Few FDA publications are as eagerly anticipated in the drug development world as the twice-a-decade PDUFA Reauthorization Performance Goals and Procedures (hereinafter the “goals letter”). When FDA published the fiscal years (FY) 2023-2027 goals letter at the end of August, making known their commitments and planned initiatives for the coming years, we were both excited by many of the announcements, while recognizing the real success will come from how the Agency implements them. From new initiatives to facilitate faster reviews for new indications under the Split Real Time Application Review (STAR) pilot program, to bringing new meetings under PDUFA goals, to continued support for rare diseases and incorporation of the patient voice, the goals letter revealed a good number of welcome announcements.
Perhaps the most welcome commitment, both the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research (CDER) plan to hire significantly more drug review staff under PDUFA VII than we had seen under PDUFA VI. The targets for FY 2023 are 132 new hires for CBER and 77 for CDER, representing a tripling and quintupling, respectively, of the equivalent hiring targets for the first FY under PDUFA VI. In total for all FYs, the hiring commitments would equal a jump from 171 (PDUFA VI) to 228 (PDUFA VII) new staff in CBER and 32 (PDUFA VI) to 123 (PDUFA VII) in CDER. However, the hiring targets drop dramatically in both centers in each subsequent FY after FY 2023. We have seen first-hand the difficult task faced by CBER review staff to keep up with the flood of innovative cell and gene therapy products, as well as the taxing influx of COVID-19 pandemic related applications requiring review resources in both Centers. Our hope is that expanding review capacity will have the secondary effect of maintaining staff retention, as there are real concerns over retention from burnout, especially with a large retirement-eligible workforce.
A lasting impact of the COVID-19 pandemic can also be seen in the FY 2023-2027 goals letter. When travel restrictions and public health precautions halt facilities inspections, many sponsors are left wondering how FDA will complete pre-approval inspections and meet their products’ respective PDUFA dates. In response, FDA memorialized its intention to use some of the new tools explored during the pandemic and potentially make them more permanent fixtures of facility inspections (e.g., requesting records in lieu of an inspection, use of information shared by trusted foreign regulatory partners).
While FDA’s plan to use new tools in facilities inspection may be welcome news to those who saw their PDUFA dates extended due to a pending inspection during the pandemic, a far more disappointing consequence of the pandemic can also be seen in the goals letter. FDA appears to be more readily equating in-person with virtual (videoconference) face-to-face meetings. Several small textual changes as well as a footnote buried amidst the meetings goals show FDA using “face-to-face” meetings to mean both in-person and virtual platforms. As our colleagues, Deborah L. Livornese and Josephine M. Torrente, explained in a previous post, in-person meetings create important opportunities for building rapport, and lead to more robust dialogue and collegial relationships between the Agency and sponsors. We echo this sentiment and hope this will merely be an artifact when the pandemic risks subside, which we certainly hope will be before the end of PDUFA VII in 2027.
Meeting requests should still include a statement with “the sponsor’s proposal for either a face-to-face/virtual/teleconference meeting or a written response.” While it’s not clear whether this inclusion of both “face-to-face” and “virtual” was an intentional distinction from earlier references in the goals letter only to “face-to-face” as opposed to an oversight, those who share our concern will have opportunities to voice such concerns during two public meetings. FDA will discuss the goals letter and field public comments, on September 28, 2021 (announcement here), as well as a separate workshop on meetings management practices, which is to be held by July 30, 2024. On the other hand, given that virtual PDUFA meetings held during the pandemic, even when over videoconference platforms like Zoom or WebEx, have been absent of video (with the exception of a few senior officials), we hope that during the time that virtual meetings continue to be necessary, that the intent of this commitment letter to allow them to include video.
