NSW Civil and Administrative Tribunal New South Wales Medium Neutral Citation: Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (SPICE III Trial) [2014] NSWCATGD 44 Hearing dates: 17 December 2013, 8 May 2014, 15 October 2014 Date of orders: 23 December 2014 Decision date: 23 December 2014 Jurisdiction: Guardianship Division Before: Fougere C, Principal Member West C, Senior Member (Professional) Porter L, General Member (Community) Decision: The SPICE III Trial approved as a clinical trial in which adults who are unable to consent may participate. Function of giving or withholding consent to be exercised by the Tribunal. Catchwords: CLINICAL TRIAL – comparison of standard care sedation strategies in intensive care units – randomisation of treatment - use of dexmedetomidine beyond TGA authority - whether a clinical trial - Clinical Trial Notification Scheme under Therapeutic Goods Act 1989 – 'delayed consent' not part of Guardianship Act. Legislation Cited: Civil and Administrative Tribunal Act 2013 (NSW) Guardianship Act 1987 (NSW) National Health and Medical Research Council Act 1992 Therapeutic Goods Act 1989 (Cth) Therapeutic Goods Regulations 1990 (Cth) Australian Code for the Responsible Conduct of Research (2007) Cases Cited: Alcan (NT) Alumina Pty Ltd v Commissioner of Territory Revenue [2009] HCA 41; (2009) 239 CLR 27, Hayne, Heydon, Crennan, Kiefel JJ, [47] Commissioner of Taxation v Consolidated Media Holdings Ltd (2012) 293 ALR 257; [2012] HCA 55, French CJ, Hayne, Crennan, Bell and Gageler JJ, [39] Amalgamated Society of Engineers v Adelaide Steamship Co Ltd (192) 28 CLR 129, 161-162 (Higgins J) Project Blue Sky Inc v Australian Broadcasting Authority (1998) 194 CLR 355, McHugh, Gummow, Kirby and Hayne JJ, 384 [78] Texts Cited: Pearce and Geddes Statutory Interpretation in Australia, 8th Edition, (2014) LexisNexis Butterworths Online [3.30] The Macquarie Dictionary (online edition) The Oxford English Dictionary (online edition) National Health and Medical Research Council, "National Statement on Ethical Conduct in Human Research" 2007 (Updated March 2014) https://www.nhmrc.gov.au/book/national-statement-ethical-conduct-human-research accessed 23 December 2014 Category: Principal judgment Parties: Dr Yahya Shehabi (Applicant) File Number(s): 10/2013 Publication restriction: Nil REASONS FOR DECISION 1. These Reasons for Decision relate to the orders made by the Tribunal on 23 December 2014 concerning a prospective multicentre randomised controlled trial of early goal directed sedation compared with standard care in mechanically ventilated patients in intensive care (SPICE III). INTRODUCTION 1. The applicant in these proceedings is Dr Yahya Shehabi, Senior Intensivist at the Prince of Wales Hospital, Randwick, NSW, Associate Professor at the Clinical School of Medicine, University of New South Wales and Medical Director of Acute Care and Director of Intensive Care Research at the Prince of Wales Hospital, Randwick. 2. The hypothesis sought to be tested in the current study (as set out in the Study Protocol, page 9) is that Early Goal Directed Sedation, compared to standard care sedation, reduces 90-day all-cause mortality in critically ill patients who require mechanical ventilation. The primary aim is therefore to determine whether Early Goal-Directed Sedation, compared to standard care sedation, reduces 90 day mortality in critically ill patients who are expected to require mechanical ventilation for longer than 24 hours. 3. The Study Protocol (page 19) describes the study as a process of care sedation trial whereby the sedative agents used in both arms, individually or in combination, are accepted sedatives currently used for mechanically ventilated ICU patients. The Study Protocol notes that many randomised control trials have documented the efficiency and safety in isolation of the three agents (propofol, midazolam and dexmedetomidine) used in the trial and these agents have also been recommended by the most recent International Sedation Guidelines and have been deemed not different in providing sedation to ventilated ICU patients. 4. Dexmedetomidine (also known as Precedex) has been used as a sedative agent in ICUs for a number of years. It is licensed by the Therapeutic Goods Administration ('TGA') for sedation of initially intubated patients during treatment in an intensive care setting for up to 24 hours. It is also licensed for sedation of non-intubated patients prior to and/or during surgical or other procedures. 5. The study proposes the use of dexmedetomidine for a period longer than 24 hours and is thereby proposed for use outside of its licensed parameters. 6. One of the critical issues in the application was whether or not the study falls within the definition of a 'clinical trial' in the Guardianship Act 1987 (NSW) ('Guardianship Act'). The applicant submitted that it does not do so and wished to have his application dismissed. For the reasons that follow, the Tribunal decided that the study is a clinical trial for the purposes of the Guardianship Act and determined to approve the proposed trial under section 45AA as a trial in which it is appropriate for patients who cannot give their own consent to be able to participate. The Tribunal also determined, pursuant to section 45AB(1)(b), that the function of giving or withholding consent for the carrying out of medical treatment on individual patients in the course of the proposed trial should be exercised by the Tribunal. 7. For a number of reasons, this matter has had a lengthy history before the Tribunal. The progress of the matter is outlined in Appendix A to these Reasons for Decision. TRANSITIONAL MATTERS 1. Whilst these proceedings commenced in the NSW Guardianship Tribunal, on 1 January 2014 the Civil and Administrative Tribunal of New South Wales ('the Tribunal') was established and on its establishment the Guardianship Tribunal was abolished. Pursuant to the transitional provisions in Civil and Administrative Tribunal Act 2013 (NSW), the matter continued in the Tribunal. The Tribunal has and may exercise all the functions which the Guardianship Tribunal previously had and the applicable legislation is that which would have applied if the Civil and Administrative Tribunal Act had not been enacted. THE APPLICABLE LEGISLATION Guardianship Act 1. The provisions relating to clinical trials are found within Part 5 of the Guardianship Act. Part 5 applies to patients who are aged 16 years or over and who are incapable of giving consent to the carrying out of medical or dental treatment (Guardianship Act, section 34(1)). 2. For the purposes of Part 5, a person is regarded as being incapable of giving consent to the carrying out of medical or dental treatment if the person: 1. is incapable of understanding the general nature and effect of the proposed treatment, or 2. is incapable of indicating whether or not he or she consents or does not consent to the treatment being carried out (section 33(2)). 1. The objects of Part 5 are contained in section 32: 32 Objects The objects of this Part are: (a) to ensure that people are not deprived of necessary medical or dental treatment merely because they lack the capacity to consent to the carrying out of such treatment, and (b) to ensure that any medical or dental treatment that is carried out on such people is carried out for the purpose of promoting and maintaining their health and well being. 1. The carrying out of medical or dental treatment other than in accordance with Part 5 of the Guardianship Act (or in accordance with an appropriate order of the Supreme Court, see s 35(1)(c)) is a criminal offence pursuant to section 35 of the Guardianship Act. 35 Offences (1) A person must not carry out medical or dental treatment on a patient to whom this Part applies unless: (a) consent for the treatment has been given in accordance with this Part, or (b) the carrying out of the treatment is authorised by this Part without any such consent, or (c) the treatment is carried out in accordance with an order made by the Supreme Court in the exercise of its jurisdiction with respect to the guardianship of persons. 