Under the GDUFA III Commitment Letter, the FDA was instructed to begin holding teleconferences and meetings related to Product-Specific Guidances (PSGs) – effectively instructions for how generic drugs can demonstrate bioequivalence to obtain FDA approval. FDA is now out with a draft guidance explaining in detail how these meetings will work and how sponsors may request them. But as our analysis shows, there’s quite a bit that may surprise industry, relative to what they had previously negotiated.
- Unlike new drug products, generic drugs do not require extensive clinical evidence to demonstrate safety or efficacy. Rather, under the terms of the 1984 Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Act), a generic drug must only show that it is bioequivalent to the reference listed drug (RLD). Under federal law, companies are required to show that “the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions.”
- Demonstrating bioequivalence can still be difficult, though. In order to help generic drug manufacturers navigate this process and increase the likelihood of generating appropriate regulatory data, the FDA publishes product-specific guidance (PSG) documents which detail how a company can demonstrate that its product is generic to the RLD through bioequivalence testing. There are more than 2,000 PSGs available from the FDA.
- PSGs typically outline key study considerations for prospective generic drug developments to follow, including the number of studies to be conducted, the types of studies (such as fed or fasting), the design of the study (e.g., crossover design, the number of periods and number of doses), specific measurements to take, the timing of measurements, specific concerns such as interactions with alcohol, and any waivers available for use.
- Since the passage of the first Generic Drug User Fee Amendments (GDUFA) in 2012, the FDA has provided extensive research funding in support of the approval of complex generic products through advances in regulatory science, which in turn are often reflected in new PSGs..
- GDUFA II renovated the complex generic drug development and approval process. In 2016, the FDA committed to various programs to enhance the pathway for complex products including guidance and policies for product development meetings, pre submission meetings, and mid-review cycle meetings; complex controlled correspondence; and – notably – PSGs.
- In 2022, Congress reauthorized GDUFA for a second time, passing GDUFA III. The program is intended to provide the FDA with financial resources to support the efficient review of generic drug products.
- A key part of the reauthorization process was the negotiation of the GDUFA III commitment letter, which was then approved by the FDA, industry and Congress. The letter, also known the “goals letter,” includes programmatic changes that the FDA commits to in return for additional user fee funding from industry. Among the specific commitments in the GDUFA III letter were several related to PSGs.
- Specifically, FDA committed to continuing to release PSGs “identifying the methodology for generating evidence needed to support [an Abbreviated New Drug Application] ANDA approval.” Further, FDA committed to releasing PSGs for 50% of all drug products approved under the New Drug Application (NDA) pathway within 2 years of the date of approval, and 75% within 3 years of approval. FDA is also set to provide information on “upcoming new and revised PSGs” to help support generic drug development efforts, with updates to this list occurring every 4 months and additional information about how it plans to prioritize development. Industry would also be able to request that FDA develop specific PSGs, and FDA would solicit public feedback on its prioritization of PSGs each year.
- But perhaps the most interesting commitment related to PSGs in FDA’s goals letter is a new set of PSG-specific meeting types. For example, there is now a PSG Teleconference, which is intended to allow a sponsor of a prospective generic drug that is already in development “to obtain Agency feedback on the potential impact of the new or revised PSG on its development program.” This hour-long meeting would be held within 30 days of the meeting request, and the sponsor would need to provide the FDA with the relevant in vivo study protocol.
- Sponsors wishing to obtain additional feedback after a PSG Teleconference would be able to make use of FDA’s Controlled Correspondence process or, alternatively, request an additional meeting of the types known as Pre- and Post-Submission PSG Meetings. “The purpose of this meeting is to provide a forum in which industry can discuss the scientific rationale for an approach other than the approach recommended in the PSG to ensure that the approach complies with the relevant statutes and regulations,” the letter explains. These meetings are granted or denied within 14 days of the sponsor’s request, and then take place within 120 or 90 days (respectively).
Now the FDA has published a new draft guidance document on the PSG meeting process, offering additional details on the meeting types
- The guidance, Product-Specific Guidance Meetings Between FDA and ANDA Applicants Under GDUFA, is focused on PSG meetings (pre- and post-submission) and PSG teleconferences. While significant portions of the guidance are simply repeating what FDA has already agreed to in the Commitment Letter, it does contain additional specific details about the meeting process.
- This analysis is going to focus on the things that FDA is asking for that aren’t included in the Commitment Letter, as we expect those to be both most helpful and most likely to attract industry criticism.
- The guidance clarifies that PSG teleconferences may either take place before or after the submission of an ANDA (pre-submission PSG teleconference and post-submission PSG teleconference), which is a specific terminology not included in the Commitment Letter.
- FDA advises that PSG teleconferences and meetings that occur after submission should still occur “before responding to a possible [bioequivalence] BE deficiency identified in a discipline review letter (DRL) or a BE deficiency identified in a complete response letter (CRL).” That operational process is meant to improve a company’s ability to respond to any identified deficiencies – or argue for a different BE approach.
