Navigating the Current US Regulatory CGT Landscape in Uncertain Times
A roundtable featuring: Kim Benton, Ph.D. (DHC Master Principal; Head of Regulatory), Heath Coats, M.S. (DHC Senior Principal; Head of Facilities and Engineering Compliance), Adnan Jaigirdar, M.D., FACS (DHC Senior Principal; Head of Clinical), Nathan Manley, Ph.D. (DHC Senior Principal, Head of Nonclinical), Kristin Baird, M.D. (DHC Master Practice Expert), Don Fink, Ph.D. (DHC Master Practice Expert, Regulatory), Tal Salz, Ph.D. (DHC Senior Practice Expert), and Julie Spyrison (BTL Partner; VP of Regulatory).
Moderated by Katy Spink, Ph.D., DHCG President & COO, Managing Partner
**Please note that this is a rapidly changing situation. All content within and links shared are accurate as of the publication date of April 16, 2025. As of April 10th, this article indicates that some sponsors have already experienced complications due to the cuts. The open letter to U.S. Senate HELP Committee chairperson Bill Cassidy can be found here.**
April 16, 2025
Katy: Thank you to everyone for joining us today. Given the significant reduction in force (RIF) at the FDA earlier this month, I felt that our clients might benefit from the deep regulatory experience gathered here as we work to address what we do and don’t know, and what we recommend as the best practices going forward. Let’s start off with an overview of how the recent layoffs may affect the standard PDUFA-based review processes that we’re used to: BLAs, INDs, Type B, C, and D meetings, INTERACTS, etc. My understanding is that the reviewer workforce, specifically, was not affected. Nonetheless, I suspect that support functions that were impacted might create some changes. What do you think?
Don: I’ll get us started. As DHC is an ARM (Alliance for Regenerative Medicine) member, I had the opportunity to listen to a members-only webinar earlier this month. To summarize some relevant details, their estimate was that in the past month there has been an approximate 23% reduction in FDA staff over the course of three waves. The first wave removed “conditional staff” (those who have been recently promoted or recently hired with less than 2 years’ experience*), the second was the “fork in the road” offering (encouraging many high-level quality reviewers and leadership to make their own choice to leave or retire), and the third was the April 1st RIF intended to cut capabilities believed by the Trump administration to be duplicative or unnecessary. The RIF primarily targeted functional groups that included Procurement, DEI, Communications, Document Control, Policy, Management, and Human Resources.
Upon scanning the horizon, ARM considers it likely there will be Prescription Drug User Fee Act (PDUFA) action date delays as well as delays in scheduling and holding meetings.
The OTP (Office of Therapeutic Products; the office within CBER/FDA that reviews Cell and Gene Therapy and related products) structure has not been as directly impacted to date, so I think in a best-case scenario we may continue to see business as usual in that review unit for the time being. I will acknowledge that it’s clear there will be some impact down the road due to the loss of support services. We don’t have a full idea yet of what the follow-on implications may be. We might see contract employees whose contracts are not extended (either intentionally or as a side-effect of a dearth of administrative staff that manages contracts), remote employees who may leave as a consequence of not being allowed to continue working remotely [ed: that order is now in doubt, as mentioned further on], or other consequences due to the vacuum of supporting personnel.
Kim: I agree with Don that the review staff in OTP and other product review offices in CBER in general do not seem to have been primary target of the cuts, so that means that reviewers and Regulatory Project Managers (RPMs) are still present, as well as review supervisory chains of command in those offices. On the other hand, supportive functions, including those who provide administrative support to the reviewers in question, were either eliminated or severely cut. The CBER center-level policy staff and communications staff and other support staff were all (or nearly all) eliminated.
