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• W2085782015 abstract "Pandora, tempted by natural curiosity and despite being warned, opened a box from which all the evils now afflicting mankind escaped. Hope, alone, remained in the box. Research on critically ill patients unable to give consent is a challenging ethical problem, but the interests of patients, clinical scientists and society are not served by the current ambiguous ethical guidelines and statutory law which exist in the UK. Open debate of these issues may precipitate all manner of ills, but this may be the only means of retaining ‘hope’ for all concerned. There are broadly two types of research involving critically ill patients: clinical trials of new treatments, and observational studies requiring only the gathering of biological samples and patient data – termed ‘non-therapeutic’ research. A subtype of non-therapeutic research involves active intervention without the specific intention of providing benefit to the patient (for example, pharmacokinetic studies), but the need for such studies in patients without their consent is limited and will not be discussed further. Many consider that research on tissue taken from patients for therapeutic purposes (for example, surgical specimens, or residual blood samples after diagnostic testing) is fundamentally different to studies of tissues taken for no other purpose. The current UK Medical Research Council (MRC) guidelines [1] recognise this distinction, stating that ‘it is acceptable to use human material surplus to clinical requirements for research without consent if it is anonymous and unlinked’. The requirement for anonymity is added to ensure that no possible harm could come to a patient through disclosure of their private medical or genomic details. However, some observational research in critical illness relies on precise knowledge of a patient's characteristics and their disease state. Sepsis, for example, is not a homogenous condition; the ability to correlate findings with the source, degree, time course and outcome of the disease can add enormously to the value of the results. However, the more data that is collected, the more difficult it is to preserve true anonymity. Furthermore, in some hypothesis-generating studies, the important phenotypic criteria may be difficult to define in advance, and it would be very useful to allow retrospective analysis of the medical records after the experimental data had been obtained. As current guidelines do not allow this, even research on biological material primarily obtained for therapeutic purposes should ideally be undertaken with consent – and hence in the UK poses the same legal and ethical difficulties as research on specimens taken solely for that purpose. The conduct of clinical trials without consent, though presenting complicated problems, is increasingly accepted as ethically permissible. If treatment A is not known to be better or worse than treatment B, both are considered safe and there are no other possible risks associated with participation in the study, it would seem quite reasonable to treat patients with either A or B. The issues are somewhat more complex than this, but are dealt with elsewhere [2, 3]. The Council of Europe recommendation (90)3 [4] states that clinical research without patient consent is possible as long as there is at least the potential of direct benefit for the individual concerned. Similar policies allow clinical trials in critically ill patients in most parts of the world. What is desperately lacking in the UK is a robust policy for the conduct of observational research which is not in the direct interest of the patient. Regulations regarding consent for medical research were first formulated in the Nuremberg Code of 1947 (following release of the details of research by Nazi physicians on unwilling prisoners), which stated ‘the voluntary consent of the human subject is absolutely essential’[5]. Recognizing this prevented all research on patients unable to give consent (including patients with mental illness and children, as well as the critically ill), the 1964 Declaration of Helsinki [6] allowed legal guardians of incompetent persons to provide consent on their behalf for clinical trials. In contrast to the principles of the Declaration of Helsinki, UK law has never recognised the general validity of proxy consent. The position with regard to non-therapeutic research in the UK was first formally made in a 1962–63 UK MRC statement, which required that any person taking part in observational studies must volunteer ‘in the full sense of the word’. Specifically, ‘the possibility or probability that a particular investigation will be of benefit to humanity or to posterity would afford no defence in the event of legal proceedings. The individual has rights that the law protects and nobody can infringe those rights for the public good’[7]. The current UK MRC guidelines for research on incompetent patients [7] note that the 1962–63 statement essentially prohibited observational critical care research. The MRC now recommends that such research be permitted subject to a number of conditions. The first recommendation is that ‘the person must not object or appear to object’. Requiring a sedated, intubated patient to ‘not appear to object’ seems rather facile. The Local Ethics Committee must agree that the patients' welfare and interests have been properly safeguarded. No doubt in the majority of cases such a judgement will be straightforward, but in some it will not: for example, how much blood is it ethically permissible to take from a critically ill patient? There will invariably be different practical applications of any broad guidelines in different institutions. Nonetheless, ethics committees are probably the best protection against actual harm coming to a patient. However, they cannot protect a patient's autonomy and at the same time allow research without consent. The fundamental protection afforded to the autonomy of patients in the UK is the need to obtain retrospective consent. Participants must be given full information about the research when they recover, and the opportunity to withdraw (with the destruction of their samples and recorded information) if they so wish. Such retrospective consent was used in studies in the United States in the 1980s and early 1990s. However, in 1993 the US Office of Protection from Research Risks determined that retrospective consent should from that time be considered unacceptable. Their argument was that it was logically impossible to consent to a procedure which has already been performed [8]. By allowing a researcher (perhaps not part of the therapeutic team) access to biological material, one could argue that whatever damage there is (and this need only be in the mind of the patient) has been irrevocably done at the time of sampling. Undoubtedly, though, retrospective consent may be acceptable to many patients, who are just grateful to have survived their stay in intensive care. However, regrettably, many critically ill patients will never recover sufficiently to give their consent. Should their samples be destroyed? To do this must limit the applicability of observational studies to those patients most likely to survive. Perhaps death should remove entirely the requirement for consent? Research on tissue from the deceased without any consent was once regarded as perfectly acceptable; however, in the UK at least this is rightly now not the case, as the report into the retention of post mortem specimens in Liverpool makes very