Q&A with Kyle Cetrulo of The Perinatal Stem Cell Society on the FDA, state laws, & more

I was interested to see that an organization called The Perinatal Stem Cell Society seems to have been upbeat about the new Utah stem cell law. That law sets up a likely conflict with the FDA and federal law over stem cells. In a nutshell, Utah now says you can sell non-FDA-approved stem cells in that state.

I also noted that the leader of The Perinatal Stem Cell Society, Kyle Cetrulo, seemed on LinkedIn and via email blasts to envision a future with a different role for the FDA or at least a very different federal oversight system on stem cell therapies.

Because of these new developments, Cetrulo and I did an email Q&A. We talked about some of these points and his view of what would work better. In the future, I’ll do a post with some of my reactions to his answers. It’s important to have dialogue and discuss different views.

Kyle Cetrulo, Perinatal Stem Cell Society
Kyle Cetrulo, leader of the Perinatal Stem Cell Society.

Interview with Kyle Cetrulo of The Perinatal Stem Cell Society

1a. What do you see as the ideal role for the FDA in oversight of stem cell treatments including perinatal cells?

KC: Although I believe that many aspects of the FDA IND/BLA process can be streamlined to create a more efficient process, the primary obstacle to patients accessing stem cell therapy is not the FDA regulatory process itself, but funding challenges and particularly the period known as “The Valley of Death” in the cell therapy world.  This is the fund-raising phase between the successful completion of a Phase I safety trial and the completion of a Phase III trial.

The costs associated with clinical trials increase significantly as they progress, with Phase I trials costing between $2-4 million, Phase II trials ranging from $20-50 million, and Phase III trials amounting to $250-500 million. The absence of successful market authorization for any Mesenchymal Stem Cell (MSC) based regenerative medicine product by the FDA, despite over 5,000 registered clinical trials, has deterred investors from funding the most expensive stages of the FDA approval process for stem cell therapies. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9732032/#:~:text=Over%205%2C000%20registered%20clinical%20trials,and%20liver%2C%20among%20other%20applications)

Furthermore, even if a company successfully completes the BLA process, the lack of strong intellectual property protection for stem cells and other naturally occurring biological materials, as determined by the Myriad Court Case in 2013, makes it difficult to justify the substantial investment required. Unlike small molecules, stem cells do not have patent protection beyond method patents, which are insufficient to provide the monopoly coverage needed to warrant a $500 million investment.

The Perinatal Stem Cell Society’s proposed bill to revolutionize stem cell therapy in the US works within the current FDA regulatory framework but provides an alternative funding pathway.  In the Perinatal plan, the company is legally allowed to charge patients to participate in the clinical trials.  I believe that the same people who travel offshore to get stem cell treatments now would gladly pay to be part of US trials.  In Japan, the national health insurance program pays for the costs of the clinical trial.  Allowing the patients to pay to join the clinical trial in the Perinatal plan is a different approach from an RMAT which only allows for the reimbursement of the actual regenerative medicine product.  We are proposing a price based on the market and supply and demand.  The hope is that after a clinical trial is successful and the stem cell therapy has gained market approval that US health insurance will pay for future treatments.  I personally believe that when we do create a system where a stem cell therapy can make it to market approval that Big Pharma will buy the most promising companies and partner with Walgreens/Alliance RX and distribute stem cells like flu shots in their Gene and Cell Specialty Pharmacies.  That is what success will look like for the Perinatal Society.  Safe, affordable, and efficacious stem cell therapy for the masses.

The combination of astronomical clinical trial costs, the absence of successful FDA approvals for MSC-based therapies, and the lack of strong patent protection have created a significant barrier to patients accessing stem cell therapies.  The Perinatal Society plan overcomes this barrier through patient-funded clinical trials supporting safe stem cell therapy access for patients while working within the existing FDA framework.

1b. By allowing charging participants to be in clinical trials, wouldn’t you be setting up an incentive for sponsors to run trials with a low probability of success simply to generate revenue? 