In the near term, keeping the reviewers in place would indicate a possibility that IND meetings, CATT (CBER Advanced Technologies Team) requests, AMT (Advanced Manufacturing Technologies) requests and designations, IND and BLA review, etc., may not be impacted. We have at least two real-time client examples (since the administration changeover in January) of notifications of submission receipt, at least, moving forward on schedule. Of course we do not yet have any examples after the April 1 RIF. While this seems like good news for now, to the best of my knowledge, the RIF cuts included staff with roles in document control. This could impact the receipt and processing of IND, BLA, meeting packages, and related submissions through the electronic gateway. One potential impact is that if filings are not logged in a timely manner to start the clock on PDUFA filings, we could actually see extension of timelines.
Tal: So, if we ask the question: will our clients’ meetings remain on schedule in the very near-term? Probably so. There may be less time or attention given to review of meeting requests than we’re used to, though. I anticipate the schedules getting less reliable over time because without support functions, FDA’s reviewers are having to address every element of the process rather than being able to focus on the review itself.
Adnan: I agree. On paper, the review divisions may seem intact for the most part. That being said, with the first and second wave, with the removal of the conditional staff—many of whom were recently hired employees—and the “fork in the road,” there could be significant impact on the reviewer workforce as well. The Clinical Divisions, in particular, have been relatively hard-hit in terms of leadership who have left of their own accord after these changes. Many branch chief and division director positions are vacant. Of course, unanswered questions include: among those who have a choice, who will want to remain? What will those who do remain be able to accomplish without the infrastructure that they rely upon, from leadership to ancillary support? The exact measure of the impact will be challenging to predict.
With these losses, we may see unintended consequences ranging from potential delays in non-PDUFA regulatory review timelines to impact in the quality of the review itself. I would advise sponsors to be as thorough as possible in submissions, as well as in engagements with the FDA review teams, so as to make the review process as convenient and seamless as it can be.
Katy: This puts the onus on the submitting entity to provide the highest-quality filings with extremely clear questions and history of interactions.
Kristin: Yes, sponsors are going to want to pay particular attention to pointing out previously resolved clinical questions, manufacturing issues, and really being very specific about when and how they were resolved. Specifically, I’m talking about hyperlinking to previous meeting minutes, prior conversations, and any other information sent to or received from FDA. We have to prepare in advance for the potential for less continuity in the review teams than we could depend on previously. I recommend acting as if the review team will be more pressed for time than usual, is potentially functioning without oversite, and may have no direct history with the Sponsor’s IND and previous filings.
Kim: I have clients calling to ask whether they’ll have the same review team, and a short answer is that even if a sponsor does get lucky and have the same review team, we need to be cognizant that everyone remaining is wearing multiple hats now and is responsible for additional work and roles that were previously covered by someone affected in these first three staff reduction waves. It comes right back to the points you’re making: ensure that everything in any filing package is crystal clear and documented to make the job of reviewing it as quick and easy as possible.
Don: One of those unintended consequences mentioned earlier can be as mundane as: how does the Agency promote staff from within to fill existing vacancies, going forward, given that the admin and HR staff who would have processed the necessary paperwork are no longer there to do that work? How do you renew a contract for temporary positions remaining that have (to date) been spared cuts? The Agency was arguably understaffed long before these cuts; meeting the necessary PDUFA deadlines was a significant challenge even with the manpower in place at the time, which has now been cut down by roughly a third.
Tal: And this does not yet take into consideration the repercussions of the April 28th “return to office” deadline for remote staff that may or may not still be in effect and could cause more employees to leave their positions if they’re unable to comply. The President issued a mandate earlier this year that Agency remote work opportunities be terminated, requiring everyone who lived within 50 miles of an FDA facility to return there to work by March 17th. Anyone further away than 50 miles was given an April 28th deadline. However, as of April 10th, it appears that at least some of those requirements are being walked back.
Kim: For context for anyone not familiar with the history of remote and contract work at FDA: when PDUFA VII was signed into law, it granted additional resources to further staff the Agency. This led to a concerted hiring effort, including an appreciable number of term-limited or fellowship-type positions that were designed to be renewable if satisfactory. Some of those positions have been affected by the first wave of cuts and many others could be affected by, as Don said, the logistics involved with processing those renewals when staff responsible for these processes have been terminated. This could result in the loss of reviewers whose jobs were not explicitly targeted for removal.
