FDA Withdraws Approval of the Only Drug for Preventing Preterm Birth (2023)

Table of Contents

1. What the FDA Did
2. The Drug and What It Was Approved For
3. Accelerated Approval and the Confirmatory Trial
4. From the 2019 Advisory Meeting to the 2022 Hearing
5. The October 2022 Hearing
6. The Reasons the FDA Gave
7. Remaining Supply, Prescribing and Compounding
8. What the Decision Does Not Do
9. Dates and Legal Status as of 18 October 2026
10. How the Decision Fits Other FDA Steps
11. Primary Documents
12. Key Research Papers
13. Connections
14. Featured Videos

1. What the FDA Did

The FDA press release of 6 April 2023, “FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of [the drug],” states that the agency “announced the final decision to withdraw approval” of a drug “that had been approved under the accelerated approval pathway.” It continues: “Effective today, [the drug] and its generics are no longer approved and cannot lawfully be distributed in interstate commerce.”

The decision covered two kinds of application:

• The new drug application (NDA 021945) for hydroxyprogesterone caproate injection, 250 milligrams per milliliter, given once weekly.
• Eight abbreviated new drug applications (ANDAs) from multiple holders that referenced NDA 021945 — the drug’s generic versions, which the press release calls “its generics.”

The decision was announced to the public in the Federal Register on 15 May 2023 (88 FR 30986–30987, FR Doc. 2023-10264, Docket No. FDA-2020-N-2029). That notice, titled “Final Decision on Withdrawal of [the drug] (Hydroxyprogesterone Caproate) and Eight Abbreviated New Drug Applications Following Public Hearing; Availability of Final Decision,” states that the Commissioner of Food and Drugs and the Chief Scientist “jointly issued the decision following an October 2022 public hearing,” and that approval of the drug and of the ANDAs that reference it “is withdrawn as of April 6, 2023.” A Federal Register docket is the public file that holds the documents and comments for one matter, here FDA-2020-N-2029.

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2. The Drug and What It Was Approved For

Hydroxyprogesterone caproate (often shortened to HPC or 17-OHPC) was given as an injection once a week; CDER’s 2021 statement groups it with “progestins (HPC and other similar drugs).” The FDA’s information page states that in 2011 the agency approved it “to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth.” In plain terms, the approved use was for a woman pregnant with one baby who had had a spontaneous preterm birth in an earlier pregnancy with one baby.

The FDA’s 2011 decision, the information page explains, “took into account, among other things, the significant public health impact of newborns born prematurely, the lack of approved treatments for prevention of preterm birth, and the potential benefits of earlier patient access to this treatment.”

Asked whether other drugs were approved for the same use, the FDA’s answer was: “No. [The drug] and the generics of [the drug] were the only products approved to reduce the risk of preterm birth.”

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3. Accelerated Approval and the Confirmatory Trial

Accelerated approval is the pathway under which the drug was first approved. A 2019 Federal Register notice locates it in the regulations at 21 CFR part 314, subpart H, and in section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). The press release describes how it applied here: the FDA approved the drug in 2011 “based on a determination that the sponsor had demonstrated a drug effect on an intermediate clinical endpoint that was reasonably likely to predict clinical benefit,” and the approval “included a requirement that the sponsor conduct a post marketing confirmatory study.”

An intermediate endpoint is a measurement that is expected to predict the outcome that matters, without being that outcome. The FDA’s information page names it: the approval “was based on a trial that showed the drug reduced deliveries before 37 weeks of pregnancy, an intermediate clinical endpoint that FDA determined was reasonably likely to predict clinical benefit to the newborn.” The benefit the confirmatory trial had to verify was the health of the babies.

According to the FDA, the confirmatory trial “was nearly four times larger than the trial that supported [the drug’s] approval,” and it “did not show improvement in the health of the babies born to mothers who were treated” with the drug. “It also failed to show that [the drug] reduced the risk of preterm birth.” A 2026 Federal Register notice on the FDA’s obstetrics advisory committee refers to this trial by its study name, PROLONG (see Key Research Papers).

