Podcast: What are the biggest challenges facing regenerative medicine developers during regulatory approval?

We caught up with Dr. Larry Couture, Vice President of the Center for Applied Technology Development, City of Hope, to discuss the challenges facing the regenerative medicine industry, especially during regulatory approval.

Where do you see the biggest challenges facing regenerative medicine developers in the next five years?

LC: The field is really beginning to take off. There are clinical trials and academic trials that are about to enter the clinic or will be entering the clinic in the next couple of years.

One of the problems that is starting to emerge is where this is going to go and what we are going to have to face. Some of the issues we are dealing with right now that I think are going to become big are cost of goods and the ability to scale-up some of the manufacturing processes. Also the purity of the cell product; not necessarily trying to achieve 100% per se, but trying to optimize purity and identify how pure these products should be.

The other big one is potency assays. At the moment, potency assays are not all that satisfying. There is usually marker expression or complex assays that involve biological activity in cell culture models, which is really not commercially scalable and not applicable long-term for product life.

There are a lot of discussions going on right now about those particular things, most notably the cost of goods. It is very expensive to produce some of these products. Some of them are some of the most expensive products that we produce in our facility. We produce everything from viral vectors, vaccines, antibodies, to a number of regenerative medicine products. The time, the effort, the resources and generally the raw materials are particularly expensive for some of these regenerative medicine products and that’s going to have to be addressed in the future.

Not to be somewhat redundant, but the big one is scale-up and defining the purity of the product. Some of these processes involve, still, a fair amount of manual manipulation during the process. In some cases it is still not clear how we are going to eliminate some of the manual processing. That means scale-up is going to be somewhat challenging. It’s going to be limited to scaling out at least for the very short, foreseeable future.

What are the hurdles regenerative medicine developers face during regulatory approval?

LC: Hands-down the biggest problem facing everyone developing regenerative medicine products, particularly based on embryonic stem cell lines and the older lines, is the compliance with code of federal regulation 1271, the so called: “Donor Eligibility Rules”.

The current guidelines written by the FDA are not consistent and not clear and are somewhat vague on what rules actually apply to early derived cell lines. In addition, there is a set of onerous regulations that currently apply to all embryonic or all pluripotent stem-celled derived lines that aren’t applied to any of the biologics. Notably, all human derived tissues are subject to the donor eligibility criteria, which is the so-called “361 Product” – tissues and cells and such derived from humans.

But as manufactured products, they are also subject to biologics regulation, so called “351 Regulations”. So, that means that because they are derived from tissues where typically there is not sufficient time to test or release or bank cells that are being transferred from patient to patient, testing is reasonably focused on donor eligibility and screening, whereas biologics are focused on testing of the manufactured product.

Unfortunately right now, embryonic stems cells are subject to both of those regulations, which means you could have a very nice product that is well characterized, beginning to show a lot of efficacy in animal models and maybe even in clinical trials, but may not be suitable for life insured by the FDA because that cell line has been around for a while and wasn’t screened properly when it was originally isolated from a patient. This is despite the fact that the cells could be completely tested as a manufactured product to at least the level of testing that could have been accomplished at screening.

So, that’s something that is being discussed internally at the FDA; it’s an issue for investigators. Certainly at the moment the FDA grants exemptions to bring these cell products into the clinic. What a lot of investigators, groups, companies and academics don’t know or aren’t fully aware of is that granting an exemption to start a clinical trial does not ensure that the FDA will grant an exemption for life insure for the product.

Folks taking regenerative medicine products into the clinic with an uncertain compliance with 1271 Regulations may be facing a very, very rude awakening when they get closer to life insure if they haven’t had those discussions with the Agency and they find a product not suitable for life insure. Whether that will actually ever happen or not, whether societal pressure, clinical evidence of efficacy type pressure on the FDA won’t force their hand and, essentially, result in a life insure for the product or not is grossly unclear at this point, but is a major regulatory problem that is facing everybody in the field. I would say that problem pretty much overshadows just about all others.

Listen to the full interview above. 

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