There’s No Going Outside the Lines – Ethical Considerations in the Conduct of Clinical Trials
The chief purpose of clinical trials is to provide benefit to the public through the generation of new and useful knowledge. Whether a study provides an enhanced understanding of a disease state or demonstrates the safety and/or efficacy of a potentially valuable therapy, clinical trials have the potential to benefit people other than those directly involved in the studies. People enrolled as participants in a clinical trial may experience benefit, harm, some of each, or neither, as a result of their participation in research. Because research trials are often conducted in clinical settings, with researchers who are also healthcare professionals and research participants who are also patients, the lines between research and clinical practice can blur. Thus, it is important to remember and manage the different purposes of each (ie, new knowledge for the public good for research, and improving or maintaining patient’s well-being for healthcare).
This chapter will explore the duty of ensuring that a clinical trial is executed in a manner that is both congruent with the spirit of the public good and not harmful to the individual participants. To accomplish this goal, a principal investigator (PI) and her or his clinical trial team must have a firm understanding of the ethical considerations involved in running a clinical trial, including how best to protect the interests of trial participants. As of October 2000, the National Institutes of Health (NIH) requires that investigators, as well as “key personnel,” submitting NIH applications or accepting awards for research involving human participants receive education on the protection of human research participants.
Significant Events in the History of Clinical Trial Ethics
The Nuremberg Code, formulated in 1947 in light of the human atrocities committed in the name of medical research during World War II, has been the blueprint for today’s principles concerning the rights of humans participating in medical research. The 10 principles that make up this code cover topics ranging from informed consent, safety, research importance, risk, participant discontinuation, and trial termination. In the Nuremberg Code, we see a strong emphasis on the autonomy of a person, in which an informed, voluntary choice must be made about whether to participate in research. The conduct of the physician researcher is also emphasized, making clear that the physician does not have the ultimate authority over that patient’s well-being. Though the Nuremberg Code brought many vital issues to the forefront, it wasn’t until 1964 that the world’s medical community, via the World Medical Association (WMA), first began a form of self-regulation for research practices when they adopted the Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects.1 The declaration was the first international statement to consider that research should be reviewed by an independent committee and was the inspiration for institutional review boards (IRB/RECs)/research ethics committees (RECs).2
In 1979, the United States National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research published a document paramount to the national and international development of clinical trial ethics called, “The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research” (Belmont Report). This document distinguishes 3 key ethical principles for medical research involving humans: 1) beneficence/nonmaleficence, 2) respect for persons, and 3) justice. Today, most (if not all) ethical principles used to guide medical research involving humans are derived from one of these 3 basic precepts.
The Big Three: Beneficence/Nonmaleficence, Respect for Persons, and Justice
The principles which dictate minimizing harm and maximizing benefit to the participant are called nonmaleficence and beneficence, respectively. Dating back at least to the time of Hippocrates, these principles have been identified as essential to the goals of medicine, and, more recently, to the protection of research participants. Taken together, beneficence and nonmaleficence entail that the clinical trial team is obliged to ensure the overall best interests of research participants. Note that the obligation to minimize harm does not require a totally risk-free clinical trial. If a clinical trial has the potential to improve a participant’s well-being and the risk-to-potential-benefit ratio is favorable, the principle of nonmaleficence does not preclude the participant from taking part in the research, even if there is some risk involved (eg, possible adverse effects of a drug). The ethical requirement in this case would be to minimize any remaining potential harms that may come from participating in the research.
Clinical trials must also be conducted with “respect for persons.” The primary means to demonstrate respect for persons in research is to respect the autonomy of research participants. Doing so recognizes that people can generally control or shape their own lives in important and meaningful ways, within limits set by society and circumstance. Ethical considerations for conducting clinical trials should include a respect for people’s desires to preserve their values, attain personal goals, and assess the options brought before them. Typical applications of this basic principle include considering what participants may feel to be in their best interest, educating potential participants about trial details, obtaining informed consent, and making it clear to participants that, if they wished to, they can discontinue participation in the trial at any time.