Pandemic influences aside, the FY 2023-2027 goals letter contained many notable new initiatives, announcements, and commitments. Some of these will be subjects of more detailed posts in the future and readers should keep an eye on the blog for additional coverage. Below we provide an overview of some of the goals letter’s most notable contents such as new initiatives as well as some large-scale enhancements to programs that have already been in the works. Programs like Advancing Real-World Evidence (RWE) and new commitments to patient focused drug development (PFDD) represent evolutions and formalizations of existing commitments, whereas examples such as STAR and Type D meetings are entirely new. As such, we present these programs and initiatives roughly in order of the newest and most substantial changes to more minor.
1. Split Real Time Application Review (STAR) Pilot Program – FDA announced this new two-stage split review program, which is similar to the existing Real Time Oncology Review (RTOR) but applicable to efficacy supplements across all therapeutic areas. STAR aims to facilitate earlier access to novel uses of existing therapies for patients with a serious condition with unmet medical needs. In brief, the process begins with a request for a presubmission informal teleconference (or alternatively, a discussion as part of a pre-sNDA or pre-sBLA meeting). If FDA accepts the application, the sponsor can then submit their supplement in two parts.
The sponsor then gets the review ball rolling by submitting all of the efficacy supplement minus the final clinical study reports and clinical summaries. Part 1 can be submitted as much as 2 months (but no more than 3 months) before completing the application with the submission of Part 2, containing the finalized clinical study reports and summaries. Although the PDUFA review timeline begins with submission of Part 2, FDA will set an action date to be at least 1 month earlier than the normal 6-month goal date for a priority review application.
Notable Dates and Timelines – Program opens, beginning of FY 2023; Expediting reviews fully implemented, by FY 2024; Webpage with detailed criteria for acceptance and participation, October 1, 2022; Interim assessment, end of FY 2025; Public workshop, end of Q2 FY 2026.
2. Rare Disease Endpoint Advancement (RDEA) Pilot Program – The challenges of establishing substantial evidence of efficacy for a rare disease treatment (small patient populations, slow disease progression, heterogenous or even variable disease presentation) manifest long before providing a final efficacy analysis to FDA reviewers. Establishing efficacy endpoints is perhaps the biggest obstacle to successfully developing therapies for patients with rare diseases. The Agency acknowledged that the current methods by which sponsors and reviewers at FDA interact “are not structured to provide repeated, intensive interactions” in the ways necessary to advance endpoint development for rare diseases.
The RDEA Program is a pilot that will provide an opportunity to submit a proposal for one or more endpoints associated with a development program in an active IND or pre-IND, or in the absence of an active development program, a natural history study. The endpoints must be novel (i.e. never been used to support drug approval) or substantially changed from a previous use. Preference will be given to those proposals for exploring endpoints that may have broad applicability to several diseases, those that reflect different types of endpoints, and, for surrogate endpoints, those with novel approaches to collecting data pre-market to accelerate validation of the endpoint.
RDEA will accept a maximum of one proposal in FY 2023 and a maximum of one proposal per quarter, capped at three per year, in each of the remaining fiscal years of PDUFA VII. Acceptance into the RDEA Program will provide sponsors with 4 meetings (in addition to any other meetings associated with their product development program) focused on developing the endpoint. However, sponsors should understand (1) that participation will require a public disclosure agreement specifying, which aspects of an endpoint development program FDA may disclose publicly, and (2) that advice given during RDEA meetings is neither a regulatory decision nor is it binding. The public disclosure agreement is important for participation in RDEA as the FDA plans to discuss endpoints developed in the program during public workshops, in guidance and on its website, potentially prior to drug approval. The Agency will hold as many as three public workshops during PDUFA VII related to rare disease endpoint development.
We commend the recognition of the increased attention needed to foster drug development in rare diseases, and believe that more iterative interactions may be able to help advance novel endpoints for use in evaluating effectiveness. At the same time, we hope that this process will be implemented in a way that embraces the need for expediency and appropriate flexibility in rare diseases, rather than instead use this heightened oversight to serve to shift these endpoint development programs into a process more akin to the Clinical Outcome Assessment (COA) Qualification Program, which is known to be slow and burdensome, such that few endpoints make it through the process.
