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CGT: Collaborate to Scale


At Pharma USA 2023, Peter Marks, MD, PhD and director of CBER described FDA and public/private partnerships working toward scalable manufacturing approaches to address commercial viability and global access for cell and gene therapies

This year, Pharma 2023 USA, a Reuters Event, added a Cell and Gene Therapy (CGT) track to its commercial information stalwarts. The track capped off two days of panels and presentations on CGT with an in-person FDA presentation from Peter Marks, MD, PhD, director of the Center for Biologics Evaluation and Research (CBER). Many of the presentations in the CGT track tackled the exact challenges that Marks outlined in his regulatory update.

Marks noted that the CGT therapies serve small populations who have the highest medical need, with 12 currently FDA-approved, five only in the last year. Currently, there are over 2,500 active applications in the space.

From Marks point of view, the autologous CAR-T cell manufacturers have largely worked out many of the kinks have been worked out basically through the use of automated closed system manufacturing. The closed system allows for the quicker turnaround and continuous chain of custody required of these therapies. Marks credited those who fabricate manufacturing instrumentation that can make the models that work for this space, given the constraints.

To date, all approved CAR-T therapies are autologous, meaning the cells are from a single patient. The next stage would be allogenic, with cells from a healthy patient, which then could be developed as an “off-the-shelf” product vs. an individualized process, with many benefits including the ability to be immediately available to patients in need.

Marks noted Zolgensma as a poster child for success as a one-time administered therapeutic that is very effective in the treatment of SMA. Approved in May 2019, the children that received Zolgensma are now 8 to 10 years old. Marks noted that uncertainties around gene therapy would be expected, however, these children are still doing well at this juncture.

Meanwhile, with these successes, there are still many challenges that Marks noted in individualized therapies, including manufacturing, non-clinical development, clinical development and product access.

In manufacturing, commercial viability begins at over 100 doses. As noted, the cost to set up 10-20 batches is the same for over 100 batches, but the revenue is not there at the smaller number and therefore not viable. The other manufacturing challenge is transfer. Marks said with much of the innovation in this area coming out of academic institutions, each one has their own methods. In turn, this becomes difficult to transfer if turned over to a CDMO/CMO. “They just don’t transfer well,” said Marks.

There are numerous programs that Marks ran through for the audience that FDA offers in CGT. First, currently, the FDA, NIH and the Bespoke Gene Therapy Consortium, a public/private partnership to learn more and develop production methodologies that can help de-risk the space.

In addition, CBER has reorganized the Office of Tissues and Advanced Therapies (OTAT) to become the Office of Therapeutic Products. This “super” office features six offices, which will focus on CMC issues, and lean into accelerated approval with biomarkers, and surrogate endpoints.

OTAT also initiated its INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER ProducTs) program, an informal, non-binding meeting at a specific time early in product development. Marks said that these early regulatory meetings have proven incredible useful for both sides. “The feedback from regulatory gives companies advice, and it gives regulatory insights into technologies we weren’t aware of and gives us a chance to see them,” he remarked.

As for regulatory pathways, with the Faster Cures Act, the Regenerative Medicine Advanced Therapy (RMAT) designation, a breakthrough designation tailored to CGTs came into being. The FDA says a drug is eligible for RMAT under the following requirements:

  1. The drug is a regenerative medicine therapy, which is defined as a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products, except for those regulated solely under Section 361 of the Public Health Service Act and part 1271 of Title 21, Code of Federal Regulations;
  2. The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
  3. Preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition.

Marks has hopes for the future of these therapies, whereby an environment of commercial sustainability is fostered. While he applauds non-profits efforts toward funding and developing therapies in specific disease targets, he urges a robust commercial enterprise from which all companies/organizations can take advantage, make a living, and thereby have more therapies available at a global scale. He also advocated for a harmonized global regulatory pathway. “If we make it easier to disseminate these therapies globally and get approvals at same time for the larger, richer countries, it could be aggregated into a viable commercial role for the smaller populations globally.”

Reference: Reuters Events: Pharma USA 2023, Regulatory update with FDA.

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