Every medical research project involving human subjects should be preceded by careful assessment of predictable risks and burdens in comparison with foreseeable benefits to the subject or to others.

Declaration of Helsinki. Principle 16

Research in the form of controlled clinical trials involves components that offer the prospect of direct health-related benefits (therapeutic components), and components that are included solely to answer the research question (non-therapeutic components). The research question is typically framed in the form of a null hypothesis that states that there is no difference between the trial arms with respect to the outcomes measured. These non-therapeutic components may take the form of invasive or non-invasive diagnostic and prognostic testing procedures, not ordinarily performed in the course of clinical care; accumulation of additional clinical and biochemical parameters; performance of investigational genetic tests on blood or tissue samples as ancillary research studies; and a greater intensity or duration of follow-up monitoring after the completion of the therapeutic interventions.

As with other forms of research, the design of the research protocol should maximize benefits and minimize risks to research participants. Research ethics committees should engage in a systematic, non-arbitrary assessment of risks and benefits associated with the clinical protocol insofar as possible (1). To this end, a systematic, component-based approach to risk-benefit assessment proposed by Weijer (2) is recommended for this section. This approach makes a clear distinction between the research components described above, and emphasizes that the associated risks and benefits should be considered separately -- risks associated with non-therapeutic components cannot be justified on the basis of the potential benefits derivative of the therapeutic components. This notion is discussed further in the sections that follow.

Interventions offering the prospect of health-related benefits

The therapeutic components are directed towards the participant as a patient. Risks associated with therapeutic components are justified by the prospect of health-related benefits (a risk-benefit calculus). Such risks are assumed by patients receiving therapeutic interventions outside of the trial setting, and this concept is generally well understood by doctors and patients. In general, it is recognized that informed patients may assume greater risks (considering both probability and magnitude) in return for the prospect of benefits they judge worthwhile. In the trial setting (assuming the presence of clinical equipoise as discussed below), the situation is conceptually analogous. The patient-subject, fully apprised of the possible risks and benefits associated with the therapeutic interventions in both arms, may then make a personal judgment with respect to trial participation.

Interventions and evaluations performed solely to answer the research question

The non-therapeutic components are experienced by the participant as a research volunteer. Risks associated with non-therapeutic components (also referred to as "demarcated research risk") are justified by the prospect of acquiring valuable and relevant knowledge (a risk-knowledge calculus). The knowledge gained is intended primarily to benefit future patients. Research ethics committees, comprising members with the necessary scientific and non-scientific expertise to evaluate the proposed trial, should make a determination that the inclusion of such interventions is scientifically necessary in relation to the methodologic and statistical aspects of the trial design, and justified in relation to the value and relevance of the knowledge to be gained.

When research involves vulnerable participants such as children or individuals with impaired decisional capacity, regulations or guidelines may specify that the risks associated with research participation be limited to minimal risk (3) or a minor increase over minimal risk. An example of this is the regulatory prescription of permissible categories of research involving children in the U.S. as codified in Subpart D of the Common Rule (4), and also formally adopted by the F.D.A. Considering the component-based approach to risk analysis, these risk limitations should be applied to the non-therapeutic research components. Thus, the need to identify and distinguish between therapeutic and non-therapeutic components is evident, and should be delineated as such in the application for research.

Establishment of clinical equipoise

The benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.

Declaration of Helsinki. Principle 29

Randomized controlled trials are performed to accomplish this purpose, and may also be used to evaluate the comparative efficacy of currently available and utilized treatments. Stated differently, a randomized trial is performed to resolve uncertainty about the efficacy of an intervention, particularly when considered in relation to other available treatments, if any (5). At the inception of a randomized trial, there should be genuine uncertainty concerning which arm of the trial may be superior, when both benefits and risks associated with the interventions are taken into account. This notion has been termed the uncertainty principle, and may be present at three levels as described by Rolleston (6) and Sackett (7). The latter's elaboration is adapted and summarized in the table below.

The notion of community uncertainty is particularly relevant to research ethics committees which must decide whether to approve the proposed trial and thus make it available to potential participants. This level of uncertainty represents the moral underpinning of randomized clinical trials, and is the state of clinical equipoise as originally conceived by Freedman (8). Equipoise implies that the expected size and probability of improvement balance the size and probability of side effects (perceived risks) of comparator treatments (9). This concept is perhaps less ambiguous than the notion of uncertainty. More recently, Weijer and colleagues (10) have again emphasized the relevance of clinical equipoise over the uncertainty experienced by the individual clinician as a precondition for trial inception. The presence of clinical equipoise permits the simultaneous accomplishment of two objectives: offering the patient-participant the best bet (in the presence of uncertainty) of getting the best treatment through the process of randomization, and acquiring valuable and relevant medical knowledge.

Investigators proposing a trial should provide the committee with relevant background information in support of a claim of equipoise, including reference to a pertinent Systematic Review (11) whenever feasible. If a Systematic Review is not available for the subject under investigation, the investigator should provide the committee with details concerning the literature review conducted in support of the conduct of a randomized controlled trial. These details should include a full description of the methods and search strategy utilized to acquire and synthesize the relevant medical literature. Guidance in this regard is available from the Cochrane Collaboration (12).

A systematic literature review will also serve to accumulate evidence in support the choice of a control arm, particularly when new therapies are being evaluated. It has been demonstrated in analysis of reported trials that inappropriate choices have been made, particularly when trials are supported by commercial sponsors (13). Analogously, the use of placebo controls must be carefully appraised to ensure that clinical equipoise is present. If equipoise is not present, the use of a placebo control must be explicitly justified. The use of placebo controls is a contentious issue (14), and a full discussion is beyond the scope of this document.

With respect to a particular trial, a physician may or may not be in equipoise. In recognition of his fiduciary status derivative of the physician-patient relationship, he may be uncertain whether to offer participation to his patient. Even if he is not in equipoise, he should inform his patient of the availability of a trial, thus fulfilling the obligation to provide information concerning alternatives to any proposed treatments. Indeed, it has been proposed that this is a moral requirement (15). Analogously, the potential participant should be provided all the necessary information about the trial so that the patient, expressive of his personal medical goals and values, may determine whether he is in equipoise and thus willing to undergo randomization.

The concept of component-based risk analysis, and the application of clinical equipoise to the analysis of a clinical research protocol is summarized in this figure from Weijer, which is reproduced with the permission of the author.

References

References available online are hyperlinked

1. The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. 1979.

2. Weijer C. The ethical analysis of risk. J Law Med Ethics 2000; 28(4):344-61.

3. 45 CFR 46. Definitions. Minimal risk.

4. 45 CFR 46. Subpart D. (46.404 to 46.407).

5. Djulbegovic, B. Acknowledgement of uncertainty: A fundamental means to ensure scientific and ethical validity in clinical research. Curr Oncol Rep 2001; 5:389-95.

6. Rolleston F. Uncertainty about clinical equipoise. CMAJ 2001; 164:1831

7. Sackett DL. Uncertainty about clinical equipoise. CMAJ 2001; 164:1831-32

8. Freedman B. Equipoise and the ethics of clinical research. NEJM 1987; 317:141.

9. Edwards SJL, Lilford RJ, Braunholtz DA, Jackson JC, Hewison J, Thornton J. Ethical issues in the design and conduct of randomized controlled trials. Health Technol Assessment 1998; 2:25.

10. Weijer C, Shapiro S, Glass KC. Clinical equipoise and not the uncertainty principle is the moral underpinning of the randomised controlled trial. BMJ 2000; 321:756-758.

11. Glanville J, Lefebvre C. Identifying systematic reviews: key resources. Evidence-Based Medicine 2000; 5:68-69

12. The Cochrane Collaboration. Cochrane Reviewer's Handbook 4.1.3. June, 2001.

13. Djulbegovic B, Lacevic M, Cantor A, et al. The uncertainty principle and industry-sponsored research Lancet 2000; 356: 635-638.

14. Emanuel E, Miller FG. The ethics of placebo-controlled trials - A middle ground. NEJM 2001; 345:915-918.

15. Marquis D. How to resolve a dilemma concerning randomized clinical trials. NEJM 1999; 341:691-693.