Generic Drug User Fee Amendments (GDUFA) III
- The Generic Drug User Fee Agreement (GDUFA) was first passed in 2012 as part of the FDA Safety and Innovation Act (FDASIA) to bolster FDA’s resources for the review and approval of generic drugs. Like the other FDA user fee agreements, the program is reauthorized every five years following years of negotiations between industry and FDA on the specific priorities and programs each entity hopes to see the Agency work on as a result of the additional fees industry agrees to pay. 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. Once the groups reach an agreement on the enhancements the user fees will be used for, the “ Commitment Letter” (or “Goals Letter”) is sent to Congress for reauthorization.
- One of the core goals of the GDUFA program has been to increase the efficiency of the generic drug review program. As a result of GDUFA enhancements (and related efforts under FDA’s Drug Competition Action Program), the Agency has issued several new policies to streamline the generic review process, including the guidance document Good ANDA Submission Practices (finalized January 2022) and the Manual of Policies and Procedures (MAPP), Good ANDA Assessment Practices. It’s within these documents and several other relatively recent MAPPs and guidances that FDA has finally provided definitions and clear criteria for how reviewers evaluate and determine the status of Abbreviated New Drug Applications (ANDAs) – the application type FDA uses to review and approve generic drugs.
- The generic drug user fee program is currently on its third iteration (i.e., GDUFA III), which reauthorized the program through 2027. Under GDUFA III, the Agency agreed to improve and expand upon the various meeting types which generic drug developers can take advantage of to discuss issues relevant to their development programs with FDA. For one, the agency created a new set of meeting types for applicants working on products that are covered by one of FDA’s product-specific guidances (PSGs) – a type of guidance which provides generic drug sponsors with a recommendation on how to demonstrate generic equivalence for a prospective drug. Now, sponsors with generic drugs already under development, which a new or recently revised PSG could impact, are eligible to request a meeting with FDA to determine how they should proceed. Depending on whether or not they have already submitted their application, sponsors in this situation can request either a pre-submission PSG meeting or a post-submission PSG meeting. Furthermore, they can now specify their preferred format: face-to-face, videoconference, teleconference, or written response only (though the FDA may overrule some format requests). [Read more about PSG meetings under GDUFA III here]
- For sponsors of other types of generic drugs (i.e., which are not subject to PSGs), there are six meeting types under GDUFA III that may be requested: Product Development (or, PDEV) Meetings, Pre-Submission (PSUB) Meetings, Mid-Cycle Review Meetings, Enhanced Mid-Cycle Review Meetings, Post-Complete Response Letter (CRL) Clarification Teleconference Meetings, and Post-CRL Scientific Meetings. Before making a meeting request, applicants should determine which type is most appropriate by considering their stage of product development, whether their product is considered complex or non-complex, and the scope of the topic they wish to discuss with the FDA.
- Determining eligibility for different meeting types: Applicants eligible to request PDEV and PSUB meetings are those with complex products who have not yet submitted their applications (i.e., they are in the pre-ANDA stage of development). In contrast, sponsors with complex products who have submitted their ANDAs may be eligible for one of the mid-cycle review meetings if they have questions about deficiencies identified by the FDA or their proposed solutions to such deficiencies. Lastly, sponsors who have received a CRL from FDA at any point during product development can request scientific advice from the agency or clarification regarding deficiencies cited in a CRL via the last two meeting types mentioned above.
Yesterday, the FDA held a meeting to clarify how pre-submission meetings have changed under GDUFA III.
- Over the course of an afternoon on May 9, 2023 speakers from FDA’s Center for Drugs Evaluation and Research (CDER) described when pre-submission meeting requests are appropriate, what the expectations are for applicants prior to and during these meetings; and how the FDA has redesigned PSUB meetings under GDUFA III. Before jumping into what we heard at the meeting though, a quick reminder that the purpose of a pre-submission meeting—per the GDUFA III commitment letter—is to “provide an applicant the opportunity to present unique or novel data or information that will be included in the ANDA submission such as formulation, key studies, justifications, and/or methods used in product development, as well as the interrelationship of the data and information in the ANDA.”