KC: Clinical trials are expensive and difficult to manage because of all of the controls and data collection required.  It would not make sense to run a clinical trial with a low probability for success because the real revenue would come from completing the clinical trial and having insurance pay for the stem cell therapy.  Rather than start a clinical trial to gain revenue as a scheme like you suggest, the company would most likely try to stay underground and continue to do what is happening now with non-FDA registered labs providing perinatal tissue products to clinics.

Additionally, if the clinical trial fails or is failing the FDA would be able to stop the clinical trial at any point like it can with any other clinical trial.  Under the Japanese model, the sponsoring company has 5-7 years to complete the trial so they could not run the revenue generating trial indefinitely. This is a low-risk scenario compared to the real world risk of not having any regulatory framework or system to advance stem cells to the clinic.

1c. Or to call their existing commercial clinic efforts “trials” even though they may not be traditional clinical trials?

KC: The only way to be part of the regulatory framework we propose would be to be granted a designation that allows the company to charge the study participants and to be part of the new regulatory pathway. Existing commercial efforts would not be considered other than perhaps as data packages to submit to apply to be part of this new pathway with the FDA.

Should perinatal stem cells be drugs?  

2. In your view should perinatal cells not be regulated as drugs? 

KC: The 361 vs 351 designation pathway to regulate perinatal tissue products has clearly failed.  The Perinatal Society would like to see the various stem cell and tissue products classified as high risk, medium risk, and low risk similar to the Japanese system.  Regardless of the risk level assessed however, all stem cell and tissue products should have a robust safety profile.  However, after a Phase I Safety trial is successful there could be lower barriers to pass before market approval for lower risk products.

One of the biggest problems in the industry now is that manufacturers can’t accurately label what is in their perinatal tissue and stem cell products under the current framework.  This creates confusion for both patients and physicians.  Manufacturers  would prefer to list all of the active components in their products.  However, to be regulated under the 361 designations, if the manufacturer labels their product as stem cell product then that product is automatically classified as a drug.  By labeling the product simply as a tissue allograft, the company evades being classified as a drug.  Although everyone knows that this is not accurate, it enables the manufacturer to sell the product under the guise of a 361 designated product and avoid clinical trials.  This is a problem that the Perinatal Society is actively working with our Manufacturing Committee to address.

We are working to first define what the various Perinatal products are based on active components in the products.  After we define and classify the various perinatal products, the Perinatal Society will offer a certification for manufacturers to have their perinatal products certified through the Perinatal Society where 3rd party labs will independently verify that the perinatal products conform to the classification put forth by the Perinatal Society.

In Japan there are 13 Regenerative Medicine Committees that determine the classification for the stem cell and tissue products.  The Perinatal Society would like to support the field in this role and perhaps play a similar role to how the National Marrow Donor Program (NMDP) oversees hematopoietic stem cell transplantation.

Stem cell clinics and risks

3a. Do you acknowledge that there are some manufacturer and clinic firms in this regenerative space that have hurt people or are selling substandard cellular offerings?

KC: The entire perinatal stem cell and tissue field is broken not just the regulatory framework.  The FDA’s failed strategy to control the industry through discretionary enforcement created a playing field that enabled the more predatory companies that do not care about patient safety and efficacious product offerings, to gain substantial market share.  There are many high-quality manufacturers in the market, but it is almost impossible for a patient and even a practitioner to discern the high-quality products from the low-quality diluted products.  The Perinatal Society’s product Certificate program will help to address this problem.

As far as people getting hurt from these products, there are so many unregulated perinatal treatments being administered daily in the US that if there was widespread physical harm happening, I think we would hear about it more.  I do acknowledge that the odds indicate that some people have been hurt but without a data registry system there is no way to confirm this and with the widespread usage of these products, I think it is more reasonable to assume that the vast majority of these products are safe.  To counter this lack of information, the Perinatal Society is working to put together a universal data registry to track both positive outcomes as well as adverse events.  This registry will also be a place for patients and practitioners to voice complaints.  This doesn’t exist now.

