FDA wants to ensure that postmarket trials get done

Have you ever wondered which nonsteroidal anti-inflammatory drug is the best choice for elderly patients with osteoarthritis? Are there risks associated with the long-term use of benzodiazepines to treat panic disorder? How do some asthma medications interact with the other pharmaceuticals? Or how does a certain drug affect women who are pregnant or patients younger than 18?

These are the kinds of questions that the Food and Drug Administration hopes will be answered when it requests a postmarketing study. These investigations, which are conducted after a drug or biologic's approval, are usually triggered by suspicions that their results could protect patients and further guide physicians in treatment decisions.

The answers, however, are a long time coming -- if they arrive at all. And the FDA is now stepping up efforts to ensure that this research, also known as phase IV studies, gets done.

According to recent FDA tracking reports, including one issued last month, a few hundred of these trials are finished each year, but hundreds more may be falling through the cracks. Meanwhile, a review of the agency's postmarketing commitment database found a multitude of uncompleted inquiries.

"We fully intend to work with sponsors to make sure these important commitments get completed," said FDA Deputy Commissioner for Medical and Scientific Affairs Scott Gottlieb, MD, in a Feb. 8 speech to the American Enterprise Institute in Washington, D.C.

But seeing this challenge through will require the FDA and the industry to address a number of technical and systemic barriers.

Addressing the stumbling blocks

Recognition is growing, for instance, that it may be possible to make the regulatory system more conducive to getting these done. The agency intends to establish a committee of people from outside the FDA to evaluate what obstacles exist to this research and how these issues can be addressed. The results of this review are expected in about a year.

The American Medical Association viewed this development as a positive step that will help improve the overall system that monitors pharmaceuticals once they hit the market.

"Companies that commit to doing phase IV studies ought to complete them," said AMA Chair-elect Cecil B. Wilson, MD. "We encourage looking at ways to make them happen." The Association issued a report on physician access to FDA data last June and called for adequate funding to improve postmarketing prescription drug surveillance.

Experts acknowledge, though, that some hindrances are already evident. The biggest, they say, is that these trials are often devised at the time of approval instead of earlier in the process. This lack of forethought may contribute to difficulties with patient recruitment, which becomes more challenging after a drug hits the market. Also, many of the requested studies examine how drugs behave in very specific populations thereby adding another layer of complexity.

"A lot of times you intend to do a study and you just cannot enroll," said Raymond Woosley, MD, PhD, president and CEO of the C-Path Institute, a Tucson, Ariz.-based group established to help the FDA implement its Critical Path Initiative, a program that seeks to increase the speed at which drugs move through the development and approval process.

The FDA also notes that many of the requested studies become irrelevant or impossible because of changes in the medical landscape. The drug may have been supplanted by another, more preferred medicine, or it may no longer be used in the manner initially outlined. According to the FDA's most recent annual postmarketing study report, about 14% of studies concluded between October 2004 and September 2005 were no longer necessary or feasible.

"We really need a thoughtful process before locking people into these commitments that may or may not be relevant," Dr. Woosley said.

But for some, the answer is to change what is sometimes viewed as the most obvious shortcoming: a lack of penalties for not completing the study. Currently, the FDA's only punitive option is to pull a drug off the market. Most say this is usually not workable because it could take a drug away that may be helping people.

"There needs to be some sort of civil and monetary penalties, and they ought to be huge," said Sidney Wolfe, MD, director of Public Citizen's Health Research Group, a Washington, D.C., advocacy group.

But pharmaceutical companies countered that, although numerous studies are considered "pending," they are still on schedule. An industry spokesman said companies take postmarketing commitments seriously and intend to complete them.

"Pending does not mean delayed," said Alan Goldhammer, PhD, associate vice president for scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America. "It does mean that the immense and vitally important tasks of developing research protocols, finding investigators and researchers and even recruiting patients to participate in the study is in process."

Physicians maintain, though, that these studies are crucial, and that strategies need to be developed to eliminate the barriers to getting them finished as quickly as possible.

"All physicians need to know is if their patient is on a drug that has an increased risk of an adverse effect and if there are alternatives that are safer and less costly," said Jerry Gurwitz, MD, executive director of the Meyers Primary Care Institute at the University of Massachusetts Medical School in Worcester. "We want to know what the best choice is for our patients."