns related to retraction and medical problems were also mentioned. 24 November Letter Battelle to Searle. 1980 (Ex. D447 at D1965). December Correy: " A Contraceptive Plan for different age groups." 1980 (Ex. D96). 1 December Westrom: " Incidence, prevalence and trends of 1980 acute PID and its consequences in industrialised countries." American Journal Obstetrics & Gynaecology. (Ex. P385). 1 December Senanayke & Kramer: "Contraception and the etiology of 1980 pelvic inflammatory disease: new perspectives." American Journal of Obstetrics & Gynaecology, Vol. 38, No. 7, Part 2. (Ex. P124). 2 December Letter from Alberti to Dr Stanton P. Goldstein of 1980 Massachusetts Re: Incidence of permanent infertility with Cu-7: (Ex. P8, Tab 7). "To the best of our knowledge, a woman becomes fertile almost immediately after the removal of an intrauterine copper contraceptive, but we have not been able to develop data which would establish any incidence of infertility as to related to the occurrence of pelvic inflammatory disease or the occurrence of an ectopic pregnancy". "…I regret that we do not have data specifically relating to the incidence of pregnancy after three years of Cu-7 usage or following the replacement with a second or third Cu-7." 4 December Letter from Katherine Finseth to Stewart. 1980 (Ex. P8, P1233). 22 December Letter from Stewart to Dr Finseth. 1980 (Ex. P8, P1235). 22 December Letter from Althouse to Agostinelli (Ex. D447 at D1983), 1980 Re: " Final Report on Development of a Suitable Material and Design Concept for Attachment to a Monofilament to Searle's Cu-7 IUD" by Althouse, Preston and Luttinger (attached). (Ex. P297 at P1236; D447 at D1984). Battelle provided Searle with alternatives to the polypropylene string and recommended: "Design 15" It stated that: "Can be adopted by Searle with a minimum of time and effort needed for conversion. Requires only one moulding change…, a small hole must be added to the bottom of the barrel. Is applicable to both the Cu-7 and the Cu-7(s). Should allow stringing an equal or less time than is presently used by Searle for heat knotting. Would allow the monofilament to be placed inside the insertion tube during insertion, thereby eliminating the loop which is otherwise formed when the monofilament is outside the tube." 1981 Burkman. 1981 Kaufman. 1981 Vessey. 1981 Koch, Reinhardt & Soyka: "Intrauterine contraception using the Copper Mini-Gravigard-7 IUD - Summary of 328 case histories." (Ex. P258, p148 at p153). 1981 Speirs et al: "When predictions don't predict." Australian New Zealand Journal of Obstetrics & Gynaecology, 1991. (Ex. D80). January Status Report Form 12 months post insertion; Investigator: 1981 Dr Jules Black. (Ex. P297 Vol 16B). 2 February Memorandum from Van de Water to Rees, Searle: 1981 " Status Reports on Gravigard-P". (Ex. D447 at D3796). 23 February Memorandum from Agostinelli to Azarnoff. 1981 (Ex. P8, P1240). 24 February Telex from Rees to Van de Water. 1981 (Ex. P297, P0399). 24 February Memorandum from Rees to Van de Water. 1981 (Ex. P297, P0398). March R T Burkman and the Women's Health Study, "Association 1981 Between Intrauterine Device and Pelvic Inflammatory Disease" , Journal of the American College of Obstetricians and Gynecologists (Ex. D420 tab 51). 13 March Letter from Dr Sobel, FDA to Searle Research & 1981 Development Division. (Ex. P8, P1246). 3 April Memorandum from Mathews to Agre & Ors. 1981 (Ex. D447 at D2052). 8 April Letter from Strathman to Dr George Verrilli. 1981 (Ex. P297, P1249). 13 April Memorandum from Van de Water to Rees, Searle 1981 "Correct statistical Approach to the IUCD data." ( Ex. D447at D3799). 16 April Letter from Searle to FDA. 1981 (Ex. D447 at D2058). 4 May Memorandum from Stewart to Agre. 1974 (Ex. D447 at D2066). June Professor McNeill, Macquarie University Mini- 1981 Gravigard Clinical Data, Appendix 5 - Statistical Analysis. (Ex. D276). 1 June Index entitled "Mini-Gravigard Clinical Data." 1981 (Ex. D272). June Clinical Research Report "Australian Experience with 1981 Gravigard-P" prepared by Van de Water. (Ex. P258, pp101 & 103). 2 June Telex from Van de Water to Rees. 1981 (Ex. P297, P0410). 3 June Memorandum from Van de Water to Rees, Searle 1981 enclosing revised version of the Gravigard-P Report. (Ex. D447 at D3801). 17 June Memorandum from Edmunds to Nicholson. 1981 Re: Thread withdrawal. (Ex. P297, P1264). 25 June Letter from Graham to Director-General of Health. 1981 "Marketing approval for Mini-Gravigard device." (Ex. P14, Tab 10, P0630). 25 June New Gravigard Clinical Trial protocol forwarded to 1981 Director-General of Health. (Ex. P258, pp 94-95). 25 June Searle's application to DOH for marketing approval of the 1981 Mini - included copy of proposed package insert for Mini, and incorporated details in accordance with section B1, including specifications for the polypropolene tailstring (Ex. D447 at D2096). 1 July Handwritten note: From Atkinson to McAuley. 1981 ( D270). 21 July Drug Registration Monitor Report. 1981 (Ex. D488 at D2116). 27 July Handwritten note: From Ashley to Atkinson. 1981 (Ex. D270). 29 July Drug Registration Monitor Report. 1981 (Ex. D447 at D2120). 30 July Memorandum from Graham to Herting. 1981 (Ex. P297, P3305). August Soderberg & Lingren: "Influence of an intrauterine 1981 device on the course of an acute salpingitis." Contraception. (Ex. D438). 20 August Letter from Atkinson to Managing Director of 1981 Searle Laboratories re: General Marketing Application. (Ex. D270). 27 August Handwritten file note of Ashley and correspondence and 1981 US Patient Brochure, Ashley. (Ex. P280). "I met with Dr L. Graham of Searle today and discussed the PIs that had been submitted. Apart from the insertion procedures and some descriptive parts the submitted PIs were essentially ' identical' . I therefore chose one, the Gravigard one as I happened, to work on with the results below being a concoction of Searle's original and the wording used in the Multiload PI. At this meeting Dr Graham produced a copy of the 1981 US Searle PI which was very similar to what I was proposing and neatly improved over the one submitted for consideration. I have given Dr Graham a copy of my concoction and she will work on that and resubmit a revised PI. She will also enquire about the patient brochure now referred to as the US PI - the Multiload PI has pre and post insertion patient booklets which I think are excellent and I strongly recommend that Searle introduce a simpler booklet here (approval required by us of course) especially as it now appears to be a requirement in the US. Could a copy of this and my " concoction go on the 'Gravigard', 'Mini-Gravigard' and 'Gravi'T' file please. When the revised PI for Gravi-T is received and approved - marketing should be OK as B1 is clear." 