1. In the case of treatment in the course of a clinical trial, the maximum penalty (on conviction on indictment) is imprisonment for seven years. The seriousness with which such an offence is regarded is evident not only from the nature of the maximum penalty but also when contrasted with the maximum penalty for the carrying out of minor or major treatment other than in accordance with s 35(1), namely, upon summary conviction, imprisonment for a maximum of one year or 10 penalty units ($1,100) or both. 2. Under section 45AA(1) of the Guardianship Act, the Tribunal may approve a clinical trial as a trial in which patients who are unable to give a valid consent to their own treatment may take part. Before doing so, the Tribunal must be satisfied as to all of the criteria set out in section 45AA(2) of the Guardianship Act. 3. Section 45AA provides as follows: 45AA Tribunal may approve clinical trials (1) The Tribunal may approve, in accordance with this section, a clinical trial as a trial in which patients to whom this Part applies may participate. (2) The Tribunal may give an approval under this section only if it is satisfied that: (a) the drugs or techniques being tested in the clinical trial are intended to cure or alleviate a particular condition from which the patients suffer, and (b) the trial will not involve any known substantial risk to the patients (or, if there are existing treatments for the condition concerned, will not involve material risks greater than the risks associated with those treatments), and (c) the development of the drugs or techniques has reached a stage at which safety and ethical considerations make it appropriate that the drugs or techniques be available to patients who suffer from that condition even if those patients are not able to consent to taking part in the trial, and (d) having regard to the potential benefits (as well as the potential risks) of participation in the trial, it is in the best interests of patients who suffer from that condition that they take part in the trial, and (e) the trial has been approved by a relevant ethics committee and complies with any relevant guidelines issued by the National Health and Medical Research Council. (3) The fact that a clinical trial will or may involve the giving of placebos to some of the participants in the trial does not prevent the Tribunal from being satisfied that it is in the best interests of patients that they take part in the trial. (4) The Tribunal's approval of a clinical trial under this section does not operate as a consent to the participation in the trial of any particular patient to whom this Part applies. The appropriate consent must be obtained under Division 3 or 4 before any medical or dental treatment in the course of the trial is carried out on the patient. (5) In this section: "ethics committee" means: (a) for so long as there is any relevant Institutional Ethics Committee registered by the Australian Health Ethics Committee established under the National Health and Medical Research Council Act 1992 of the Commonwealth--an Institutional Ethics Committee so registered, or (b) in the absence of such a committee, an ethics committee established by: (i) a local health district or a public hospital, or (ii) a university, being an ethics committee concerned, wholly or partly, with medical research, or (iii) the National Health and Medical Research Council. 1. As is clear from section 45AA(4), if the Tribunal approves a trial as one in which patients who are unable to give a valid consent to their own treatment may take part, consent for the participation of particular patients in the trial must be obtained under Division 3 or 4 before any medical or dental treatment in the course of the trial may carried out in relation to the patient. 2. The Tribunal may determine, pursuant to section 45AB(1), that * the function of giving or withholding consent for the carrying out of medical or dental treatment on patients in the course of the trial is to be exercised by the persons responsible for the patients (in which case Division 3 applies), or * the Tribunal is to exercise that function itself (in which case Division 4 applies). 1. Before making a determination that the function of giving or withholding consent for the carrying out of medical or dental treatment on patients in the course of a trial is to be exercised by the persons responsible for the patients, the Tribunal must be satisfied that the form for granting consent and the information available about the trial provide sufficient information to enable the persons responsible to decide whether or not it is appropriate that the patients should take part in the trial (section 45AB(2)). 2. The definition of clinical trial is set out in section 33(1) as follows: 'clinical trial' means a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial. 1. Section 33(1) relevantly defines 'medical treatment' or 'treatment' as meaning: (a) medical treatment (including any medical or surgical procedure, operation or examination and any prophylactic, palliative or rehabilitative care) normally carried out by or under the supervision of a medical practitioner, or … (c) any other act declared by the regulations to be treatment for the purposes of this Part, (and, in the case of treatment in the course of a clinical trial, is taken to include the giving of placebos to some of the participants in the trial)… 1. The clinical trial provisions in the Guardianship Act are also subject to the general principles set out in section 4 of the Act. Under section 4, it is the duty of everyone exercising functions under the Guardianship Act with respect to persons who have disabilities to observe the following principles: 1. the welfare and interests of such persons should be given paramount consideration, 2. the freedom of decision and freedom of action of such persons should be restricted as little as possible, 3. such persons should be encouraged, as far as possible, to live a normal life in the community, 4. the views of such persons in relation to the exercise of those functions should be taken into consideration, 5. the importance of preserving the family relationships and the cultural and linguistic environments of such persons should be recognised, 6. such persons should be encouraged, as far as possible, to be self-reliant in matters relating to their personal, domestic and financial affairs, 7. such persons should be protected from neglect, abuse and exploitation, 8. the community should be encouraged to apply and promote these principles. National regulatory framework 1. The Guardianship Act provisions do not sit in isolation and there is a broader regulatory framework that exists for the consideration and approval of clinical trials. As will be outlined, this framework, and in particular the inclusion of SPICE III in the clinical trial notification scheme created pursuant to the Therapeutic Goods Act 1989 (Cth) ('TG Act'), was particularly relevant in the circumstances of this matter. 2. Before the Tribunal may consider whether or not to approve a trial, it must already have been approved by 'a relevant ethics committee and compl[y] with any relevant guidelines issued by the National Health and Medical Research Council' (Guardianship Act, section 45AA(2)(e)). 3. Human research ethics committees ('HREC') registered with the National Health and Medical Research Council ('NHMRC') must act in accordance with the National Statement on Ethical Conduct in Human Research 2007 (updated March 2014) ('National Statement'). [1] [2] 4. The role of HRECs and the obligations placed upon them are set out in detail in Chapter 5 of the National Statement. 5. All research involving humans with more than a low level of risk must be reviewed and approved by an HREC that is constituted and functioning in accordance with the National Statement. Research is 'low risk' where the only foreseeable risk is one of discomfort. Where the risk, even if unlikely, is more serious than discomfort, the research is not low risk. [3] This includes research discussed in Chapter 3.3 of the National Statement dealing with Interventions and therapies, including clinical and non-clinical trials, and innovations. All clinical trials in Australia require review and approval of trial proposals by an ethics committee. [4] The definition given to 'clinical trial' in the National Statement is 'a form of research designed to find out the effects of an intervention, including a treatment or diagnostic procedure.' [5] 6. Also part of the national framework relevant to clinical trials are the clinical trial notification scheme and the clinical trial exemption scheme created pursuant to the TG Act. Under the TG Act, therapeutic goods for human use that are imported, manufactured in Australia, supplied by a corporation, supplied interstate or to the Commonwealth, or exported must be included in the Australian Register of Therapeutic Goods ('ARTG'). [6] However, some therapeutic goods are exempted under the TG Act from the requirement for inclusion in the ARTG. This includes therapeutic goods for use in clinical trials and is achieved by way of the clinical trial notification scheme [7] ('CTN') or clinical trial exemption scheme ('CTX'). 7. Pursuant to the TG Act and Regulations, either notification under the CTN scheme or application under the CTX scheme is required for all clinical investigational use of a product where that use involves, relevantly: use of a product beyond the conditions of its marketing approval, including new indications extending the use of a medicine to a new population group and the extension of doses or duration of treatments outside the approved range 1. This category is particularly relevant in this matter given the proposed use of dexmedetomidine outside of its TGA licensed parameters and the evidence of the applicant and the Chairperson of the relevant HREC that Notification has been provided to the TGA, under the Clinical Trial Notification Scheme, for all participating sites according to the approved Protocol V3 June 24 2013 including the use of dexmedetomidine outside its registered use. 1. Under the CTN scheme, the use of such products is referred to as being used 'for experimental purposes in humans'. [8] A product may be exempted from the ARTG provided that the following conditions are met: [9] • the sponsor notifies the TGA using the approved CTN form and paying the appropriate fee • the trial must be approved by the sponsor of the goods and the sponsor of the trial (if not the sponsor of the goods) having regard to the advice of the HREC which reviewed the protocol and is assuming responsibility for the monitoring of the trial. • the terms of approval of the sponsor or the body or organisation conducting the trial for the sponsor must be no less restrictive than terms advised by the HREC. • the TGA must not: • have become aware that to start or continue the trial is not in the public interest • have directed that the trial not start or be stopped. • The sponsor has not received advice from the HREC that is inconsistent with continuation of the trial. • The conditions set out in regulation 12AD must be complied with. Regulation 12AD sets out that use of therapeutic goods must be in accordance with Good Clinical Practice, the protocol approved by the HREC and the National Statement. Regulation 12AD also requires that the trial must cease if the ethics committee inform the principal investigator that the use is inconsistent with the protocol they have approved or any other condition to which approval for use was given. 