| 5 Web JCLI|
* The authors would like to thank Dr Salla Lötjönen for her perspicacious comments on this article.
Corresponding author: Dr Shaun Pattinson (firstname.lastname@example.org).
Copyright © Deryck Beyleveld and Shaun D Pattinson 2006. First published in Web Journal of Current Legal Issues.
In England and Wales, the existing legislation adopts inconsistent principles with regard to ethically comparable research involving those requiring emergency care and incapable of consenting to participation. There are moves to amend the UK Clinical Trials Regulations to move emergency research on medicinal products towards the more permissive position taken towards other types of invasive emergency research. While arguments of ethical principle and regulatory coherence can be made to support such an amendment, we argue that it threatens to render the UK in contravention of the Clinical Trials Directive.
The UK’s implementation of the Clinical Trials Directive (emergency trials using medicinal products)
Cardiac arrest, severe strokes, anaphylactic shock, severe head injuries, and severed arteries can occur suddenly and kill quickly. These are examples of conditions whose potentially lethal consequences might be avoided by the immediate administration of appropriate treatment. Not all potential treatment options are, however, equally appropriate. Treatment options can differ in terms of their effectiveness, their complications, the skill or equipment required for their administration, and their cost. Satisfactorily determining the relative safety and effectiveness of particular treatment options requires research. There are, of course, legal and ethical constraints on the design of research protocols (see e.g. Lötjönen 2002). The participant’s prior informed consent has been widely recognised as an important safeguard since at least the Nuremberg trials. Indeed, the first of the ten principles of the Nuremberg Code asserts: ‘The voluntary consent of the human subject is absolutely essential’. Prior consent from the participant is not, however, possible in many situations where the participant faces an unexpected and immediate treat to his life. This paper is concerned with those situations where the prospective participant is unable to consent at the time that the emergency treatment needs to be administered. In this paper we consider the extent to which alternative safeguards can be legally and ethically utilised in this context. We argue that the legal position adopted in England and Wales is ethically problematic, unduly complex, and the victim of piecemeal (present and prospective) reform. Current attempts to render the position more coherent will, we argue, result in contravention of the requirements of European law.
Randomised controlled trials (RCTs) have been considered to represent the ‘gold standard’ for the testing of therapies since the 1940s (see Miller et al. 2002, 3). These involve comparing the effects of a treatment in one group (the test group) with the effects of treatment in at least one other group (the control group), whereby membership of a particular group is randomised from the same population (see further ICH 2000 and Pattinson 2006, 340–341). To focus our discussion, this paper will examine the issues raised by RCTs on participants selected because they have been victims of an unanticipated and potentially lethal condition. Victims of an unanticipated cardiac arrest might, for example, be considered suitable participants in a trial on the relative safety and efficacy of two medicinal products or two types of cardio-pulmonary resuscitation. The control in such situations would be concurrent and involve the administration of the standard treatment. The prospective participant would be unconscious or under severe stress/shock and consequently unable to give contemporaneous informed consent to participation. Examples include
When evaluating such trials consideration needs to be given to the adequacy of mechanisms other than contemporaneous consent for protecting the rights and interests of potential participants.
Prospective consent is not an option unless the condition has been anticipated and the prospective participant made fully aware of his possible future entry into the trial. For some emergency trials, participants could be recruited from within populations known to be at particular risk of admission for future emergency care, such as (where appropriate) those with known cardiac problems or those known to have severe asthma. As already stated, in this paper we are only concerned with trials on those with an unanticipated need for emergency treatment, where it is not possible to obtain consent in advance. Prospective consent might be unfeasible or inappropriate where, for example, the relevant population cannot be identified in advance or where to identify a population in advance would significantly bias the results. Other mechanisms for protecting the rights or interests of the participant include preventing such emergency research; relying on proxy or deferred (retrospective) consent; or conducting such trials with safeguards that do not include consent.
The no research approach will mean relying on historical treatment or best-guess predictions when administering emergency care. It has been said that ‘this discriminated population of patients will receive untested “standard” treatment and new treatments that clinician-researchers develop and apply anecdotally’ (Karlawish and Hall 1996, 499). Preventing the type of RCT envisaged above, however, need not involve a blanket rejection of research into the safety and efficacy of emergency treatment options. Alternative forms of research, of varying degrees of scientific adequacy, will often be available. Information on cardiac resuscitation techniques could, for example, be obtained from data on historical and contemporary use of alternative techniques for treating patients in cardiac arrest. The proposed control and the experimental treatment might already be in exclusive use in different facilities. Alternatives might not reach the ‘gold standard’ that randomised concurrently-controlled trials are considered to represent, but they could evade the consent problem. This will mean, however, that some disputes over effective and best treatment practices will become irresolvable. There will continue to be what the late Benjamin Freedman termed ‘clinical equipoise’, i.e. genuine uncertainty within the expert medical community about the comparative therapeutic merit of the different treatment options (see Freedman 1987). (Freedman suggested that clinical equipoise was a necessary condition for an RCT to be morally legitimate.)
Proxy consent is only an option where there is sufficient time to inform and request the agreement of an appropriate family member or other proxy decision-maker. The nature of an emergency is such that time is usually very limited. The collaborators on the CRASH trial, for example, reported that there was ‘a significant difference in the mean time to randomisation between hospitals that waived consent and those that required the consent of a relative’ (CRASH Trial Management Group 2004). To insist on delaying necessary emergency treatment so that consent can be obtained from a proxy is contrary to the very point of seeking proxy consent in the first place, i.e. to protect the interests of the participant. It has also been reported that the availability of family members to act as proxies can vary according to the socioeconomic background of the prospective participant and that ‘the poor and minorities generally do not have available surrogates’ (Karlawish and Hall 1996, 504). There is, however, little data on the availability of proxies and what little data there is is largely derived from the US, which is considered to have particularly sharp social divisions.
