Ep. 17: FDA leader talks cellular therapy with Sanford

Peter Marks, MD, PhD, and David Pearce, PhD, discuss trusted providers of cellular therapy

Episode Transcript

Simon Floss:
Hello, and welcome to Innovations. A podcast series brought to you by the experts at Sanford health. I’m your host Simon Floss with Sanford Health News.

Over the last few years, the topic of regenerative medicine and orthobiologics has been subject of many headlines as it relates to treatment of orthopedic joint pain.

Orthobiologics can mean a variety of treatment options based on a patient’s specific needs. As it may seem relatively new, what do we know about these treatments and what oversight is there of these programs to make sure patients are getting the best treatment?

For this episode, we bring you a conversation on this topic. Recently, Dr. David Pearce, Sanford Health president of innovation, research and Sanford World Clinic sat down to talk with Dr. Peter Marks, director of the Center for Biologics, Evaluation and Research at the Food and Drug Administration in Washington, D.C.

David Pearce, Ph.D.:

Dr. Marks, it’s a pleasure to be here with you today. Could you just tell us a little bit about who you are and what you do?

Peter Marks, M.D., Ph.D.:

Yeah, thanks for having me today. I’m the director of the center for biologics evaluation and research at the food and drug administration. We handle the regulation of complex biologic products like cell and gene therapies, blood products, and vaccines.

David Pearce, Ph.D.:

Ok. So obviously right now during the pandemic, lots of approvals with vaccines and treatments for COVID, but we’re really interested in hearing a little bit about what your thoughts are on the way, the direction of what cellular therapies actually encompass.

Peter Marks, M.D., Ph.D.:

I think right now that cellular therapies are a very wide range of products, everything from simple cell therapies or tissues that might be used for local treatment of wounds or issues, to more complex things like cellular products where cells are laid down on scaffolds. And those can be used as a tissue-like thing. There are cells laid down on scaffolds that are like organs and those are under investigation too. So all of those things are under investigation, as cellular therapies, and then there are some of the approved cellular therapies now. Most of those right now are genetically modified cell therapies, the chimeric antigen receptors. So there’s a whole range from simple things to kind of intermediate really complex things, to very complex things.

David Pearce, Ph.D.:

Exactly. I mean, it’s a very booming business. Business is probably not the correct word for it right now, but Sanford as a health system obviously, wants to do the right thing for its patients constantly. So I was wondering if you just tell us a little bit about the approval process for a cellular therapy.

Peter Marks, M.D., Ph.D.:

For cellular therapies, they go through different processes depending on whether or not they meet certain requirements. Some products don’t actually even have to come to the FDA for an approval. They are exempt because they are not manufactured significantly and they’re used in the body in a manner in which they came from another person.

So let me just try to explain what that means. There are products you can imagine, like a skin graft where you take it from skin going onto skin, and one doesn’t do anything more than maybe size it or wash it, or maybe put in some antibiotic solution. Those we don’t even require investigation, new drug applications or biologics license applications. They fall under what I call our tissue rules, which are just a way of making sure that one doesn’t pass along communicable diseases when one uses those products. They don’t have to come in for an approval. One makes them according to these regulations and one is OK.

Then there are products where they are more complicated. They might be a product where one does very significant manufacturing, such as remove cells from a tissue and then grows them in culture and then formulates them and puts them back into a location that’s different from where they came from. And that’s some of what has been done with mesenchymal stem cells or other stem cell therapies. And for those because one can’t say that they’re going to work just the way they worked, because they’ve been manufactured and they’re being used in a different place than where they came from. There, one needs to go through the normal investigation process that we expect, which is an investigator comes to FDA, files an investigational new drug application.

That application is reviewed by the agency. And if everything looks in order after 30 days, we say, OK, it’s fine for you to proceed with a clinical trial. And then once that investigator gets clinical trials data together in a sufficient manner, usually through multiple stages of trials, they come back to the agency. We have another conversation and if everything looks good, they file a biologics license application. If everything looks good there, they get an approval and then they have an approved product. So if it sounds like a lot of work it’s because it is a lot of work, right?

David Pearce, Ph.D.:

Yeah. Forgive me. If I were to do an executive summary here, what it takes to get a cellular therapy approved is it’s a lot of work and there’s a lot of rules and regulations and at Sanford, we’re no different from other health systems where, it’s a complicated process and we’re trying to do right by our patients. The environment we’re in right now, we know there’s many groups offering cellular therapies that are unapproved. Sanford Health clearly can’t be in that group. We obviously want to do the safe thing and we all want to do the efficacious thing. So I’m just wondering if you could comment a little bit about the environment right now out there, what we are calling the wild west and with respect to some of these regenerative cellular therapies.

