FDA Issues Draft Guidance on Tentatively Approved ANDA Submissions

On Wednesday, January 16th, the FDA published its first draft guidance since the partial government shutdown took effect on December 22, 2018.  The draft guidance, entitled “ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs,” is intended to assist Sponsors in preparing and submitting amendments to tentatively approved abbreviated new drug applications (ANDAs), including requests for final approval.  The document provides recommendations regarding the timing and content of amendments to tentatively approved (TA) ANDAs.  The Agency’s goal is to encourage timely submissions to ensure final approval based on patent and/or exclusivity protections for the earliest possible approval date.

What is an ANDA?

The ANDA pathway is the process used to obtain approval to market a generic drug in the United States. Unlike an NDA Sponsor, an ANDA applicant is not required to demonstrate the safety and effectiveness of the drug for the conditions of use for which they are seeking approval of. Instead, the applicant must identify the reference listed drug (RLD) and relay that “FDA’s finding that the RLD relied upon by the ANDA applicant is safe and effective”. Sponsors must also include sufficient information “(1) to demonstrate that the proposed product is bioequivalent to the RLD5 and (2) to ensure the product’s identity, strength, quality, and purity”.

What is tentative approval?

Tentative approval is granted by the FDA if an ANDA meets the substantive requirements for approval but cannot obtain final approval due to unexpired patents or exclusivities. To gain final approval, applicants may submit changes to the application, request final approval, or propose changes and request final approval through amendments. The nature of these amendments may delay final approval of the ANDA until after the earliest lawful ANDA approval date. A drug product may not be marketed until the ANDA gains final Agency approval.

Requesting Final Approval for Tentatively Approved ANDAs

FDA’s recent draft guidance includes the provision that the President’s Emergency Plan for AIDS Relief (PEPFAR) will not experience a delay in the assessment of submitted and tentatively approved ANDAs. PEPFAR allows certain TA antiretroviral to be distributed for use outside the United States regardless of patent and/or exclusivity protection in the US.

When an amendment is submitted to a tentatively approved ANDA, FDA has the option to assess the amendment or defer it. If the Agency decides to assess the amendment, the status of the submitted ANDA will be changed from “TA” to “under review”. After review, if the ANDA meets all requirements for final approval, approval will be granted by the Agency. If the amendment has not resolved all deficiencies, the status of the ANDA will be converted to a complete response status as communicated in the complete response letter (CRL). The complete response status will remain in effect until the deficiencies are addressed in a subsequent amendment and FDA reinstates TA or grants final approval.

GDUFA Review Goals

The GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II Commitment Letter) provides review goal dates for the different amendment types in general terms. FDA provides additional information and recommendations on review goal dates in a separate guidance document, entitled “ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA”, which was issued in July 2018.  All final approval requests are considered amendments to the ANDA application and given a major or minor classification. With these recommendations, it is the applicant’s responsibility to plan the timing of the final approval request.

Regardless of when TA was granted, “if an ANDA applicant submits a request for final approval that contains no new data, information, or other changes to the ANDA less than 3 months from the earliest lawful ANDA approval date but (1) could have identified the earliest lawful ANDA approval date and (2) failed to submit a timely standard request for final approval, the ANDA applicant risks the application not being approved by that date.”

If the applicant has provided a paragraph III certification (a date the patent will expire), “FDA recommends the applicant submit the request 15 months before the earlier lawful ANDA approval date”. The Agency suggests that final approval requests are sent no later than three months before final approval for ANDAs receiving a TA status less than three years before the earlier lawful approval date. This will allow time for FDA to assess before the approval date. Any amendment without new data, information or other changes is considered a minor amendment and should be assessed within three months.

ANDAs which have been in TA status for three or more years, “may result in a more extensive assessment of the ANDA before final approval may be granted.” FDA then recommends that final approval requests are submitted as a major amendment. Major amendment submissions allow FDA to “(1) assess any changes that have been made since the application was granted TA, (2) complete any necessary inspection(s) of the ANDA’s referenced facilities, and (3) grant final approval on the earliest lawful approval date.” Therefore, amendments of this type should be submitted ten months before the earlier lawful approval date.

Post TA Changes

In its draft guidance, FDA identified various “common developments that may require an applicant to make changes that should be submitted in an amendment to its tentatively approved ANDA before final approval is granted.” The Agency’s non-exhaustive list includes a number of updates regarding:

  • Product quality
  • Bioequivalence
  • Labeling
  • Orange book listings, patents, and exclusivity

Requesting Final Approval

The final approval request for the ANDA should include a cover letter which details all changes since the TA was granted. The Agency also recommends including additional content for approval, such as:

  • An accurate Form FDA 356h
  • A clear statement that no changes has been made to the ANDA between TA and the request for final approval
  • An editorial about the changes and were they were made in the document if changes has occurred
  • A side by side labeling comparison of proposed labeling with current RLD labeling
  • A statement indicated if the final amendment should be considered a major or minor classification

Providing Feedback to FDA

Draft guidance documents are published on the Federal Register’s website and are open to the public for comment. However, because of the partial government shutdown, the Federal Register is not publishing new documents or accepting new comments.  Once publication becomes available, details will be released on fda.gov on how to submit comments on the document.

Are you in the process of submitting an ANDA for approval by the FDA? We can help make sure your application is complete and ready to be submitted.  To learn more about our ANDA submission consulting services and how we can help you achieve successful interactions with FDA, contact us today.