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Chapter 16 - Capacity to Consent to Research
16. 1. IntroductionClinical research with cognitively impaired adults is important. It is essential for improving the treatment of several conditions. Moreover, cognitively impaired adults should not be denied the opportunity to participate in research from which they may benefit.[1], [2] However, such patients should only be enrolled in clinical research when their participation is consistent with their competent choices. [3] This chapter will address some of the principles of research governance designed to safeguard the interests of adults who lack capacity to consent to research as well as providing guidelines as to the assessment of capacity to consent to research.
The chapter also discusses the legislation in New South Wales, Queensland and Victoria relating to substitute consent to “experimental” medical treatments and treatments available through clinical trials.
The relevance of capacity to consent to participate in research was first recognised formally in the Nuremberg Code, which was an attempt to codify principles to guide human experimentation in response to the perpetration of the Nazi atrocities.[4] The Code deemed essential the voluntary legal consent of the subject, which meant that the subject must have legal capacity to give consent.[5]
The next major attempt to codify research governance was the promulgation of the Declaration of Helsinki in 1964 by the World Medical Association. Hitherto unacknowledged by the Nuremberg Code, a provision for involvement of subjects lacking capacity to participate in research was included in the Declaration. Research was divided into two categories based on the researcher’s intent, both categories allowing for consent of a third party (referred to as a ‘legal guardian”) to be substituted for that of an incompetent subject. These categories included:
(i) Therapeutic research - procedures primarily aimed to benefit a particular patient but incidentally also broadened knowledge of the condition or its treatment;
(ii) Non therapeutic research - where the intent was to extend knowledge to benefit future patients but made no claim to benefit individual patients.[6]
By 2000 it was increasingly argued that this distinction, developed in an attempt to protect vulnerable patients by discouraging their involvement in non-therapeutic and theoretically more hazardous research, was outmoded and misleading, and the World Health Medical Association set out general standards for all research to be assessed according to the same criteria of risks and benefits. Nevertheless, the distinctive risk- benefit context of research as opposed to treatment and the notion of a risk hierarchy are important considerations in modern research codes.
Subsequently, research regulations have been developed in legislative frameworks and policies of major health governing bodies in both Europe[7],[8] and the United States, to implement uniform rules on clinical trials and to protect those who cannot give consent. For example, the National Institutes of Health established the following guidelines for conducting research with cognitively impaired individuals:[9]
1. The consent process must clearly differentiate between accepted treatment and research,
2. The Institutional Review Board should include at least one member who is independent of the proposed research project and has expertise in issues of decisional capacity,
3. Adequate assessment of participant capacity must be addressed in the research protocol,
4. There should be safeguards for the additional protection of participants as the severity of impairment increases,
5. Ongoing education should be conducted to enhance participant understanding, and
6. Additional safeguards such as the use of advanced directives for research, may be necessary when greater than minimal risk is involved.
Similarly, in the United Kingdom, the Medical Research Council published guidelines for Ethical Conduct of Research on the Mentally Incapacitated which covered issues related to consent and safeguards for including mentally incapacitated people in research in 1991[10] and guidelines for good clinical practice in clinical trials in 1998.[11] The Medicines for Human Use (Clinical Trials) Regulations 2004 (UK) came into force in the 2004 to cover the conduct of clinical trials on medicinal products. The latter allowed a legal representative of the person not connected with the conduct of the trial to consent to the participation of incompetent adults in medical research.[12] The Mental Capacity Act 2005 (UK) which came into force in April 2007, governs decision-making on behalf of adults who lack mental capacity, both where they lose capacity at some point in their lives, or where the incapacitating condition has been present since birth. It has clarified and enshrined in legislation the requirements for when adults who lack the capacity to consent are included in medical research studies.[13]
In Australia, the National Health and Medical Research Council (NHMRC) has published guidelines for ethical conduct in human research, updated in 2007.[14] This statement emphasises the entitlement of people with a cognitive impairment, disability or mental illness to participate in research and the need for care in the research design both to take into account factors that may affect the capacity to receive information, to consent and participate, and to determine if the person’s condition makes them susceptible to discomfort or distress. Because of the person’s vulnerability, the risks to and burdens imposed on them by the research must be justified by the potential benefits of the research. The NHMRC guidelines regarding consent for people with cognitive impairment, intellectual disability or mental illness include:
1. Consent must be sought either from the person themselves if they have the capacity to consent, or the person authorised to consent on their behalf;
2. Consent should be witnessed by a person who has the capacity to understand the merits, risks and procedures of the research and is independent of the research team, knows the person and is familiar with their condition;