Deferred consent, where a participant or proxy is asked to consent after the participant has been entered into the research trial, is not truly consent at all. At most a refusal would prevent the use of the research results or prevent further interventions; it can have no affect on what has already taken place. The justification for the initial intervention must therefore be something other than the participant’s consent. The process of asking for retrospective consent might, however, serve to protect other important moral goods or goals. Brody and Miller suggest, for example, that deferred consent
‘would at least have the advantages of (1) openly informing patients or families of the nature of the research, hence allowing public scrutiny of research practices, and (2) allowing a veto when the patient or family had especially strong feelings about participation in a randomized trial’ (1981, 14–15).
Thus, deferred consent could be viewed as a useful device for providing participant-information and supporting participant-veto at a later stage, but not as a justification for the initial research.
The no consent option rejects the safeguard of consent, but is perfectly compatible with the existence of other safeguards. It is sometimes claimed that research on those incapable of providing consent is incompatible with deontological moral theories. According to McCarthy,
‘Those who subscribe to one or another of the deontological theories of ethics that draw inspiration from Immanuel Kant…contend that it is always and everywhere wrong to ‘use’ human subjects without their informed consent. The benevolent intentions of the researchers cannot, they contend, make an intrinsically wrong action morally acceptable’ (1996, 507).
Deontological theories need not subscribe to such a restrictive view on the use of human participants. Consent can only be a necessary requirement for morally permissible research on human participants if there could be no other moral justification for removing the burden of prohibitive and binding duties owed to the participant. While deontological positions do not allow the moral interests of any group to be aggregated or averaged to outweigh those of another group or an individual, such positions can coherently permit the interests of one individual to be outweighed by that individual’s more important interests or by the more important interests of another individual. Not all rights and interests need be absolute and if they can come into conflict with other rights and interests they cannot all be absolute. Thus, deontological perspectives (and, a fortiori, teleological perspectives) need not hold that those who cannot consent cannot be entered into any research trial. Similarly, deontological positions are not required, as a matter of principle, to support a blanket procedural requirement to the effect that prior consent must be obtained from a proxy decision-maker before the incompetent are entered into a research trial. The interests of the participant must not be artificially devalued or treated as if overridden by interests that are equal or even less important, but this is not the same thing as asserting that first or third party consent is a moral precondition.
Properly designed emergency research can carry benefits recognised as such by moral theories of both deontological and non-deontological persuasion. Research could directly benefit those participants who receive non-standard treatment that proves to be safer or more effective than the standard treatment and should benefit those future patients in need of emergency care. It follows that few, if any, moral theories will, as a matter of principle, prohibit emergency research as such.
The existing legislation draws a sharp distinction between research using medicinal products and other types of medical research. We shall see that the result has hitherto been to effectively prohibit emergency research on medicinal products without prior consent, while permitting other types of emergency research without prior consent. While it is difficult to find a principled rationale for this position, attempts to remove this inconsistency threaten to render the UK in contravention of the requirements of European law.
Clinical trials on medicinal products have been directly addressed by two EC directives: the Clinical Trials Directive (Directive 2001/20/EC) and the Good Clinical Practice (GCP) Directive (Directive 2005/28/EC). In the UK, the Clinical Trials Directive was implemented by the Medicines for Human Use (Clinical Trials) Regulations 2004/1031 (hereafter the Clinical Trials Regulations). Amendments have been made to implement the GCP Directive by the Medicines for Human Use (Clinical Trials) Amendment Regulations 2006/1928, which came into force on 29 August 2006. The Clinical Trials Regulations, in line with the Directive, apply to clinical trials of ‘investigational medicinal products’ (Reg. 2). That is to say, that they apply to the testing on human participants of medicines that are under development or used outside of their market authorisation.
The Clinical Trials Directive requires the prior consent of a legal representative before those who lack the capacity to consent are entered into a clinical trial. Article 3 states that a clinical trial may only be undertaken if the participant, or the legal representative of a participant who is not able to consent, ‘has had the opportunity, in a prior interview…to understand the objectives, risks and inconveniences of the trial’ (Art. 3(2)(b)) and ‘has given his…consent after being informed of the nature, significance, implications and risks of the clinical trial...’ (Art. 3(2)(d)). The Directive goes on to declare that clinical trials on children (Art. 4(a)) and adults who are not able to consent (Art. 5(a)) can only be undertaken if the informed consent of the legal representative ‘has been obtained’. In addition to use of the past tense in these provisions, Recital 4 explicitly states that in the case of those unable to consent,
‘the written consent of the patient’s legal representative, given in cooperation with the treating doctor, is necessary before participation in any such clinical trial’ (Emphasis added).
In our view, these provisions unequivocally rule out the no consent and deferred consent approaches to emergency research on medicinal products. The current Clinical Trials Regulations are entirely consistent with these provisions and state that the ‘legal representative’ must have ‘given his informed consent’ to the participant taking part in the trial (Sch. 1, Part 4, para. 4 (minors) and Sch., Part 5, para. 4 (incapacitated adults)).
