Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (TRANSFUSE Trial)

[2015] NSWCATGD 18

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 (TRANSFUSE Trial) [2015] NSWCATGD 18
Hearing dates:	1 May 2015 and 22 May 2015
Date of orders:	03 June 2015
Decision date:	03 June 2015
Jurisdiction:	Guardianship Division
Before:	C Fougere, Principal Member H Creasey, Senior Member (Professional) J Koussa, General Member (Community)
Decision:	The TRANSFUSE Trial does not fall within the definition of clinical trial in section 33(1) of the Guardianship Act 1987 (NSW). Application dismissed.
Catchwords:	CLINICAL TRIAL – randomised double blinded phase III trial – whether administration of freshest available red blood cells reduces 90-day mortality in critically ill patients – not a trial of ‘drugs’ or ‘techniques’
Legislation Cited:	Civil and Administrative Tribunal Act 2013 (NSW) Guardianship Act 1987 (NSW)
Cases Cited:	Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (SPICE III Trial) [2014] NSWCATGD 44 Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (AMOUNT Rehabilitation Trial) [2015] NSWCATGD 1
Texts Cited:	Macquarie Dictionary (online edition)
Category:	Principal judgment
Parties:	Professor David James Cooper (Applicant)
Representation:	Ms Susan Harris Dr Ashley Tsacalos
File Number(s):	5/2015
Publication restriction:	Nil

REASONS FOR DECISION

INTRODUCTION

1. On 1 April 2015, the original applicant, Professor Pauline Nestor, who was subsequently replaced as applicant by Professor David Cooper, made an application to the NSW Civil and Administrative Tribunal in relation to the 'TRANSFUSE' trial: a 'multi-centre randomised double blinded phase III trial of the effect of standard issue red blood cell blood units on mortality compared to freshest available red blood cell units' (TRANSFUSE Protocol ANZIC-RCDJC006, Version 1.4, 20 November 2014 ('Study Protocol')).

2. The TRANSFUSE trial gains its name from its longer title - 'Standard Issue TrANsfusion versuS Fresher red blood cell Use in intenSive care - a randomised controlled trial.'

3. The hypothesis sought to be tested in the trial (as set out in the Study Protocol, page 15) is that in critically ill patients who require a red blood cell ('RBC') transfusion, compared to standard practice, the administration of the freshest available compatible RBC reduces 90-day patient mortality.

4. This is a trial in which participants are likely to be incapable of providing informed consent due to the effects of sedation and their critical illness.

5. The TRANSFUSE trial is funded by a grant from the National Health and Medical Research Council and is being conducted across 45 sites in Australia. The first person was recruited in Victoria in November 2012.

6. The trial is conducted on the basis of waiver of consent, that is, that prior informed consent for entry into the trial is not required from the patient or their person responsible.

7. The trial received approval in NSW, including approval for a waiver of the need to obtain consent from patients enrolled into the study, from the Sydney Local Health District Human Ethics Review Committee by letter dated 27 September 2012 (in relation to an earlier version of the Study Protocol) and 15 December 2014 (in relation to the current Study Protocol).

8. The Tribunal was informed that although the trial commenced operation in NSW in April 2013, it was suspended in NSW following decisions of NCAT in Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (SPICE III Trial) [2014] NSWCATGD 44 ('SPICE III') and Application for approval for adults unable to consent to their own treatment to participate in a clinical trial (AMOUNT Rehabilitation Trial) [2015] NSWCATGD 1 ('AMOUNT').

9. A letter dated 20 March 2015 that formed part of the original application noted that Monash University had not at that stage made a determination as to whether TRANSFUSE is a 'clinical trial' pursuant to Part 5 of the Guardianship Act 1987 (NSW). However, if the Tribunal determined that the trial fell within this definition, then the applicant sought the Tribunal's approval for the trial pursuant to section 45AA of the Guardianship Act.

10. The critical issue in this case was therefore whether or not TRANSFUSE meets the definition of 'clinical trial' in section 33(1) of the Guardianship Act.

