FDA Bulks Up in 2008: part 2

Dolly A. Judge, Pfizer Vice President of Federal Government Relations, says:

I think more interactions are better for drug safety management purposes. But I know the optics of the industry and agency meeting more frequently is not necessarily better politically. Senator Grassley and others have been critical of the relationship between industry and FDA, so more meetings could further enhance a false perception that the relationship is too close or somehow it is unholy, so to speak.

Certainly, the FDA has met with drug company representatives in the past, both before and after drug approvals, but the agency’s leverage has been limited. In the past, for example, the CDER’s negotiations with a company like GSK about adding or upgrading a warning about heart attacks to a drug like could go on for years, as happened with Merck and its pain reliever rofe-coxib (Vioxx), for example. It has been happening, apparently, with Avandia in the wake of the publicity around Dr. Nissen’s article and an FDA advisory committee meeting last summer.

In the past, the only power the FDA had in ordering a label change, after a drug went on the market, was to threaten to force a company to take the drug off the market. The FDA rarely used that authority, because such an action might have hurt patients already taking the drug. The FDAAA sets up a quicker pathway for making label changes. With the new step, the company and the FDA would move quickly through a process of proposals and counterproposals. If there is no agreement, there is a time limit for ending the company’s appeals and forcing it to make changes dictated by the FDA. Normally, these negotiations would last no longer than 120 days and might be substantially shorter.
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Why have these labeling discussions taken so long? Part of the reason is the absence of clinical trial data; this lack has fostered much uncertainty. Again, when the FDA approved Avandia in 1999, the drug was considered a real benefit for patients with type-2 diabetes. At that time, the FDA knew that adverse reactions might be a problem, but it had little leverage to force GSK to conduct a major postmarketing clinical trial directed at pinning down the risk of a heart attack.

Because of the cost of clinical trials, GSK had little incentive to undertake such a trial on its own. Subsequently, many small studies were performed on Avandia medication, but heart attack was not an endpoint in any of them. This series of events led to Dr. Nissen’s hysteria-promoting article in May 2007.

Under the FDAAA, the FDA can force a study or a clinical trial in conjunction with a new drug approval if the scientific data are deemed appropriate. That authority has been absent in the past. A study can be ordered (1) to assess a known serious risk, (2) to evaluate signals of serious risks, and (3) to identify an unexpected serious risk when the available data indicate the potential for such a risk.

If any of these three objectives can be achieved by the active postmarketing risk-identification and analysis system, which this bill charges the FDA to set up, the agency cannot order a study. A clinical trial can be mandated only when a study cannot accomplish the three objectives. The pharmaceutical company sets the timetable for completing the study or trial. If those deadlines are missed, the FDA can levy civil penalties. canadian antibiotics

The FDAAA allows the FDA to fine a company $250,000 for missing a deadline by 30 days; that fine is doubled every 30 days until it reaches $1 million. The FDA has this same authority to impose a penalty if a company fails to make post-approval label changes after the FDA mandates them.

The FDA’s authority to order post-approval studies and clinical trials is constrained somewhat by the need to consider whether it can obtain the information it needs from the new ac­tive postmarketing risk-identification network. With this new network, the FDA would link up with databases currently established by the Department of Veterans Affairs, the Centers for Medicare and Medicaid Services, and by private health insurers.

The new network will supersede MedWatch (the current system for reporting adverse reactions); however, this system is considered almost useless. MedWatch depends on reports from health care providers and individuals. Unfortunately, duplicate reports are often filed. Moreover, the FDA must then go back and interview those who sent in reports. All of this takes an enormous amount of time. Even after this step, the agency has no “denominator” (hard facts on how many other patients had the same adverse reaction, much less how many people are taking the drug).

With the new postmarketing database, those data will no longer be available from MedWatch; the FDA will be able to go into the database and look for trends (e.g., cardiovascular events tied to a particular drug). Setting this network up is going to take time, though. The FDA will have two years to develop the data sources. By July 1, 2010, at least 25 million patients must be in the database; by 2012, 100 million must be included. On its own, the FDA had already awarded contracts in this area. The new user fees for drug safety, flowing into the CDER budget starting in fiscal year 2008, will allow the FDA to accelerate its efforts to meet the timelines in the FDAAA. Although FDA officials claim that they will be able to meet those deadlines, this new network might cost considerably more than what the FDA will have in user fees to pay for it.


So Many Advances in Medicine, So Many Yet to Come