The context: Marks on tour to discuss CGT Products

• CBER Director Peter Marks was among several FDA staffers who made the rounds at conferences last week, appearing on several panels to discuss accelerated approval, the promise of gene therapies, and the general operations of CBER’s new Office of Therapeutic Products (OTP) as it continues to work on scaling up its operations to meet the needs of sponsors working on regenerative medicines.
• Where he spoke: Last week, Marks first kicked off his conference tour with a panel discussion on Accelerated Approval at the American Society of Gene & Cell Therapy Annual (ASGCT) Meeting, followed by a discussion later that afternoon at the Food and Drug Law Institute Conference on CBER’s current and future activities. Thursday, he returned to ASGCT to take part in a fireside chat with his counterpart, Yoshiaki Maruyama of the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) and again on briefly on Saturday to discuss the progress and importance of the Bespoke Gene Therapy Consortium. Finally, he capped off the week with an interview on the BioCentury Show. Overall, some of what we heard last week were repeats of previous remarks, while other comments provided a new glimpse into the current thought process of one of the FDA’s top officials.
• In addition to speaking at the ASGCT and FDLI conferences, he has also participated recently on panels at the Stanford Drug Discovery Symposium, Global Genes/UPenn’s Rare Drug Development Symposium, and NORD’s Patient and Family Forum. He’s also participated in several recent advisory committee meetings. During these meetings, he hasn’t said much, but the few remarks he has made along with the timing of those remarks still garnered a fair amount of attention.
• And finally, Marks was a panelist at yesterday’s Friends of Cancer Research (FOCR) Meeting on the next generation of cellular therapies.

Marks’ vision for how FDA can use advanced AI

• Yesterday’s FOCR meeting marks one of the first times we’ve heard the CBER Director comment on today’s explosion of interest in the use of AI tools. Recently, AgencyIQ has heard about the use of AI in combination with big data to develop things like “digital twins” or complex mechanistic models to predict a product’s performance in vivo for different dosing regimens. FDA also published a discussion paper on the use of AI in drug manufacturing. Marks seems to be most interested in the use of AI tools for manufacturing—at least for now.
• “I suspect that if we do our jobs right, the next ten years will bring us great advances in biologics manufacturing… Again, if we apply AI in the right place, rather than making funny cat videos.” He suggested, “It’s certainly something that could be used to help us do process improvement.” For example, AI can continuously monitor hundreds of data points collected from different process sensors to alert manufacturers in real-time if there are deviations to the process which could affect critical process attributes and ultimately impact the product’s quality.
• But Marks is also interested in how AI can assist FDA to perform the numerous, repetitive tasks the Agency is charged with. Marks provided the example of adverse event reporting, “We get thousands upon thousands adverse event reports. With natural language processing, we could probably flag the 1% or 2% that really should be looked at by a medical officer and the rest of it could be categorized and essentially best described through AI as ‘okay.’ […] So, I think identifying what actually requires human touch is something that AI can help us with.”
• He also hopes AI can assist in combing through all the data the Agency receives to proactively flag trends in safety or efficacy that humans might miss (especially as more and more applications are filed electronically). Marks elaborated, “You could imagine that if we’re able to use AI internally, we might be able to—across programs—find trends in safety, or effectiveness using given factors for cell and gene therapies.” He wrapped up his comments on AI by acknowledging that this evolution will take time for the agency to develop.

