Our panel of former-FDA regulatory experts: a discussion

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At this year’s Advanced Therapies Week in Miami, DHC is going to be doing something unprecedented. We’re convening our full panel of ex-FDA regulatory experts together at the Dark Horse Lounge (booth #700) for four events. Stop by to meet them during our #DHCespresso opportunities: during the morning coffee breaks both days from 10:30-11. And then, also on both days, grab some food and join us for a Lunch & Learn hour-long panel discussion. Wednesday’s Lunch & Learn will focus on early-stage regulatory strategies and questions, while Thursday’s will focus on late-stage.*

We got them all together for a discussion about what to expect at our Lunch & Learns.

It’s wonderful to have all of you here in the same virtual space! We have with us Don Fink, DHC Master Practice Expert and ex-CBER OTAT CMC reviewer with 28 years of experience, specializing in cell therapy…Heath Coats, DHC Senior Practice Expert and ex-DMPQ inspector with expertise in late-stage commercial facility readiness preparations…Kevin Whittlesey, DHC Principal and ex-CBER cell therapy CMC reviewer and Commissioner’s Fellow, specializing in gene therapy and regenerative medicine early-stage development…Tal Salz, DHC Practice Expert and ex-CBER OTAT CMC reviewer, specializing in gene therapy with expertise in comparability…

…and finally, Kimberly Benton, our newest Dark Horse! Dr. Benton specialized in cell and gene therapy products for her 22+ years at the US FDA/CBER. She bid FDA a fond farewell at the end of December after 6 years as the Associate Director for Regulatory Management in the Office of Tissues and Advanced Therapies.  She previously served as Deputy Director of the Division of Cellular and Gene Therapies, and as Chief of the Cell Therapies Branch. We’re thrilled to have you here, Kim!

Kim Benton: Thank you! FDA was an integral part of my life for so long, and it’s exciting to now be able to use that experience to help DHC’s clients. I’m sure my colleagues will also recognize the anticipation I feel at the opportunity to scale my skillset so as to ultimately assist [innovators in the cell gene therapy space achieve their goal of helping] that many more individual patients.

Don Fink: Absolutely. My sense when I moved over to Dark Horse was very similar. And I’m thrilled to be working together again with both Kim and Tal, given our shared work history in CBER OTAT.

Let’s kick this off by considering some of the types of questions we’re anticipating hearing from the audience at the Lunch & Learn panels.

Don: For innovators across the space I’m seeing questions about expedited options. Everyone’s in a hurry, pushed by development timelines that are at best challenging (if not unrealistic)—and for rare diseases, recruiting enough patients to meet study enrollments is in and of itself a limitation—so naturally, sponsors are interested in expedited development pathways and guidance as to which one (Fast Track, Breakthrough or RMAT designation) might be best suited.

Kevin Whittlesey: And there’s always confusion among sponsors because an expedited program doesn’t provide assurance that you’ll get your license faster. It does mean that you’ll have the opportunity to seek more interactions with the FDA, though.

Heath Coats: Recently I was giving a talk about various programs and regulatory bodies’ options for accelerated pathways, working to clear up expectations in this very area. I’ve been noticing consistent confusion around which accelerated timelines mean what. Spoiler alert: “Priority Review” is the only time-shortening option and applies only to BLA Review – and does not lower the bar for expectation of full cGMP compliance.

Kevin: So, we’ll likely be looking at offering a brief review of the differences between Priority Review, Breakthrough Therapies, Accelerated Approval, RMAT, and Fast Track.

Kim: Let me circle back quickly to Kevin’s point about having more interactions with FDA. A primary benefit of BT or RMAT designations is increased interaction with FDA. Through these additional interactions, it becomes more likely that expectations are aligned and that the sponsor is aware of any changes they need to make.  I’d also like to emphasize that the quality of the interactions, not just the quantity, is key. This means that sponsors need to be strategic about when to request meetings with FDA and what questions to ask.

