[Clinical Research and Regulatory Affairs 1998; 15: 145-157]
Udo Schuklenk, Ph.D.
All modern societies require that new drugs undergo rigorous testing before market approval. The new drugs are required to demonstrate safety and efficacy. People suffering terminal illnesses have no successful standard therapies on which they can rely. They often find themselves in a situation where they have the choice between joining a research clinical trial or dying without any treatment. Often such trials are designed in ways required to speed up market approval rather than with the patients' survival interests at heart. As a consequence of this many people with terminal illnesses have lost trust in their doctors’ and/or principal investigators. Widespread breaking of clinical trial protocols by the research subjects has been reported by AIDS researchers. This article analyzes the ethical issues resulting from these problems.
Imagine for a moment that one day, after a lengthy differential-diagnostic process had come to an end, your doctor looks at you, somewhat sad, and tells you that her fears have been proven correct, and that you have contracted a lethal illness which is bound to kill you after a one to two year period of time. She explains further that at this stage no life-saving medications are available, and all that you could do is to either wait for your certain death, or to join one of a number of clinical trials designed to test potentially life-saving medications. You realize that access to such an experimental agent is a better deal than doing nothing, because in the event of the agent failing, the outcome is still the same as it was before you joined the trial, you are going to die within a short period of time. – What would you do? Many people with catastrophic illness decide to join such clinical trials.
There can be little doubt that the vast majority of people living in modern Western societies are supportive of medical research. They accept that scientifically sound clinical research is in the best interest of future patient generations. They also accept a corollary of this view that research subjects are required to participate in such trials. Indeed, many low-risk clinical trials have little trouble recruiting autonomously volunteering research subjects in numbers sufficient to satisfy the demands of drug regulatory bodies. So, seemingly everything is in order: people believe that they have a moral responsibility to join clinical trials and are prepared to volunteer their services if called upon.
Unfortunately, things are not so simple. At least for one particular group of patients empirical evidence has accumulated which indicates that they do not believe themselves to be true volunteers. These people may well support the necessity of ongoing clinical research, and they might also think that people should, generally speaking, join clinical trials, yet interestingly, they themselves are not prepared to volunteer as research subjects. The group of people I am concerned with in this article is that of patients suffering terminal illnesses.
Sufficient evidence is available to prima facie support the following claims:
Why would people with life-threatening illnesses, who clearly understand the importance (and urgency) of valid scientific research conduct themselves in this manner? One reason can be found in statements such as the following, taken from an electronic mailing-list designed to allow people with AIDS to communicate with each other: "I hate to say it but … we are no more than lab rats to these people [researchers]. As time passed by my (CD4/8) levels dropped to almost their original levels and I gracefully bowed out of the study. … Thank you Mr. Lab Rat. … No more I say. Life is too precious to do this. I can honestly say that I am sorry that I did this." Irrespective of skepticism directed toward individual researchers or clinical settings, it seems that a major motive has to do with doubts concerning the clinical equipoise of the arms in a given trial. Many patients seem to be worried whether their chances are as good or bad as those of the patients in one of the other trial arms. It is intersubjectively understandable that one might be willing to accept minor reversible setbacks as a consequence of being assigned to a trial arm that isn’t performing as well as some of the other arms. However, it is obvious that one is less likely to do so, when two conditions are met: i) the set-back is irreversible, and/or ii) the disease one is suffering from is terminal. Furthermore, as some commentators have pointed out, if investigators are genuinely convinced that a placebo control arm is equally likely to succeed or fail as the arm with the experimental agent, one ought to be sceptical of the trial’s rationale. It doesn’t augur well for the agent that is scheduled to be tested to be seen in the eyes of the principal investigators to be no more likely to work than the placebo.
That research subjects in general, and those with catastrophic illness in particular have often good reason to be concerned about the design of clinical trials has been conceded by a number of researchers who are not suspect to be political activists trying to score points against scientific research. For instance, Dr Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases (NIAID) makes no secret of his views on this subject matter. He has reportedly conceded that "the randomized clinical trial routinely asks physicians to sacrifice the interests of their particular patients for the sake of the study." Gray et al. agree with Fauci’s assessment. They argue "that direct benefits generally do not accrue to participants in AIDS research." The reasons for this have to do with the (scientific) rationale of research clinical trials, in which the emphasis is placed on producing results designed to achieve market approval and to help future patients rather than those who participate in the trial. Additionally, drug approval regulations sometimes require researchers to neglect the interests of their research subjects for the sake of future patients.