Deferred consent and the Clinical Trials Directive
The relevant UK regulatory authority, the Medicines and Healthcare products Regulatory Agency (MHRA), takes the view that the prior consent requirement is not an absolute requirement of the Clinical Trials Directive. In a consultation document issued on 1 August 2005, the MHRA proposed an amendment to the Clinical Trials Regulations to provide that,
‘in certain emergency situations, an exception [should be made] to the general requirement that informed consent must be obtained from an incapacitated patient’s legal representative prior to his/her participation in trials of medicines’ (MHRA 2005, para. 1).
According to the MHRA,
‘Whilst there are no specific provisions in the Directive allowing an exception from the general requirement of prior consent, we consider that the proposed exception is within the spirit of the Directive. It is also consistent with the position adopted by the International Conference on Harmonisation (ICH)...’ (MHRA 2005, para. 9).
This argument has two strands: that the amendment is ‘within the spirit of the Directive’ and that it is ‘consistent with’ the ICH guidelines on good clinical practice. With regard to the second strand, the MHRA calls attention to paragraph 4.8.15 of the ICH guidelines (ICH 1995), which provides that in emergency situations where it is not possible to obtain the prior consent of the participant and his legal representative is not available,
‘The subject or the subject’s legally acceptable representative should be informed about the trial as soon as possible and consent to continue and other consent as appropriate should be requested.’
The ICH guidelines thereby support the deferred consent approach to emergency research, which is also the essence of the amendment proposed by the MHRA. In our view, the two claims made by the MHRA are not sufficient to establish that deferred consent is consistent with the Directive. (We made many of the following points in Beyleveld and Pattinson 2006, on which this section draws.)
The spirit of a Directive must be determined by reference to its terms. We have already seen that the Directive explicitly requires prior consent and no argument has been made to the effect that these provisions produce ambiguity or incoherence if applied without qualification. The Directive directly or indirectly prohibits many types of clinical trials that are capable of producing results that could benefit future patients and society in general, so incoherence is not established by the mere existence of restrictions on potentially beneficial research. The MHRA’s view on the spirit of the Directive is, in fact, difficult to reconcile with its view on the scope of the Regulations. If deferred consent is within the spirit of the Directive and thereby compatible with the Directive’s terms, why is it not compatible with the terms of the Regulations? The Regulations only require amendment if they prohibit reliance on deferred consent, but the Regulations are (if anything) less explicit on the need for prior consent than the Directive.
We also contest the assertion that the ICH guidelines permit an exception to be made to the prior consent requirement of the Clinical Trials Directive. As the Government acknowledges in its response to a report on the influence of the pharmaceutical industry:
‘The ICH Note of Guidance on GCP is a guideline and is not legally binding in the UK. As such, it does not take precedence over the relevant EC and UK legislation (specifically, Directive 2001/20/EC on clinical trials, the Medicines for Human Use (Clinical Trials) Regulations 2004 and the Medicines Act 1968)’ (HM Government 2005, 13).
The ICH guidelines are not given interpretative primacy by the Clinical Trials Directive. Recital 6 simply states that the harmonisation of technical requirements for the development of medicinal products should ‘be pursued through the appropriate fora, in particular the International Conference on Harmonisation’ (which is a provision that we overlooked in Beyleveld and Pattinson 2006). Recital 8 of the Good Clinical Practice (GCP) Directive elaborates by declaring that the ICH guidelines should be ‘taken into account’ for the purpose of the GCP Directive, and consequently they should be taken into account for the purpose of the Clinical Trials Directive, since the former Directive elaborates the latter Directive. Nevertheless there is an enormous difference between a recommendation to take something into account and treating this consideration as setting the goal that decisively lays down the parameters of permissible implementing legislation. We therefore suggest that the legal case for considering the proposed amendment to be consistent with the Directive has not been sufficiently made out in the consultation document.
In our view, the spirit of the Clinical Trials Directive must be taken to include the objective of protecting the interests of participants. Article 5(h) of the Clinical Trials Directive requires that ‘the interests of the patient always prevail over those of science and society’. (This gives effect to a key provision of the 1996 version of the Helsinki Declaration: ‘the interest of science and society should never take precedence over considerations related to the well-being of the subject’ (our emphasis).) Similarly Article 2 of the GCP Directive states that: ‘The rights, safety and well being of the trial subjects shall prevail over the interests of science and society’. The spirit of the Directive is, therefore, at least in part, encapsulated by a principle of priority for the interests of actual and prospective participants over those of science and society. It surely follows that protections applying to prospective participants should not be read down to facilitate the interests of science and society.
While we concede that it is sometimes legitimate to rely on a purposive interpretation of a legal instrument to limit its explicit terms, such a purposive interpretation of the Directive would, at best, support only narrow grounds for dispensing with the prior consent requirement (cf. Liddell et al. 2006, esp. 399–406). Since protecting the interests of participants must be viewed as an important requirement of the Directive, at best, the explicit requirement that prior consent be obtained would have to be interpreted as a general rule to which it is permissible to make an exception if (and only if) the exception was necessary to protect or advance the interests of (actual and prospective) participants. It is, nonetheless, difficult to imagine circumstances in which this condition would be satisfied. An example, perhaps, would be a situation where participation in an emergency trial was the only means by which a patient could gain access to a medicinal product that might benefit his health or save his life and he has not been illegitimately denied access unencumbered by the burdens of participating in a research project. In such a situation, obtaining the consent of a legal representative as soon as possible after entry into the trial, rather than denying access to the trial, could be said to track the participant’s interests. We add the proviso about legitimate denial of access, because it would clearly not be in the interests of prospective participants for them to be denied access to a potentially therapeutic product solely to ensure their participation in a clinical trial without the need for prior consent. Such a narrow exception to the requirement of prior consent is, we suspect, not sufficient to satisfy those who support the proposed amendment (see e.g. Liddell et al. 2006) and might be difficult to apply in practice. Even if the narrow exception were thought to be compatible with the Clinical Trials Directive, it would be preferable for the Government to seek to amend the Directive rather than simply amend the implementing Regulations. Directives are, after all, intended to harmonise the substantive effect of regulatory approaches throughout Europe, albeit leaving individual countries discretion as to means by which the approach is implemented. The fact that Brussels has raised no complaint about those States that have implemented laws waiving the consent requirements in no way implies that such approaches are compatible with a proper interpretation of the Clinical Trials Directive (cf. Liddell 2006, 405).