3b. What should the overall field do about them, especially if in the future there’s a potentially decreased role for the FDA?

KC: I think the best way to eliminate the lower quality companies is through the certification program.  Making it advantageous for companies to conduct a Phase I clinical trial will also empower the higher quality companies. This barrier alone will force the lower quality manufacturers to improve the quality of their products or close shop.

State laws on stem cells

4. Are you working toward similar new laws as the Utah one in other states or aware of such efforts? If so, can you say more about which states, etc.?

KC: I was not responsible for the Utah bill. I think that the Utah bill is lacking in an oversight system.  I would like to see a better bill be adopted by other states rather than to copy the Utah bill.

The Perinatal Society is drafting a bill to share with all states that are interested.  I am aware of significant efforts to pass state legislation in FL, AR, AZ, AL and MT.

In Montana there is a bill (SB422) that is being considered that will expand the state’s right to try bill.  The amended bill will allow not just the terminally ill but anyone to try any drug that has passed a Phase I trial.  This bill does not clarify how the company will provide the drug and the company does not have to comply, so it has a lot of holes in it.  I think that a federal law that mirrors the Japanese approach is the best long term solution to adopt.

SB422 https://leg.mt.gov/bills/2023/SB0499/SB0422_X.pdf

Does The Perinatal Stem Cell Society have authority? Who are the members?

5. What gives the Perinatal Stem Cell Society the authority or expertise to certify cell therapy products? 

KC: The Perinatal Society has been a 501(c)3 organization since 2013. We have edited 3 textbooks in the Perinatal Space and numerous chapters in scientific journals.   Our faculty is comprised of the leading perinatal and stem cell scientists in the world over the past decade.  We also organized 10 international conferences and have a library of over 85 scientific lectures.  We understand the manufacturing of perinatal products having previously been involved with the manufacturing of perinatal products through a company called Auxocell Laboratories, Inc. which is no longer operational.   As such, we are not currently affiliated with any manufacturers but understand challenges the manufacturers face.  We hold a unique agnostic position in the field. We have been in the field for the entire development of the perinatal stem cell and tissue scientific field.  We are recognized as international experts. The way to change the field for the better is through a certification process.

6. Other than yourself, who are the other leaders of the Society and who is on your Manufacturing Committee? 

KC: The entire faculty for the perinatal society remain active in the society as advisors. We are organizing an Advisory Committee of world class scientists that we plan to announce shortly.  We welcome anyone that is interested in volunteering to support our efforts to contact us and get involved.

10 thoughts on “Q&A with Kyle Cetrulo of The Perinatal Stem Cell Society on the FDA, state laws, & more”

  1. The reason the clinical trial Phase 1-3 paradigm exists is to validate that any intervention actually works.

    Sure. And it can also be used as a tool to prevent promising therapies from ever coming to the fore based on their expense. The high costs of Phase I,II and III trials effectively stop smaller entities outside of the big pharma organization from getting approval based not upon necessarily safety or efficacy but economics. I’ve actually suspected this for some time. Kyle Cetrulo seems to confirm my suspicions. (More on this later.)

    We all want MSC and other stem cell medicine to work.

    I’m not sure I believe that. The current system allows for very invasive and expensive procedures in the field of, for instance, orthopedic surgery. And it’s not just the MD’s who are well compensated for the likes of joint replacement surgeries. It’s the designers and manufacturers of the medical devices, the government employees who have to regulate and approve them, nurses, physical and occupational therapists, insurance and pharmaceutical companies all stand to lose a consistent source of income should something come along that is less invasive and less costly. The medical standard of care for patients with debilitating arthritis for example is represented by lobbying groups. They can contribute funds to ensure that laws are designed where treatments that actually damage joints (cortisone shots) remain in place and generate revenue for all power players.

    In terms of money, it complicates the matter greatly.