Heath: It’s also important to note that there isn’t a single magic bullet for shortening development timelines. None of these opportunities for additional FDA interaction associated with any of these programs are a replacement for stringent quality systems and a strong CMC package.

An excellent reminder, thank you! What’s another question you anticipate receiving, or hearing about, at ATW23 this week?

Tal Salz: I’m seeing interest in manufacturing platform approaches and will be intrigued to see what comes up in Miami on that front. For example, development of different guide RNAs, each targeting a different sequence within the same genomic locus to address a panel of mutations resulting in the same disease. These types of manufacturing conundrums don’t exactly fit under the recently published FDA guidance, “Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial”, especially when we are talking about a very large number of product versions. I think this will be a topic of healthy debate.

Don: The studying multiple versions of cell and gene therapies guidance dials up a number of questions, doesn’t it? Does each unique product need to have its own IND? What if they’re for the same clinical indication? The same master clinical protocol? These are details that aren’t decided yet, so working hand-in-hand with a regulatory body to help identify some strong practices is a win for the industry. And the great unknown is: could all of these be consolidated into the same platform BLA? It's fair to say that the answer to this question remains TBD.

Tal: The issue is that at the of the day FDA approves products, not platforms. Each version of the product using a particular platform will need to be demonstrated to be safe and effective. For example, there are rare diseases causes by different mutations in the same gene. To address that you may want to develop several genome editing products manufactured with the same platform that target different mutations. But, each might have a different safety profile. Without regulatory precedent, the right answer is to communicate with the FDA early and often.

Kevin: This topic is a timely example of something that we often see: cell and gene being ahead of the game and pushing the envelope on the regulatory paradigm. By definition, CGT incorporates newer technologies and manufacturing processes that simply haven’t been around long enough to coalesce around regulatory guidance that is anything other than case-by-case. That’s daunting to a manufacturer of innovative cell and gene therapy investigational products for very good reason. However, that doesn’t mean that there aren’t best practices that can be followed.

Speaking of areas of guidance, let me toss in a quick reminder of the new rAAV white paper that’s just come out, authored by Christina Fuentes, Ph.D., Jacob Staudhammer, J. Fraser Wright, Ph.D., Nicole Paulk, Ph.D., and Scott Cross, M.S.
Scott and Jacob and Christina are part of DHC, of course, and Drs. Wright and Paulk need no introduction!

Kim: Yes. I just recently reviewed it myself and I think it’s going to be a strong offering to the industry.

How did that white paper come into being?
It started as an extension of the draft FDA guidance we initiated last May. It was the first time that anyone had ever taken advantage of FDA’s essentially open-door policy on Instructions for Submitting Drafts of Proposed Guidance Documents Electronically to submit a proposed guidance focused on a topic pertaining to the safety of investigational gene therapies (I talked about this in more detail in an earlier Straight from the Horse’s Mouth that you can read here.) It got such positive feedback that many of us felt it was time to provide a more expansive review on the topic of AAV product composition.

Love it! Don, you were an author on that initial draft guidance but played only a supporting role here. Why is that?
Well, Christina, Jacob, and Scott bring deep technical experience on AAV manufacturing and characterization, so it’s appropriate that a deep dive like this should come from them. Their experience compliments that of our regulatory team.

So, back to some of the conversations you might anticipate having while at #ATW23:
What’s something common that a sponsor does that worries you, as their consultant?
I hate to see a sponsor focus on cost-consciousness rather than the appropriate quality of raw material. Vendors are expanding offerings of different quality levels of material, and an emphasis on what contaminants may or may not be removed is definitely increasing, but for many clients it would be wise to move the needle still further on this front. An upfront comparison of the different grades of material in a process is warranted in order to prevent surprises when a switch is made to a higher-grade material down the line in later stages of process/product development. Sometimes use of a non-GMP-produced material is necessary based on market availability, and in order to get past those earliest hurdles with respect to cost containment. The sponsor should ensure the manufacturer is demonstrating appropriate comparability of the different grades and providing adequate documentation, which would also be part of the sponsor’s material and vendor qualification programs. The sponsor should also perform a risk assessment early in the process assessing the use of different grades of material, or possibly multiple vendors of the same material. (We all remember the supply chain challenges everyone had over the past 2.5 years). Waiting until too late in the product lifecycle to address this, someone could find themselves with an issue that they cannot resolve, which in the end would likely cost far more than the difference between grades of a raw material

