Stephanie Fox-Rawlings, PhD, National Center for Health Research, October 29, 2019
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings, the Center’s Research Manager. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
The mortality and morbidity associated with preterm birth is a serious issue, which puts children at risk for long-term developmental problems. Treatments that decrease risk for preterm birth and improve neonatal outcomes are needed, but any drug given for this purpose must accomplish this purpose without undue risks. Based on the evidence being discussed today, there is not consistent evidence that Makena does this.
When the FDA approves a drug, even if based on accelerated approval, there is a lot of pressure to keep it on the market regardless of post-market data. But in this case, there is no evidence that this drug decreased neonatal death or morbidity – which are the most important outcomes and the outcomes required for full approval. Although the first study showed a statistically lower rate of births before 37 weeks — from 55% to 37% — that could still have occurred by chance. In the confirmatory study, the rate of births before 35 weeks was 11% instead of 12% and a similarly small difference for births before 37 weeks, which was not statistically significant and would not have been sufficient to merit approval. At the same time, there were about twice as many stillbirths for babies whose mothers took Makena: 2% vs 1% in the first trial and 1% vs 0.5% in the confirmatory trial.
FDA’s reputation depends on admitting when a promising new treatment is later found to not be so promising. The purpose of an Advisory Committee meeting is to provide objective advice –to encourage the FDA to stick to the science and admit when there is not evidence that the benefits outweigh the risks for a product. Such is the case with Makena.
At most Advisory Committee meetings, the sponsor has recruited clinicians and/or patients to speak on behalf of their product. As scientists, physicians, and patient and consumer representatives, please keep in mind that just because a patient has a good outcome after using a medical product, it does not mean that the medical product caused that good outcome.
As you already know that randomized, double-blind, controlled clinical trials give us a more accurate assessment of whether a product works than anecdotal information, however heartbreaking or compelling.
Makena may possibly reduce preterm births for some pregnant women who have previously had a spontaneous preterm birth. However, with the conflicting results in the two studies, the sponsor needs to determine if there is a subgroup of pregnant women who are likely to have benefits that outweigh the risks – and if so, to be able to define that group for an indication. But the benefit has to be clinically meaningful: The sponsor needs to demonstrate a clinically meaningful impact for neonates, such as improve survival or health outcome. Unless the sponsor can do these two things, then approval for this product should be rescinded.
Thank you.
The Bone, Reproductive and Urologic Drugs Advisory Committee voted on three questions related to Makena. The first question asked if the confirmatory trial found an improvement in health for newborns. This was required because the drug was approved based on the expectation that reducing preterm birth would improve the health of newborns. The committee voted unanimously that it did not. The second question asked if Makena reduced the risk of repeat preterm birth and 13 Committee members voted that it did not compared to 3 that voted that it did. The final question asked whether the drug should remain on the market, with or without additional studies. Nine Committee member voted that it should be removed from the market, and 7 voted that it should remain on the market but that more studies on its efficacy were needed. None of the committee members voted that it should remain on the market and that new studies were not needed.