    This is exactly why the practice of medicine, generally speaking, should not be a business. It should be a service that is non-profit and based upon only the needs of people; not one that places market forces ahead of them. After all, don’t executives within the drug and medical device industry make similar types of decisions of the sort you’ve just cited when it comes to placing their wares onto the public with black box warnings? Don’t they fully realize desperate patients are likely to ignore these cautions when in need? Might the organizations executives belong to within big pharma influence government regulators as lobbyists to place artificial barriers for entry into cellular treatments for patients outside of the current big pharma/FDA paradigm? (The words More Than Minimal Manipulation and Homologous Use come to mind here.) The idea of using our own body parts which generally cannot be patented has got to be nightmarish for the current crop of power players. All the while the research community keeps on with the rhetoric that our human cellular material is not quite ready for prime time until decades more basic research takes place. These and other statements like them seem pretty self-serving to me. And the Phase I,II,III clinical trials which Kyle Cetrulo seems to be offering alternatives for does not have a prayer of success if the established powers that be ( the collusion between FDA and big pharma for example) cannot benefit without retaining their dominion. The one thing I learned from Cetrulo, which I’ve long suspected and have already referenced, is that “the primary obstacle to patients accessing stem cell therapy is not the FDA regulatory process itself, but FUNDING CHALLENGES” And there it is. Autologous stem cells as drugs requiring “Robust” phase I,II & III clinical trials seems also a pretty robust stalling tactic ensuring a very slow change… if that. MSC’s and ASC’s as drugs has, in my estimation, less to do with safety and efficacy and more to do with the almighty dollar benefiting the current crop of the powerful. Such might not be the case had autologous stem cells and their use in donor patients simply become the practice of medicine. Sub Specialties within fields like Physical Medicine and Rehabilitation & Orthopedics could have been launched. Doctors within these practices and others have instead been relegated to performing spinal fusion procedures. Ouch! Good for the bottom line but long term decidedly not very good for patients. Far greater amounts of practical knowledge could have been more quickly learned in terms of safety and efficacy for patients rather than dragging autologous stem cells into the highly questionable category of a drug.
    Dr. Knoepfler just recently referenced an article in Nature regarding a Phase I clinical trial involving adipose derived stem cells (OR SVF) injected into the damaged spinal cords of patients. https://www.nature.com/articles/s41467-024-46259-y Seriously??!! This should have been done at least ten years ago. Oh boy! I’m just waiting on pins and needles before some bureaucrat decides a decade from now that we are ready for a Phase Ia clinical trial! And, on and on it goes. (Or doesn’t!)

    In terms of publications, Dr. Knoepfler and many other have also provided published papers and clinical trial reference showing NO effect of many forms of MSCs. What about all the negative publications? Remember, science must be testable and repeatable.

    The problem here is that it is hard to know what truth or what “the science” is really saying. This is true even with published research of the sort that I provided and of the kind you referenced. The advantage of the internet is that we lay people have much faster access to information….(and BS as well). But at least it is more conveniently available. And, it can help patients and consumers more quickly than ever before formulate questions and become skeptical of the official narrative of things. And, it’s not science that I don’t trust either. I do have a little harder time with scientists/doctors who for obvious reasons can have a political/financial/ axe to grind. In the final analysis they can be just as prone to bias as are the rest of us. I’ve read how others have taken apart bad published peer reviewed studies that actually justified the use of cortisone over regenerative techniques involving PRP. Most people cannot decipher bad studies and tell you why they are bad. The point is that BS can find its’ way into peer reviewed literature as well when you consider the amount of ghost writing and advertising that is published right alongside it. And, sure! Science must be testable and repeatable. But at what point do you quit cutting bait and start fishing? Who gets to decide that in light of human, institutional and financial bias? What quantity of research and publishing is truly necessary or simply ends up wasting tax payer dollars under the guise of rigorousness? This phenomenon has been written and lectured about a number of times. Just do a search on Dr. John Ioannidis MD some time.
    In the end though, I believe our system of health care and research is driven not just by money & politics. It is kept in place essentially by incrementalism. We hear about “exciting”, “hopeful” and “promising” research constantly. But these words which often times are used to justify further studies (ad infinitum) ring hollow and frequently make me feel as though I am simply being strung along. Our “system” really does not embrace revolutionary change and in fact may even be opposed to it. Power players favor incrementalism because it keeps the system and them in positions of dominion. Sometime this year, the 9th circuit court of appeals is going to decide on whether or not adult autologous stem cells (SVF) derived from adipose tissue is a drug or can it be considered the practice of medicine. I fully expect the power players (Judges in the 9th circuit) to decide with other power players (Bureaucrats within the FDA). Judges are powerful as are FDA regulators and commissioners. That seems to be the nature of power. The powerful consistently side with the powerful. Not good for democracy, but it’s good for the elite.

