Shehabi v Attorney General

The hearing

1. The Tribunal registry received the application and supporting documents on 13 May 2020. The Tribunal listed the matter for hearing just two days thereafter.
2. Professor Ian Seppelt, Senior Specialist in Intensive Care Medicine at Nepean Hospital appeared via video link at the hearing and made submissions as the applicant. Also participating via video link were members and representatives of the clinical trial team: Professor Iona Novak, the Clinical Trial Coordinator and Head of Research at the Cerebral Palsy Alliance Research Institute; Dr Killian Kelly, Chief Operating Officer of the trial's sponsor company, Cynata Therapeutics Limited; and Dr Madison Paton, Research Fellow at Cerebral Palsy Alliance Research Institute.

Trial Overview

1. Part 1 of the Protocol gives a comprehensive background and explanation of the rationale for the trial.
2. According to the research cited in the Protocol, one reported effect of COVID-19 is "Cytokine Storm Syndrome", an immune response which, in essence, means rapid inflammation in parts of the body, sometimes in multiple organs including the lungs, heart, gut and brain. This hyperinflammation contributes to the progression of COVID-19, admissions to the ICU, and fatalities.
3. The clinical trial seeks to determine early efficacy of Mesenchymal Stem Cells ("MSCs") in treating COVID-19. The rationalisation for using MSCs in the trial is, primarily, their anti-inflammatory effect.
4. MSCs are the active ingredient in the trial drug, CYP-001. The MSCs in CYP-001 have been derived from a single donation and mass-produced in a way which does not rely on a continuous supply of new donors, called the "Cymerus" process. The MSCs used in the trial drug are therefore called "Cymerus MSCs".
5. As a pilot trial, the primary objective of the trial is to evaluate early efficacy and to confirm safety of the drug. It is proposed that 24 patients be recruited into the clinical trial at either Nepean Hospital or Westmead Hospital with 12 patients randomly selected to receive standard ICU care only, and 12 patients randomly selected to receive such care together with CYP-001.
6. The primary endpoints, or results used to measure success in the study are: proportion of participants showing a 50% improvement in P/F ratio by D7 (day 7); incidence and severity of trial emergent adverse events; safety laboratory evaluations; and vital signs.

Guardianship Act 1987 (NSW)

1. 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: the Act, s 34(1).
2. 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: the Act, s 33(2).
3. 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.
4. 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.
5. 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 Divs 3 or 4 of Part 5 of that Act before any medical or dental treatment in the course of the trial may carried out in relation to the patient.
6. 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 Div 3 of Part 5 of the Act applies); or
• the Tribunal is to exercise that function itself (in which case Div 4 of the Act 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: the Act, s 45AB(2).
2. 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 Div 3 of Pt 5 of the Act. Section 40 of the Act, which accounts for all of Div 3, 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.
3. 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.

MATTERS FOR DETERMINATION

1. As described in Shehabi v Attorney General, the Tribunal has the following relevant matters to determine: 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"?
2. Professor Ian Seppelt addressed the Tribunal on each of these questions at the hearing. We deal with each of them in turn below.

Does the trial meet the requirements of s 45AA of the Act?

Is CYP-001 intended to cure or alleviate a particular condition from which the patients suffer?

1. CYP-001 is not intended to cure COVID-19, rather, it is intended to improve respiratory function in patients experiencing ARDS as a result of COVID-19. In essence, the hypothesis of the study is that treatment with CYP-001 can improve the condition of COVID-19 patients with ARDS being treated in the ICU, by alleviating inflammation.
2. As outlined in Professor Seppelt's submissions: Given the substantial unmet medical need and known poor outcomes of those with COVID-19 admitted to ICU, CYP-001 is being proposed as a treatment in this clinical trial. The main goal will be to measure just how much CYP-001 can improve lung outcomes in the short term (up to day 7) and if this improvement can be seen faster than those receiving standard ICU care.
3. We are satisfied that CYP-001 is intended to alleviate symptoms of COVID-19, from which the patients suffer.