The argument that the Directive is consistent with deferred consent could not be strengthened by invoking Article 8 of the European Convention on Human Rights (ECHR), even though deferred consent might be compatible with that Article. This is not an argument made by the MHRA but one that might be thought to bolster their position. It is true that the case law implies that the European Court of Human Rights would consider a clinical trial on a patient without the patient’s consent to engage Article 8(1) of the ECHR (see e.g. Pretty v UK (2002) 35 E.H.R.R. 1 and Peck v UK (2003) 36 E.H.H.R. 719) and that Article 8(2) permits public authorities to provide exemptions from Article 8(1) for a number of reasons, including to protect health or the rights of others (provided that this is necessary, in accordance with the law in a democratic society, and proportionate). Consequently it is open, at least in principle, for Clinical Trials legislation to replace the patient’s consent with that of a legal representative under the conditions required by Article 8(2) or to dispense with consent altogether. Thus, on the hypothesis that the amended regulations would meet the conditions of Article 8(2), they would not fall foul of the ECHR. This hypothesis derives additional support from the European Convention on Human Rights and Biomedicine and its Additional Protocol concerning Biomedical Research, which are addressed in section IV, and the jurisprudence of the European Court of Human Rights supports the view that the Biomedicine Convention is relevant to the interpretation of the ECHR (see Glass v UK  1 F.L.R. 1019, para. 58). (In our view, interpreting a binding Convention in the light of a non-binding Convention is only acceptable where the relevant provision from the non-binding Convention is plausibly implicit in the binding provision, at least when read as a living provision.)
However, the fact that the proposed amendment might be compatible with the ECHR and (consequently) with the Human Rights Act 1998 does not mean that it is compatible with Clinical Trials Directive. It is the case that the Directive does need to be consistent with the rights enshrined in the ECHR, because those rights are recognised by the European Court of Justice as fundamental principles of EC law with which all legislation of the EU must be compatible (see The Second Nold Case (Case 4/73)  E.C.R. 491). It must, however, be borne in mind that Article 8(2) of the ECHR merely creates a permission for legislators to provide exemptions from Article 8(1), and does not lay down a requirement. It is therefore, open to the EU legislator to judge that there are cases where an exemption from Article 8(1) is not permitted, and to legislate a Directive provision to this effect. When this happens the UK is legally bound by its EC Treaty commitments to give effect to such provisions, regardless of how it itself judges the matter in relation to Article 8 of the ECHR. It follows that reliance on Article 8 does not enable the UK to dispense with the need for prior consent contrary to the provisions of the Directive.
Other options and safeguards
It had been suggested that emergency research could be permitted under the Clinical Trials Directive where prior consent could be obtained from an available professional legal representative, such as the paramedic attending a patient in an emergency situation. The Clinical Trials Directive does, after all, leave the details about who may be a legal representative to the State implementing the Directive (as stated in Recital 5). The MHRA, however, noted that,
‘The Government does not consider this to be an acceptable option because there are grave concerns that interpreting “legal representative” to extend to paramedics would not be compatible with the Directive. It is implicit in the Directive that the legal representative should be entirely independent of the trial. There is a strong argument that a paramedic in not independent of the trial if he/she is responsible for administering the trial medicine’ (MHRA 2005, para. 7
We agree. To rely on legal representatives who are not truly independent of the trial is to violate the primacy of the interests of participants over those of science and society. Relying on an insufficiently independent proxy would be inconsistent with the very purpose of seeking the approval of a proxy, i.e. to ensure that the interests of the participant are not conflated with those of the research team.
The MHRA has yet to publish its response to the consultation, but seems likely to seek to amend the Clinical Trials Regulations to allow deferred consent. As of April 2006, the Medical Research Council (MRC) certainly expects the amending regulations along these lines to come into effect early/mid 2007 (see MRC 2006).
In any event, the other safeguards of the Regulations (which mirror those of the Directive) will continue to apply. All trials must be approved by the MHRA and an independent ethics committee and satisfy the conditions and principles of good clinical practice specified in Schedule 1 (regs 12 and 28). The GCP safeguards applying to those who lack capacity include the requirement that
(i) the trial be ‘designed to minimise pain, discomfort, fear and any other foreseeable risk’ (Sch. 1, Part 4, para. 14 (children) and Sch. 1, Part 5, para. 13 (incapacitated adults. See Arts 4(g) (children) and 5(f) (adults) of the Clinical Trials Directive) and
(ii) be essential to validate data obtained by other methods (Sch. 1, Part 4, para. 11 (child) and Sch. 1, Part 5, para. 10 (incapacitated adult). See Arts 4(e) and 5(e) of the Clinical Trials Directive).