Peter Marks, M.D., Ph.D.:

I think we actually also sometimes think it’s the wild west out there. We are in an environment now where for a while it’s true, people kind of cite back that maybe FDA wasn’t clear enough in the 2010-2015 period of time, we weren’t clear enough about what was not allowed. And because of that, there were a lot of stem cell clinics that proliferated saying, ‘well, I’m just taking cells from somebody and I’m giving them back.’ And so they meet this kind of exception I told you about, but they weren’t just taking the cells out and putting them back, taking cells out and putting them back – that’s something like doing bone marrow transplantation. There you take someone’s bone marrow out, you give them chemotherapy and you give it back to them. That’s actually, that’s OK. That’s actually legit that way.

On the other hand, if you take cells out, destroy some of the cells, grow the cells in culture, and then formulate them in some mixture with some other chemicals and then give them back, that’s a very different thing. And so, we’re seeing people do that. And they’re doing it without having the normal process of coming in and having an investigational new drug application in place.

But what’s worse is they’re actually charging people for it. And that’s really a problem. It’s bad enough to kind of violate the regulations by not having the right the right paperwork in place. We’ll call it kind of venial sins and moral sense. It’s bad, it’s not good not to have the right paperwork in, but it’s charging is really a problem here because they’re selling products that are unapproved.

And it’s not just unapproved, most of the time they’re unproven, that’s the bigger problem, right? And that means people are paying money for something that we have no idea whether or not it will help them. And in some cases we do know that can hurt them because there have been some pretty bad things that have happened over the years when people got stem cells stuck into their eye or to their kidney or to their spinal column.

So, the goal here would be to try to see people kind of get the wild west under control by having people know enough about what they’re getting into. So they don’t get involved and pay money for things that aren’t going to be effective.

David Pearce, Ph.D.:

Yeah. Education is a huge part of this. I mean, that’s one of the things that Sanford focused on initially, as we started to explore some of these clinical trials. Our focus initially is being, ‘Let’s walk before we can run.’ You alluded to some of the oncology trials, which are really the more advanced areas, but we’ve really sort of focused a little bit in orthopedics right now which is an area where we have people coming into our footprint and basically saying, ‘Hey, we can inject this into your knee and 50% off for the second knee,’ and they’re not really telling people what they’re injecting and they are charging these ridiculous amounts of money. So, our mission is to legitimize and explore the appropriate types of products right now. So, I thank you because I’ve had conversations you with respect to, what Sanford is doing and we’re a champion for the FDA.

Peter Marks, M.D., Ph.D.:

I very much know that. I think to the extent that what you’re trying to do here is the right thing, which is, this is an area where there’s a demand. It’s great, actually people want to get the therapy, but you’re trying to do it the right way by actually letting them get the therapy, but also get the information that you need, that we need to actually understand whether the therapy is safe and that it actually works. Right? And that’s what’s so critical here.

So that at the end of the day, the beauty of participating in a clinical trial is that even if ultimately the product doesn’t work, you haven’t done something for nothing, right. You’ve helped advance knowledge because even a negative trial helps us learn something. And if it’s positive, that’s really great because then you’ve probably benefited some, and society’s benefited as well. So, that’s the reason for hoping that clinical trials like you’re doing people are aware of them and they enroll in them.

David Pearce, Ph.D.:

Exactly. So, we’re particularly proud of that approach. One thing you did mention previously was about people charging, and then that’s one of the things that really upsets me when we have people come in and they say, ‘I spent thousands of dollars on this therapy,’ and they don’t know what they got. But, I was wondering if you could sort of just elaborate a little bit on what cost recovery is for trials.

Peter Marks, M.D., Ph.D.:

If you’re getting an investigational therapy, something that isn’t proven to work, you shouldn’t be paying like retail price for it. Right? What we do allow at FDA is if there is at least some evidence, some manufacturer, someone who’s making it, it has to show us that they’ve done at least some safety studies, that there’s at least some chance that it could work, right? They have to have some good rationale that it might work and they have to have some safety information. The person who’s making it can apply to FDA for something called cost recovery. And what that means, is they provide us with an accounting of what it actually costs to make the product, and then they can charge the patient or the patient’s insurance company for that amount. They can’t charge to make a profit.

They can’t charge for all of the other care that goes in. They can’t charge for the research nurse for the clinical trial, but they can charge to recover the cost of actually making the product. And that’s felt to be fair in that it helps small entities be able to continue to move forward research. So I think that’s kind of the public health benefit of allowing that. But it doesn’t mean that people should be making a profit on this. That’s not what they’re doing. And that’s why there’s this requirement for an accountant to actually certify what’s going on.

David Pearce, Ph.D.:

Absolutely. No, thank you for that. I’m just going to mention what our trial is, and I know you can’t endorse that, but I think for the filming that I’m just going to talk a little bit about what our trial is. Obviously I talked a little bit about Sanford trying to legitimize this space right now in leading in orthopedics.

