The FDA has taken action to accelerate the approval of Abbreviated New Drug Applications (“ANDAs”). With a goal of reducing the number of review cycles needed to reach approval, the FDA will save generic drug companies money on the cost of approval and simultaneously facilitate earlier market entry of generic drug products. On January 3, 2018, the FDA released two important documents aimed at streamlining and improving the submission and review of ANDAs. The first is a draft guidance for industry titled “Good ANDA Submission Practices”; the second is a new Manual of Policies and Procedures (“MAPP”) titled “Good ANDA Assessment Practices.” This represents the FDA’s latest efforts to promote generic competition as it continues to implement its Drug Competition Action Plan.
The draft guidance underscores common defects in ANDA submissions that frequently slow the approval process. A major cause of delay in ANDA approvals can be tied to repetitive review cycles that many ANDAs must undergo. A typical ANDA requires an average of four review cycles before reaching approval. These additional review cycles increase the cost and decrease the efficiency of approval. The extra cycles are often unnecessary – ANDAs are many times submitted without all of the information that the FDA needs to determine whether the ANDA meets FDA standards for approval. The draft guidance has been devised to assist applicants in averting the most common defects in ANDA submissions that cause delays in approval and lead to unnecessary additional review cycles.
The draft guidance specifically addresses deficiencies commonly arising with respect to four components of ANDA submissions: patents and exclusivities, labeling, product quality, and bioequivalence. We highlight some of the important takeaways of the guidance below.
Regarding patents and exclusivities, applicants often do not submit required information concerning the timely dispatch of a Paragraph IV notice letter, filing of a legal action by a patent owner, or failure by a patent owner to file any such legal action within the specified time frame. Also, when a new patent is listed for an Reference Listed Drug (“RLD”), applicants mistakenly file “serial submissions” of amendments to their paragraph IV certifications before FDA regulations allow such amendment or, alternatively, fail to provide the requisite certification for a newly listed patent altogether.
With respect to labeling deficiencies, applicants have improperly submitted draft container labels that do not accurately portray the formatting factors used with the final printed labels. Also, applicants have submitted container labels with insufficient color differentiation for the different strengths of a drug product. For parenteral drug products, applicants have mistakenly proposed package types that differ from the type approved for the RLD.
Regarding product quality deficiencies, the draft guidance addresses common issues associated with in vitro dissolution (biopharmaceutics) and manufacturing facilities, among many other subtopics. For in vitro dissolution testing, applicants commonly omit solubility data for the full physiologic pH range, a detailed description of the proposed dissolution test for evaluation of the product (including developmental parameters used in selecting the proposed method), data demonstrating the dissolution method’s discriminating ability, and complete dissolution data and information for all strengths of the test and reference products. For manufacturing facilities, applicants frequently neglect to provide complete information in their Form FDA 356h and in the correct modules within their applications.
With respect to bioequivalence deficiencies, applicants should include in their bioanalytical study reports complete dilution integrity data (as well as stock stability and recovery data), analytical raw data from all study runs, serially selected chromatograms (representing 20% of study subjects), and bioanalytical standard operating procedures. For differences in formulations and inactive ingredients, applicants have sometimes failed to provide necessary justifications and documentation addressing these differences. If a different inactive ingredient or amount of an inactive ingredient was used in a placebo test formulation for bioequivalence testing, then the applicant must explain why this change did not affect their showing of bioequivalence of the proposed drug product to the RLD.
While the draft guidance addresses ANDA submissions, the new MAPP intends to improve the review of those ANDAs by the FDA. The new MAPP requires ANDA reviewers to be more detailed in their communications with applicants. If a reviewer determines that an ANDA cannot currently be approved, then the reviewer should thoroughly explain any defects in the application, describe the nature of any missing information, and provide detail on how said missing information should be submitted. The stated goal of this new MAPP “is to make sure that generic drug makers are made fully aware of the problems that are delaying the approval of their application and understand how to fix them.” This, in turn, should improve the efficiency of the ANDA review process and consequently lessen the amount of time and money it takes to reach approval.
The FDA believes that this pair of documents will continue to accentuate recent trends at the FDA. The FDA approved a record number of generic drugs in 2017; the number of review cycles that a typical ANDA must undergo is decreasing; and the FDA acted on more applications during the second half of 2017 than any other six-month period in its history. Additionally, the FDA plans to make it harder for brand companies to delay generic entry into the market by issuing further guidance targeted to accelerating generic approvals. Forthcoming guidance to industry will target abuses of the citizen petition process, improper restrictions on access to branded drugs for testing, and inappropriate treatment of the Risk Evaluation and Mitigation Strategy (“REMS”) negotiation process.
The impact of this guidance will continue to alter the ANDA submission, review, and approval process going forward.