On a related note, the COVID-19 pandemic obviously instituted a significant increase in positions at FDA and beyond that were granted the flexibility of remote work. Individuals hired into OTP at that time may also find themselves subject to the April 28th deadline…or maybe not, due to the possible reversal in this administration’s policy that Tal mentioned. Across the board there’s just a lot of uncertainty and fluctuation, and that affects not only any next steps that individuals can take, but could also affect productivity, at least temporarily.
Adnan: I’d like to shift slightly to consider the degree of harmonized, consistent advice we are to expect with all these significant changes. FDA has historically prioritized harmonization and consistency of advice and decision-making process. These disruptions and extensive staffing changes could have dire consequences in regards to these efforts. I have a real-time example of a client who engaged FDA in a meeting last fall and was given a particular set of responses to their questions. The same client then recently submitted a new IND for the same product but for a different clinical indication. They anticipated consistency in strategy/advice/questions, but that was not the case. Rather than being just alarmed by this example, I’d like to re-iterate that it is critical that sponsors highlight in their submissions all pertinent details and provide direct references to any and all previous communication(s) between the sponsor and the FDA. We advise clients to not only make the review process as clear as possible, but help ensure that review team for one clinical indication or IND has easy access to details on steps taken for previous indications in other INDs. In the past, we could expect that harmonization to occur naturally as a function of the interworking’s of the review teams, but now we need to be proactive and prepared not to expect this to happen organically going forward.
Katy: Adnan’s comments on consistency in reviews brings to mind the topic of guidances. Guidance documents are one of the most efficient and effective mechanisms FDA uses to establish and communicate consistent standards for review expectations across the industry. DHC and industry organizations such as ARM, ASGCT and ISCT have long advocated for more guidance documents to assist sponsors in navigating the unique challenges space of CGT. We even offered our own proposed draft guidance (on the Testing of Adeno-Associated Viral (AAV) Vector-Based Human Gene Therapy Products for Empty Capsids During Product Manufacture) back in 2022 as a concrete example of the sorts of guidance needed in CGT. Am I correct in anticipating a possible downturn of new guidance documents in the near-future due to these staffing changes?
Kim: Yes. Guidance documents require participation from multiple groups including the product review offices like OTP, and center-level policy and communications staff. The latter 2 groups were eliminated in their entirety. I am loath to make any sweeping predictions due to the ever-changing landscape at the moment but I don’t see how guidance documents (or town halls or any other education on expectations) can occur without any communications staff. We’ll likely need to work with only what is in place as of now, in conjunction with the experiences we’ve accumulated through our clients’ submissions.
Adnan: Similarly, without adequate human resources (HR) and budgeting functions, anything requiring a contract or contract extension as well as any personnel actions will be limited. Currently, there isn’t even an ability for people who choose to exit to be processed out appropriately. All communications, outreach, and development are limited and potentially without a mechanism now, meaning inquiries to the center may not be processed or responded to in a timely fashion, in addition to the other education elements being curtailed as mentioned above. There may also be a limitation to—or elimination of—advisory committees, potentially due to the removal of staff responsible for organizing them.
Katy: Another area of great interest to our clients is requests for designation (RFD) related to product jurisdiction. Since CGT products can often be complex combination products spanning two or more FDA review centers (Biologics, Drugs, Devices), these filings can be important to provide clarity on which center will be playing the lead role in product review. We’ve supported quite a few clients with these designation request filings in recent years. Do we have any idea whether RFDs are likely to be impacted by the recent changes at FDA?
Don: RFDs are under the category of things I’m expecting to slow down due to a lack of personnel involved in decision-making and procedures to process them. The jurisdictional officers who were responsible for RFDs were among those impacted in the recent RIFs. Informal queries are often made before or instead of RFD filings, and informal queries do not have an associated deadline for response. When there’s insufficient staff or an excess of work, leadership has to prioritize what needs addressing. My instinct is that RFDs could be something that gets deprioritized.
