FDA officials discuss strategies for answer-ready controlled correspondence
To ensure that the US Food and Drug Administration (FDA) address questions raised by the generic drugmakers through controlled correspondence, sponsors need to ensure that sure that submissions are complete, have a valid letter of authorization, and have valid formulation information.They also noted that for quality-related control correspondence, applicants should submit a separate controlled correspondence for each specific discipline, and discussed the most common questions the agency receives via controlled correspondence pertaining to bioequivalence. These insights were presented by FDA officials at the 10 April Generic Drug Forum (GDF), which was held virtually and onsite in Bethesda, MD.
FDA issued a final guidance in March 2024 setting out the process for how generic drug manufacturers can submit controlled correspondence when requesting information related to their applications. Such correspondence can reflect a specific element of generic drug product development prior to submitting an application or can be related to postapproval submission requirements. Some of the changes compared to the GDUFA II program are the establishment of a level 1 category and a level 2 category for controlled correspondence requests.
Controlled correspondence can be sent to a number of divisions within the agency, including the Office of Generic Drug’s (OGD) Office of Bioequivalence, OGD’s Office of Research and Standards Evaluation, OGD’s Office of Safety and Clinical Evaluation, and the Office of Pharmaceutical Quality (OPQ).
Consistency in acceptable filings
Marcia Fields, a controlled correspondence coordinator for the Office of Regulatory Operations (ORO) in FDA’s Center for Drug Evaluation and Research (CDER), said the percentage of valid and non-valid controlled correspondence has been pretty consistent over the years; 67% of such correspondence were deemed acceptable while 33% were not deemed adequate from FY 2019 to FY 2023.
To ensure their correspondence is answered, applicants should confirm that documents are submitted on corporate letterhead, include complete contact information, and attach a letter of authorization, if applicable.
Some common reasons why correspondence is rejected are due to missing or an expired letter of authorization, the key quantitative and qualitative formulation information, or Q1 and Q2 data does not reflect ANDA submission, or the submission is incomplete.
Quality related controlled correspondence
Jennifer Anim, a pharmacologist and policy lead with CDER’s OPQ, offered some tips on best practices for submitting answerable quality-related controlled correspondence.
She said that these correspondences should be submitted to each division for which there is a question. For example, questions related to the drug product should be submitted to the drug product division within OPQ and not the drug substance and manufacturing divisions. Also, if applicable, applicants should include a copy of the complete response letter (CRL) with the correspondence.
Certain questions cannot be answered in a quality-related controlled correspondence, these include the acceptability of a specification, in-process control or study plans, the acceptability of an overage of active pharmaceutical ingredient (API) in the final product, the approach for impurity clearance, the adequacy of characterization studies, and proprietary information from the reference listed drug (RLD).
The top questions for quality-related correspondence in 2023 were related to bracketing and matrixing and were raised in 15.8% of the correspondence, followed by questions on stability data (15.4%), and packaging questions (11.9%), Other top areas were related to batch size, container closures, and microbiology.
Zhen Zhang, a master pharmacologist with OGD’s Division of Bioequivalence (DB) said that OGD received 903 bioequivalence-related controlled correspondences from April 2021 to March 2023. Among them, the most common related to the maximum daily exposure (MDE) of inactive ingredients with 759 correspondences, followed by 43 correspondences related to retention samples associated with in vivo pharmacokinetic (PK) BE and in vitro BE studies, while 101 correspondences fell into other categories.
Generic Drug Forum
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