  2. A. Rahman Ford, JD, PhD

    Thank you for this interview.

    His responses are reasonable, thoughtful and forward-thinking. His overall vision balances the need for some system of state/federal regulatory oversight with the enhanced health options that people with intractable pain and disease are calling for.

    Patient safety is extremely important, and the few reported cases of injury are regrettable, but the campaign of making SCT affordable for and available to all Americans must continue. SCT requires a New Paradigm in FDA approval. It’s necessary and it’s inevitable.

    Thanks again.

    1. Well written, I agree.
      A certification process seems reasonable, the FDA should support the adoption of a creatively designed regulatory system to ensure safety, quality, and data keeping.
      This translational medical potential should be promoted and fast tracked so that one does not need to leave the US to seek treatment. The world wide market is growing, more clinics offering treatments with umbilical cord derived MSCs are increasing in number; especially along the Mexican-US border.

  3. We know that tissue cells from placenta, fat, bone marrow, umbilical cord, or anywhere else don’t usually cause problems when they are transplanted or infused. There are notable tragic exceptions in which people were blinded or infected. The problem is that they are no better at treating injuries or disease than a sugar pill. I know that people are asked to pay a lot for these treatments, and also for homeopathic treatments. Is it wrong to charge money for something that is known to not work? I think so. I’m being ironic, but why not label them with the word “placebo”, so that people will know what they are getting?

    1. A. Rahman Ford, JD, PhD

      With all due respect, SCT is far more than a “sugar pill.” I had it 14 years ago so I can personally attest to its powerful anti-inflammatory effects.

      1. StemCellSciGuy

        That is an assumption and not a clinically based scientific observation. I had some tic-tacs one time and my flu got better real quick. Think about that.

        Again, medical science needs to be based on robust research, and validated clinical trial work to prove both safety and efficacy. Testimonials are not evidence of efficacy or any scientific process. Otherwise, tic-tacs would be medicine.

        1. https://pubmed.ncbi.nlm.nih.gov/30835956/

          Many of the results and conclusions on these fairly simple searches in PubMed don’t appear to be examples of “Tic Tac” medicine or sugar pill or placebo effect to me. And there are many other examples as well. I’m no scientist either. But, as a patient who has been on the receiving end of a number of regenerative therapies, these studies come across as pretty robust to me. It seems anything further is just reinventing the wheel.

          1. StemCellSciGuy

            The main point was that any testimonial is not a scientific study. Claiming it as so is definitely ‘Tic-tac’ medicine. Many people believe an intervention has worked for them, and if they truly feel or are better, that is great. It does not make it vetted medicine.

            I’ve spoken to well over a dozen people, including one family member, who have had ‘adipose stem cells’ and it did nothing for them. Some had infections at the site. The clinics bar discussion, and have in their contract an effective NDA. So for ever testimonial one sees, one must wonder how many dozens have no effect at all or worse.

            Quote from your sources “Larger sample size and long‐term follow‐up are required”. Second study is woefully underpowered and claims safety established “haMSCs were preclinically assessed in vitro and in BALB/c-nu nude mice.” No evidence of non-intervention controls. Last quote “Long-term results are needed”. So even these journal come nowhere close to any evidence by and reasonable standard.

            To date no phase III clinical trial has passed in the US and demonstrated Safety and Efficacy in the US.

