28 Mar 2014 11:00am

Drug Safety and Vioxx® Controversy

Event Location
Dr KyungMann Kim
University of Wisconsin-Madison

Recently there has been a number of drug safety concerns involving, for example, cyclooxygenase-2 (COX2) inhibitors such as Vioxx® (rofecoxib) and Celebrex® (celecoxib), erythropoiesis-stimulating agents such as Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa) and Procrit® (epoetin alfa), and anti-diabetic drugs such as Avandia® (rosiglitazone maleate). Celebrex® (celecoxib) and Vioxx® (rofecoxib) are both a non-steroidal anti-inflammatory drug selectively inhibiting cyclooxygenase-2, an enzyme responsible for inflammation and pain, and were approved by the US Food and Drug Administration in December 1998 for treatment of osteoarthritis and rheumatoid arthritis and May 1999 for treatment of osteoarthritis, acute pain and dysmenorrhea, respectively.  The US National Cancer Institute launched the Adenoma Prevention with Celecoxib (APC) trial in November 1999, and shortly afterwards Merck launched the Adenomatous Polyp PRevention On Vioxx (APPROVe) trial in February 2000. 

A regularly scheduled review of the interim safety data from the APPROVe trial by its external safety monitoring board led to a voluntary withdrawal of Vioxx® on 30 September 2004, followed by early termination of the APC trial due to safety concern on 17 December 2004 by the NCI. In this review I will provide the general background on the drug safety issues and illustrate the challenges, with post-marketing trials of COX2 inhibitors as an example.  More specifically, I will review the development of Vioxx®, the events leading up to its voluntary withdrawal by Merck, subsequent publications about cardiovascular adverse events for the APPROVe and APC trials, and surrounding controversy, with liability litigations in the background.  I will attempt to draw lessons in terms of clinical trials design, conduct, monitoring, analysis and publication.  In particular, I will highlight the controversy surrounding the analysis of cardiovascular events and the interpretation of emerging difference in the Kaplan-Meier estimates from the APPROVe trial.