Abstract
Biomedical research involving human participants is highly regulated and subject to stringent ethical requirements. Clinical research ethics, regulation and policy have tended to focus almost exclusively on the protection of participants' interests against harms that might result from taking part in research. Less consideration, however, has been given to the interests that patients may themselves have in research participation, even in trials that may be beyond the bounds of current clinical research practice. In this paper, we consider the case of a suggested extension to clinical trial protocols to explore the ethics of participation in ‘risky’ research. We argue that patients may have a strong interest in taking part in research, and that even when greater-than-usual risks may be present, such research can be both ethically and scientifically justified. Finally, we suggest that there might be scope in some cases to assert a right to participate in research, and that the possibility of such a right merits further consideration.
Introduction
Research involving human participants, particularly biomedical research such as clinical trials, is highly regulated and subject to stringent ethical requirements. The focus of most policy and regulatory instruments is overwhelmingly on protection of participants' interests against harm that might result from research. Less consideration, however, is given to supporting the interests that patients may themselves have in participating, even in research that may be beyond the bounds of current clinical research practice. In this paper we consider the case of a suggested extension to clinical trial protocols to explore the ethics of participation in ‘risky’ research. We argue that in some cases patients may have a strong interest in taking part in research, and that even when greater-than-usual risks may be present, such research can be both ethically and scientifically justified.
The case
Anjali was a 40-year-old family doctor who was diagnosed five years ago with early stage ovarian cancer associated with an inherited mutation in the BRCA1 gene. Following optimal surgery and chemotherapy for ovarian cancer, Anjali underwent prophylactic bilateral mastectomies. Sadly, her ovarian cancer relapsed a year and a half later, at which point she received carboplatin and paclitaxel chemotherapy inducing a complete biochemical and radiological response. Over the subsequent three years Anjali received four further lines of cytotoxic chemotherapy, including entry into phase 2 clinical trials of antiangiogenic and vascular disrupting agents. Towards the later stages of her disease, trials of poly(ADP-ribose) polymerase (PARP) inhibitors, drugs that have activity in patients with tumours secondary to BRCA mutations, were about to open at our centre. While Anjali remained reasonably fit, she was denied access to PARP inhibitors either because her clinical situation warranted aggressive treatment with conventional cytotoxic agents or because her blood results precluded entry to these clinical trials.
One day, following one of several discussions with Anjali concerning PARP inhibitor trials, one of the authors walked into the trials unit and saw a bottle of PARP inhibitor tablets that were due to be destroyed, having been returned by another patient who had been on the trial. According to conventional trial protocols and the regulations governing clinical trials of such medications, there was no possibility of distributing such ‘spare’ drugs to patients who, like Anjali, were ineligible for the trial. This provoked some questions. Why should Anjali be deprived of a potential therapy when the drugs were otherwise due for destruction? Is there scope for a new trial design where patients in Anjali's situation can take drugs that are otherwise due for destruction? What might be the ethical concerns involved in establishing such ‘phase 2C’ 1 studies?
Phase 2C clinical trials
The aim of phase 2 clinical trials is to evaluate the dosage requirements and efficacy of new drugs, as well as to monitor safety and toxicity. Conventional phase 2 clinical trial entry criteria usually mandate that patients should have good performance status, limited co-morbidity, adequate organ function and reasonable life-expectancy. Is there, then, a place for a ‘phase 2C’ trial that uses drugs otherwise destined for destruction to treat patients who are excluded from conventional phase 2 trials on the basis of performance status, insufficient organ function or other traditional phase 2 trial entry criteria?
Research, treatment, both or neither?
Two important issues to be addressed in considering the introduction of phase 2C trials are whether the trials would in fact contribute useful scientific data; and whether participation in the trial regimen would have any chance of providing therapeutic benefit to participants. In other words: Is it research? Is it treatment?
The concept of a phase 2C clinical trial arose from our observations of the volume of drug that was destroyed in clinical trials and the perceived ethical conflict in destroying these drugs when other patients could potentially benefit from them. This assumes that there may be some therapeutic benefit to the patients in participating in such trials. But can the chance of a benefit that is still unproven itself serve as justification for allowing participation in a study aimed at proving (or disproving) it? While the line between research and treatment is inevitably a blurred one and there may be little ethical utility in attempting to distinguish between them, 2 it is clear that phase 2C trials must serve some useful purpose if they are to be at all justifiable.
We will discuss the notion of benefit to participants, whether it is required and what form it may take, in greater detail later. As far as direct therapeutic benefit is concerned, however, at the stage these phase 2C trials would take place, some data on efficacy as well as toxicity will already be available from early phase 2 evaluation of the new agent. Phase 2C trials are not, therefore, a complete ‘shot in the dark’; there is at least some reasonable likelihood that the drug will have a beneficial effect. It must also be remembered that for patients such as Anjali who have exhausted all other possible avenues of treatment, participation in phase 2C trials may offer a last hope: even a small chance that it will prolong life or improve quality of life is better than none.