Kevin: And of course, early strong choices related to selection of quality materials are excellent for risk mitigation and quality…later when you have to do a tech transfer, your risk is much lower.

What’s another common hang-up that you often see?
I’d say one of the #1 hang-ups we see is sponsors coming to late-stage product development with a potency assay that the agency simply isn’t happy with in terms of suitability. Back in the by-gone early days of cell and gene therapy (when I was still just a child, of course!) regulatory messaging was not to obsess about measuring potency at the early phases of product development. TODAY, if you’re contemplating doing IND-enabling preclinical work without a well-characterized potency assay or set of assays, you’re behind the 8-ball.

There are three common elements around the globe that tend to trip sponsors up when it comes to CGT regulatory bodies. Comparability, potency, and synchronicity. What do I mean when I say synchronicity? I mean that you need your clinical development and maturity of CMC development to be synchronized. If clinical stage testing and CMC maturity are out of alignment, you won’t, for example, be able to rely on early clinical study results to support your argument for efficacy unless you have a well-qualified potency assay that the Agency recognizes as suitable.

Kevin: Speaking of CMC, let’s not forget the recurring theme that Katy [DHC COO and Managing Partner] was telling us she heard at J.P. Morgan last week. It takes us back to that Scott Gottlieb quote from 2018: "In contrast to traditional drug review, where 80 percent of the review is focused on the clinical portion of that process, and maybe 20 percent is focused on the product issues, I’d say that this general principal is almost completely inverted when it comes to cell and gene therapy."
This is a reality that we’re all very used to, but it can come as a surprise for a client new to the space, particularly if they have a background in small molecule drugs or well-characterized traditional biologics like monoclonal antibodies and recombinant therapeutic proteins.

Kim: Definitely. I appreciated Dr Gottlieb’s comment in 2018, because it was a high-level public acknowledgment of what OTAT and companies in the CGT space were experiencing on a daily basis. I also understand from Anthony that that recognition is why DHC was founded based on CMC for cell and gene back in 2014, and why CMC continues to be a large fraction what we do to this day.

Don: I agree. Hearing these words escape the lips of the FDA Commissioner was music to the ears of every card-carrying cell and gene therapy CMC regulatory reviewer since for literally nearly two decades prior we had been arguing that it is product manufacturing and quality testing that will drive the boat when it comes to a successful product approval.  

While we’re considering often-cited quotations from a few years ago, would any of you be amenable to taking a look into your crystal ball? Do you have any opinions on whether Gottlieb and Marks’ 2019 projections for the number of new approvals might hold true? They’d guessed within the ballpark of 10-20 approvals per year by 2025.

Don: Alliance for Regenerative Medicines members are expecting 13-14 FDA regulatory decisions related to BLA filings for cell and gene therapies in 2023 (admittedly, they’re including “cord blood” filings, which in my book is different) so at least in the next 12 months, the projected target could be met.

Thank you all! Lastly, what are some things you can be sure the panel will not be discussing?
None of this should come as a surprise, but obviously we won’t provide specific recommendations on where to source materials, any supposed personal preference on CDMOs, etc. And certainly everyone in attendance will have the good sense not to ask about anything proprietary. This will be a high-level, FDA-focused conversation in which we can shed light on some general questions people may have.

Sounds amazing—can’t wait to see you all in action in Miami!

* By the way - early/late stage is our intended structure but if you can only make one day and have a question that isn't a perfect fit, go ahead and ask it!

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