Cardinal Health Q&A: Navigating cell and gene therapies through clinical and regulatory hurdles
Gene and cell therapies are at the cutting-edge of biomedical research, promising potentially curative options for a host of disorders such as certain forms of blindness, blood cancers and inherited diseases.
But being so new and so cutting-edge, navigating through regulatory bodies such as FDA and EMA can be challenging, with decisions on: cost and scalability; clinical focus; manufacturing and pharmacovigilance paramount to getting to market, and staying on the market.
We speak to two experts from Cardinal Health Specialty Solutions: Michael Day, Ph. D, Director, Chemistry, Manufacturing & Controls, Regulatory Affairs and Debra Aub Webster, Ph. D, Principal Scientist, Regulatory Affairs and Product Development, at Cardinal Health Regulatory Sciences about these issues.
Q: What are some of the biggest challenges in navigating cell and gene therapy through the regulatory process?
DAW: I think there is a tendency to lump these therapies together, when really the challenges can be quite different. For gene therapies, I think one of the big issues is evaluating the long-term benefit, or durability of effect, based on a short-term endpoint, which is frequently a biomarker that may need to be validated. Additionally, at present gene therapies can only be administered once. What happens when an adolescent "outgrows" the response? How long will patients need to be monitored?
On the other hand, patients can typically receive multiple cell therapy treatments, the response is more immediate and may or may not need to be durable. For multipotent cells derived from amniotic tissues or autologous cells isolated from bone marrow or adipose tissue, one of the challenges that occurs here, particularly for autologous cells, is the variability from patient to patient or donor to donor, given the role of genetics or even age.
And then you have autologous cell therapies that has been genetically manipulated, which may face both sets of challenges. So, it’s a spectrum, and I think the challenges vary – hence the "case-by-case" approach taken by regulators.
MD: FDA has begun to directly address the regulatory hurdles with the release of 6 guidance documents in July of 2018 pertaining to the development and approval of gene therapy products. In order to be acceptable from a regulatory perspective the challenges remain largely in viral vector-manufacturing capacity, where an estimated 1–2 orders of magnitude increase will likely be needed to support eventual commercial supply requirements for many of the promising disease indications. In addition, the expanding potential commercial product pipeline and the continuously advancing development of recombinant viral vectors for gene therapy require that products are well characterized and consistently manufactured to rigorous tolerances of purity, potency and safety.
Q: How can you find your way across these challenges?
DAW: That’s a big question, but again, we have to look at each individually. Thinking about the challenges for cell therapies that are autologous and allogeneic: These are issues related to functional variability of the cell product. In addition, the patient response to cell therapies can be more variable than for traditional therapies such as seen in the use of mesenchymal stem cells for the treatment of GvHD. This raises the question: Why are some people responding really well, but others are not? Is it due to the functional quality of the cell or the disease state of the patient? So, the challenge here is not only establishing clinically relevant measures of potency but also teasing out the difference between responders and non-responders.
MD: Outside of the clinical view, it goes without saying that cost is also a major challenge, as well as the fact that these therapies need to be scalable. So, for cell therapies, you’re talking about needing to build a cell culture process that companies want to make scalable, but a lot of these therapies are, necessarily, individualistic. So, for example in gene therapies, a viral vector...
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