In considering the possible scientific merit of phase 2C trials, an important question is whether the inclusion of participants who would otherwise have been excluded according to standard eligibility criteria would somehow compromise the validity of the trial data, for example by introducing too many confounding factors into the study.
Phase 2C trials would be designed to meet the needs of patients who have exhausted conventional treatment options, who would like to enter clinical trials but who are ineligible on conventional entry criteria. They would thus have relatively broad inclusion criteria, which might make it difficult to assess toxicity issues. However, phase 2C studies could focus simply on efficacy, accepting that the trials would not provide useful data on toxicity. The information derived from these studies would more quickly allow identification of sensitive tumour types, potentially accelerating development of the new drug.
Although the application of broader eligibility criteria may raise concerns about the usefulness of the information obtained, if phase 2C trial results are handled and analysed separately so as not to confound the results of standard trials, then the applicability of the standard trials could be maintained while at the same time gaining valuable information and additional data on the effects of the drug in various clinical situations.
Impact on the pharmaceutical industry
What might the implications of phase 2C trials be in terms of the pharmaceutical industry? Clearly, for phase 2C trials to gain industry support, the trial design must be acceptable and not jeopardize the drug development process.
The purpose of phase 2C investigations would be to identify potentially sensitive disease groups that could then be investigated in the more traditional phase 2/3 setting. As discussed above, data from phase 2C trials would need to be interpreted carefully to take account of the broader inclusion criteria for patients. Although toxicity should be recorded and protocol amendments made as required, the principal intention of such a trial would be to detect antitumour activity that the company could then investigate in further trials.
Phase 2C studies could potentially increase the demand for the drug from the company involved, if patients involved in the trials require long-term provision of treatment. There might also be increased costs of development associated with conducting the additional trials. Even so, if earlier clinical activity is seen through such an approach then this will benefit the company's development strategy. Another possibility might be the establishment of academic collaborations to facilitate the trials and offset costs.
While industrial models of innovation and drug development in their present form are necessarily tied to concerns of cost-effectiveness and commercial viability, the primary concern of oncologists is how best to care for their patients. The many patients who would like to enter trials but who are excluded through eligibility criteria are not necessarily best served by current drug development strategies and are essentially deprived of access to novel agents when they most need them. Why should they be excluded from accessing new and potentially beneficial agents when there are bottles of such drugs being destroyed every day? If patients would possibly benefit from inclusion in a trial, if they want to be included and if the risk–benefit ratio is acceptable to them, then there seem to be powerful reasons to use drugs that would otherwise be wasted to carry out these studies.
Beneficence, respect and justice
As with all clinical trials, a number of ethical considerations related to research participation must be taken into account. 3 There are various international and national standards addressing the ethical conduct of phase 2 studies and the protection of human subjects in research. These include the Declaration of Helsinki and the International Conference on Harmonization's Guideline for Good Clinical Practice. 4 In addition, the Belmont report 5 defined three ethical principles that should underpin research involving human subjects: beneficence, where benefits are maximized and harms minimized; respect, where individuals should be treated as autonomous beings who can make informed choices; and justice, in which research participants are treated fairly and the benefits and burdens of research are distributed equitably. But how do we interpret and apply these key principles, and what might they mean in the context of phase 2C trials?
Risks and benefits
A primary concern in clinical trials is whether the treatment will cause harm to the patients. Of course, in experimental treatment (indeed in all treatment) there is always a risk of unforeseen and possibly adverse consequences. Furthermore, most cancer drugs by their very nature are harmful agents, possibly producing severe side-effects along with the intended therapeutic results. In research as well as treatment, however, the ethical principle of beneficence does not require us to avoid inflicting any and all harms, whatever the cost. The key is to balance necessary harms and risks of harm against the benefits gained, as well as minimize unnecessary harm.
Some may argue that the risks of participation in phase 2C studies are greater for patients excluded by conventional phase 2 eligibility criteria. Indeed, it is possible that treatment of patients unfit for conventional phase 2 studies will cause harms that may even be severe. However, despite the higher risk of toxicity, these patients should not necessarily be precluded from participation: the benefits for them evaluated antecedently may still outweigh the risks of harm, especially where no other treatment options remain to them; and even if in the event the evaluation proves to have been optimistic it still remains a rational and justifiable choice for the patient to make. When there is the chance to prolong life, albeit at some risk, in a situation where no alternative treatment is available, it cannot be unethical to try, so long as the patient understands and accepts the possible risks and the possible benefits.
