In giving its unanimous backing to the safety and efficacy of HRA Pharma's emergency contraceptive Ella (ulipristal), FDA's Reproductive Health Drugs Advisory Committee wanted to make sure that pregnancy tests and other risk management measures that members deemed unnecessary would not get in the way of patients using the product.

"Because it's going to be a prescription drug, if a patient walks into a doctor's office and asks for emergency contraception, the physician will test if she is already pregnant first. But I don't want to add that as a requirement and create an undue burden," Valerie Montgomery Rice, Meharry Medical College School of Medicine, said. "Instead, we should reach out to providers to try to get information into a registry."

"We should be very clear that a pregnancy test is not required so it does not become a point of indication with this medicine," Julia Johnson, University of Massachusetts Medical School, said.

Comfortable With The Existing Data

Unusually for an advisory committee review of an NDA - and a new chemical entity at that - there was very little discussion after the separate 11-0 votes in favor of Ella's safety and efficacy and few reservations expressed.

The clinical data were "adequate and showed that if ulipristal is taken within 120 hours after intercourse, it would be effective," Montgomery Rice said.

A partial dissent came from Scott Emerson, University of Washington, who had earlier said that "very little data" supports the drug's efficacy in preventing pregnancy up to 120 hours after intercourse, and that which does exist comes from "a single-arm uncontrolled study." That is Study 509, an open-label Phase III trial that evaluated whether a single 30 mg dose of Ella prevented pregnancy.

However, Emerson did vote yes on efficacy in the end, "with the proviso that the 120 hour data was not as strong as it could be and came from a single trial."

Three panel members who voted along with the rest that Ella is safe added qualifications for the record about the need to gather more data.

"I voted yes with the proviso that we don't have enough information on risks in pregnancy yet," said John Kittelson, University of Colorado-Denver. Examining what could happen to the woman and unborn fetus if the product fails to prevent pregnancy can be "handled through pharmacovigilance," he said.

"We also need information on the use of combination hormones with this drug," Kathleen Hoeger, University of Rochester Medical Center, suggested.

There is no data on use of Ella in lactating mothers, and the drug should not be prescribed to them, committee chair Sandra Carson, Warren Alpert Medical School of Brown University, said.

Filling those kinds of gaps in the data through post-marketing efforts would likely present a significant challenge for the company, especially if the product is approved without a restrictive risk management plan that could enhance data capture (see ¹ Also see "Post-Marketing Study Of Emergency Contraceptive Ella Would Be Challenging" - Pink Sheet, 21 June, 2010.).

The panel was unconcerned about off-label use, voting 11-0 that there is no "need for measures beyond product labeling/healthcare provider education to address potential off-label use of ulipristal."

Reduced Efficacy In Overweight Women

The only split in the advisory committee came over the question of whether the drug labeling should include any recommendations on use in specific subpopulations - particularly women with a body mass index greater than 30 kg/m, in whom the clinical trials showed evidence of reduced efficacy.

FDA had not actually asked for a vote on this question, but Carson called for one to "clarify" matters. Five members said the drug's labeling should include such recommendations for subpopulations, while six said it should not.

As with the risk management issue, those who voted no weren't denying that the drug showed less efficacy in heavier women, but were concerned that adding recommendations on this point to the label would be interpreted as a contraindication for use in such women.

Putting such a recommendation in the label would "create an unfair implication" about Ella as compared with Teva's Plan B (levonorgestrel), Melissa Gilliam, University of Chicago, said.

Arguing the other side, Diane Aronson, the acting consumer representative on the panel, stated, "More consumer information is good. There could be language to compare it with other drugs."

Similarly, Johnson said, "We have this information and need to provide it to women on the effect of weight. I want to give positive feedback to the manufacturer for examining the BMI issue, and I hope others will do the same in the future."

The issue is "interesting and needs further research, but is not ripe for labeling at this point," Kittelson said. Carson added that HRA should look at dosing data since it could be that an increased dose would help overweight women.

- Martin Berman-Gorvine ( ² m.berman-gorvine@elsevier.com)

Emergency Contraceptive Ella Needs Minimal Risk Management, Panel Says

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