Notable Dates and Timelines – Applications open, Q4 of FY 2023.
3. CMC Development and Readiness Pilot (CDRP) and Support for Accelerated Development Programs – Acknowledging that drug development programs eligible for accelerated clinical development (i.e. those that address a serious condition with unmet medical needs) through tools like Breakthrough Therapy Designation may not result in more timely approval if CMC development does not keep pace, FDA announced plans aimed at addressing this mismatch. First, CDER will publish a new MAPP (the Manual for Policies and Procedures, meant to guide CDER staff in their review activities and interactions with sponsors) describing: (1) early engagement with sponsors and (2) “science- and risk-based approaches” for CMC development that “may be warranted and utilized . . . based upon the anticipated clinical benefit of earlier patient access to the product.”
In addition, a new CMC pilot program, CDRP, will provide an opportunity for additional meetings and Agency feedback during product development under an IND. Sponsors accepted into the pilot will receive “two additional CMC-focused Type B meetings and an additional limited number of CMC-focused discussions based on readiness and defined CMC milestones.” Few details regarding the CDRP’s procedures or additional eligibility criteria are available until FDA publishes a notice in the Federal Register announcing the program, except that FDA plans to accept 8-10 proposal per FY over a 4-year period.
Both the new MAPP and the CDRP program are intended to assist sponsors with CMC development associated with products that have accelerated development timelines by facilitating better understanding about how to demonstrate and achieve CMC readiness for their products. Although the additional approaches expected in the MAPP will be helpful, the increased communication under the CDRP to provide direct feedback to sponsors about CMC earlier in development will be crucial to fulfilling FDA’s goal.
We have seen first-hand that our clients would benefit from earlier focused engagement with the Agency on their CMC plans. Such engagement should help to avoid discovering only late in a review cycle or even in the context of a complete response letter that their process controls or potency assay are not sufficient, especially in the context of complex products like cell and gene therapies. The Agency also intends to use lessons learned during the CDRP to further improve processes, which will be discussed in a public workshop and potentially inform revisions to MAPPs, SOPPs or guidance documents. The Agency will publish a strategy document following the workshop detailing how they intend to incorporate the lessons learned from the program.
Notable Dates and Timelines – New MAPP published, by Dec. 31, 2022; Publish notice of the CDRP program, by Dec. 31, 2022; CDRP start, FY 2023; Public workshop, by July 31, 2025; Strategy document published, by April 30, 2026.
4. Other CMC Enhancements (Four-Part Harmony Information Requests (IRs), Inspections Tools, Plans to Advance Innovative Manufacturing) – Beyond the initiatives targeted at CMC programs with accelerated clinical timelines above, the PDUFA VII goals letter contained several additional CMC-targeted enhancements including a new structure for IRs (Four-Part Harmony), continued use of tools developed during the pandemic for facilities inspections, and plans to develop a strategy for advancing the use of innovative manufacturing. The first of these CMC-related announcements, the Four-Part Harmony IR, is meant to improve efficiency and clear communication of information requests during application review. The IR format should clearly indicate (a) what information was provided, (b) what is the issue or deficiency, (c) what is needed, and (d) why it is needed.
As mentioned at the outset, the pandemic forced FDA to use alternatives to in-person visits to conduct facilities inspections. These alternative tools have included requesting records and other information from facilities/sponsors, using information and inspection reports from foreign regulatory authorities, and alternative technology platforms. Informed by experiences during the pandemic and likely in acknowledgement of the potential for future travel restrictions, FDA plans to issue new draft guidance. This guidance will lay out the Agency’s plans and intentions regarding carrying these alternative inspection tools and technologies forward.
To improve adoption of innovative manufacturing techniques, FDA plans to hold a public workshop to discuss the following: best practices and lessons learned from the CDER Emerging Technology Team and the CBER Advanced Technology Team, case studies from sponsors, barriers to adoption, regulatory strategies to improve adoption, and science- and risk-based approaches to development. The discussion and public comments during this workshop will inform a new strategy document with actions the Agency will take during PDUFA VII to advance the utilization of innovative manufacturing technology.