Katy: Continuing in that vein, what other non-PDUFA mandated activities might we expect to see impacted?
Tal: I’d also expect meetings that fall outside of PDUFA timelines to take a back seat. For example, informal meetings are common during BLA review but the recent cuts may affect the ability of reviewers to accommodate those.
For formal meetings, prior to the recent cuts at FDA, we had observed a positive effect on the rate of all types of meetings (including CATT, Type C and Type D) being granted by OTP as a result of the staff increase under PDUFA VII. OTP was using the Written Response Only mechanism only if that was requested by the sponsor. I would expect that the rate of granting meetings could decline in addition to an increasing inability to meet PDUFA timelines for meetings that are granted.
Katy: All right, thank you. Let’s turn to the topic of inspections. Heath, what can you tell us about what we’re likely to see in this realm?
Heath: As with the rest of this discussion, it’s complicated and in flux. The real-time example I’ll offer is that of a client scheduled to have pre-license facilities inspections this month. DMPQ (Division of Manufacturing and Product Quality) did confirm that these inspections are still scheduled as of this time. Similar to the other issues discussed earlier, though, I would anticipate seeing significant changes sometime soon. Some questions on my mind right now are: when timelines are in jeopardy will inspections simply be waived (and what are the implications of such a scenario and what are the criteria for deciding when to waive them)? Will thresholds for inspection be lowered instead of waived? Will we see more virtual audits and inspections as we did due to necessity during the early pandemic years? If inspections do continue being held in person, what will the mechanism be to fund that travel? What about renewal of inspection credentials? Some of these are big picture issues and some are logistical issues but they will all affect what we see happening.
I can certainly confirm that, from the DHC and BTL side of things, we’ll be working with our clients to communicate any change in expectation or schedule and how best to respond to any of these changes.
There is some good news amidst today's volatility, which is that no developer need ever wait for an official inspection to identify and remediate compliance issues. It's expected that sponsors take control of their own compliance responsibilities. I would caution that any developer doing so should utilize guidance from experts who can ensure that it's being done correctly. Remember that you have both DHC and BTL available to assist in the process. Our collective depth and breadth of compliance experience is unmatched and we can help as much or as little as needed.
Katy: Thanks, Heath. I also asked BioTechLogic’s VP of Regulatory, Julie Spyrison, and DHC’s Head of Nonclinical, Nate Manley, to join this group of former-FDA experts because you both experience a high number of filings with our clients. Julie, Nate, I know it’s early days yet, but are either of you seeing an impact on client filings or strategies? Are clients increasingly looking at shifting strategies to ex-US given the current uncertainties at FDA?
Julie: Still too early to tell, I’d say, but most clients I’m currently supporting are in Phase 1 or 2 (or in some case gearing up for Phase 3) so a switch in strategy to ex-US is not an option for them. I’d like to go back to the point Adnan made about the change in expectations from one CMC Reviewer to a new one. My clients are concerned that recent agreements that have been made with the FDA on CMC strategy (e.g. analytical comparability) in Type C meetings may get revisited when the data are filed in IND amendments. As such, I absolutely endorse the recommendation to link extensively to past history with regulators within our submissions, documenting every step of the way. The goal will be for regulators to be aware of (and hopefully not unnecessarily revisit) decisions that have already been made.
Nate: Yes, my experience with clients thus far is that they’re voicing understandable concern and uncertainty as to whether their filing strategy is going to be feasible within the timeline they’ve planned and whether they’ll have continuity of personnel at FDA. Thus far I haven’t seen timelines stretch for INTERACT or pre-IND specifically, but as you say, it’s early days. Along with all my colleagues, I’m keeping a very close eye on whether timelines are changing or if any pandemic-era solutions will be applied, such as written responses only or those virtual audits Heath mentioned.