28 August Meeting of ADEC Committee. 1981 (Ex. P258, p154 at pp156-157, 159-160, 162, 165, 169-175). 28 August Minutes of A.D.E.C. Committee. 1981 (Ex. D447 at D2133). 10 September Memorandum from Stewart to Krzeminski. 1981 (Ex. P8, P1285). 15 September Drug Registration Monitor Report. 1981 (Ex. D447 at D2143). 15 September Letter from Graham to Department of Health. 1981 (Ex. D447 at D2145). 16 September Memorandum from Limpe to Krzeminski. 1981 (Ex. D447 at D2146). 21 September Searle document,entitled "Description of the Cu-7 1981 device". (Ex. D442 at FBO'B13). 21 September Letter to Searle Illinois from Marion J Finkel, Associate 1981 Director for New Drug Evaluation, Bureau of Drugs, re failure of drug review application for the Small Cu-7. (Ex. D443 at FBO,B2A). 22 September Memorandum from Stairs to King. 1981 (Ex. D447 at D2151) 23 September Drug Registration Monitor Report. 1981 (Ex. D447 at D2152). 29 September Memorandum from Coy to Graham. 1981 (Ex. P297, P0431). October Modern Medicine in Australia. (Ex. D64). 1981 26 October Letter from Searle Laboratories to Ashley, Department 1981 of Health re: Mini-Gravigard. (Ex. D270). 28 October Letter to Assistant Director-General, Department of Health 1981 from Dodson, enclosing evaluation of chemistry and quality control of mini-Gravigard. (Ex. P297 at P1695). 29 October Compliance Committee Submissions 4584, Re: Stick on 1981 label for Cu-7 when string is changed. (Ex. P297, P1291). This is an example of a sticker for use on Cu-7 boxes to alert users of a change, in this case a new retrieval thread assembly (this was never implemented). November Fourth insertion for Ms Denzin. 1981 November File note: Rohde. 1981 (Ex. D488 at D2189). 2 November Memo from Alberti to Strand, 1981 PID in association with the Cu-7: (Ex. P297, P1292). "Our marketing experience since the introduction of the Cu-7 now involves well over 1 million women and, while we recognise all pelvic infections are not reported to us, it is our impression that the incidence of such infections in general usage is still less than 1%. Searle is in possession of no reliable data which would establish the incidence of sterility resulting from these cases of PID, and I am aware of no valid statistics in this regard." 2 November Drug Registration Monitor Report. 1981 (Ex. D447 at D2182). 4 November Letter from King to FDA. 1981 (Ex. D447 at D2183). 5 November Letter from Willson, Assistant Director-General, 1981 Department of Health to the Managing Director, Searle Laboratories. (Ex. P297, P04447). 5 November Letter from Department of Health to Searle Laboratories. 1981 (Ex. D447 at D2184). 6 November Letter from Anderson to National Biological Standards 1981 Laboratory. (Ex. D488 at D2187). 10 November Letter from Department of Health to Searle Laboratories. 1981 (Ex. D447 at D2188). 16 November Memo from Minarich to Burbank, 1981 Re: Gravigard string change. (Ex. P297, P0449). This memo was copied to Searle Australia and stated: "The major problems caused by the polypropylene resin were due to stiffness and ' memory' . This problem will be addressed in two phases. Phase 1 of this plan calls for loading the string down through the inside of the insertion tube. This procedure effectively eliminates the current ' loop' configuration created by the polypropylene's resin's stiffness and inherent and ' memory'. " It further stated that the finished product would be available in mid-April 1982 and that this modification will resolve concerns voiced by the US FDA and inserting physicians. It then noted the following points: "String loss/withdraw into the cervix due to memory and looping the plastic. Bacterial entry into the uterus during insertion with string outside." Phase 2 of implementation involved the actual change of the resin from polypropylene to polyethylene. 25 November Memorandum from Robson to Greener. 1981 (Ex. P297, P1297). 2 December Memorandum from Stairs to Joshi & Ors. 1981 (Ex. D447 at D2203). 3 December Letter from Graham to Director-General of Health. 1981 (Ex. P297, P0453). 3 December Advertising/Promo Piece titled " Mini-Gravigard a Fitting 1981 alternative for Nullips ." (Ex. P297, P0454). 7 December Letter from National Biological Standards Laboratory 1981 to Searle Laboratories. (Ex. P297, P1696). 7 December Letter from Department of Health to Searle Laboratories. 1981 (Ex. D447 at D2219). 14 December Letter from Assistant Director-General, Department of 1981 Health to Managing Director, Searle Laboratories. (Ex. P297, P0458). 14 December Memorandum from Stewart to Simes. 1981 (Ex. P297, P1302). 1982 Zimmerli et al 1 January Advertising Brochure. (Ex. P297, P0459). 1982 January Modern Medicine in Australia. (Ex. D63). 1982 14 January Memorandum from King to Anderson & Ors. 1982 (Ex. D447 at D2264). 1 February Memorandum from Tomalin to Cotterill & Ors. 1982 (Ex. D447 at D2284). 16 February Australian Mini-Gravigard A1/A2 product insert 1982 distributed from this date. 18 February Memorandum from Koch to Joshi. 1982 (Ex. D447 at D2302). March Vessey et al, "PID risk from IUD varies according to 1982 acuteness of disease" , Modern Medicine of Australia (Ex. D65). March Modern Medicine in Australia. (Ex. D66). 1982 3 March Memorandum from Goss to Blatt. 1982 (Ex. P297, P0463). 5 March Mini-Gravigard International Clinical Trial, Third Interim 1982 Report, data as of September 17, 1981: Nulliparous women only. (Ex. P158, P177 at P195-197). 5 March "Australian Mini-Gravigard Clinical Trial - Table 11. 1982 Patients with infection during course of the clinical trial. (Ex. P259). 25 March Final Report on small Cu-7. 1982 (Ex. P297, P0466). 1 April Letter from Anderson to Assistant Director-General, 1982 TGA - Cmth DOH. Re: Gravigard - change in threading. (Ex. P297, P0469). Searle Australia requested the Department of Health to approve a change to the threading of the Cu-7: "The Polypropylene string has a ' memory ' that causes a ' loop' at the point of exit from the top of the tube that is undesirable. By removing the orientation knob…we can run the string down the inside of the tube and eliminate this ' looping' problem. It should also provide a more sterile insertion procedure." This change was never implemented. 14 April Memo from Urheim to Bose & Ors Re: Actinomyces/ 1982 PID/IUD current issues + attached " Dear Doctor" letter. (Ex. P297, P1322). 22 April Letter from Anderson to the Assistant Director-General, 1982 Department of Health. (Ex. P297, P1324). 23 April Telex from King to Anderson. 1982 (Ex. D447 at D2359). 28 April File Memorandum by Helms. 