Employing the principle of “respect for persons” is also important for those who may not be fully autonomous (eg, children, the cognitively impaired, those who are pressured due to circumstance). In these cases, the principle guides researchers to protect individuals with diminished autonomy, out of respect for their worth as human beings. This means responding to their vulnerability by protecting their interests, while at the same time recognizing and respecting their dignity.
Clinical trials must also abide by the principle of justice, which, in research, generally means a fair distribution of the research’s benefits and burdens. Those sharing in the burdens of research participation (eg, by exposing themselves to risks) also are entitled to share in the potential benefits (eg, potential to access or make use of products derived from the research). Applying this principle also requires that clinical trial participants receive equivalent care to what they could reasonably expect to have if they had chosen not to participate in the trial. They should not knowingly be given substandard care/interventions due to their participation in research.
Furthermore, the principle of justice requires that clinical trials should not exploit particular research populations (eg, overuse of a population, such as 18-25 year-old Caucasian males, because it is cheaper or convenient to do so). Research should also aim to benefit a wide population (eg, men and women of all ages, races and ethnicities), if possible, as to allow more than only a small population (eg, Caucasian males between the ages of 18 and 25 years) to benefit.
We Need Clinical Trials. Do We Need This One?
Not only do clinical trials allow us to develop and test new treatments of potential use to society, but those who have exhausted standard therapeutic options (or have had suboptimal results) sometimes benefit greatly from participating in studies. Therefore, conducting clinical trials appears to be something that is desirable.
But what about this trial? According to the Nuremberg Code, “The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature”. In other words, the trial must be the most appropriate or necessary means for obtaining results that potentially serve a public good. Furthermore, if there exists an alternative to the trial that does not carry as much risk, or the investigational therapy has already been shown to be less efficacious than a less risky alternative, then that alternative should be pursued in lieu of conducting the trial. The same applies to the design of the trial. For example, it would be unethical to design a trial that investigated a highly toxic but effective cure for colon cancer on healthy individuals. Another more ambiguous sort of study that presents significant risk is exemplified in trials with “washout periods” incorporated into their design. These types of trials owe special attention to ethical principles. Participants must be informed that, at some point during the study, some or all of their pretrial therapies will be discontinued or replaced with a placebo. Not only must participants be made aware of the risks associated with withdrawal from their specific therapeutic regimens, but the clinical trial team member conducting recruitment and enrollment must consider also these risks when determining whether a person is suitable to become a study participant.
Ethical Considerations in Study Design and Execution
Because the design and conduct of a trial must not be random or unnecessary in nature, the design and execution should be carefully planned. Firstly, clinical trials should not be more complicated than they need to be. For example, a trial with 8 arms is more likely to have complications or errors than a trial with only 3 arms. Also, flaws and errors can contribute to unnecessary risk. Thus, since the design and execution of a particular study dictate the associated benefit or harm, conducting a well-designed and efficiently-run clinical trial is an ethical imperative.
Secondly, it is ethically imperative that the central research question be of significant scientific value. That is, the clinical trial must be motivated by a scientifically valid and worthwhile question, and the study design must be equipped to address that question. The trial should be designed in such a way where there is an uncertainty as to which arm (including intervention and control arms) is better. To put it in technical terms: the study design must abide by the principle of “clinical equipoise” such that at the beginning of a clinical trial there is genuine uncertainty in the relevant expert community about which of the intervention or control arms being compared in the trial has greater overall merit. Clinical trials should be designed with this concept of “clinical equipoise” in mind, and it should also be reasonable, upon trial completion, to expect an answer to which (intervention or control) arm is to be preferred.
Who Should Participate?
Determining whether or how a specific trial should be conducted involves knowing who the participants should be. Questions about participant recruitment and enrollment call upon all 3 of the basic ethical principles surrounding clinical trials.
