The US Food and Drug Administration (FDA) has finalized its guidance to generic drug manufacturers on how to seek drug development information through the controlled correspondence process. The guidance incorporates changes that were part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA II). Revisions include clarification about how the agency handles controlled correspondence related to a pending petition, what information should be submitted for requests related to an inactive ingredient, and when the agency may determine that an inquiry is a “complex” controlled correspondence.
Standard vs. complex
The final guidance defines “standard” versus “complex” controlled correspondence. Standard submissions are requests for information on a specific element of generic drug product development or are related to post-approval submission requirements that are not covered in guidance and are not specific to an abbreviated new drug application (ANDA).
Complex submissions, on the other hand, involve the evaluation of clinical content or the review of bioequivalence (BE) protocols for drugs that reference listed drugs with risk evaluation and mitigation strategies (REMS) with elements to assure safe use (ETASU). Additionally, complex controlled correspondence could involve requested evaluations of alternative BE approaches within the same study type, such as pharmacokinetic, in vitro, or clinical.
Pending petitions, matters under consideration
In the case of requests that are related to pending petitions (citizen petitions, petitions for stay of action, or petitions for administrative reconsideration of action), the agency does not start its response to the controlled correspondence until it has responded to the petition. Requesters will not be notified that the FDA has started its review of the controlled correspondence. Instead, the agency advises requesters to monitor the status of petitions at https://www.regulations.gov/.
If a controlled correspondence request is related to a matter under active consideration by the FDA, the request will stay open until the FDA issues a response.
When requesters are seeking clarification on an existing controlled correspondence response that they consider ambiguous, they must submit their request for clarification within 7 calendar days of the FDA original response. If the request is not sent within 7 days, the agency will consider it to be a new controlled correspondence.
Inactive ingredients
The guidance also clarifies what information requesters should include when seeking information on inactive ingredients in a drug product. The FDA recommends that requesters submit no more than three inactive ingredients for evaluation in a controlled correspondence, and no more than three proposed levels for a drug product. Requests should also identify the reference listed drug (RLD), including the specific drug product strength.
“The Agency believes this is a reasonable limit based on what can be evaluated for a particular drug product within the GDUFA II goal date period. This also encourages applicants to provide targeted submissions to the Agency and allows applicants to refine their subsequent formulation proposals based on FDA’s previous responses,” the FDA wrote.
Outside controlled correspondence scope
Not all requests for information from generic manufacturers are appropriate for the controlled correspondence process.
“For example, a pre-ANDA meeting may provide a better forum in which to discuss certain issues, such as methods of characterization for complex products or clinically critical BE considerations. Other topics that are general in nature would be more appropriately considered as part of the Regulatory Science Initiative, such as the proposed use of in vitro data to support demonstration of BE for a class of [RLD] products for which no ANDAs have been submitted,” the agency wrote in the final guidance.
Specifically, the agency will address BE guidance requests as part of the public process described in the Agency’s guidance for industry on “Bioequivalence Recommendations for Specific Products” and FDA’s good guidance practices regulation. The FDA is also excluding requests for BE clinical protocol review from controlled correspondence if the RLD product is not subject to REMS ETASU. Additionally, pre-ANDA meeting requests are not considered controlled correspondence.
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