Notable Dates and Timelines – Inspection tools draft guidance, by Sept. 30, 2023; Public workshop on advancing innovative manufacturing technology, by end of FY 2023; Publish advancing innovative manufacturing technology strategy document, by Sept. 30, 2024.
5. Advancing Real-World Evidence (RWE) Program – The 21st Century Cures Act mandated that FDA develop a program for using RWE to support approval of new indications for approved drugs and support or satisfy postapproval study requirements. While elements of an RWE program to satisfy this statutory mandate have been underway for a few years now, the PDUFA VII goals letter proposal for a process to submit RWE proposals and gain direct feedback from the Agency prior to study initiation appears promising. Similar to the RDEA program, described above, the drawback is that participation is contingent upon willingness and agreement with the Agency about public disclosure of elements of the RWE proposal.
Although a formal announcement of the program is expected by end of 2022, the rough description of the program is as follows – (a) FDA solicits applications twice per year; (b) Applications should describe the regulatory question that the RWE is intended to answer, the RWE study design, and the intended sources of real-world data (RWD) (for the unfamiliar reader, think of RWD as the building blocks and components that make up RWE , similar to the way data from a particular clinical outcome is one component of the clinical evidence of a drug’s safety or effectiveness that a clinical study may provide); (c) FDA will evaluate and rank the applications, accepting one to two applications per cycle for the first two years and one to four per cycle thereafter; (d) Sponsors may then request up to four meetings under the program to discuss data, design, and regulatory issues with FDA staff from across review divisions as well as other offices and senior leadership with RWE expertise. As the program is intended to both support sponsors directly through interactions, as well as broadly inform FDA practices and guide industry when adopting RWE approaches, the Agency will publish annual reports containing application details that have been aggregated and anonymized, hold a public workshop, and update existing RWE guidance documents or publish new guidance.
While use of RWE has largely been focused on the postapproval setting, it remains to be seen if prior experience with RWE under prior PDUFAs will provide the comfort needed to extend the use of this data more broadly into the preapproval setting. This would be of particular value to the development of drugs for rare diseases where it is incredibly valuable to triangulate safety and efficacy data from multiple sources to gain confidence in the findings.
Notable Dates and Timelines – Initiation of the pilot program, by December 31, 2022; Annual reports, starting by June 30, 2024 and at least annually thereafter; Public workshop, by December 31, 2025; Revise RWE guidance documents and/or publish new guidance, by December 31, 2026.
6. Patient Focused Drug Development (PFDD) – FDA continues its legacy of PFDD (see our previous coverage here) when it announced that it will continue its efforts to incorporate the patient voice into drug development and regulatory decision-making in several ways. First, the Agency committed to continued internal staff training and outreach to industry and patient groups to facilitate integration of PFDD methods into regulatory decision-making, as well as use the Intergovernmental Personnel Act to leverage outside expertise to support review of patient experience data. The Agency also announced that it will issue a Request for Information soliciting “public input on methodological issues, including the submission and evaluation of patient experience in the context of benefit-risk assessment and product labeling” and plans for two public workshops to discuss these methodological issues, culminating in a report on the findings of the RFI and public workshops and how these will inform priorities for PFDD work in the future. Other PFDD announcements include continued development of a virtual catalog of standard core Clinical Outcome Assessments (COAs) and Related Endpoints, continued work to understand how patient preference may inform benefit-risk determinations, and the intention to use public input to understand stakeholder perspective on priority areas for both core COA development and incorporation of patient preference in regulatory decision-making. Finally, FDA plans to publish a new draft guidance on use and submission of patient preference information (PPI).
