Non-completion

Trials may fail to complete for various reasons. A trial may be stopped because there are too many adverse events, or because a superior intervention has been introduced, or because of inadequate recruitment. The recruitment rate may vary with the type of disease, the type of sponsor and the incentives that are offered. For example, one study suggests that research sponsored by pharmaceutical companies is more likely to complete than government funded or academic research. A recent study of research approved by one REC in The Netherlands reported that almost half (46%) the academic or non-profit sponsored studies were terminated before the requisite number of subjects was reached. This percentage was notably lower in studies that were initiated by a pharmaceutical company (12.5%).6

Although I lack solid comparative data, it appears that oncology research is less likely to complete than research on many other diseases, and within that category, adult oncology research is much less likely to complete than paediatric oncology research where there is a greater history of integration of paediatric care and research.7 A recent article maintains that one out of five studies sponsored by the National Cancer Institute failed to enrol a single subject, and only half reached the minimum number for meaningful results.8 One study maintains that only 3% of adult cancer patients are enrolled in clinical trials.

There are several reasons as to why many studies fail to complete for lack of enrolment. Some patients recoil at the notion that their treatment will be chosen randomly even when the arms of the trial are in equipoise. Some patients may not understand why research-related procedures are necessary, and may overestimate the burden they pose. But while it is rarely discussed in these terms, participation in net risk research—that is, research in which the risks and burdens exceed the benefits to subjects—constitutes a classic collective action problem. It is in the ex ante interest of most people that socially valuable net risk research be conducted, but participation in such research is contrary to the interests of each individual. And to the extent that people are self-interested, they will seek to reap the benefits of research without paying the cost of participation. In many other collective action contexts (such as paying taxes) we use coercion to solve the problem. In medical research, however, we insist that subjects give their voluntary consent with the predictable result that participation rates are often quite low.

In addition, some of the ‘blame’ for inadequate enrolment lies with doctors who do not refer their patients to trials or tell their patients about them, either because they do not know what trials are available or, as seems common, because referral is time consuming and costly if only because they may lose a patient. But whatever the aetiology of inadequate accrual, many researchers seem to follow Lasagna's law (after Louis Lasagna, MD), namely, that they systematically overestimate the pool of available patients who meet the inclusion criteria and would be willing to enrol.9

Objections

I cannot see any plausible objections to the proposed principle in terms of respecting the interests and aims of prospective subjects. At worst, the information will fall on deaf ears. If the reasonable subject would participate for self-interested reasons because the expected personal benefits outweigh the risks and burdens of participation, then it will not matter whether the protocol will yield valid scientific data. But if participation is likely to be a net risk or net burden to subjects and is justified by the expected benefits of the knowledge, then the disclosure of non-completion information (for lack of recruitment or for other reasons) will enable prospective subjects to more intelligently consider whether the expected benefits to others warrants their sacrifice.

But therein lies a potentially serious difficulty. For while non-completion information should be disclosed, other things being equal, it may be objected that other things are decidedly not equal. It is difficult to recruit prospective subjects into clinical trials that involve net risks or burdens when they are not told that there is a reasonable probability that the study will not complete. It may well prove more difficult to recruit them when they are told, and the effect will be greatest on those studies that are least likely to complete in the absence of such disclosure. And so we should consider whether there are good reasons to refrain from such disclosures.

One objection to the principle of non-completion disclosure rests on an analogy with charitable organisations, which may deliberately or unintentionally rely on donor ignorance or misunderstanding about the purpose or recipients of their aid or the extent to which their donation will further their aims. Donors may not understand that their donation may be used for purposes other than what they intended, or that a portion (perhaps a large portion) of their contribution goes to administrative costs and additional fund raising. If such organisations need not disclose such facts, then perhaps research subjects need not be informed about the possibility of non-completion.

There are two replies. First, it may be argued that the analogy should go the other way. Perhaps charities do have a positive obligation to disclose data about the actual beneficiaries of such aid, and the proportion of donations that reaches the intended beneficiaries. Second, it may be argued that there is a distinction between the biomedical context in which we have decided that there should be a formal consent process with disclosure of relevant information and charitable giving where we have always been satisfied with less rigorous criteria for what constitutes valid consent. I am not sure which position is correct, but on the assumption that investigators have an obligation to provide the sort of information that is likely to be relevant to a prospective participant's decision, then there is a presumption that non-completion information should be disclosed.

A second objection takes on the presumption just noted. It claims that while it is seriously wrong not to disclose information about the personal risks and burdens of participation, it is much less wrong not to disclose information about the probability of non-completion or, more generally, about the social value of the research. And given that the disclosure of non-completion information may impede research of potential social value, the beneficial consequences of non-disclosure are sufficient to justify non-disclosure.

I think this objection fails. If the point of insisting on informed consent is to allow people to make decisions about participation that is consistent with their interests, values and aims, then, and as I suggested above, I see no reason to privilege information that is relevant to considerations of self-interest over information that is relevant to altruistic aims, and this is particularly so if we think it desirable that people participate in research for altruistic reasons.

Finally, it may be objected that my proposal should be rejected mainly because it would seriously hamper valuable medical research. Now the potential adverse effect on recruitment is hardly a decisive objection to my proposal. After all, the negative effect on recruitment is a cost to the entire informed consent process. Baruch Brody describes a placebo-controlled study of the benefits of arthroscopic surgery in which subjects were required to write by hand that they understood that they might be receiving ‘sham surgery’.13 Although this procedure generated a ‘significant refusal rate’, Brody maintains that this is ‘the price you may have to pay if you increase potential subjects’ understanding’. No one said that ethics comes cheap.

Still, even if ethics does not come cheap, it is possible that the price of my proposal is too high. The Belmont Report, for instance, adopted a pluralistic approach with respect to the three core values—autonomy, beneficence and justice. It did not claim that respect for autonomy trumps or is even weightier than considerations of beneficence, which might support rejecting the proposed principle. As Beauchamp and Childress put it, ‘The principle of respect for autonomy does not by itself determine what, on balance, a person ought to be free to know or do, or what counts as a valid justification for constraining autonomy’.14 We might well decide on grounds of beneficence that, all things considered, it is morally preferable not to provide subjects with non-completion information full well knowing that we are thereby exploiting prospective subjects’ ignorance or misunderstanding about the probability that their participation will contribute to medical knowledge. If so, we should do so with our eyes open. We should face up to the fact that we have knowingly compromised the principle that prospective subjects should be provided with the information that is relevant to their decision to consent.