TRIBUNAL'S FINDINGS

11. The Tribunal determined that that TRANSFUSE is neither a trial of drugs nor a trial of techniques.

12. For this reason, TRANSFUSE does not fall within the definition of 'clinical trial' in section 33(1) of the Guardianship Act and the application is dismissed.

PROCEEDINGS BEFORE TRIBUNAL

13. The hearing of the application took place on 1 and 22 May 2015. The Tribunal reserved its decision on 22 May 2015.

14. The procedural history and progress of the matter is set out in Appendix A.

LEGISLATIVE FRAMEWORK

15. 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)).

16. 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.

17. 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.

18. 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.

19. Once a trial has been approved, section 45AB provides for consent for participation in clinical trials in individual cases.

20. The definitions for a number of key terms referred to in Part 5 are set out in section 33(1). The definitions relevant to the present case are 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.

'medical or dental treatment' or 'treatment' means:

(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

(b) dental treatment (including any dental procedure, operation or examination) normally carried out by or under the supervision of a dentist, 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), but does not include:

(d) any non-intrusive examination made for diagnostic purposes (including a visual examination of the mouth, throat, nasal cavity, eyes or ears), or

(e) first-aid medical or dental treatment, or

(f) the administration of a pharmaceutical drug for the purpose, and in accordance with the dosage level, recommended in the manufacturer's instructions (being a drug for which a prescription is not required and which is normally self-administered), or

(g) any other kind of treatment that is declared by the regulations not to be treatment for the purposes of this Part.

21. The provisions in Part 5 are also subject to the general principles set out in section 4 of the Guardianship 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:

(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.

EVIDENCE CONCERNING THE TRIAL

22. The Tribunal was provided with evidence and submissions in the form of the Study Protocol, written submissions dated 20 March 2015 and 15 May 2015, the completed National Ethics Application Form dated 22 August 2012, correspondence with the Sydney Local Health District Ethics Review Committee, a powerpoint presentation and relevant journal articles.

23. Oral evidence was provided by a number of people listed in Appendix A.

Background to trial

24. According to the evidence, anaemia is common in critically ill patients: up to 90% of patients will be anaemic by day three of their intensive care unit (ICU) stay. Blood transfusion to address this, while potentially life-saving for individual patients, has also been associated with an increased risk of morbidity and/or mortality in critically ill, surgical and trauma populations. Literature reports have increasingly focused the attention on the possible harmful impact of red blood cell ('RBC') storage on the outcome of ICU patients.

25. This is because the storage of RBCs in a preservative medium is associated with metabolic, biochemical and molecular changes to erythrocytes commonly referred to as 'storage lesion'.

26. Studies in trauma, ICU and patients undergoing cardiac surgery have demonstrated adverse outcomes potentially attributable to storage lesion.

27. In recent years, observational studies have shown that older compared to fresher blood increased patient mortality and morbidity. However, some investigators have not demonstrated any association between RBC storage lesion and clinical outcomes.

28. According to the Study Protocol (at page 14), most of clinical studies in this area are observational: they are mostly retrospective, small, and subject to bias. Only two small randomised controlled trials have been performed: they were very small and under-powered to answer the question. Accordingly, systematic reviews and a meta-analysis have been inconclusive.

29. The impact of storage lesion on clinical outcomes therefore, according to the evidence, remains uncertain and no definitive conclusions may be made. According to the evidence, the available literature supports further research to determine the effect of storage lesion on clinical outcome in critically ill patients.

Evidence concerning details of the trial

30. The evidence before the Tribunal is that the age of 'standard issue' blood varies according to a number of factors. In Australia, blood collected for transfusion has a 'use by' date of 42 days after collection. The actual age of blood given to patients depends on what is available at the time and the rate of usage. In standard practice, haematology staff at a blood bank will dispense blood by taking out a bag from the front of the refrigeration unit, which has the shortest time to expiry (or is the 'oldest' blood stored). The physician prescribing the transfusion does not typically have any say in, or give direction as to, the age of the blood to be transfused.

31. Patients enrolled in the TRANSFUSE trial are randomised to receive either the freshest blood or the oldest available blood via a web based computer system that will assign to each patient a unique study identification number. This number is placed on the patient's chart and on the RBC request sent to the transfusion service. Study group allocation is concealed from the treating medical and nursing staff and the research coordinator. The patient will continue to receive the randomised treatment arm for any additional blood transfusion episodes during their hospital stay.