1982 (Ex. D447 at D2364). May Attila Toth & Ors: " Evidence of microbial transfer by 1982 spermatozoa." Journal of Obstetrics & Gynaecology , Vol. 59, No. 5. (Ex. D204). 3 May Memorandum from Stairs to Brennan & Ors. 1982 (Ex. D447 at D2372). 10 May Letter from Department of Health to Therapeutic Goods 1982 Branch. (Ex. D447 at D2381). 25 May Memorandum from Stewart to Agre. 1982 (Ex. D447 at D2413). 7 June Letter from Atkinson to Anderson, 1982 Re: Gravigard - change in threading. (Ex. P297, P0474). "I refer to your letter of 22 April concerning Gravigard Change in Threading. This Department has no objection to the change." 7 June Memo from Van de Water, 1982 Re: " String inside tube approved by DOH June 7/82." (Ex. P297, P0475). This is a handwritten note written on the note paper of Bill Van de Water which stated in part: "String inside tube approved by DOH June 7/82..? When will this be implemented. - Recall". The word " recall" is written and various dates are crossed out ending in May 1984. The new inserter design was never implemented. July World Health Organisation - Task Force on Intrauterine 1982 Devices for Fertility Regulation, "Interval IUD Insertion in Parous Women: A Randomized MultiCentre Comparative Trial of the Lippes Loop D, Tcu22OC and the Copper 7" , Contraception, Vol. 26 no. 1 (Ex. D420 tab 58). 7 July Memorandum from Krzeminski to Brennan and Ory. 1982 (Ex. P8, Tab 5; P297, P1329). 13 July Memo from Anderson to Sprod, 1982 Re: Gravigard package insert. (Ex. P297, P0479). "We note that the current printed package insert (Code No. A3380/6) is not the same as the September 15, 1981 draft which was sent to you on September 29, 1981, presumably. This is because we are running out the old inserts. Is that true?" 15 July Memo from Sturtevant to Bose et al. (Ex. P297, P.1332) 1982 attaching a draft. This memo circulated a draft of the O'Brien, Sturtevant article entitled " Incidence of Pelvic Inflammatory Disease in Clinical Trials with Cu-7 (Intrauterine Copper Contraceptive: a Statistical Analysis)". The draft contained the following passage: "PID is a severe disease and can be tragic when occurring in a young, nulliparous patient. It will be expected to appear more frequently in young patients upon whom the IUD has conferred increased sexual freedom. Whether the IUD plays a more intimate pathogenic role cannot be affirmed or refuted, but in absence in proof to the contrary, it is conservative to supply appropriate warnings to the individual considering employing this method of contraception." This paragraph did not appear in the final published version (see Exhibit D442 page 000153). 22 July Memo from Sprod to Anderson, 1982 Re: Reply letter - Gravigard insert. (Ex. P297, P0480). "Referring to your memo of 13 July, 1982, you are correct in your assumptions that we are still using up the old A3380/6 inserts." 2 August Memorandum from Miller to Brennan. 1982 (Ex. D447 at D2508). 11 September Moore et al: "Increased frequency of serum 1982 anti-bodies to chlamydia trachomatis in infertility due to distal tubal disease." The Lancet. (Ex. P209, Tab B). 14 September Searle memorandum re FDA Report expressing 1982 concern at unusually high incidence of PID amongst Cu-7 users (Ex. P297, P1336). 21 September Letter from Sturtevant to Dr Amir Ansari stating that the 1982 Searle legal department had been " anxious to have the data published ". The data related to PID incidence in Cu-7 clinical trials. (Ex. P297, P1337). October Werner et al: " Pathogenesis of foreign body infection : 1982 Description & characteristics of an animal model". Journal of Infectious Diseases, Vol. 146, No. 4. (Ex. P231). 1 October Letter from Sturtevant to Vessey. 1982 (Ex. D447 at D2567). 15 October Letter from Ory to Sturtevant. 1982 (Ex. D447 at D2578). 29 October Letter from Turtle, Sydney University to Assistant 1982 Director-General of Therapeutic Goods Branch Re: General marketing for the Multiload Cu250 short contraceptive device submitted by Organon Australia. (Ex. D267). 2 November Letter from Sturtevant to Mishell. 1982 (Ex. D447 at D2598). 12 November Ashley: Overview - Nova-T. 1982 (Ex. P268). November Lumber: Evaluation of a submission for general 1982 marketing of the Cu-200 Ag Intrauterine device. (Nova-T). Schering Pty Limited. (Ex. 268). December Statement for agenda papers for 106th meeting of ADEC. 1982 Application for short-stemmed version of marketed IUD. (Ex. D267). 23 December Feinstein & Horwitz: " Double standards scientific 1982 method of epidemiological research." Journal of Epidemiological Research, Vol. 307, No. 26. (Ex. P291). 29 December Letter from Mishell to Sturtevant. 1982 (Ex. D447 at D2669). 1983 Wang and Grayson, "Micro-Immunofluorescence Serology of Chlamydia Trachomatis" (Ex. P226, p87). 1983 Irving Sivin, "Incidence of ectopic pregnancy" , Studies in Family Planning (Ex. D384 tab 24). 1983 Bundle of Advertisements from A/NZ Journal of Obstetrics and Gynaecology (See p.683). 1983 Eschenbach: Book, Ch. 7 Pelvic Inflammatory Disease. (Ex. P134). January Amsel et al: " Non-specific vaginitis: Diagnostic 1983 Criteria and Microbial and Epidemiologic Associations". American Journal of Medicine, Vol. 74. (Ex. P232). 3 January Project Progress Report Cu-7 Product Redesign. 1983 (Ex. D447 at D2707). 8 January M P Vessey at al, "Fertility after stopping use of 1983 intrauterine contraceptive device" , British Medical Journal, vol 286 (Ex.D420 tab 51). 21 January Article O'Brien, Stewart and Sturtevant. (Ex. P5, Tab 49). 1983 This article set out PID incidence rates. January Eschenbach et al: " Criteria for diagnosis and grading 1983 of salpingitis." Journal of Obstetrics & Gynaecology, Vol. 61, No. 1. (Ex. P281). January Goh et al, "A Randomised Comparative Evaluation of the 1983 Copper 7, Multiload Copper 250 and T Copper-22OC IUDs" , Contraception, Vol.27, no.1 (Ex. D384 tab 7). February Bundle of advertisements from Australian/New Zealand 1983 to Journal of Obstetrics & Gynaecology. November (Ex. P14, P457, Folder I). 1985 February Report on clinical trials of IUD & incidence of PID. 1983 Contraception. (Ex. P109). 3 February Inter-office memo O'Brien, Searle to Burgrabbe: 1983 "IUD news clip". (Ex. P466). April World Health Organization Task Force on Intrauterine 1983 Devices for Fertility Regulation, Special Programme of Research Training in Human Reproduction, "IUD Insertion following Spontaneous Abortion: A Clinical Trial of the Tcu220C, Lippes Loop D, and Copper 7" Studies in Family Planning Vol.14, no.4 (Ex. D420 tab 56). April World Health Organization Task Force on Intrauterine 1983 Devices for Fertility Regulation, Special Programme of Research, Development and Research Training in Human Reproduction, "IUD Insertion following Termination of Pregnancy: A Clinical Trial of the Tcu220C, Lippes Loop D, and Copper 7" Studies in Family Planning Vol.14 no.4 (Ex. D420 tab 57). 