The FDA today released a widely anticipated goals letter as part of its efforts to reauthorize the Prescription Drug User Fee Act. While the letter has been slowly negotiated between regulators and industry stakeholders since last year, today is the first time that the public has been able to dive into the details of the proposals. Rather than skim over the details, AgencyIQ has conducted a thorough review of the 71-page document and has a tight summary of key details you need to know.
The Split Real Time Application Review (STAR) Pilot Program
- Among regulatory policy folks, there’s one FDA pilot program that’s received quite a lot of attention in recent years: The Real-Time Oncology Review (RTOR) pilot program. The basic idea of the program is that the FDA can massively accelerate the review of certain product applications by starting the review before all of the data is in (sort of like a rolling review) for applications in which there are no obvious issues. While RTOR has been used to review a few novel drugs, it’s mostly been used to review new indications (i.e., supplemental applications) for existing drugs.
- Now, as part of the PDUFA VII agreement, the FDA is slated to greatly expand these reviews into new areas. According to the letter, the STAR program would apply to efficacy supplements “across all therapeutic areas and review disciplines that meet specific criteria.” Like the RTOR, the pilot’s goal is to accelerate the review process “to allow earlier patient access to therapies that address an unmet medical need.”
- Eligibility for the STAR program would be reserved for novel uses of existing therapies and require the submission of clinical evidence to demonstrate that the drug intended to treat a serious condition with an unmet medical need and provide substantial improvement over available therapies. Applications would be rejected if there were an element which could extend the review process (e.g., requiring a REMS plan) or if the applicant would require a facility inspection to support approval.
- How the STAR program would actually work: An applicant would request “an informal pre-submission teleconference with FDA and provide FDA with topline trial results and proposed labeling.” It could also take place as part of a pre-sNDA/sBLA meeting. The actual application would then be split into two parts. The review would begin upon submission of Part 1 of the application (including complete datasets, proposed labeling, clinical protocols, and topline results). The submission of Part 2 of the application would start the PDUFA date clock and would contain the clinical study reports from Phase III clinical studies and any remaining eCTD Module 2 clinical summaries.
- The review would be at least one month faster than the standard priority review process (i.e., five months instead of six months). The FDA is slated to make information about the program available by October 1, 2022, with the program becoming available to participants starting in FY2023 and fully operational in FY2024. The letter explains that the gap in timing is meant to ensure the FDA has sufficient time to hire staff to support the program.
The Advancing Real-World Evidence (RWE) Program
- Building on the 21st Century Cures Act’s RWE foundation, the new PDUFA VII agreement would take meaningful steps to advance regulatory use of RWE. One of the main goals outlined in the letter is to provide “earlier and increased agency advice” related to RWE.
- This includes a new pilot program, the Advancing RWE Program. The pilot “seeks to improve the quality and acceptability of RWE-based approaches in support of new intended labeling claims, including approval of new indications of approved medical product or to satisfy post-approval study requirements.” The use of RWE for post-marketing requirements (PMRs) could have major implications for industry, which currently spends enormous amount of money and time collecting data about the use of their products to further confirm the safety and efficacy of their products, either in specific sub-populations or the entire indicated population.
- Under the Advancing RWE Program, targeted for implementation by the end of 2022, the FDA would focus on the development of agency processes to promote consistency related to RWE decision-making and promote “awareness of characteristics of RWE that can support regulatory decisions by allowing FDA to discuss study designs considered in the Advancing RWE Program in a public forum.” Under the program, the agency would solicit proposals for RWE-based research programs from sponsors twice a year. FDA would then rank the applications and accept between three and eight applications per year into the pilot.
- The program “represents an optional pathway for sponsors submitting RWE proposals to an IND with CBER or CBER. Regardless of whether an Advancing RWE application is accepted, not accepted, or was never submitted to the ARWEP, established procedures … will continue to be available.” The FDA and sponsor would then work together to agree on what information could be shared publicly. If the two sides can’t come to an agreement, then the sponsor’s participation in the program related to that application would end.
- The goal of the program is twofold: To allow both sponsors and the agency focus on data, design and regulatory issues “that have the potential to generate RWE in support of a proposed regulatory decision,” and to support the FDA’s own experience with RWE-based study designs, informing updates to the FDA’s RWE guidance documents to be issued by the end of 2026.
CMC Development and Readiness Pilot
- One longstanding challenge for developers of accelerated-track products is that data about the safety and efficacy of an application may be complete before data about a product’s quality or its manufacturing capacity is ready (manufacturing is often referred to as Chemistry, Manufacturing and Controls, or CMC). In practice, this can lead to an application that is otherwise ready to approve, but for which an FDA approval decision cannot be made.