Operation Warp Speed but for rare diseases

• Marks plans to launch a communication pilot program which would “attempt to reproduce some of the benefits of Operation warp speed, in particular, the element of constant contact.” In speaking to the audience at Stanford Drug Discovery Symposium, he clarified that he’s not planning to give out his telephone number or to field calls at two o’clock in the morning. However, he wants to get the communications pilot program up and running by the end of 2023. In his words, the field is teetering on the brink with the potential to slow down significantly or to accelerate and get promising products to patients more quickly. The goal of harnessing the constant contact offered by OWS would be to see if engaging in ongoing informal conversations with sponsors for “very promising products” will allow them to get to patients faster.
• The U.S. Operation Warp Speed: Operation Warp Speed (OWS) was a partnership of the U.S. Department of Health and Human Services (HHS), Department of Defense (DOD), and industry that aimed to “accelerate control of the COVID-19 pandemic by advancing development, manufacturing, and distribution of vaccines, therapeutics, and diagnostics.” In contrast to the traditional approach for vaccine development and approval, which is costly and can take anywhere from years to decade, the U.S. government initiated the OWS program with the ambitious goal of moving promising investigational products (using primarily nonclinical data) through clinical trials, product approval, and scaled-up production in the extremely compressed timeline of just 18 months. The OWS program was initiated under the Trump administration, but is continuing on under the Biden administration (beyond the COVID-19 public health emergency) after being rebranded “Project Next Gen”.
• According to Marks, we should see a Federal Register Notice announcing this new pilot program in the coming months. The volume of applicants accepted into the program is going to depend on CBER’s bandwidth, but Marks said they will be looking for very promising products for the treatment of rare diseases that have already made it into humans but are still in the early phases of clinical trials. FDA would then assist in speeding the approval of the products by applying a “warp speed approach” with the benefit of more informal and constant communication with CBER review staff. According to the estimate Marks provided during the UPenn symposium, it sounds like the pilot will initially be limited to somewhere between 5-10 very rare diseases.
• If the pilot program is a success, Marks hopes to be able to go back to Congress and ask for additional resources to expand the program further. He believes the program will be successful based on the numerous interactions he’s had with sponsors during his time at FDA and his insight on what the most common obstacles are in gene therapy development and approval (e.g., scaling up manufacturing). He also believes that despite current staffing challenges, CBER is uniquely situated to take the lead internationally on enabling the development and approval of life-saving gene therapies.

Making gene therapies commercially viable is front of mind for Marks.

• During Saturday’s ASGCT Session on the Bespoke Gene Therapy Consortium (BGTC), Marks discussed the factors that led to the BGTC’s creation in October 2021 and the evolution of the challenges faced by gene therapy developers. For context, the goal of the Bespoke Gene Therapy Consortium—per the NIH—is to “develop platforms and standards that will speed the development and delivery of customized or ‘bespoke’ gene therapies that could treat the millions of people affected by rare diseases.” The consortium is funded by a public-private partnership called the Accelerating Medicines Partnership (AMP), whereby the Foundation for the NIH (FNIH) administers funds provided by industry, government, and nonprofits to scientists working on applicable basic or clinical research to advance gene therapy development for rare diseases. Research must be focused on enhancing the therapeutic benefit of gene therapies delivered using an adeno-associated viral (AAV) vector or on improving and/or accelerating the manufacture of viral vectors.
• According to Marks, the BGTC was originally created to de-risk and incentivize the timely development of gene therapies to treat noncommercially viable rare diseases (i.e., diseases in which the cost to develop a treatment is anticipated to outweigh its estimated revenue generation). At the time of its inception, the organizers hoped the BGTC would help to stimulate the flow of venture capital to companies working on gene therapies to treat rare diseases. Ironically, due to the pandemic and other economic developments since then, venture capital has continued to dry up and is today even harder for companies in this space to come by. Marks stated that this reason alone points to the continued importance of the BGTC’s work, explaining “Right now I think that when people look at this area, they see challenges in getting things through clinical trials, challenges in endpoints, challenges in manufacturing, and challenges in reimbursement.” Marks expressed optimism that the program will continue to pick up steam as it is utilized more, despite these current challenges “I think the idea is if you can get together a playbook and show that it works for a couple of these, then we can start cranking things through.”

