Washington Editor

WASHINGTON - When a drug company asks the FDA to clear a product for marketing, the parties often agree that the company will conduct a postmarketing, or Phase IV, study.

So the company gets clearance and subsequently begins pumping its drug into the market. Meanwhile, the FDA goes back to work and the two never meet again unless serious problems surface with the drug.

At least that's what one member of the House of Representatives contends.

Rep. Bart Stupak (D-Mich.) had the chance to question Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER), in reference to the agency's practices regarding the tracking of Phase IV studies.

Stupak said that in the drug approval process, companies volunteer to conduct Phase IV studies or are ordered to conduct them, but then don't.

He asked Woodcock if she could recall a time when a product was pulled from the market because of a company's failure to finish a Phase IV. Her answer was "no."

And there's a simple reason why - the FDA doesn't have that kind of authority. However, the agency does have the ability to flex its muscles in others ways, for example, embarrassing a company into compliance.

Beginning in October, as part of the Food and Drug Administration Modernization Act (FDAMA) of 1997, the FDA will help consumers get a clearer picture of who is doing what in postmarketing studies when the agency initiates its annual report on industry performance in this area. The report will be available in the Federal Register, and already it has its critics.

"We are talking about putting out a public inventory of what studies are and the status of the studies, which is a way of shaming the companies into doing them," William Vodra, a partner with the Washington law firm Arnold & Porter, told BioWorld Today. "There was a proposal to actually impose criminal penalties on the companies or monetary fines. But I think the companies have rightfully said that some of these studies are not doable for a variety of reasons."

Operating Without Authority

The first Phase IV study was requested back in 1970 as part of the approval agreement for L'Dopa, a drug considered a breakthrough in the treatment of Parkinson's disease. In the late 1980s, AZT for AIDS was approved in a similar fashion - that is, without Phase III data, but with a commitment for additional studies.

Fast-forward to May 1996 when the Office of the Inspector General issued a report saying the FDA had limited resources available to police postmarketing studies and could not enforce compliance.

Indeed, the FDA couldn't enforce compliance because the agency didn't have the statutory authority to require the trials, Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development in Boston, told BioWorld Today.

So FDAMA in 1997 gave the agency that authority, but failed to grant the agency power to penalize. Kaitin said sooner or later the FDA may get that power. "You're talking about an industry that has very strong profit goals and is under tremendous competitive pressure. What in the world is the incentive for a firm to do a study if they know that nobody has any authority to do anything about it if they don't do the study? The FDA definitely needs some teeth."

If the FDA gets teeth, then the industry gets something too - an appeals system.

"One of the things I know from previous clients is that some of these studies, while they are elegant and interesting, are difficult to get done. Not because it is hard to design the study, but because they can't get researchers interested in them," Vodra said. "Academic researchers want to move on to new compounds."

Also, Vodra said, often the information being sought in a Phase IV can be found in other data.

For example, "Let's say someone found out in the first year that a drug was unsafe for pregnant women. Then don't give it to pregnant women. You don't need a registry of 3,000 women to answer that question. You already have the answer," Vodra said.

The FDA says that most companies volunteer to conduct Phase IV studies, many times to expand a label.

In a recent report to Congress, the FDA cited postmarketing studies associated with interferon alfa-2b (Intron A), a product of Madison, N.J.-based Schering-Plough Corp. The biologic was initially approved to treat chronic hepatitis C with a six-month treatment regimen, but postmarketing studies showed that treatment for at least 12 months provided a higher rate of efficacy, doubling the number of patients obtaining benefit from the product, the FDA said.

Power Created By FDAMA

The FDA says it usually requests a Phase IV if it concludes that additional information is important to improving the prescription and use of the product, product quality or consistency in product manufacturing. (Mandatory postmarketing studies are required on fast-track products and for products in which safe use in children needs to be determined or more clearly defined.)

Before FDAMA, John Jenkins, director of the Office of New Drugs for CDER, told BioWorld Today that part of the problem associated with Phase IV studies is related to the agency's failure to clearly define requirements for the companies. "[The regulations] often were written in a fairly vague manner and they usually did not state a completion date so it is hard to assess in many cases what the intended time frame was in many of these old commitments. We now have guidance for our staff on how to write these commitments and we always include dates that are projected for when the study will be complete - that gives a better ability to say whether something is on schedule or overdue."

The upcoming annual report published in the Federal Register will include information such as the total number of drug applications approved with postmarketing commitments as well as the number that have been completed in the previous year and the status of the others.

The FDA has a long history of requesting that postmarketing studies be performed when there is reason to believe additional studies would improve how the product is used. From 1991 to 2000, the agency approved 163 biologics license applications, 79 of which had at least one postmarketing commitment. Those BLAs, combined with supplemental applications received during this period, generated 927 postmarketing commitments. Of that number, 193 commitments addressed clinical safety and efficacy studies and would be subject to status reporting under FDAMA.

During those same years, from 1991 to 2000, the agency approved 1,090 new drug applications. Those NDAs plus supplemental applications generated a total of 2,328 postmarketing commitments. Of them, 1,737 commitments addressed clinical safety and efficacy and would be subject to status reporting under FDAMA implementation.