1 April Editorial: "Ectopic pregnancy". JAMA, Vol. 249, 1983 No. 13. (Ex. P209, Tab C). 25 April Memorandum from Stolt to Food and Drug Administration 1983 File, regarding an update on the New Drug Evaluation review of the Cu-7. (Ex. D443 at FBO'B2C). 15 May Gump et al: " Evidence of prior pelvic inflammatory 1983 disease and its relationship to chlamydia-trachomatis antibody and intrauterine contraceptive device use in infertile women." American Journal of Obstetrics & Gynaecology, Vol. 146, No. 2. (Ex. D223). June Fifth insertion for Ms Denzin. 1983 July Lee et al: "Type of intrauterine device and the risk of 1983 pelvic inflammatory disease." Obstetrics & Gynaecology, July, 1983. (Ex. P125). 24 August Letter from Smith to Tomalin. 1983 (Exs. P8, Tab 2; P8, P1369). 1 September Letter from Sobel, FDA to Merino, Searle. 1983 (Ex. P297, P1370). 6 September Memorandum from Tomalin to Matthews. 1983 (Ex. P297, P1371). 29 September Annual Report of the Fertility and Maternal Health Drugs 1983 Advisory Committee. (Ex. D443 at FBO'B2B). 22 November Memorandum from O'Brien to Tomalin. 1983 (Ex. D447 at D3044). 22 November Memorandum from Stolt to FDA Communication File, Re: 1983 Summary Basis of Approval for the Small Cu-7. (Ex. D443 at FBO'B2D). 28 November Memorandum from Cotterill to Tomalin. 1982 (Ex. D447 at D3047). 12 December Australian Gravigard A7/A8 product inserts 1983 distributed. 1984 Witoonpanich January Bank et al: "Fluid migration through the tail of the 1984 Dalkon Shield intrauterine device." Contraception. (Ex. D495). February Burford, Stewart & Herting -.Report of "Physician 1984 impressions regarding a modified insertion technique for the Cu-7 intrauterine copper contraceptive". (Ex. D447 at D3077). 15 March Letter from Tomalin to Smith, 1984 Re: Complaints of fraying of retrieval string. (Ex. P297, P1384). Tomalin wrote with regard to fraying of retrieval threads in the Cu-7: "Canada… In the past seven years we have received two complaints…UK…in 1980 there was one complaint…US since 1978 the following complaints of frayed threads have been received in the US, total for six years 11." 22 March Memo from Tomalin to McLeod & Milochik. 1984 Re: Dr Smith's concerns relating to string composition. (Ex. P297, P1385). "She commented, however, that it appeared the polypropylene thread had this problem and that polyethylene and nylon did not. I said that the incidence with Cu-7 was so low, that this comment did not seem reasonable. She asked if we had a firm date for putting the thread down the centre of the inserter tube. I said we did not." 10 May Telex from Mathews to Anderson & Coy. 1984 (Ex. P297, P0552). 16 May Letter from Searle to FDA. 1984 (Ex. D447 at D3097). 15 June Letter from Anderson, Searle Australia to Director- 1984 General of Health, re: Mini-Gravigard. (Ex. D271). 10 October Agreement between Battelle and Searle. 1984 (Ex. D447 at D3116). 25 October Memorandum of meeting between Searle and the Food and 1984 Drug Administration. Purpose of Meeting : To discuss the status of the NDA for the Small Cu-7 IUD. (Ex. D443 at FBO,B2F). November Collins et al: "Microbiological & histological findings 1984 in the fallopian tubes of women using various contraceptive methods." Contraception. Vol. 30, No. 5, November 1984. (Ex. P297, P3017). 1 November Final Clinical Research Report on the Mini. 1984 (Ex. P297, P0562). 1 November Final Clinical Research Report: " International Clinical 1984 Trial of Mini-Gravigard in nulliparous women". (Ex. P402, Vol. 7, Tab M). 1 November Final Report: "Mini-Gravigard in nulliparous women." 1984 (Ex. P258, pp343-345, 348-349, 351-352, 354, 356, 358, 361-263, 264, 366-367, 371, 395-397, 401, 404-407, 411, 415-417, 441-463. 9 November Letter from L. Ivanauskas Mathews (Director, Regulatory 1984 Affairs) to Division of Metabolism & Endocrine Drug Products, Center for Drugs and Biologics, Re: Drug Evaluation of the Small Cu-7. (Ex. D443 at FBO'B2G). 1985 Westrom: "Influence of sexually transmitted diseases on sterility and ectopic pregnancy." (Ex. P297, P2311). 1985 " A multi-national case control study of ectopic pregnancy." Clinical Reproduction & Fertility. 1985, Vol. 3. WHO special program of research ,development and research training in human reproduction. (Ex. D437). 15 February Daling et al : "Ectopic pregnancy in relation to 1985 previous induced abortion." JAMA, Vol. 253, No. 7. (Ex. D210). 14 March Memo prepared by Timms and Page 1985 to Faden Re: PID, IUDs & Cu-7s in relation to legal exposure + bibliography & slide presentation. (Ex. P297, P1399). This memorandum stated: "The best estimates seem to be that overall users of IUD are 2 x more likely to get PID than non-users of any method of contraception, but within that statistic, it is clear that the greater part of the increased risk is due to Dalkon Shield users who are between 4-14 x more likely than non-users to have PID. Use of IUDs other than Dalkon Shield is associated with risks of 2-4 x the risk of PID of non-users. For Copper-7 the risk range appears to be 2 x non-users." 11 April Kramer et al: "Tubal infertility and the intrauterine 1985 device." New England Journal of Medicine, April, 11, 1985. (Ex. P129). 11 April Daling et al: "Primary tubal infertility in relation to the 1985 use of an intrauterine device." New England Journal of Medicine, April 11, 1985. (Ex. P130). 14 May Handwritten notes Re: Japan string changes. 1985 (Ex. P297, P1419) The handwritten notes state in part: "Corporate legal has met with S. Cole on subject of Japan's request to modify product. It does not look like we will be " allowed" to pursue string change as desired by Japanese. Keeping all of this out of writing is a difficult task…" 15 May Letter from Battelle to Stewart. 1985 (Ex. D447 at D3177). 30 May Telex from Hopkins to Hackett, 1985 Re: Fronding - only isolated reports received. (Ex. P297, P0575). In response to Exhibit P0574 the Medical Information Manager reported that: "We have received isolated reports of this nature,… The fraying has not been shown to affect the performance, integrity or quality of the device." 31 May Memorandum from Versteegh to Marino. 1985 (Ex. D447 at D3180). June Sixth insertion for Ms Denzin. 1985 2 July Letter from Stewart to Battelle. 1985 (Ex. D447 at D3185). 