These Reasons for Decision relate to the orders made by the Tribunal on 24 April 2020 concerning An Open Label, Multi-Centre Study to Determine the Safety and Efficacy of STC3141 Administered as an Infusion for up to 5 Days in Subjects with COVID-19 Acute Respiratory Distress Syndrome Requiring Intensive Care, as described in Protocol GPGIP-0201 ("the clinical trial"). The orders are replicated in Appendix A to these Reasons for Decision.
[2]
The Tribunal's decision
For the reasons which follow, the Tribunal approved the clinical trial under s 45AA of the Guardianship Act 1987 (NSW) ("the Act").
The Applicant's request that the Tribunal order under s 45AB(1)(a) of the Act that the function of giving or withholding consent for patients in the course of the clinical trial be exercised by the persons responsible for the patients was adjourned to a date to be fixed by the Registrar to allow the Applicant to submit amended Person Responsible Information and Consent Forms.
[3]
Background
Whether directly or indirectly, the COVID-19 global pandemic has touched upon the life of every Australian.
As at the date of the hearing in this matter, there were 6,661 confirmed cases of COVID-19 in Australia, with 75 deaths. New South Wales has been impacted greater than any other Australian state - with 2,976 confirmed cases, and 31 deaths reported. Relevantly for the present matter, it is reported that there are currently 47 confirmed cases admitted to hospital in NSW, with 21 of those requiring intensive care. The nature of the virus means that most, if not all, of these numbers will have likely increased by the time these reasons are distributed to the parties and published.
Whilst there are signs that the rate of infection is slowing, and it appears Australia has managed to contain the spread of the outbreak relatively well, the public interest in conducting clinical trials to developing a greater understanding of this virus, its prevention and treatment, cannot be overstated.
In that context, the Tribunal's role is to consider whether to allow a trial to use human subjects who are unable to give their own consent to participation in the trial, and whether a person responsible can provide consent on the subject person's behalf if the subject person is unable to give their own consent.
[4]
The hearing
The Tribunal registry received the application and supporting documents late on 23 April 2020. The Tribunal was very much alive to the public interest in having the matter heard as soon as practicable, so the matter was heard less than 24 hours after the documents were received.
Ms Megan Ford, Executive Director of Clinical Trials at Ingham Institute for Applied Medical Research & South Western Sydney Local Health District (SWSLHD), and Professor Anders Aneman, Senior Staff Specialist, appeared via telephone at the hearing. Updated versions of both the trial protocol document GPHIP-0201 ("the Protocol") and proposed person responsible consent forms for both Stage One and Two ("the consent forms") were sent in to the Tribunal during the course of the hearing. A summary of changes made in the latest version of the Protocol (Version 2.0) was also provided.
Upon further examination of the documents at the hearing, it was agreed by the Applicant that further amendments to the consent forms were needed, and that the Applicant's request to permit a person responsible to consent to a patient to participate in the clinical trial should be adjourned to allow for further amended documents to be filed. We made it clear that the Applicant was now responsible for submitting the amended documents and the matter would be relisted before the Tribunal for determination once the amended documents were received.
We note that whilst we have approved the clinical trial under s 45AA of the Act, until such time as we have determined whether a person responsible should be permitted to provide substitute consent for a patient to participate in the trial, only the Tribunal can consent for an individual patient to participate in the trial.
[5]
Trial Overview
As described in the Protocol at page 5, the study is a two-stage study:
Stage 1 is a single arm study to determine the safety of STC3141, while Stage 2 is a randomised open-label, two-arm study to observe safety and preliminary efficacy of personalized optimal dosage of STC3141 compared to standard of care.
The study is designed to test the hypothesis stated on page 11 of the Protocol, that:
STC3141 treatment will lead to an improvement in the clinical status of patients presenting with COVID-19 ARDS [acute respiratory distress syndrome] as determined by the primary clinical measure, namely, the ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2)
In layman's terms, an increase in the primary clinical measure in this study (PaO2/FiO2) means an improvement in the ability of oxygen to move from the lungs to the blood (put simply, improvement in lung function). It follows that a secondary efficacy endpoint of the study is the number of "ventilator free days".
The trial, to be conducted at Liverpool Hospital, would include 160 adult ICU patients with confirmed COVID-19 infection and Acute Respiratory Distress Syndrome (ARDS). Stage 1 would involve testing the safety of the drug STC3141 on 10 patients. Stage 2 would test the efficacy of STC3141 in alleviating the symptoms associated with COVID-19 infection. That would involve 150 patients, 75 of whom would be randomised to receive STC3141 for up to five days, and 75 patients who would be randomised to receive standard care.
STC3141 is a new medication designed by researchers at the Australian National University developed to be a potential treatment for patients with ARDS. A useful and succinct plain explanation of the clinical trial's purpose was provided in the document entitled "Participant Information Sheet" submitted with the application :
The purpose of the study is to work out whether a new drug called STC3141 could improve the treatment of patients with virus associated Acute Respiratory Distress Syndrome (ARDS). ARDS is a life-threatening condition that is part of a syndrome which develops when your body has a very strong immune response to an infection. Your immune system protects you from many infections, however, with some infections, such as COVID-19, your immune system goes into overdrive releasing many chemical substances into the bloodstream that trigger widespread inflammation, damage to cells that line your blood vessels and blood clotting. This can lead to damage to your organs such as your lungs, causing breathing complications, and kidneys, leading to kidney failure and a decreased ability to clear waste products from your body. As such, it can develop into a very serious and life-threatening condition.
