Recent problems with Vioxx highlight need for post-marketing changes

Experts discuss fallout from most recent controversies

The clinical trial industry watched with concern late last year as the national media drew attention to the problems with some painkillers — COX-2 inhibitors, including rofecoxib (Vioxx) and celecoxib (Celebrex) — which were linked to increased risk for heart disease. Two days before Christmas, the FDA issued a public health advisory recommending limited use of COX-2 inhibitors.1

Last year’s controversy over the COX-2 inhibitors falls on the heels of the ongoing controversy over the use of selective serotonin reuptake inhibitors (SSRIs) in adolescents. In recent years, some parents have attributed their teenagers’ suicides to the youths being prescribed paroxetine (Paxil) for depression.2

"The most important lessons from this are that the system we’ve had in place and relied upon for a long time now is really not accomplishing what it was intended to do," says Greg Koski, PhD, MD, CPI, senior scientist for the Institute for Health Policy and an associate professor of anesthesia for Massachusetts General Hospital, Partners HealthCare System, Harvard Medical School in Boston.

"It’s clear that although the FDA has the primary responsibility for ensuring safety of all of the new drugs and devices and biologics that come out, they simply can’t do that job unless they have all of the necessary information," he says. "And we’ve no system to ensure that they, in fact, get all of the information."

Some news reports said that earlier clinical trials involving rofecoxib had noted increased heart disease risk, and these findings also may give clinical trial professionals cause for concern, Koski notes.

"We learned that the [pharmaceutical] industry often is in possession of information that they’d just as soon neither the FDA nor public have access to because it might have adverse consequences for marketing and sales of their product," he says. "And that’s — in my mind — an unacceptable situation."

The immediate impact of the problems involving COX-2 inhibitors will be changes in post-marketing studies, says LaDale George, JD, senior counsel in the health law department/health care business counseling practicing group of Foley & Lardner in Chicago.

"Right now, I’m seeing a lot of impact planning by the industry where they are evaluating the placement of post-marketing studies in their marketing departments rather than in their R&D departments," he says.

"Typically, post-marketing, post-regulatory approval studies have more often than not been conducted or overseen by the marketing department of large pharmaceutical companies rather than by the research department," George explains. "In many ways, this has given those post-marketing studies less of a view toward scientific merit and more of an expression of expanding market opportunity for the product."

By re-housing the research post-approval research in the research department, investigators will have a better opportunity to connect statistical data to earlier trial adverse events, he adds.

A big lesson to be learned from the rofecoxib experience is the research industry needs a more careful review of clinical trials while they are ongoing, says Elizabeth E. Hill, RN, MS, DNSc, assistant professor and director of clinical research management program at the Duke University School of Nursing in Durham, NC.

"I’m concerned because I feel like there’s not anyone who has the big picture with all of the adverse events," Hill says. "Who knows whether they are being reported accurately and whether the right judgments are being made of them."

Return to drug safety

The FDA also will need to make changes, particularly by returning its focus to drug safety, say Anthony T. Dren, PhD, consulting professor and George "Trey" Turner, BScPharm, MA, RAC, assistant clinical professor in clinical research management program at Duke University School of Nursing.

"It’s a very difficult situation because a few years ago the FDA really was being faulted for not approving new drugs, and there was a shortage of new products coming on the market in the U.S. vs. Europe," Dren says. "So the funding has gone to the new drug approval area and not on the drug safety area."

This shift has resulted in some slack in the evaluation of long-term safety and a shortage of personnel in that area of the FDA, Dren adds.

After the Prescription Drug User Fee Act, which gave the FDA fees from drug companies to help expedite the review process, was passed in 1992, Congress cut back FDA funding, which shifted resources away from the area that conducts post-market surveillance, Turner says.

"Drug companies point to the $800 million cost of bringing a new drug to market," he adds. "What I’d like to see is some commitment by the people profiting from the drug to support an agency that would do long-term follow-up."

One way to do this is through long-term clinical trials, but they’re large and expensive and include multisites that are costly to track, evaluate, and record, Turner says.

However, if the FDA was given adequate funding for post-market surveillance and long-term tracking, some of the current problems might be avoided, he notes.

"Ongoing monitoring is more important now than ever before because of the direct-to-consumer marketing [by drug companies] that in the past didn’t exist," says Ellen Hyman-Browne, JD, MPH, director of research compliance at the New York University School of Medicine in New York City.

"I’m not a physician, but I assume that doctors feel under some degree of pressure to satisfy the request of their patient for a particular drug," she says.

Also, there is a growing public sentiment that the FDA and its mission have been adversely influenced by the pharmaceutical industry, Koski says.

"There have been concerns raised about the FDA advisory committees that are an important part of overall safety and efficacy reviews," Koski notes. "And the industry seems to have a strong influence within those committees by virtue of the fact they often have consulting relationships and other types of financial or nonfinancial relationships with actual members of those committees."

While these relationships are not necessarily evil and while there are many individuals involved who have a high degree of integrity, the problem is the system, which needs a greater measure of accountability, Koski adds.

Will database improve safety?

One way to restore accountability is through the use of a clinical trials database, Koski and Dren say.

"This will help alert practicing clinicians that there are studies that have been done and they should at least ask about the outcome," Dren adds.

With such a register or database, then no one would be able to hide the existence of clinical trials in which the outcomes were unfavorable, Koski says.

Medical journal editors have begun to push the clinical trial industry for a public register, and in early January 2005, the pharmaceutical industry announced its plans to publish detailed information about all clinical trials, except for Phase I trials.3

The exact form, location, and management of a clinical trial database are big issues, Koski says.

"There are tens of thousands of clinical trials going on around the world and how you actually coordinate the collection and review and deposition and processing of that information is not a trivial problem at all," he says. "It’s easy to say, Let’s have a database,’ but to have a properly constructed database that would have data available in a way that’s meaningful and not have it misused is a very large logistical problem, and we’re not there yet."


1. FDA issues public health advisory recommending limited use of COX-2 inhibitors. FDA Talk Paper. Dec. 23, 2004. Web site:

2. Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Public Health Advisory. Oct. 27, 2003. Web site:

3. Hirschler B. "Drug industry agrees to disclose more trial data." Jan. 6, 2005.