SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel recommended against approval of an 8% vaginal formulation of progesterone gel for use in reducing the risk of preterm birth in women with a short cervix.
The Reproductive Health Drugs Advisory Committee on Jan. 20 voted 13 to 4 that the product did not have an acceptable risk-benefit profile and that the manufacturer had not provided sufficient evidence to conclude that the gel reduced the risk of preterm birth in women with a singleton gestation and a short cervix at mid-trimester – the proposed indication.
Panelists were not concerned about safety. But those voting against approval said that while they agreed the treatment appeared to have potential and recognized the need for such a product, they were not convinced that it had been shown effective in the pivotal, international study. The overall results were not robust enough to convince them the treatment was effective in reducing preterm birth, they noted, adding that no benefit was seen in the study participants from the United States.
The study compared progesterone gel 8% with placebo, administered daily, in 450 women with a short cervix (1.0-2.0 cm). All women had singleton pregnancies and enrolled from 19 to almost 24 weeks’ gestation. The rate of preterm birth before 33 weeks’ gestation, the primary end point, was 8.9% among those randomized to receive the gel, compared with 15.2 % among women randomized to placebo. This was a statistically significant difference that represented a 44% reduction in risk, according to the manufacturer, Columbia Laboratories Inc.
In the subgroup of women enrolled in the United States, however, the differences between the two groups in the preterm birth rate was not significant (16.8% in the gel group vs. 19.2% in the placebo group) – a major concern raised by the FDA reviewers. The overall compliance rate among the U.S. women was lower than among those enrolled internationally (23% vs. 2%), which the company said could have affected the results.
The FDA analysis, which adjusted for different factors, did not find a significant effect of the gel in reducing the risk of preterm birth, and raised concerns about the generalizability of the results to the U.S. population and variations of the treatment effect in different countries.
The product is a bioadhesive formulation of progesterone packaged in a prefilled, single use vaginal applicator that delivers 90 mg of progesterone. It has been on the market since 1997 and is approved for use in treating infertility in women with progesterone deficiency; it’s also approved as a treatment for secondary amenorrhea in women who have not responded to a 4% formulation. (For these indications, it is marketed as Crinone, by Watson Pharmaceuticals, which is in a partnership with Columbia Laboratories).
Currently, no product is approved for reducing preterm birth in women with a short cervix, a well-recognized predictor of preterm birth. Last year, an injectable progesterone formulation, hydroxyprogesterone caproate (Makena), was approved to reduce preterm birth in women with a singleton pregnancy who have a history of spontaneous preterm singleton birth. That product has been controversial because of its extremely high cost.
The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting. Occasionally, a panelist may be given a waiver, but not at this meeting.