- What types of questions or topics can be addressed via a PSUB meeting? A Supervisory Regulatory Health Project Manager within the FDA’s Office of Generic Drugs (OGD), KAREN BENGTSON, explained that PSUB meetings should be used to “present unique or novel data or information that will be included in an ANDA submission.” This allows for generic drug developers to “orient identified FDA assessors in preparation for review of your upcoming ANDA submission and receive feedback on items or information that should be clarified.” However, she emphasized that these meetings should not be thought of as an opportunity for reviewers to check over an application and tell applicants whether it would be considered acceptable for receipt. Instead, the meetings should be narrowly focused on clarifying one specific aspect of an application, such as a decision regarding product formulation, methods used in product development, or the “interrelationship of the data and information” contained in the application.
- What should be provided by sponsors in the PSUB meeting request? Two items should be submitted concurrently to the FDA by sponsors seeking a PSUB meeting: 1) the actual meeting request and 2) the meeting package. Both items should be submitted electronically using CDER’s NextGen Portal. An important factor to keep in mind when prepping materials, said Bengston, is that PSUB meeting requests should not include questions. Moreover, applicants should not request written response only or teleconference meeting formats. However, sponsors should be sure to review FDA’s guidance on formal meetings between FDA and ANDA applicants, include information on the product’s regulatory history, list the main topics which the meeting will focus on, and strongly consider submitting the meeting package in draft presentation format. Requests should generally be submitted around 6-8 months ahead of ANDA submission.
- What to expect on the day of the meeting? Meetings run about one hour total and should flow according to the applicant’s presentation. While FDA attendees may ask clarifying questions about the presentation and will attempt to inform applicants of any items or information that should be clarified prior to ANDA submission, they will not address specific questions (e.g., Is the application acceptable for filing?). The intended outcome of PSUB meetings for FDA assessors, explained YAN WANG, Lead Pharmacologist in OGD’s Division of Therapeutic Performance, is that they will come into the application review process with a better understanding of the complex issues to be aware of.
- For ANDA applicants, the PSUB meeting provides several strategic benefits. Aside from meeting the minimum requirements (i.e., that the applicant has yet to submit their ANDA and that their product is considered complex), there are a few additional factors that FDA uses to determine whether to grant or deny a PSUB meeting request. Overall, several panelists during the Q&A portion of the meeting emphasized that FDA prioritizes meeting requests which offer the best “bang for your buck.” In other words, given the FDA’s limited resources, assessors carefully weigh the value a meeting would provide to applicants and reviewers. As a rule, the FDA will grant PSUB meetings to applicants who have already met with the FDA during a product development (PDEV) meeting for the same product, said Bengston. However, GDUFA III also provided FDA “sole discretion” to grant PSUB meetings even when this isn’t the case. If reviewers feel that having a PSUB meeting with an applicant would offer significant benefit, such meetings may be granted to applicants with complex products that haven’t previously been discussing during a PDEV meeting, or even to those planning to submit applications for non-complex products.
- In a joint presentation, Wang and ELEFTHERIA TSAKALOZOU (Senior Pharmacologist & Acting Team Lead of OGD’s Division of Quantitative Methods and Modelling) offered a few, specific examples of situations where requesting a PSUB meeting would be beneficial. The first hypothetical involved a topical gel product with two active pharmaceutical ingredients (APIs). As recommended in the PSG for the product, the applicant sought to demonstrate product sameness using in vitro methods; however, they decided to use a new analytical method for characterizing particle size distribution of APIs in the gel which deviated from the PSG. Additionally, the applicant ran into challenges in attempting to demonstrate that the generic product is equivalent to the reference listed drug (RLD) in API release. In this instance, Wang explained that a PSUB meeting could be used to present these challenges alongside the solutions selected by the sponsor to address these issues. In addition to better understanding the issues, Wang said the FDA may also offer “constructive feedback” on whether additional data should be collected or presented to “facilitate the scientific assessment.” In concluding her remarks, she emphasized that sponsors do not need to wait until their development program is complete to request a PSUB; a meeting can be requested as long as the studies relevant to that particular issue have been completed.
