NSW Civil and Administrative Tribunal New South Wales Medium Neutral Citation: Application for approval to conduct clinical trial and for approval for patients unable to consent to their own treatment to participate (GWP42003-P Trial) [2017] NSWCATGD 30 Hearing dates: Monday 23 January 2017 at Sydney Date of orders: 03 March 2017 Decision date: 03 March 2017 Jurisdiction: Guardianship Division Before: A Britton, Principal Member Dr J M Hollis, Senior Member (Professional) L Porter, General Member (Community) Decision: 1. The GWP42003-P Trial is approved as a clinical trial in which patients unable to consent may participate. 2. The function of giving or withholding consent is to be exercised by the 'person responsible'. 3. The proposed form for granting consent and the information available about the Trial provide sufficient information to enable persons responsible to make an informed decision about whether consent to participate in the Trial should be given. Catchwords: CLINICAL TRIAL – double-blind, randomised, placebo controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P) as add-on therapy in the treatment of tuberous sclerosis complex – inadequately-controlled seizures – cannabidiol not approved by the Therapeutic Goods Administration – Phase III trial – consideration of s 45AA and 45AB of the Guardianship Act – trial approved – appropriate for approval by 'person responsible' – proposed form and information available about the trial capable of being understood by "persons responsible" Legislation Cited: Guardianship Act 1987 (NSW), Pt 5, ss 4, 33(1), 33(2), 33A, 34(1), 45AA, 45AA(2), 45AB Cases Cited: Shehabi v Attorney General (NSW) [2016] NSWCATAP 137 Texts Cited: National Statement on Ethical Conduct in Human Research, 2007 Category: Principal judgment Parties: Amy Boland (applicant) Representation: Applicant (in person) File Number(s): 14/2016 Publication restriction: It is an offence under s 65 of the Civil and Administrative Tribunal Act 2013 to publish or broadcast the name of any person who appears as a witness before the Tribunal in these proceedings or to whom these proceedings relate or who is mentioned or otherwise involved in these proceedings except with the consent of the Tribunal. A reference to the name of a person includes a reference to any information, picture or other material that identifies the person or is likely to lead to the identification of the person. REASONS for decision 1. Amy Boland, Clinical Manager, Sydney Children's Hospital, applies to NCAT under s 45AA of the Guardianship Act 1987 (NSW) (the Act), for approval to conduct a clinical trial, "a double-blind, randomized, placebo-controlled study to investigate the efficacy and safety of cannabidiol (GWP42003-P)". In these reasons we will refer to the proposed trial as "the Trial". 2. The stated purpose of the Trial is to determine whether the drug, cannabidiol (CBD) as an add-on therapy, is safe and effective to use in the treatment of tuberous sclerosis complex (TSC), a genetic disorder characterised by the formation of non-malignant tumours in multiple organ systems. The most common clinical manifestation of TSC is epileptic seizures, which afflict about 70 per cent of people with the condition. In approximately two-thirds of people with TSC, seizure onset occurs in the first year of life. Early management of seizures is considered critical in preventing epileptic encephalopathy and in reducing associated cognitive and neuropsychiatric consequences. 3. To date, CBD has not been approved by the Therapeutic Goods Administration (TGA), Australia's regulatory authority for therapeutic goods or any other drug regulatory body in the world. 4. For the reasons that follow we have decided to approve the Trial. Outline of the Trial 1. The Trial is a commercially sponsored clinical trial. It has been approved by Hunter New England Human Research Ethics Committee (HREC) to be conducted at five sites throughout Australia. The Application relates to the sole NSW site, the Sydney Children's Hospital, Randwick. 2. Dr John Lawson is the Coordinating and Principal Investigator of the NSW site. He foreshadowed that he may wish to enrol participants who are aged over 16 years with a decision-making disability. Dr Lawson points out that around 60% of people with TSC have an intellectual disability and 50%, an autism spectrum disability. 3. The stated purpose of the Trial is to determine whether CBD is safe and effective to use in children and adults with TSC. 4. The Trial is in two parts. During the first phase, which runs for 21 weeks, participants will be randomly allocated to receive treatment of 25 mg/kg/day of CBD, 50 mg/kg/day of CBD, or, a placebo. Throughout this phase, neither the participants, their carers, nor the clinical team administering the Trial will be aware of whether the participants are being given CBD or a placebo. 5. At the end of the first phase, all Trial participants, including those given a placebo, will be invited to participate in the "Open Label Extension" phase. All participants in that phase will receive 25 mg/kg/day of CBD. 6. The clinical protocol submitted and approved by the HREC (the Protocol), details the research methodology, which is required to be followed in the Trial, and the reporting requirements. The hypothesis outlined in the Protocol is that there will be a decrease in "focal seizure frequency" in participants taking CBD. Statutory framework 1. Part 5 of the Act governs the conduct of clinical trials involving persons with a decision-making disability. 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: s 34(1) of the Act. 2. Section 33(2) of the Act states that for the purposes of Pt 5, a person is regarded as being incapable of giving consent to the carrying out of medical treatment if the person: (a) is incapable of understanding the general nature and effect of the proposed treatment, or (b) is incapable of indicating whether or not he or she consents or does not consent to the treatment being carried out. 1. "Medical treatment" is defined in s 33(1) of the Act to include: "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 ... (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)...[subject to a number of exceptions which are not relevant for present purposes]". 1. "Clinical trial" is defined in s 33(1) of the Act to mean "a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial". 2. 