1] Means, Ends and the Interests of Future Generations
It has been argued that this current status quo violates a widely supported research ethics principle. For instance, Samuel Hellman suggests: "Individual patients should not be used as a means to achieve even a societally desired end, if in so doing the individual right to medical care is compromised." Clearly, Hellman’s language is that of a true Kantian. He rejects possible utilitarian justifications of the status quo. Individual research subjects should not be sacrificed for the sake of the greater good of society. Individual rights or entitlements are given greater weight than the interests of the wider public. It seems as if this idea has also some legal backing. A US Court of Appeals provided cautious support for this interpretation, and ruled in 1989 that "the needs of the many do not always outweigh the need of the few or the one."
Utilitarians might of course argue that the harm done to a small number of people during a research clinical trial may well be outweighed by the overall benefits generated by the results of such studies for the wider community (i.e. other current and also future patient generations).
However, one doesn’t have to be a Kantian, libertarian or be otherwise in favor of individual rights in order to support the view Hellman holds. Even utilitarians such as the author of this article can support this conclusion. The reason for this is simple: If the ethically required sacrifices become supererogatory there is little point in insisting that people ought to behave like that. Preference utilitarians such as Peter Singer proposed, for instance that we ought to give more than a token donation in order to support starving people living in developing countries, yet he realizes that there is little point in requiring us to give a donation "so high as to be beyond all saints." If in the average AIDS clinical trial more than one out of two participants violate the trial protocol, because he or she considers the ethical demands placed on her or him too high, researchers better take notice and reconsider the way they design trials, the way they recruit subject, and the clinical trial design. The utilitarian reasons for this are straightforward, and have to do with the counterproductive consequences of such situations: the number of violations of trial protocols has reached staggering proportions, indicating that in major research clinical trials, the results of which were reported recently to the world media, between 49% and 82% of all participating patients broke the trial protocol. Such trials produce results with very limited or no predictive value for future generations of patients. Trials that lose more than one out of two of their research subjects are unable to deliver statistically sound results that can be used as the basis for regulatory decisions pertaining to drug approval. It is possible both for Kantian, and for consequentalist varieties of bioethical reasoning to support the demands of people with terminal illnesses to be given access to experimental drugs. Clearly, this has worrying implications for current clinical research and the drug approval process as a whole. A numbers of authors have expressed these worries quite eloquently. George Annas, for instance, argues, "making unproven drugs available is poor policy, [because] if unproven remedies are easily available it will be impossible to do scientifically valid trials of new drugs." I will attend to these problems in a moment. Suffice, at this stage, to suggest that we might do all sorts of good things for the greater good society by committing heinous crimes against individuals, yet we never do such things, because it is deemed incompatible with our respect for individual autonomy and the value of persons. This respect may well be based on individualistic perspectives or on consequentalist ones. Before I attend to the concerns raised by Annas, let me have a brief look at another bioethical argument put forward in defense of the status quo.
2) Paternalism
Not all bioethical arguments are exclusively concerned with the benefits of such research for future generations. Many bioethicists seem to think that there is little point in allowing people with terminal illnesses access to experimental drugs, largely because the likelihood that such drugs work is so exceedingly small. Hence, they conclude, it is not in the best interest of such patients to be given access to chemicals that are unlikely to be beneficial. These arguments, which are concerned with the well-being of current patients have been brought forward in a variety of different versions. They argue essentially that out of concern for the well-being of current patients (including the potential prospective research subjects) we should not give such desperate people access to agents that are likely not to work, and that may well turn out to harm those people who used them. The type of paternalism that we are concerned with here is strong paternalism. Strong paternalism is distinct from weak paternalism in that the people affected are perfectly competent adults. That is in our case study they are people we would consider competent to join a research clinical trial. Yet, authors such as Annas, Arras, and Shorr believe that we should interfere with choices such people might make as soon as they decide to test an experimental drug. Shorr, most clearly, suggests that if people make choices other than joining research clinical trials, we have good reasons to be suspicious of their competence and autonomy. This argument is somewhat circular. It basically maintains that if people make choices supportive of what I want them to do, they are competent, while dissent renders them with some likelihood incompetent.