3. If the cognitive impairment is episodic consent should be sought when the condition does not interfere with the person’s capacity;
4. The process of seeking consent should include discussion of any possibility of the person losing their capacity to consent and the person’s wishes in that circumstance followed unless to do so would not be in their best interests;
5. Where consent is sought by a proxy, the researcher should still explain to the participant as far as possible what the research is about
6. Researchers should inform Human Research and Ethics Committees how they propose to determine capacity (including how the decision will be made and by whom, criteria used and process for reviewing capacity during the research)
7. Refusal or reluctance to participate should be respected.[15]
The Guardianship Act 1987 (NSW) came into force in August 1989 well in advance of the National Health and Medical Research Council’s guidelines and the inclusion of Australian hospitals and other medical institutions in clinical trials particularly those that might involve those unable to give a valid consent. Initially the Act dealt only with particular medical or dental treatments that were “experimental” in the sense that they were new treatments that has not yet gained the support of a substantial number of medical practitioners or dentists specialising in the area of practice concerned.[16] Only the NSW Guardianship Tribunal and not the incapable person’s person responsible could give its consent to such treatment. Before it could give its consent, the Tribunal had to be satisfied that:
1. the treatment was the only or most appropriate way of treating the person and was manifestly in their best interests, and
2. in so far as the National Health and Medical Research Council had prescribed guidelines that were relevant to the carrying out of that treatment—those guidelines had been or will be complied with as regards the person.[17]
Amendments to the Guardianship Act which came into force in 1998, after the Standing Committee on Social Issues of the New South Wales Legislative Council recommended their enactment.[18] The effect of these amendments is that the NSW Guardianship Tribunal must give its approval to a clinical trial before that clinical trial may include among its patients people aged 16 years and above who are unable to give a valid consent to their own treatment. The Tribunal may not give its consent unless it is satisfied as to all of the following.[19]
First, that the drugs or techniques being tested in the trial are intended to cure or alleviate a particular condition from which the patients suffer. Consequently, the Tribunal looks at the matter from the perspective of the prospective patients and must be satisfied from the Trial Protocol that only those with the condition that the drug or technique being tested the trials is intended to cure or alleviate will be included in the trial.
Second, that the trial will not involve any known substantial risks 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 existing treatments.
Thirdly, that the development of the drug or technique has reached stage at which safety and ethical considerations make it appropriate that it be available to patients who suffer from that condition even if those patients are not able to consent to take part in the trial.
Fourthly, that having regard to the potential benefits, as well as the potential risks, of participation in the trial, it is in the best interests o f the patients who suffer from the relevant condition that they take part in the trial.
Fifthly, the trial has been approved by the relevant ethics committees of the hospitals or other institutions in New South Wales that intend to take part in the clinical trial and finally that the clinical trial complies with any relevant guidelines issued by the National Health and Medical Research Council.[20] As a matter of practice, the Tribunal will not deal with an application to approve a clinical trial until after proof that the relevant ethics committee has approved that clinical trial has been lodged with it.
The legislation specifically states that the fact that a clinical trial will or may involve the giving of placebos to some of the participants does not prevent the Tribunal from being satisfied that it is in the best interests of patients that they take part in the trial.[21]
If the Tribunal gives its consent to the clinical trial, that completes the first part of the process. The second part of the process is for the Tribunal to decide whether it will decide in each case whether an incapable potential patient can take part in the trial or whether it will give the function of giving or withholding consent for the carrying out of medical or dental treatment on patients in the course of the trial to the “person responsible” for each of the incapable patients.[22] It is the practice of the Tribunal to give this consent function to the “person responsible”. However, before deciding to do so, it must be satisfied that the forms for granting consent and the information available about the trial developed by the hospital or other institution taking part in the trial provide sufficient information to enable the “persons responsible” to decide whether or not it is appropriate that the incapable patient they are “person responsible” for should take part in the clinical trial.[23]
The Tribunal is required to provide details of any clinical trial that it approves in its Annual Report.[24] In fact it provides details of any clinical trial it is asked to approve, whether it approves the clinical trial or not. Examples of the kinds of clinical trials that come to the Tribunal for approval are trials for patients who are critically ill, who have sepsis, suffer from a stroke or have Alzheimer’s Disease.
The Guardianship and Administration Act 2000 (Qld) follows the approach of the New South Wales Act broadly in relation to experimental treatment and closely in relation to clinical trials.
