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7.3.2 Enrolling Patients in Clinical Research

Daryl Pullman, PhD, and Andrew Latus, MD, PhD

Educational Objectives

  1. To explore the notion of informed consent in research settings.
  2. To appreciate the ethical challenges clinicians face when their patients are also their research subjects.
  3. To understand the concept of "therapeutic misconception."

Case

Jane Simmons, age 57 years, has a two-year history of rheumatoid arthritis (RA). Despite early initiation of methotrexate, both of her hands are severely affected and attempts to reduce the burden of clinical inflammation and radiologic damage have been largely unsuccessful. Jane is a highly motivated patient as her condition makes it virtually impossible for her to continue her career as a painter. She has the financial resources to try new treatments, including biological agents, but is discouraged as she has seen little benefit from previous interventions.

Dr. Fraser, Jane's rheumatologist, is currently enrolling patients in a Phase III trial of a new biological agent that targets a novel cytokine implicated in the pathogenesis of RA. Based on her reading of the preliminary research, Dr. Fraser is optimistic about its potential for patients like Jane. At Jane's next appointment Dr. Fraser explains the details of this 24-week, double-blind, placebo-controlled study. She says, "There's no guarantee this treatment will be successful, but I have a good feeling about it." Jane enthusiastically agrees to take part.

The study protocol requires visits every two weeks. Over the next several weeks Dr. Fraser notices a clear improvement in Jane's mood and in Jane's perception of her own symptoms, although there is no objective evidence of this. By the end of the study, however, there is an observable improvement in Jane's condition, particularly in her right "painting hand," and Jane has resumed painting. She makes frequent references to the "new lease on life" this "new treatment" has given her. On reflection, Dr. Fraser realizes that she also sometimes refers to Jane's improvement as resulting from the new agent, even though neither she nor Jane knows whether Jane is receiving the study drug or placebo.

As the trial comes to an end, Jane becomes increasingly concerned about what will happen when she stops receiving "this wonderful new drug." She begins to pressure Dr. Fraser to find a way to continue her access to it.

Questions

  1. How do standards of consent differ between research and treatment settings?
  2. What is meant by "therapeutic misconception" and how is it relevant to the current case?
  3. What are the key elements of the consent process in the research context?
  4. Would it be appropriate for Dr. Fraser to attempt to obtain the new biological agent for Jane when the trial ends?

Discussion

Q1. How do standards of consent differ between research and clinical settings?

Consent is perhaps the most familiar topic in clinical ethics, but new aspects emerge when discussing the research setting. In general, standards of consent are more stringent in the research setting than in the clinical context. This was established in law in Canada in the 1965 case of Halushka v. U. of Saskatchewan1 and it is recognized in the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans,2 the primary code of ethics governing medical research in Canada. Informed consent is a process; it begins with the initial contact with the research subject and carries through to the end of his/her involvement in the study.

Although the patient/subject's participation in either a clinical intervention or medical research may be justified with reference to well-known ethical principles of autonomy, beneficence and non-maleficence, the manner in which those principles are interpreted and applied differs in each setting. Clinical interventions are offered primarily on the basis of the principle of beneficence, with the reasonable expectation that the intervention will benefit the patient. In the clinical setting the patient's autonomy is generally assumed. The fact that the patient approaches the clinician to seek his/her professional advice is taken to imply consent to treatment, and thus the vast majority of clinical interventions do not require a written authorization on the part of the patient. While considerations of autonomy require that the clinician explain various options to the patient, the general expectation is that each clinical option brings with it a reasonable prospect of benefit.

In the research setting it is the researcher who initiates contact with the potential subject rather than the reverse. Research, by definition, implies a process of discovery. While it is possible that a patient/subject's participation in clinical research could provide benefit, this is not known when the invitation to participate is offered. For this reason, the principle of non-maleficence plays a greater role in the research setting than the principle of beneficence. Inasmuch as both the researcher and the patient/subject are often blinded as to the arm of a clinical trial in which the subject will be enrolled, the research cannot be justified with reference to the individual patient's good. Instead, extra precautions must be taken to ensure that no harm will come to the patient as a result of his/her participation. This, in turn, impacts on considerations of autonomy and the nature of consent because—when the therapeutic benefits are still unknown—the patient/subject is being asked to assume additional risks. Given these circumstances, the patient/subject's consent must be explicit and a written authorization is almost always required.

Q2. What is meant by "therapeutic misconception" and how is it relevant to the current case?

"Therapeutic misconception" refers to a phenomenon that can arise when a patient in the care of a physician is invited to participate in medical research. Given the patient's desire to benefit from the intervention offered by the clinician, it is possible that the patient will fail to distinguish between the physician's dual roles as clinician and researcher, and also the patient's own roles as both patient and research subject. The more desperate the patient, as Jane appears to be in the presented case, the more likely she might misconstrue the invitation to participate in a clinical trial not as research but as an offer of an alternative intervention.

Clinicians who assume the role of health researcher have certain practices imposed on them in relation to that role that may conflict with conventional medical care. It is the patient/subject's failure to appreciate this fact that is at the core of therapeutic misconception. For example, patients rightly expect that their physicians will tailor all aspects of their care to meet their individual needs. However, this assumption is misplaced when a clinician takes on the role of researcher and the patient assumes the role of research subject. The very design of a randomized clinical trial requires that subjects are randomized to an intervention by chance and not on the basis of the investigator's clinical judgment. Furthermore, the process of double-blinding such that neither the clinician/researcher nor the patient/subject is privy to the exact nature of the intervention entails that research results should not be interpreted as pertaining to the individual patient, but are rather aggregate data about all subjects enrolled in a particular arm of the trial.

