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Abstract
The paucity of research data to guide current paediatric practice has led to children being termed therapeutic orphans. This difficulty is especially pertinent to research in emergency situations, such as acute resuscitation or critical care, where accepted ethical standards for overall research, have historically created practical difficulties for researchers. The welcome establishment of organisations to support UK paediatric research is helping to ensure safer and more effective medications for children, however as the balance between protection and access at the heart of the paediatric research ethical debate shifts to ever increasing access for researchers to children, it remains crucial to ensure the protection for these vulnerable participants. The fundamental protection for research subjects, namely their full informed consent before any recruitment, is not tenable in true emergency situations and so other approaches are warranted if standards are to be improved by human subjects research in such areas. Proxy, deferred and retrospective consent have all been advocated as solutions to this difficulty and this paper explores the ethical justification for these approaches and their utility in safeguarding children and families in emergency situations when traditional informed consent, as currently defined, cannot be obtained in the necessary time frame to enable research.
- Minors/parental consent
- newborns and minors
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Background
The medical care of critically ill babies and children should be based on the best available research evidence. A fundamental ethical requirement for research involving human subjects is the voluntary informed consent of participants.1 2 Evidence that such consent will be properly sought is a key element of the independent ethical review of research projects.3 4 Furthermore, the majority of journals will require proof that the voluntary consent of research subjects has been obtained prior to publication5 and, indeed, may refuse to publish even heavily anonymised case reports without the explicit consent of the individual involved.6 7
There are two sets of circumstance in which obtaining appropriate consent raises especial practical, ethical and legal difficulties, namely those involving emergency situations and those involving children. When the two sets of circumstance combine, as they do in research that involves the care and treatment of acutely sick infants and children, there may be particular difficulties in satisfying the requirement to obtain voluntary informed consent. The purpose of this paper is to analyse how this requirement might be ethically fulfilled in practice.
The provisions of the Declaration of Helsinki2 have increased the safety of medical research in children and reduced the likelihood of future recurrence of past abuses.8 Yet the risks of harm and the need to protect children have to be set against the latter's rights to the best available treatments; research is necessary to provide evidence for the provenance for such treatment. Unfortunately, a considerable proportion of medicines used in daily paediatric practice, and the overwhelming majority used in the treatment of the most acutely and critically sick have been tested only in animals and adults, and remain unlicensed for paediatric use.9 Similarly treatments involving the use of medical equipment, especially in emergency situations, should take into account the developing biochemical and physiological responses of infants and children. Because the responses of children cannot necessarily be extrapolated from those of animals or adults in similar circumstances or with similar conditions, it is important that this type of research does involve children. Finally, some diseases that result in the critical illness of children, for example, surfactant deficiency in preterm babies may be specific to children and have no adult or even animal counterpart. Research remains the optimal way of providing data on which to base future treatments: the Medical Research Council has acknowledged that ‘Medical research involving children is essential for advancing child health and wellbeing.’10
Where children are unable to give consent to medical treatment, those with parental responsibility have the legal authority to do so, provided that they act in the children's best interests. This principle also applies to research in emergencies, but here circumstances may produce difficulties.