1. Under the CTN scheme, the TGA does not review any data relating to the clinical trial. Rather, the HREC is responsible for assessing the scientific validity of the trial design, the safety and efficacy of the medicine or device and the ethical acceptability of the trial process, and for approval of the trial protocol. In some institutions a scientific review or drug subcommittee may review the proposal before consideration by the HREC. The institution or organisation at which the trial will be conducted, referred to as the 'Approving Authority', gives the final approval for the conduct of the trial at the site, having due regard to advice from the HREC. [10] 2. The TGA 'Notification of Intent to Conduct a Clinical Trial' form (the CTN Form) is submitted by the investigator on behalf of the sponsor to the HREC and to the Approving Authority. Once the sponsor, the principal investigator, the Chairman of the HREC and the person responsible from the Approving Authority have signed the CTN Form, it is submitted by the sponsor of the trial to the TGA along with the appropriate notification fee. [11] THE EVIDENCE 1. The evidence provided to the Tribunal is that the study will form part of the SPICE (Sedation Practice in Intensive Care Evaluation) Project, which is being coordinated by the Australian and New Zealand Intensive Care Research Centre ('ANZIC') at Monash University in Victoria. The objectives of ANZIC are to: * Identify and define current sedation and delirium management practice * Develop candidate interventions for optimal sedation strategy * Demonstrate that candidate interventions can be implemented in pilot randomised control trials * Test the hypothesis that sedation strategy influences survival and quality of survival 1. According to the material provided in support of the application (Study Protocol, page 8), more than 50,000 critically ill patients in Australia undergo ventilation and sedation every year. The 2012 Society Critical Care Medicine guidelines on the management of pain, agitation and delirium reviewed more than 18,000 published articles and concluded there was no evidence to judge that any of the commonly used sedative medications – midazolam, propofol and dexmedetomidine – were superior and that definitive studies on sedation practices are urgently required. Over the last decade, clinical practice has moved towards the use of lighter levels of sedation whenever clinically safe, better management of pain and recognition of delirium as occurring commonly in patients with critical illness. 2. A longitudinal prospective cohort study on sedation practice in Australia and New Zealand conducted in 2010 as part of the SPICE Project showed that Australian and New Zealand intensive care clinicians used midazolam and/or propofol and/or dexmedetomidine in 66.7%, 80.1% and 27% of patients respectively, commonly in combination. The application material (Study Protocol, page 8) noted the use of dexmedetomidine is unlikely to have decreased since that study was conducted in 2010. The study also showed that deep sedation is common early (within the first 48 hours) after initiation of mechanical ventilation and independently predicts delayed time to extubation and higher risk of hospital and 180-day mortality. 3. The SPICE investigators concluded that future trials testing different strategies for achieving sedation in patients who are critically ill should have the following features: * Randomisation should occur soon after intubation or arrival in the ICU (early) * Dexmedetomidine should be used as a the primary sedative agent and that use of benzodiazepines should be minimised * Sedation should be titrated to achieve light sedation (goal directed) * Should have sufficient statistical power to detect plausible differences in patient centred endpoints, particularly mortality and * The control group should receive standard care, with predominant use of midazolam or propofol or both, as determined by the treating clinician, and if directed to a sedation target as determined by the treating clinician. 1. The feasibility of delivering a sedative intervention that had these design features was tested in a pilot trial comparing a dexmedetomidine based algorithm focused on Early Goal Directed Sedation (EGDS) with Standard Sedation. 2. This pilot trial formed the basis of an earlier application by the same applicant to the then Guardianship Tribunal (Trial No. 6/2011). Orders were made by the Tribunal on 27 July 2011 that the entirety of the 'SPICE Trial', the pilot prospective randomised control trial of sedation practices, was a clinical trial within the terms of the Guardianship Act and met the criteria established in section 45AA of that Act. The Tribunal approved the proposed trial as a trial in which it was appropriate for patients who could not give their own consent to be able to participate. The Tribunal also determined that the function of giving or withholding consent for the carrying out of medical treatment on patients in the course of the proposed trial should be exercised by the 'persons responsible' for the patients sought to be recruited to the trial pursuant to the provisions of section 45AB(1)(a). 3. Evidence was provided that the current study will be conducted in approximately 35 study intensive care units and will recruit approximately 4000 patients worldwide. According to Dr Shehabi, the study commenced in Victoria in November 2013, in Tasmania and New Zealand in around April 2014 and in Queensland, South Australia and the Northern Territory in May 2014. 4. The sites at which the proposed study would be conducted in NSW are Prince of Wales Hospital, Randwick; Nepean Hospital, Penrith; St Vincent's Hospital, Darlinghurst; Hornsby Ku-ring-gai Hospital; Lismore Hospital; and Westmead Hospital. Royal North Shore Hospital and Blacktown Hospital may also take part in the study but this is not yet confirmed. 5. Patients who satisfy the inclusion criteria and have no exclusion criteria will be randomly assigned in a 1:1 ration to either the intervention arm, Early Goal-Directed Sedation, or the control arm, standard sedation practice. 6. Patients in the 'intervention arm' will receive a dexmedetomidine infusion starting at 1mcg/kg/hr without loading dose to achieve a target Richmond Agitation Sedation Scale (RASS) of -2 to +1 at all times, unless otherwise clinically indicated. Dexmedetomidine infusion will be continued until sedation is no longer clinically indicated up to a maximum of 28 days after enrolment. 7. If dexmedetomidine alone is insufficient, propofol will be administered, by bolus or infusion or both in order to achieve the targeted level of sedation. The use of midazolam is precluded in the Early Goal-Directed Sedation group except for defined clinical situations in which it can be used at the direction of the treating clinician. 8. Patients in the "control arm" will receive sedative medications (either midazolam or propofol or both), as determined by the treating clinician, to achieve a clinically appropriate sedation target as chosen by the treating clinician, although according to the Study Protocol (page 9), a target of RASS -2 to +1 is encouraged at all times in this arm 9. The inclusion criteria for the trial are stated to be as follows: 1. Subject has been intubated and is receiving mechanical ventilation 2. The treating clinician expects that the patient will remain intubated until the day after tomorrow (unlikely to be extubated the following day) 3. The patient requires immediate ongoing sedative medication for comfort, safety and to facilitate the delivery of life support measures 1. As noted in the Study Protocol (page 19) and confirmed in Dr Shehabi's oral evidence, by virtue of the study's entry criteria none of the patients who are eligible for the study will be competent to provide informed consent for their treatment. Evidence and submissions concerning use of dexmedetomidine beyond its TGA licence 1. Dr Shehabi and his colleagues, in written submissions and in their oral evidence, submitted that the use of dexmedetomidine beyond its licensed parameters is clinically accepted practice in Australia. It was also submitted that the proposed use of the drug in this study outside of its licensed parameters should not dissuade the Tribunal from making a finding that the study is not a clinical trial given, as the applicant put the argument, the study is a process of care sedation study and the sedative agents used in both arms are accepted sedatives used for mechanically ventilated ICU patients. 