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4. From the 2019 Advisory Meeting to the 2022 Hearing

The FDA documents give this sequence:

• 2011. Accelerated approval for the reduction of preterm-birth risk, with a required confirmatory trial.
• 29 October 2019. The FDA’s Bone, Reproductive and Urologic Drugs Advisory Committee meets to discuss a supplemental application for the drug (notice at 84 FR 50049, 24 September 2019). The notice recalls that the drug “received approval under the accelerated approval pathway” in 2011.
• 5 October 2020. The FDA’s Center for Drug Evaluation and Research (CDER), the part of the agency that oversees prescription drugs, proposes withdrawal “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show [the drug] is effective for its approved use.”
• 26 March 2021. CDER issues a statement on a newly published meta-analysis, the Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC), which pooled individual patient data on several progestogens given by different routes (vaginal progesterone, oral progesterone and intramuscular hydroxyprogesterone caproate). CDER wrote that in proposing withdrawal it had also reviewed earlier studies of progestins for preterm birth, including the studies relevant to this drug that were part of EPPPIC, and that “the publication of the EPPPIC meta-analysis does not change CDER’s proposal to withdraw the approval.”
• The sponsor’s hearing request. The press release states that “the sponsor requested a hearing.”
• 17 August 2022. The FDA announces in the Federal Register that it “has granted a hearing” on CDER’s proposal (87 FR 50626–50629, FR Doc. 2022-17715). The notice gives the time, date and format of the hearing and the questions to be posed to the advisory committee. A correction on 7 September 2022 (87 FR 54700, FR Doc. 2022-19293) fixes a deadline that had been “published with an incorrect” date.
• 17–19 October 2022. The hearing is held in a virtual format. Written or electronic comments on the hearing were accepted until 3 November 2022.
• 6 April 2023. Final decision; approvals withdrawn.
• 15 May 2023. Notice of the final decision published in the Federal Register.

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5. The October 2022 Hearing

According to the FDA’s information page, the Office of the Commissioner conducted the hearing “under 21 CFR 314.530.” Members of the public, including the generic (ANDA) holders, could ask to make a formal presentation; requests were due by 14 September 2022, together with a comment to the docket marked as a “Request for Oral Presentation.”

As part of the hearing, the FDA’s Obstetrics, Reproductive and Urologic Drugs Advisory Committee voted on three questions, as the FDA describes them:

• whether the confirmatory trial verified the clinical benefit of the drug on illness and death in newborns from complications of preterm birth;
• whether the available evidence shows that the drug is effective for its approved use; and
• whether the FDA should allow the drug to remain on the market while an appropriate new confirmatory study was designed and conducted.

The FDA’s page refers readers to the hearing transcript in the docket for the committee’s votes. A 2026 Federal Register notice renewing the committee’s charter summarizes the outcome in one line: “Their recommendations informed FDA’s decision to withdraw approval” in 2023.

After the hearing, the press release states, the Commissioner and the Chief Scientist “reviewed the record for this matter, including the submissions by CDER and [the sponsor], public comments to the docket, the transcript of the hearing and the Presiding Officer’s report,” and on that basis decided to withdraw approval of the drug and its generic versions.

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6. The Reasons the FDA Gave

The press release gives the agency’s central reason: the approvals “have been withdrawn because the drugs are no longer shown to be effective and the benefits do not outweigh the risks for the indication for which they were approved.” The FDA’s question-and-answer page adds that the drug and its generics are not shown to be effective “for any subgroup of this population, including in women at high risk of preterm birth,” that “there are known risks associated with” the drug, and that the FDA “determined that given effectiveness has not been shown, no level of risk is justified.”