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: s 45AA(1) of the Act. Before doing so, the Tribunal must be satisfied as to each of the criteria set out in s 45AA(2) of the Act. Section 45AA states: 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. If satisfied of the matters specified in s 45AA(2) of the Act, the Tribunal may make one of the following orders listed in s 45AB of the Act, providing it is satisfied that the proposed form for granting consent provides "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 of the Act states: 45AB Consent for participation in clinical trials in individual cases (1) If the Tribunal is satisfied as to the matters specified in section 45AA (2) in relation to a clinical trial, it may, by order, determine: (a) 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 (b) that the Tribunal is to exercise that function itself (in which case Division 4 applies). (2) Before making a determination referred to in subsection (1) (a), 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. 1. As explained by the Appeal Panel in Shehabi v Attorney General (NSW) [2016] NSWCATAP 137 at [67], ss 45AA and 45AB of the Act establish a three-step process for obtaining consent to medical treatment as part of a clinical trial for patients to whom Pt 5 of the Act applies: (1) First, the Tribunal must determine whether to approve the trial, under s 45AA but that approval does not operate, by itself, as consent to the participation in the trial by any particular patient. (2) Secondly, if the Tribunal is satisfied in accordance with s 45AA(2) that the clinical trial should be approved, the Tribunal then has to determine whether consent to treatment as part of that trial should be given by the "person responsible" or by the Tribunal. (3) Thirdly, depending on whether the consent is to be obtained from the person responsible or the Tribunal, consent must then be obtained under s 40 or under ss 42 to 45, respectively, for the medical treatment in the course of the trial to be carried out on the patient. 1. In exercising the power conferred by Pt 5 of the Act to approve a clinical trial, the Tribunal must observe the "general principles" listed in s 4 of the Act: 4 General principles It is the duty of everyone exercising functions under this Act with respect to persons who have disabilities to observe the following principles: (a) the welfare and interests of such persons should be given paramount consideration, (b) the freedom of decision and freedom of action of such persons should be restricted as little as possible, (c) such persons should be encouraged, as far as possible, to live a normal life in the community, (d) the views of such persons in relation to the exercise of those functions should be taken into consideration, (e) the importance of preserving the family relationships and the cultural and linguistic environments of such persons should be recognised, (f) such persons should be encouraged, as far as possible, to be self-reliant in matters relating to their personal, domestic and financial affairs, (g) such persons should be protected from neglect, abuse and exploitation, (h) the community should be encouraged to apply and promote these principles. Does the trial meet the requirements of s 45AA of the Act? Is CBD intended to cure or alleviate a particular condition from which the patients suffer? 1. The Trial drug, CBD, is not intended to cure TSC but rather to reduce the frequency and incidence of seizures in patients with that condition. As explained by Dr Lawson in the letter to NCAT dated 6 December 2016 in support of the Application, early management of seizures is important in preventing epileptic encephalopathy and in reducing associated cognitive and neuropsychiatric consequences. 2. We are satisfied that CBD is intended to alleviate one of the key symptoms of TSC, namely epileptic seizure activity. Will the Trial 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. The Trial is a Phase 3 trial, that is, as the name suggests, a clinical trial that has undergone two previous trials: a Phase 1 trial evaluates the safety of the trial drug on a small group of people (e.g. to determine a safe dosage range and identify side effects); a Phase 2 trial is used to determine efficacy (that is, whether the drug works as intended) and to further evaluate the safety of the trial drug. (National Health and Medical Research Council, "Phases of clinical trials" https://www.australianclinicaltrials.gov.au/what-clinical-trial/phases-clinical-trials accessed 3 March 2017. 2. According to the Protocol, reported studies involving adults and children with intractable epilepsy reveal that doses of up to 800 mg CBD per day have been well tolerated in adults and up to 22 mg/kg/day in children. The Protocol states that the sponsor reviews all safety information on an ongoing basis and is not aware of any safety issues arising from the dosing used to date. 3. As conceded by Dr Lawson, CBD is an "experimental agent" and its safety and efficacy is not yet fully known. However, in his opinion there are "no known substantial risks to patients" from the use of the drug. He describes the known side effects — mild drowsiness, diarrhoea and weight loss — as "minor and reversible". He states that the only other known problem with the drug is liver abnormality, which generally settles within a short period and does not result in any permanent damage. Under the Protocol, the liver function of participants must be monitored regularly. 4. Dr Lawson explained that the pharmacological therapies currently available for TSC-associated epilepsy are not optimal. According to the Protocol, internationally the drug of first choice for the treatment of infantile spasms secondary to TSC is Vigabatrin (VGB). Although, VGC is generally well tolerated, long-term treatment is associated with irreversible peripheral visual field defects, the risk of which increases with increasing dose and cumulative exposure. In Australia, oral corticosteroids (prednisone/prednisolone) are also used to treat infantile spasms, but with limited success. 