clear [9]. To overcome this difficulty the MRC recommends the agreement of carers or relatives should also be sought before taking tissue from patients unable to give their own consent. Pragmatically, the argument becomes specious if the patient subsequently dies: the only people left to object will be the relatives, so their permission is all that matters. However, the law (in contrast to the MRC guidelines) in England, Wales and Northern Ireland does not allow consent for any procedure to be given on behalf of any adult, competent or not. This may indeed be sensible: one study found likely proxys gave consent for inclusion in ICU research when 16–20% of their patient-relatives would not [10]. The MRC recognises this potentially critical anomaly, specifically noting ‘researchers should be clear that, although appropriate on ethical grounds, the approval of an ethics committee or a relative or some other independent person is unlikely to be recognised by the law as an adequate substitute for the consent of the research subject’[7]. Surely this is a theoretical problem, which would never cause difficulty in practice? Experience suggests that on the contrary, the problem is potentially very real. The political gain to be made from ‘exposing’ practices technically outside the law, even if within the medical profession's consensus definition of ethical conduct, is too large to remain unexploited. The media may have little difficulty finding a few patients or relatives to complain that tissue or blood was taken without consent during critical illness, only to be told ‘when it was convenient for the doctor’, ‘when it was too late’. Any conflict between what is legal, and what is deemed by the profession to be ‘ethical’, in the UK would no doubt highlight the policy of some European countries, which prohibit any research without the consent of the patient [11], and which thus essentially prevents observational (or any other) research in intensive care. The Council of Europe [12] in 1996 recognised this problem, and recommended that consent for studies of incompetent patients could be given by a representative authorised by law, but only when there was the potential for direct benefit to the patient. More recently, in its revised ‘Draft additional protocol to the convention on human rights and biomedicine, on biomedical research’, the requirement for direct benefit to the patient is relaxed. Research is permissible if there is possible benefit to ‘other persons in the same age category or afflicted with the same disease or disorder’, but there must be only minimal risk to the participant, and ‘the necessary authorisation has been given specifically and in writing by the legal representative … provided for by national law’[13]. In many countries such representatives are statutorily defined, but at present in the UK this would involve a court ruling in the case of every patient. This is obviously impractical; the adoption of this recommendation in the UK would effectively end research on critically ill patients. There is no means of fully satisfying both respect for a patient's autonomy, and the desire to perform research during critical illness. Does the value of observational research on critically ill patients outweigh this cost? In research into septic shock, for example, a large bulk of useful information comes from studies of animals or human isolated cells. However, evidence is continually emerging that even cellular changes in clinical human disease can be very different to those in more readily available experimental models, as we have recently reviewed [14]. As molecular technology rapidly improves our knowledge of the fundamental mechanisms of disease, it will become increasingly important to validate hypothesises generated on cell and animal models by studying cells from patients with clinical disease. So what is the solution? In the US, the need for retrospective consent was replaced by the permission to waive the requirement for any consent, provided the research ‘poses no more than minimal risk, the waiver does not adversely affect the participant's rights, informed consent or proxy consent is not feasible, and the participant will be provided with additional information after participation' [15]. A recent US review suggests the best course is to allow this non-therapeutic research in the absence of informed consent to continue, but that ‘empirical study should determine whether this is the case’[8]. Pity the person who first falls foul of such empiricism. UK experience strongly suggests that the rules, in law, must be specifically spelt out. There are four possible solutions which might allow samples to be collected from patients unable to give consent: permission to collect samples (as long as this poses minimal risk to the patient), with the need for retrospective consent by the patient (or relative, if the patient dies); the opportunity and requirement to prospectively consent to research studies in the event of critical illness; formal legalisation of consent by a relative (perhaps incorporating a definition of who that relative should be), as is the case in much of Europe, or removal of the need for consent (after ethical approval by a local or, preferably, national body), as is the case in the United States. The problems of retrospective consent are outlined above. A requirement for ‘opt-in’ prospective consent would impose enormous limitations on the types of studies which could be done. Legal recognition of proxy consent, or removal of the need for consent unless an objection is recognised, would seem the most practical and just solution. Neither solution fully respects the autonomy of the patient, but this is simply not possible if research involving incompetent patients is to be allowed. They do, however, attempt to balance autonomy with social responsibility. Though unfashionable, this is a concept which might do well to be reinforced, especially in a nationalised health care system where society takes responsibility for an individual's health, but individuals are encouraged to have no thought for society. Could consent to participate in observational studies involving minimal risk (with all the appropriate safeguards) not be implicit in accepting free medical care? If this is politically untenable, could the law at least be changed to provide some certainty as to the validity of consent on behalf of a relative? It may be helpful to link the arguments surrounding consent in incompetent patients, especially those relating to ‘opt out’ and relative's consent, with very similar discussions in the UK relating to organ donation. The policy of organ retention for research, without the consent of relatives, was once widely accepted by the medical profession, though it now seems this was in the context of general public ignorance. Such views have rightly been condemned as paternalistic and no longer tenable. However, to assume the public is similarly unwilling to tackle difficult issues of autonomy and consent, and so to restrict medical research, seems equally paternalistic. A public debate is needed, followed by unambiguous legislative reform. Without tackling these issues openly, only disaster awaits – to the ultimate greater detriment of every patient in our intensive care units. Pandora only discovered hope when the box was opened." @default.
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• W2085782015 title "Consent for observational studies in critical care: time to open Pandora's Box" @default.
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