FDA Draft Guidance on Tentatively Approved ANDA Submissions

January 21, 2019

FDA Draft Guidance on Tentatively Approved ANDA Submissions: On Wednesday, January 16th, the FDA published its first draft guidance since the partial government shutdown took effect on December 22, 2018.  The draft guidance, entitled “ANDA Submissions – Amendments and Requests for Final Approval to Tentatively Approved ANDAs,” is intended to assist Sponsors in preparing and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. On September 28, 2020, the FDA announced it’s final version of the draft guidance, which further clarifies the Agency’s recommendations.

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. 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”.

Tentative Approval Meaning

Tentative approval (also known as “TA”) is a notification granted by the FDA if an ANDA meets the substantive requirements for approval, but cannot obtain final approval for marketing due to unexpired patents or exclusivities. A grant of tentative approval does not mean the drug is approved, it is merely a letter that notes the circumstances which prevent the drug from gaining final approval.

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

The FDA considers requests for final approval as amendments to the ANDA. When an amendment is submitted to a tentatively approved ANDA, the 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 “tentative approval 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.

It’s important to note that final approval for a tentatively approved ANDA is not automatically granted when the patent or exclusivity barriers expire. The FDA will still need time to assess the ANDA amendment in order to grant final approval, so Sponsors should file these requests far in advance of the goal approval date.

GDUFA Review Goals for ANDA Amendments

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. The 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. As noted earlier, 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 to provide adequate time for the FDA to assess the amendment.

Regardless of when tentative approval 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.”

Minor vs Major Amendment Considerations and Timing

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 tentative approval status less than three years before the earlier lawful approval date. This will allow time for the 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 tentative approval status for three or more years, “may result in a more extensive assessment of the ANDA before final approval may be granted.” The FDA then recommends that final approval requests are submitted as a major amendment. Major amendment submissions allow the 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 Tentative Approval Status Changes

In its draft guidance, the 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 for an ANDA

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

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

As mentioned earlier, a final approval request that contains deficiencies will result in the ANDA being labeled with the “complete response” status until the issues are addressed by the Sponsor.

Get Expert Guidance for Your ANDA Application

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. ProPharma Group has over 37 years of regulatory consulting experience and can help you achieve a successful interaction with the FDA during your ANDA submission. No matter where you are in the process or what your approval status is, our experts will provide guidance to help you every step of the way.

To learn more about our ANDA submission consulting services and how we can help you achieve successful interactions with FDA, contact us today.


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