5. Dr Lawson's opinion that there are no known substantial risks from CBD is supported and uncontradicted. We are satisfied that the Trial will not involve any known substantial risks to patients. Has the development of CBD reached a stage at which safety and ethical considerations make it appropriate that CBD 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 noted above, the Trial is in its third phase. The Protocol claims that, to date, there have been no reported adverse consequences associated with the use of CBD in controlled studies. We are satisfied that the development of CBD has now reached a stage at which safety and ethical considerations make it appropriate that CBD be available to patients with TSC, including those who are not able to consent to taking part in the Trial. Having regard to the potential benefits (as well as the potential risks) of participation in the Trial, is it in the best interests of patients who suffer from that condition that they take part in the Trial? 1. While the available material indicates that there are no known substantial risks associated with the use of CBD in both adults and children, as conceded by Dr Lawson the safety and efficacy profile of the drug is not fully known. 2. The risk of taking a drug that has not yet been approved by any regulatory authority must be weighed against the potential benefits of the drug. Frequent seizures, a common symptom of TSC have a significant impact and can result in a significant diminution in quality of life. The treatment currently available to persons with TSC-epilepsy is neither risk-free nor, in many cases, effective. A cautious approach must always be taken to any drug that has not yet been fully tested on humans. This is especially so where the person proposed to participate in the trial lacks the capacity to weigh the risks and benefits of the proposed trial. However, on the material available, the potential benefits of the Trial would appear to outweigh the potential known risks. We are satisfied that it is in the best interests of persons who suffer from TSC that they have the opportunity to take part in the Trial. Has the Trial been approved by a relevant ethics committee and does it comply with any relevant guidelines issued by the National Health and Medical Research Council? 1. As noted above, the Trial has been approved by the Hunter New England Human Research Ethics Committee on behalf of all participating sites. The Hunter New England Human Research Ethics Committee is registered with the National Health and Medical Research Council and as a consequence of its registration must comply with the National Statement on Ethical Conduct in Human Research, 2007 (updated March 2014). Summary 1. Each of the criteria listed in s 45AA(2) of the Act is satisfied. Should the Tribunal leave the issue of consent to "persons responsible"? 1. Section 45AB of the Act states: (1) If the Tribunal is satisfied as to the matters specified in section 45AA (2) in relation to a clinical trial, it may, by order, determine: (a) 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 (b) that the Tribunal is to exercise that function itself (in which case Division 4 applies). (2) Before making a determination referred to in subsection (1) (a), 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. 1. Section 45AB of the Act requires us to decide whether the function of giving or withholding consent for the carrying out of medical treatment on patients in the course of the Trial should be exercised by the "persons responsible" for the relevant patients, or the Tribunal. The Act provides no express guidance on the factors to take into account in making this determination. 2. The Applicant seeks the function of giving or withholding consent to be exercised by the "persons responsible" for the patients. See s 33A of the Act for the definition of "person responsible". 3. According to Dr Lawson, the participants in the Trial at the NSW site will be drawn from the 150 patients who attend the TSC clinic at Sydney Children's Hospital. In our view, in the circumstances of this Application, where it is likely that each of the proposed participants will have a person responsible with whom they are in close regular contact, it is preferable that the function of giving and withholding consent be exercised by the person responsible, not the Tribunal. 4. However, before a final decision can be made about whether the Tribunal or the relevant "person responsible" should be given the function of giving or withholding consent to participating in the Trial, s 45AB(2) directs that we be satisfied that the form for granting consent, and the information available about the Trial proposed to be provided to the persons responsible, 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. Does the proposed 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? 1. In support of the Application, the Applicant filed 14 proposed consent forms and associated participant information sheets. At the hearing there was some confusion about the purpose of each proposed form. Specifically, it was unclear which form(s) the Tribunal was being requested to evaluate for purpose of s 45AB(2) of the Act. 2. Following the hearing, as directed by the Tribunal, the Applicant submitted the final version of the forms and accompanying information proposed to be given to the person responsible for patients invited to participate in the Trial. 3. The form and information sheets were written in plain English. They provided a cogent explanation of the purpose of the Trial and the known side effects of TSC. While the material refers to the possible benefits of the drug, it did not overstate the potential benefits of trial participation. The information sheets were expressed in simple language and helpfully included diagrams and pictorial images. They appeared to be capable of being understood by persons responsible, including individuals with limited education and language skills. 4. We are satisfied that the form for granting consent and the information available about the Trial provide sufficient information to enable persons responsible to decide whether or not it is appropriate that the patients should take part in the Trial. Conclusion 1. The precondition to give an approval under s 45AA of the Act has been satisfied. Given the potential benefits of CBD to persons with TSC, we have concluded that the power to approve the Trial should be exercised. In addition, we have decided that the function of giving or withholding consent to participate in the Trial should be exercised by the persons responsible, not the Tribunal. Further, we are satisfied that the proposed form for granting consent and the information available about the Trial, will enable persons responsible to make an informed decision about whether consent to participate in the Trial should be given. ********** 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: 05 February 2018