The FDA Commissioner was quoted in the release: “It is tragic that the scientific research and medical communities have not yet found a treatment shown to be effective in preventing preterm birth and improving neonatal outcomes—particularly in light of the fact that this serious condition has a disparate impact on communities of color, especially Black women.” The Commissioner added: “Fundamentally, however, the touchstone of FDA drug approval is a favorable benefit-risk assessment; without that favorable assessment, the drug should not have the status of being FDA-approved.”

The FDA’s page also answers two questions about who was studied:

• Black women. The trial conducted before approval “enrolled approximately 60% Black women,” and in that trial there was a reduction in preterm birth in both Black and non-Black women. “In the post-approval confirmatory trial, there was no evidence of an effect” in either group. The FDA’s conclusion: the drug “is not shown to be effective in Black women – or any group of women.”
• Differences between the two trials. The FDA ran additional analyses of the confirmatory trial using several statistical methods. They showed, the agency says, that factors that differed between the trials, “such as the population of women enrolled (e.g., with respect to race of the mother or whether the mother was being treated outside the U.S.), did not explain the different findings.” The drug “is not shown to be effective in low, medium, or high-risk groups.”

The FDA Chief Scientist was quoted: “We acknowledge at the outset the serious problems of preterm birth with respect to both maternal and neonatal health and the contribution of institutional forces that have led to health disparities, including preterm birth, among Black women,” adding that “our hope is that this decision will help galvanize further research.”

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7. Remaining Supply, Prescribing and Compounding

Supply already shipped. The press release states that “the agency recognizes that there is a supply of product that has already been distributed.” Its message to patients with questions was to “talk to their healthcare provider,” and the FDA’s page gives the same answer to patients who were partway through treatment.

Prescribing the remaining supply. The FDA’s page notes that a limited supply had been distributed “including to physicians’ offices and pharmacies,” and “acknowledges that some health care providers might continue to prescribe or administer that limited remaining supply.” The agency’s stated recommendation to practitioners was to “consider FDA’s conclusion that these drug products are not shown to be effective for the indication for which they were approved and do not have benefits that outweigh their risks to patients.”

Compounding. A compounded drug is a pharmacy-prepared version of a medicine, not an approved product. The FDA’s page states that drug products containing hydroxyprogesterone caproate “may be compounded under certain sections of the Federal Food, Drug, and Cosmetic Act if the conditions described in those sections are met.” It adds that a practitioner considering a compounded version “should be aware of FDA’s determination” on effectiveness, and that compounded drugs, including those containing this ingredient, “do not undergo FDA premarket review for safety, effectiveness, or quality.”

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8. What the Decision Does Not Do

• It is not a finding about other progestogens. The decision covers hydroxyprogesterone caproate injection under NDA 021945 and the eight ANDAs that reference it. It does not address vaginal or oral progesterone; CDER’s 2021 statement on the EPPPIC meta-analysis discussed those only as part of the pooled evidence it had reviewed.
• It did not recall product already distributed. The FDA acknowledged remaining supply in offices and pharmacies and some continued prescribing of it (section 7).
• It did not ban compounding of the ingredient. The FDA’s page states that compounding may occur if the conditions in the relevant sections of the law are met. A later FDA step on compounding is described in section 10.
• It did not name a replacement. The FDA stated that these were the only products approved to reduce the risk of preterm birth; the decision did not approve another one.

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9. Dates and Legal Status as of 18 October 2026

• Accelerated approval: 2011.
• Withdrawal proposed by CDER: 5 October 2020.
• Hearing granted: 17 August 2022 (87 FR 50626); corrected 7 September 2022 (87 FR 54700).
• Hearing held: 17–19 October 2022; comment deadline 3 November 2022.
• Final decision and withdrawal effective: 6 April 2023.
• Federal Register notice of the final decision: 15 May 2023 (88 FR 30986).

Status as of 18 October 2026: final; the withdrawal is in effect. A check of the Federal Register through 18 October 2026 for “hydroxyprogesterone” found no later FDA document reversing, staying or modifying the withdrawal. The later documents found, a 2023 public-meeting notice, a 2024 compounding advisory committee notice and a 2026 advisory committee renewal notice, are described in section 10.