I also agree with extensive documentation being one of the best steps we can take at this time. It won’t be a comprehensive solution across the board, of course. I did have one experience in February, as an example: a client had a pre-IND meeting for one program last fall and another for a different program earlier this year and received differing guidance. We probed into the differences and specifically cited the previous feedback, but the response was that the discrepancy was explicitly due to a shift of thinking at the Agency.
To fully understand the Agency's revised position, we also utilized the post-meeting clarification request mechanism available for pre-IND meetings. If you conclude an FDA meeting with any degree of uncertainty about their feedback, I highly recommend submission of a follow-up clarification request. On a related note, some of us have experienced the Agency starting to take a more conservative view with respect to use of laboratory-developed tests in early clinical trials. This was before the recent court decision regarding the LDT Final Rule, and the FDA stance is likely to remain highly product- and application-specific. We’re watching all of this very closely and will continue to gather real-time data from our Sponsors' submissions to understand the FDA's evolving mindset regarding LDTs and other key aspects of product development strategy.
Katy: What about the preliminary ideas we’ve seen reported regarding a potential reorganization of FDA that would merge the product centers?
Adnan: Yes, we have heard that there is a proposal to consolidate the current FDA centers into “shared services offices” in order to “streamline evaluation processes, align regulatory standards, and reduce duplication.” This idea sort of makes sense conceptually but gets much more complicated when you implement it, taking into consideration the diverse product types and therapies regulated by the various centers at the FDA. Particularly for CGT, which up until recently has required specialized and innovative review support from the multi-faceted technical teams in CBER. A generalized, “cookie cutter” review method simply will not suffice for the assessment and approval of these cutting-edge therapies that have unique manufacturing, preclinical, and clinical considerations and require special attention that do not necessarily align with other therapies regulated across the FDA.
Katy: That brings us directly to Peter Marks’ departure, doesn’t it? I think it’s undeniable that Marks was an advocate for CGT and for thinking creatively about how to accelerate this class of products, especially in cases of rare disease and significant unmet medical need. What do you think his departure will mean for CGT?
Don: There’s no doubt he’s a significant figure and has been championing CGT creatively and effectively for a number of years. I think he is patient-oriented and focused, and this has been very helpful in terms of securing product approvals. The good news for me is that we still have staff in place at FDA about whom I could say those same things so there could theoretically be some continuity of approach in a best-case scenario.
Tal: It will be interesting to see how this all plays out, because on the one hand there is a push for less restriction on development…and on the other hand we have these manpower cuts which lead to less hand-holding and support, which could slow down development. Where will it all land? While we’re speculating, how will raw materials be impacted by tariffs and global politics? Some clients are already trying to figure out new sourcing but not everything can be sourced from the U.S. That’s a topic for another day.
Kristin: There’s one other question I wanted to posit before we’re out of time: the potential impact of staff reductions on the PDUFA (Prescription Drug User Fee Agreement) program, and/or the upcoming PDUFA VIII negotiations, which are scheduled to begin in a matter of months. There was an article recently about staff potentially dropping below the levels mandated by the PDUFA agreements. The user fee program is a very complex topic and reduction of staffing affecting it certainly falls under the realm of possible unintended consequences. I recommend this article on the user fee program and this related article, as well.
Overall, I believe it’s widely agreed that the industry and the American people benefited from the engagement of PDUFA in 1992, in that the Agency’s reviews became higher quality and more efficient, thus making drug development more efficient and cost-effective. I think we would experience considerable problems if the program is diminished or eliminated.
Katy: Thank you for this interesting discussion today. I appreciate knowing that the DHCG stable is collectively following and assessing the impacts of changes that have occurred at FDA so far this year, and additional changes that may come, as we help our clients navigate the uncertainties.
* These staff have sometimes been referred to as “probational” staff, but the correct term for these new and recently promoted staff within FDA is “conditional.”
.jpg)