2. The Tribunal invited the applicant to make further written submissions addressing this issue. By letter dated 2 January 2014, the applicant provided detailed written submissions that may be summarised as follows: * The TGA drug/device registration is a regulatory framework for market authorisation and is commonly not congruent with actual clinicians' use and current standard practice driven by contemporary practice * Drugs and devices are commonly used and can be 'standard practice' despite a lack of TGA approval for that specific indication – they just cannot be marketed commercially for that indication * Conversely, many newer agents and devices have received TGA approval for marketing but despite often aggressive marketing attempts have not been accepted into current practice and in some instances further research has demonstrated clear harm * In the specific case of dexmedetomidine, the current TGA registration is based on data from 15 years ago and is outdated by more recent phase III trials and registration in Europe and Canada * Dexmedetomidine is now commonly used in Australian intensive care units by prolonged infusion, but there is no commercial reason for the pharmaceutical company to seek this license as the patent is about to expire in Australia. This does not change the need for a high quality process of care study to evaluate sedation practices in Australia, with a long term patient centred endpoint 1. In the adjourned period following the hearing on 17 December 2013, the Tribunal became aware of the contents of an article in the Medicines Safety Update, Vol 4, No 4, August 2013 (page 134) issued by the Therapeutic Goods Administration entitled 'Dexmedetomidine hydrochloride and cardiovascular events'. In that article, the TGA referred to a study conducted in 2012 aimed to investigate the safety and effectiveness of dexmedetomidine for emergency department patients with acute behavioural disturbance and who were difficult to sedate. According to the article, the authors concluded that the use of intravenous dexmedetomidine in such situations was unsafe. 2. After noting that the sedation of patients with an acute behavioural disturbance is not an approved indication for dexmedetomidine and factors other than the use of the drug may have contributed to the patient outcomes discussed in the study, the article nevertheless reminds health professionals to carefully consider patient selection and the setting in which dexmedetomidine is administered to ensure its safe use. Dexmedetomidine should only be used for the approved indications and should be administered in accordance with the instructions in the [Product Information]. A controlled infusion device should be used for the administration of dexmedetomidine, and the dose and rate of infusion should not exceed that recommended in the PI. 1. In order to afford procedural fairness to the applicant, by way of email dated 24 March 2014 from the Divisional Deputy Registrar of the Tribunal, the applicant was invited to respond to the following two issues: * Whether the applicant and the South Eastern Sydney Local Health District are aware of the Medicines Safety Update article and whether the applicant wishes to make a submission as to the relevance of the article to the application * Whether the South Eastern Sydney Local Health District, or any other organisation, provided notification of the proposed study to the Therapeutic Goods Administration under the Clinical Trial Notification Scheme given the proposed use of dexmedetomidine beyond its registered use 1. By way of letter dated 3 April 2014, Dr Shehabi, in summary, responded as follows: * The Medicines Safety Update article emphasised what is already known about dexmedetomidine and supports the way in which it is prescribed in both usual intensive care practice and in the study protocol. The article also states that over the last 10 years, there have only been a small number of reports of cardiovascular events such as those described in the product information. It clearly warns against the use of dexmedetomidine in indications such as that described in the emergency department study referred to in the article but that what is proposed in the current study that is the subject of the current application before the Tribunal is in line with the current clinical use supported by extensive safety data * Notification has been provided to the TGA, under the Clinical Trial Notification Scheme, for all participating sites according to the approved Protocol V3 June 24 2013 including the use of dexmedetomidine outside its registered use 1. In separate correspondence dated 4 April 2014, Professor James Isbister, Chairman of the South Eastern Sydney Local Health District ('SESLHD') Human Research and Ethics Committee, confirmed that the SESLHD was one of four signatories that provided notification to the TGA under the Clinical Trial Notification Scheme as noted by Dr Shehabi. 2. Professor Isbister also advised that In August 2013 the SESLHD HREC reviewed and approved protocol version 3 dated June 24 2013. The HREC also reviewed supporting documents including previous randomised controlled trials of dexmedetomidine, propofol and midazolam and current international guidelines. The HREC was satisfied that the study protocol is consistent with current and standard practice for sedation of mechanically ventilated patients in an intensive care unit. The HREC acknowledges that the study inclusion and exclusion criteria are in line with safety profile of all sedative agents used including dexmedetomidine. 1. At the hearings on 8 May and 15 October 2014, further evidence was provided and submissions were made in support of the view that dexmedetomidine is routinely used in ICUs in NSW and across Australia and in a manner beyond its TGA registration. The evidence and submissions may be summarised as follows: * [Data removed for publication] * The applicant gave evidence that in Australia, dexmedetomidine is used primarily in ICUs for sedation and very little use is made of it outside ICUs. * The applicant attributed the increased utilisation of dexmedetomidine over this four year period to the results of two pivotal randomised control trials. The first was conducted in 2009 and compared the use of dexmedetomidine and midazolam. The second rise in useage is, according to the applicant, attributable to the published results of European studies that compared the use of dexmedetomidine and midazolam with dexmedetomidine and propofol. * According to the applicant, the increased use of dexmedetomidine in ICUs is also attributable to the guidelines for sedation practice published in 2013 by the US Society of Critical Care. These guidelines listed dexmedetomidine, midazolam and propofol as equal agents to be used for the sedation of critically ill patients. * In August 2014, the ANZICS Clinical Trials Group conducted a survey amongst the nine proposed sites at which the current study would be carried out. In response to a question from the Tribunal, Dr Shehabi confirmed that the study was specifically carried out for the purposes of the hearing on 15 October 2014. * According to Dr Shehabi, the results of the survey showed that: o The default target sedation in all patients in the nine ICUs was light sedation o Seven of the nine ICUs use the following three agents: dexmedetomidine, propofol and midazolam o Two of the nine ICUs use dexmedetomidine and propofol and another, with midazolam used as a rescue therapy if needed o All ICUs reported a significant increase in the use of dexmedetomidine in their ICU over the last two years. In addition: - The dose range in all units is ≥ 1mcg/kg/hr - All units use dexmedetomidine for longer than 24 hours and as long as clinically indicated o Once a patient is critically ill and ventilated, whether they are a ventilated surgical ICU patient or a ventilated medical ICU patient, the approach to sedation in the nine sites is the same. According to Dr Shehabi, this indicates that whether the patient comes to the ICU with a surgical background or with a medical background, the survey results indicate that there is no difference in terms of the choice of sedation medication or intensity o Current practice in ICUs mirrors the SPICE III protocol * SPICE III is a comparison of standard care sedation strategies. It is not a comparison of sedative drugs. * The SPICE III study population is the same population of patients receiving the same sedative drugs including dexmedetomidine. * SPICE III is not a study of a new or investigational medical therapy. * SPICE III was assessed by the UK Medicines and Healthcare Products Regulatory Agency (HMRA) for inclusion of UK sites into the study. The HMRA concluded that SPICE III is not a trial of an investigational medicinal product and there was no need for clinical trial authorisation. * In all other Australian sites that have commenced the study, surrogate consent provided after the patients has been enrolled in the study by the treating physician has been provided in every case. 1. Professor Bellomo, Professor of Medicine at Monash University, University of Melbourne and Co-Director of the Australian and New Zealand Intensive Care Research Centre, submitted that from the point of view of Austin Hospital in Melbourne that has entered the most patients into the trial, the evidence provided by Dr Shehabi represents the fact that all of the clinicians involved in the randomisation process are very comfortable that both treatment arms represent what they would currently do according to personal preferences. The only difference created by the study is that patients are being randomised so that the researchers can learn from the two different approaches. Evidence and submissions concerning randomisation 1. The Study Protocol sets out the role of randomisation in the allocation of patient to the two arms of the study. According to the Study Protocol (at page 19), patients who satisfy the inclusion criteria and have no exclusion criteria 'will be randomly assigned in a 1:1 ratio to either Early Goal Directed Sedation or to standard care sedation using a block randomisation with variable block size'. 