Draft FDA guidance clarifies a new process to boost competition, speed generic drugs in emergencies

A new process created by the GDUFA III Commitment Letter, and outlined in an FDA draft guidance document published this week, has potential to accelerate the review of a subset of generic drugs by allowing the FDA to more quickly review Drug Master Files – a type of submission containing detailed, confidential information about the way that a product is made by another company. For prospective sponsors of some generic drugs, including those intended to address public health emergencies and drug shortages, the new approach could confer significant benefits.

Regulatory background

• The Generic Drug User Fee Program is a negotiated series of commitments made between the FDA and industry. In short, its aim to is provide additional resources for the FDA (paid for by industry through various fees) that the agency will then use to hire additional staff and make other programmatic and operational improvements. Ultimately, industry is wagering that increased regulatory efficiency – which it pays for – will benefit its products through faster review times, more certainty and more time on the market for its products.
• The GDUFA program was first passed in 2012 as part of the FDA Safety and Innovation Act (FDASIA) and is now on its second reauthorization. The latest reauthorization is known as GDUFA III. In additional to legislation that reauthorizes the GDUFA program, a Congressionally-approved “ Commitment Letter” (or “Goals Letter”) details the “performance goals and program enhancements” to be made as part of the program. The letter describes things like the specific number of staff the FDA plans to hire, review times for various types of applications submitted to the FDA, new meeting types and more.
• The program goals represent a commitment by both the FDA and industry. It is understood that the FDA may be unable to meet specific commitments if, for example, industry’s applications do not meet regulatory expectations for completeness or quality. As a result, the FDA’s guidance documents describing how companies should meet their obligations related to GDUFA III are critical.
• AgencyIQ has compiled a list of all the Commitments under GDUFA III and when the FDA is expected to meet them, which you can read here.
• Among the commitments made in GDUFA III are several related to the review of Drug Master Files (DMFs). A DMF is a type of submission containing detailed, confidential information about the way that a product is made, processed, packaged and stored. While some of this information might ordinarily be contained within a standard drug application (i.e., a New Drug Application or Abbreviated New Drug Application), the benefit of a DMF is that it allows third parties to reference a DMF without the owner of the DMF needing to disclose its contents to the third party. The FDA maintains control of tens of thousands of DMFs.
• There are a few important things to know about DMFs. First, the FDA does not approve or disapprove a DMF; neither are they required by any law or regulation. Rather, they are used as sort of in-depth reference materials for regulators.
• Second, there are four different types of DMFs: Types II, III, IV and Vs. Type II refers to DMFs containing information about a drug substance, intermediates and materials used in preparation. Type III DMFs contain information about a drug’s packaging materials. Type IV DMFs contain information about drug excipients (including colorants, flavors and essences). Finally, Type V DMFs contain FDA-accepted reference information.
• DMFs, especially Type II DMFs, are an important part of the generic drug review process. Type II Active Pharmaceutical Ingredient DMFs are frequently referenced in both full ANDA applications as well as Prior Approval Supplements to ANDAs. This may happen, for example, if a single API manufacturer supplies ingredients to multiple companies.
• To support the use of Type II DMFs for APIs, the FDA has long required the payment of user fees to facilitate its review of DMFs referenced in a submission. Starting in 2012 with the passage of GDUFA I under the FDA Safety and Innovation Act, the agency required the owner of each DMF to pay a one-time fee of $21,340 in FY2013. As of FY2022, that fee had risen to $74,952 per DMF. These fees – paid when the DMF is first referenced in a generic drug submission – help support things like Completeness Assessments, which indicate if the DMF is capable of supporting the approval of other applications or if it has deficiencies.

Each successive user fee program has included additional elements intended to improve upon the DMF use and assessment process.

• For example, the FDA Reauthorization Act of 2017 authored the GDUFA II program and, with it, enhancements such as “first adequate letters to indicate a DMF has no open issues related to the review of a referencing ANDA, no further comment letters, and expanded opportunities for DMF holders to request teleconferences with FDA regarding first cycle DMF deficiency letters.” FDA also issued guidance on post-approval changes to a Type II API DMF and the submission of ANDAs referencing Type II DMFs in an ANDA.

• The latest improvements were made as part of the GDUFA III authorization commitment letter. According to that letter, the FDA is supposed to finish its initial completeness assessment for 90% of Type II API DMFs within 60 days of either the date of DMF submission or payment – whichever is later. In addition, the letter establishes a Pre-Submission Facility Correspondence (PFC) requirement to be submitted along with an ANDA submission that is “complete and accurate,” including information about the DMF and “a certification by the applicant that any Type II DMF has similarly complete and accurate facility information.” This information is meant to facilitate pre-approval inspections – the topic of another FDA guidance published this week.
• The GDUFA III Commitment Letter also contains an extensive section on DMF Assessment Program Enhancements. For example, the FDA is now supposed to ensure that DMF assessment comments are issued roughly simultaneously to both the DMF holder and to the sponsor of the ANDA reliant on the DMF. There is also a new teleconference meeting intended to clarify first-cycle DMF assessment deficiencies, which must be held within 30 days of being requested. A sponsor may also request email correspondence instead of a teleconference.
• FDA is also supposed to issue “First Adequate” letters, indicating that a DMF has been reviewed and there are no further issues, as well as “No Further Comment Letters” to indicate that the DMF has been reviewed and the ANDA referencing the DMF has been approved or tentatively approved.

