SUPPLEMENTARY INFORMATION:

I. Background

Section 506 of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 356) provides that a drug sponsor may request to expedite the review and approval of a drug intended to treat an unmet need related to a serious or life-threatening disease or condition. Under the accelerated approval pathway, FDA may grant accelerated approval based on the drug's effect on a surrogate or an intermediate clinical endpoint. FDA's regulations, at § 314.510 (21 CFR 314.510), require that accelerated approval be subject to a sponsor's engaging in further study “to verify and describe [the drug's] clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.”

Under section 506(c)(3) of the FD&C Act, FDA may withdraw approval of a drug approved under this pathway if, among other reasons, the required study fails to verify “the predicted effect on irreversibility morbidity or mortality or other clinical benefit.” Under § 314.530(a) (21 CFR 314.530(a)), FDA may withdraw accelerated approval of a drug when “[a] postmarketing clinical study fails to verify clinical benefit” or “[o]ther evidence demonstrates that the drug product is not shown to be safe or effective under its conditions of use,” among other circumstances.

To initiate the process for withdrawing accelerated approval of a drug, the Director of CDER must provide the applicant with notice of an opportunity for a hearing on the proposed grounds for withdrawal under § 314.530(b). To obtain a hearing, the applicant must, pursuant to § 314.530(c), request one within 15 days after receiving CDER's notice and submit “the data and information upon which [it] intends to rely at the hearing” within 30 days thereafter.

Pursuant to § 314.530(e)(1), FDA conducts hearings under § 314.530 in accordance with part 15 (21 CFR part 15), with certain modifications. The key modification under § 314.530(e)(1) is that an advisory committee is present at the hearing and provides advice and recommendations to the Commissioner. Under § 314.530(e)(2), the presiding officer, the members of the advisory committee, and up to three representatives from both the applicant and CDER may ask questions of the presenters at the hearing. The presiding officer, as a matter of discretion, may also permit questions of presenters posed by others participating in the hearing upon submission of such questions in writing. After receiving advice and recommendations from the advisory committee, the Commissioner of Food and Drugs makes the final decision on whether to withdraw accelerated approval of the drug product at issue (see § 314.530(f)).

On February 3, 2011, FDA approved the NDA for MAKENA under the accelerated approval pathway to reduce the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth. As described in CDER's proposal to withdraw approval, the MAKENA NDA “relied on evidence from the Maternal Fetal Medicine Unit (MFMU) Network trial (referred to as `Trial 002') for primary support of efficacy and safety.” CDER granted accelerated approval based on the results for Trial 002. Consistent with section 506(c)(2) of the FD&C Act and § 314.510, CDER's approval letter required, inter alia, that the sponsor complete a postmarketing confirmatory study, described as “a clinical trial of MAKENA in women with a singleton pregnancy who had a previous spontaneous preterm birth (Protocol #17P-ES-003)” (Trial 003).

On October 5, 2020, CDER proposed withdrawing accelerated approval of MAKENA and provided Covis with an opportunity to request a hearing on the proposal.^[1] In the proposal, CDER cited two grounds under section 506(c)(3) of the FD&C Act and § 314.530(a) for withdrawing approval: (1) the confirmatory study failed to verify clinical benefit of the drug and (2) the evidence does not establish that the drug is effective under its conditions of use. CDER's proposal to withdraw approval also provided notice to all holders of approved abbreviated new drug applications (ANDAs) referencing the NDA for MAKENA (NDA 021945) that, if the Agency withdraws ( printed page 50628) accelerated approval of MAKENA, CDER would proceed to withdraw approval of the ANDAs under 21 CFR 314.151(b)(3).

On October 14, 2020, Covis timely requested a hearing and sought an additional 30 days in which to submit data and information in support. On December 4, 2020, after receiving an extension of time within which to do so, Covis further responded to CDER's proposal to withdraw accelerated approval of MAKENA. The response included data and information and incorporated other data and information in FDA's administrative files by reference.^[2]

By letter to CDER and Covis dated August 18, 2021, FDA's Chief Scientist granted Covis's hearing request and appointed Celia M. Witten as presiding officer.

II. Notice of Hearing Under Part 15 and § 314.530

This public hearing will be held in accordance with part 15 and § 314.530. The presiding officer will conduct the hearing, and an advisory committee will be present at the hearing for purposes of considering the data and information presented by CDER and Covis with respect to CDER's proposal to withdraw accelerated approval of MAKENA and providing advice to the Commissioner of Food and Drugs on that proposal (see § 314.530(e)).