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10. How the Decision Fits Other FDA Steps

Drug development for preterm birth. On 22 November 2023 the FDA announced a public meeting, “Advancing Drug Development for the Prevention of Spontaneous Preterm Birth,” held on 23 and 24 January 2024 (88 FR 81421, FR Doc. 2023-25816, Docket No. FDA-2023-N-4996). It was convened by a university health-policy center under a cooperative agreement with the FDA, to gather input from industry, families, clinicians, researchers, ethicists, professional societies and others on the impact of preterm birth and on “the ethical, regulatory, and clinical trial considerations surrounding the drug development for the prevention of spontaneous preterm birth.”

Compounding. A Federal Register notice of 18 September 2024 (89 FR 76478, FR Doc. 2024-21241) announced a 29 October 2024 meeting of the FDA’s Pharmacy Compounding Advisory Committee. The notice explains that one condition for a compounded drug to qualify for the exemptions in sections 503A and 503B of the FD&C Act, the two sections of the law that the notice cites for compounded drugs, is that the drug “does not appear on a list published by the Secretary of drugs that have been withdrawn or removed from the market because such drug products or components of such drug products have been found to be unsafe or not effective,” the Withdrawn or Removed List at 21 CFR 216.24. The committee was to discuss a revision the FDA was considering: adding an entry for “hydroxyprogesterone caproate: all drug products containing hydroxyprogesterone caproate to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous birth.” A search of the Federal Register through 18 October 2026 found no later proposed or final rule adding that entry.

The advisory committee’s record. When the FDA Commissioner renewed the Obstetrics, Reproductive and Urologic Drugs Advisory Committee for two more years (notice of 18 March 2026, 91 FR 13031, FR Doc. 2026-05313, charter in effect until 23 March 2028), the notice listed the 2022 discussion of this drug as one of the committee’s accomplishments, describing it as “the only drug product approved to reduce the risk of recurrent preterm birth” in that population.

Accelerated approval in other cases. The same pathway can end the other way. In July 2023 the FDA converted an Alzheimer’s antibody from accelerated to traditional approval after its confirmatory trial verified benefit; that action is reported on FDA Grants Lecanemab Full Approval for Early Alzheimer’s Disease (2023).

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11. Primary Documents

1. U.S. Food and Drug Administration (2023). FDA Commissioner and Chief Scientist Announce Decision to Withdraw Approval of [the drug] (hydroxyprogesterone caproate injection). Press release, 6 April 2023 — fda.gov, News & Events → Press Announcements, 6 April 2023 (not linked here because its address carries the brand name)
2. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. [The drug] (hydroxyprogesterone caproate injection) Information: CDER statements of 5 October 2020, 26 March 2021, 25 August 2022 and 18 January 2023, and Frequently Asked Questions; content current as of 6 April 2023 — fda.gov, Drugs → Postmarket Drug Safety Information for Patients and Providers (not linked here because its address carries the brand name)
3. Food and Drug Administration, HHS (2023). Final Decision on Withdrawal of [the drug] (Hydroxyprogesterone Caproate) and Eight Abbreviated New Drug Applications Following Public Hearing; Availability of Final Decision. Notice. Federal Register 88:30986–30987, 15 May 2023. Docket No. FDA-2020-N-2029 — FR Doc. 2023-10264
4. Food and Drug Administration, HHS (2022). Proposal To Withdraw Approval of [the drug]; Hearing. Notice of hearing. Federal Register 87:50626–50629, 17 August 2022. Docket No. FDA-2020-N-2029 — FR Doc. 2022-17715
5. Food and Drug Administration, HHS (2022). Proposal To Withdraw Approval of [the drug]; Hearing; Correction. Federal Register 87:54700, 7 September 2022. Docket No. FDA-2020-N-2029 — FR Doc. 2022-19293
6. Food and Drug Administration, HHS (2019). Bone, Reproductive and Urologic Drugs Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments. Federal Register 84:50049, 24 September 2019. Docket No. FDA-2019-N-4203 — FR Doc. 2019-20656
7. Food and Drug Administration, HHS (2023). Advancing Drug Development for the Prevention of Spontaneous Preterm Birth; Public Meeting. Federal Register 88:81421, 22 November 2023. Docket No. FDA-2023-N-4996 — FR Doc. 2023-25816
8. Food and Drug Administration, HHS (2024). Pharmacy Compounding Advisory Committee; Notice of Meeting; Establishment of a Public Docket; Request for Comments—Bulk Drug Substances Nominated for Inclusion on the Section 503A Bulk Drug Substances List; Revisions to the Withdrawn or Removed List. Federal Register 89:76478–76481, 18 September 2024. Docket No. FDA-2024-N-4188 — FR Doc. 2024-21241
9. Food and Drug Administration, HHS (2026). Advisory Committee; Obstetrics, Reproductive and Urologic Drugs Advisory Committee; Renewal. Federal Register 91:13031, 18 March 2026. Docket No. FDA-2026-N-0008 — FR Doc. 2026-05313
10. Public docket FDA-2020-N-2029 (hearing record, transcript and comments) — regulations.gov FDA-2020-N-2029