2. Randomisation 'will be conducted through a password protected, secure website using a central, computer based randomisation program. Treatment allocation will be stratified by site and by whether there is presence or absence of suspected/proven sepsis'. 3. At the hearing on 15 October 2014, the Tribunal invited the applicant and other participants to address the issue of randomisation in the study, that is, given that the treating physician would no longer be responsible for the decision as to which treatment is to be administered to a particular patient, how could the study be regarded as something other than a trial. 4. Dr Shehabi described the process of randomisation as essentially a scientific and academic way of reducing bias. The clinician would be using similar agents and similar procedures to achieve a similar sedation target that they would have otherwise achieved without the patient being part of the study. Dr Shehabi noted that the trial is unblinded and the physician may therefore adjust the treatment administered to the patient at any time according to the patient's clinical needs. 5. When asked to address the issue that a treating physician would normally make a decision about sedation treatment for a particular patient based on their knowledge and expertise and the needs of that patient and that randomisation of a patient into one of the two treatment arms changes this, a number of witnesses made reference to the concept of equipoise. 6. Professor Bellomo submitted that before a patient's entry into the study and randomisation, the physician must believe that neither one of the protocols would be better for the particular patient and that both treatments are equivalent in his or her mind for the particular patient. 7. The Tribunal understood Professor Bellomo to be emphasising that a decision is in fact made about the treatment for a particular patient and that this occurs prior to the act of randomisation. The relevant decision is that either treatment arm is equivalent for the particular patient. 8. Professor Ian Seppelt, an Intensive Care Physician at Nepean Hospital and a Principal Investigator at that proposed site, noted that it would be reasonable and ethical to put a patient into the study if the treating clinician honestly did not know which of the two arms was better for the patient in question. If a physician had strong reason to believe that one arm is better than the other, then it would not be ethical to randomise the patient. 9. Professor James Isbister, the Chairman of the SESLHD HREC, advised that the HREC was very happy with the question of equipoise in this study and the survey conducted in August 2014 confirmed that the clinicians who administer these treatments are also very comfortable that there is no difference between the two treatment arms. 10. Dr Barbara-Ann Adelstein, Deputy Chair of the SESLHD, gave evidence that when the HREC considered the study from the ethical perspective and whether or not there was any specific evidence that one treatment was better than the other, on the evidence the HREC was provided with, it accepted that there was no evidence to show that one was definitely better than the other. 11. Dr Shehabi noted also that the reality is that a decision about sedation treatment is mostly an arbitrary one. A lot of times it is the nurse at the bedside who will inform the physician that a particular infusion is ready to go and the physician will authorise it. 12. According to Dr Shehabi, the fact that the study in unblinded makes it easy for the clinician to adapt and change the treatment based on the clinical needs of the patient. 13. The Tribunal queried that part of the study that precludes the use of midazolam (subject to certain exceptions) once a patient is entered into the early goal directed arm of the study, and whether this reflects normal practice or whether it lends weight to the view that a the study should properly be regarded as a 'clinical trial'. 14. Dr Shehabi responded that current practice is that most clinicians use dexmedetomidine in combination with propofol and not in combination with midazolam. This is because dexmedetomidine and propofol work in a synergistic way and midazolam is kept for situations where dexmedetomidine and propofol is not enough. If the clinician would have used midazolam anyway, for example, if the patient is agitated, has convulsions or seizures, or is someone who needs to be adequately asleep because they are on muscle relaxants, then the clinician, under the protocol, can use midazolam as they like. According to Dr Shehabi, that is where the study protocol mimics what clinician do in normal practice. 15. It was acknowledged by all witnesses that the circumstances in which patients are admitted to an ICU and require mechanical ventilation and sedation will usually take place as a matter of urgency and often without the consent of the patient or the patient's person responsible. 16. Treatment may be lawfully administered in this manner pursuant to section 37(1) of the Guardianship Act. This section provides that medical treatment may be carried out on a patient without consent being given in accordance with Part 5 of the Guardianship Act if the medical practitioner carrying out or supervising the treatment considers the treatment is necessary, as a matter of urgency: * to save the patient's life * to prevent serious damage to the patient's health or * to prevent the patient from suffering or continuing to suffer significant pain or distress 1. If the study is found not to be a 'clinical trial' as that term is defined in the Guardianship Act, the applicant and other participants were asked by the Tribunal to address the question of whether a medical practitioner administering treatment without the informed consent of the patient or a person responsible for the patient, could satisfy the provisions of section 37(1) if the patient was randomised into one of the two treatment arms. In particular, how could the practitioner satisfy him or herself, in accordance with the requirements of s 37(1) that the 'treatment' in question is necessary for the particular patient if in fact the decision about the treatment arm is removed from the physician and is the result of a randomisation program. 2. Professor Isbister again noted the evidence that clinicians are completely happy with equipoise in the study, noting again the results of the August 2014 survey as confirmation of this. 3. Dr Shehabi submitted that the treatments in the study are given to achieve a particular goal, that is, alleviation of suffering and to allow for life sustaining therapies to be provided. This can be done equally with either of the treatment arms and the agents given within those arms. 4. The patient is delivered a package that gives them pain relief and sedation and allows interventions to be given to them without the patient feeling them. Whichever package is chosen, according to Dr Shehabi, it will deliver the same thing. 5. In relation to this latter submission, the Tribunal put to Dr Shehabi that the fact that the study is being carried out indicates that the outcome of the two packages is not known. 6. Dr Shehabi responded that at the 'bedside' the two packages will deliver the same thing. What is not known is the long term effects of the two packages. However, as an emergency intervention for patients who need sedation, the package of care in both treatment arms will provide the same thing. 7. Professor Seppelt submitted that in order for the patient to be entered into the study, the clinician must have determined that early, targeted, light sedation is required and he or she must be comfortable to follow either of the two pathways in the study. Professor Seppelt suggested that the provisions of section 37(1) would be satisfied if it is accepted that 'the treatment' in section 37(1) is protocolised sedation regardless of the specific components. IS THE PROPOSED STUDY A 'CLINICAL TRIAL'? – TRIBUNAL'S REASONING 1. The Tribunal understood the applicant's argument in this case to be that an interpretation of the term 'clinical trial' that limits the application of section 45AA to new or experimental drugs or treatments should be the approach adopted by the Tribunal. The Tribunal should find that SPICE III is therefore not a clinical trial within the Guardianship Act because it is a comparison of standard care sedation strategies and is not new or experimental treatment. 2. In relation to the meaning of 'clinical trial', as previously noted in these Reasons for Decision, the Guardianship Act defines 'clinical trial' as 'a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial'. 3. Medical treatment is defined as treatment 'normally carried out by or under the supervision of a medical practitioner' and includes 'any medical or surgical procedure, operation or examination and any prophylactic, palliative or rehabilitative care'. 4. There are no other relevant definitional sections contained within Part 5. 5. A focus of previous Tribunal decisions has been the meaning that should be given to the word 'trial' contained within the definition of 'clinical trial'. 