This Article Free upon publication Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Roth-Cline, M. D. Search for Related Content PubMed PubMed Citation Articles by Roth-Cline, M. D. Related Collections Other Ethics and Policy AHA Statements and Guidelines

(Circulation. 2006;113:2253-2259.)
© 2006 American Heart Association, Inc.

Special Report

Clinical Trials in the Wake of Vioxx

Requiring Statistically Extreme Evidence of Benefit to Ensure the Safety of New Drugs

Michelle D. Roth-Cline, BS

From the Department of Statistics, University of Wisconsin, Madison.

Correspondence to Michelle D. Roth-Cline, BS, Department of Statistics, University of Wisconsin-Madison, K6 Box 4675, 600 Highland Ave, Madison WI 53792. E-mail mdrothcline@wisc.edu

Key Words: clinical trials • ethics • statistics

An extract of the first 250 words of the full text is provided, because this article has no abstract.

	Introduction

 
Clinical trials have become the preeminent tool for investigating new diagnostic, therapeutic, and preventive treatment strategies. During these trials, periodic interim data analyses are conducted by data monitoring committees (DMCs) to ensure participant safety. If accumulated data indicate harm to participants, clear evidence of superior efficacy, or futility of collecting additional data, studies may be terminated before their planned conclusion.

Editorial p 2173

These termination decisions are invariably complex and involve important subjective and ethical elements.¹ Of greatest concern when studies are terminated because of clear benefit is the possibility that the superior intervention has toxicities that remain undiscovered. Early termination entails the abbreviation of clinical experience that would permit assessment of the longer-term safety profile. However, study continuation when treatments are not equally effective also means that some participants will continue to receive a less effective therapy.

The tension between protecting both trial participants and future patients has been increasingly acute since rofecoxib (Vioxx [Merck]) and other cyclooxygenase-2 inhibitors were implicated in a greater risk of myocardial infarction. Thrombotic side effects of cyclooxygenase-2 inhibition were postulated as a result of the propensity for selective antagonists to decrease vascular prostacyclin production and possibly affect the balance between prothrombotic and antithrombotic eicosanoids.² Little evidence of toxicity was evident in preapproval trials, however, and rofecoxib was approved in 1999 for relief of the signs and symptoms of osteoarthritis, the management of acute pain, and the treatment of primary dysmennorhea.³

The possibility of cardiac toxicity in human trials was recognized in the Vioxx . . . [Full Text of this Article]

This article has been cited by other articles:

				C. D. Furberg, A. A. Levin, P. A. Gross, R. S. Shapiro, and B. L. Strom The FDA and drug safety: a proposal for sweeping changes. Arch Intern Med, October 9, 2006; 166(18): 1938 - 1942. [Abstract] [Full Text] [PDF]

				J. Avorn Evaluating Drug Effects in the Post-Vioxx World: There Must Be a Better Way Circulation, May 9, 2006; 113(18): 2173 - 2176. [Full Text] [PDF]