- When it comes to the PSG teleconference itself, FDA notes that it will provide feedback on the potential impact of the recommendations in its PSG, but will not “discuss the applicant’s questions regarding an approach” other than the one in the PSG. If a sponsor wishes to discuss that topic, they may do so in a PSG meeting, controlled correspondence, or another meeting type offered by the FDA. The guidance also notes that FDA will generally look favorably upon the submission of in vivo BE data, even if the relevant PSG has recommended the submission of in vitro BE data. “Therefore, applicants in such a situation in general should not request a PSG teleconference,” according to the draft guidance, which also adds that an applicant should “include supporting information with its ANDA to justify the in vivo approach used that deviates from the in vitro approach recommended in the PSG to demonstrate BE.”
- FDA’s timeline for PSG teleconferences: Another detail not in the guidance is FDA’s request that sponsors “submit a request for a PSG teleconference within 60 days after publication of the new or revised PSG so that FDA can provide timely feedback to applicants.” It also noted that FDA has “agreed to hold a PSG teleconference within 30 days after the receipt of the meeting request if the request is granted,” but only if the PSG teleconference is submitted within 60 days after the PSG publication. However, we are unable to locate where this 60-day requirement is in the Commitment Letter, and the draft guidance doesn’t substantiate this claim, either.
- Asking for additional information: In the commitment letter, FDA asks applicants to submit just one piece of information along with their meeting request for a PSG Teleconference: “the signature page of the relevant in vivo study protocol signed by the study sponsor and/or the contract research organization.” FDA’s guidance, however, asks for additional information, including the title page and protocol summary of the in vivo BE study.
- Additional opportunities for post-submission teleconferences: The term “post-submission PSG teleconference” does not exist in the Commitment Letter, but in FDA’s guidance, it is specific enough that FDA explains that sponsors can benefit in two additional situations that FDA acknowledges are “not described in the GDUFA III Commitment Letter.” First, an applicant can request a post-submission PSG teleconference “when FDA publishes a new PSG which includes a recommendation to conduct an in vivo BE study and the ANDA applicant did not conduct an in vivo BE study.” Second, an applicant can make a request for the meeting “when FDA publishes a revised PSG which includes a recommendation to conduct an in vivo BE study, the previous PSG did not include a recommendation to conduct an in vivo BE study, and the ANDA applicant commenced or completed the in vitro BE study or studies either that were recommended by FDA in the previous PSG or that the ANDA applicant decided to pursue after a prior product development meeting.”
- Don’t mix your meetings: FDA’s guidance notes that an applicant should not request any PSG meeting or teleconference “if the applicant has requested or has been granted but not yet had another meeting with FDA, such as a pre-submission meeting, an enhanced mid-cycle review meeting, or a post-CRL scientific meeting.” Applicants are also advised not to submit controlled correspondence around the same time they might have a meeting “with the same or similar questions,” or else FDA will determine “which request to grant and may deny the other(s).”
- Make submissions through the CDER Direct NextGen Collaboration Portal, the guidance advises. Specifically, applicants should request a teleconference or a meeting through the Enterprise Submission Gateway (ESG). The document also contains a list of between 10-12 pieces of information that each applicant should include in their submission, such as the ANDA number, the meeting type requested, the RLD and application number, the meeting package, and (for certain submissions) a brief history of the development program and the status of development.
- What does a rejection look like? FDA’s guidance explains the reasons why it may deny a PGS meeting or teleconference request. Reasons include an incomplete request, if an in vivo BE study started after the PSG was published, if a teleconference was not held before a meeting was requested, if the inquiry would be better handled through controlled correspondence, if the request for information is duplicative, or if the applicant already responded to the possible BE deficiency.
- How meetings will actually happen: FDA’s guidance explains that PSG teleconferences and meetings will be chaired by an FDA staff member, and generally contain either no or minimal presentations to make more time for discussion (“the length of the meeting will not be increased to accommodate a presentation”). Prior to the end of the meeting, FDA attendees and the applicant attendees “should summarize the important discussion points, agreements, clarifications, and action items,” which should then be agreed to by FDA staff.
- This draft guidance includes a lot of detail – including quite a few details that are likely to serve as a surprise for industry. Because of the many different types of meetings (meetings and teleconferences; controlled correspondence; and pre- and post-submission variants), much of the guidance feels repetitive and it wouldn’t surprise us if industry asks the FDA to figure out a way to consolidate this information somewhat.
- Much of this guidance is pretty routine, with descriptions of the practical details of how to submit requests and what to include.
- But the biggest concern for industry is likely the extent to which this guidance differs in some meaningful ways from the commitment letter that it signed with the FDA. For example, we made note of several instances in which FDA requests information that wasn’t made explicit in the commitment letter, or says it doesn’t intend to review requests that fall outside of specific timelines. Let’s be clear: While that stance is generally reasonable for the FDA to make (to facilitate efficient reviews), guidance documents should be about interpreting existing requirements – not creating new ones. If we see comments from generics companies or its industry groups, we expect that they’ll likely be focused on this point.
- Comments on the draft guidance are due on April 22, 2023.
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])