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Key Research Papers

1. Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O’Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network (2003). Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. New England Journal of Medicine 348(24):2379-2385 — PubMed PMID: 12802023
2. Blackwell SC, Gyamfi-Bannerman C, Biggio JR Jr, Chauhan SP, Hughes BL, Louis JM, Manuck TA, Miller HS, Das AF, Saade GR, Nielsen P, Baker J, Yuzko OM, Reznichenko GI, Reznichenko NY, Pekarev O, Tatarova N, Gudeman J, Birch R, Jozwiakowski MJ, Duncan M, Williams L, Krop J (2020). 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG Study): a multicenter, international, randomized double-blind trial. American Journal of Perinatology 37(2):127-136 — PubMed PMID: 31652479
3. EPPPIC Group (2021). Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet 397(10280):1183-1194 — PubMed PMID: 33773630
4. Care A, Nevitt SJ, Medley N, Donegan S, Good L, Hampson L, Tudur Smith C, Alfirevic Z (2022). Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: systematic review and network meta-analysis. BMJ 376:e064547 — PubMed PMID: 35168930
5. Baxter C, Crary I, Coler B, Marcell L, Huebner EM, Rutz S, Adams Waldorf KM (2023). Addressing a broken drug pipeline for preterm birth: why early preterm birth is an orphan disease. American Journal of Obstetrics and Gynecology 229(6):647-655 — PubMed PMID: 37516401

The 2003 paper is a randomized trial of the drug for recurrent preterm delivery run by the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. The 2020 paper reports the PROLONG trial, the study a 2026 FDA Federal Register notice names when describing the advisory committee’s 2022 review. The 2021 paper is the EPPPIC meta-analysis addressed in CDER’s statement of 26 March 2021. The 2022 paper compares several approaches to preventing spontaneous preterm birth, and the 2023 paper discusses the drug-development pipeline for preterm birth.

PubMed Topic Searches

1. PubMed: hydroxyprogesterone caproate and preterm birth
2. PubMed: progestogens for the prevention of preterm birth
3. PubMed: accelerated approval, confirmatory trials and withdrawal

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Connections

• FDA Actions of 2023
• FDA and Regulation
• Preterm Labor
• Reproductive Medicine
• Probiotics for Preterm Infants Warning (2023)
• Lecanemab Traditional Approval (2023)
• OTC Daily Birth Control Pill (2023)
• Breast Density Notification (2023)
• Stimulant Boxed Warnings (2023)
• Acetaminophen Pregnancy Label Change (2025)
• First MASH Liver Drug (2024)

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