6. In accordance with well accepted principles of statutory construction, the task of statutory interpretation 'must begin with a consideration of the text itself'. [12] The starting point is to consider the ordinary and grammatical sense of the statutory words to be interpreted having regard to their context and legislative purpose. [13] 7. Without a definition of 'trial' being included in the statute, recourse may be had to dictionary definitions of the word (Pearce and Geddes Statutory Interpretation in Australia, 8th Edition, (2014) LexisNexis Butterworths Online [3.30]). 8. The Macquarie Dictionary (online edition) includes the following definition: Trial - the act of trying or testing, or putting to the proof; tentative or experimental action in order to ascertain results; an experiment. 1. The Oxford English Dictionary (online edition) provides as follows: 'trial' – Action, method, or treatment adopted in order to ascertain the result; investigation by means of experience; experiment. 1. The ordinary, plain English meaning therefore offers a number of alternatives to the meaning of 'trial' in these dictionary definitions and does not limit its meaning to new or experimental treatment. 2. The evidence in this case is that SPICE III is testing something, or putting something to the proof, namely, the hypothesis that Early Goal Directed Sedation, compared to standard care sedation, reduces 90-day all-cause mortality in critically ill patients who require mechanical ventilation. Patients are randomised into one of two arms in order to test the hypothesis. It is artificial to describe this process as anything other than a 'trial' as per the ordinary meaning of that term. 3. It is not, however, necessary to undertake a detailed examination of the context and legislative purpose of the clinical trial provisions in Part 5 of the Guardianship Act to determine whether the meaning of 'trial' should be limited in the manner suggested by the applicant and as referred to in earlier Tribunal decisions. This is because the Tribunal was satisfied that even if, for the sake of argument, the meaning of 'clinical trial' was to be limited in the manner suggested by the applicant, SPICE III satisfies this narrower view of the term on the basis that the trial proposes the use of dexmedetomidine beyond its TGA registration. 4. The Tribunal was provided with detailed submissions by the applicant and others concerning the use of dexmedetomidine beyond its licensed parameters in clinical practice in NSW and Australia. In the absence of a contradictor and having regard to the expertise of the applicant and his colleagues, the Tribunal placed weight on the evidence made available to it that since 2011, the use of dexmedetomidine has increased to such an extent that it is used regularly and widely as an alternative sedative agent to benzodiazipines in intensive care units in NSW and Australia by physicians treating the clinical needs of individual patients. The Tribunal also noted that the relevant HREC has accepted, based on the material placed before it by the applicant, that dexmedetomidine is a 'comparative investigation of two routinely used sedation strategies both of which are used routinely and are consistent with current standard practice in ICUs in Australia' (contained in correspondence from Professor James Isbister dated 30 September 2014). 5. In the Tribunal's view, however, different considerations arise when such treatment occurs in the context of a randomised trial. A specific regulatory regime is brought into effect. As with all human research involving more than a low level of risk, the research must be reviewed and approved by an HREC that is constituted and functioning in accordance with the National Statement. Significantly, the use of a drug beyond its licensed parameters in the context of a trial necessitates notification pursuant to the clinical trial notification scheme under the TG Act and brings with it the statutory obligations placed on the sponsor and HREC as set out earlier in these Reasons. 6. The Tribunal notes the applicant's submissions concerning the regulatory framework created by the TGA and that TGA drug registration is 'commonly not congruent with actual clinicians' use and current standard practice driven by contemporary practice'. The Tribunal also had regard to the applicant's submission that drugs and devices are commonly used and can be 'standard practice' despite a lack of TGA approval for that specific indication – they just cannot be marketed commercially for that indication. 7. However, in the Tribunal's view, there is an important distinction between the use of a drug beyond its TGA license in every day clinical practice and the use of such a drug in the context of a randomised trial. In relation to the latter, a specific legislative scheme applies in order to allow the use of the drug in this manner and also for the close monitoring of its use in a trial. The fact that the clinical trial notification scheme is engaged in these circumstances lends weight to the view taken by this Tribunal that the use of the drug in the same circumstances falls within the meaning of 'clinical trial' under the Guardianship Act. 8. The Tribunal had careful regard to the written and oral submissions of the Chairman and Deputy Chair of the SESLHD HREC concerning the view of the HREC that SPICE III is a comparison of two accepted forms of treatment and noting the equipoise of the study. However, this view does not appear to alter the fact that the clinical trial notification scheme is engaged in relation to SPICE III. There was nothing on the evidence before the Tribunal to suggest that the HREC, as a result of accepting the applicant's submission, is seeking to, or would be able to, alter the fact that the trial is subject to the clinical trial notification scheme or that it would alter the manner in which the HREC carries out its role in accordance with the TG Act and Regulations. 9. The Tribunal concluded that whilst dexmedetomidine retains its current TGA registration and is therefore captured by the clinical trial notification scheme of the TG Act, then the SPICE III trial, which proposes to use the drug beyond its licensed parameters in the context of a randomised trial, amounts to a 'clinical trial' for the purposes of the Guardianship Act. 10. This finding is consistent with the objects of Part 5 of the Guardianship Act, the general principles set out in section 4 of the Act and the additional level of scrutiny that the clinical trial provisions of the Act provide when approval is sought for the participation of people in a trial who lack the capacity to provide their own consent to do so. STATUTORY CRITERIA IN SECTION 45AA(2) OF THE GUARDIANSHIP ACT Are the drugs or techniques being tested in the clinical trial intended to cure or alleviate a particular condition from which the patients suffer? 1. Critically ill patients who are treated with invasive mechanical ventilation require an intravenous infusion of one or more sedative agents to provide comfort and alleviate the anxiety and distress that occurs on a breathing machine. Only patients who meet the inclusion criteria will be enrolled in the study. The criteria, as previously noted, include that the patient has been intubated and is receiving mechanical ventilation and requires immediate ongoing sedative medication for the comfort and safety of the patient and to facilitate the delivery of life support measures. 2. On the basis of this evidence, the Tribunal was satisfied that the use of dexmedetomidine in the manner outlined and in the context of the Early Goal Directed arm of the trial, is intended to alleviate a particular condition from which patients suffer by providing sedation so that patients may receive life support measures whilst undergoing mechanical ventilation. The use of the drug in this manner is also intended to test the hypothesis that the sedation regime that forms the Early Goal Directed arm provides better clinical outcomes for patients 90 days following treatment. The trial will not involve any known substantial risk to the patients (or, if there are existing treatments for the condition concerned, will not involve material risks greater than the risks associated with those treatments) 1. As noted in the Study Protocol (at page 21), patients randomised to the Early Goal Directed Sedation arm of the proposed trial will receive a sedative infusion of dexmedetomidine commencing without a loading dose at a rate of 1.0 mcg/kg/hour and will be varied between 0-1.0 mcg/kg/hour to maintain a light sedation. Dexmedetomidine infusion will be continued until sedation is no longer clinically indicated up to a maximum of 28 days after enrolment. 2. As previously noted, the Tribunal accepted on the basis of the detailed evidence placed before it that the use of dexmedetomidine has increased to such an extent that it is used regularly and widely as an alternative sedative agent to benzodiazapines in intensive care units in NSW and Australia. The evidence is that physicians regularly administer dexmedetomidine for individual patients as long as is clinically indicated, which may be for longer than 24 hours, and at dosages greater than 1mcg/kg/hr. 3. The Study Protocol (at pages 13 and 14) provides an overview of evidence relating to the safety and efficacy of dexmedetomidine. It refers to the results of a number of Phase II clinical randomised control trials and, notably, to a 2012 randomised control trial (Propofol vs dexmedetomidine and Midazolam v dexmedetomidine, PRODEX and MIDEX) that confirmed the safety and efficacy of dexmedetomidine as an alternative sedative drug for mechanically ventilated patients for longer than 24 hours. It also confirmed the safety of dosing dexmedetomidine up to 1.5g/kg/hour. These studies have led to the registration of dexmedetomidine in Europe for use in ICU sedation to a maximum dose of 1.5g/kg/hour with no time restriction. Based on the body of evidence available to-date, the most recent 2012 International Sedation Clinical Practice Guidelines produced by a special taskforce of the Society of Critical Care Medicine suggested that midazolam, propofol, dexmedetomidine or combinations be used for ICU sedation in mechanically ventilated critically ill patients. 