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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 FDAs 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 sessions 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.

CONSISTENT CMC PLAYBOOK NEEDED

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 cant 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 dont have the systems.

MORE ON WHY DEVICE-LIKE REVIEW COULD HELP

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 analytics so that we can gain product and process understanding so that we can facilitate rapid changes that we know will not negatively impact the health of the patients.

KYMRIAH TECHNOLOGY ALREADY OUTDATED

Walker said a constriction point for her is not keeping up to date with current technologies. She said that a technology platform developed today may be outdated tomorrow. The rate of change of innovation is now every two or three years, she said.

That mirrors the rate of the device cycles that Marks mentioned, lending further credence to the idea that cell and gene therapies should be reviewed similarly.

Walker said that the technology that Kymriah has been based on has been eclipsed. It took three years for start up to approval and now no one is using the same technology as the basis for their platform. The technology and the state of the art is advancing very rapidly. This is a challenge for regulators. They need to understand we can be early adopters of these technologies without changing the product.

Kymriah was the first gene therapy product approved to treat B-cell acute lymphoblastic leukemia (ALL) and diffuse B-cell lymphoma (DLBCL). The product used spherical beads to isolate, activate and expand T-cells. After the cells are modified, they are infused back into the patient. The FDA approved the drug in August 2017 (Also see FDAs NDA And BLA Approvals: Kymriah, Vabomere, Cyltezo Pink Sheet, 1 Sep, 2017.) and the EU approved it in June 2018. (Also see First CAR T-Cell Therapies OKd In EU: Novartiss Kymriah And Kites Yescarta Pink Sheet, 29 Jun, 2018.)

Walker said there also needs to be flexibility from regulators to allow new technologies. The technology is advancing very rapidly, and that is another challenge for regulators. To understand where they can have flexibility.

AVAILABLE TALENT POOL A MAJOR CHALLENGE

Michael Paglia, senior VP of CMC operations for ElevateBio, said that his main constriction point has to do with staff and talent and supply chain and the cost of goods and quality and access to capacity.

To address the capacity challenges, the company came up with a model of funding multiple start-ups and to utilize the same R&D and manufacturing facility, rather than individual companies whose cell and gene therapy R&D is slowed by the need to build their own lab and production spaces. (Also see ElevateBio Brings Centralized Model To Cell And Gene Therapy Scrip, 13 May, 2019.)

We took the approach to build our own and to build an integrated research to support out cell and gene therapies.

The company in July 2019 announced a partnership with Massachusetts General Hospital. Under the agreement, which runs for 10 years, MGH has access to ElevateBios research, process development and manufacturing facility in Waltham, MA, for development and production of cell and gene therapies.

Paglia said that there are now more skilled employees compared to seven or 10 year ago, but that it is still challenging to find talent. We are fortunate to have experienced staff. It is necessary to put procedures in place to have rigorous training. Training is very important, and we are involved with local universities as well to give them an idea of if you come out of this how do you get into cell and gene therapy.

This article was first published in the Pink Sheet on June 18, 2020.

Image: iStock/IvelinRadkov

Joanne Serpick Eglovitch is a senior editor for Pink Sheet where she writes about manufacturing and quality issues.

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FDA Official: New "Playbook" Needed for CMC Reviews of Gene Therapy Products - Xconomy

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