32. The written and oral evidence was that the TRANSFUSE study design does not use an arbitrary cut-off age for defining the youngest RBC, but instead uses the 'freshest available' RBC versus standard care. According to the evidence, this design best reflects the clinical practice change which would be practical to implement if fresher blood was beneficial in ICU patients. As the Tribunal understood Professor Cooper's evidence, for the trial to be meaningful, all that is needed for comparison is two equally sized groups of patients receiving the freshest available blood in one, and the oldest available blood in the other. If there is a difference in outcome between the two groups at the end of the trial, then this will answer the question as to whether one treatment arm is better than the other. If no difference in outcome is found between the two treatment arms, practice change would not be necessary.

33. The inclusion criteria for the trial are as follows (Study Protocol, page 16):

• ICU patients with an anticipated stay of at least 24 hours, in whom the decision has been made by medical staff to transfuse at least one RBC unit

• A patient can be included in the study in the Emergency Department if the decision to admit the patient into the ICU has been taken

34. Patients will be excluded for any of the following reasons (Study Protocol, page 16):

• Age younger than 18

• Previous RBC transfusion during the current hospital admission (including transfusion in another hospital for transferred patients)

• Diagnosis of transplantation or haematologic malignancy

• Pregnancy

• Cardiac surgery during the present hospital admission

• Expected to die imminently (<24 hours)

• The treating physician believes it is not in the best interests of the patient to be randomised into this trial

• Known objection to the administration of human blood products

• Participating in competing study

35. Patients will be screened in the ICU and emergency department for their potential eligibility. Eligible patients will be enrolled when the clinical decision is made to transfuse. Patients in the Emergency Department who are going to be admitted to the ICU may also be randomised when a clinical decision is made to transfuse if time permits.

36. Professor Cooper gave evidence that within the critical care environment, all blood transfusions are considered urgent. When asked by the Tribunal about the actual timeframe in such circumstances, Professor Cooper gave an estimate of between 15 minutes and one hour between the making of the clinical decision that a blood transfusion is required for an individual patient and the need for the transfusion to commence.

37. According to page 19 of the Study Protocol, randomised patients will be followed up to death or 180 days post-randomisation. Data collection is restricted primarily to variables necessary to define clinical patient characteristics including: baseline demographics, primary diagnoses, physiological parameters, diagnostic interventions, therapeutic interventions and documentation of death and other adverse events. For patients discharged alive from ICU, follow up will be restricted to information concerning duration of hospital stay and vital status at hospital discharge, 90 days and 180 days post randomisation. In addition, patients (or a proxy - generally a close family member) that are alive at 180 days after randomisation will be asked to undertake a quality of life questionnaire by telephone.

38. It is anticipated that a total sample size of 5000 patients will be attained across Australia. So far, approximately half this number have been recruited into the trial from Australia and New Zealand. So far, 323 patients had been recruited into the trial in NSW.

IS TRANSFUSE A 'CLINICAL TRIAL'

39. A critical issue in this case was whether TRANSFUSE meets the definition of 'clinical trial' in section 33(1) of the Guardianship Act. 'Clinical trial' is defined in section 33(1) as meaning 'a trial of drugs or techniques that necessarily involves the carrying out of medical or dental treatment on the participants in the trial'.

40. No-one in this matter suggested, and nor does the Tribunal find, that the substance that forms the basis of the trial, blood, falls within the ordinary meaning of 'drug' ('a chemical substance given with the intention of preventing or curing disease or otherwise enhancing the physical or mental welfare of humans or animals': Macquarie Dictionary (online definition)). This is despite, as noted in the evidence, the life saving nature of blood transfusions for ICU patients suffering anaemia.

41. The Macquarie Dictionary (online definition) defines 'technique' as:

1. Method of performance; way of accomplishing

2. Technical skill, especially in artistic work    

42. Superficially, it may appear reasonable to describe the 'technique' being trialled in TRANSFUSE as being that of taking a different approach (when compared to current practice) to the choice of age of blood for transfusion in ICU patients and whether this will make a difference to long term patient outcomes.