As stated in the Nuremberg Code, “The voluntary consent of the human subject is absolutely essential” to the conduct of a proper clinical trial. For potential participants to grant truly voluntary consent, however, they must be properly informed about the nature of the trial, the duration, its purpose, associated methods, possible inconveniences, and potential hazards. An obvious example of an unethical practice is the clinical trial team that intentionally hides risks or inflates potential benefits in order to boost recruitment. A more subtle violation may be an elaborate informed consent form that is of excessive length or contains a lot of technical language. After all, the participant must not only be informed about the study but must also understand what they have agreed to. Additionally, recruitment advertising must be clear and not contain any false claims. Even when well thought out, recruitment advertising may unintentionally mislead people or play too strongly upon their hopes and fears.
Some potential research participants are not capable of giving informed consent. In these cases, a surrogate decision-maker may be able to give informed consent for research participation on the person’s behalf. Researchers should not enroll any person for which there is doubt as to whether she or he, or their surrogate decision-maker, understands, and has provided, informed consent. There are varying legal and regulatory constraints on enrolling people not capable of giving informed consent for research participation. Researchers must follow the regulations and laws that apply to their area.
Potential participants should also not be turned away unnecessarily. This might happen when inclusion criteria are unduly narrow, which may also inhibit a broad application of the results. For example, a study that only enrolls men may preclude a new treatment from being used in women, or it may result in a new intervention being available to women even though it has not been tested on women. Therefore, justice and safety both are at stake in the selection of research participants. Investigators should consider to whom a particular intervention will be available if the trial produces results that will forward the research and development of a new intervention; the inclusion and exclusion criteria of clinical trials must be designed accordingly.
All Good Things Must Come to an End
Research participants reserve the right to discontinue participation at anytime and for any reason. Institution of this right is derived from the principle of autonomy. It is also sometimes necessary to withdraw a participant from the study if it is in her or his best interests. At all times, the participant’s interests must supersede the interests of the research. Participants who discontinue participation, either voluntarily or per the trial team, are entitled to receive or be referred to appropriate follow-up treatment, as are those who remain in the study through its completion.
There are situations that necessitate early termination of a clinical trial. For example, if, during the course of the trial, clinical equipoise is lost, the trial must be discontinued. It would be unethical to knowingly allow for one group to receive inferior treatment or assume a disproportionate amount of the risk. If, for example, during an interim review, it is determined that Intervention A is statistically significantly more efficacious than Intervention B, then the trial should be discontinued. This is because it is now known that the participants on Intervention B are receiving inferior care. Similarly, the study may be stopped if Intervention B is associated with significantly more safety concerns than Intervention A.
As mentioned above, when a clinical trial ends, participants should be assured access to the best proven and reasonably available therapies. When that therapy happens to be the treatment investigated in the trial, but the treatment is not yet commercially available, it is a matter of debate as to what is owed to research participants. In some cases, particularly when the stakes to the participants are very high, sponsors will choose to continue such treatments in the post-trial period and prior to commercial availability. Otherwise, a “compassionate use” petition can be filed with the relevant national authority (eg, the United States Food and Drug Administration [FDA]) on behalf of the participant, which allows for her or him to continue on that therapy even after the trial has been completed. In resource-poor countries, however, access to the best proven care is often not financially or geographically viable, unless the sponsor takes on the responsibility of providing that continued care for the participants. This has also been debated within the WMA. The current WMA position is that the sponsor need not provide treatment, only identify access to it. Researchers who object to a sponsor’s post-trial treatment policy (as with their objections to other aspects of the protocol or clinical trial agreement), should decline to participate in the clinical trial.
Finances
Many ethical issues relating to clinical trials focus on finances. Financial conflicts of interest, maybe the most obvious of finance-related ethical considerations, have received much attention in the medical community. In the United States, the Public Health Service, National Science Foundation, and FDA all have finance-related regulations that individual investigators must follow. However, these regulations are mostly relegated to disclosure of certain financial connections and arrangements to the investigator’s sponsor and, depending on the regulatory agency, the researching institution as well. Financial arrangements and connections that must be reported to trial sponsors include the receipt of significant payments from stipends, speaking and consultancy fees, gifts, and royalties. Investigators must also alert their sponsors to ownership of any equity interest (stock or otherwise), patent, copyright, or other intellectual property associated with the sponsoring company or the therapy under investigation. All of the above must also be disclosed to the IRB/RECs so that their potential impact on the ethical conduct of the clinical trial can be assessed and managed. Note that the level of disclosure to sponsors, research institutions, or IRB/RECs is not identical with disclosure to potential research participants. The former will help to assess and determine what must be disclosed to the latter.
