Howard Mann, M.D.

Program Associate, Division of Medical Ethics and Humanities, University of Utah School of Medicine, Salt Lake City, Utah.

Note to Reader

The ASSERT statement is no longer under development, having been subsumed into the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) initiative. Please use a Search Engine to find the latest information about SPIRIT on the Internet..

The conduct of clinical trials

Each year thousands of randomized controlled clinical trials are performed worldwide. These typically involve marketed drugs or investigational agents, with the control arm involving an active agent or placebo. Other medical interventions may also be evaluated, such as surgical procedures and radiation therapy. Trials may be sponsored by a variety of institutional or public agencies, a pharmaceutical company seeking regulatory approval for a new drug, or conducting a formal efficacy comparison of an approved drug with another commonly used agent.

Randomized controlled trials are recognized as providing the highest quality of evidence to guide clinical practice (1), and to demonstrate relative efficacy to drug approval agencies in the case of investigational agents (2). The results of multiple trials may be aggregated and analyzed in the context of systematic reviews and meta-analyses of the published literature (3,4). Such reviews and analyses may also be used by agencies that make decisions concerning health-care expenditures, or consumers in the context of personal health-care decisions (5). Thus, the results of clinical trials are of considerable importance in many interrelated health-care contexts.

Clinical trials and research ethics committees

National and international codes of conduct applicable to research involving human participants stipulate independent review, approval and monitoring of research protocols (6,7). Clinical trials commonly involve the recruitment of participants in multiple centers and are often international in scope. Research ethics committees in different countries are governed by institutional, regional and national regulations that may result in varying, but not incompatible, approaches to the pre-inception review and subsequent monitoring of clinical trials. As detailed in the next section, the ASSERT statement proposes a structured approach to the review and monitoring of clinical trials that is both derivative and expressive of certain requirements necessary for the ethical conduct of research involving human participants. In addition, the statement is intended to operationalize certain requirements in recognition of the complex medical, social and commercial environments in which clinical trials are often conducted.

Requirements for the ethical conduct of clinical research

In 2000, Emanuel and colleagues (8) enumerated seven universally applicable requirements for the ethical conduct of clinical research, all of which are included, explicitly or implicitly, in national and international regulations or codes of conduct: social and scientific value; scientific validity; fair subject selection; favorable risk-benefit ratio; independent review; informed consent; and respect for potential and current research subjects. These requirements are ordered chronologically from the design and inception of the protocol through the monitoring of ongoing research activities. Thus, a trial concept that is not scientifically or medically relevant, or a trial design that is not scientifically valid, renders the research proposal ethically illicit, irrespective of the extent to which the other requirements are met.

Although specific principles enumerated in international codes, such as the Declaration of Helsinki, are alluded to herein, the ASSERT checklist items represent a practical expression of five of these requirements in the context of a review of proposed clinical trials.

The reporting of clinical trials

Publication of the results of clinical trials in the medical literature represents a traditional means of public dissemination of the knowledge gained. Such dissemination is implicit in the notion of scientific and social value. The CONSORT statement (9), adopted by many medical journals, represents an important advance in ensuring an appropriately informative means of disseminating clinical trial results. The CONSORT checklist (10) comprises items that must be included in the manuscript submitted for publication. A flow diagram detailing the flow of patient-subjects during the trial is also recommended. The CONSORT statement is associated with a Working Group (11) that continuously evaluates its applicability, revising the statement as necessary.

The ASSERT checklist is modeled directly on the CONSORT concept of identifying and elaborating on specific items known to be crucial in evaluating the reports of controlled clinical trials. The ASSERT checklist includes pertinent items from the CONSORT checklist that are relevant to an assessment of social and scientific value and, in particular, scientific validity. Investigators who address these items in their research applications and verify their inclusion in the trial design will be well positioned to comply with CONSORT's requirements when submitting a trial report for publication. Thus, adoption of ASSERT by research ethics committees will directly promote valued ends common to both statements -- ends in service of the ethical conduct of clinical research.

Provision of trial-related information

As mentioned previously, ASSERT addresses items that are pertinent to the ongoing monitoring of trials in progress by research ethics committees. This is necessary to promote the safety and welfare of enrolled and potential research subjects. This necessitates meaningful, and ongoing, communication between committees, investigators and other involved parties, such as Data and Safety Monitoring Boards (DSMB). This is a challenge in the context of protocols involving multiple centers and their associated research ethics committees. Investigators and sponsors should consider the use of electronic communication made possible by the Internet to effect adequate communication. In particular, each multicenter trial should have an associated Web site whereby important trial-related information is made readily available to participating centers and research ethics committees. Items that may be addressed on a trial-related Web site include updated information concerning subject and center recruitment; the occurrence, nature and relevance of adverse events involving trial participants (including summaries of DSMB deliberations and recommendations); clinically important protocol changes; and, after completion of the trial, progress towards public dissemination of the research results. An example of such a Web site is that associated with the CRASH trial (12) studying the use of corticosteroids in head injury. The Web site may also be hyperlinked from a publicly-accessible trial register as discussed in the elaboration document. Readers should also note the CRASH trial's protocol has been published in an online journal (13).

Formulation of a Working Group and feedback

This is an initial formulation of the ASSERT statement. It is intended as a dynamic statement, subject to critical appraisal and revision. If you interested in joining the Working Group or commenting on the statement, I encourage you to do so by contacting me.

Click here to review the ASSERT checklist and associated elaboration.


References available online are hyperlinked.

1. Oxford Centre for Evidence-based Medicine. Levels of Evidence (May 2001).

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

3. Egger M, Smith GD, Altman D (editors) Systematic Reviews in Health Care. BMJ Books. 2001

4. Greenhalgh T. How to read a paper: Papers that summarize other papers (systematic reviews and meta-analyses) BMJ 1997; 315: 672-765.

5. Bero LA, Jadad AR. How consumers and policymakers can use systematic reviews for decisionmaking Ann Int Med 1997: 127:37-42

6. World Medical Association. Declaration of Helsinki. Revised 2000.

7. Council for International Organisations of Medical Sciences. (CIOMS) International ethical guidelines for biomedical research involving human subjects. Draft revision 2001.

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

9. The CONSORT statement.

10. The CONSORT checklist.

11. The CONSORT Working Group.

12. The CRASH trial Web site.

13. CRASH trial management group. The CRASH trial protocol. BMC Emergency Medicine 2001; 1:1.