Some of these safeguards depend on whether the incapacitated participant is a child or an adult. With regard to children, the Regulations provide that the trial must either relate directly to a clinical condition from which the child suffers or only be capable of being carried out on children, and some direct benefit must be obtained by the group of participants involved in the trial (Sch. 1, Part 4, paras 9 and 10. See Art. 4(e) of the Directive). With regard to incapacitated adults, the Regulations provide that there must be grounds for expecting that the trial will produce a benefit to the participant outweighing the risks or produce no risk at all, and the trial must relate directly to a life-threatening or debilitating clinical condition from which the participant suffers (Sch. 1, Part 5, paras 9 and 11. See Art. 5(e) and 5(i) of the Clinical Trials Directive). This is a potentially significant difference. For adults the research will usually have to be therapeutic or carry no risks, whereas for children it need only carry a benefit for the group of participants as a whole.
There are a number of possible explanations as to why these provisions (derived from the Directive) render it potentially easier to justify research on children than on adults. One possible explanation is that children are much more likely to have the benefit of a proxy who will prioritise their interests, namely, a parent. Such a rationale (which might not have entered the minds of those composing the Directive) would have far less relevance where the researchers do not seek prior consent. Another (more likely) explanation is that the Directive seeks to encourage research on children, who are not (biologically speaking) small adults, over research on incapacitated adults. The European Commission has recently initiated the adoption of a Regulation on medicinal products for paediatric use to stimulate the research, development, and authorisation of medicines to treat children (European Commission 2004 and 2006).The Commission notes that children represent over 25% of the total population of the 25 Member States, yet
‘more than 50% of the medicines used to treat the children of Europe have not been tested and are not authorised for use in children’ (European Commission 2004, 1).
It also notes that
‘market forces alone have proved insufficient to stimulate adequate research into and authorisation of medicines for children…’ (European Commission 2004, 2).
Making it easier to enrol children in clinical trials over incapacitated adults should encourage more research on children, but could also result in children being used before or instead of incapacitated adults. This is less likely to raise objections insofar as research on adults who lack capacity can be substituted by research on adults with capacity and research on children cannot be so substituted. The type of research that we are concerned with, however, necessitates the use of those who cannot consent. Since adults with capacity cannot be substituted for adults who lack capacity in such research, the biological differences between adults and children do not support the application of this regulatory disparity to emergency research. It is therefore difficult to discern a coherent rationale for applying different safeguards to child participants in emergency research than to adult participants in emergency research.
Some moral theories will generally grant greater protection to adults than to young children on the basis of the respective cognitive abilities typically displayed by such individuals (see e.g. Beyleveld and Pattinson 2000, 39–53). Such moral positions do not, however, provide support for applying weaker safeguards to all children than to all incapacitated adults, because not all incapacitated adults will display greater cognitive abilities than all children.
We have seen that the Clinical Trials Regulations, like the Directive they implement, are restricted to clinical trials involving medicinal products. Research not falling under these Regulations will usually be caught by other domestic laws. In England and Wales, these include the Mental Capacity Act 2005 (to be implemented in April 2007) and the Human Tissue Act 2004.
The Data Protection Act 1998, which implements Directive 95/46/EC, will also be relevant to any research that uses a participant’s personal data. This means that this Act will capture some research, such as data analysis or some types of observational research, falling outside of other legislative regulation. The import of this Act will not, however, be examined here. (For an overview of this Act see Pattinson 2006, 184–189.)
The common law and the Mental Capacity Act 2005
In the absence of specific case law, the common law position on research involving participants is largely a matter of supposition guided by the case law on medical treatment. The common law distinguishes between those over the age of 18 (adults) and those under that age (children). (In contrast to the Clinical Trials Regulations and the Mental Capacity Act, which define a child as someone who is under 16.) At common law, no one can consent on behalf of an incapacitated adult, but, by virtue of the legal doctrine of necessity, medical treatment will be lawful if it is in the patient’s best interests (Re F  2 A.C. 1). This includes any treatment that is necessary to preserve the life or health of a temporarily incapacitated adult. Where treatment is needed to avert an immediate and irreversible threat to life or health, the doctrine of necessity will similarly allow the treatment of a child without consent (Gillick v West Norfolk and Wisbech AHA  A.C. 112, 138, 181–182, 189, 200, 204). Outside of emergencies, prior consent for the treatment of a child should be obtained from someone with parental responsibility, from the child (if the child is over 16 or ‘Gillick competent’), or from the court (see, in particular, s.3(1) of the Children Act 1989, s.8(1) of the Family Law Reform Act 1969, and Gillick v West Norfolk and Wisbech AHA  A.C. 112).
At first sight, the invocation of the best interests test might appear to present difficulties for any type of invasive research on those unable to consent. This is probably not the case (see Pattinson 2006, 371–373). The best interests test has been interpreted broadly by the courts to encompass emotional, social, and other welfare interests (Re MB  2 F.L.R. 426, 439 and Re A  1 F.L.R. 549, 555) and indirect benefits (see Re Y  Fam. 110). There is also some (limited) authority for the view that, in some circumstances, it might be possible to rely on the ‘not against the interests’ test (S v S  A.C. 24). We shall see that the soon-to-be-implemented Mental Capacity Act 2005 dispenses with the best interests test in research situations. Where the Act does not apply, especially in relation to those under 16, it is likely to influence the general common law approach to the best interests test and the Act takes a wide approach to the interests to be protected in research.