But perhaps the biggest change under GDUFA III is a new process permitting the FDA to assess certain DMFs even before a generic drug is submitted. Now the FDA is out with a new guidance on that very subject.

• Under the GDUFA III Commitment Letter, a major change is that the holder of a DMF may “submit a request for assessment of the DMF” prior to the planned submission of a generic drug. This applies to the planned submission of an ANDA, an ANDA amendment responding to a Complete Response letter, or an ANDA amendment seeking approval for a product which previously received tentative approval.
• The request must come six months prior to the planned submission of those three types of submissions, and additional caveats apply (all patents must expire within 12 months; the submission may only be for certain types of drugs, such as those in shortage or without much competition; or the drug may help address a public health emergency).
• The benefit is that a generic drug sponsor would avoid a potential bottleneck that might be caused by a DMF. For drugs under development to solve significant public health needs – emergencies, drug shortages, or providing competition to expensive drugs – this review could greatly accelerate development. However, it does come at a cost to the FDA since it will need to review DMFs more quickly than it might have otherwise.
• FDA’s new draft guidance document, Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA, goes into depth on the process for requesting an assessment of a DMF in advance of the submission of certain ANDA submissions and amendments.
• Perhaps the most important point of emphasis is that while the ANDA sponsor is who is likely to benefit from this 6-month head start on the assessment, it’s the DMF holder that is required to take most of the actions. It is the DMF holder who must submit the request for assessment. It is the DMF holder who will likely need to pay the GDUFA user fee. It is the DMF holder who will need to tell the FDA about the ANDA and how it qualifies for the pre-submission assessment. As a result, the FDA recommends “close communication and coordination” between the DMF holder and the ANDA applicant “to maximize the chance of a successful request by ensuring that all appropriate materials are provided with the request.”
• Information that the DMF holder will need to submit includes things like a Letter of Authorization (LOAD) with a pre-assigned ANDA number, information about the Reference-Listed Drug (RLD) on which the generic drug’s approval will be based, and documentation that the DMF holder has paid a GDUFA DMF fee to the FDA.
• There is significant information that a DMF holder may need to submit to the FDA that would only be known to the ANDA holder. This includes information about patents and exclusivities relevant to the RLD (which must expire within 12 months of the planned submission date), the number of competitive products available on the market, the conditions of approval sought by the ANDA sponsor (since labeling “carve-outs” are not permitted under this pathway), whether the drug would alleviate any drug shortages, whether it could address a public health emergency, or whether this is a drug intended to compete with a sole-source drug.
• There are separate but similar criteria for Prior Approval Supplements intended to add a new API source. Those are requirements that the PAS is for a drug product intended to mitigate, resolve or prevent future drug shortages; and that the PAS is for a drug that could help address a public health emergency.
• When it comes to submissions, there are a few things that DMF holders need to know. First, DMF prior assessment is only available for API information – not drug substances themselves. In addition, requests should be limited to a single DMF per API (more than one request won’t be accepted). However, there is one important exception: If the drug product has multiple APIs (for example, a combination product), the FDA will accept one DMF per API included in the drug product.
• FDA also recommends each submission contain a few administrative elements, including an appendix checklist explaining why the DMF holder believes the submission qualified for the DMF prior assessment. That appendix checklist is included in the guidance, and FDA recommends its use by DMF holders to ensure the request meets all eligibility criteria. Requests should be accompanied by an email to [email protected] to “ensure timely processing,” the FDA said.
• Once submitted, the FDA will review the request and come to one of three decisions. It may grant the request, which it would do through the issuance of a “grant letter” sent to the DMF holder. It may decide that additional information is needed, which will come in the form of an Information Request to the DMF holder. Or the FDA may deny the request, which it would do through the issuance of a “deny letter” to the DMF holder. A “deny letter” would also include the “reason for the denial,” according to the FDA.

Analysis

• While much of the guidance reiterates what is already known about the prior assessment requests through the GDUFA III commitment letter, DMF holders should benefit from additional clarity about the submission process and specifically what the FDA is looking for.
• The need for coordination between the DMF holder and the ANDA sponsor is perhaps the most important point in the guidance, since DMF holders are unlikely to have much of that information at their own disposal. The FDA’s checklist is likely to find use not only for submissions, but for conversations preparing for submissions between DMF holders and ANDA sponsors.
• We could easily see this model expanding in future iterations of the GDUFA program. As the guidance notes, this prior assessment model specifically excludes multi-facility requests and requests beyond the API (i.e., drug substance DMFs). Given sufficient resources, the FDA might be able to better address this potential bottleneck in generic drug development.

To contact the author of this analysis, please email Alec Gaffney ( [email protected])
To contact the editor of this analysis, please email Kari Oakes ( [email protected])

Key Documents and Dates

• • • Draft Guidance: Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA
    • Docket Number: FDA-2022-D-2061
    • GDUFA III Commitment Letter
    • FDA Guidance on Completeness Assessments for Type II API DMFs Under GDUFA Guidance for Industry
    • Guidance Document Backup Download: Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA