Scientific background, rationale and relevance

Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation

Declaration of Helsinki. Principle 11

The conduct of a controlled clinical trial is ethical if it will contribute valuable and relevant knowledge that promotes health and well-being (1). Clinical trials encompass a wide range of objectives, which must be of scientific and social value to be deemed ethical. Examples include trials evaluating the efficacy and safety of investigational drugs (compared with an active control or placebo), typically used to support an application for regulatory approval for marketing purposes (2); trials comparing the relative efficacy and safety of approved therapeutic agents or interventions; trials performed to acquire additional or more pursuasive data when substantial doubt exists concerning the net therapeutic effectiveness of an approved drug or commonly applied intervention. The notion of social value necessitates judgments on the part of all members of the committee -- those with and without scientific expertise in the field of research under consideration. The research question must be meaningful in that the results should help resolve an issue of substantial clinical import to patients and communities. Furthermore, communities from which the participants are recruited should be judged able to utilize or implement the knowledge gained. In this respect, health-care consumers and policymakers involved in the allocation of health-care resources have an important potential role in determining the salience of proposed trials. Trials that propose to evaluate clinically trivial treatment effects may be judged unethical. This background section of the research application should address these issues in a manner comprehensible to those without specialized scientific knowledge of the clinical issues under consideration.

The notion of scientific relevance is equally important, and connotes an assessment of the trial's objective in light of existent knowledge. The latter may be voluminous or scanty. The evidentiary quality of existing knowledge exists on a continuum from questionable to pursuasive, and is incorporated, for example, in formal measures of trial quality (3). Hence, the relevance of a proposed trial must be considered in relation to a comprehensive assessment of both the quantity and validity of existent knowledge. In addition, the proposed trial should not (absent substantial scientific justification) duplicate or substantially overlap other completed or ongoing trials. Inadequate knowledge of the results of completed trials may lead to the choice of a clinically inappropriate control arm (4). These factors necessitate and justify a requirement that relevance be referenced, whenever possible given the nature of the trial proposed, to a current Systematic Review of the pertinent literature.

As noted by Emanuel et al. (5), there are two fundamental reasons why scientific and social value (and relevance) should be considered an ethical requirement: responsible use of limited societal resources and avoidance of exploitation. The latter invokes the notion of exposing research participants to possible harm without the potential for acquiring valuable and relevant knowledge.

Systematic Reviews and assessment of value and relevance

As declared in principle eleven of the Declaration of Helsinki reproduced above, the conception and design of a clinical trial should be informed by a "...thorough knowledge of the scientific literature..." In recognition of the large volume and varying quality of the published reports of clinical trials associated with almost any important clinical issue, the necessity and utility of referencing a proposed trial to a pertinent Systematic Review are compelling. Assessing the objective of a proposed trial in relation to the results of a Systematic Review will enable a determination of relevance, avoidance of duplication of previously conducted trials, and inappropriate exposure of participants to interventions known to lack net therapeutic efficacy. Conversely, a Systematic Review may support the conduct of a trial by confirming the scientific need for replication of a previously conducted study. These, and other, reasons for referencing a proposed trial to a Systematic Review have been explicated by Chalmers (6), and are summarized in the table below. Further elaboration is found in other sections of this document.

Utility of Systematic Review in assessing a proposed trial
Assessment of clinical value and relevance
Assurance of clinical equipoise
Assessment of significance of interim results analysis
Contextual reporting of results

The application for research may reference an existent up-to-date Systematic Review such as may be found in the Cochrane Library (7), or provide a review performed by an investigator involved in the trial. If, due to the novel nature of the trial's subject matter, a Systematic Review is not pertinent, the primary investigator should clarify this in the application.

Growing recognition of the relevance of referencing Systematic Reviews in proposals for clinical trials is evidenced in statements by agencies such as the European Science Foundation (8), and funding agencies such as the U.K.'s Medical Research Council (9).


References available online are hyperlinked

1. Declaration of Helsinki. Principle 6.

2. F.D.A. Guidance for Industry. Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products. 1998.

3. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized trials: is blinding necessary? Control Clin Trials 1996; 17:1-12.

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

5. Emanuel EJ, Wendler D, Grady C. What makes clinical research ethical? JAMA 2000; 283:2701-2717

6. Chalmers I. Using systematic reviews and registers of ongoing trials for scientific and ethical trial design, monitoring, and reporting. In, Egger M, Davey SG, Altman DG (editors) Systematic Reviews in Health Care: Meta-analysis in Context. London. BMJ Books. 2001, pp 429-443.

7. The Cochrane Library

8. European Science Policy Briefing No.13. Controlled Clinical Trials.

9. U.K. Medical Research Council. Proforma for funding applications for controlled trials.