1. The exclusion criteria ensure that patients who have a known sensitivity to any of the study medications or constituents of propofol will be excluded from the trial. Patients with other specified conditions (including cardiovascular conditions, acute fulminant hepatic failure and proven or suspected acute primary brain lesion) will also be excluded. 2. Having regard to all of this uncontradicted evidence, which the Tribunal accepted, the Tribunal was satisfied that the use of dexmedetomidine in the manner proposed in the trial will not involve any known substantial risk to the patients and is in accordance with existing treatments. The development of the drugs or techniques has reached a stage at which safety and ethical considerations make it appropriate that the drugs or techniques be available to patients who suffer from that condition even if those patients are not able to consent to taking part in the trial 1. As previously noted, the hypothesis to be tested in this trial is that Early Goal-Directed Sedation compared to standard care sedation reduces 90 day all-cause mortality in critically ill patients who require mechanical ventilation. 2. The justification for the trial is based on what is described in the Study Protocol (at page 8) as growing evidence that dexmedetomidine facilitates rousable sedation, shortens ventilation time and attenuates the occurrence of delirium. These effects were shown in the results of two randomised control trials, dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation (MIDEX and PRODEX JAMA 2012) and the Safety and Efficacy of Dexmedetomidine Compared with Midazolam (SEDCOM JAMA 209). The Protocol notes that whether these advantages are associated with improvement in patient-centred outcomes, such as long term mortality and cognitive function, is not known. Most clinical trials of sedation practice have been inadequately powered and did not account for the model of care, thus lacking external validity. The Protocol also outlines (at page 14) what the authors regard as the shared limitations of a number of those trials including that randomisation did not occur until up to 96 hours after initiation of mechanical ventilation leading to significant contamination at baseline and reduced separation between the intervention and the control group, few studies have assessed long term patient centred outcomes and there have not been any large phase III trials using mortality as the primary outcome. 3. Having regard to this evidence and taking into account the results of the Phase II studies referred to previously in relation to safety issues, the Tribunal was satisfied that it is appropriate that dexmedetomidine is made available to patients in the manner proposed in the trial, even if those patients are not able to consent to taking part in the trial, particularly given the hypothesis that dexmedetomidine reduces 90 day all-cause mortality. Having regard to the potential benefits (as well as the potential risks) of participation in the trial, it is in the best interests of patients who suffer from that condition that they take part in the trial 1. The potential benefits of participation in the trial have been referred to earlier in these Reasons for Decision. The evidence is also that, as previously noted, physicians in NSW regularly administer dexmedetomidine for individual patients outside of its TGA licensing without risk to patients. 2. The Tribunal was satisfied on the balance of the evidence before it that the potential benefits to patients being included in the trial outweighs any potential risks and it is in the best interests of patients who require sedation in ICUs to take part in the trial. The trial has been approved by a relevant ethics committee and complies with any relevant guidelines issued by the National Health and Medical Research Council 1. The Tribunal was provided with correspondence from the South Eastern Sydney Local health District Human Research Ethics Committee dated 29 August 2013 confirming that ethical approval was given for the SPICE III trial. The correspondence confirms that this HREC is constituted and operates in accordance with the National Health and Medical Research Council's National Statement on Ethical Conduct in Human Research (2007), NHMRC and Universities Australia Australian Code for the Responsible Conduct of Research (2007) and the CPMP/ICH Note for Guidance on Good Clinical Practice. 2. Given this evidence, the Tribunal was satisfied that this statutory criterion was satisfied. Who should be the substitute decision maker? 1. As previously noted in these Reasons, section 45AA(4) provides that if the Tribunal approves a trial as one in which patients who are unable to give a valid consent to their own treatment may take part, consent for the participation of particular patients in the trial must be obtained under Division 3 (from a person responsible) or Division 4 (from the Tribunal) before any medical or dental treatment in the course of the trial may carried out in relation to the patient. 2. Before making a determination that the function of giving or withholding consent for the carrying out of medical or dental treatment on patients in the course of a trial is to be exercised by the persons responsible for the patients, the Tribunal must be satisfied that the form for granting consent and the information available about the trial provide sufficient information to enable the persons responsible to decide whether or not it is appropriate that the patients should take part in the trial (section 45AB(2)). 3. At the conclusion of the hearing on 8 May 2014, the Tribunal adjourned the hearing. The Tribunal did so after indicating to the applicant that, whilst it had not arrived at final determination, it was minded to approve the study as a clinical trial and, as a result, noted that the draft 'person responsible' forms submitted along with the original application would need to be amended and resubmitted to the Tribunal in order to remove all references to 'delayed consent' if the applicant wished to have the Tribunal authorise persons responsible to provide consent for individuals to enter into the trial. 4. The Tribunal subsequently received an email from Dr Shehabi dated 12 August 2014 that attached a letter dated 14 July 2014 from Ms Deborah Adrian, Executive Officer of the SESLHD Human Research Ethics Committee, that advised that the Committee had considered the proposed amendment to the draft 'person responsible' forms and rejected the amendments for the following reasons: 1. The amendment compromises the scientific validity of the study 2. The amendment would introduce an insurmountable logistical obstacle in that obtaining consent (either from the patient or person responsible) would necessitate a delay in treatment which would be highly unethical 3. For the above reasons the proposed amendment would prevent the success of this important study. The Committee has therefore determined that obtaining consent from a person responsible prior to participant enrolment in this study is in itself unethical. 1. The person responsible forms submitted to the Tribunal do not, in the Tribunal's view, meet the requirements of section 45AB(2) as they are drafted on the basis of 'delayed consent'. They do not provide sufficient information to enable a person responsible for a patient to decide whether or not the patient should enter into the trial. Rather, the focus of the forms as drafted is whether or not the patient should remain enrolled in the trial. 2. Given this finding, the Tribunal was left with no alternative but to determine, pursuant to section 45AB(1)(b), that the Tribunal is to exercise the function of giving or withholding consent to an individual patient's participation in the trial. 3. The Tribunal notes for completeness that, as was raised with the applicant at the first hearing on 17 December 2013, whilst the notion of 'delayed consent' may exist in other jurisdictions in Australia and is referred to in the National Statement on Ethical Conduct in Human Research (2007) [Chapter 2.3], it does not exist in the Guardianship Act. The National Statement makes express reference to the fact that an opt-out approach or a waiver of consent approach to recruitment must not be prohibited by state, federal or international law [paragraphs 2.3.6 and 2.3.10]. 