10/5/2020 – CDER proposes withdrawal of approval for Makena
The U.S. Food and Drug Administration’s Center for Drug Evaluation and Research (CDER) proposed that Makena (hydroxyprogesterone caproate injection) be withdrawn from the market because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use. See CDER Statement: Makena withdrawal request.
Frequently Asked Questions
Q. CDER granted Makena accelerated approval in 2011. What is accelerated approval, and how does it differ from traditional (regular) approval?
A. For traditional (regular) approval of a drug, there must be substantial evidence of effectiveness, and the benefits of the drug must outweigh the risks. To establish effectiveness, the drug generally must be shown to have a direct benefit on how a patient feels, functions or survives (clinical benefit). Alternatively, the drug may be shown to cause improvement on a validated surrogate endpoint, meaning that the endpoint is known to predict clinical benefit. A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, or other measure that does not directly measure benefit to the patient. Accelerated approval can be based on studies showing the drug has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit to patients.
Accelerated approval is intended to speed the availability of drugs that treat serious or life-threatening diseases or conditions and that may provide a meaningful advantage over available therapies. For accelerated approval, the applicant still must provide substantial evidence based on adequate and well-controlled clinical investigations that the benefits of the drug outweigh its risks, but the effect is shown on a surrogate endpoint that is reasonably likely (not known) to predict benefit in how patients feel, function, or survive. For Makena’s approval, the surrogate endpoint was reducing the risk of preterm birth (birth before 37 weeks); a surrogate endpoint that CDER determined was reasonably likely to predict clinical benefit to the newborn. Compared to traditional approval, there is uncertainty at the time of accelerated approval whether the drug will ultimately be shown to provide clinical benefit to patients. Therefore, drugs approved under accelerated approval must undergo confirmatory clinical trial(s) after approval to verify that the drug improves how patients feel, function, or survive and to describe the extent of such improvement. The FDA may withdraw approval of a drug granted accelerated approval if the confirmatory trial(s) fail to verify clinical benefit.
Q. Why did CDER grant accelerated approval to Makena?
A. CDER approved Makena to reduce the risk of preterm birth in women pregnant with a single baby who previously had spontaneous (unexplained) preterm birth. Preterm birth refers to delivery before 37 weeks of pregnancy. The goal of reducing preterm birth is to improve health outcomes of the baby (the clinical benefit), as premature babies can have significant health problems. CDER granted Makena accelerated approval after concluding that the drug reduced deliveries before 37 weeks of pregnancy, a surrogate endpoint that CDER determined was reasonably likely to predict clinical benefit to the newborn.
CDER’s decision to grant accelerated approval to Makena took into account the significant public health impact of newborns born prematurely, the lack of approved treatments for prevention of preterm birth and the delay in patient access to this promising treatment that would occur if the larger confirmatory trial measuring direct benefits to newborns was required pre-approval.
Q. Why did CDER propose withdrawal of Makena’s approval?
A. As a condition of Makena’s accelerated approval, CDER required the manufacturer to conduct a confirmatory clinical trial after approval to verify and describe the anticipated clinical benefit to newborns. This trial, called PROLONG or Trial 003, did not show improvement in the health of the babies born to mothers who were treated with Makena. This trial also failed to show a reduced risk of preterm birth with Makena, contradicting the findings of the original trial conducted for approval. After extensive review of the findings, CDER could not identify a treatment benefit of Makena for any subgroup of patients in Trial 003, including those at higher risk for preterm birth.
Based on our analysis of the data, CDER has concluded that the evidence does not show Makena to be effective for its approved use. If data from the postmarket study (Trial 003) was available in addition to Trial 002 in 2011 when the FDA was reviewing the application for Makena, the agency would not have approved the drug.
Q. The trial used for Makena’s approval (Trial 002, also known as the Meis trial) was conducted in American women whereas the confirmatory trial after approval (Trial 003, also known as the PROLONG trial) was an international trial. Could the differences in the women enrolled in these two trials explain why Trial 002 was positive and Trial 003 was negative for Makena’s effectiveness?