International harmonization/timing of gene therapy applications

• “We want to explore concurrent submission and product review with other regulatory authorities and other countries to make small populations somewhat larger and more attractive,” said Marks, also during the Stanford event. He explained that the use of multiregional clinical trials could make it easier for gene therapy developers to conduct trials for products intended to treat rare diseases. One known challenge for developers working on products to treat rare diseases are that the patient populations are small. Marks said that enrolling patients with rare diseases in other countries would not only make it easier for developers to enroll their trials, but it would importantly mean that patients who might normally end up waiting years before gaining access to treatment (especially those in low- or middle-income countries) could get life-saving treatment significantly earlier.
• Collaborative review, as we’ve already seen in OCE’s Project Orbis, is another option Marks wants to explore for gene therapy. “We’re starting to very seriously talk with the EMA and PMDA, which is the Japanese Medicines Agency, and some of our other regulatory colleagues to see if we can do something that mirrors what’s already been done in the oncology world,” he said at the UPenn Symposium.  The intent in expanding this type of program would be to enable one gene therapy application (or at least its content) to be submitted to multiple countries/regions at once for simultaneous review by the different health authorities to increase parity in the time it takes for a product that is approved in one region to be approved and accessible to patients in another. He connected this concept of collaborative review back to the importance of making gene therapies commercially viable, suggesting that this process would also lead to a reduction in resources demanded from sponsors to develop these treatments in terms of production costs and time.

Marks is ready to start applying a platform approach for gene therapies

• During Saturday’s ASGCT panel discussion about the Bespoke Gene Therapy Consortium, Marks agreed that the term “platform approach” could be used to describe the extrapolation of BGTC’s approach to streamline regulatory requirements for the development of gene therapies using AAV viral vectors to more prevalent diseases. Several panelists mentioned that the BGTC steering committee (SC) has been internally debating and discussing how to ensure the sustainability of the program. One opportunity for expanding the success of the BGTC program (e.g., after its initial goals or aims have been completed), could be adapting it to more prevalent rare diseases (e.g., Duchenne’s). Marks equated the use of a platform approach for gene therapies to treat more common rare diseases as a “large task” that has to be broken into small tasks before the field can get there. These smaller tasks would include de-risking the clinical development, manufacturing, use of accelerated approval, and other novel approaches to get bespoke gene therapies across the finish line. Along with the completion of those smaller tasks, Marks explained that use platform technologies “like the authority that’s been given to us through FDORA” legislation of 2022 could be the answer to expanding this approach to larger indications. Basically, BGTC’s approach to making the development of bespoke gene therapies more efficient and less expensive for sponsors up-front, could serve as a template for adapting the program and de-risking the development of more gene therapies in the future.
• The BGTC specifically chose the eight diseases in its clinical trial portfolio based on their potential to enable a streamlined regulatory approval process. During the National Organization for Rare Disorders (NORD) Patient and Family Forum, PJ Brooke (NIH’s National Center for Advancing Translational Sciences) and Marks laid out the process the group went through to select the diseases. The rigorous process started with over sixty diseases submitted and after several rounds of expert input and feedback, the BGTC was able to narrow down to those that they thought were most suitable for expediting regulatory review, for example those with clinical endpoints that could be used to detect improvement following the gene therapy very quickly. At the time of the NORD meeting, the list of diseases hadn’t been released yet but was newly published by the organizations one week ago. The NIH plans to publish the standard templates and an instructional “development playbook” developed by the group in the future. The same day the eight diseases were announced, NCATS Director Joni Rutter published an article in Nature on her charge to lead the Center to achieve its goal of enabling the translation of basic research into clinical programs, resulting in 25% of known diseases with a treatment in the pipeline by 2032.
• At Stanford, he also discussed the BGTC and was even more specific about how platform approaches could be leveraged to “reduce the burden on manufacturing and on the regulatory process.” He again specifically called out FDORA, explaining that “The concept here is that if one has a well-characterized platform or originator product, then one could swap out—within reason, obviously, because we would have to have parameters on it—different inserts, and not have to do all of the rework.” As for an example, he said a given AAV serotype could be reused multiple times. In those cases, the sponsor might not need to reproduce the manufacturing or toxicology information “over and over again.” In his words, even gene therapies produced for small populations, despite being uniquely tailored for the individual, could be considered “cut from the same cloth” if they all use the same vector. [ Read AgencyIQ’s analysis of CBER’s April 2021 guidance on ‘n-of-1’ products]
• For sponsors looking to move towards a platform approach, Marks sees AAV vectors as the best place to start: During the Global Genes/UPenn’s Rare Drug Development Symposium, he indicated that information from the originator product application that could be leveraged by a sponsor reusing the same AAV vector for a new gene therapy might be limited to manufacturing and toxicology data to start. During the panel, Marks equated the review of gene therapies as akin to the birth of a new baby—that is, regulators and sponsors are treating each therapy as a completely new and unique entity. “We haven’t really today taken advantage of the fact that we’re reusing the vector portion of the gene therapy over and over again,” he said. In contrast, regulators and sponsors should be capitalizing on the fact that many gene therapies use the same vector serotype, he went on, comparing these related treatments to razors with disposable razor blades (yes, really) where the insert is like the razor blade that can be swapped out, while the razor blade handle (i.e., the vector) stays the same.