13 August Ritman: " Evaluation data presented to substantiate the 1985 claim of efficacy and safety of Gyne-T -380" by Ethnor . (Ex. D269). September Wolner-Hanssen: "Silent Pelvic Inflammatory Disease: 1985 Is it overstated?" Obstetrics & Gynaecology, Vol. 86, No. 3, September 1985. (Ex. P297, P3163). September L Randic et al, "Return to Fertility after IUD removal for 1985 Planned Pregnancy" , Contraception (Ex. D420 tab 38). 5 September Cramer, letter to NEJM 1985 9 September Deposition of Dr Stewart: Simon v Searle, 1985 US District Court case, Minesotta. (Ex. P486). 11 September Transcript of evidence by Stewart. 1985 (Ex. P5, Tab 14). October Report entitled " Core Communications Plan 1985 Discontinue IUD Product Line, October 1985" at the direction of the General Counsel Attorney-Client Communication. (Ex. P297, P1424). This report stated: "The Searle IUD Product Line will be discontinued world-wide by December 31, 1985 due to economic factors in the United States." 9 October Memo from Villers to Coy, 1985 Re: Corporate reactions to Business Week's article - litigation. (Ex. P297, P0580). In regard to the Issue Statement of P0578 Mr Villers stated: "In taking stock of our present situation it is quite apparent that we fall short of the mark in providing any sort of meaningful disclosure to anyone. The first step therefore was to update our current patient information booklet ' Here's What You'll Want to Know About your Gravigard' which is hopelessly inadequate. This proved not a difficult assignment as I was able to use an American patient booklet as a guide…that it reads like a horror story is unfortunate but at least it exculpates us from the charge that we are not making known all the facts." 23 October Memo of Meeting from Ripper to Versteegh and 1985 Sturtevant, Re: Allegations in article published in Business Week on 14 October, 1985 concerning preclinical and clinical studies on the Cu-7. (Ex. P297, P1430). This memorandum of a meeting between Searle Research and Development and the FDA stated: "When asked how long patients were included in the study after the date of their last physician visit, Searle replied that at the time of the original NDA submission the date of last visit was used. However, the next medical monitor at Searle used the time until the record was marked lost to follow up, which varied. When Dr O'Brien became monitor, he used three months after last visit." "Conclusions: …..Although the agency does believe that IUDs are associated with an increased incidence of PID, it considers the incidence to be an acceptable one for women needing this kind of contraceptive who are informed of the risk and willing to accept it." 25 October Memorandum from Louise B. Tyrer to Affiliate Executive 1985 Directors. (Ex. D447 at D3200). October- UA2 Culture Sheets. (Ex. D183) November 1985 7 November Ashley: Overview: " Gyne-T-380 Copper bearing 1985 intrauterine device ". (Ex. D269). 1 December Chow, Daling et al: " Vaginal douching as a potential 1985 risk factor for tubal ectopic pregnancy". American Journal of Obstetrics & Gynaecology, Vol. 153, No. 7. (Ex. D215). 1 January The fourth defendant begins to carry on the Cu-7 business. 1986 1986 D A Edelman and C W Porter, "The intrauterine device and ectopic pregnancy" , Advanced Contraception, vol 2, (Ex. D384 tab 6). 1986 Wolfe & Krieger: " Bacterial colonisation of intrauterine devices (IUDs)." Archives of Gynecology, No. 239, 1986. (Ex. P346). 1986 L.G. Keith, R. Bailey & M. Method . " The Ljubljana IUDs : Further observations on surface morphology." Advanced Contraception, No. 2. (Ex. D162). 1986 Keith: "Possible of Trichomonas vaginalis as a 'vector' for the spread of other pathogens." International Journal of Fertility, 31(4): 272-277, 1986. (Ex. D334). 1986 H F Sandmire, "Fertility after intrauterine device discontinuation" , Advanced Contraception, vol 2 (Ex. D420 tab 40). 30 January Memo from Blith to Joshi Re: IUDs volume, 1986 sourcing pattern and material cost of Cu-7. (Ex. P297, P1457) This is a handwritten note which records the cost of the Cu-7… "Cu-7s fully absorbed cost per-unit of $2.69 materials are .88." "Based on deemed forecasts including the US Searle is carrying sufficient string for 5 years, tubes and rods for 3 to 4 years and Copper wire to 2-3 years." 30 January Letter from Battelle to Stewart. 1986 (Ex. D447 at D3248). 31 January Telex from Merino to Country Regulatory Managers 1986 and Country Managers, Re: Discontinuation of IUD sales in USA. (Ex. P5, Tab 6B). This document confirms the discontinuance of sales of Cu-7s in the USA effective from 1 January, 1986. "In addition, all distributors of Searle IUDs in the US (including physicians and wholesalers) will be requested to return their unused inventories to Searle for a full refund." 31 January News Release from Searle Pharmaceutical Group. 1986 (Ex. P297, P1458). 31 January Statement by the American College of Obstetricians 1986 & Gynaecologists. (Ex. D447 at D3250). 31 January Statement by Planned Parenthood Federation of America, 1986 Inc. (Ex. D447 at D3255). 3 February Memo from Hullin to Parrish, 1986 Re: Discontinuance announcement Friday/Saturday media coverage. (Ex. P297, P1463). This memo concludes: " Bottom line : the defined objective was to focus the story on litigation/insurance/business aspects and not focus on medical and safety aspects. To date, that objective has been achieved." 3 February Press Release regarding Cu-7 Re: Due to litigation climate 1986 in the US, it is discontinuing Cu-7 and Tatum-T + 40 Q's & A's. (Ex. P297, P0592). This telex which was forwarded to the Department of Health advised that Searle had announced that the Cu-7 was to be discontinued from sale in the US. The questions and answers state that: "They (the Copper-7 and Tatum-T) are a safe and effective form of contraception when used in accordance with FDA approved prescribing information." 3 February Memorandum from FDA to major Metropolitan Health 1986 Departments. (Ex. D447 at D3257). 21 February Dr Ritman's evaluation of Searle's submission to the 1986 Department of Health. (Ex. P15 tab 5). 26 February Letter from Ireland, Professional Public Relations Pty 1986 Limited to Boyd, Re: " Close the books on Copper-7 as requested by Mr Van de Water." (Ex. P297, P0595). "We do stand by our comments on 10 February that the product be withdrawn. This would enable Searle to be placed in a positive situation where it can then announce to the media that it has been forced, through misinformation, to withdraw a ' safe' form of contraception from the Australian market." March Jacques Olson & Costerton: "Microbial colonisation of 1986 tailed and tailless intrauterine contraceptive devices: influence of the mode of insertion in the rabbit ." American Journal of Obstetrics & Gynecology, March, 1986. (Ex. D155). 