A. No. CDER conducted additional analyses of Trial 003 using several statistical methods. These analyses focused on the factors that differed between Trial 002 and Trial 003, including whether the woman lived in the U.S. or not, and factors that may increase the risk of a preterm birth, such as Black race and number of prior spontaneous (unexplained) preterm births. Of note, the number of U.S. women enrolled in Trial 003 (N=391, Trial 003 U.S. subgroup) was close to that in Trial 002 (N=463). CDER’s analyses showed that factors that differed between Trial 002 and Trial 003, such as race or being outside the U.S., did not explain the different findings between these two trials.
CDER also looked at a combination of factors in Trial 003, such as race, level of education, partner status, number of prior preterm births, and substance use in pregnancy, that together may represent low, medium, and high risk for recurrent preterm birth. There was no evidence that Makena was effective in these low, medium, or high risk groups.
After multiple analyses, CDER was unable to identify a group of women for whom Makena had an effect in Trial 003.
For more information about the available data for Makena, please view materials from the Bone, Reproductive and Urologic Drugs Advisory Committee meeting about Makena.
Q. Trial 002, which was the basis of Makena’s accelerated approval, enrolled approximately 60% Black women. Do the data from Trial 002 or 003 show that Makena is more effective in Black women compared to non-Black women?
A. No. In Trial 002, Makena appeared to reduce preterm birth in Black and non-Black women. In Trial 003, there was no effect of Makena in Black or non-Black women.
Q. What is the next step now that CDER has proposed a withdrawal of Makena?
A. CDER has proposed to withdraw the approval of Makena and its generic equivalents and is providing the application holder of Makena (AMAG Pharmaceuticals) as well as the application holders of the generics of Makena with a notice of opportunity for a hearing. The process that follows will depend, in part, on these companies’ decisions. AMAG Pharmaceuticals could voluntarily agree to let FDA withdraw approval of Makena and waive the opportunity for a hearing. If AMAG does not agree to voluntary withdrawal, it may request a public hearing. The application holders of the generics of Makena can submit written comments on CDER’s proposal to withdraw approval of Makena and its generic equivalents. The FDA Commissioner would decide whether to grant AMAG’s request for a hearing and, if granted, would conduct a hearing and decide whether to withdraw approval following the hearing. This process can take months. During this time, Makena and the approved generics of Makena will remain on the market until the Commissioner makes a final decision about these products.
Q. What should a health care professional tell patients about the possible removal of Makena from the market?
A. Health care professionals can explain that CDER is requesting removal of Makena from the market for the reasons explained on this webpage and that Makena and its generic equivalents remain on the market until the application holders of these products voluntarily withdraw them from the market or the FDA Commissioner determines that these products must be withdrawn (or the Commissioner may decide after a hearing not to withdraw approval). Health care professionals should discuss the benefits, risks and uncertainties with their patients to decide whether to use Makena while it remains on the market.
Q. Will the withdrawal of Makena impact the approved generics of Makena?
A. Yes. There are multiple approved generic equivalents of Makena that are approved for the same use as Makena. If approval of Makena is withdrawn, the approval of these generic drugs will also be withdrawn, after which these products will no longer be available on the market.
Q. Are there other drugs available for the same indication as Makena?
A. No, Makena and the approved generics of Makena are the only products approved to reduce the risk of preterm birth.
Q. If Makena is withdrawn from the market and hydroxyprogesterone caproate (HPC) is placed on the withdrawn or removed list for the indication “to reduce the risk of recurrent preterm birth,” can compounders use HPC, the active ingredient in Makena, to compound drugs for patients?
A. HPC cannot be compounded for the specific indication “to reduce the risk of recurrent preterm birth” if Makena is withdrawn from the market and HPC is placed on the withdrawn or removed list for this indication.
See Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act and Compounded Drug Products That Are Essentially Copies of Approved Drug Products Under Section 503B of the Federal Food, Drug, and Cosmetic Act for more information.