- The next two examples, provided by Tsakalozou, focused uniquely on the use of PSUB meetings when applicants are considering the use of a modeling and simulation approach. While she stated that questions about whether the use of a modeling and simulation approach—or any alternative approach, for that matter—is acceptable are outside the scope of PSUB meetings, they do offer an “excellent venue” for applicants to discuss the proper documentation to be submitted when a modeling and simulation approach is used. Since these techniques are typically leveraged by ANDA applicants as an alternative method to demonstrate bioequivalence (BE), Tsakalozou underscored that “proper communication [about the approach] is extremely important.”
- In particular, ANDA applicants that use modeling and simulation approaches need to indicate the source of the data used. Applicants should identify whether the data is “generated by the applicant, within the scope of the ANDA, or if the applicant is including in their submission relevant datasets that are provided but have not been generated within the scope of the ANDA.” For example, Tsakalozou said it’s very common for modeling and simulation approaches to draw information from literature sources. As the underlying dataset plays a critical role in developing a model under certain assumptions, sponsors should clearly reference the specific dataset used within the study protocol, study reports, and when describing the specific analyses performed.
- Instances when modeling and simulation can be used as an alternative approach for demonstrating BE: In one example, Tsakalozou described an orally inhaled drug product (OIDP) where the hypothetical PSG recommends a combined in vitro and in vivo approach to demonstrating bioequivalence. For the in vivo portion, the guidance states that applicants should conduct: 1) An in vivo pharmacokinetics (PK) study in fasting condition for both product strengths with healthy volunteers, and 2) an in vivo comparative clinical endpoint or pharmacodynamic (PD) study with patients.” However, she said that an applicant might, instead, choose to forego the second in vivo study and use “alternative in vitro and in silico studies, including in silico regional deposition model.” In this case, she said that a PSUB meeting could be proposed by the applicant to ensure that the “critical components of the modeling and simulation approach within the alternative BE approach they’re proposing are accurately captured in their ANDA submission.” Likewise, a PSUB meeting could also be leveraged to “ensure that all the information regarding the validation of their proposed model for its intended purpose will be included in their prospective ANDA submission.”
- Overall, PSUB meetings have been redesigned under GDUFA III to improve the efficiency of FDA’s review process and to reduce the number of assessment cycles required for generic product approval. ROBERT LIONBERGER, the Director of OGD’s Office of Research and Standards, clarified why certain changes have been made to the scope and format of the meeting and how they are intended to impact applicants. Perhaps the biggest change to the process is that, while previously, questions could be included in PSUB meeting requests, PSUB meetings are no longer framed as “question-based meetings” between the FDA and ANDA applicants. The new process is meant to enable applicants to describe the complex issues they’ve addressed during their development programs for FDA reviewers, so that the “story” for why certain decisions were made is clear. One of the common misconceptions, per Lionberger, is that ANDA applicants misunderstand the purpose of the PSUB meeting. “You’re not asking like, what studies you should do,” he remarked, “It’s really getting input on what you intend to submit.” They are not meant to gain prospective feedback about a potential approach, but rather for applicants to describe how and why they addressed a certain issue during product development.
- In short, the new meeting process is meant to address topics that are simply easier to explain live during a meeting, versus in a written correspondence. This is also part of the reason that the redesigned process has done away with allowing for written communications back and forth between applicants and FDA prior to the meeting, said Lionberger. Another factor in making this change was to increase the speed at which applicants could get feedback from the FDA. To fully take advantage of the new meeting format, he suggested that applicants think carefully about the timing of their requests in terms of their anticipated submission date. “You don’t have to have your submission complete when you submit it—you have to know what you’re going to submit… The studies can be in progress, the stability data can be still running out, etc.”
- His advice to sponsors considering the use of a PSUB meeting? “I think what will make this successful is really recognizing how this is different than other meetings and to try and take advantage of its unique features and the higher speed of interaction, and then fit that into your development program,” he concluded.
To contact the author of this analysis, please email Rachel Coe ( rcoe@agencyiq.com)
To contact the editor of this analysis, please email Alexander Gaffney ( agaffney@agencyiq.com)