Abstract
Introduction
In recent years, there has been much debate about participation in first-in-human (FIH) trials of new drugs and biotechnologies. The focus has been on critically ill patients and whether their consent to participate in such studies is rendered invalid by the therapeutic misconception (the false belief that participation will provide clinical benefit). The role of healthy volunteers in Phase I trials has been discussed less frequently, and the role of ‘stable’ volunteers such as those with diabetes or atherosclerosis has hardly been mentioned in the literature. This last group of patients is likely to be the target of several new synthetic biology and nanomedicine applications.1,2
In this essay, we examine the difficult choices research ethics committees (RECs) have to make, and conclude that it is unfair for them to make unilateral decisions about the risks that patients in each of these groups should face. Patients should have a much greater level of involvement in risk assessment and trial approval, and the presence of actual patients rather than ‘patient representatives’ and ‘lay members’ on RECs is essential. In clinical research, patients are told the risks and asked to make a decision; as such, they should be much more involved in risk assessment in research.
FIH trials and potential participants
Most FIH trial participants are terminally ill patients or healthy volunteers. The use of such patients in trials is regarded with some scepticism. The fear is that such patients will fall victim to the ‘therapeutic misconception’ and believe that they will benefit from a drug, even when this is improbable. Some RECs have rejected studies that they regard as posing too high a risk, even when such trials constitute the last hope of treatment for many of these patients. 3
Although healthy participants are preferred for most FIH trials, for some drugs it is regarded as too dangerous to expose this group to a high risk of toxicity, and patients are used instead. The infamous TGN1412 trial, in which six healthy volunteers nearly died, indicates the potential risks posed to healthy participants (and illustrates how even ‘subclinical’ doses 500× weaker than those found safe in animals can be potentially fatal). 4 Exposing healthy volunteers to more than minimal risk is also regarded with suspicion by RECs, and studies that aim to do so tend to be rejected. While most controversial phase 0 and 1 trials have concerned conventional treatments for cancer, some have involved novel biotechnology such as gene and stem cell therapies. The novel interventions in such trials are normally for the benefit of those with acute terminal conditions, making it relatively easy to decide whether high-risk trials are worthwhile. If novel therapies are tested on patients with relatively mild forms of a disease and a normal or slightly reduced life expectancy, fatal outcomes possibly related to a trial are particularly problematic and can stop developments of new treatments in an entire area as happened in the field of gene therapy. 5
A third group of potential participants has seldom been discussed in the literature. Stable patients are affected by chronic disease such as atherosclerosis or diabetes but are not terminally ill. Assessing the risk/benefit profile for this group of participants is perhaps even more difficult than for healthy participants and terminally ill patients; although stable patients are not dying, they might be willing to take relatively high risks in order to improve their quality of life. RECs are likely to reject the involvement of such patients in trials of novel nanotech and synthetic biology applications because of the extreme uncertainties involved in such trials.
RECs and risk/benefit assessment
While individual potential participants in FIH trials can decide for themselves whether to consent to involvement, RECs must first decide whether a trial should be allowed to begin. To do so, RECs rely on a wide range of expertise, with many different specialties represented. As well as doctors from different specialties, they routinely include statisticians, ethicists, nurses and psychologists. In the UK, at least one-third of the members of each National Health Service ethics committee must be lay members ‘who are independent of care services’ and at least half of these members must never have worked in healthcare. 6 In the US, where institutional review boards need not have any lay members and can operate with only five members, requirements are less stringent. 7 In Switzerland, ethics committees do not need to have lay members.