- PDUFA aims to address this in a few ways. For products with accelerated clinical development, the FDA aims to develop a Manual of Policies and Procedures (MAPP) by the end of 2022 on “approaches to address CMC challenges for CDER-regulated products.” The document will “describe early engagement with sponsors of such products and the different science- and risk-based approaches … that may be warranted and utilized in CMC development based on the anticipated clinical benefit of earlier patient access to the product.”
- The FDA is also set to develop a “CMC Development and Readiness Pilot” (CDRP) in FY2023 that would accelerate the CMC development of products under an Investigational New Drug (IND) application based on anticipated clinical benefit. Criteria for the pilot program would likely differ between CDER and CBER, due to product complexity differences, but the goal would be the same for both centers: To accelerate clinical development timelines.
- Companies would benefit from two additional CMC-focused Type B meetings and other discussions based on CMC milestones. The intent is to help ensure a mutual understanding of what activities need to be completed, when and by whom.
- The FDA would also be tasked with holding a public workshop on CMC issues by July 21, 2025 and create a strategy document outlining how it plans to proceed with developing or revising other policies and lessons learned.
The Development of Cell and Gene Therapies
- If there’s been a common refrain in recent years from industry, it’s been that the FDA doesn’t have the staff capacity necessary to review cell and gene therapies (CGT) efficiently. Among the direst concerns, shared by CBER leadership, is that the already time-and-resourced constrained FDA review staff will face a wave of new and highly complex products for FDA review.
- Under the PDUFA VII agreement, the FDA plans to “substantially strengthen staff capacity” for CGTs. The intent is that more staff will allow the FDA to support additional meeting requests, which are often needed on these products given the phenomenal complexity of both these products themselves and their development processes.
- In addition to staff capacity, the FDA is also planning to develop new policies. By the end of FY2025, it plans to issue a draft guidance on the evaluation of efficacy in small patient populations using novel trial designs and statistical methods. The agency also plans to issue a Q&A-style draft guidance by the end of FY2024, based on FAQs and commonly identified sponsors face during CGT reviews. By the end of FY2024, FDA will convene a meeting to solicit input on capturing post-approval safety and efficacy data for CGTs, including the potential to use RWE. That, in turn, would lead to the publication of a draft guidance document on the same subject by the end of FY2025. Also in FY2025, the FDA plans to update its standing guidance document on Regenerative Medicine Advanced Therapies (RMATs) to include information about post-approval requirements, including the use of RWE to confirm clinical benefit for products granted accelerated approval, long-term follow-up and specific considerations about CMC topics.
Sentinel and BEST
- Over the past decade, the FDA has made major investments into safety monitoring systems. Two of its most prominent efforts are the Sentinel Initiative and the Biologics Effectiveness and Safety (BEST) System, which are used to proactively monitor real-world data sources (including clinical records data, data from providers and claims and billing data from payers) to monitor safety and detect emerging signals.
- The FDA is gearing up to make significant enhancements to both systems in the hopes of enabling Sentinel and BEST to help support post-market monitoring requirements – and maybe even replace some of them. According to the goals letter, the FDA will use user fee funds to “maintain the quality and quantity of data available through the Sentinel initiative (Sentinel and BEST), to maintain the processes and tools for determining when and how those data are utilized, and to support comprehensive training of review staff on the use of Sentinel.”
- The system is also slated to open up considerably to both sponsors and the public. By 2025, FDA intends to “publish on its website an update on facilitation of public and sponsor access to Sentinel’s distributed data network to conduct safety surveillance.” It will also report on the use of Sentinel for regulatory purposes, such as in the context of labeling changes, Post-Marketing Requirements (PMRs) and Post-Marketing Commitments (PMCs). PMRs are studies required of a sponsor as a condition of approval for certain types of drug products. Notably, the Sentinel Initiative’s Active Risk Identification and Analysis (ARIA) function was originally developed to potentially replace PMRs – and under section 505 of the Federal Food, Drug and Cosmetic (FD&C) Act, the FDA must find that adverse event reporting and ARIA “will not be sufficient” for postmarket surveillance before requiring a post-market study.
- The letter also asks FDA to enhance the capabilities of Sentinel System to conduct analysis, especially in relation to how it could be used to study drug effectiveness and specific safety issues. For example, FDA plans to enhance it to inform drug labeling on the safety of a product when used during pregnancy and to detect or evaluate issues more quickly. This could then be used to replace or augment certain PMRs.
The Digital Health Technologies Framework
- The FDA has been on something of a digital health kick in recent months. In September 2020, the agency officially launched its Digital Health Center of Excellence (DHCoE) to serve as a sort of command center for all things digital health at the FDA. As with other focus areas, PDUFA VII seeks to build on the FDA’s existing efforts with an emphasis on what might be able to benefit product development.