In addition to potential harms to research participants, research institutions, and sponsors, conflicts of interest which are not addressed are likely to foster an erosion of trust and respect between members of the public, researchers, and the research community. Thus, it is imperative to address and resolve (or manage) any conflicts of interest or appearances of conflicts of interest, and extra protections may be necessary in some cases to ensure the safe and ethical conduct of the research.
Other financial aspects of clinical trials also merit ethical consideration. Participant remuneration can have profound effects on a person’s ability to make appropriate decisions regarding enrollment and continued trial participation. Thus, it is recommended by organizations such as the World Health Organization (WHO), that participants be fairly compensated for their participation in the trial (eg, travel and child-care costs, lost wages, etc) but not paid based on their completion of the trial.
In addition, the United States National Bioethics Advisory Commission, along with many prominent international organizations, including the Council for International Organizations of Medical Sciences, the International Conference on Harmonisation, and the Joint United Nations Programme on HIV/AIDS, support the concept of sponsors compensating participants for research-related injuries. Support for this concept is rooted in the belief that the principle of justice dictates that individuals who take risks for the benefit of the group should be compensated for the harm they experience as a result. Because society and sponsors benefit from the actions of research participants who expose themselves to risks through their participation in clinical trials, participants are entitled to compensation when they are injured as a result of their participation in a trial. Normally, the sponsor of the clinical trial establishes its plan regarding potential compensation at the outset of the clinical trial.
Though clinical trial team members should be compensated for their efforts, the manner in which this is accomplished also has potential for ethical oversights. Medical staff are often paid on a basis of per-patient-seen and pharmacists on a basis of per-item-dispensed. Thus, enrollment targets can be a great source of conflict if institutional funding or staff compensation are contingent upon enrolling a certain number of participants in the trial. A desire to enroll a large number of participants should not be allowed to influence recruiting practices such that people who should not participate in the trial are enrolled.
Doing the Right Thing: Occasionally, It Is Pretty Simple
For the PI, there is much to consider when conducting an ethical clinical trial. Fortunately, quite a few aspects of ethical trial administration are common sense and simply require a PI’s awareness in the moment. For example, it is clear that a PI should not falsify data or hide research results. Likewise, confidentiality of a participant’s identity and the study data is also crucial. Accordingly, researchers should ensure that their research practices abide by the privacy laws in their region (eg, The Health Insurance Portability and Accountability Act in the United States).
Furthermore, clinical trial team members are often health professionals who come to research with a good understanding of their ethical obligations as health professionals. These individual obligations remain when health professions become part of a research team, and are even elevated, meaning that ethical standards for research are generally higher than those for clinical practice.
Conclusions
Principles of beneficence/nonmaleficence, respect for persons, and justice are the foundation of ethical research involving human participants. Researchers must follow these ethical principles when conducting clinical trials, and should never agree to participate in a clinical trial where they feel that either the trial is unethical or an ethically dubious aspect of the trial cannot be managed or rectified in an ethical manner. There are numerous local, national, and international guidelines, laws, and scholarly reflections pertaining to biomedical research. These provide much in the ways of practical assistance in putting ethical principles into action. The WHO’s Handbook for Good Clinical Research Practice is one excellent ethical resource, containing guidelines based on many of the ethical principles outlined in this chapter. Researchers are also encouraged to seek advice from their local research institutions and IRB/RECs to identify what specific research regulations are required in their area.
1At the time of this writing, the World Medical Association has undertaken a major revision to its Declaration of Helsinki, which includes a proposal to change the title to Ethical Principles for Biomedical Research Involving Human Beings
2Also called Research Ethics Committees or Research Ethics Boards
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