[Federal Register Volume 88, Number 93 (Monday, May 15, 2023)]
[Notices]
[Pages 30986-30987]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-10264]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-2029]


Final Decision on Withdrawal of MAKENA (Hydroxyprogesterone 
Caproate) and Eight Abbreviated New Drug Applications Following Public 
Hearing; Availability of Final Decision

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing 
the availability of the final decision withdrawing approval of MAKENA 
(hydroxyprogesterone caproate injection, 250 milligrams (mg) per 
milliliter (mL), once weekly), under the new drug application (NDA) 
021945, held by Covis Pharma Group/Covis Pharma GmbH (Covis), and the 
eight abbreviated new drug applications (ANDAs) from multiple ANDA 
holders that reference NDA 021945. The Commissioner of Food and Drugs 
(the Commissioner) and the Chief Scientist jointly issued the decision 
following an October 2022 public hearing.

DATES: Approval of MAKENA and the ANDAs that reference MAKENA is 
withdrawn as of April 6, 2023.

FOR FURTHER INFORMATION CONTACT: Patrick Raulerson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 51, Rm. 6260, Silver Spring, MD 20993-0002, 301-
796-3522, [email protected].

SUPPLEMENTARY INFORMATION: 

I. Background

    On February 3, 2011, FDA's Center for Drug Evaluation and Research 
(CDER) approved NDA 021945 for MAKENA (hydroxyprogesterone caproate) 
Injection to reduce the risk of preterm birth (PTB) in women with a 
singleton pregnancy who have a history of singleton spontaneous PTB 
(sPTB). FDA approved MAKENA under the accelerated approval pathway, 
pursuant to section 506(c) of the Federal Food, Drug, and Cosmetic Act 
(FD&C Act) (21 U.S.C. 356(c)) and 21 CFR 314.510, based on evidence of 
the drug's effect on

[[Page 30987]]

an intermediate clinical endpoint that was considered reasonably likely 
to predict the drug's clinical benefit.
    As a condition of MAKENA's approval, the sponsor was required to 
complete a postmarketing trial to verify and describe the clinical 
benefit of MAKENA in reducing neonatal morbidity and mortality from 
complications of PTB among babies born to women with a singleton 
pregnancy who had a previous singleton sPTB. This postmarketing 
confirmatory trial, Trial 003, failed to show that MAKENA reduced the 
risk of neonatal morbidity and mortality from complications of PTB and 
failed to show a treatment effect of MAKENA on the intermediate 
clinical endpoint that was the basis of MAKENA's approval.
    On October 5, 2020, CDER issued a proposal to withdraw approval of 
MAKENA and a notice of opportunity for hearing (NOOH) on two 
independent grounds using expedited procedures under section 506(c)(3) 
of the FD&C Act and 21 CFR 314.530(a): (1) the confirmatory trial 
failed to verify the clinical benefit of the drug and (2) the evidence 
demonstrates that the drug is not shown to be effective under its 
conditions of use. CDER's NOOH and proposal to withdraw approval of 
MAKENA also provided notice to all holders of approved ANDAs 
referencing the NDA for MAKENA (NDA 021945) that, if the Agency were to 
withdraw approval of MAKENA, CDER would withdraw approval of those 
ANDAs under 21 CFR 314.151(b)(3).
    MAKENA's sponsor submitted a hearing request dated October 14, 
2020, followed by a submission of data and information in support of 
the hearing request. The Agency granted the sponsor's hearing request 
on August 18, 2021, and on August 17, 2022, published a notice of 
hearing (87 FR 50626). The hearing was held on October 17, 18, and 19, 
2022. The Obstetrics, Reproductive and Urologic Drugs Advisory 
Committee was present at the hearing to review the issues involved and 
to provide advice and recommendations to the Commissioner. The 
presiding officer issued a report, dated January 19, 2023, that 
summarized the legal and factual background, content of the hearing, 
and her analysis and recommendations. On April 6, 2023, after 
considering CDER's and Covis' March 6, 2023, post-hearing submissions, 
the Commissioner and Chief Scientist jointly issued a final decision 
withdrawing approval of MAKENA and the ANDAs that referenced MAKENA.
    FDA has withdrawn approvals of the following NDA and eight ANDAs:

------------------------------------------------------------------------
      Application No.                  Drug             Holder/sponsor
------------------------------------------------------------------------
NDA 021945.................  Makena                   Covis Pharma Group/
                              (hydroxyprogesterone     Covis Pharma
                              caproate) Injection,     GmbH.
                              250 mg per mL.
ANDA 208381................  Hydroxyprogesterone      Sun Pharmaceutical
                              Caproate Injection       Industries, Ltd.
                              USP, 250 mg/mL.
ANDA 210618................  Hydroxyprogesterone      Slayback Pharma
                              Caproate Injection       LLC.
                              USP, 250 mg/mL.
ANDA 210723................  Hydroxyprogesterone      American Regent,
                              Caproate Injection       Inc.
                              USP, 250 mg/mL.
ANDA 210724................  Hydroxyprogesterone      Do.
                              Caproate Injection
                              USP, 250 mg/mL.
ANDA 210877................  Hydroxyprogesterone      Slayback Pharma
                              Caproate Injection       LLC.
                              USP, 250 mg/mL.
ANDA 211070................  Hydroxyprogesterone      Eugia Pharma
                              Caproate Injection       Specialities Ltd.
                              USP, 250 mg/mL.
ANDA 211071................  Hydroxyprogesterone      Do.
                              Caproate Injection
                              USP, 250 mg/mL.
ANDA 211777................  Hydroxyprogesterone      Aspen Pharma USA
                              Caproate Injection       Inc.
                              USP, 250 mg/mL.
------------------------------------------------------------------------

    Withdrawal of approval of the applications listed in the table 
includes all strengths, dosage forms, amendments, and supplements to 
these applications, effective April 6, 2023. As discussed in the 
decision of the Commissioner and Chief Scientist, FDA has withdrawn 
approval of the MAKENA NDA for reasons of safety or effectiveness, as 
well as approval of the ANDAs that reference MAKENA.
    Section 505(j)(7) of the FD&C Act (21 U.S.C. 355(j)(7)) requires 
FDA to publish a list of all approved drugs. FDA publishes this list as 
part of the ``Approved Drug Products With Therapeutic Equivalence 
Evaluations,'' which is known generally as the ``Orange Book,'' 
available at https://www.accessdata.fda.gov/scripts/cder/ob/index.cfm. 
Under FDA regulations, drugs are removed from the list if the Agency 
withdraws or suspends approval of the drug's NDA or ANDA for reasons of 
safety or effectiveness or if FDA determines that the listed drug was 
withdrawn from sale for reasons of safety or effectiveness 21 CFR 
314.162. Accordingly, the Agency has removed the applications listed in 
the table from the list of drug products published in the Orange Book. 
FDA will not accept or approve ANDAs that reference MAKENA.

II. Electronic Access

    Persons with access to the internet may obtain the final decision 
at https://downloads.regulations.gov/FDA-2020-N-2029-0385/attachment_1.pdf. The final decision, a transcript of the hearing, and 
other documents pertaining to the withdrawal of the NDA for MAKENA (NDA 
021945) are available at https://www.regulations.gov under the docket 
number found in brackets in the heading of this document.

    Dated: May 8, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-10264 Filed 5-12-23; 8:45 am]
BILLING CODE 4164-01-P