While this PFDD commitment sounds much more lackluster than the original PFDD meetings under PDUFA V and the subsequent PFDD guidance series under PDUFA VI, this commitment feels like the prudent approach. The PFDD meeting initiative, including its expanded externally-led PFDD meeting program, continues on. Further, the Agency is still finalizing the drafts of the full PFDD guidance series, such that using PDUFA VII to reflect on the application of these programs and guidance is the right approach, while providing the Agency resources through PDUFA to keep these earlier programs running.
Notable Dates and Timelines – RFI announced, by end of June 2023; RFI summary published, by end of December 2023; Two public workshops, by end of FY 2024 and FY 2025, respectively; Summary of RFI and public workshop learning with new priorities, by end of FY 2026; Publish new PPI draft guidance, by Sept. 30, 2026.
7. Changes to Pre-Approval and Post-Approval Postmarketing Requirements (PMRs) Communications – The goals letter contained new plans and timelines to improve Agency communications with sponsors regarding anticipated PMRs during the review cycle as well as adding new procedures for sponsors to request a review of and release from a PMR post-approval. As our HPM colleagues plan to spell out the details more fully in a subsequent post, we will briefly note that the PDUFA VII commitments require the Agency to communicate detailed thinking about potential PMRs no later than 8 weeks, for standard review, and 6 weeks, for priority review, ahead of the action date for NME NDAs and original BLAs. PMRs can require significant additional time and resource commitments on the part of drug sponsors after already investing years and millions of dollars getting a product successfully to the end of the review cycle and to approval. As such increased communication and predictability, both pre-approval and post-approval, will be a welcome development for sponsors and patients to know that PMRs are both thoughtfully planned and released.
Notable Dates and Timelines – Expect revisions to MAPPs, SOPPs and guidance, starting in FY 2023.
8. Expansion of INTERACT Meetings, New Type D Meeting, and Meeting Follow-up Questions – Initial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs (INTERACT) meetings first started in CBER in 2018 as an informal way for sponsors to get pre-pre-IND advice on innovative biological products with new and unique challenges. Sponsors with novel questions, those for which there is no existing FDA guidance, will now be able to use the INTERACT meetings to seek FDA guidance for products regulated in both CDER and CBER (previously, the ‘C’ in INTERACT stood solely for CBER). In effect, this program aims to reduce bottlenecks in the IND-enabling phase by answering questions about, for example, appropriate preclinical models and toxicology studies for novel drugs, design of proof-of-concept studies, or adequate CMC testing to demonstrate safety for first-in-human studies. Direct feedback earlier in development will help get sponsors to the pre-IND meeting with fewer major questions and better equipped to launch the clinical phase of their development programs. However, as the INTERACT meeting framework is rolled out more broadly, we have seen a recent an increase in these meetings being denied by CBER and the sponsor asked to wait to request a Pre-IND meeting, so it will be important for the Agency to more clearly describe more clearly elucidate when an INTERACT is appropriate.
PDUFA VII also brings a new meeting type to the drug development armamentarium: the Type D meeting. These meetings will be available when a sponsor needs input on a narrow set of questions such as a follow-up question that raises new issues after a formal meeting. However, the sweet spot for the scope of such a question is one that would be narrower than spanning multiple disciplines but broader than just a clarifying question. FDA will limit Type D meetings to no more than 2 topics and questions that require input from no more than 3 disciplines or Divisions.
Even narrower in scope than the Type D meeting question, FDA also added follow-up opportunities or questions in the form of a Request for Clarification to the goals letter. This memorializes a more recent practice adopted by the Agency given the increased use of WRO meetings during the COVID-19 pandemic, allowing follow-up questions to clarify the Agency’s feedback in a WRO or something captured in meeting minutes. Now formalized, this request should be submitted by a sponsor within 20 calendar days of receipt of the meeting minutes or WRO. Similarly, FDA committed to responding to such requests within 20 days.
Finally, FDA will hold a public workshop on meeting management. In addition to issues applicable to all meeting types such as submission of meeting requests, time management, and coordinating agenda and development of meeting background packages, the workshop will discuss lessons learned while implementing the two new meeting types as well as those learned during the COVID-19 pandemic.