Sections 30 to 34 of the Mental Capacity Act 2005 are dedicated to research on those who are 16 or over (adults for the purposes of the Act) and lack the capacity to consent. This Act will apply to research of the kind that would be unlawful to carry out on a person who had capacity without his consent (s.30(2)); that is to say, research that would involve a trespass if not authorised by consent or other lawful justification. The Act does not apply to clinical trials covered by the Clinical Trials Regulations (s.30(3)), but could still apply to, for example, an investigation into a new surgical technique or a trial of alternative forms of cardio-pulmonary resuscitation. The Act requires research on those who lack capacity to be part of a protocol approved by, in effect, a research ethics committee (REC) and carried out in accordance with specified conditions (s.30(1)).
Section 31 specifies the requirements for approval. The REC must be satisfied that the research relates to the participant’s condition and cannot be done as effectively using those who have capacity (s.31(2)–(4)). This section also requires the benefits of the research to justify the risks in one of two ways. The research could be permitted if it has the potential to produce a benefit to the participant without imposing on him any burden that is disproportionate to this benefit (s.31(5)(a)). Alternatively, the research must be intended to provide knowledge that will benefit those affected by the same or a similar condition where the risks to the participant are ‘negligible’ and the research will not significantly interfere with the participant’s freedom or privacy, or be unduly invasive or restrictive (s.31(5)(b)/(6)). The Mental Capacity Act thereby permits research that is of no direct benefit to the participant as long as it is considered to carry minimal risks and involve minimal intrusion and interference. This is, taken at face value, slightly more permissive than the Clinical Trials Directive/Regulations, which require that research on adults carry ‘no risk at all’ where it is not expected to benefit the participant (Sch. 1, Part 5, para 9 of the Regulations and Art. 5(i) of the Directive).
Researchers must consult and generally follow the advice of a carer or someone interested in the participant’s welfare, or an independent nominated person on whether an incapacitated adult can be entered into the trial (s.32(1)–(6)). An exception is made to the consultation requirement where urgent treatment is being provided and the researcher considers it (a) necessary to take action as a matter of urgency and (b) not reasonably practicable to consult (s.32(8)). The researcher must also have the agreement of an independent doctor or, if this is not reasonably practicable, the protocol must have been approved by an appropriate body (s.32(9)). This exception ceases to apply if the researcher has reasonable grounds for believing that it is no longer necessary to take the action as a matter of urgency (s.32(10)). Thus, the Mental Capacity Act explicitly allows researchers to dispense with prior consent in specified circumstances. The explanatory notes to the Act assert that the arrangements for emergency research ‘are similar to those provided for in the Clinical Trials Regulations’ (para. 104). We disagree for the reasons that we have already given.
The Human Tissue Act 2004
The Human Tissue Act 2004 is relevant to some emergency research. Under this Act, the storage and use of tissue obtained from a living person for research usually requires ‘appropriate consent’. (More specifically, the tissue covered by these provisions is ‘relevant material’, defined in s.53 as all material that ‘consists of or includes human cells’ with specified exclusions.) An exception is made to this requirement by s.6, which empowers the Secretary of State to issue regulations allowing the use of relevant material for research on an incapacitated adult who has not previously made a decision on this issue. Regulations, which came into force on 1 September 2006, provide that consent is deemed to have been given in a number of specified circumstances: The Human Tissue Act 2004 (Persons who Lack Capacity to Consent and Transplants) Regulations 2006/1659, reg. 3. These include those where the storage and use for, inter alia, research is done for the purpose of a clinical trial that is authorised and conducted in accordance with the Clinical Trials Regulations(1) or for the purpose of a trial that is conducted under, and in accordance with the requirements of, the Mental Capacity Act 2005. The Human Tissue Act will, therefore, not hinder research conducted in accordance with other legislation and is potentially compatible with deferred or no consent. Instead it reproduces the arbitrary distinctions created by these divergent regulatory instruments.
The Scottish position
Scotland has its own variants of the legislation outlined above: the Adults with Incapacity (Scotland) Act 2000 and the Human Tissue (Scotland) Act 2006. The first of these two Acts applies to adults (defined as those 16 or over: s.1(6)) who lack capacity. It does not specifically address emergency research. Consent to recruit a participant must be obtained from a guardian or welfare attorney who has power to consent to the adult’s participation in research or, where there is no such guardian or welfare attorney, from the adult’s nearest relative (s.51(3(f)). The Scottish equivalent of the Mental Capacity Act, thereby requires prior consent for emergency research. It follows that the existing Scottish legislation is not bedevilled by the regulatory inconsistency displayed by the English and Welsh legislation with regard to the prior consent requirement.
Just over a decade ago a stricter interpretation of US Federal Regulations led to emergency research being regarded as prohibited where it is not possible to obtain consent or proxy consent (see Marwick 1995). In October 1996, new regulations were passed to permit emergency research, subject to a number of conditions and safeguards (21 CFR 50.24). In particular, the participants must be in a life-threatening situation in which available treatments are unproven or unsatisfactory; the participant must be unable to consent as a result of their condition and the intervention must be made before consent can be obtained from a legally authorised representative; the risks must be reasonable in the light of expected benefits; and the research must be impractical without the waiver. Other conditions include community consultation, i.e. consultation with representatives of the community from which the participants will be drawn. (These provisions are compared to their counterparts in European instruments in Plomer 2001.) Views differ on whether the US has succeeded in protecting the particularly vulnerable from exploitation, while avoiding unduly hindering the acquisition of the benefits of emergency research (see e.g. Plomer 2001, esp. 337–340). The position in England and Wales is certainly no paragon of regulatory clarity and coherence. The existing regulatory position adopts inconsistent principles towards ethically comparable research on the basis of whether or not the research involves medicinal products. Since the Clinical Trials Directive limits the room for manoeuvre, the UK must continue to operate according to inconsistent principles, seek to amend the Clinical Trials Directive to enable adoption of the more permissive position for research on medicinal products, or amend the Mental Capacity Act to prohibit emergency research for which prior consent is not obtainable in a sufficiently timely manner.
