FDA clarifies it's position on Vioxx

The U.S. Food and Drug Administration has released the following statement by Acting Commissioner Dr. Lester M. Crawford:

For the past several weeks, various allegations and characterizations have circulated and been reported on regarding FDA's approval and post market review of the drug Vioxx, a "Cox-2 inhibitor," that its sponsor, Merck, voluntarily withdrew from the market September 30th, 2004. I am issuing this statement to further clarify the Agency's activities in this area. It covers four topics:

• Issues involving allegations about the performance of FDA's Office of Drug Safety;
• Allegations about a scientific paper submitted to the British medical journal, The Lancet;
• The possible participation of Dr. Curt Furberg in an upcoming FDA advisory committee to discuss Cox-2 inhibitors; and
• Further information about FDA's recent announcements to strengthen its safety program for marketed drugs.

First, allegations have surfaced about the handling of the post-market review commissioned by the FDA and managed by the Center for Drug Evaluation's Office of Drug Safety (ODS). In particular, there has been concern about the process used to complete that study and publish it, including allegations that ODS managers disagreed with the project officer's conclusions and sought to modify them. It is critical that all the facts be presented in this case to assure public confidence in our drug safety programs.

In 2001, a project officer in ODS expressed interest in a scientific collaboration between the Office of Drug Safety and Kaiser Permanente of Northern California on the cardiovascular safety of cox-2 drugs. FDA provided partial funding for this pilot project in August 2001 and again a year later, and our project officer served as the project manager.

Last February, our project officer submitted an abstract to the International Society for Pharmacoepidemiology (ISPE) for presentation at the group's August meeting in Bordeaux, France. It described the final study population of nearly 1.4 million patients and the events being studied, but it included no results.

When this draft was shared with the project officer's supervisors within ODS to obtain review and clearance on August 11th, ODS supervisors immediately recognized the importance of the project officer's work and the need to complete a study report for FDA review and publication in a peer-reviewed scientific journal.

Some FDA scientists questioned some of the conclusions in the abstract and, as a result, the project officer voluntarily chose to revise his conclusions, and he did so, in his own words, "without compromising my deeply held convictions."

This poster was presented in Bordeaux in August and discussed publicly at that time. When he returned, his supervisors in ODS asked him to submit a draft report on his findings within two weeks. It was not submitted to the Center for review until September 30th, after Vioxx was voluntarily withdrawn from the market. Senior drug experts in FDA did not have this report or the underlying data prior to that time.

Second, more recently, the project officer notified his supervisors that he had submitted his findings in a paper to The Lancet. He did this without going through the long-established peer review and clearance process established for scientific papers submitted by FDA scientists. When FDA scientists learned that this paper had been accepted for publication in The Lancet, despite not having gone through the normal peer review process, the director of FDA's Center for Drug Evaluation and Research contacted the journal's editor, out of respect for the scientific peer review process.

Third, recently much has been made of FDA's dealings with Dr. Curt Furberg, an expert on the design of clinical trials. The agency intends to discuss cox-2 inhibitors at an upcoming Arthritis Drugs Advisory Committee meeting in early 2005. Dr. Furberg is not an Arthritis Drugs Committee member; however, as part of our preparatory procedures, last week the Advisory Committee staff anticipated that Dr. Furberg could make a valuable contribution to the meeting as a consultant and following normal operating procedures contacted him to ascertain his availability. Dr. Furberg discussed with a staff member his recent activities related to the cox-2 inhibitor controversy at a recent American Heart Association meeting. Based on their discussion, Dr. Furberg concluded that he would not be allowed to participate because of potential bias. However, the advisory committee preparation process is still underway, so it was premature for any FDA official to suggest that Dr. Furberg could not participate in the upcoming meeting. A decision on Dr. Furberg's participation has not been made because all of the relevant information is not yet available.

Fourth, FDA has a well-documented and longstanding commitment to openness and transparency in its review of marketed drugs. Indeed, the post-market review of Vioxx and antidepressants were initiated and funded by FDA and managed by its Office of Drug Safety. That is evidence that the system is working. Even so, two weeks ago I announced additional steps to strengthen that program in the form of a major initiative designed to improve the monitoring of drug products recently on the market.

The major components of that FDA initiative include:

• Sponsoring a major study of the Drug Safety System by the prestigious Institute of Medicine;
• Appointing a permanent director for the Office of Drug Safety;
• Conducting a series of workshops and meetings on drug safety and risk management; and
• Publishing risk management guidances

Let me emphasize the importance of scientific peer review in the management of drug risks. Peer review is so important that, as part of this drug safety initiative, we are also improving our process for ensuring that internal differences of scientific opinion are fully incorporated into the FDA's decision-making process.

Science at FDA, as elsewhere, typically proceeds by frank discussion and open exchange, followed by a consensus. The organization reaches its conclusion and everyone carries it out.

There are times when honest scientific disagreement cannot be resolved, however, and such disagreements can have a potentially significant public health impact. That is why our new program provides for a review by an ad hoc panel not directly involved in the decisions, by FDA, and by outside experts.

FDA encourages open and vigorous internal debate about the often difficult scientific questions it routinely faces. In the end, we must weigh the evidence -- in this case the benefits and risks of cox-2 inhibitors -- and then decide on behalf of our citizens whether the products should be available. It is a daunting task, and it is one that the FDA has been -- and continues to be -- committed to carrying out every day.