Although the patient/subject's misconception is the proper focus of a discussion on therapeutic misconception, it is important to recognize that, at times, physicians can also become lost in the ambiguity of their dual roles as clinician and researcher. Desperate to find an effective intervention for a patient, a clinician could wrongly attribute a perceived change in symptoms to be the product of a yet unproven intervention. Irrespective of the locus of the misconception, its existence threatens the adequacy of the patient's initial and continuing consent. It is therefore essential for the clinician/researcher to remain clear as to when the patient is being offered a validated medical treatment, and when the offered intervention is still at the research stage. It may be necessary to remind research participants of this difference throughout the duration of the study.

Q3. What are the key elements of the consent process in the research context?

A legitimate consent must be freely given by a competent individual based on an adequate understanding of all relevant information. The Tri-Council Policy Statement discusses each of these requirements at length under the categories of "voluntariness," "competence," and "informing potential subjects."2

The "voluntariness" requirement entails that consent must be obtained without manipulation, undue influence or coercion. This is a particularly important requirement in the context of clinical research in that the existence of a therapeutic relationship between the clinician and the patient can exert undue influence on the patient, despite the best efforts and intentions of the clinician. A patient may wish to please the physician, or feel that the physician expects him/her to participate in the research. Given the vulnerability of patients in these circumstances and the additional risks associated with clinical research, it is especially important to be sensitive to the issue of undue influence.

On the other hand, some patients are willing to volunteer for clinical trials out of a genuine sense of altruism. Even when they are informed of the risks and understand they could receive no benefit from participating in the study, some patients may still express a willingness to participate out of a desire to assist in learning more about their disease and the treatment of it. While this is a legitimate reason for an individual to enrol in a research study, researchers must be careful not to place too much weight on the patient/subject's perceived altruistic motivation, especially when the risks to the patient could be significant. In general, the degree of caution about a patient's perceived altruistic motivation should be proportional to the perceived risk of harm to the patient.

"Competence" refers to the patient's ability to understand the information presented and to appreciate the consequences of decisions made in light of that information. The matter of legal competence is generally straightforward when dealing with mentally competent, adult participants. However, the individual's ability to make a free and informed decision can be compromised in the research context. As noted previously, the phenomenon of therapeutic misconception can lead to confusion on the part of research subjects as to their role and the character and quality of the information they must process.

It is with regard to what constitutes adequate information that the clearest Canadian rules have been established. The 1980 Supreme Court of Canada ruling in Reibl v. Hughes established the standard of information disclosure for a therapeutic intervention.3 A patient must be provided with the information that a reasonable person in the patient's position would want in order to make an informed decision. Given the need for greater stringency in the research setting, a researcher would be held to at least the Reibl standard. Thus, Dr. Fraser must inform Jane of any potential risks that might be of particular concern given her occupation. For example, she should discuss any possible permanent damage to her painting hand should Jane participate in the study. Given the design of the trial it is possible Jane could receive a placebo, the study drug could prove to be ineffective or there could be unforeseen side effects associated with the new biological agent. Even rare risks must be disclosed, particularly if the harm involved could be severe. Assuming that adequate information has been provided, researchers have an obligation to ensure that this information has been understood. The rules governing this are less clear than the standards of information disclosure, but it is important to ask questions of potential participants to ensure they have grasped the information that has been communicated.

Adequate information includes full disclosure of any real or potential conflicts of interest that the physician might have in participating as a researcher in this study. For example, if Dr. Fraser has ever worked as a consultant to the pharmaceutical company sponsoring the trial, or if she has a financial interest in a company that might profit from the approval of this new drug, she would be required to disclose this information during the consent process.

Q4. Would it be appropriate for Dr. Fraser to attempt to obtain the new biological agent for Jane when the trial ends?

If Dr. Fraser is convinced that this new intervention is benefiting Jane, it is easy to see why she might be inclined to do something to ensure ongoing access. At this point, however, there is still no solid evidence that Jane is receiving the active treatment rather than placebo. Indeed, the very fact that Jane is pressuring Dr. Fraser to find a way for her to stay on the trial drug is an indication that she has not fully appreciated the nature of her participation in this clinical trial, and could even call into question the validity of her continuing consent. It is possible that either Dr. Fraser, Jane, or both have been deluded by therapeutic misconception.

The placebo effect in such trials can range as high as 20–30%, so while Jane may really be doing much better while in the trial, there is no objective evidence to warrant putting her on this as yet unproven therapy. There could well be safety concerns that will become evident only when the aggregate data are analyzed. In short, it would be inappropriate to advocate for Jane in this regard.

References

  1. Halushka v. University of Saskatchewan et al. 53 DLR (2d) 436 (Sask. CA) 1965.
  2. Tri-Council Policy Statement. Ethical conduct for research involving humans. Ottawa: Interagency Secretariat on Research Ethics; 2005. Available from: http://www.pre.ethics.gc.ca/english/pdf/TCPS%20October%202005_E.pdf.
  3. Reibl v. Hughes (1980) 114 DLR (3d) 1 (SCC).

Further Reading

  • Canadian Medical Protective Association (CMPA). Consent: A guide for Canadian physicians, 3rd edn. Ottawa: CMPA; 1996.
  • Kimmelman J. The therapeutic misconception at 25: Treatment, research, and confusion. Hastings Center Report 2007; 37: 36–42.
  • Pullman D. Subject comprehension, standards of information disclosure and potential liability in research. Health Law Journal 2001; 9: 113–27.
  • Weijer C, Dickens B, Meslin EM. Bioethics for clinicians: 10. Research ethics. Canadian Medical Association Journal 1997; 156: 1153–7.