One difficulty relates to the impracticability of obtaining informed consent and this has been recognised by amendments to the clinical trials regulations that enable research to proceed without prior informed consent subject to certain conditions.11 Essentially they are: the treatment to be given as part of the trial needs be given urgently; it is impracticable to obtain informed consent from the person with parental responsibility or the legal representative and the action to be taken is in accordance with a procedure approved by the ethics committee. While these conditions apply in circumstances where parents are absent or urgent action needs to be taken there are other circumstances that are problematical. In particular there remains debate about the validity of informed consent in these circumstances12 13 and how it may best be obtained. Nonetheless parents greatly value involvement and although they may not recall giving formal consent they have expressed reluctance to see the process abandoned.14 15
Acute illness in children and its impact on parental decision-making
The acute illness of a child has immense emotional and psychological effects on parents and may impair their capacity for rational informed decision-making especially in relation to research participation.12 In the ECMO trials of the 1980s on acutely sick neonates, subsequent interviews of parents revealed that some were neither clear that their babies had been in a trial, nor that they had been randomised to receive a particular treatment.16 Similarly a more recent trial of CNEP was accompanied by allegations, since resolved, that valid consent had not been obtained.17 In clinical practice parental recollections of decision-making that preceded deaths in neonatal care may not accord with those of professionals.18
For adults (over 16 years) who lack capacity the Mental Capacity Act,19 makes explicit provision for another person to give proxy consent. Moreover the amendments to the Clinical trials regulations have proved helpful in conducting emergency research involving adults20 However, under the Mental Capacity Act the consent giver is required to make the decision that the incapacitated individual would have made had s/he been competent, basing that decision on their knowledge of his/her personality, values and beliefs, and with regard to any antecedent directives s/he may have given. While it may be feasible to fulfil some of these conditions on behalf of older children it is clearly not possible in the case of those children, for example, neonates and infants, who have never achieved the capacity to develop or express beliefs, values and wishes.
Paediatric emergency research
There may be grounds to believe that parents of critically ill children may be temporarily incapacitated by the urgency of the situation. Therefore it is not clear whether they can give the voluntary informed consent that enrolment in research requires and difficulties in obtaining informed consent have been identified in these circumstances.12 14 Moreover, in some clinical trials patients must be allocated to one or other treatment arm within minutes of a clinical emergency. Such trials would include alternative methods of ventilating babies in respiratory failure or the best way to resuscitate extremely sick infants. In these circumstances it will be impossible for parents to assess the trial protocol in a fully informed way and it may also be impossible to forewarn parents by predicting which babies will present in such fashion. However these are precisely the situations in which parents are expected to make decisions about the urgent medical treatment of their acutely sick child.
In acute medical emergencies, for example, emergency life-saving removal of extradural haematoma or laparotomy for acute volvulus, parental ability to give consent is not usually questioned unless there is clear evidence of parental incapacity, for example, alcohol intoxication. If such overt parental incapacity precludes informed consent for a life-sustaining treatment, it can be undertaken without consent under the doctrine of necessity, provided that it is the child's best interests. In less urgent situations, appropriate court orders to permit treatment can be obtained, but the overarching determinant is that such treatment should be in the child's best interests.
But what of the situation with research, especially if it may benefit the individual by producing evidence of best treatment, and where it may be of minimally increased risk within the context of the child's underlying condition? In such cases it might be argued that ethically justifiable research is in the child's best interests or at least not against their interests. Harris has suggested that, all things being equal, such research is in a child's best interests and that children (and adults, whether vulnerable or not) do have a moral obligation, but not a compulsion, to take part in research.21 22 Given there is an ethically justifiable case to perform research in circumstances where both parents and child have, in essence, ‘situational incapacity,’ how might we enrol children in research and fulfil requirements for consent?
Three approaches to this conundrum will be further explored: they entail (a) deferring the obtaining of voluntary informed consent, but obtaining assent in principle, (b) the use of proxies to obtain consent on behalf of parents and (c) retrospective consent.
Deferred consent or continuing consent
In circumstances where truly informed consent from those with parental responsibility is thought impossible, initial assent or approval in principle to enter the study can be obtained. Full consent is deferred until the parents are able to satisfy the necessary ethical and legal conditions for voluntary informed consent. The model has clear application when parents cannot travel with their sick child or the sole possible consent giver is physically unable to give consent, for example, a mother who is anaesthetised or sedated. This situation would seem to be covered by the amendments to the clinical trials regulations.11 In other cases an initial assessment of the parents' competence to appreciate the information required to provide consent is necessary. However this assessment may also need to be made in situations where there are time pressures and when parents may be expected to provide consent for other therapeutic interventions (even if the latter have not been validated by research). If parents lack capacity to assimilate information about a research project, it might be logical to infer that they may also lack capacity to make decisions about clinical treatments in the same circumstances. In day-to-day medical practice, such a concept of situational incapacity is rarely considered and it would be rare that the use of an alternative mode of decision-making is considered for both parents and child. The context dependent nature of capacity is important, as parents may appear competent to deal with other aspects of their lives.