In Queensland experimental treatment is called special medical research or experimental health care and is defined as either medical research or experimental health care relating to a condition the adult has or has a significant risk of being exposed to or medical research or experimental health care intended to gain knowledge that can be used in the diagnosis, maintenance or treatment of a condition the adult has or has had.[25] QCAT is the only consent authority for such treatment and has to be satisfied about a substantial list of matters before it may give its consent to the research or health care. The treatment could be consented to as health care[26]
In a 2006 case that is relevant to the question of experimental treatments in New South Wales, the then Queensland Guardianship and Administration Tribunal held that the only treatment for a particular genetic condition that a 38 year old man with severe intellectual disability had was not experimental health care (experimental treatment).[27] This was because it had long been accepted by specialists in the field and by the leading texts in the field. The Tribunal also considered that the treatment was not special medical research. There was no systematic inquiry or investigation into the treatment and the fact that it had not been the subject of approval or included on the Australian Register of Therapeutic Goods established under the Therapeutic Goods Act 1989 (Cth) did not make it special health care.[28]
In relation to clinical trials, the Act provides that QCAT must first approve the clinical trial, according to criteria essentially similar to the New South Wales criteria.[29] QCAT does not give the individual consents as to who may take part in a clinical trial that it has approved. Those consents are to be sought first according to any relevant direction in a health care directive if the incapable person has made one. If not then the decision will be made by a guardian if QCAT has appointed one for the incapable person. If that is not the case but the incapable person has appointed an attorney under an enduring power of attorney to deal with the matter, then consent should be sought from that person. No such attorney has been appointed, then consent should be sought from the person’s statutory health attorney.[30] The Adult Guardian is the default statutory health attorney for the incapable person who would otherwise have no one to act as a substitute decision-maker for them in relation to this matter.[31]
The Guardianship and Administration Act 1986 (Vic) was amended, with effect from July 2006, to provide for a four step process for authorising the carrying out of a medical research procedure on an incapable adult.[32] However, unlike the New South Wales and Queensland legislation, it does not require that VCAT approve the medical research procedure before any adult unable to give a valid consent to their own medical treatment may take part. Also, the Victorian legislation allows doctors to include an incapable person in a research project and to carry out the research procedure on them without obtaining substitute consent in certain circumstances.[33]
No adult unable to give a valid consent to their own medical treatment may be treated according to a medical research procedure unless it has been approved by the relevant human research ethics committee.[34] A medical research procedure is a procedure carried out for the purposes of medical research. It may be part of a clinical trial or involve the administration of medication or the use of equipment or a device; or it may be a procedure that is prescribed by the regulations to be a medical research procedure.[35] Both the incapable person’s “person responsible”[36] and any doctor proposing to carry out the procedure on an incapable person must satisfy themselves that the required approval has been given for the procedure.[37]
The next step is for the treating doctor to determine whether the person they are proposing to carry out the procedure on is likely to become capable of giving consent before that procedure would have to be performed. When deciding this, the doctor must have regard to the person’s the medical or physical condition or the stage of their treatment or care at which the procedure would need to be performed or other relevant circumstances specific to the person. If the doctor considers that the person is likely to be capable before the procedure would have to be performed, they must not carry out the procedure on the person.[38]
If the person is not likely to regain their capacity to give a valid consent to the procedure before it would need to be performed, then the consent of the person responsible, if there is one, is to be sought. However, before they may give their consent, they must believe that the carrying out of the procedure would not be contrary to the best interests of the patient and that the consent was consistent with any requirements for consent specified by the relevant human ethics committee in its approval or with the conditions of that approval.[39] In order to assess these matters, the person responsible would need access to the research project proposal and the terms of its approval by the by the relevant human research ethics committee. In forming their opinion about whether the medical research procedure would or would not be contrary to the best interests of the
person, the person responsible must take the following matters into account:
1. the wishes of the person, so far as they can be ascertained,
2. the wishes of any nearest relative (if they are not the person responsible) or any other family members of the patient,
3. the nature and degree of any benefits, discomforts and risks for the person in having or not having the procedure; and
4. any other consequences to the patient if the procedure is or is not carried out.[40]
However, where the medical research procedure has been approved and the person is unlikely to be capable of giving their own consent but the person responsible for the person cannot be ascertained or contacted after reasonable steps have been taken, a doctor may carry out a medical research procedure on the person without consent.[41] The doctor must believe, on reasonable grounds, that being the subject of the procedure would not be contrary to the best interests of the person, taking into account the matters set out in the last paragraph and that having the procedure carried out on them would not be against the person’s wishes.[42]
The doctor must also believe, on reasonable grounds, that:
1. the relevant human research ethics committee has approved the research project in the knowledge that a person may participate in the project without their prior consent of the patient or the consent of their person responsible,
2. one of the purposes of the research project is to assess the effectiveness of the therapy being researched,
3. the medical research procedure poses no more of a risk to the patient than the risk that is inherent in the person's condition and alternative treatment,
4. the relevant research project is based on valid scientific hypotheses that support a reasonable possibility of benefit for the person as compared with standard treatment.[43]
The doctor must certify as to those matters and then inform the person responsible as soon as practicable of the person’s inclusion in the project and the option to refuse consent to the procedure or further participation in the project.[44] A number of other requirements must also be met.[45]
Despite these complex arrangements and requirements, a doctor, acting in good faith, may carry out, or supervise the carrying out of, a medical research procedure on an incapable person without either obtaining consent or going through the processes outlined if they believe on reasonable grounds that the procedure or treatment is necessary, as a matter of urgency to:
1. save the person's life,
2. prevent serious damage to their health, or
3. prevent the person from suffering or continuing to suffer significant pain or distress.[46]
Doctors acting in this way are protected from civil or criminal proceedings against them except in relation to breach of their duty of care to the person.[47]
At the time or writing, none of the other States or the two territories had legislation dealing directly with those who lack capacity to consent to their own treatment receiving experimental treatment or taking part in clinical trials. While it might be arguable in some of those States or the two Territories that incapable people could be given treatments that are new treatments that have not yet gained the support of a substantial number of doctors specialising in the area of practice concerned or could be given treatment available only if they took part in a particular clinical trial, there are two immediate difficulties. First, it may not be in the best interests of the person that they receive the treatment or take part in the clinical trial. It may be in the interests of others that they do. Second, in many clinical trials some of the participants receive a placebo and not the existing treatment. As many of these trials are randomized and double-blinded, it not possible to work out who is receiving the treatment and who is not. Consequently, an incapable person may take part in such a trial and not receive the medication being tested.