            Many of us in the field feel MSC’s and other stem cells will be vital to the future of our scientific medicine. However history has clearly shown when we don’t follow a rigorous, repeatable, and transparent path of clinically based testing that bad things happen to the general population. Sample size matter, review of the data matters, unobstructed reporting of all averse events matter, and more.

            We all want MSC’s to work. We all want MSC’s to be useful. But medicine must be done correctly to be safe.

            1. The studies I included above, and there are MANY others, are not testimonials. But comparing your tic tac example to the therapy the patient you responded to above sounds like a false equivalency to me. And the dozen or so plus people you interviewed…..isn’t that just one much larger testimonial? Most preliminary literature on experimentation of any sort is usually going to call for further studies with a larger sample size. Nothing new there. There is a reason these articles made it into the published literature. They are significant. I think they form the basis for evidence of safety and efficacy in utilizing our own body parts to bring about treatments; treatments that sound like much better options when compared to the side effects of prescription drugs and much of conventional medicine. The interview Dr. Knoepfler performed with Kyle Cetrulo seemed to offer alternatives to the Phase III clinical trial pathway you mentioned which traditionally has been excepted by the medical and scientific establishment here in the states. There may be other ways in testing for safety and efficacy.

              1. StemCellSciGuy

                The reason the clinical trial Phase 1-3 paradigm exists to to validate that any intervention actually works. The problem with testimonials is they aren’t scientifically sound. What if those people were to get better on their own? Was it the intervention or something else?

                Take this scenario: You interview 12 people. All have an MSC treatment from a single location. 11 of the 12 claim improvement. So it works, right? But then you review 10,000 records of people who have received an MSC intervention. This data shows that only 11 people have actually shown a benefit. Clearly the vocal 11 people are not proof that the intervention is working. This is a real thing that happens all the time. Either for positive outcomes or negative outcomes.

                In terms of money, it complicates the matter greatly. If your business hopes to make $25 million dollars annually selling a ‘stem cell therapy’, it is easy to imagine some executive leadership wanting to promote those 11 ‘success’ stories, and not wanting to report the 99.99% that don’t have an effect. Or this scenario: The MSC intervention has a mild positive result, about 20% of the people treated have a positive outcome. But 10% have a very bad outcome that requires further medical intervention (ie infection, reaction). Does the facility standing to make $25 million want to advertise that 1 in 10 will not just have no results, but harm may occur? Would that facility want to voluntarily report to the FDA? Maybe… maybe not. That where a pay-to-participate has massive risk and ethical issues. The presence of very large sums of profit will inevitably make people want to report positive results and suppress negative ones. It can’t be helped. And of course ‘paid testimonials’ or competition of any sort (or discounts) muddy those waters even more.

                With both of these scenarios its just a small example of the dangers of moving outside a robust safety system that has been designed over the decades to prevent incredibly bad outcomes from happening.

                Take ‘Prayer’ as a final example. Many people believe the power of prayer is more effective than modern medicine (drugs, surgery, stem cells, etc). There are literally tens-of-thousands of testimonials that a deity or some religious force has healed them. Far many more testimonials that for stem cells. By the ‘larger testimonial’ thought process offered for stem cells, then the same logic must come the conclusion that prayer is superior to standard medicine, or any new experimental form of stem cells. Of course science has unequivocally show that in a population this is completely untrue. But at an individual level, people have prayed, and cancer has gone into remission, or arthritis had gotten better. These things do happen. But they also happen to people who don’t pray. So, testimonials really don’t help.

                In terms of publications, Dr. Knoepfler and many other have also provided published papers and clinical trial reference showing NO effect of many forms of MSCs. What about all the negative publications? Remember, science must be testable and repeatable. One lab gets good results and two do not, it must be further investigated and studied.

                We all want MSC and other stem cell medicine to work. And it will. But the current offerings of profiteering ‘clinics’ masquerading as medical science, where a random ‘stem cell’ injection will cure ‘everything’ (look at many of their websites and nearly everything is listed) is definitely concerning.

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