Health Letter, December 2021
By Michael Carome, M.D.
The Food and Drug Administration (FDA) must make certain that the advisory committee for a planned hearing that will consider whether the agency should withdraw approval for the drug hydroxyprogesterone caproate — an injectable drug marketed under the brand name Makena and in several generic versions to reduce the risk of preterm birth — is fairly balanced to ensure the integrity of the hearing process and public trust in the committee’s advice, Public Citizen said in an Oct. 27 letter to the agency.
The letter urged the FDA to reject the proposal from Covis Pharma GmbH, the current manufacturer of Makena, to essentially stack the jury in its favor by significantly expanding the agency’s Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) roster for the hearing with individuals whom the company believes will be sympathetic to its view that Makena should remain on the market.
About hydroxyprogesterone and preterm birth
Hydroxyprogesterone is a synthetic hormone that was approved by the FDA in 2011 for the prevention of preterm birth in certain women with a history of spontaneous preterm birth. The drug is administered once a week beginning at 16 weeks of gestation and continuing until 37 weeks of gestation. It can be self-administered with an autoinjector.
Preterm birth, which is defined as birth prior to 37 weeks of gestation, is a significant public health problem that affects one out of every ten infants in the U.S. It is a complex disorder that most often occurs spontaneously. Black race, low or high maternal age, infections, carrying more than one fetus (twins, triplets or more), smoking and late prenatal care are just some of the many risk factors associated with preterm birth. Babies born too prematurely may experience lifetime disability, developmental delays and even death.
FDA’s accelerated approval of Makena
The FDA approved hydroxyprogesterone in 2011 to reduce the risk of preterm birth under a process known as accelerated approval. This process allows the FDA to fast-track the approval of a new drug that has been studied for safety and effectiveness in treating a serious or life-threatening disease or condition and that is likely to provide meaningful clinical benefits to patients over existing treatments.
Using the accelerated approval process, the FDA can approve a drug based on its effect on a surrogate endpoint or outcome that is considered reasonably likely to predict meaningful clinical benefit. But for a drug approved under the accelerated approval pathway, the FDA can require that the manufacturer conduct another trial after approval (known as a postmarket trial) to verify that the drug does have meaningful clinical benefit. If the required postmarket trial fails to show such benefit, the FDA can withdraw approval of the drug.
The FDA’s 2011 accelerated approval of Makena was based largely on evidence from a single randomized, placebo-controlled clinical trial that enrolled 463 women at 19 medical centers in the U.S. and was rife with flaws. Results of the trial, which was funded by the National Institutes of Health (NIH), were published in 2003 in the New England Journal of Medicine. The NIH-funded trial found a significant decrease in the rates of preterm births prior to 37 weeks of pregnancy in women who received hydroxyprogesterone compared with those who received placebo.
However, an FDA statistical expert raised serious concerns about the design and conduct of the NIH-funded trial. For example, the statistical expert noted that the trial was not designed for drug approval and that preterm delivery before 37 weeks of pregnancy was not an appropriate surrogate endpoint to establish whether the drug is effective for reducing the rate of fetal and neonatal (newborn) health problems and death — the key meaningful clinical outcomes related to preterm birth. The statistical expert repeatedly opposed approval of Makena because data from that trial had failed to provide convincing evidence that the drug was effective.
Moreover, a large majority (16 of 21 members) of an FDA advisory committee that was convened in 2006 to consider whether the agency should approve Makena concluded that a reduction in preterm birth before 37 weeks of pregnancy was not an adequate surrogate endpoint for predicting a reduction in fetal and neonatal (newborn) health problems.
Despite these concerns, the FDA eventually approved Makena but required that the drug’s manufacturer complete a larger randomized postmarket clinical trial to confirm that the drug provides clinically meaningful benefit.