11 April Statement for agenda papers for 123rd meeting of ADEC 1986 re: New drug application - Mini-Gravigard. (Ex. D275). May Chow et al: "IUD use and subsequent tubal ectopic 1986 pregnancy." American Journal of Public Health, Vol. 76, No. 5. (Ex. P209, Tab E). 7 May Memorandum from Hackett to Bryant & Murray. 1986 (Ex. D447 at D3285). 19 May Memorandum from Bryant to Hackett. 1986 (Ex. P297, P0609). 28 May Minutes of A.D.E.C. meeting. 1986 (Ex. D447 at D1091). 6 June Letter from Department of Health, NZ to G D. Searle 1986 NZ Limited. (Ex. P8, P1476). 18 June Letter from Phillips to Stewart. 1986 ( Ex. P297. P1478). 30 July Admissions by Stewart in testimony in the matter of 1986 Simon v Searle. (Ex. P486). 6 August Medical Records: UA32. 1986 - (Ex. D181). 2 February 1989 9 October Letter from Louise B. Tyrer to Professor Robert A. Hatcher. 1986 (Ex. D447 at D3315). 20 October Letter from Van de Water to Department of Health. 1986 (Ex. D488 at D3818). 11 December Mueller et al: " Appendectomy and the risk of 1986 tubal infertility". New England Journal of Medicine, Vol. 315, No. 24. (Ex. D211). 1987 Bisset et al, "A study of event rates of intrauterine devices over a two year period" The British Journal of Family Planning, Vol.13 (Ex. D384 tab 3). March Dr Paula Fives-Taylor: " Materials & Methods". 1987 (Ex. P168, Tab 3.) 1987 Costerton et al. "Bacterial Biofilms in Nature and Disease" (Ex. P339). 1987 World Health Organisation: " Mechanism of action, safety and efficacy of intrauterine devices". (Ex. D323). 1987 Kajanoja et al: "Intrauterine contraceptive devices (IUDs) in relation to uterine histology and microbiology." ACTA Obstet. Gynaecol. Scand. 66: 445-449, 1987. (Ex. P297, P3062). 1987 Chow et al: "Epidemiology of ectopic pregnancy". Epidemiologic Reviews Vol. 9. (Ex. P209, Tab M). January Sherman et al: "Sexually transmitted diseases and to March 1987 t ubal infertility in sexually transmitted diseases." Vol. 14, No. 1. (Ex. P209, Tab F). 1987 Daling et al: " Cigarette smoking and primary tubal infertility". Smoking & Reproductive Health, Ch. 9. (Ex. 212). February Friberg: "Chlamydia Trachomatis attached to 1987 spermatozoa recovered from the peritoneal cavity of patients with salpingitis." Journal of Reproductive Medicine, 32(2): 120-122, February 1987. (Ex. D333). 16 February Gilbert: "Therapeutics - treatment of chlamydial 1987 and mycoplasmal genital infections". The Medical Journal of Australia, Vol. 146. (Ex. D493). May Eisenstein: Thesis "Use of Intrauterine device as a 1987 model system for the study of bacteria adhesion to artificial implants." (Ex. P208). May ACOG Technical Bulletin: "The Intrauterine Device." 1987 (Ex. D447 at D3380). 15 June Letter from Phillips to Stewart. 1987 (Ex. P297, P1491.) July Grimes: "Intrauterine devices and pelvic inflammatory 1987 disease: Recent developments." (Ex. D324). July Confino & Ors: " Penetration of bacteria & 1987 spermatozoa into bovine cervical mucus." Journal of Obstetrics & Gynaecology, Vol. 70, No. 1. (Ex. D185). July Westrom: "PID: Bacteriology & sequelae". 1987 Contraception, Vol. 36, No. 1. (Ex. P386). 19 September Letter from Stein to Berens, Oppenheimer, Wolff & 1987 Donnelly, Re: Results, charts and conclusions of study attached. (Ex. P297, P1500). With regard to tests of new tailstrings to determine the distribution, lengths and widths of voids it was stated that: "While the [sic] are somewhat more voids than we originally thought were present. The number and average size of these is such that there is a negligible probability of forming a connected path of any significant length. Of special interest are the results on the samples treated with acid and detergent. It is apparent that there is no significant changes in the distribution of sizes, confirming that they are not caused to grow by these media. It is a bit puzzling that there appears to be an appreciably lower number of voids per string in the strings that were clinically treated than in the untreated ones. It is inconceivable that treatment can cause a decrease in number of voids." October Thejls et al: " Correlation between chlamydia infection 1987 and clinical evaluation, vaginal wet smear and cervical swab tests in female adolescents." American Journal of Obstetrics & Gynaecology, Vol. 157, No. 4, Pt. 1. (Ex. P389). 9 October Handwritten excerpt from Dr Fives-Taylor's Cu-7 Book 3 1987 (Ex. P202 vol 2). 1988 Manuilova and Dubnitskaya, "A Comparative Study of the Acceptability of the Inert and Copper-Containing IUDs" Soviet Ministry of Health (Ex. D420 tab 26). 1988 F Skjeldestad and H Bratt, "Fertility after complicated use of IUDs. A controlled prospective study" , Advanced Contraception, Vol. 4 (Ex. D420 tab 43). 1988 Blank Epidemiological Information Sheet. Epidemiological Information requested from patients whose IUDs were used in the Clinical Study. (Ex. P168 Tab 3). February Chow et al: " Maternal cigarette smoking and tubal 1988 pregnancy". Journal of Obstetrics & Gynaecology, Vol. 71, No. 2. (Ex. D213). 19 April Professor Robertson: Re: Transmission electron- 1988 microscopy study - IUD tailstring, No. 64. (Ex. D149). July Lee et al: " The intrauterine device and pelvic 1988 inflammatory disease revisited: New results from the Women's Health Study." Obstetrics & Gynaecology, July, 1988. (Ex. P126). 1 July Professor Fives-Taylor: Culture Sheets, "Demonstration 1988 & identification of bacterial populations colonising intrauterine contraceptive devices insitu." (Ex. D184). 7 December " Third Analysis of IUD data": 7 December, 1988. 1988 Handwritten notes. (Ex. D174). 1989 Apelo et al, "A 3-year evaluation of the Tcu380Ag and the Cu-7" Int J Gynecol. Obstet., Vol.28 (Ex. D384 tab 1). 1989 Gupta et al, "Return of Fertility in Various Types of IUD Users" International Journal of Fertility. (Ex. D420 tab 15). 1989 Forrest, Daling et al: " Vaginal douching as a possible risk factor for pelvic inflammatory disease." Journal National Medical Association, Vol. 81, No. 2. (Ex. D214). January Kessel: "Pelvic Inflammatory Disease with intrauterine 1989 device use: Reassessment." Fertility & Sterility, Vol. 51, No. 1, January 1989. (Ex. D488 at D3532). February Wilson: "A prospective New Zealand study of fertility 1989 after removal of copper intrauterine contraceptive devices for conception and because of complications: A four year study". American Journal Obstetrics & Gynaecology, 160(2): 391-396. (Ex. D325). April Patton & Ors: "A comparison of the fallopian tubes' 1989 response to overt and silent salpingitis." Obstetrics & Gynaecology, Vol. 73, No. 4, April 1989, p.622. (Ex. P297, P2139). May/June Lee: "What we've learned about IUDs." American 1989 Journal of Gynaecological Health, Vol. III, No. 3.S, May/June, 1989. (Ex. D488 at D3855). 