FDA and its Reproductive Health Drugs Advisory Committee could not agree on the shape that post-marketing surveillance of HRA Pharma's emergency contraceptive Ella (ulipristal acetate) should take.

Ulipristal was approved by the European Commission in May 2009 under the brand name ellaOne (¹ 'The Pink Sheet,' May 27, 2009). The drug's year-long post-market track record probably eased the way for the panel's unanimous recommendation that FDA approve the drug (see ² Also see "Emergency Contraceptive Ella Needs Minimal Risk Management, Panel Says" - Pink Sheet, 21 June, 2010.).

FDA asked panel members to discuss two post-marketing requirements and two other risk management measures. The post-marketing requirements would be for HRA to expand to the U.S. the pregnancy outcomes study it is planning in Europe, for which the company is recruiting 1,000 physicians in different countries to obtain clinical follow-up information on pregnancies that develop despite the patients taking ulipristal, and to conduct a retrospective survey of hospitals and providers to identify cases of incomplete pregnancy loss following the use of ulipristal.

Those requirements seem a bit heavier than the ones for Teva's Plan B (levonorgestrel), likely reflecting ulipristal's status as a new molecular entity. Plan B did not appear to have any post-marketing requirements when it was approved in 1999, and when it was switched OTC for adults in 2006, the sponsor agreed to conduct its own surveys and use CDC data to ensure that the age restrictions were being followed and the product was being used appropriately.

Case Control A Point Of Contention

During Ella's review, committee members expressed aversion to FDA's proposed risk management measures: labeling to recommend pregnancy testing prior to dosing and pharmacovigilance monitoring of spontaneous reports for pregnancy outcomes.

As for monitoring spontaneous pregnancy reports, Scott Emerson, University of Washington, quipped, "That just means that 'I won't plug my ears if you happen to tell me.'"

Data collection would have to be more systematic than that implies, he said. "If we want to gather data on the pregnancies, we have to realize we have this very strange denominator, which is people who didn't want to become pregnant, and if they did become pregnant, terminate the pregnancy anyway." Therefore, he suggested "surveillance of identified providers who are giving you information and then perhaps going to a case-control-type setting within that context."

The idea of a case-control study received backing from John Kittelson, University of Colorado-Denver, but such a setup might not provide enough information either, Scott Monroe, director of FDA's Division of Reproductive and Urologic Products, warned.

The agency shares Emerson's concerns about how to get "a good estimate of the denominator as well as the numerator, and the problems of following up on those situations where nothing unfavorable occurs," Monroe said.

The problem with a case control study is that it "would involve a fairly long delay, because you have to gather enough cases to do that, and then you're only thinking of a subset anyway," Monroe added. In Europe HRA has identified about 1,000 physicians who are willing to provide "both good and bad outcome data, although I think the ability to track the outcomes in these situations will be challenging."

Post-marketing surveillance has built-in problems, Monroe said. "Physicians are certainly more inclined to report information when something unfavorable occurs. Without full disclosure it's going to be difficult to interpret. However, sometimes these data, as crudely as they may be collected, if something qualitative occurs which is a rare type of event and we have the information, it may give us a signal. So we do recognize it has limitations."

"While pharmacovigilance monitoring of pregnancy outcomes is problematic, no further measures are required," committee chair Sandra Carson, Warren Alpert Medical School of Brown University, said in summing up the discussion. "We were happy with the planned expansion of surveys and post-marketing requirements to the U.S."

- Martin Berman-Gorvine ( ³ m.berman-gorvine@elsevier.com)

Post-Marketing Study Of Emergency Contraceptive Ella Would Be Challenging

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