Will We Ever See 17-P for PTB?

On August 31, I posted a note entitled "Preterm Birth: An American Tragedy." In that post, I reported that Adeza Biomedical Corp. had filed application with the FDA to have exclusive rights to the production of 17-hydroxy-progesterone caproate ("17-P"), a synthetic progesterone that had been shown to reduce preterm birth rates by about one-third in 'high risk' women with histories of preterm deliveries. Over the past few years, Adeza had been supplying the drug to pharmacies which were then compounding the formulation and selling it to providers at a fairly reasonable cost. My immediate concern was that if Adeza got exclusive rights to production and distribution, the cost of the drug would skyrocket. On the other side of the coin, they would also then be held to higher quality standards of production and probably assume a large share of the liability that could be incurred by unexpected deleterious side-effects of its use.

Adeza announced today that the FDA had determined that "Gestiva (TM)...is approvable subject to the completion of an additional animal study..." to assess the safety of 17-P. The primary reason for this is that in the sentinel placebo-controlled trial, there did appear to be a slightly higher rate of fetal loss in the 17-P group during the first two months of administration of the drug (Meis P, et al., NEJM. 2003; 348:2379-85). Interestingly, an animal study published almost 20 years ago also demonstrated a dose-response embryolethality, but not teratogenicity (i.e., killed fetuses, but did not cause birth defects) with long-term in utero administration of 17-P to pregnant rhesus and cynomolgus monkeys at doses ranging between 0.1 and and 10 times the "human therapeutic dose" (Hendrickx AG, et. al., Teratology 1987;35:129-136). An explanation for the higher rate of fetal wastage was not determined.

It is also interesting to me that the FDA has requested another 'animal study' and not another clinical trial in humans. The FDA usually requires two adequate and well-controlled clinical trials proving efficacy of a drug before granting approval for a specific indication. The only adequate trial to date performed in the U.S. has been the one mentioned above, and that was aborted prematurely (now isn't that ironic) because the investigators felt that it was unethical to continue the trial in view of the efficacy demonstrated at the time of an interim analysis of the data. With the new questions that have been raised regarding fetal wastage, if that should again be confirmed in another animal study, will the FDA then require another large clinical trial in humans before we can hope to see 17-P on the market???? The last one took several years to complete. And what will the cost of any further trials add to the final cost of the drug???? Guess we will have to wait and see....

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