In Tasmania, for example, treatment without consent may only take place where the treatment is necessary.[48]
Capacity to consent to research is assessed in the same way as capacity to consent to medical treatment but with additional safeguards. [49] Importantly, participants involved in clinical research should understand the difference between treatment and research protocols, including such things as randomisation and the use of placebos.[50]
A number of standards to define capacity to consent to research have evolved over the last 25 years but most comprise various combinations of four commonly used elements which are conceptually similar to those used to define capacity to consent to treatment. They are:
1. factual understanding of the issues including an understanding of the procedure or treatment its risks and side effects, available options and their advantages and disadvantages and the consequences of participation and non-participation;
2. rational manipulation of information or reasoning;
3. appreciation of the nature of the situation; and
4. evidencing a choice.[51]
A number of instruments have been developed to structure and standardise the assessment of capacity. The MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR) is probably the most widely used instrument for the study of decision making capacity in research. This tool, administered by a structured interview which takes approximately 15-20 minutes to administer, comprises 21 items assessing all of the four elements of capacity: understanding, appreciation, reasoning and evidencing a choice.[52] The understanding subscale, in particular, has been shown to have reliability and predictive value in identifying patients with mild to moderate Alzheimer’s disease who are capable of giving consent.[53] The MacCAT-CR also had predictive value in determining capacity for informed consent in schizophrenia research.[54]
Since the development of the MacCAT-CR there have been a number of attempts to develop more parsimonious but still valid and reliable tests for capacity to consent to research participation, particularly for cognitively impaired individuals who may have limited ability to concentrate as a result of both physical and cognitive problems. [55]
Another commonly used measure is the California Scale of Appreciation (CSA), which specifically assesses the "appreciation" component of capacity. It comprises 18 items which assess whether or not participants form adequate beliefs about how the information provided applies to them. The CSA is a reliable and potentially useful instrument for measuring the appreciation component of capacity in persons with psychotic disorders,[56] although some doubt has been cast about its validity because the majority of participants were found to be fully "capable" on the CSA.[57]
The Evaluation to Sign Consent (ESC) tool is a five-item measure developed to better assess the “understanding” component of capacity in response to previous findings that suggested that study participants could not correctly state the purpose of the research study in which they had consented to participate. [58]
An even shorter 3 item decisional capacity questionnaire showed strong correlation with the Mac CAT-CR understanding, and moderate, but still significant correlations with appreciation and reasoning in subjects with schizophrenia, Alzheimer’s disease and type 2 diabetes mellitus. Although the optimal cut-off score gave 100% sensitivity, specificity was only 77%.[59] In this study the level of cognitive deficits measured with the Mini-Mental State Examination was generally the best predictor of decisional capacity, particularly in the understanding component.
Differentiating capable from incapable subjects remains an issue despite the aid of standardised tools.[60] The currently identified goal of research in this area is to find markers of potential impaired capacity. Ideally they are, sensitive, brief questionnaires targeting key aspects of disclosed information which effectively screen for participants warranting more comprehensive capacity evaluations.[61] In many research centres, the assessment of decisional capacity, particularly of subjects with dementia, lacks uniformity, when it is performed at all. Where decisional capacity is either formally or informally assessed, a variety of methods are used ranging from clinical judgment to extrapolation from psychometric performance. [62] In a study of clinicians’ perceptions of videotaped capacity interviews involving two scenarios of different risk (i.e. a medication-randomized clinical trial and a neurosurgical clinical trial), Kim and others showed that although clinicians used a risk-sensitive model of capacity determination (a higher degree of capacity required in higher-risk situations), there is considerable unexplained variability in their judgments. [63]
Considerable discussion still surrounds issues related to the capacities of patients with neuropsychiatric disorders to consent to research. It is agreed, however, that age and diagnosis should not be viewed as determinants of decisional capacity.[64] The presence of disorder does not imply impairment in capacity. Although some studies have found, for example, that even relatively mild Alzheimer's Disease significantly impairs consent-giving capacity [65] there is considerable heterogeneity in decision-making capacity even within each diagnostic group, particularly amongst those with schizophrenia, and sufficient to warrant individualized consideration of capacity.[66] [67] Of course, this will clearly depend on how capacity is defined or tested, and on the capacity task. Using an 11 item test based on the eight elements of informed consent stated in the Unites States Code of Federal Regulations (1991), Buckles and others found that 92% of mildly demented subjects provided correct answers for at least 80% of the items compared with 67% of moderately demented subjects.[68] However, this test only assessed the understanding of consent information which is but one component of the capacity construct and probably the less cognitively demanding. Accordingly, mildly demented subjects may perform as well as non-demented subjects on the less demanding standards such as making a choice to participate and for appreciating the personal consequences of participation, but be unable to provide rational reasons for their choices or understand the treatment situation, particularly associated with complicated research protocols involving placebo randomisation and serious adverse events.[69]
Individual consideration of capacity is equally important for those with mental illness. Although the presence of bipolar disorder appears to be a risk factor for impaired understanding of information disclosed under standard consent procedures, the diagnosis should not be equated with a lack of competence to consent.[70]