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 Protocol states at Part 1.6: MSCs from a range of sources have been the subject of extensive clinical investigations in recent years in many indications, with recent reports of its use for COVID-19. To date, all evidence supports that MSCs are very well tolerated, with no significant safety concerns identified…[P]articipant safety will be a key focus, and steps will be taken to ensure that safety is monitored closely throughout.
2. In written submissions to the Tribunal, the author on behalf of Cynata Therapeutics describes safety results in a Phase I trial of CYP-001 as follows: There were no adverse events related to infusion of CYP-001. The incidence of treatment emergent adverse events (TEAEs) was similar between groups regardless of assigned treatment dose. There were no serious adverse events (SAEs) considered to be possibly, probably or definitely related to Cymerus MSCs. There were five TEAEs in four participants reported on study that were considered to be possibly related to Cymerus MSCs treatment, and no TEAEs considered to be probably or definitely related. "Possibly related" to CYP-001 was defined as an "AE with a reasonable time relationship to CYP-001 administration, but which could also be explained by disease or other drugs" The possibly related TEAEs reported were abdominal pain, diarrhoea, febrile neutropenia, arthralgia and renal impairment…No participants discontinued treatment due to adverse events. [The Phase I trial], along with substantial preclinical evidence, supports the dose and use of CYP-001 for this current COVID-19 trial, and demonstrates the favourable benefit:risk. Overall, given the known substantial unmet medical need and known poor outcomes of those with COVID-19 admitted to ICU, it is favourable to trial CYP-001 in this study.
3. Patients with COVID-19 ARDS are currently without disease-specific treatment. Only supportive treatment is available, often involving invasive respiratory support.
4. Having considered the uncontested submissions and material before us, we are satisfied that there is likely no known substantial risks to the patients, and to the extent there are risks, they are not greater than those posed by current treatment, which is only supportive (not therapeutic) and involves invasive ventilation.

Has the development of CYP-001 reached a stage at which safety and ethical considerations make it appropriate that CYP-001 be available to patients who suffer from COVID-19 even if those patients are not able to consent to taking part in the Trial?

1. The Cymerus MSCs used in the trial drug have been through pre-clinical and Phase I trials. The Investigator's Brochure, submitted with the Protocol, outlines at Parts 4 and 5 numerous pre-clinical and non-clinical trials of Cymerus MSCs. It also reports a Phase I clinical trial of CYP-001 (mentioned at [31] above) conducted in 2017-18 on patients with Steroid-Resistant Acute Graft Versus Host Disease (GvHD), which concluded: The results of this study show that two IV infusions of CYP-001 were safe and well tolerated in these steroid-resistant GvHD patients.
2. Relevantly, GvHD is described in Part 2.5.3 of the Investigator's Brochure as: [A] disease with considerable immune and cytokine involvement and the closest human disease model to COVID-19 for stem cell modelling.
3. Given the extent of trialling and research of CYP-001 and its active ingredient to date, as outlined in the material before us, we are satisfied that the development of CYP-001 has reached a stage at which safety and ethical considerations make it appropriate that CYP-001 be available to patients who suffer from COVID-19, including patients 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 COVID-19 that they take part in the Trial?

1. The potential benefit of participation in the trial is that patients with COVID-19 being treated for ARDS in the ICU see an improvement in their condition where the risk of mortality from the disease is statistically at its highest.
2. Again, there is currently no disease-specific treatment for COVID-19 ARDS, and there is evidence for its safety for use in healthy volunteers.
3. For those reasons, we are satisfied that the potential benefits outweigh the potential risks, and it is in the best interests of patients who suffer from COVID-19 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. The Trial was approved by the Bellberry Human Research Ethics Committee ("HREC"), for the Nepean and Westmead sites, on 7 May 2020.

Conclusion

1. For the reasons provided, we found the clinical trial meets the criteria in s 45AA of the Act, and thereby approved the clinical trial.

Should consent to treatment as part of the trial be given by the "person responsible"?

1. Section 45AB of the Act provides as follows: (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.
2. The Act provides no express guidance on the factors to take into account in making the determination as to whether consent should be given by the person responsible for each patient. Of course, the principles in s 4 of the Act are taken into account in all decisions made by entities carrying out substantive division functions under the Act. The paramount consideration among those listed in s 4 is the subject person's welfare and interests: the Act, s 4(a).

