FDA Guidance Breakdown: ANDA Submissions—Amendments and Requests for Final Approval to Tentatively Approved ANDAs

A revised final guidance helps applicants in preparing and submitting amendments to tentatively approved ANDAs including requests for final approval.

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The FDA just revised its final guidance on amendments and requests for final approval for tentatively approved ANDAs.

“This guidance provides recommendations on the timing and content of amendments to tentatively approved ANDAs to facilitate submission in a timely fashion to enable final approval on the earliest date on which the ANDA may lawfully be approved based on patent and/or exclusivity protections ("earliest lawful ANDA approval date"),” the agency said.

The previous final version of the guidance was released in September 2020. It details the agency’s policies based on performance goals agreed with the industry under the latest Generic Drug User Fee Amendment (GDUFA III) deal.

It also discusses how the FDA plans to address ANDA sponsor requests for final approval that meet GDUFA III expectations—and clarifies the patent certification process and exclusivities and how they may affect ANDA approval times.

“The timing of ANDA approval depends on, among other things, the patent and/or exclusivity protections for the RLD … An ANDA must contain an appropriate patent certification for each patent that claims the RLD or a method of using the RLD for which the ANDA applicant seeks approval in its ANDA and for which the NDA applicant is required to submit information.”

The sponsor is required to submit one out of four certifications to the FDA concerning the patent in question. These include:

• a certification that the patent information has not been filed;

• a certification stating that the patent has expired;

• a certification specifying the expiry date of the patent, or

• a certification claiming that the patent is invalid, unenforceable, or willing to be infringed by the patent-holding manufacturer.

The FDA notes that if a sponsor submits the first two types of certifications, it will not delay their ANDA approval. But if a sponsor submits the third kind of certification, they will have to wait until the patent has expired. Sponsors may also challenge a patent or argue that the patent-holding manufacturer is willing to allow their patent to be infringed by submitting the fourth kind of certification.

Below, we briefly distill the key points of the guidance and provide some recommendations for impacted firms in light of it.

Background

The guidance’s background sets the stage for understanding the complexities of the ANDA process and the nuances of submitting amendments and requests for final approval.

The agency highlights the evolution of its approach to managing generic drug approvals and the ongoing efforts to streamline the process.

There are four key elements here:

• Generic Drug User Fee Amendments (GDUFA): Originating with the GDUFA I in 2012, this set of amendments to the Federal FD&C Act authorized the FDA to collect fees to enhance resources for ensuring the availability of safe, effective, and high-quality generic drugs. GDUFA has been reauthorized every five years, with the most recent reauthorization being GDUFA of 2022. These amendments have brought greater predictability and timeliness to the review of generic drug applications.

• ANDA Approval Pathway: The document contrasts the approval process for new drug applications (NDAs) and ANDAs. For NDAs, evidence of safety and effectiveness is required, whereas ANDA applicants rely on the FDA's findings about the reference-listed drug (RLD). ANDAs must demonstrate sameness with the RLD in various aspects, including active ingredients, dosage form, and strength, among others.

• Patent Certifications and Exclusivities — Effect on Timing of ANDA Approval: The timing of ANDA approval is influenced by patent and/or exclusivity protections of the RLD. The ANDA must contain appropriate patent certifications for each patent that claims the RLD. The type of certification submitted (I, II, III, or IV) affects the timing of ANDA approval.

• Tentative Approval and Amendments to Tentatively Approved ANDAs: When an ANDA meets approval requirements but cannot receive final approval due to patent or exclusivity reasons, it receives Tentative Approval (TA). The document discusses how amendments to tentatively approved ANDAs are handled, including their impact on the timing of final approval.

Amendments to tentatively approved ANDAs

Regulators lay out the review process and goals for amendments submitted to tentatively approved ANDAs. The revised guidance details how the FDA classifies and reviews these amendments, including the distinction between different types of amendments and the associated review goal dates.

The section also explains the impact of submitting an amendment on the status of a tentatively approved ANDA, discussing how the FDA's internal status of the ANDA changes upon submission and how this affects the approval process.

Breaking it down further:

• Review Goals for Amendments Other Than Requests for Final Approval: Amendments submitted after an ANDA receives Tentative Approval (TA) are subject to review goals outlined in the GDUFA III commitment letter. These amendments are classified based on their content and assigned a review goal date accordingly. FDA may defer the assessment of certain amendments if the earliest lawful approval date for the ANDA is several years away.

• Status of a Tentatively Approved ANDA Upon Submission of an Amendment: Submission of an amendment changes the status of the ANDA in FDA's internal systems from TA to under review or complete response, depending on the nature of the amendment and the agency's response.

Submission of and review goals for requests for final approval

This section emphasizes that final approval for an ANDA is not automatic upon the expiration of patent or exclusivity periods.

Applicants with a tentatively approved ANDA must explicitly request final approval through an amendment. The timing of this submission is crucial and should be aligned with the GDUFA III commitment letter's review goal dates.

The document provides specific guidance on submission timelines based on the duration of TA status before the earliest lawful approval date.

• General Approach: Again, the FDA does not automatically grant final approval upon the expiration of patent or exclusivity barriers. Applicants with an ANDA in TA status must submit an amendment explicitly requesting final approval.

• Timing of Submission: The submission timing for final approval requests should be planned based on when TA was granted, considering possible review goal dates.

• Applications With TA Status Less Than 3 Years Before Approval Date: These should be submitted at least 3 months before the sought approval date if they contain no new data or changes (considered minor amendments).

• Applications Granted TA Status 3 or More Years Before Approval Date: These may require a more extensive assessment, and it's recommended to submit requests at least 10 months before the approval date.

Post-TA changes that may impact final approval

Here, the FDA lists common developments that may necessitate amendments to a tentatively approved ANDA before final approval. These include updates in product quality, bioequivalence, labeling, Orange Book listing, patent, and exclusivity.

The agency advises ANDA applicants to consider whether such changes would be classified as major or minor and to plan their submissions accordingly.

Content of requests for final approval

The final section provides detailed guidance on what should be included in requests for final approval.

It underscores the need for applicants to document all changes made to the ANDA since TA was granted. This includes:

• A complete and accurate Form FDA 356h.

• A clear statement of any changes (editorial or substantive) to the ANDA.

• A side-by-side labeling comparison if there have been changes in labeling.

Our recommendations

In light of this revised final guidance, impacted firms should consider the following action items:

• Ensure timely submission of amendments. Plan and submit amendments to tentatively approved ANDAs well in advance of the earliest lawful approval date, considering the different review goal dates for major or minor amendments as outlined in the GDUFA III commitment letter. We recommend reviewing the GDUFA III commitment letter for amendment review timelines and setting internal reminders for submission deadlines.