Science, Safety, and Ethics of Designing Clinical Trials

Proper clinical trial design is critical to ensuring the scientific validity of research results, the potential benefits that will accrue to society from the knowledge gained, and the ethics of conducting experimentation on human research participants. Different design choices have different implications for the applicability of research results to clinical practice, and for the risks and benefits to human participants in a trial. For example, in some cases, there is no clear consensus on what comparison arms should be included in a clinical trial testing a new or existing intervention. A classic approach in many trials is to compare an intervention of interest to standard treatment. Yet, whether and how to include such a comparison arm is a complex determination in situations where multiple modalities are used, or where there is a lack of consensus in the professional community regarding which treatment is best.

The absence of consensus about how to handle such clinical trial design issues has led to controversy and even to the temporary halt of a clinical trial. Thus, the CRpac program aims to create a broad dialogue about these matters and develop "points to consider" as guidance for clinical investigators, ethical review committees, and other stakeholders to inform the design and oversight of future studies.

As a step toward this end, the CRpac program convened a conference November 14-15, 2005 titled, "Considering Usual Medical Care in Clinical Trial Design: Scientific and Ethical Issues." The planning committee for this activity included experts from NIH, OHRP, FDA, CMS, and AHRQ. Speakers addressed such matters as the fundamental scientific and statistical principles pertinent to clinical trial design, ethical considerations in the selection of comparison arms in clinical trials, and other topics to set the intellectual foundation for discussion. These foundational principles were applied to case studies involving several different areas of clinical practice. The scientific and ethical implications of different design choices were also discussed, and these parameters will be articulated in a draft "points to consider" document for broader consideration by relevant stakeholder communities. In the meantime, a proceedings of the meeting is available.

Pertinent Resources, Policies, and Regulations

National Institutes of Health:

• Proceedings from the conference, "Considering Usual Medical Care in Clinical Trial Design: Scientific and Ethical Issues"

Food and Drug Administration:

• Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials - Draft Guidance for Industry and FDA Staff (May 23, 2006) - This draft document discusses important statistical issues and provides guidance on statistical aspects of the design and analysis of clinical trials for medical devices that use Bayesian statistical methods; it does not describe the content of a medical device submission.

• Guidance on Emergency Use of an Investigational Drug or Biologic (1998) - The emergency use of test articles frequently prompts questions from Institutional Review Boards (IRBs) and investigators. This information sheet addresses three areas of concern: emergency Investigational New Drug (IND) requirements; IRB procedures; and informed consent requirements.

International Conference on Harmonization:

• Harmonized Tripartite Guideline: Statistical Principles for Clinical Trials (E9)

• IHarmonized Tripartite Guideline: Choice of Control Group and Related Issues in Clinical Trials (E10)