- One of the major announcements in the letter is that the FDA plans to establish a Digital Health Technologies (DHT) Framework by the end of Q2 FY2023. The framework would act as a guide to the use of data derived from digital health technologies data in regulatory decision-making. It would also establish a committee of FDA staff from CBER and CDER to oversee the creation of the framework and digital health consistency across centers (though it would need to coordinate with the DHCoE –which is notably engaged in a new collaborative community specifically focused on best practices for levering data from digital health tools in research and development programs).
- As part of the framework effort, the FDA would identify three or more demonstration projects “to inform methodologies for efficient DHT evaluation,” covering “key issues to inform regulatory policy development and regulatory advice” such as validation methods and multi-channel inputs as an endpoint (for example, a wearable that can collect several different types of data, used to make a determination about a patient’s health). Also by Q1 FY2023, the FDA commits to publishing draft, revised or final guidance on the use of DHTs in both traditional and decentralized clinical trials, validation of measurements and the development of novel endpoints using DHTs, and the use of patient’s own wearable devices to generate these data.
- FDA would also be tasked with developing some new draft guidance documents, including those “identified areas of need informed by stakeholder engagement” and on Prescription Drug Use-Related Software (PDURS) that provide information about the appropriate way to use a medical product and is distributed along with a specific drug.
More Assistance for Post-Marketing Required Studies
- Beyond the enhancement of existing systems to help support PMRs (see the item above about Sentinel and BEST), the PDUFA VII goals letter has lots of other plans for PMRs.
- Perhaps the biggest shift is moving discussions about PMRs from the post-approval setting (where many discussions now take place) to the pre-market setting. The goal of this effort is to balance the approval of products (and especially those intended for accelerated approval, for which PMRs are generally mandatory) and the “timely availability” of information confirming a drug’s safety or efficacy.
- As part of the new process, the FDA said it will begin to conduct pre-approval reviews of PMRs “to ensure the timely availability of information on the safety and efficacy of therapies.” FDA said it will establish “processes to support consistency and predictability.” This new process will involve the FDA making details about anticipated PMRs available to a sponsor at least 6-8 weeks in advance of the PDUFA action goal date (6 for priority applications, 8 for standard). The FDA’s communications will summarize preliminary evaluations, the study’s purpose, critical study design elements, timelines and specific risks to be evaluated. These communications will be subject to PDUFA performance evaluations.
- In terms of related deliverables, the FDA plans to publish new MAPPs and guidance documents about the pre-approval process for PMRs between 2023 and 2027. It will also train staff, including on “processes and procedures for ARIA sufficiency determination[s].” As mentioned above, the FD&C Act requires the FDA to find that Sentinel’s ARIA function is not sufficient before it can require a sponsor to do a post-market study, which is intended to ensure that, if possible, the burden to run a study will fall on the technology function before it is required of a sponsor. However, operationalizing this function in ARIA has been challenging, and most ARIA assessments are still “Level 1” (descriptive analyses).
- The FDA will begin to review existing PMRs and will allow applicants to “request review” of their existing PMRs to be able to request release from the obligations if they are no longer deemed to be necessary. The FDA will “establish an additional process for reviewing sponsor-initiated requests.” That process is detailed in the letter, with specific timelines for FDA action.
- Mid-cycle communications: The new letter now states that as part of companies’ mid-cycle communications with the FDA, they should discuss the “potential need for any post-marketing requirements” and “the ability of adverse event reporting and FDA’s Active Risk identification And Analysis (ARIA) system under the Sentinel Initiate to provide sufficient information about product risk,” instead of a PMR. These discussions will be reconsidered as part of the late-cycle meeting as well.
Other Proposals Outlined in the Letter
The 71-page letter contains dozens and dozens of proposals – some large, and others small. Let’s dig into some of the most noteworthy.
- A new pilot program on rare disease endpoints: The FDA intends to create a new Rare Disease Endpoint Advancement (RDEA) Pilot Program. The goal of this program is to support the development to efficacy endpoints that can be used in research for drugs that treat rare diseases. Under the program, sponsors of these products will have the opportunity to access additional engagement with regulators for specific development programs that meet the criteria under the pilot. The FDA will also add staff capacity “to enable and facilitate appropriate development and use of these types of novel endpoints.” Endpoints would be eligible for the pilot program if they meet specific criteria (an active development program using a novel endpoint, with a few caveats). However, the FDA says it won’t be able to accept many of these reviews – just one in 2023 and three per year thereafter.