Notable Dates and Timelines – Response to meeting requests, Type D 14 days, INTERACT 21 days; Meeting scheduled or WRO Issued, Type D 50 days, INTERACT 75 days; Submission of meeting background, at time of request (both); Preliminary responses sent; 5 days before meeting (both); Meeting minutes issued, 30 days (both but INTERACT meeting preliminary responses will only be annotated and resent if necessary); Publish revised formal meetings guidance, by September 30, 2023; Public workshop, by July 30, 2024.
9. Enhanced CBER Capacity for Cell and Gene Therapy Products – FDA looks to expand the Cell and Gene Therapy Program (CGTP) primarily by increasing CBER staff capacity (hiring targets discussed above) and hinted at potential reorganization by stating “[t]he current CGTP organization will be evaluated, with input from external consultants, to determine the optimal organization to effectively integrate new staff and facilitate operations and customer service.” New hires and organizational changes will be aimed towards “direct review activities, indirect activities (e.g., policy, external outreach, postmarket safety), and supporting activities in the CGTP.” Many of the indirect activities include fostering industry development activities through external outreach, workshops, public meetings, webinars, as well as updating guidance and SOPPs, amongst others.
The goals letter specifically called out continuing commitments in key several areas of interest for cell and gene therapy (CGT) sponsors – advancing manufacturing, testing and implementation of new technologies, continued use of surrogate endpoints, RWE, complex innovative designs and disease natural history, as well as new approaches to establish safety and efficacy for rare and ultra-rare diseases. FDA committed to CGT specific workshops and public meetings: (1) a PFDD workshop focused on understanding patient perspective regarding benefit and risk with CGTs and involvement in study design and execution (in addition to the two PFDD workshops noted above), (2) approaches to capturing post-approval safety and efficacy data, and (3) leveraging knowledge from across therapeutic contexts to facilitate CGT development and review. Novel approaches to development will receive additional attention through public-private partnerships to understand challenges to development of CGTs such as novel endpoints, less defined natural histories, and other challenges common to individualized therapies and rare diseases.
FDA committed to publish new guidance on (1) evaluation of efficacy in small patient populations using novel trial designs and statistical methods (and how to apply these methods to more common diseases), (2) question and answer (Q&A) format for FAQs and on common issues from CGT sponsors, (3) approaches for gathering post-approval safety and efficacy data for CGTs, and (4) leveraging prior knowledge regarding CMC, non-clinical and clinical development across therapeutic contexts to facilitate CGT development and BLA review. The Agency also committed to revising the existing guidance Expedited Programs for Regenerative Medicine Therapies for Serious Conditions.
Notable Dates and Timelines – PFDD workshop on CGTs, by end of FY 2023; PFDD workshop report, by mid FY 2024; Draft guidance on efficacy in small patient populations, end of FY 2025; Draft Q&A guidance on common CGT issues, end of FY 2024; Draft guidance on post approval safety and efficacy data, end of FY 2024; Revised guidance Expedited Programs for Regenerative Medicine Therapy for Serious Conditions, end of FY 2025; Public meeting on leveraging knowledge across therapeutic contexts, end of FY 2025; Draft guidance on leveraging knowledge, end of FY 2026.
10. Allergenic Extract Products Added to PDUFA Review – Although few additional details are available, review of allergenic extract products will be added to PDUFA and benefit from all performance goals, procedures, and commitments. Those allergenic extract products added to PDUFA under PDUFA VII and licensed after October 1, 2022 will generally be included in user fees.
Although we provide this overview of our top ten major changes, commitments and program enhancements, the PDUFA VII goals letter contained several other notable changes. Check back for new posts on the FDA Law Blog as our HPM colleagues take a deeper look at certain programs of interest, address topics excluded from this overview (e.g., safety initiatives, combination product review, digital technology enhancements), and update our readers on ongoing developments regarding PDUFA VII.