Further, it is difficult to find correlations between specific cognitive deficits and the elements of capacity to consent to research. In studies of patients with bipolar disorder and schizophrenia, although the strongest correlates of capacity (particularly, understanding and appreciation of disclosed information) were cognitive test scores, there was little evidence of differential relationships between individual cognitive abilities on neuropsychological testing and specific dimensions of capacity. Understanding was correlated with severity of negative symptoms and of general psychopathology.[71] [72]
The evidence-base for the treatment of many of the conditions which affect cognition and potentially impair capacity (particularly involving older people) is lacking and more research is needed. New medical treatments, whether they are drug or procedure-related, are discovered and proved effective and existing treatments are made more effective only through research. Research is also necessary to develop new and improve upon existing treatments to be used to alleviate or cure the conditions that render people permanently incapable of giving a valid consent to their own treatment. Such treatments cannot be proved effective unless they are carried out on those who have the particular conditions the treatment is designed to address. It follows from this that treatment must be carried out on incapable people, but only under controlled circumstances. One of the major areas of research is that of looking for treatments that alleviate the impact of or prevent the development of dementia in individuals. Thus limiting research to people who are able to decide for themselves would deprive people who lack capacity of proven therapies for the conditions which specifically affect them.[73]
People with cognitive impairment and mental illness should have the right and be given the opportunity to participate in research, even if they lack capacity.[74] Safeguards are however needed to ensure that participants who lack the capacity to give informed consent are protected.[75] It has been suggested that as a general rule of thumb, people who lack capacity to consent for themselves should only ever be involved in projects from which they are likely to benefit or which benefit people in the same category and which cannot be undertaken on people who are able to consent.[76] As already noted, the New South Wales legislation requires that State’s Guardianship Tribunal to be satisfied that, having regard to the potential benefits, as well as the potential risks, of participation in the trial, it is in the best interests of the patients who suffer from the relevant condition that they take part in the trial before it may approve that trial as one in which those unable to give a valid consent to their own treatment may take part.[77] To meet this criterion, the Tribunal has to be presented with some evidence that taking part in the clinical trial will be of benefit to the incapable participants themselves. The evidence has to go beyond the suggestion that, if they had capacity, they would feel good about themselves taking part in the trial.
There are a number of ways of supporting the involvement of cognitively impaired adults in such research. The first is by facilitating their own consent. The second is by considering their previously expressed opinions as there is some scope for including those who have made advance directives dealing with the question of medical research. The third is by obtaining the consent of proxy decision-makers.
However, the ways of using the second and third approach to include people in clinicial trials are limited by the legislation in New South Wales, Queensland and Victoria as has already been seen and is further discussed below.[78]
Decisional capacity is not necessarily an unmodifiable trait.[79] A variety of interventions can enhance understanding of informed consent for research. Capacity may be enhanced by providing information in an easily understandable form. Even among individuals with psychiatric illness or cognitive impairment, deficits in understanding can be remedied with certain educational interventions. Deficits in patients' understanding of informed consent may be related partially to poorly conceived, written, or organized consent materials. These deficits may be remediable with educational interventions. Effective interventions include corrected feedback, multiple learning trials, and more organized or simplified consent forms.[80] For example Jeste and others found that an interactive dialogue between patient and investigator with clarification of key elements in the consent form and repeated presentation of information is likely to aid understanding of disclosed information among patients with schizophrenia. [81],[82]
The wording of questions in the consent process can affect the responses of the participant. For example, in a study of 102 middle-aged and older outpatients with schizophrenia or related psychotic disorders and 20 normal comparison subjects, patients had more difficulty than normal comparison subjects on open-ended questions, including those asking about study procedures, time involved, and potential risks and benefits. Among patients, the enhanced procedure was associated with better performance on questions about potential risks and time required than the routine procedure. It is these “problem areas” in the understanding of informed consent that should be the focus of attempts to improve the consent process for patient participants with severe mental illness.[83]
Codes of conduct in certain states in America and Canada have proposed that research involving cognitively impaired adults should be restricted to those who have completed a formal, documented research advance directive while competent. [84] Yet, this requirement may impede the carrying out of important research. One study from the United States found that only 11% of adult inpatients had completed a research advance directive, even when given the opportunity to do so in a clinical research setting. Of those who completed research directives, 76% were willing to participate in research that might help them, 49% were willing to participate in research that would not help them and posed minimal risk, and 9% were willing to participate in research that would not help them and posed greater than minimal risk. The authors suggested more flexible approaches to protect these individuals such as:
1. developing advance directives that address both research and clinical care;
2. requiring research advance directives for subjects at high risk for losing the ability to consent such as individuals with mild AD enrolling in longitudinal studies; and
3. developing mechanisms to allow individuals to reject future research participation, while making them aware that formally documenting a preference to decline future research may preclude them from all research include research with the potential to benefit them. [85]
As has already been noted, in Queensland an incapable adult may be included in a clinical trial if they have given a relevant direction in a health care directive.[86] The matter may only be dealt with under that direction. Guardians, attorneys under enduring documents and statutory health attorneys may not override that direction.