Under 21 CFR 15.30(f), the hearing is informal, and the rules of evidence do not apply. In accordance with § 314.530(e)(2), however, only the presiding officer, the members of the advisory committee, and up to three representatives from CDER and Covis may pose questions to the advisory committee at the hearing itself. The presiding officer may nonetheless exercise her discretion under § 314.530(e)(2) to allow others to propose questions by submitting them in writing for her consideration. In the interest of economy and efficiency, particularly given the virtual platform, the presiding officer has determined that only the holders of ANDAs referencing the NDA for MAKENA (ANDA holders) will be permitted to submit questions; that all proposed questions must be submitted to the docket for this proceeding in advance of the hearing; and that the questions selected will be posed to CDER and Covis at the close of their respective presentations (see section IV of this document).

III. Questions To Be Addressed at the Public Hearing

The questions to be posed to the advisory committee at the hearing are as follows:

1. For discussion and vote:

Do the findings from Trial 003 verify the clinical benefit of MAKENA on neonatal morbidity and mortality from complications of preterm birth?

2. For discussion and vote:

Does the available evidence demonstrate that MAKENA is effective for its approved indication of reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth?

3. For discussion:

Should FDA allow MAKENA to remain on the market? As part of that discussion, you may discuss:

• whether the benefit-risk profile supports retaining the product on the market;
• what types of studies could provide confirmatory evidence to verify the clinical benefit of MAKENA on neonatal morbidity and mortality from complications of preterm birth?

For vote:

Considering your responses to the previous questions both in the discussions and votes, should FDA allow MAKENA to remain on the market while an appropriate confirmatory study is designed and conducted?

IV. Participating in the Public Hearing

Persons wishing to view the hearing may access the webcast at the following separate links on the respective days of the hearing:

Day 1: https://youtu.be/​EEm7pM_​LgsM.

Day 2: https://youtu.be/​Nt2bcDVgpag.

Day 3: https://youtu.be/​Dal27hktzcg.

Request for Oral Presentations: We currently expect public participation to occur from 2 p.m. to 4 p.m. Eastern Time on the first day of the hearing and from 8 a.m. to 10 a.m. on the second day. Persons interested in participating in the hearing by making an oral presentation during the 4 hours currently reserved for such presentations must submit requests by 11:59 p.m. Eastern Time on September 6, 2022, as further described below.

If you wish to make a formal presentation or present oral comments during the session for public participation, you must register at the following link by 5 p.m. Eastern Time on September 6, 2022: https://www.surveymonkey.com/​r/​B72THCF. When registering, please provide complete contact information, including name, title, affiliation, address, email, and telephone number. To complete your request for an opportunity to make a presentation at the hearing, you must also submit a comment to the docket for this hearing matter (see ADDRESSES ) by 11:59 p.m. Eastern Time on September 6, 2022, and clearly indicate in the heading and/or cover page that your comment is a “Request for Oral Presentation.”

In the “Request for Oral Presentation” submitted to the public docket, you must identify yourself and others who will join you for your presentation, list the affiliation (if any) of each individual participating in your presentation (including your own), and request a specific amount of time for your presentation. You must also include a summary of what you plan to present at the hearing and a copy of any slide deck, along with any data or information on which you intend to rely at the hearing that is not already referenced or included in the public docket for this hearing matter. No commercial or promotional material will be permitted to be presented or distributed at the public hearing.

We urge organizations with common interests to consolidate or coordinate their presentations. In accordance with 21 CFR 15.21(c), the presiding officer may require joint presentations by persons with common interests.

The presiding officer will determine the amount of time allotted to each presenter and the approximate time each presentation is to begin and will select and notify participants by September 30, 2022. If you are notified that you will be a presenter, we encourage you to be online well in advance of the approximate time provided in the notice. Actual presentation times may vary based on how the hearing progresses.

Proposed Questions: To propose a question to either CDER or Covis, an ANDA holder must submit a comment to the docket for this hearing matter (see ADDRESSES ) by 11:59 p.m. Eastern Time on September 30, 2022; indicate in the heading and/or cover page that the comment includes “Proposed Question(s)”; and state in the submission that the question or questions are being proposed by a specific ANDA holder or someone authorized to do so on that specific ANDA holder's behalf. The comment should also indicate whether each proposed question is intended for CDER, Covis, or both. ( printed page 50629)

Transcripts: Please be advised that as soon as a transcript of the public hearing is available, it will be accessible at https://www.regulations.gov. It may also be viewed at the address where Dockets Management Staff is located (see ADDRESSES ). A link to the transcript will also be available on the Agency's website.

87 FR 50626