24 July Letter to Dr D R Beech (Assistant Secretary, Medical 1989 Devices and Dental Products Branch, Department of Community Services and Health) from Walter J Hilsden (Searle Australia Pty Ltd), Re: updated information on safety and efficacy of Searle's Gravigard and Mini-Gravigard. (Ex. P297 Vol 17B). September Holt, Darling et al: "Induced abortion and the risk of 1989 subsequent ectopic pregnancy". American Journal of Public Health, Vol. 79, No. 9. (Ex. D216). 1989 K.M. Wilkins et al: "The influence of critical surface tension and microrugosity on the adhesion of bacteria to polymer monofilaments." International Journal of Pharmaceutics, No. 57, 1989. (Ex. D205). 30 August Letter from Faro to Stewart enclosing a final manuscript of 1989 research report "A Study of the Migration of Bacteria Through Cervical Mucous in the Presence and Absence of the Copper 7 IUD String". (Ex. D447 at D3583). 25 September Letter from Beech to Managing Director, Searle 1989 Australia. Re: Review of all IUCDs in Australia. (Ex. P297, P0672). "To ensure the continuing safety and efficacy IUD use in this country the Therapeutic Device Branch (TDB) under the auspices of the Therapeutic Device Evaluation Committee and its Advisory Panel on intrauterine contraceptive devices is to review the marketing status for intrauterine contraceptive devices supplied in Australia. Current import permits will be revolved on 31 March 1990 and sponsors of IUDs who wish to continue to supply their devices after this date will be required to submit an application…. Submissions for registration are required to be in the format outlined… They must include: i) clinical data to show that the particular IUD is safe and effective to be used by Australian women ii) draft patient information literature iii) a statement of known adverse events and their incidence iv) a sample of their device and their packaging v) copies of all intended advertising and promotional material vi) provision of post-market surveillance." November Hemsell et al: "Endometrial bacteria in asymptomatic 1989 non-pregnant women". Journal of Reproductive Medicine, Vol. 34, No. 11, November 1989. (Ex. D319). 1990 Westrom et al: "Sexually Transmitted Diseases". Part 6, Ch. 49 Acute PID. Approach to common clinical syndromes. (Ex. D358). 17 April Letter from Wachtel to Coughlin. 1990 (Ex. P245). June Daling et al: "Previous abdominal surgery & tubal 1990 pregnancy". Journal of Obstetrics & Gynaecology, Vol. 75, No. 6. (Ex. D218). 21 June Hand-written notes and diagrams on IUDs. 1990 (Ex. D239). 29 June Hand-written notes and diagrams 1990 (Ex. P240). 15 August Handwritten notes on migration experiment in agar tube, 1990 mixing E coli and S epidermidis. (Ex. D240). September H Buchan, L Villard-Mackintosh, M Vessey, D Yeates, K 1990 McPherson, "Epidemiology of pelvic inflammatory disease in parous women with special reference to intrauterine device use", British Journal of Obstetrics and Gynaecology (Ex. D384 tab 5). 1991 James O'Drife, "Intrauterine Contraceptive Devices", Handbook of Family Planning (Ex. D420 tab 10). 1991 Warner et al (including Fives-Taylor): "Performance of the polypropylene fiber tailstring on the Cu-7 intrauterine device." (Ex. P109, P2292). 1991 B J Struthers, "Copper IUDs, PID and fertility in nulliparous women", Advances in Contraception. (Ex. D420, tab 44). 1991 Daling et al: "Maternal cigarette smoking and the risk of tubal pregnancy." American Journal of Epidemiology, Vol. 133, No. 4. (Ex. D220). 1991 Paula Fives-Taylor & Channing Robertson. "Letters to the Editor." Journal of Applied Bio-materials, Vol 2. (Ex. D156). 2-6 January Costerton: Lecture on Obstetrics & Gynaecology 1991 Perinatal medicine, bioethics and the law. (Ex. D357). January Daling et al: "Vaginal douching and the risk of tubal 1991 pregnancy." Epidemiology, Vol. 2, No. 1. (Ex. D219). 11 January Note of contact with Brooks from MDDPB, Cmth 1991 DOH by Colette Re: Stocks of Gravigard are to be depleted. "We will not be recalling the product." (Ex. P297, P0650). 13 November J G Kahn, C K Walker, A E Washington, D V Landers and 1991 R L Sweet, "Diagnosing Pelvic Inflammatory Disease: A Comprehensive Analysis and Considerations for Developing a New Model" JAMA (Ex. D420 tab 20). 13 November A E Washington, S O Aral, P Wolner-Hanssen, David A 1991 Grimes, King K Holmes, "Assessing Risk for Pelvic Inflammatory Disease and its Sequelae", JAMA (Ex. D420 tab 52). 16 January Daling et al: "Intrauterine device and primary tubal 1992 infertility". New England Journal of Medicine, January 16, 1992. (Ex. P128). 28 March Farley et al: "Intrauterine devices and pelvic 1992 inflammatory disease: An International perspective." The Lancet, Vol. 339, March 28, 1992. (Ex. P127). 6 April Letter from Clayton Utz to Cashman & Partners referring to 1992 factual inaccuracies in document entitled "Master Statement of Claim" (Ex. P297 at P3308) July/August Nugent et al: "Muco-purulent cervicitis as a predictor 1992 of chlamydial infection and adverse pregnancy outcome". Sexually transmitted diseases. Vol. 19,No. 4, Journal. (Ex. P388). 25 July Rossing & Weiss: "IUDs and PID". Letter to 1992 The Lancet, Vol. 340. (Ex. P209, Tab B). 1993 Mahmoud et al, "Bacteria migration along polymer fibres" J Biomater. Sci. Polymer Ed. (Ex. P237 tabs 1 and 2). 1993 Directory & address of Warren Peter Joseph D'Ambrosis. (Ex. D510). 1993 Alphabetical directory listing of David Charles Ross Macourt. (Ex. D512). 1993 Bromham: "Intrauterine contraceptive devices - a reappraisal". British Medical Bulletin, Vol. 49, No. 1. (Ex. D359). 1993 D. Roylance: "Assessment of Olefin-based IUD tail- strings". Journal of Applied Bio-materials, Vol. 4, No. 4. (Ex. D163). 1993 Coughlin et al: Journal of Applied Bio-materials. Vol, 4, No. 363. Title: Errata. (Ex. D242). 1993 Mahmoud, Vieth and Coughlin, "Migration of Bacteria Along an IUCD Retrieval Thread and Other Synthetic Fibres" (Ex. D312). May Rossing et al: "Current use of an intrauterine device 1993 and risk of tubal pregnancy." Epidemiology, Vol. 4, No. 3. (Ex. P209, Tab G). May Rossing et al: "Past use of an intrauterine device and risk 1993 of tubal pregnancy." Epidemiology, May, 1993, Vol. 4, No. 3. (Ex. P132). 1993 Eschenbach: "Bacterial vaginosis & anarobes in Obstetric-Gynaecological infection." CID, 1993: 16 (supplement). (Ex. D121). August Faro: "Vaginal floor and pelvic inflammatory disease." 1993 American Journal of Obstetrics & Gynaecology, 169(2, Pt.2): 470-474, August 1993. (Ex. D331). 24 September Explanation on PID . MMWR Journal, Vol. 42. 