The role of persons responsible and other substitute decision-makers in giving consent for incapable people to take part in clinical trials and the matters they must take into account before giving that consent are discussed above.[87] In Victoria, a person responsible must take into account the views of the incapable person if they can be ascertained. [88] If the incapable person has set out those views in an advance directive and wished to take part in clinical trials of the type proposed, then the person responsible would, it is suggested, be obliged to give their consent to the person taking part in the clinical trial.
In New South Wales persons responsible must, under the general principles, take the views of the incapable person into account although the welfare and interests of that person must be given paramount consideration.[89] Nevertheless, it is suggested, particularly since the 2009 case Hunter and New England Area Health Service v A[90] that if they were faced with an advance directive as discussed in the last paragraph, they would similarly be obliged to consent to the incapable person taking part in the clinical trial.
Research already undertaken in the United Kingdom and the United States shows that future research involving incapacitated older patients there is likely to be heavy reliant on proxy consent provision.[91] The research also shows a burgeoning interest in, as an alternative to making an advance research directive, appointing a proxy for research consent.[92] It is thought that persons suffering from neurodegenerative disorders such as dementia may retain significant abilities-including sufficient capacity for delegating one's authority for giving consent to research-even if they are not capable of giving independent consent themselves. [93], [94]As with any situation of proxy consent, in the absence of an advance directive as is often the case, surrogates have to make research decisions based on informal evidence of the person’s preferences. [95] Yet, consent decisions of legal representatives will not necessarily reflect those of patients themselves and may result in under-recruitment of patients, who if given the choice themselves may have chosen to participate. From 2445 potentially eligible but incapacitated patients, proxy consent from a relative resulted in trial participation of only 3.6% patients. The reasons for this were that a large number of incapacitated patients had no relative available for assent (i.e. 2286 out of 2445), but also 45% of relatives approached refused to provide assent compared with 18% of patients who declined participation in the trial. Proxy consent allowed only a small increase in trial recruitment of incapacitated patients. The fact that a greater proportion of relatives than patients refused to provide assent implies that they were more cautious than the patients themselves, or perhaps used different criteria, when making their decision. Conversely, proxies are not able to override the refusal of a cognitively impaired patient to participate in research.[96]
Similarly, Stocking et al interviewed 149 dyads of dementia patients and family proxies about future enrollment in five types of research and while they found that patients chose to cede future decision making to their proxies in 82.9% of the trials, patients ceded decisions to their proxies in 80.7% of those trials about which the dyad had given opposite answers.[97]
Karlawish et al examined the views of Alzheimer’s disease patients and their proxies at 13 research sites in the Unites States and found that proxies made research enrollment decisions based on what they thought would maximize the patient's well-being as opposed to a substituted judgment standard. [98] Reasons proxies give for participating in research include: hope of direct or indirect benefits to the patient, caregiver, or patient's descendents; desperation; trust in the investigator; belief in the goodness of research; and altruism, although these reasons vary according to the type of research such that in drug trials hope of direct benefit prevails while in studies not evaluating a potential therapy more altruistic concerns predominate. [99]
[1] Muthappan P, Forster H, Wendler D. Research advance directives: protection or obstacle? Am J Psychiatry. 2005 Dec;162(12):2389-91.
[2] British Medical Association and The Law Society, Assessment of Mental Capacity – Guidance for doctors and lawyers, London, BMJ Books, 2nd. Ed. 2004, p. 137
[3] Wendler, 2001 Annals of Internal Medicine 135:514-523.
[4] Applebaum P.S. Roth L.H. Competency to consent to research Arch Gen Psychiatry 1982; 39, 951- 958.
[5] Ibid.
[6] British Medical Association and The Law Society op. cit. (footnote 2) 136.
[7] Ibid., p137
[8] Lemaire F. The European Directive 2001/20 for clinical research: friend or foe? Intensive Care Med. 2006 32(11):1689-90.
[9] Resnick B, Gruber –Baldini A.L, Pretzer-Aboff, Galik E Custis Buie V, Russ K, Zimmerman S. (2007) Reliability and validity of the evaluation to sign consent measure The Gerontologist 47, 69-77.
[10] http://www.mrc.ac.uk/Utilities/Documentrecord/index.htm?d=MRC002409
[11] Medical Research Council. MRC Guidelines for Good Clinical Practice in Clinical Trials. London: MRC, 1998.
[12] Mason S, Barrow H, Phillips A, Eddison G, Nelson A, Cullum N, Nixon J.Brief report on the experience of using proxy consent for incapacitated adults. J Med Ethics. 2006 32(1):61-2.
[13] http://www.mrc.ac.uk/PolicyGuidance/EthicsAndGovernance/InformedConsent/index.htm#P18_1070
[14] National Health and Medical Research Council, Australian Research Council Australian Vice- Chancellors’ Committee. National Statement on Ethical Conduct in Human Research, 2007, Australian Government: Canberra., p65-66.