One of the proteins released by your immune cells, called histones, is responsible for causing this damage. The trial drug STC3141was specifically developed to attach to histones stopping them from causing damage to the body. STC3141 has not been approved for marketing by any government agency such as the TGA and is not yet approved anywhere in the world. Therefore, the use of STC3141in this study is considered experimental. It has, however, been given to 48 healthy human volunteers and was well tolerated with no serious or life-threatening side effects.
[6]
Guardianship Act 1987 (NSW)
The provisions relating to clinical trials are contained within Pt 5 of the Act. Part 5 of the Act deals primarily with medical treatment for patients aged 16 or over, and who are incapable of giving consent to the carrying out of medical or dental treatment: s 34(1) of the Act.
For the purposes of Pt 5 of the Act, 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: s 33(2) of the Act.
Under s 45AA(1) of the 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 s 45AA(2) of the Act.
Section 45AA of the Act 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.
As is clear from s 45AA(4) of the Act, 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 Divisions 3 or 4 of that Act before any medical or dental treatment in the course of the trial may carried out in relation to the patient.
The Tribunal may determine, pursuant to s 45AB(1) of the Act, 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 of the Act applies); or
the Tribunal is to exercise that function itself (in which case Division 4 of the Act applies).
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: s 45AB(2) of the Act.
In determining whether the forms proposed are sufficient to permit a person responsible to fulfil the role contemplated by Pt 5 of the Act, the Tribunal must have regard to the statutory requirements of decision making imposed upon persons responsible as outlined in Division 3 of Pt 5 of the Act. Section 40 of the Act, which accounts for all of Division 3 of that Act, provides as follows:
40 Consents given by persons responsible for patients
(1) Any person may request a person responsible for a patient to whom this Part applies for that person's consent to the carrying out of medical or dental treatment on the patient.
(2) Such a request shall specify:
(a) the grounds on which it is alleged that the patient is a patient to whom this Part applies,
(b) the particular condition of the patient that requires treatment,
(c) the alternative courses of treatment that are available in relation to that condition,
(d) the general nature and effect of each of those courses of treatment,
(e) the nature and degree of the significant risks (if any) associated with each of those courses of treatment, and
(f) the reasons for which it is proposed that any particular course of treatment should be carried out.
(3) In considering such an application, the person responsible for the patient shall have regard to:
(a) the views (if any) of the patient,
(b) the matters referred to in subsection (2), and
(c) the objects of this Part.
(4) The regulations may make provision for the manner and form in which:
(a) requests under this section shall be made, and
(b) consents under this section shall be given.
In Shehabi v Attorney General (NSW) [2016] NSWCATAP 137 at [67], the Appeal Panel described ss 45AA and 45AB of the Act as establishing 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 of the Act 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) of the Act 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 of the Act or under ss 42 to 45 of that Act, respectively, for the medical treatment in the course of the trial to be carried out on the patient.
[7]
Matters for Determination
As described in Shehabi v Attorney General, the Tribunal had the following relevant matters to determine given the application before us
1. Does the trial meet the requirements of s 45AA of the Act?
2. Should consent to treatment as part of the trial be given by the "person responsible"?
As outlined at [10] above, as the Applicant wished to place amended documents before the Tribunal relevant to consideration of the issue of whether consent to treatment as part of the Trial should be able to be given by a "person responsible", we were only required at this stage to determine the first question: Does the trial meet the requirements of s 45AA of the Act?
Professor Aneman addressed us on each of these questions at the hearing. We deal with each of them in turn below.
[8]
Does the trial meet the requirements of s 45AA of the Act?
[9]
Is STC3141 intended to cure or alleviate a particular condition from which the patients suffer?
In essence, the hypothesis of the study is that treatment with STC3141 can improve the clinical status of COVID-19 patients being treated in the intensive care unit. STC3141 is not intended to cure COVID-19, rather, it is intended to improve respiratory function in patients experiencing acute respiratory distress syndrome (ARDS) as a result of COVID-19.
As outlined in Part 5.3 of the clinical trial protocol:
The potential benefits of STC3141 being administered to subject admitted to ICU with COVID-19 ARDS is a reduction in the damage by circulating histones resulting in faster recovery times, reduced number and severity of medical complications of ARDS, and better survival rates in these subjects.
We were satisfied that STC3141 is intended to alleviate symptoms of COVID-19, from which the patients suffer.
[10]
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)?