The members of the REC must look closely at the rationale for proceeding to an FIH trial. As already mentioned, RECs are generally happy to approve minimal risk studies for healthy participants and high-risk studies for terminally ill patients (provided concerns about the therapeutic misconception are addressed). However, higher-risk studies for healthy participants and stable patients are more problematic. RECs almost always reject high-risk studies involving healthy participants, as they do not stand to benefit and the benefit to medicine is not perceived to outweigh the risk. This inherently paternalistic stance is likely to lead to the high risk of participation ruling out the involvement of stable patients. By taking decisions about acceptable levels of risk on behalf of participants, RECs exercise more paternalism than is acceptable in clinical care, where patients are provided with the relevant information and asked to make a decision. While this caution is perhaps understandable in the case of healthy volunteers, for stable patients (and terminally ill ones judged potential victims of the therapeutic misconception) it actually disenfranchises patients of the right to participate in research. 8
Furthermore, the reluctance to expose patients to high-risk research is normally related to the fact that it is unlikely to benefit them. This contrasts with high-risk clinical interventions, which are often deemed worthwhile because of the potential benefit. It is generally true that terminally ill patients will not benefit from research participation, and any benefit that is conferred will be relatively short-lived; similarly, healthy participants are not normally exposed to high risks because they will not benefit from participation. However, stable patients are much more likely to benefit than either of the other groups. While the chances of benefit during the trial are similarly low, stable patients differ in that they will still require treatment for their conditions in 10, 20 or 30 years, meaning that they are highly likely to benefit from any treatments that result from the research (and are highly likely to suffer for decades unless a treatment is found). This in turn means that any benefit that is conferred is likely to be of much longer duration than that conferred upon terminally ill participants. This increased prospective benefit does not in itself justify high risks, but does go some way towards mitigating the potential risks of participation in an FIH trial. RECs should not decide that these risks rule out participation without consulting the relevant patients themselves.
Putting patients on RECs
Given the vast uncertainty at play in the risk assessment of new drugs, and particularly in risk analysis of novel new biotechnologies, it is understandable that RECs err on the side of caution. However, it is also unfair that patients and healthy participants are being excluded from the discussion about acceptable levels of risk. One solution to this problem would be to mandate that RECs have actual patients among their members on a study-by-study basis. It is often argued that this is unnecessary because ‘everyone is a patient’ or because lay members can represent patients adequately. This latter claim is true inasmuch as lay members can assess the readability of consent forms and information sheets, but false in that many lay members do not suffer from chronic or acute medical conditions (it is true that healthy lay members do represent the interests of healthy participants to a large extent). Some RECs have patient representatives instead of or as well as lay members, but these advocates frequently do not have the specific knowledge that comes with having a disease oneself, which also applies to lay members.
If RECs are to make truly informed decisions about the acceptability of research risks, there must be direct input into their deliberations from the relevant group of potential patients. This might sound impractical, but RECs frequently invite experts to supplement the REC’s expertise when a proposed trial is outwith the knowledge base of the REC members. RECs should ask at least two patients with the relevant condition to attend the deliberations about a novel new drug relevant to them (except in cases of minimal risk). For example, if a new nanomedical application targets atherosclerosis but poses an uncertain level of risk, the REC should invite current atherosclerosis patients to help decide whether the trial should go ahead. When the risks of a novel drug or biotechnology are uncertain, patients are in the best position to decide whether an uncertain risk is worth taking, and will hopefully help RECs avoid refusing approval to trials that would in the past have been rejected. This would empower patients both by allowing them to influence decisions and by increasing the transparency of REC deliberations, which are relatively opaque to patients and members of the public. (Two alternatives would be to have RECs approve more or less everything and leave risk assessment to individual patients, 9 or to conduct rigorous empirical research to establish patient views.)
While inviting stable patients to attend REC meetings would be relatively easy, arranging for the participation of terminally ill patients could be more challenging, particularly if they require constant care. Also, given the short time they have left in their life, they might not want to spent it in REC meetings. However, it would still be possible for some of these patients to attend, particularly if they have only recently been diagnosed. Furthermore, the main focus of this proposal is on stable patients, who are more likely to have high-risk trials relevant to them rejected. (As already mentioned, healthy participants are already represented to a large extent by most committee members.) Another possible disadvantage is that the patients involved in the decision might be annoyed if the trial does not go ahead, and complain about the REC to other patients. While this would be unfortunate, it is a necessary risk to take when attempting to increase transparency and the integrity of the risk/benefit assessment process.
The obvious objection to this proposal is that it is impractical. RECs can evaluate dozens of studies per month, and it would take a lot of time and effort to identify the right patients for participation in the meeting. However, given that the idea is to obtain patients’ perspectives on the risks and benefits of the trial, it makes sense to choose only those patients who meet the inclusion criteria. If the recruitment design is good, physicians involved with the trial could instead provide the REC with contact details for them; this would form part of the formal REC application. Getting the researchers to find suitable candidates will avoid adding too much to the already considerable workload of RECs, while also allowing the REC rather than the researcher to pick the actual patients. While some RECs review different types of research project, some focus exclusively on FIH trials, and could easily incorporate this additional question into application forms. While the patients chosen cannot be representative of all patients, they will nonetheless provide much greater insight into the acceptability of risk than is currently available to committees.
Checklist for patient participation in RECs.
