As Prescribed


While the Biden-Harris administration and US Congress continue to debate ways to address perceived prescription drug pricing concerns, the Food and Drug Administration (FDA) is taking action. Under its Drug Competition Action Plan (DCAP), administered by the Office of Generic Drugs (OGD), FDA has published approximately 24 guidance documents since 2017, directing industry stakeholders on how to develop, prepare, and submit abbreviated new drug applications (ANDAs), so that generic drugs can obtain timely FDA approval and more quickly reach the market. In January 2022, FDA published three more guidance documents in the DCAP series.

By helping to make additional lower-priced generic drugs available, FDA believes it can impact the overall drug price burden. For example, according to the latest Congressional Budget Office (CBO) report, the average net price of a prescription drug in the Medicare Part D and Medicaid programs fell from 2009 to 2018, and that decrease “reflects the increased use of lower-cost generic drugs.” In FDA’s words, the DCAP is “helping remove barriers to generic drug development and market entry in an effort to spur competition so that consumers can get access to the medicines they need at affordable prices.”

When we asked OGD about the significance of the latest three guidances, Maryll Toufanian, Director of the Office of Generic Drug Policy, responded:

As presented in DCAP, FDA understands that it is critical to provide as much transparency as possible into our regulatory expectations. This allows for maximum efficiency for applicants submitting generic drug applications and for our assessment of those applications. Guidances like those recently issued are a key tool in our toolkit for doing so.

Below is a listing of the recently published DCAP guidance documents and a brief description of each. While most of the information has been provided previously to industry stakeholders in various forms, it is important for every company that is planning to submit an ANDA (or has a pending ANDA) to carefully review these published versions of FDA’s advice and update their regulatory procedures accordingly.

Information Requests and Discipline Review Letters Under GDUFA, Guidance for Industry

Updating a 2017 draft, this final guidance details how OGD will provide ANDA applicants with “preliminary thoughts on possible deficiencies” after OGD’s initial assessment for ANDAs submitted between 2018 and 2022 under the Generic Drug User Fee Amendments of 2017 (GDUFA II). Although the future “GDUFA III” legislation will likely change some of the details, this guidance is also instructive for planning purposes for those ANDAs to be filed in 2023 and later.

The guidance explains that, at the mid-point of FDA’s assessment of the first assessment cycle for an ANDA (the mid-cycle date), OGD will send a Discipline Review Letter (DRL) to the ANDA applicant to convey preliminary thoughts on possible application deficiencies. Alternatively, an Information Request (IR) may be sent to request further information or clarification that is needed to proceed with a discipline assessment (e.g., bioequivalence, labeling, or quality). These letters will not be sent, however, when the discipline believes that it can act on the ANDA with the information in the application.

The use of these letters is intended to provide applicants with FDA’s thoughts as soon as possible so that they can amend the ANDAs and keep the assessment process going. FDA hopes that this mid-cycle communication will minimize the number of assessment cycles necessary for approval. Applicants’ responses will not be classified as a major or minor amendment to the ANDA and, thus, will not delay the assessment clock (formerly, the “review clock”), unless the response contains information not requested by FDA or information that requires a more thorough assessment. The letters do not guarantee that a Complete Response Letter (CRL) will not be issued, since the letters reflect the comments of the assessment team but not the input from all supervisory levels within OGD.

Good ANDA Submission Practices, Guidance for Industry

In this guidance, OGD highlights common ANDA deficiencies and provides detailed recommendations, so that ANDA applicants can file compliant submissions under GDUFA II, and avoid CRLs, multiple assessment cycles, and lengthy approval delays. The information is an update of an OGD guidance published in 2018, and further details the OGD program enhancements crafted under GDUFA II. By describing common mistakes, OGD intends to foster the development of high-quality submissions and promote the timely correction of ANDA deficiencies.

The guidance covers almost every type of information that is required in an ANDA, such as patent certifications and exclusivity requirements, labeling, drug substance and drug product descriptions, impurities and intermediates, product quality and manufacturing processes, and bioequivalence and dissolution data. OGD has particular submission and formatting requirements for each eCTD module in all of these areas, so the deficiency descriptions are helpful and may answer questions that have plagued Regulatory Affairs staff.

The guidance also provides useful information for maintaining pending ANDAs, since the initial filing of an ANDA is only step one for obtaining an ANDA approval. During the assessment cycle, applicants must continually update the information in the ANDA related to numerous topics, including Paragraph IV patent litigation, Orange Book changes, manufacturing changes, batch validation and stability data, risk evaluation and mitigation strategy implementation, and launch plans for commercial marketing. Avoiding submission deficiencies when submitting updates to a pending ANDA are just as critical as the initial ANDA submission.

Revising ANDA Labeling Following Revision of the RLD Labeling, Draft Guidance for Industry

This draft guidance updates information that OGD previously published in April 2000 via a guidance of the same name. Twenty-two years later, FDA reminds ANDA holders of their ongoing obligation to ensure that product labeling is accurate, is not false or misleading, and is the “same” as the corresponding reference listed drug (RLD) labeling. For these reasons, after FDA approves relevant changes to the labeling for the RLD, an ANDA holder must update its labeling at the “earliest time possible.” To learn about RLD labeling changes, ANDA applicants and ANDA holders must proactively monitor public information, such as the Drugs@FDA webpage and the CDER New ListServ.

OGD also explains that ANDA labeling changes must be organized according to eCTD modules and submitted in electronic format through the Electronic Submissions Gateway. A side-by-side annotated comparison of the proposed ANDA labeling and approved RLD labeling continues to be required.