Professor Aneman informed the Tribunal that STC3141 has been well-tolerated by healthy volunteers in short infusions (two hours) and continuous long-term infusions (72 hours). The Protocol gives greater detail to this in Parts 5.2.2-5.3. On page 37, the Protocol reports the following from a Phase I clinical study of STC3141:
[F]ound to be well tolerated in short infusions…and continuous long-term infusions, with comparable [adverse event] profile across active treatment groups and Placebo. There were no deaths, [serious adverse events] or discontinuations due to AEs reported during the study.
Patients with COVID-19 ARDS are currently without disease-specific treatment. There are no proven pharmaceutical treatments for COVID-19 other than supportive care.
We were satisfied that the clinical trial does not involve any substantial risk to patients enrolled to participate.
Those who are randomised not to receive SCT3141 will receive standard ICU care to endeavour to alleviate the symptoms of COVID-19 ARDS. For those who are randomised to receive STC3141, there was no evidence before us to indicate that there was any known likelihood of adverse events or other substantial risk to health.
[11]
Has the development of SCT3141 reached a stage at which safety and ethical considerations make it appropriate that STC3141 be available to patients who suffer from COVID-19 even if those patients are not able to consent to taking part in the Trial?
The trial is a Phase II trial. The drug has already been through pre-clinical and Phase I trial development, as described in the Protocol.
The evidence of Professor Aneman was that the Phase I trial of STC3141 was undertaken in 48 healthy Australian volunteers with short (two hours, 32 subjects) and long-term (72 hours, 16 subjects) infusions in escalating doses. The drug was found to be well tolerated with non-serious adverse events occurring with equal frequency between those volunteers who received the drug and those who received placebo. There were no deaths, no serious adverse events or discontinuations due to adverse events reported during the study.
Professor Aneman did note that an expected mild anticoagulant effect had been measured in those receiving the drug in the Phase I trial. This was reported to us as not being a side-effect, but a beneficial therapeutic effect in COVID-19 patients. He advised that all enrolled patients would be closely monitored as would be the case with any other anticoagulant therapy.
As to the issue of the drug being given to patients who could not provide their own consent, Professor Aneman confirmed that the study could only be conducted on critically ill patients who would be unable to provide consent due to mechanical ventilation and continuous sedation.
We accepted the uncontradicted evidence of Professor Aneman as to the development and testing of STC3141 to date and were satisfied that the drug has reached a stage at which safety and ethical considerations make it appropriate that STC3141 be made available to patients who suffer from COVID-19 even though those patients will be not able to consent to taking part in the Trial.
[12]
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 COVID-19 that they take part in the Trial?
The potential benefits of participation in the trial is described in Part 5.3 of the Protocol, and includes faster recovery times, reduced number and severity of complications arising from ARDS, and better survival rates.
Again, there is currently no disease-specific treatment for COVID-19 ARDS, and there is evidence for its safety for use in healthy volunteers.
Professor Aneman submitted to us that there is a relatively high morbidity rate amongst those diagnosed with COVID-19 once in the ICU setting and ventilated. He was of the view that it is the best interests of those patients who satisfy the relevant criteria to be included in the trial. Those who are randomised not to receive STC3141 will receive the best available ICU care. Those who receive the drug will not be subjected to any known serious adverse risk and may well benefit if the potential benefits come to fruition.
We were satisfied that, on balance, it is in the best interests of patients who suffer from COVID-19 and meet the clinical trial protocol criteria for inclusion be able to take part in the Trial. Those who meet the inclusion criteria will be critically unwell without recourse to disease-specific treatment and subject to a significant risk of death. It is in such patient's best interests that they receive the best form of available ICU setting care, or, that same care as well as the trial drug, for which there are no know significant risk of adverse events.
[13]
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?
The Trial was approved by the South Western Sydney Local Health District Human Research Ethics Committee ("HREC") on 21 April 2020. Amendments to the study were also approved by the HREC on 23 April 2020.
[14]
Conclusion
For the reasons provided, we found the clinical trial meets the criteria in s 45AA of the Act, and thereby approved the clinical trial.
[15]
APPENDIX A
On 24 April 2020 the following orders (and/or directions) were made:
Clinical Trial
The Tribunal has considered the clinical trial known as:
An Open Label, Multi-Centre Study to Determine the Safety and Efficacy of STC3141 Administered as an Infusion for up to 5 Days in Subjects with COVID-19 Respiratory Distress Syndrome Requiring Intensive Care (GPHIP-0201, Protocol Version 2.0 dated 8th April 2020):
The Tribunal is satisfied that the clinical trial (both Stage 1 and Stage 2) meets the requirements of section 45AA(2) of the Guardianship Act 1987(NSW) ("the Act") and approves the clinical trial pursuant to s 45AA(1) of the Act. Consent for medical treatment on patients in the course of the trial may only be given or withheld by the Tribunal (section 45AB (1)(b)).
The consent is effective for Liverpool Hospital for the duration of the clinical trial.
The Applicant's request that the Tribunal order under section 45AB (1) (a) of the Act that the function of giving or withholding consent for patients in the course of the clinical trial be exercised by the persons responsible for the patients is adjourned to a date to be fixed by the Registrar to allow the Applicant to submit amended Person Responsible Information and Consent Forms (both Stage 1 and Stage 2).
[16]
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: 17 June 2020
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.