4. The Tribunal also notes that to the extent that the applicant looks to section 37(1) of the Guardianship Act as the basis upon which treatment in accordance with the SPICE III protocol could be provided to patients in NSW, as previously noted this provision enables medical treatment to be carried out on a patient without consent being given in accordance with Part 5 if the medical practitioner carrying out or supervising the treatment considers the treatment is necessary, as a matter of urgency: * to save the patient's life * to prevent serious damage to the patient's health or * to prevent the patient from suffering or continuing to suffer significant pain or distress 1. Whilst a decision as to whether the elements of section 37(1) are satisfied in respect of an individual patient is a matter for the medical practitioner carrying out the treatment, it would appear that difficult questions are raised when treatment is provided in the context of a randomised trial. It is unclear how a practitioner could satisfy him or herself that the elements of section 37(1) are satisfied if the decision about which treatment the patient is to receive is removed from the practitioner and is the result of a randomisation program. Even if a broader view is taken of 'the treatment' in section 37(1) so as to encompass entry into a trial as well as any treatment that results from a randomisation process, it is difficult to easily envisage a circumstance in which a practitioner could be satisfied that entering a patient into a randomised trial is treatment that is 'necessary, as a matter of urgency'. APPENDIX A – PROGRESS OF HEARING 1. The Tribunal first convened to hear the application on 17 December 2013. At the conclusion of the hearing, the Tribunal adjourned the matter so that the applicant could make written submissions, if he wished to do so, concerning the relevance of the proposed use of dexmedetomidine in SPICE III outside of its TGA registration. By letter dated 2 January 2014, the applicant provided detailed written submissions about this issue (as summarised earlier in these Reasons for Decision). 2. Following receipt of the applicant's written submissions, the Tribunal became aware of the contents of an article in the Medicines Safety Update, Vol 4, No 4, August 2013 (page 134) issued by the Therapeutic Goods Administration entitled 'Dexmedetomidine hydrochloride and cardiovascular events'. 3. After noting that the sedation of patients with an acute behavioural disturbance is not an approved indication for dexmedetomidine and factors other than the use of the drug may have contributed to the patient outcomes discussed in the study, the article reminds health professionals to carefully consider patient selection and the setting in which dexmedetomidine is administered to ensure its safe use. Dexmedetomidine should only be used for the approved indications and should be administered in accordance with the instructions in the [Product Information]. A controlled infusion device should be used for the administration of dexmedetomidine, and the dose and rate of infusion should not exceed that recommended in the PI. 1. In order to afford procedural fairness to the applicant, by way of email dated 24 March 2014 from the Divisional Deputy Registrar of the Tribunal, the applicant was invited to respond to the following two issues: * Whether the applicant and the South Eastern Sydney Local Health District were aware of the Medicines Safety Update article and whether the applicant wished to make a submission as to the relevance of the article to the application * Whether the South Eastern Sydney Local Health District, or any other organisation, provided notification of the proposed study to the Therapeutic Goods Administration under the Clinical Trial Notification Scheme given the proposed use of dexmedetomidine beyond its registered use 1. Dr Shehabi provided a written response by way of letter dated 3 April 2014 (set out in the Reasons for Decision). In separate correspondence dated 4 April 2014, Professor James Isbister, Chairman of the South Eastern Sydney Local Health District ('SESLHD') Human Research and Ethics Committee, also provided information relevant to the matter. 2. On 8 May 2014, the Tribunal reconvened to consider any further submissions or evidence from Dr Shehabi. During this hearing, Dr Shehabi reinforced his submission that the study in question was not a clinical trial within the meaning of the Guardianship Act. 3. At the conclusion of the hearing on 8 May 2014, the Tribunal adjourned the matter. The Tribunal did so after indicating to the applicant that, whilst it had not arrived at final determination, it was minded to approve the study as a clinical trial and, as a result, noted that the draft 'person responsible' forms submitted along with the original application would need to be amended and resubmitted to the Tribunal. This was necessary in order to remove all references to 'delayed consent' if the applicant wished to have the Tribunal authorise persons responsible to provide consent for individuals to enter into the trial. 4. The Tribunal next heard from Dr Shehabi by way of email dated 12 August 2014 that attached a letter dated 14 July 2014 from Ms Deborah Adrian, Executive Officer of the SESLHD Human Research Ethics Committee, that advised that the Committee had considered the proposed amendment to the draft 'person responsible' forms and rejected the amendments for the following reasons: 1. The amendment compromises the scientific validity of the study 2. The amendment would introduce an insurmountable logistical obstacle in that obtaining consent (either from the patient or person responsible) would necessitate a delay in treatment which would be highly unethical 3. For the above reasons the proposed amendment would prevent the success of this important study. The Committee has therefore determined that obtaining consent from a person responsible prior to participant enrolment in this study is in itself unethical. 1. In his email, Dr Shehabi requested a reconsideration of the Tribunal's view of the status of the study. 2. In order to address Dr Shehabi's request, the Tribunal convened a directions hearing on 22 August 2014. The Tribunal adjourned the matter to a hearing date in six weeks time and directed that any party wishing to submit further documentary evidence or written submissions was required to do so no later than 14 days prior to the hearing date. 3. Dr Shehabi and Professor Isbister both provided further written submissions. 4. The Tribunal reconvened on 15 October 2014. Participating in the hearing were Dr Shehabi, Professor Rinaldo Bellomo (Professor of Medicine at Monash University, University of Melbourne and Co-Director of the ANZIC), Associate Professor Ian Seppelt (Intensive Care Physician at Nepean Hospital, Clinical Associate Professor at Macquarie University and Director Research, Nepean Hospital - Principal Investigator), Dr Barbara-Ann Adelstein (Deputy Chair of the SESLHD Human Research Ethics Committee), and Ms Deborah Adrian (Executive Officer of the SESLHD Human Research Ethics Committee). Professor Isbister, Chairman of the SESLHD Human Research Ethics Committee, participated in the hearing by telephone. 5. At the conclusion of this hearing, the Tribunal reserved its decision. The Tribunal's final orders were made on 23 December 2014. ********** Endnotes 1. https://www.nhmrc.gov.au/book/national-statement-ethical-conduct-human-research. 2. The National Health and Medical Research Council Act 1992 (NHMRC Act) establishes the NHMRC as a statutory body and sets out its functions, powers and obligations. Section 10(1) of the Act requires the Chief Executive Officer to issue human research guidelines precisely as developed by the Australian Health Ethics Committee (AHEC) and provided to the CEO by the Council. AHEC is established by the NHMRC Act as a Principal Committee of the NHMRC. All the guidelines in the National Statement that are applicable to the conduct of medical research involving humans are issued by the NHMRC in fulfillment of this statutory obligation. 3. National Statement, paragraph 2.1.6 (https://www.nhmrc.gov.au/book/chapter-2-1-risk-and-benefit). 4. The Australian Clinical Trial Handbook, 'a simple guide to the conduct of clinical trials to International Standards of Good Clinical Practice (GCP) in the Australian context', March 2006, TGA. 5. National Statement, Glossary (https://www.nhmrc.gov.au/book/glossary). 6. Access to unapproved therapeutic goods, Clinical Trials in Australia, October 2004, TGA, 8. 7. See TG Act, section 18; Therapeutic Goods Regulations 1990, Regulation 12; and Therapeutic Goods Regulations 1990, Schedule 5A. 8. Therapeutic Goods Regulations 1990, Schedule 5A, item 3. 9. Therapeutic Goods Regulations 1990, Schedule 5A. 10. Access to unapproved therapeutic goods, Clinical Trials in Australia, October 2004, TGA,13. 11. Access to unapproved therapeutic goods, Clinical Trials in Australia, October 2004, TGA, 13. 12. Alcan (NT) Alumina Pty Ltd v Commissioner of Territory Revenue [2009] HCA 41; (2009) 239 CLR 27, Hayne, Heydon, Crennan, Kiefel JJ, [47]. 13. Alcan (NT) Alumina Pty Ltd v Commissioner of Territory Revenue [2009] HCA 41; (2009) 239 CLR 27, Hayne, Heydon, Crennan, Kiefel JJ, [47]; Commissioner of Taxation v Consolidated Media Holdings Ltd (2012) 293 ALR 257; [2012] HCA 55, French CJ, Hayne, Crennan, Bell and Gageler JJ, [39]. See also Amalgamated Society of Engineers v Adelaide Steamship Co Ltd (192) 28 CLR 129, 161-162 (Higgins J); Project Blue Sky Inc v Australian Broadcasting Authority (1998) 194 CLR 355, McHugh, Gummow, Kirby and Hayne JJ, 384 [78]. I hereby certify that this is a true and accurate record of the reasons for decision of the Civil and Administrative Tribunal of New South Wales. Registrar 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. Decision last updated: 13 February 2015