42. However, when the nature of this trial is carefully considered, and hence the need to set out above the details of the trial and the justification for the study, it becomes evident that what is being trialled is not a new method of performing blood transfusions or a new way of accomplishing such transfusions.

43. Rather, what is being tested and compared is the impact of the substance itself and whether the relative age of the blood available for transfusion (due to the effect of storage lesion) makes a difference to 90 day patient mortality outcomes.

44. The unique characteristics of the TRANSFUSE trial are such that the substance being trialled is not a drug. Nor is it a trial of a technique. The Tribunal was therefore not satisfied that TRANSFUSE is a trial of drugs or a trial of techniques.

45. For this reason, TRANSFUSE does not fall within the definition of 'clinical trial' in section 33(1) of the Guardianship Act and the application is dismissed.

APPENDIX A

47. The hearing of the application commenced on 1 May 2015. Leave was granted pursuant to section 45(3)(a) of the Civil and Administrative Tribunal Act 2013 (NSW) (‘CAT Act’) for Ms Susan Harris, Associate General Counsel of Monash University, to represent the applicant. At the conclusion of that hearing, the Tribunal adjourned the matter for three weeks and directions were made for the filing of written submissions within 14 days.

48. The Tribunal reconvened on 22 May 2015 to provide the applicant with the opportunity to make final submissions. On that date, leave was granted to Dr Ashley Tsacalos, solicitor and partner at Norton Rose Fulbright Australia, to represent the applicant.

49. Late on 21 May 2015, written submissions had been lodged at the Tribunal on behalf of the Sydney Local Health District (‘SLHD’) following an invitation made by the Tribunal during the hearing on 1 May 2015 for the Chair and Deputy Chair of the SLHD Human Research Ethics Committee to make submissions if they wished to do so concerning the matters that the applicant was asked to address in the directions that followed that hearing. The SLHD did not seek to be joined as a party to these proceedings and the applicant’s representative indicated that an objection would be made should joinder be proposed. It was put to the Tribunal by both the author of the SLHD submissions and the applicant’s legal representative that the Tribunal could have regard to the submissions without needing to join the SLHD.

50. The Tribunal is not bound by the rules of evidence and may inquire into and inform itself on any matter in such manner as it thinks fit, subject to the rules of natural justice, and is to act with as little formality as the circumstances of the case permit and according to equity, good conscience and the substantial merits of the case without regard to technicalities or legal form (CAT Act, section 38(2) and (4) respectively). Having regard to these matters, and the guiding principle contained in section 36(1) of the CAT Act, the Tribunal had regard to the written submissions filed by SLHD and heard oral submissions from the author of those submissions without joining the SLHD (or the State of NSW) as a party.

51. At the conclusion of the hearing on 22 May 2015, the Tribunal reserved its decision.

52. The following people participated in one or both of the hearings:

• Professor David James Cooper, applicant and Chief Investigator for the TRANSFUSE study. Professor of Intensive Care Medicine at Monash University and a Senior Specialist in Intensive Care in the Department of Intensive Care at the Alfred Hospital in Melbourne.

• Associate Professor Craig French, Chief Investigator ‘C’ on the TRANSFUSE trial, Principal Investigator for the TRANSFUSE trial at Western Health and Director of the Intensive Care unit, Western Health, Victoria

• Associate Professor David Gattas, Principal Investigator for the TRANSFUSE trial at Royal Prince Alfred Hospital, Sydney and Senior Staff Specialist in Intensive Care at Royal Prince Alfred Hospital

• Ms Bridget Ady, Project Manager for the TRANSFUSE trial, ANZIC Research Centre at Monash University (by telephone)

• Professor Robert Loblay, Chair of Sydney Local Health District Human Research and Ethics Committee

• Professor David Cook, Deputy Chair of Sydney Local Health District Human Research and Ethics Committee

• Dr Roy Donnelly, Legal Director (Health Law and Research), Sydney Local Health District

• Ms Ann O’Neill, Associate Director for the Office for Health and Medical Research in NSW Ministry of Health

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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

Decision last updated: 28 July 2015