FDA Clears Drugs With Post-Market Safety Questions Faster Than It Re-labels

FDA's "¹ early communication" program for alerting the public about potential drug safety issues produces a clean bill of health for products about 40 percent of the time, according to an analysis by "The Pink Sheet." And those positive decisions come much quicker than labeling changes the program has produced for drugs where genuine concerns have emerged.

FDA took an average of just under seven months to complete preliminary or final analyses in cases where it concluded that safety risks for the drugs in question did not exist.

In the cases where FDA's examination led it to conclude that safety labeling changes were warranted, the agency took an average of 15 months to make the request.

Of course, there are exceptions: FDA had already completed its data analysis for Novartis' Xolair when it issued an early communication which notified the public that a boxed warning was being requested because of the risk of anaphylaxis.

A Frequently-Used Program

Altogether, FDA has released 22 early communications on safety issues encompassing a total of 43 drugs, and has taken 11 actions (see chart: " ² FDA Early Communications About Ongoing Safety Reviews ").

In actions so far, FDA has found four instances in which data failed to support a linkage to the adverse event in question, five in which labeling changes were warranted, one in which a drug needed to be withdrawn (Bayer's Trasylol ), and one in which the agency affirmed the utility of the endpoint used in the product's pivotal trials (Merck's Vytorin ).

The shortest timeframe for clearing the safety issues was four months. AstraZeneca's Prilosec and Nexium , which were the subjects of the first early communication, have so far also been the fastest questions resolved.

The outlier in clearances was the 13 months needed to determine that there no clear association between bisphosphonates and atrial fibrillation based on the data at hand. In that case, FDA reviewed placebo-controlled trial data for 10 drugs.

Formally known as "Early Communication About An Ongoing Safety Review," the program was launched in 2007 to replace the Drug Watch Web site (³ (Also see "Prilosec/Nexium Alert Is Debut Of FDA’s Early Communication Of Safety Issues" - Pink Sheet, 13 Aug, 2007.)). The announcements advise health care providers and the public that safety concerns have been raised by new data and the agency is reviewing the information.

Many sponsors felt that the early communications would inappropriately suppress prescriptions and utilization by patients who might need the treatment. While some products have seen sales decline after the announcements, others generally were unaffected. The severity of the potential risk in question and the prominence of the drug in the public consciousness appear among the factors governing the market impact of FDA safety announcements ("⁴ Communication Conundrum: Is Early Drug Safety Disclosure Better?," The RPM Report, October 2008).

Opportunities For Sponsors

For sponsors, the fact that FDA seems to clear drugs relatively quickly allows them to provide positive messaging shortly after there have been concerning reports about the products. Still, seven months can feel like a long time to be in that kind of limbo.

For drugs that eventually get labeling changes, sponsors can take some solace from the fact that since the evaluation time was longer, it was not a hasty decision. And for those wondering what the fate of their product might be following an early communication, it might be fair to predict they'll have to wait longer for bad news.

One of the driving factors behind the early communication program was concerns raised in the wake of the Vioxx withdrawal that FDA often was aware of safety issues with a product well in advance of the labeling being updated to inform patients and practitioners.

The current labeling format itself is being discussed as the best medium for offering useful information about risk trade-offs (see sidebar: " ⁵ Can FDA Ambiguity Improve Drug Labeling? ").

- Cathy Dombrowski ( ⁶ [email protected] )