So we currently have a clinical trial which we like to call a registry where we have five indications. So, osteoarthritis in five joints basically. We’re very much looking forward to sharing the results with respect to that. I can tell you the uptick from just our community and the fact that people are looking for this from outside of our footprint as well is very encouraging. I think there’s a good base of people out there that want to do the right thing and also want to understand that getting the right treatment.

Peter Marks, M.D., Ph.D.:

Look, we are nothing but supportive of this type of work that needs to happen where clinical trials done in a way that’s getting advancing knowledge is exactly what people should be doing. And it’s exemplary of what we want to see happen across the spectrum of this area. It’s only too bad that this isn’t happening more broadly across the country.

David Pearce, Ph.D.:

In closing, is there anything else that you think you’d like to share with them?

Peter Marks, M.D., Ph.D.:

For me, I think this area of regenerative medicine is so exciting. And I think to date, it has not flourished as well as it could because people haven’t done what you’re doing. Which is actually systematically going through and finding out if things work or not. Hopefully you’ll find out that this actually works. It might work in three out of the five. It might work in all out of the five, but you’ll figure out what works and then you’ll improve upon that. And that’s how a field actually grows is you find out what’s working and what’s not working, and then you improve upon what’s working. And so to date, people haven’t been actually really interested as much. Some of these people are just looking to make a buck in advancing knowledge. They’re just looking to make a buck. Right? Whereas this is actually what you’re doing is actually taking the field forward. Which is so important because I think we’d like to believe that there’s a lot there that biology can offer us. Right? And by doing this, we’ll hopefully make those advances.

David Pearce, Ph.D.:

That’s funny you say that. When I talk about these trials, I tell people there’s a lot of biology in there, so I’m going off script. And I just want to ask you one other thing, based on your background. Peter, there’s so much advance in immunotherapies in cancers right now, so much advance in different cellular therapies. I’m wondering where you think that will go? CAR-T engineering advancing, and now we’ve got the NKT cells story that is developing, you know, where do you see things going with this?

Peter Marks, M.D., Ph.D.:

I think a couple things can happen right now. Shorter term, I think we’ll see, hopefully see the autologous CAR-T cell therapy manufacturing that’ll come down in costs, because of some of the automated systems that are beginning to be developed. And whether that will remain at kind of centralized manufacturing, like what’s happening now, or whether it gets to be distributed with places manufacturing locally, I don’t know for sure, but those models will be interesting. So I think in the short term, we’ll see some advances in autologous CAR-T cells.

The reason why that’s important is because I think if the cost comes down, people will use them for earlier stage disease and they actually might be more effective. I’m an oncologist by training and you know, what we’ve done with them is where we always know that if you use any oncology drug in the most advanced setting in metastatic cancer, you don’t get the greatest results always.

And some of the times when you bring it into earlier stage disease and it’s really great and you make a big difference in adjunct therapy, that’s been shown for breast cancer, et cetera. Now here for CAR-T cells, it may be that once you, once you can bring them back to earlier stages of disease, you might, you might actually be able to take people in their second remission, rather than their fifth remission and mop up disease so they don’t have recurrence in the longer run. I think we may really see advances here that might really be transformational.

If we get to allergenic CAR-T cells off the shelf products where, because you can take them off the shelf, they’ll be ready right away for people who need them. The cost should come down and more so, the ability when you’re making these batches where you’re not, it’s just not one-offs, you’re making very large batches, maybe a hundred doses from one donor. You can do the genetic modifications to make these cells start to have the kind of logic where it’s not just, they’re recognizing one receptor, they’re recognizing two or three, and then you can actually start to think about addressing solid tumors. Right? And that would, to me, be really exciting because I think that’s where that to me is the place where so far, we haven’t been able to go with these. People have tried to get CAR-T cells to work for solid tumors, and it hasn’t been an unabashed success yet, but I think we may see that if we can get to allergenic CAR-T’s.

David Pearce, Ph.D.:

Certainly, there’s a lot of work being done on modifying these right now. And again, at Sanford Health the next step for us is actually in-house, making sure we have the cellular processing in the point of care, with respect to that. So one last walnut is, is that some of our medical oncologists are very excited about NK cell.

Peter Marks, M.D., Ph.D.:

The idea here is that here you have something that, I mean, that’s what these things do, right? These are cells that are designed to eliminate things. They have the potential to hone in and kill. And if you can get them to there to understand the right target to kill, to train them to kill the right target, potentially have a very powerful therapy that could also be potentially even off the shelf therapy, which is very exciting.

David Pearce, Ph.D.:

And that’s one of the cellular processing steps that we’re taking right now in partnership with obviously one of the leading groups with respect to that. So, Peter, it was a pleasure. Thank you so much.

Peter Marks, M.D., Ph.D.:

As always. It’s great. Thank you.

Simon Floss: For more information on what Sanford Health is doing in orthobiologics and regenerative medicine, please visit sanfordhealth.org.

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Thanks for listening. I’m Simon Floss with Sanford Health News.

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Posted In Innovations, Orthopedics, Research, Sports Medicine