There is growing international support for the view that emergency research can be legitimately conducted, under strict conditions, without prior consent. This view is reflected in paragraph 4.8.15 of the 1996 ICH guidelines (cited above), Article 26 of the 2000 version of the Helsinki Declaration (see the text at www.wma.net/e/policy/b3.htm)(2) and the European Convention on Human Rights and Biomedicine (the Biomedicine Convention), interpreted by reference to its Additional Protocol concerning Biomedical Research (see Council of Europe 1997 and 2005). The most recent of these is the Additional Protocol to the Biomedicine Convention, which opened for signature on 25 January 2005. While the UK has not signed the Biomedicine Convention, let alone its Additional Protocols, the explanatory notes to the Mental Capacity Act indicate that the Act’s research provisions are based on those laid down in the Biomedicine Convention (para. 96). The Convention could also have an interpretative impact on the ECHR, as given domestic effect by the Human Rights Act (HRA) 1998, as mentioned earlier.
Article 17(2) of the Biomedicine Convention permits research that will not benefit the participant, as long as it is intended to benefit those with the participant’s condition or of the same age and entails only minimal risk and minimal burden for the participant. The Convention thereby adopts provisions for research on all those who lack capacity that are similar to those adopted by the Clinical Trials Directive for children but not incapacitated adults. Emergency research is addressed by the Additional Protocol concerning Biomedical Research, the provisions of which will constitute additional articles to the Convention once the Protocol is in force (Art. 33 of the Protocol ‘Relation between this Protocol and the Convention’). Article 19 of the Protocol states that where the urgency of the situation renders it impossible to obtain consent in a sufficiently timely manner from the participant or a legal proxy, research may still take place as long as a number of conditions are satisfied. These require that research of comparable effectiveness cannot be carried out in non-emergency situations, the result is approved by the competent body, that the participant’s previously expressed objections are respected, and research that is not intended to produce a benefit to the participant must seek to benefit persons in the same population and entail only minimal risk and burden (Art. 19(2)). Consent for continued participation must be requested ‘as soon as reasonably possible’ (Art. 19(3)). These provisions are very similar to those adopted by the Mental Capacity Act. The disparity between the Clinical Trials Regulations and the Mental Capacity Act can therefore be seen to reflect that between the Clinical Trials Directive and the Biomedicine Convention. This will no doubt lend support for the view that the Clinical Trials Directive requires amendment. The existing tension appears to be caused by oversight rather than considered choice.
The Medicines for Human Use (Clinical Trials) Amendment (No. 2) Regulations 2006/2984
The Government laid the above Regulations (2006/2984) before Parliament on 21 November 2006 and they will come into force on 12 December 2006. These Regulations amend the Clinical Trials Regulations (2004/1031) to create an exception to the requirement that an incapacitated adult cannot be included in a clinical trial unless the conditions of paragraphs 1 to 5 of Part 5 of Schedule 1 have been met. These conditions include, in particular, that the incapacitated adult’s legal representative has given informed consent (para. 4). The exception (laid down by reg. 2 of the Amendment Regulations) applies where: (i) treatment is required urgently; (ii) the nature of the trial requires urgent action; (iii) it is not reasonably practicable to meet the conditions in paragraphs 1 to 5 of Part 5; and (iv) the procedure adopted has been approved by an ethics committee. These Regulations also amendment the Adults with Incapacity (Scotland) Act 2000. The Amendment Regulations therefore permit clinical trials into emergency treatment on incapacitated adults (but not those under 16) without prior consent, which was the essence of the proposal in the MHRA consultation document. We continue, however, to hold that such an amendment to the UK Regulations is not consistent with a proper interpretation of the Clinical Trials Directive and that, in any event, it would have been better to amend the Directive itself.
Beyleveld, D and Pattinson, SD (2000) ‘Precautionary Reasoning as a Link to Moral Action’ in M. Boylan (ed.), Medical Ethics (Upper Saddle River New Jersey: Prentice-Hall).
Beyleveld, D and Pattinson, SD (2006) ‘Amending the Clinical Trials Regulations 2004’ 13(5) Medical Law Monitor 2.
Brody, H and Miller, BL (1981) ‘Informed Consent in Critical and Emergency Care Research’ 3(2) Topics in Emergency Medicine 11.
Council of Europe (1997) Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the application of Biology and Medicine: Convention on Human Rights and Biomedicine (Oviedo, 4.IV.1997).
Council of Europe (2005) Additional Protocol to the Convention on Human Rights and Biomedicine, concerning Biomedical Research (Strasbourg, 25.I.2005).
CRASH Trial Collaborators (2004) ‘Effect of Intravenous Corticosteroids on Death within 14 days in 10 008 Adults with Clinically Significant Head Injury (MRC CRASH trial): Randomised Placebo-Controlled Trial’ 364 The Lancet 1321.
CRASH Trial Collaborators (2005) ‘Final Results of MRC CRASH, A Randomised Placebo-Controlled Trial of Intravenous Corticosteroid In Adults With Head Injury—Outcomes at 6 Months’ 365 The Lancet 1957.
CRASH Trial Management Group (2004) ‘Research in Emergency Situations: With or Without Relatives Consent’ 21 Emergency Medicine Journal 703.
European Commission (2004) Proposed Regulation on Medicinal Products for Paediatric Use: Overview and Explanation of the Proposal. September 2004.