Postmarket trial fails to show any benefit
The FDA-mandated postmarket clinical trial, which was not completed until more than seven years after the drug was approved, failed to demonstrate that Makena provided clinically meaningful benefit. The trial, dubbed PROLONG, enrolled 1,708 pregnant women with a history of spontaneous preterm birth, 75% of whom were from outside the U.S. The postmarket trial’s design was similar to, but significantly better than, that of the preapproval trial. Notably, the trial’s primary endpoints were preterm birth before 35 weeks of gestation and, most importantly, an overall measure of neonatal health problems and death.
On March 8, 2019, AMAG Pharmaceuticals, the manufacturer of Makena at the time, announced the key results of the PROLONG trial: there were no statistically significant differences between the hydroxyprogesterone and placebo groups in the rate of preterm birth prior to 35 weeks of gestation or the rate of overall neonatal health problems and death. The study also did not find any differences between the two study groups in the rates of other adverse pregnancy outcomes, such as miscarriage and stillbirth, or the rates of preterm birth before 32 or 27 weeks of gestation.
Public Citizen’s petition and testimony
On Oct. 8, 2019, Public Citizen and an expert on maternal–fetal medicine petitioned the FDA to withdraw approval of Makena. In our petition, we emphasized that the drug never should have been approved by the FDA in 2011 under the accelerated approval pathway given the serious flaws identified in the conduct and design of the NIH-funded trial. We also argued that the failure of the much larger and better-designed postmarket PROLONG trial to show any meaningful clinical benefit of Makena necessitated removal of the drug from the market. We asserted that it was inconceivable that the FDA would have approved Makena if the results of the PROLONG trial had been available prior to approval.
On Oct. 29, 2019, Public Citizen testified at a meeting of an FDA advisory committee that was convened to consider whether Makena should remain on the market. We urged the committee to recommend that the FDA withdraw Makena from the market because there was a lack of substantial evidence demonstrating that the drug is effective for preventing preterm birth and complications of preterm birth.
Most of the committee (nine of 16 members) voted in favor of removing Makena from the market. A larger majority of the committee (13 members) also voted that there was not substantial evidence showing that Makena reduces the risk of preterm birth. Finally, the committee unanimously agreed that the postmarket trial failed to verify that Makena provides meaningful clinical benefits in terms of reducing neonatal health problems and death.
FDA initiates process for withdrawing approval of Makena
On Oct. 5, 2020, the FDA denied our petition requesting the “immediate” withdrawal of Makena and related generic-drug products from the market because the administrative process for such regulatory action cannot be carried out immediately. However, that same day, the FDA did send a letter to AMAG and the manufacturers of all generic versions of Makena proposing to withdraw approval of the drug because the postmarket trial failed to verify its clinical benefits.
The agency’s letter notified AMAG of the opportunity for a public hearing on the proposal to withdraw approval of Makena. AMAG subsequently requested a hearing, and the FDA granted that request.
Finally, after a lengthy delay, the FDA recently informed Covis Pharma, which acquired AMAG in late 2020, that the agency’s BRUDAC will be convened as part of the to-be-scheduled hearing to provide advice and recommendations on the FDA’s proposal to withdraw approval of Makena.
In its Oct. 27, 2021, letter to the FDA, Public Citizen emphasized that the BRUDAC panel must be fairly balanced in terms of the points of view represented; constituted in a manner to ensure independent judgment; and the members must have both relevant expertise and diverse professional education, training and experience.
Public Citizen endorsed the position of the FDA’s Center for Drug Evaluation and Research that the composition of the committee for the upcoming hearing should include multiple members with expertise in biostatistics — including at least one member with expertise in meta-analysis — as well as members with expertise in epidemiology, neonatology, understanding real-world evidence and the regulation of pharmaceuticals.
Public Citizen recommended that no more than one-third of the voting committee members be practicing obstetricians. We further recommended that if any of the practicing obstetricians on the committee currently prescribe hydroxyprogesterone to reduce the risk of preterm birth, there should be an equal number of obstetricians on the committee who do not prescribe the drug for this purpose.
At press time, the date for the planned hearing had not been announced.