[15] Ibid.
[16] Guardianship Act 1987 (NSW) s 33.
[17] Ibid. s 45(3)(c) and (d).
[18] Parliament of New South Wales, Legislative Council, Standing Committee on Social Issues, Clinical Trials and Guardianship: Maximising the Safeguards, Report No. 13 September 1997.
[19] Guardianship Act 1987 (NSW) s 45AA(2).
[20] The term “ethics committee” is defined in Guardianship Act 1987 (NSW) s 45AA(5).
[21] Ibid. s 45AA(3).
[22] Ibid. ss 45AA(4) and 45AB(1). The term “person responsible” is defined in s 33A.
[23] Ibid. s 45AB(2).
[24] Ibid. s 76A(2A).
[25] Guardianship and Administration Act 2000 (Qld) Schedule 2 s 12.
[27] Re MP [2007] QGAAT 86.
[28] Ibid. [37]-[39].
[29] Guardianship and Administration Act 2000 (Qld) Schedule 2 s 13.
[30] Ibid. s 66. Who is a statutory health attorney is set out in the Powers of Attorney Act 1998 (Qld) s 63.
[31] Powers of Attorney Act 1998 (Qld) s 63.(2)
[32] Guardianship and Administration Act 1986 (Vic) s 42P(2).
[33] Ibid. s 42T.
[34] Ibid. s 42Q. The definition of relevant research ethics committee is in s 3. The definition of relevant research ethics committee is in s 3.
[35] Ibid. s 3. At the time of writing no procedures had been prescribed under the Act.
[36] Ibid. s 37 for the definition of person responsible and s 3 for definitions of spouse, domestic partner, primary carer and nearest relative.
[37] Ibid. ss 42Q and 42T(2)(e).
[38] Ibid. s 42R.
[39] Ibid. s 42S.
[40] Ibid. s 42U.
[41] Ibid. s 42T(1) and (2)(a) and (b)..
[42] Ibid. ss 42T(2)(c) and (d) and 42U.
[43] Ibid. s 42E(e)-(g).
[44] Ibid. s 42T(3) and (4).
[45] Ibid. s 42T(5)-(8). For further information on this matter see, Office of Public Advocate, “Medical Research for Pateints Who Cannot Consent”, www.publicadvocate.vic.gov.au/publications/medical-consent/medical-research.
[46] Ibid. s 42A.
[47] Ibid. s 42A(2).
[48] Guardianship and Administration Act 1995 (Tas) ss 36-41, 41(1)(c) in particular.
[49] British Medical Association and The Law Society op. cit. (footnote 10) 136.
[50] Resnick B, Gruber –Baldini A.L, Pretzer-Aboff, Galik E Custis Buie V, Russ K, Zimmerman S. (2007) Reliability and validity of the evaluation to sign consent measure The Gerontologist 47, 69-77.
[51] Applebaum P.S. Roth LJ. op cit. (footnote 4).
[52] Applebaum P.S. Grisso T (2001) The MacArthur Competence Assessment Tool for Clinical Research (Mac CAT-CR) Sarasota Florida: Professional Resource Press.
[53] Karlawish J, Kim SY, Knopman D, van Dyck CH, James BD, Marson D Interpreting the clinical significance of capacity scores for informed consent in Alzheimer disease clinical trials. Am J Geriatr Psychiatry. 2008 Jul;16(7):568-74.
[54] Kim SY, Appelbaum PS, Swan J, Stroup TS, McEvoy JP, Goff DC, Jeste DV, Lamberti JS, Leibovici A, Caine ED. Determining when impairment constitutes incapacity for informed consent in schizophrenia research. Br J Psychiatry. 2007 Jul;191:38-43
[55] Resnick and others op. cit. (footnote 50 )
[56] Saks ER, Dunn LB, Marshall BJ, Nayak GV, Golshan S, Jeste DV.The California Scale of Appreciation: a new instrument to measure the appreciation component of capacity to consent to research. Am J Geriatr Psychiatry. 2002 Mar-Apr;10(2):166-74.
[57] Resnick and others op. cit. (footnote 50 )
[58] Ibid.
[59] Palmer BW, Dunn LB, Appelbaum PS, Mudaliar S, Thal L, Henry R, Golshan S, Jeste DV.Assessment of capacity to consent to research among older persons with schizophrenia, Alzheimer disease, or diabetes mellitus: comparison of a 3-item questionnaire with a comprehensive standardized capacity instrument. Arch Gen Psychiatry. 2005; 62(7):726-33
[60] Kim SY, Caine ED, Currier GW, Leibovici A, Ryan JM Assessing the competence of persons with Alzheimer's disease in providing informed consent for participation in research. Am J Psychiatry. 2001 May;158(5):712-7
[61] Palmer BW, Jeste DV. Relationship of individual cognitive abilities to specific components of decisional capacity among middle-aged and older patients with schizophrenia. Schizophr Bull. 2006 32(1):98-106.