Similar arguments have been raised regarding phase 1 clinical trials, in which the risks are also greater compared with the chances of benefit. Most first-in-human phase 1 trials do not benefit the patients, particularly the first ones to enter the study, since we do not know the right dose with which to treat the patients and therefore tend to use very low doses as the starting dose level. Thus these trials have every risk of toxicity and very low likelihood of benefit. Nevertheless, studies of patients participating in these trials have shown that patients have a good understanding of the risk–benefit ratio, and that given the alternatives (or rather lack thereof), they are prepared to accept these odds. 6,7 Furthermore, patients benefit both from the chance to participate in the trials as a way of ‘not giving up’, 6 as well as the small but real chance of therapeutic benefit from the treatment.
Due and undue inducements
One of the ethical dangers incurred by recruiting patients who have a worse performance status or other ineligibility for traditional phase 2 trials is whether a phase 2C trial exploits the desperate predicament of ill patients by offering an inappropriate degree of incentive, or giving them no real choice as to whether to participate.
If research participation might bring some therapeutic benefit, then given the alternatives for patients such as these, this chance of benefit is certainly likely to be an incentive but is not necessarily an unethical or undue incentive. It is true that, faced with a choice between participating in a trial that offers some hope of improvement to their condition or doing nothing, most patients would probably choose to participate; moreover, it would seem to be the prudent choice for them to do so. Of the two options, one would appear to be highly preferable. However, this does not mean that patients have no choice in the matter, or that it constitutes unethical exploitation to offer them the opportunity to exercise that choice and participate if they so wish; quite the reverse, in fact. Permitting participation allows a choice, whereas to bar them from participating for fear of exploitation would leave them with none!
Ethical concern about undue inducements stems from the worry that a disproportionate or inappropriate level of incentive offered to participants may undermine their choice and induce them to participate in research against their best interests. In this case, if the trial treatment itself is likely to be in the patient's interests, the benefit gained by participation cannot be an undue or an unethical inducement. 8 When for example we do something for money (like go to work) which we would never do without such an inducement, or accept a new job because rewards are exceptionally good, these facts alone provide no evidence that the inducement might be undue in the sense of being unethical or coercive. In other words, even irresistible inducements are not necessarily inimical to autonomy.
Similarly, as with inducements, exploitation (despite the negative connotations of the word) does not always have to be unethical. Phase 2C studies might be criticized for taking advantage of patients in extreme circumstances, but in fact the advantage gained is mutual. Late-stage cancer patients with no standard treatment options remaining are undoubtedly in a desperate situation, but that should not preclude them from taking part in research if they so choose; it is unfortunate for any patient to be in such a situation, but how much more unfortunate to add insult to injury by denying them the chance to improve it? Allowing the patient to enrol does not represent unethical exploitation, provided that their choice is genuine and that they have a reasonable understanding (1) of the realistic chances that participation will have a beneficial effect on their condition, that it is not a certainty but a chance; and (2) that there is an increased risk that they may suffer side-effects compared with patients in a standard trial, because of the very factors that exclude them from standard trials in the first place.
Best interests, choice and participation
So far we have argued in favour of phase 2C trials not least on the grounds that they represent a potential benefit to the patients involved. However, some readers may consider that participation in such research is not of immediate potential benefit or, indeed, that it is actually against the patient's medical interests. How should we regard participation in phase 2C trials if this is indeed the case?
To begin with, we allow patients to refuse medical treatment or clinical trial participation even where it would clearly be in their best interests, medically speaking, to accept. Why then should we not allow them to participate in research despite it being potentially against their medical interests to do so? Of course, that someone wills something is not always sufficient reason to allow it, morally or legally, and there may be reasons as to why patients should be prevented from participating even if they wish to do so. It is crucial, however, to recognize that for the patients who may wish to participate in phase 2C trials, their interest lies not just in the chance that participation may improve their condition but in their freedom of choice as to whether or not to take that chance. What reasons do we have to deny patients that choice?
There may well be good scientific reasons to regulate who the participants in a trial are, and if risk to patients' safety is also going to compromise the scientific merit of the study, then that is a reason to prevent them from participating. As discussed above, however, there will be valid ways to handle the data from phase 2C trials in order to gain scientific value from them.
It might be argued that allowing risky research is a violation of scientific responsibility and that public trust in science will be degraded if scientists are seen to be conducting research that places participants at too great a risk of harm. Although the concept of ‘scientific responsibility’ is much invoked, its content and justification and how these should apply in a given context are not always well defined. If we accept, though, that scientific responsibility in its most basic definition entails ‘doing good science’, and that ‘doing good science’ requires awareness of the broader consequences, the ethical implications and social context of research as well as attention to the research itself, 9,10 it is hard to see that phase 2C trials will contravene these requirements.