Something we’re increasingly hearing: FDA is concerned about insurance coverage

• The tenuous relationship between FDA and CMS has been thrust into the limelight more and more in recent years in regard to coverage for accelerated approval products, vaccines, medication abortion, and more. For Marks, coverage of new gene therapies (whether or not they take advantage of the Accelerated Approval pathway) is especially important. “We don’t actually deal with reimbursement at FDA, but we obviously interface with it. We are working with the Centers for Medicare and Medicaid Services to try to make sure that as we start to see more gene therapies come along, there is a way to pay for it.” He stated during NORD’s Patient and Family Forum.

The Accelerated Approval Pathway should be used for gene therapy products – even at the risk of using it improperly.

• At just about all of the events, Marks spoke out about the promise of the Accelerated Approval pathway for gene therapy products. To him, leveraging the AAP provisions is just common sense and furthermore, he believes FDA owes it to patients.
• During the UPenn event, he said some staff within CBER have been “reluctant to use our accelerated approval provisions.” He seemed to signal that CBER will be turning a corner on the use of AAP though moving forward though, “The problem is that if you take that attitude in rare diseases, you’re essentially relegating many rare diseases to never get a gene therapy because it’ll take too many years to get there.”
• Marks said he’s not afraid of making a few mistakes when it comes to expedited approval. Using a surgical analogy he explained, “Good surgeons know that about 5% of the time when they get the pathology back on an appendix that they took out, it’s going to be normal. And they don’t lie awake at night and say they thought they did a bad operation—they actually say ‘No, that’s good because it means I’m actually being aggressive enough in taking people to the operating room to look for a hot appendix.’ Because if you don’t, it means you’re going to miss some.” In his mind, CBER should be aggressive enough in using accelerated approval that sometimes, after the postmarketing data has been analyzed, it turns out that a few products were not as efficacious as they originally thought they would be.

Yes, CBER has staffing challenges

• “I’m just going to speak freely, we haven’t had the bandwidth to help the field as much as I think we could have,” he said during the event at UPenn. One of the first places it sounds like he will be trying to bolster CBER’s expertise on is by hiring reviewers with experience in the manufacturing of cell and gene therapies. In some cases, he said that gene therapies have demonstrated great potential but have been foiled by manufacturing challenges once the sponsor attempted to scale up production. In a few of these instances, the scaled-up manufacturing process might be so flawed that the product ends up almost counterproductive to what its intended purpose was. He believes that CBER will finally be able to assist sponsors dealing with these issues though, thanks to the additional 125 staff the Center was allocated to assist with CGT products per the sixth reauthorization of the Prescription Drug User Fee Agreement.

https://fda.agencyiq.com/article/00000188-4b9f-d54f-af8b-ff9f74e70000