Do the proposed forms 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. The consent forms and other information available to the persons responsible must be sufficiently informative to enable a person responsible, when making decisions about treatment under Pt 5 of the Act, to carry out their function having regard to the considerations listed in ss 40(2)-(3) of the Act, including: 1. The objects of Pt 5 of the Act: 1. 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 2. 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 views (if any) of the patient; 2. the grounds on which it is alleged that the patient is a patient to whom this Part applies; 3. the particular condition of the patient that requires treatment; 4. the alternative courses of treatment that are available in relation to that condition; 5. the general nature and effect of each of those courses of treatment; 6. the nature and degree of the significant risks (if any) associated with each of those courses of treatment; and 7. the reasons for which it is proposed that any particular course of treatment should be carried out.
2. The Tribunal was provided with copies of a "Participant Information Sheet/Consent Form" ("PICF") and a "Person Responsible/Third Party Form" which is where a person responsible would physically indicate their consent by signing in person, after reading the PICF.
3. Owing to pandemic infection control procedures that prohibit visitors to hospitals for safety reasons, a "Person Responsible Telephone Participant Information and Consent Form" ("the Telephone Consent Form") was also submitted for approval. The Telephone Consent Form details a telephone script which will be read to a person responsible over the phone if initial consent to begin the study procedures needs to be obtained, and the person responsible is unable to attend the relevant site within 24 hours of the patient's admission. The PICF will be provided via email to the person responsible, and their written consent will then be sought at their next visit to the hospital.
4. Among other things, the PICF outlines in detail and in "plain English":

• the purpose of the trial;
• some background information about COVID-19 and the trial drug;
• the drug's known effects and the rationale for testing the trial drug as a treatment for COVID-19;
• what the trial involves, including potential benefits, risks and known side-effects; and
• the alternative treatments available (standard care treatment alone).

1. The Telephone Consent Form provides a condensed version of the information provided in the PICF, and leaves specific space for any questions to be asked by the person responsible, to ameliorate the risk of any gaps in their understanding. It operates as an interim measure to ensure consent can be given to participation in the trial quickly, until the PICF can be read in full, and written consent provided (or withheld) at the earliest practicable opportunity thereafter.
2. We are satisfied that the information contained in the PICF and the Telephone Consent Form provided at or before the time consent is sought by the person responsible (as the case may be), fulfils the requirement of being sufficiently informative to enable a person responsible, when making decisions about treatment under Pt 5 of the Act, to carry out their function having regard to the considerations listed in ss 40(2)-(3) of the Act and having regard to the principles in s 4 of the Act.

Conclusion

1. There was no evidence or submissions before us suggesting that the authority to provided substitute consent on behalf of a patient to receive treatment as contemplated in the clinical trial should be restricted to the Tribunal and not extended to a proposed patient's persons responsible.
2. Having concluded that the information in the consent forms and other materials provided to persons responsible is sufficient to enable the persons responsible to decide whether or not it is appropriate that the patients should take part in the Trial, we were satisfied that we should exercise our discretion to grant the approval sought by the applicant under s 45AB(1)(a) of the Act.

appendix a The Tribunal has considered the clinical trial known as: The MEND (MEseNchymal coviD-19) Trial: A Pilot, Open Label, Randomised Controlled Clinical Trial to Investigate Early Efficacy of CYP-001 in Adults Admitted to Intensive Care with COVID-19 (Protocol Version 2.0 dated 30 April 2020). 1. The Tribunal is satisfied that the Clinical Trial 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. 2. The consent is effective for Nepean Hospital and Westmead Hospital for the duration of the Clinical Trial. 3. The Tribunal notes that the consent mechanism contemplated by clause 4.1.2 of the Clinical Trial Protocol is not permitted in NSW. 4. The Tribunal is satisfied that the form for granting consent, and the information available about the Clinical Trial, will enable a patient's person responsible to decide whether or not it is appropriate that the proposed patient should take part in the Clinical Trial. 5. 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 a person responsible is granted. 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: 06 July 2020