- INTERACT Meetings aren’t new to the FDA. The Initial Targeted Engagement for Regulatory Advice on CBER Products (INTERACT) meetings are available for sponsors seeking early engagement with the FDA. These meetings are intended to help answer novel questions and unique challenges early in the development process for CBER-regulated products, and CGTs in particular. In practice, they can act as a sort of pre-pre-IND meeting for sponsors, offering preliminary and informal advice to sponsors. As outlined in the new goal letter, FDA would seek to make these meetings formal, with 21-day response timelines (the same as Type B and C meetings) and the intent to release guidance on their use by September 2023. In addition, for all meeting types sponsors will now be able to submit clarifying questions (other question types, such as new questions, aren’t permitted) within 20 days of receiving FDA’s written response.
- Type D Meetings: The FDA already has a few different meeting types. Type A meetings are used to address major issues for an otherwise stalled development program. Type B meetings are for development milestones (e.g., pre-IND, pre-NDA, end-of-phase). Type C are a sort of catch-all meeting. Now the FDA has proposed the creation of Type D meetings, which will address “a narrow set of issues” such as a follow-up question that raises a new issue after another meeting type, questions about a minor topic, or a “general question about an innovative development approach that does not require extensive, detailed advice.” Per the FDA, these meetings should be limited “to no more than two focused topics.” Type D meetings have a 14-day response time, making them ideal for (relatively) rapid advice.
- Patient Engagement: The goals outlined in the letter would continue to expand on the Patient-Focused Drug Development (PFDD) meeting approach that was established in 2012 and then expanded in 2017. Specifically, the FDA will “continue to strengthen capacity to facilitate development and use of Patient-Focused methods to inform drug development and regulatory decisions.” The FDA would be tasked with the development of a “virtual catalog of standard core sets of Clinical Outcome Assessments (COAs) and Related Endpoints… which will be available for public use.” FDA would need to publish draft guidance by the end of FY2026 related to the use and submission of patient preference information.
- Risk Evaluation and Mitigation Strategies (REMS): The letter seeks to “modernize and improve REMS assessments” – a long-standing issue for some REMS programs. The FDA will issue new (or update standing) policies and procedures about how to evaluate a REMS program by the end of March 2024. By March 2026, it would need to issue draft guidance on the format and content of a REMS assessment report (i.e., evaluating whether it is effect). FDA also outlines its goal to review and respond to sponsors regarding REMS assessment methods and protocols within 90-days.
- Enhanced transparency and technology modernization: No later than Q4 FY2023, the letter states that FDA will establish a data and technology modernization strategy that “reflects the vision in FDA’s Technology and Data Modernization Action Plans,” including leveraging cloud technologies, enterprise-wide approaches to data governance and strategies to support PDUFA goals. CBER would begin to retire its older IT systems and capabilities in favor of newer ones as part of a multi-year modernization roadmap set to be published by the end of FY2022. By FY2026, the FDA would seek to support cloud modernization of the Electronic Submission Gateway, which is used to submit NDAs and BLAs, among other applications.
- Alternative tools to assess manufacturing facilities: During the pandemic, the FDA experienced a host of issues with inspecting regulated facilities. Instead, it leveraged existing authority to use record requests and mutual recognition agreements with foreign regulators to conduct (admittedly limited) inspections. In the PDUFA VII goals letter, the agency outlines its plan to learn from its experience during the pandemic and think about “the use of such methods beyond the pandemic.” As part of this effort, FDA would issue draft guidance by September 30, 2023 “on the use of alternative tools to assess manufacturing facilities named in pending applications.” This guidance would include information about “requesting existing inspection reports from other trusted foreign regulatory partners through mutual recognition and confidentiality agreements, requesting information from applicants, requesting records and other information directly from facilities and other inspected entities, and, as appropriate, utilizing new or existing technology platforms to assess manufacturing facilities.”
- Hiring: The goals letter also provides details about the number of staff that the FDA plans to hire each year during the PDUFA program through CDER and CBER. CBER would add another 123 staff, while CDER would add 228 staff. Most of the staff (210 in total) would be added the first year for both Centers. In addition, FDA would work with an independent contractor to conduct a targeted assessment of the hiring and retention of FDA staff working for the human drug review program. The aim is to improve hiring and retention by understanding factors within and outside of FDA’s control.
- Combination products: The letter outlines review procedures for Use-Related Risk Analysis (URRA). Based on an URRA, a sponsor can ask the FDA to determine that a human factors validation study isn’t needed for drug-led combination products. The URRA process will involve a request from the sponsor related to the IND. The request should contain scientific justifications and supporting information. The FDA then has 60 days to make a determination. According to the goal letter, the FDA would publish draft guidance by 2024 related to the URRA process and how it can inform decision-making. If a human factors (HF) validation study is needed, the sponsor would need to submit the protocol to the IND with specific questions. The FDA would then offer a written response within 60 days.