Multi-disciplinary teams tasked with the design of phase III clinical trials face a series of challenges. These include: determining the number of subjects required for statistically meaningful results, the time to complete the trial, budget and regulatory hurdles and guideline implications of the trial design.

The first three issues are at least approachable with quantitative methods. However, in trial design, there is an inherent conflict between the pragmatic objective of supporting the broadest possible indication and the scientific reality that in the clinical world, it is difficult to acknowledge, let alone quantitate subgroups of individuals who will have favorable or unfavorable treatment responses.

The development of inclusion/exclusion criteria for a trial is the operational battleground for this conflict. Adoption of liberal inclusion criteria that may enroll a substantial number of potential non-responders might ultimately result in a broad indication, but that approach also increases the numbers of subjects, decreases the overall impact of treatment and increases the likelihood of an unsuccessful trial. More restrictive inclusion criteria can do the opposite.

In TOPCAT, a recent spironolactone-heart failure trial, inclusion required either a heart failure hospitalization or an elevated BNP level. Eastern European investigators enrolled many subjects on the basis of a hospitalization who later proved to have no or mild heart failure. The intervention benefited patients in North and South America, but failed in Eastern Europe. The overall trial also failed.

Sponsors, CROs and site teams must look carefully at inclusion criteria; hitting a smaller target beats missing a big one.

Guest Contributor Roger M. Mills, M.D. is a graduate of Amherst College and the University of Pennsylvania medical school. After completing his medical residency, he served in the U.S. Navy before beginning a 30-year career in academic clinical cardiology. He joined Scios Inc., a Johnson & Johnson operating company, in 2005, and later moved to J&J’s Janssen Research and Development, LLC. He retired after a 10 year career with J&J.

This article was reprinted from Volume 24, Issue 05, of The CenterWatch Monthly, an industry leading publication providing hard-hitting, authoritative business and financial coverage of the clinical research space. The Action Items section features short columns  focusing on actionable or how-to advice from clinical trial professionals. To submit an Action Item, please contact editorial@centerwatch.com. Subscribe >>