1993 (Ex. D277). December Sheffield et al: "The Association between Chlamydia 1993 Trachomatis serology and pelvic damage in women with tubal ectopic gestations." Fertility & Sterility, Vol. 60, No. 6. (Ex. P209, Tab L). 1994 Basuki et al, "Intrauterine Device Use and Risk of Tubal Pregnancy: An Indonesian Case-Control Study", International Journal of Epidemiology (Ex. P209 tab 1). 1994 Bisno & Waldvogel: "Infections associated with indwelling medical devices." 2nd Edition. (Ex. 295). 1994 Rivera: "Is there an effect of the IUD string in the development of Pelvic Inflammatory Disease in IUD Users?" Proceedings from Fourth International Conference on IUDs. (Ex. D321). 21 February Judgment of Smart J of Supreme Court of NSW. 1994 re: 11899/89, 12257/89. (Ex. D509). March-April Hemsell et al: "Endometrial bacteria in asymptomatic 1994 non-pregnant women." Journal of Reproductive Medicine, Vol. 34, No. 11, November 1989. (Ex. D319). April Soper: "Observations concerning the microbial etiology 1994 of acute salpingitis". American Journal of Obstetrics & Gynaecology, 170(4): 1008-1017, April 1994. (Ex. D335). April Costerton et al: "Mini-review: Bio-films, the customised 1994 microniche". Journal of Bacteriology, 1994, Vol, 176, No. 8. (Ex. P343). 15 April Letter from Cashman & Partners to Clayton Utz re 1994 Cu-7 litigation - choice of lead cases pursuant to Orders of Smart J. (Ex. D508). June Roy and Azen, "Table III: Crude pelvic inflammatory 1994 disease rate (percent) of 1614 users" Am J Obstet. Gynecol. (Ex. D301 at SR4). 21 June Letter from Bampton, Fisher Jeffries, Solicitors to 1994 Exhibits Clerk, Supreme Court of NSW, Sydney. Re: Subpoena for production to Dr Fuk-Chan. (Ex. D505). 22 June Annexure "A" (letter from Dr Denzin) to Affidavit 1994 of Julie Geary. (Ex. D507). July Patton et al, "Detection of Chlamydia trachomatis in 1994 fallopian tube tissue in women with postinfectious tubal infertility" Am J Obstet Gynecol (Ex. D316). 1995 Drs Ashley and Ritman: Review of Mini clinical trial data - Table 1. (Ex. P258 p554). 1995 Sweet & Gibbs: Infectious diseases of the female genital Tract." 3rd Ed. (Ex. P294). 1995 Costerton et al: "Microbial bio-films". Annual Review of Micro-biology, 1995. (Ex. 340). 1995 Parazzini et al: "Past contraceptive method use at risk of ectopic pregnancy". Contraception. (Ex. P209, Tab3). 1995 Mol et al: "Contraception and the risk of ectopic pregnancy: a meta analysis". Contraception. (Ex. P426). 1995 Xu Xiong et al: "IUD use and risk of ectopic pregnancy: Analysis of case control studies." Contraception (Ex. P209, Tab 3(B). 1995 "Current status of intrauterine devices" update. American College of Obstetricians & Gynaecologists. (Ex. D488 at D3770). 17 October Handwritten observations made in early experiments of 1995 swarming by B cereus. (Annexure SK4 to Ex. D305 - Statement of Prof Kaplan). 19 October "FaAA Protocol for Test Specimen Selection of the Cu-7 1995 Retrieval Monofilament and its Subsequent Handling" (Annexure RLP-5 to Ex. D306 - Statement of Dr Piziali). 22 October Statement/Curriculum Vitae of Professor John Richard 1995 Newton. (Ex. D299 at JRN1). 1996 Brisbane Telephone Directory Yellow Pages - Medical Directory Listing of W.P. D'Ambrosis, Obstetrician & Gynaecologist & Infertility therapy. (Ex. D511). 1996 1996 Sydney Telephone Directory Yellow Pages - Directory listing of D.C. Macourt, Gynaecologist & Infertility. (Ex. D513). 1996 Piziali et al: "Evidence against tailstrings increasing the rate of PID among IUD users".Contraception. (Ex. D361). 28 January Statement of Dr Ashley (Ex. P258). 1996 25 April Affidavit of Dr Mounsey. 1996 (Ex. P249). 1996 Handwritten table: "Admission, follow-up and status Reports" re classification of possible, probable or proven PID. (Ex. P279). 4 July Notice to admit facts of Clayton Utz to Dr Cashman. 1996 (Ex. D416). 30 August Affidavit of Joan Fitzgerald, MD. 1996 Filed for defendants. (Ex. D487). 1996 Advertisement prepared by Australian Iron Status Advisory Panel: "Iron deficiency in adults: a comprehensive management guide." (Ex. D491). C 1996 Piziali: Chart showing tailstring retraction rates. (Ex. D362). 1996 Table on Report of O'Brien article. Contraception. (Ex. P411). 1996 Handwritten notes and calculations on crude rate and pearl index. (Ex D414). 1996 Table of results of studies on symptoms of women wearing IUDs. (Ex. D430). 1996 Table "Thirteen clinical cases reported as PID". Data collected from case report forms. (Ex. D434). Undated A. Bogucki: Hand-written notes: "Observations of the results of e-coli tests." (Ex. P246). Undated Further witness statement of Dr Daling. (Ex. P209, Tab 3.) Undated Balfour Jnr. & Heussner "Herpes without sex: from cold sores to encephalitis." Book: Herpes Diseases and your Health. (Ex. P417). Undated Dr Gollan's medical records. (Ex. D381 at P02677). Undated David A Grimes MD, "Biases: The Saboteurs of Science". (Ex. D384 tab 10). Undated David A Grimes MD, "Making Sense of Research Findings" (Ex. D384 tab 9). Undated David A Grimes MD, "'Risky'" Business: Measuring Associations in Clinical Research". (Ex. D384 tab 13). Undated Irving Sivin, "Extrauterine Pregnancies and Intrauterine Devices Reassessed" (Ex. D384 tab 25). Undated Eschenbach: "Pelvic Inflammatory Disease." (Ex. D134). Undated String Memory Video (Ex. D306 at attachment RLP-B). Undated Piziali: SEMS of the Cross Sections of a Cu-7 and a Dalkon Shield Tailstring (Ex. D306). Undated Dr Piziali: SEM Images of Tailstring Video (Ex. D306 at RLP-A attachment). Undated Third Statistical Analysis of Prof Fives-Taylor's data (Ex. D175). Undated Letter from Prof Fives-Taylor to a plaintiffs' attorney in the United States asserting that 70% of the women had their IUDs removed for "pain and bleeding, infection or actinomyces noted on pap smear!!!" (Ex. P168 tab 8). Undated Curriculum Vitae - Samuel Kaplan (Ex. D305 at SKI). Undated Mini-Gravigard Package Insert - Version A1 (Ex. D309). SCHEDULE II - OVERVIEW OF PLAINTIFF'S PLEADINGS COMMON LAW NEGLIGENCE - GRAVIGARD NOT AVAILABLE IN ELECTRONIC FORM - TO OBTAIN A COPY PLEASE ENQUIRE VIA THE COURT REGISTRY AT TELEPHONE 61 O2 9230 8111 SCHEDULE III - OVERVIEW OF COMMON LAW PLEADINGS NOT AVAILABLE IN ELECTRONIC FORM - TO OBTAIN A COPY PLEASE ENQUIRE VIA THE COURT REGISTRY AT TELEPHONE 61 O2 9230 8111 Last Modified: 06/28/2007 DISCLAIMER - Every effort has been made to comply with suppression orders or statutory provisions prohibiting publication that may apply to this judgment or decision. The onus remains on any person using material in the judgment or decision to ensure that the intended use of that material does not breach any such order or provision. Further enquiries may be directed to the Registry of the Court or Tribunal in which it was generated.