CMC Considerations for Gene Therapy and Regenerative Medicine Studies


Applied Clinical Trials

The unforeseen challenges with clinical trial execution in gene therapy and regenerative medicine studies, such as unchanging FDA regulations, discussed.

The fields of gene therapy and regenerative medicine are well underway, as many emerging biopharmaceutical companies are focusing on developing numerous therapies in a variety of disease indications. However, there are many unforeseen challenges with clinical trial execution including supply chain, therapy preparation, and administration. In this interview, Mo Heidaran, Vice President Technical, Regulatory and Technical CMC Consulting Cell, Gene Therapy and Tissue Engineering at Parexel, will discuss these challenges.

Moe Alsumidaie: You provide chemistry, manufacturing, controls (CMC) technical and regulatory support during all stages of cell and gene therapy product development. What is the biggest challenge you see from a clinical operations perspective, particularly in the new area of regenerative medicine and gene therapy development?

Mo Heidaran: With cell and gene therapy, clinical operation logistics are unique, particularly if you have a

Mo Heidaran

product with a limited shelf life as compared to smaller molecules. They also have unique transportation requirements. Sometimes they are transported fresh, and other times they are frozen. If you cannot meet the quality standard within that shelf life, and the patient is pre-treated, then it can be a significant issue. The other aspect that’s unique is the involvement of human source materials and collection of the starting materials in manufacturing the product. Autologous products come from the patient. However, if the product is allogeneic, it comes from a third-party donor, and there are FDA donor eligibility requirements for preventing transmission of disease that are relevant for allogeneic products. Accordingly, collection at the clinical site can be challenging because you have to collect the material in a manner that is reproducible. Lastly, being able to receive the material at the clinical site is also a challenge. Sometimes, additional manipulation of the drug product is needed, and in some cases, people also need to conduct further manufacturing at the clinical site. Ultimately, all these challenging aspects are unique to cell and gene therapy products and should be considered in clinical operations.

Moe Alsumidaie: When you do some manipulation of the drug product at the clinical site, you are further manufacturing it, and you have to ensure that the quality of the product is not impacted during that preparation. Given that manufacturers are going to be ultimately responsible for doing some of these operations in an environment that they don't have much control over, how can that risk be mitigated?

Mo Heidaran: One way that some manufacturers are reducing risk is by defining facilities within hospitals that are designated and more controlled. Sometimes sponsors use a cell processing center close to the hospital. Sometimes they can use some of the hospital’s facilities used to manufacture peripheral blood or bone marrow-derived stem cells, which provides a more controlled environment, and sometimes manufacturers can get access to American Association of Blood Banks (AABB) accredited, cell processing facilities located close to hospitals From a facility perspective, having better-controlled environments - as well as operators trained to perform these operations based on the SOPs provided - would help mitigate risk.

Moe Alsumidaie: Can you discuss how regulations are changing with the introduction of gene and regenerative therapies? For example, how is the FDA changing its regulations based on these new products?

Mo Heidaran: The industry follows the same regulations, 21 CFR [Code of Federal Regulations Title 21]. It has not changed, as it’s written very broadly. For these products, 21 CFR 600s, which cover all the biologics, 21 CFR 210 and 211, which refer to all drug products, and 21 CFR 1271, subpart C, donor eligibility, donor screening and testing all apply. What is changing is how CMC reviewers interpret the regulation as it applies to these new products, and execution is a matter of policy interpretation and how CMC reviewers apply an evidence-based approach. While integrating and meeting these regulations can be challenging, there is sufficient flexibility to apply those regulations to these products.

One other aspect I’d like to mention is that with some of these products, delivery of the therapeutic to the patient is unique. In some cases, devices are used. Some of these devices are not intended for cell and gene therapy products; rather they were cleared for drug products or others. So that aspect is another complication because, on the clinical side, there must be sufficient training that enables the operator to be able to deliver the product accurately and according to the trial protocol. During clinical trials, the FDA allows for some of those devices to be used, provided that the device’s compatibility is established with the actual drug product. To use them, you need to provide sufficient evidence and demonstrate that the product’s quality is not affected by the device doing the infusion.

Moe Alsumidaie: Do you expect that the regulations will change any time soon to adapt to new therapies?

Mo Heidaran: No. FDA has not changed any of its regulations that are applicable to some of these products, and I don't anticipate any changes in the near future. What will happen is there will be guidance documents published that capture the best thinking the FDA has in each area, and we'll get some more clarification on how the regulation is being applied to each specific issue.

Moe Alsumidaie: When it comes to CMC in clinical trial supply chains, what considerations should clinical project managers be concerned with investigational therapy production? What are some of the hiccups that have happened as a result of inadequate CMC procedures that result in the disruption of the supply chain?

Mo Heidaran: The issue is about the chain of custody from the start to the end of the process. In some cases, if the chain of custody is not established, you may receive a wrong product. The second part is about the collection of the material and being able to deliver the product in a timely fashion to the patient within the shelf life of the product. That's important, and to do this, there are new technologies available that monitor each manufacturing step in real time. Tracking a product during manufacturing is critical, and this advanced automation allows clinical folks to know where a product is at any given stage, and then coordinate the treatment of the patient based on that knowledge.

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