FDA Official: New “Playbook” Needed for CMC Reviews of Gene Therapy Products

Xconomy National — 

A “new playbook” is needed to ensure consistent chemistry, manufacturing, and controls (CMC) reviews for gene therapy products, the lack of which is hindering the development of these products, asserted a top official at the US Food and Drug Administration .

“Now is the time to get things right” asserted Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, who spoke at a 15 June virtual Drug Information Association annual meeting session on how innovation can help overcome hurdles for these products.

The session’s moderator, Nancy Myers, president of Catalyst Healthcare Consultants, asked the panelists to describe some of their main CMC “constriction” points in developing gene therapy products, and to identify potential solutions. The other panelists were Karen Walker, the senior advisor for cell and gene therapy at Genentech, who formerly was at Novartis (NYSE: NVS) and worked on the development of Kymriah, and Michael Paglia, director of CMC for ElevateBio.

Myers said that there are two common types of roadblocks to getting gene therapy products through the development pipeline, and these are logistical and technical challenges. The logistical challenges are having a well-trained workforce, managing global distribution networks and ensuring products are transported in cold temperatures, while the technical challenges are ensuring the quality of the starting materials and scaling up production from the research site to commercial manufacturing.

Another roadblock is the lack of standards and lack of a regulatory framework for these products. Myers said that “this is a new and growing field and companies are trying to lay the track as they are trying to drive the train down the track at the same time.”


Myers first asked the panelists to discuss what they see as constriction points in manufacturing gene therapy products. In response, Marks said that a lack of consistent reviews is hindering their development.

“It has become apparent over the last couple of months that, while we have excellent reviewers, it does happen that people can have differences of opinion. I think we will have to come around and have a clear playbook so that everyone gets the same advice especially as we have grown. I know that someone out there will say, ‘we had two different CMC reviewers and two differences pieces of advice.’ I am not going to argue with that. That is an issue here. As we come to the post-COVID period we should to try to have more unity in what comes from our CMC reviews. I cannot say the problem is solved but the problem has been identified and is amenable to solutions.”

He further noted that the lack of clear regulatory pathway for these products is a major roadblock in accelerating their development. “We do not have the preclinical pathways set up and the clinical set up and the regulatory paradigm is yet to be fleshed out. Now is the ripe time to get things right.”

Marks also noted some of the manufacturing challenges in the cell and gene therapy space: “We are in a place where our current vectors are limiting what we can address in terms of our ability to product them on a very large scale, and what will probably take some years to get there. On the other hand, the piece that really interests me is how do we deal with hundreds and thousands of rare diseases that we can’t address right now through the production of gene therapy products where we simply do not have the manufacturing capacity to be able to produce these products in a rapid manner because we just don’t have the systems.”


Marks expanded on an idea he had suggested in February, that reviews for gene therapies should be more aligned with the device model. (Also see “Individualized Gene Therapy: US FDA Considering Device-Like Manufacturing Approval Process” – Pink Sheet, 28 Feb, 2020.)

“It is becoming increasingly clear that for cell and gene therapies, the manufacturing is more like a device paradigm with continued innovations,” he said. “With a traditional drug you come up with a chemical process to make a small molecule and you are probably using the process similarly across the lifecycle, but you are not constantly finding ways to do things that fundamentally change the yield or quality of a product. Here we have issues that manufacturing changes can potentially change the product for the better.”

He added that “we have to find some balance here between the traditional drug manufacturing model of ‘once and done’ to something that is asking you go through multiple cycles of a device every two to three years where you are changing the technology. With device cycles, you may have multiple generations of the device over years. With a device you can measure things nicely, with biologicals you cannot measure easily.”

Walker concurred that “these are not well-characterized products and so we need to invest heavily in … Next Page »

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