On April 5, 2023, the U.S. Food and Drug Administration (“FDA”) announced its decision to withdraw the approval of Makena® hydroxyprogesterone caproate injection (“Makena”) – a drug that was approved in 2011 to reduce the risk of preterm birth in certain pregnant women.^[1] The final decision followed a hearing and appeal process that took nearly three years, and cited the failure of post-approval studies to prove the drug’s effectiveness as the reason for the withdrawal.^[2] 

How Was Makena Approved?

Makena’s new drug application (“NDA”) was approved in 2011 under FDA’s accelerated approval process, which allows FDA to approve drugs for serious conditions that fulfill an unmet clinical need before safety and effectiveness has been fully proven.^[3] Under the accelerated approval process, clinical trials need only identify an “intermediate clinical endpoint,” which is a measure of therapeutic effect that is considered reasonably likely to predict a drug’s clinical effectiveness, but, on its own, does not prove a drug’s clinical effectiveness. Thus, accelerated approvals are granted on the reasonable likelihood that a drug is effective for its intended purpose. For this reason, at least one post-approval confirmatory study (i.e., a study aimed at verifying the predicted clinical effectiveness) is required for drugs granted accelerated approval.^[4]

Why Was Makena’s Approval Withdrawn?

A post-approval confirmatory study was required to verify clinical effectiveness of Makena in order for the drug to continue being lawfully marketed in the United States.^[5] However, FDA found that Makena’s study failed to show any clinical benefit, despite the fact that the study was nearly four times larger than the pre-approval study.^[6] Moreover, FDA could not justify continued approval in view of the degree of risk presented.^[7]

Thus, on October 5, 2020, FDA issued a proposal to withdraw the approval of Makena, as well as any drugs that had been granted approval as generic versions of Makena.^[8] Following the proposal, the maker of Makena, Covis Pharma Group (“Covis”) was granted a hearing, during which it proposed to rectify the results of the post-approval study by (i) focusing labeling on the high-risk patient population, (ii) conducting a new randomized-controlled trial to confirm Makena’s clinical effectiveness for only the high-risk patient population, and (iii) conducting an observational study to validate the therapeutic effect of the drug’s intended purpose on neonatal morbidity.^[9] The hearing began a nearly-three year discourse between Covis, FDA, and interested industry participants over Makena’s approval status, which resulted in a docket of more than 250 documents.^[10] Ultimately, FDA was unpersuaded by Covis’ proposed remediation and, on April 5, 2023, issued its final decision to withdraw the approval of Makena and its generics. 

What is the Takeaway for Manufacturers of Drugs Granted Accelerated Approval?

Given the abbreviated scope of evidence required under FDA’s accelerated approval process, the risk of subsequent withdrawal based on lack of clinical effectiveness may be higher for drugs that are approved under the accelerated approval pathway than those approved through a traditional approval pathway. Although the accelerated approval process presents an expedited option for getting a drug to market (assuming that the drug fills an unmet need for a serious condition), manufacturers of drugs granted accelerated approval should be aware that around ten percent (10%) of accelerated-approval drugs are subsequently withdrawn.^[11] And this number may continue to grow as FDA has, in recent years, emphasized the need to ensure a higher level of safety and efficacy for accelerated-approval drugs by more closely scrutinizing the accelerated approval process.

At the same time, as part of its improvement of the accelerated approval process, FDA has placed an enhanced focus on strategies to avoid post-approval withdrawals. As a preventative approach, FDA has urged accelerated approval applicants for oncology drugs to have confirmatory trials “fully accrued and underway” before submitting an accelerated approval application.^[12] As part of this recommendation, FDA noted that the limited scope of evidence required for accelerated approval may not be appropriate in all clinical settings and that applicants for certain drugs, such as oncology drugs, would benefit from providing more confirmatory evidence upfront.^[13] FDA has also demonstrated an increased willingness to discuss creative solutions for identifying paths forward when post-approval confirmatory studies fail to verify clinical effectiveness.^[14] Thus, as is evidenced by the lengthy docket associated with Makena’s proposed withdrawal, even those manufacturers who do not conduct early confirmatory trials will likely have an adequate opportunity to propose solutions before ultimately being withdrawn from the market. 

FOOTNOTES

^[1] Makena was initially approved to reduce the risk of preterm birth in women pregnant with at least one baby who have a history of spontaneous preterm birth. See Approval Letter for Makena hydroxyprogesterone caproate injection, FDA (Feb. 3, 2011).

^[2] See Press Release, FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of Makena, FDA (Apr. 6, 2023); FAQs – Makena, FDA (Apr. 6, 2023); Final Decision, Proposal to Withdraw Approval of Makena, Docket No. FDA-2020-N-2029 (Apr. 5, 2023).

^[3] See Accelerated Approval, FDA (current as of Feb. 24, 2023); Approval Letter at p. 4.

^[4] 21 CFR 314.510.

^[5] See Approval Letter at p. 5.

^[6] See Final Decision at p. 6.

^[7] See FAQs – Makena.

^[8] See Proposal to Withdraw Marketing Approval, Docket No. FDA-2020-N-2029 (Oct. 4, 2020).

^[9] See Transcript, Hearing Involving the Obstetrics, Reproductive and Urologic Drugs Advisory Committee, Docket No. FDA-2020-N-2029 at p. 37 (Oct. 19, 2022).

^[10] See Docket, FDA-2020-N-2029.

^[11] See, e.g., Report, Drug and Biologic Accelerated Approvals Based on Surrogate Endpoint, FDA (March 31, 2023); Report, Drug and Biologic Accelerated Approvals Based on Surrogate Endpoint, FDA (December 3, 2022).

^[12] See 88 Fed. Reg. 18149.

^[13] See id. Although FDA’s discourse on increased evidentiary standards for accelerated approval is currently limited to the oncology space, it may predict a future shift in accelerated approval requirements for the industry at large.

^[14] For example, in recent years, FDA’s Oncologic Drug Advisory Committee had devoted significant time and resources to assessing whether there are feasible paths forward for accelerated-approval drugs with unfavorable post-approval confirmatory studies. See Project Confirm, FDA Oncology Center of Excellence (current as of April 13, 2023).