In deferred consent the continuing consenting process requires that parents who are competent are given sufficient information to make a free choice about entering the study. As in other research they should be given the opportunity to ask questions and to seek further information, without undue pressure, and with time to consider the options, before deciding to proceed to have their child enrolled. Consent in such settings is in fact permission to continue in the study, or-if the study has ended- to use the data obtained.
If parents are present at the time of recruitment a potential justification for not obtaining full consent is situational incapacity. However, some limited explanation, constrained by the emergency situation, should be given concerning the nature of the trial it would seem ethically appropriate, in the context of clinical research, that parental refusal should be honoured… even if there were grounds to question the rationality of such a decision, in the context of medical research.
One critical objection to deferring or continuing consent arises from the fact that, in some cases at least, no one actually consents to participation or actual enrolment of a child into a study. Although the absence of consent in some clearly defined circumstances has, relatively recently, been accepted in the UK11 and elsewhere,23 24 such acceptance seems to run counter to schools of UK ethical and legal thought.25 26 In particular it has been claimed that it runs counter to the obligation to treat patients with respect.27 Even though a failure to provide sufficient information might not produce direct physical harm, it might produce other types of harm and have adverse consequences, for example, distrust of researchers and the ethical review process, which cannot be predicted. A key question is whether this potential breach of the requirement to obtain consent is sufficient and reasonable justification to reject deferred consent in favour of a system of proxy consent.
Proxy consent by a third party
Here some other appropriate person gives consent for a child to enter a clinical research trial. In most clinical circumstances parents already act as legal proxy consent givers for their child. The sociological and legal basis for this is the presumption that the parents' particular bond with their children makes them the most appropriate people to make decisions in a child's best interests. If parents and child have ‘situational incapacity’, it is not clear who might have the moral and legal authority to give consent. While the Mental Capacity Act makes provision for decision-making on behalf of adults who themselves lack capacity it is not clear what might be the appropriate process in the situation we have described.
The initial Clinical Trial Regulations28 stipulated that, without exception, consent must be given on behalf of minors before a trial of investigational medicinal product. It has subsequently been amended to permit research to be initiated without consent in some circumstances11 but subsequent informed consent is necessary from a person with parental responsibility. However, someone other than parent can consent as a ‘legal representative’, if the parent is unable to do so. This can be the clinician primarily responsible for child's treatment, if s/he is not involved in the study. If this is acceptable practice in drug trials it might be equally applicable to all paediatric emergency research, thereby solving the dilemma. But it appears that UK clinicians and researchers are reluctant to use this approach in emergency research. It may be that clinicians are so deeply committed to the principle of respect for the autonomy of potential research subjects that they are unwilling to use the ‘legal representative’ approach, even if the alternative is no research. Or, it could be that the challenge of finding a suitably independent proxy in these situations is too difficult. Moreover it may be even harder for families to accept the concept of an independent legal representative if that person appears to be closely involved with the research and treating teams and they do not perceive themselves as lacking capacity.
The MHRA were so concerned with this in a previous adult trial using paramedics attending emergencies to consent that it stated:
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 is not independent of the trial if he/she is responsible for administering the trial medicine.29
It is perhaps unlikely that an attending paediatrician can be a truly independent legal proxy if s/he has pre-existing knowledge of the study, an interest in improving their own specialty and some form of collegiate relationship with the clinical research staff. Certainly it might be inferred that a practicing clinician will have many vested interests in the undertaking of clinical research, for example, the need to increase medical knowledge to guide practice, and have their own professional relationships with the research team. There are difficulties in accepting the abilities of such an individual to balance the interests of the child in front of them with children in general with fairness and objectivity.
It seems to us that 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, that is, to ensure that the interests of the participant are not conflated with those of the research team.