European Commission (2006) Communication from the Commission to the European Parliament pursuant to the second subparagraph of Article 251 (2) of the EC Treaty concerning the common position of the Council with a view to the adoption of a regulation on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. Brussels, 13.3.2006. COM(2006) 118 final.
Freedman, B (1987) ‘Equipoise and the Ethics of Clinical Research’ 317 New Journal of Medicine 141.
HM Government (2005) Government Response to the Health Committee’s Report on the Influence of the Pharmaceutical Industry (Cm 6655) September 2005.
ICH (International Conference on Harmonisation) (1995) Note for Guidance on Good Clinical Practice CPMP/ICH/135/95.
ICH (International Conference on Harmonisation) (2000) Choice of Control Group and Related Issues in Clinical Trials. (E10) 20 July 2000.
Karlawish, JHT and Hall, JB (1996) ‘The Controversy Over Emergency Research: A Review of the Issues and Suggestion for a Resolution’ 153 American Journal of Respiratory and Critical Care Medicine 499.
Kipnis, K, King, NMP and Nelson, RM (2006) ‘An Open Letter to Institutional Review Boards Considering Northfield Laboratories’ PolyHeme Trial’ 6(3) American Journal of Bioethics 18.
Liddell, K, et al. (2006) ‘Medical Research Involving Incapacitated Adults: Implications of the EU Clinical Trials Directive 2001/20/EC’ 14(3) Medical Law Review 367.
Lötjönen, S (2002) ‘Medical Research in Clinical Emergency Settings in Europe’ 28 Journal of Medical Ethics 183.
Magnus, DC (2006) ‘Blood, Sweat and Tears’ 6(3) American Journal of Bioethics 1.
Marwick, C (1995) ‘Research in Emergency Circumstances’ Journal of the American Medical Association 687.
McCarthy, CB (1996) ‘Editorial: Ethical Considerations of New Guidelines for Emergency Research’ 153 American Journal of Respiratory and Critical Care Medicine 507.
MHRA (Medicines and Healthcare products Regulatory Agency) (2005) Consultation on Amendment to the Medicines for Human Use (Clinical Trials) Regulations 2004 (S.I. 2004/1031). MLX 326. 1 August 2005.
Miller, FG, Franklin, G and Brody, H (2002) ‘What Makes Placebo-Controlled Trials Unethical?’ 2(2) American Journal of Bioethics 3.
MRC (2006) Research in Emergency Settings Involving Adults Who Lack Capacity. 20 April 2006.
Pattinson, SD (2006) Medical Law and Ethics (London: Sweet & Maxwell).
Plomer, A (2001) ‘Protecting the Rights of Human Subjects in Emergency Research’ 8(4) European Journal of Health Law 333.
Sibergleit, RW, Watters, D and Sayre, MR (2006) ‘What Treatments Are ‘Satisfactory’? Divining Regulatory Intent and an Ethical Basis for Exception to Informed Consent for Emergency Research’ 6(3) American Journal of Bioethics 24.
Spöhr, F. et al. (2000) ‘International Multicentre Trial Protocol
to Assess the Efficacy and Safety of Tenecteplase during Cardiopulmonary Resuscitation
in Patients with Out-of-Hospital Cardiac Arrest: The Thrombolysis in Cardiac
Arrest (TROICA) Study’ 35 European Journal of Clinical Investigation 315.
(1)These Regulations declare that the informed consent of the incapacitated adult’s legal representative ‘shall represent that adult’s presumed will’ (Sch. 1, Part 5, para. 12). Interpreted in the light of the Directive, which uses the word ‘must’ instead of ‘shall’ (Art. 5(a)), this appears to require that the legal representative must act in accordance with the presumed will of the incapacitated adult. In England and Wales, these legal representatives include persons not connected with the conduct of the trial who are suitable by virtue of their relationship to the adult to act as their legal representative (presumably such as a person previously designated by the adult or a close relative), or the doctor primarily responsible for the adult’s medical treatment, or a person nominated by the relevant health care provider (Schedule 1, Part 1, para. 2). It should, however, be clear that the basis under which the consent of these proxies relates to the consent of the incapacitated adult varies. In the case of persons designated by the adult, their consent may not merely be deemed to be the consent of the adult or to represent the adult’s presumed will: it is the adult’s will that this consent be acted upon. To act with this consent is to act with the adult’s consent. On the other hand, where the proxy is in a position to provide evidence about what the will of the adult might have been, then provided the evidence is good, and the consent of the proxy is based on this evidence, it is surely reasonable and proper to deem the proxy’s consent to represent the adult’s will. The problem with the Regulations is that many of those empowered to act as legal representatives are in no position to discharge such a role and some incapacitated adults will never have been able to display any relevant will. Consequently, it is clear that the Regulations will deem consent to have been given in circumstances where there is no evidence that it would have been given. What is the justification for this? In our view, there is no need for this unless an adult’s consent is thought of as an absolutely necessary condition for the research to go ahead. What the Regulations effectively do is elevate an adult’s consent to this position and then render the requirement virtually meaningless by treating the consent of others as the adult’s consent when the basis for acting on the consent of others is most properly thought of as giving effect to wider interests of science and society that in principle could be in conflict with the adult’s will. Much more might be said about this fiction, but to pursue the issues raised would take us too far a field and will be left for another paper.
(2) Art. 26 requires that it not be possible to obtain consent, that the condition preventing the participant’s consent being obtained is a necessary characteristic of the research population, the approval of an independent ethics committee, and that the protocol states that consent to remain in the research should be obtained as soon as possible from the participant or a legally authorised proxy.