Providing the trial data are interpreted appropriately and the risks to the participants are properly assessed, minimized wherever possible and made clear to participants, phase 2C studies can have both scientific integrity and be ethically justified. Public faith in science will be maintained if they are seen to exhibit both these qualities and to be doing good and serving the interests of desperate patients. Even research in which there is a high chance of harm can be ethically justified, if we recognize two things: first, the importance of serving human needs and choices; second, the role of science as a valuable social institution, in which choices to participate should be supported, not discouraged. Risky sports are tolerated and even encouraged, despite the dangers they pose, because of the perceived value to society of both the activity itself and the freedom to choose to engage in it. A true appreciation of the social value of scientific research should lead us likewise to recognize and support the interests of persons in participating in research, even at risk to themselves.
Concerns might be raised about the potential health-care costs incurred by participation in ‘risky research’, if adverse effects occur, requiring further treatment. (This same concern, indeed, arises with respect to risky sports; for example over the cost of rescue efforts for stranded mountaineers or sailors.) One solution to this eventuality might be to make provision for future treatment costs within the research budget. However, we should also note that we continue to allow people to incur added health-care costs through the choices they make in terms of lifestyle and other activities. While the extent to which public health measures should be imposed to counteract detrimental health choices remains a matter for debate, at the least research participation should not be viewed more harshly than other activities of choice.
Research participation: a right as well as a duty?
It is also appropriate to consider that in addition to potential personal benefit, research participants may be motivated by a desire to contribute to science and to assist in generating knowledge that may help other patients with the same condition. It has been argued elsewhere that in light of the benefits that science has produced and is likely to produce in future, there may be a duty to contribute to this by participating in research where required. 3,8,11–14 Given the interests that persons may themselves have in participation and in choosing to participate, perhaps it is worth considering another possibility: that research participation may be not just a duty but a right. The idea of a right to experimental treatment has received a limited degree of attention in a legal context 15 but the associated ethical issues remain to be considered.
Of course, it takes more than just demand or desire to create a right, and we would need to think carefully about on what such a putative right would be based, what its scope might be and what it might imply: how far it might extend to impose duties on others, how it would intersect with other rights and so forth. Although this is not the place for a detailed exploration of these ideas, we raise the possibility here as a prelude to further discussions and offer some brief suggestions as to how a right to participate in research might be conceptualized and justified.
We have discussed in the context of phase 2C clinical trials the strong interest some patients may have in taking part in such research and the possible health-care benefits that might result. A useful comparison here, therefore, may be the right to health care, which although much-debated in itself, is nevertheless an established concept for discussion. Where health-care benefits accrue from research, as in the case of phase 2C trials, we could perhaps conceive of the right to participate as related to a right to health care; more so if we understand health care not just as an event that takes place at the point of treatment, but as a system that encompasses the research needed to generate new treatment interventions as well as the delivery of the treatments themselves.
Beyond this, however, could we also justify a right to research participation even where there is no direct health benefit? If we view science as a social institution which helps to sustain us and is necessary for the flourishing of society, then it may be arguable that as members of society we should have the right to participate in this institution, in the same way that we have the right to participate in government and social policy, through voting, exercising our freedom of speech, and all the other forms familiar in a participatory democracy. The idea of ‘science as democracy’ and the associated concept of ‘scientific citizenship’ are gaining currency in sociopolitical studies of science. 16–22 Although such accounts have previously been deployed largely in the context of participation in the policy process and the process of public engagement and discourse over research, they might also provide a good starting point for the construction of a right to participate in science directly.
Conclusions
Most oncologists are aware of the large numbers of patients in clinics who would like to enter clinical trials but who are excluded by extensive eligibility criteria. This is therefore an issue that is of great concern to our patients. Phase 2C trials offer a way to address the unmet need of patients who are ineligible for conventional phase 2 studies while using the significant amount of drug that would otherwise be destroyed by pharmaceutical companies.
Phase 2C trials, as proposed, do not require a great degree of ethical and scientific reconceptualization. This trial design is ethically justified in that it provides patients a chance of benefit that they would not otherwise have and it does so at very little real cost or effort to others by using resources that would otherwise be discarded and wasted. It is scientifically justified in that such trials have the potential to add to the body of useful knowledge about a drug and its application. This potential for generating useful knowledge and further benefit to other patients adds further weight to the ethical reasons in favour of allowing it in the first place.
Whether or not research is a right it is, we believe, certainly a duty and an activity of high social importance. When it can also be therapeutic and offer hope to people in a desperate situation, it gains a power and a legitimacy that is benignly irresistible.
Epilogue
What happened to Anjali and the bottle of PARP inhibitors? Sadly, Anjali was never eligible to enter a trial of PARP inhibitors as she wished to do, and the bottle of redundant PARP inhibitors remained in the trial office to be picked up and destroyed. Anjali died peacefully at home in 2009.
Footnotes
Acknowledgements
SC and JH would like to acknowledge the stimulus and support of the Wellcome Trust Strategic Programme on The Human Body: Its Scope, Limits and Future in the preparation of this paper.