Retrospective consent
Although retrospective consent appears a contradiction in terms, it appears in several standards for performing emergency research, including the European guidelines for informed consent in biomedical research involving paediatric populations.30 While obtaining deferred or continuing consent in emergency situations seems intrinsically logical, the enrolment of participants in a study without explicit prior consent but using some form of ex post facto permission to satisfy inapplicable standards is logically incongruent. We suggest that this is an example of flawed thinking in order to comply, inappropriately, with the Helsinki declaration. This surely involves turning the standard of fully informed consent, namely that a decision is given freely after that person is informed of the nature, significance, implications and risks of the study, on its head. Is any individual that so ‘consents’ agreeing they would have participated if they had been asked before recruitment, or merely agreeing to continue in an ongoing study or for use of their data? This troubling status neither satisfies the Declaration of Helsinki, nor morally facilitates Ramsey's ‘joint adventurer’ concept of the competent consented research participant and well-intentioned researcher ethically justifying research from recruitment.31 If participants are, in fact, agreeing to continue participation, then the more accurate term deferred consent is surely preferable.
Conclusions
Improving the medical management of acutely ill children in emergency situations requires that research be done on that population itself since useful results cannot easily be extrapolated from adult or animal studies. Yet there are ethical difficulties in satisfying the regulatory requirements that such research demands, including that for voluntary informed consent. An approach in which researchers are advised in effect to ‘sin wisely’ in breaching ethical standards to perform research in this group remains as unsatisfactory now as when it was written.31
Those who research in paediatric emergency medicine appear to be caught between the ethical if not legal Scylla of performing research without properly informed consent or the Charybdis of proxy consent by those with an often tenuous professional separation from the research team, and perhaps little knowledge of the child and family.
In our experience, the proxies suggested in paediatric emergency research might prove neither sufficiently independent of the research team nor sufficiently trained in the process of obtaining consent or of the representation of children in medical research. This contrasts to the approach to welfare decisions about children used by UK courts when truly independent highly trained and experienced individuals are involved in advocating for particular children and their rights. In order to satisfy concerns about the validity of proxy consent in the emergency situations, reliable trained individuals who are truly independent of the research team need to be readily available. However, in healthcare settings with children presenting to local hospitals the provision of 24-hour cover for such an eventuality is unreasonable, and would essentially prevent such research.
If we really believe that research in emergency situations is necessary both for individual and wider societal benefit, especially where the standard conditions for informed consent cannot be met, one possible conclusion is that attempts to secure some (any?) form of consent for emergency research in children are unsustainable. Perhaps a more ethically robust approach is to accept that no true immediate consent is possible, but that approval in principle or assent would allow consent to be deferred (or at least the process continued) until (parental) competence is achieved. We discount the concept of retrospective consent as fundamentally ethically unsound, and as being a forlorn attempt to justify recruitment without consent by not honestly accepting it as such.
Unlike in the perinatal research arena, there is rarely, in emergency medicine in older children, a prospectively identifiable high-risk group of parents who might be approached to consider accepting presumed consent if their child eventually requires resuscitation. However for specific diseases where the likelihood of some future emergency situation is somewhat predictable, we would agree with Manning that prospective information for families is superior.32 Although the difference may be semantic we prefer to remove any notion of there being consent in emergency situations, until this can be obtained in the usual manner. Such an approach would have to be negotiated with parents who would seem from limited available information to prefer a process that involved consent rather than central ethical approval.15
With this proviso, we suggest that the most logical, practical and ethically robust approach in performing emergency research with children, is to enrol children in studies which have undergone vigorous research ethics review, perhaps by committees with special training in this area, without explicit consent—nor the consent of some nominated, yet questionable ‘proxy individual’. This would be consistent with a wider application of the amended clinical trials regulations.11 Those who will ultimately give consent must receive information as early as possible and this must continue throughout—and indeed after—the period of the actual trial. Once it is deemed that any ‘situational’ incapacity has been resolved—and this will usually be within hours of enrolment—then fully informed consent, must be secured as part of an ongoing process. We believe that such an approach protects the interests of individuals without compromising their right to have the best evidence based treatment appropriate for their condition.
References
Footnotes
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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