[62] Karlawish JHT., Knopman D., Clark CM., et al Informed consent for Alzheimer’s disease clinical trials: a survey of clinical investigators. IRB Ethics Human Research 2002; 24: 1-5.
[63] Kim SY, Caine ED, Swan JG, Appelbaum PS. Do clinicians follow a risk-sensitive model of capacity-determination? An experimental video survey. Psychosomatics. 2006 Jul-Aug;47(4):325-9.
[64] Palmer BW, Jeste DV, op. cit. (footnote 61).
[65] Kim et al., op. cit. (footnote 63).
[66] Palmer BW, Jeste DV, op. cit. (footnote 61).
[67] Jeste DV, Depp CA, Palmer BW. Magnitude of impairment in decisional capacity in people with schizophrenia compared to normal subjects: an overview. Schizophr Bull. 2006 ;32(1):121-8.
[68] Buckles V.D. Powlishta K.K., Palmer J.L., Coats M., Hosto T., Buckley A., Morris J.C. Understanding of informed consent by demented individuals Neurology. 2003; 61: 1662- 1666.
[69] Ibid.,
[70] Palmer BW, Dunn LB, Depp CA, Eyler LT, Jeste DV.Decisional capacity to consent to research among patients with bipolar disorder: comparison with schizophrenia patients and healthy subjects J Clin Psychiatry. 2007 68(5):689-96.
[71] Jeste DV and others op. cit. (footnote 67).
[72] Palmer BW, Dunn LB, Depp CA, Eyler LT, Jeste DV.Decisional capacity to consent to research among patients with bipolar disorder: comparison with schizophrenia patients and healthy subjects J Clin Psychiatry. 2007 68(5):689-96.
[73] British Medical Association and The Law Society op. cit. (footnote 2) 136.
[74] Katona C., et al WPA Consensus Conference on Ethics and Capacity in older people with mental illness (submitted document)
[75] Ibid.
[76] British Medical Association and The Law Society op. cit. (footnote 2) 136.
[77] Guardianship Act 1987 (NSW) s 45(2)(d). See 16. 3. 1. above.
[78] See 16. 3. 1, 2 and 3 as well as 16. 5. 2 and 3.
[79] Jeste DV, Dunn LB, Palmer BW, Saks E, Halpain M, Cook A, Appelbaum P, Schneiderman L. A collaborative model for research on decisional capacity and informed consent in older patients with schizophrenia: bioethics unit of a geriatric psychiatry intervention research center.Psychopharmacology (Berl). 2003;171(1):68-74.
[80] Dunn LB, Jeste DV.Enhancing informed consent for research and treatment. Neuropsychopharmacology. 2001; 24(6):595-607
[81] Jeste DV, Depp CA, Palmer BW. Magnitude of impairment in decisional capacity in people with schizophrenia compared to normal subjects: an overview. Schizophr Bull. 2006 ;32(1):121-8.
[82] Jeste DV, et al op cit., (footnote 79).
[83] Dunn LB, Jeste DV. Problem areas in the understanding of informed consent for research: study of middle-aged and older patients with psychotic disorders. Psychopharmacology (Berl). 2003 171(1):81-5.
[84] Muthappan P, Forster H, Wendler D. Research advance directives: protection or obstacle? Am J Psychiatry. 2005 Dec;162(12):2389-91.
[85] Ibid.
[86] Guardianship and Administration Act 2000 (Qld) s 66(2). See 16. 3. 2. above.
[87] See 16. 3. 1., 2. and 3. above.
[88] Guardianship and administration Act 1986 (Vic) s 42U.
[89] Guardianship Act 1987 (NSW) s 4.
[91] Mason S, Barrow H, Phillips A, Eddison G, Nelson A, Cullum N, Nixon J.Brief report on the experience of using proxy consent for incapacitated adults. J Med Ethics. 2006; (1):61-2.
[92] Stocking CB, Hougham GW, Danner DD, Patterson MB, Whitehouse PJ, Sachs GA. Speaking of research advance directives: planning for future research participation. Neurology. 2006; 66(9):1361-6.
[93] Kim SY Kieburtz K. Neurology Appointing a proxy for research consent after one develops dementia; the need for further study Neurology 66(9): 1298-9.
[94] Kim SY, Appelbaum PS.The capacity to appoint a proxy and the possibility of concurrent proxy directives. Behav Sci Law. 2006;24(4):469-78
[95] Muthappan and other op. cit. (footnote 84).
[96] Mason and others op. cit. (footnote 91).
[97] Stocking CB, Hougham GW, Danner DD, Patterson MB, Whitehouse PJ, Sachs GA. Speaking of research advance directives: planning for future research participation. Neurology. 2006;66(9):1361-6
[98] Karlawish J, Kim SY, Knopman D, van Dyck CH, James BD, Marson D.The views of Alzheimer disease patients and their study partners on proxy consent for clinical trial enrollment Am J Geriatr Psychiatry. 2008 16(3):240-7
[99] Sugarman J, Cain C, Wallace R, Welsh-Bohmer KA.How proxies make decisions about research for patients with Alzheimer's disease. J Am Geriatr Soc. 2001 Aug;49(8):1110-9
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