The paternalist’s argument is, unsurprisingly, that they might hurt themselves. Robert Young, for instance, argues that in order to preserve long-term autonomy we often are forced to interfere with the short-term dispositional autonomy of persons. He clearly has a point. After all, we tend to consider it legitimate to interfere with questionable acts people would like to undertake if the likely negative consequences of such acts for the people themselves are substantial. John Stuart Mill, for instance, champion of individual liberties suggests we ought to stop people who would like to cross a bridge we know to be faulty. He also believes we are not entitled to permanently give up our autonomy, when he argues that we have no right to sell ourselves into slavery. This would obviously entail losing our autonomy for the rest ouf our life. It is doubtful whether this argument is compatible with the overall strategy advanced in Mill’s tractatus On Liberty. The oddity of this argument becomes clearer when we consider that we are concerned here with patients suffering terminal illnesses. Their lives are highly likely to end anyway in the short-term future. Yet the designers of current drug-approval regulation seem to think they know what’s best even for such people. If the same people would decide to risk their lives on a rock-climbing exercise or during hang-gliding nobody would stop them. In fact, many of us even support terminally ill people should they opt out of their misery and choose voluntary euthanasia. Interestingly, however, as soon as they decide to take their chances with an experimental agent, they will have to face the full force of law enforcement agencies bent on enforcing drug approval regulation designed to bring even terminally ill people back into the fold of clinical trials.
Weak and strong paternalistic arguments which have been proposed to lend support to current regulations designed to prevent terminally ill people from accessing experimental agents fail. As last century German philosopher Arthur Schopenhauer put it so eloquently: "What I do to myself is always only what I will, and consequently it is never a wrong or injustice."
If my analysis is correct, then it would follow that we have neither a democratic consensus nor an ethical justification for preventing people with terminal illnesses from accessing experimental (i.e. unapproved) agents in a last-ditch attempt to save their individual lives. At the same time, however, it is self-evident that we need to conduct adequately controlled research clinical trials. After all, even people trying to access experimental agents are not likely to desire so if a clinically adequately tested drug is available. They are only often unwilling to sacrifice their individual survival interests in research clinical trials. The success of such trials depends on the existence of true volunteers. Such volunteers might have altruistic motives, or they might be truly convinced that clinical equipoise between the different trial arms does exist, and that the investigators will allow them to switch to a more successful arm as soon as sufficient evidence is available.
What is needed in my view is that, as a first step, we increase the voluntariness of research subjects in trials the viability of which depends on people suffering catastrophic illnesses. Possible ways of doing this are obviously linked to giving such people access to experimental drugs. Only people who have this alternative, and who decide to join a research clinical trial are true volunteers in any meaningful interpretation of this phrase. Clearly, the alternative of taking the desired agent immediately, without having to join a clinical trial will put extra pressure on principal investigators to think more carefully about possible ways to respect the survival interests of their research subjects than it has been the case in the past. This kind of ‘competition’ seems to have mostly beneficial effects. Voluntariness is increased, and with it compliance with trial protocols. Trust between research subjects and principal investigators is likely to improve.
Undesirable side-effects are to do with the consequences of a more liberal approach when it comes to access to experimental drugs. People might suffer from unanticipated side-effects of an experimental agent. They might require to be taken care of at a substantial cost to the wider community. Clearly, the same applies to people who suffer irreversible harm from risks they decide to take, i.e. while going rock-climbing, scuba-diving or simply riding at high-speed on a rainy day on a motor-bike. As of yet no Western society has declared that such risks are ‘uninsured’ and not covered by societal solidarity with the risk-taker. In fact, we are not only willing to foot the bill for such undesirable of risk-takers, we even seem to consider the victims of some of these situations as some sort of heroes. This is certainly true for injured rock-climbers.
What would such liberalized access imply for pharmaceutical companies? Should we allow them to charge for people accessing their chemicals that are only experimental? Should they be allowed to reap profits from people who are willing to take their chances with experimental agents? Clearly the answer is that no profits should be allowed to be generated, or else the incentive for pharmaceutical companies to conduct or sponsor clinical trials would be radically diminished and access to experimental agents would likely replace adequately controlled clinical trials. At the same time the pharmaceutical industry ought to have an interest to have their drugs tested in this manner, too. The data gathered by means of a controlled access (see paragraph below) to experimental drugs are still valuable means and ought to help applications for market approval.
I have proposed elsewhere that autonomous people with terminal illnesses ought to be given access to experimental drugs if that is what they request. However, this access ought to be given in a controlled form. That is their doctors ought to monitor closely which kinds of experiences people have when they take such drugs. These results ought to be fed into national data-bases and be evaluated by competent personal. This cannot be a substitute for a clinical trial, but such a process may well complement ongoing clinical research. In fact, such access is likely to mirror the real world circumstances under which people would use such drugs more closely than many research clinical trials.
Several conclusions can be drawn from this analysis: