The Panelists

David R. Brown, MD, FACE, Children’s MN

Dr. Brown, a staff physician at Children’s Hospitals and Clinics of Minnesota and in practice at Pediatric Endocrinology and Metabolism, has served as a member of the clinical faculty at the University of Minnesota. He completed a fellowship in Pediatric Endocrinology and a National Institutes of Health post-doctoral research fellowship.

Meri Firpo, PhD, Stem Cell Institute

Ms. Firpo, an assistant professor in the Stem Cell Institute, Diabetes Institute, and the Department of Medicine at the University of Minnesota, focuses her research on stem cell biology and therapies for diabetes. She uses human stem cells as a model of development and disease progression, and differentiating stem cells into functional tissues for transplantation.

Amy Fowler, RAC, JD, Pathmaker FDA Law

Ms. Fowler, the founder of Pathmaker FDA Law, has over 25 years of experience in commercializing medical devices, pharmaceuticals, and combination products. Regenerative medicine law is a recent addition to the firm. While specializing in FDA law, her firm also provides marketing compliance, clinical, reimbursement, and quality systems support.

Ron Hanson, MD, OrthoCure Clinic

Dr. Hanson, a pioneer and innovator in the field of orthopedic regenerative medicine, is the first sports, orthopedic, and pain care-trained physician to perform platelet-rich plasma and stem cell therapies in the upper Midwest. He started the first regenerative medicine fellowship and training program for a coordinated group of physicians.

Roger S. Hogue, MD, MN Regenerative Medicine

Dr. Hogue—founder and CEO of Hogue Clinics, along with Hogue Surgical LLC, a Minnesota medical device company—is board-certified by the American Board of Laser Surgery and a Diplomate of the American Board of Venous & Lymphatic Medicine. At Minnesota Regenerative Medicine, he performs autologous biocellular treatments.

Blake A. Johnson, MD, FACR, CDI

Dr. Johnson, a board-certified neuroradiologist, is the Twin Cities medical director and director of neuroimaging at the Center for Diagnostic Imaging (CDI), serving as national section leader for interventional procedures and as national medical lead for regenerative medicine practice. He completed a fellowship at the Barrow Neurological Institute.

The Sponsors

Paul Orchard, MD, University of Minnesota

Dr. Orchard is the medical director of the Inherited Metabolic and Storage Disease Program and a professor in the University of Minnesota’s Department of Pediatrics, Division of Blood and Marrow Transplantation. He is interested in the use of hematopoietic stem cell transplantation and other cell therapies for inherited metabolic diseases.

Regenerative Medicine

Efficacy, Economics, and Evolution

Minnesota Physician Publishing’s 48th Minnesota Health Care Roundtable focused on the topic of Regenerative Medicine: Efficacy, Economics, and Evolution. Seven panelists and our moderator, Minnesota Physician Publisher Mike Starnes, met on December 12, 2017, to discuss this topic.

It is fair to say that regenerative medicine is a lot like the Wild West. Things are happening fast, laws are sometimes hard to find, and sometimes things are made up on the fly. It is a field that is evolving so quickly that it is not widely understood, though this is quickly changing. Let’s start by defining regenerative medicine.

David Brown: Rarely do two people agree on what constitutes regenerative medicine. Last October, a combined group of the National Academies of Sciences, Engineering, and Medicine got together at a workshop exploring the state and science of regenerative medicine. The workshop introduced it as technology with the potential to create living functional cells and tissues that can be used to repair or replace those that have been irreparably damaged due to specific diseases, age, trauma, genetic, or congenital defects. They then looked at four targeted therapies in the areas of cell therapies, gene therapies, tissue engineering, and non-biologic constructs such as signal models and scaffolding. The operating paradigm for this was identifying the right cell to the right target with the right function to the right patient.

Blake Johnson: We are looking at not just replacement, but also rejuvenation of tissue, restoring tissue and organs to their original function when they have been injured or undergone degeneration. We are simply facilitating the innate ability of the body to do that, rather than using pharmacology or surgery as our primary modalities. Instead, we harness the body’s own ability to perform those functions, concentrating them, and serving as both a catalyst and an accelerator for the body’s natural processes.

Ron Hanson: It is a little broader than that. It is all of the things that change the issues within the body and the body’s ability to heal on its own—not just the procedural, not just the cellular aspects, but what is the diet, what is the exercise, what is the sleep, what is the mindset of the individual, and doing this from a very broad approach rather than just what is the cell, what is the area that you are putting it into?

Roger Hogue: Regenerative medicine has a very large scope. As a physician that performs regenerative medicine, I view myself as a mere catalyst. I look at being able to take a patient’s regenerative capabilities, whether it comes from their bone marrow, their blood, or their fat, and, as a catalyst, allowing them to be able to repair and rejuvenate and replace what is ailed. If you replete regenerative cells that have been depleted, the body has the capability to heal itself. We don’t call these stem cell treatments—because “stem cell” has certain connotations—but autologous [patient-derived] biocellular treatment using a pool of regenerative cells contained within the patient’s own body.

Meri Firpo: In the laboratory we can use regenerative medicine to identify drugs, for example. We use stem cells all the time as a model system to understand diseases, and we can make stem cells from people who have diseases and do comparative studies. We can model through these degenerative diseases in the laboratory and even come up with novel drug therapies, and I would still call that regenerative medicine. I think it is the approach of looking at these cellular processes in a way of trying to work within the cellular functions to heal the body.

Does that touch on the concept of the difference between the structure and function of regenerative medicine?

David Brown: To me, regenerative medicine is enhancing or reintroducing where a particular biologic expression has been incapacitated. It focuses on the normal mechanisms the body uses, biochemically or genetically, to carry out these functions. Whether it is by drug, whether by cell, or whether by genome editing, we simply facilitate that normal biologic expression. I would look more at the phenotypes that result from those underlying processes in terms of either healing disease or improving the status of the individual as what you referred to as the structural component. I was discussing the functional first, and those phenotypic expressions would be the structural component.

Are there conflicts between different kinds of regenerative medicine?

Amy Fowler: Some key FDA definitions differ from the way a physician might look at it. The Food and Drug Administration defines many different types of HCT/Ps [Human Cells, Tissues, and Cellular and Tissue-Based Products] that, under the 361 PHS [Public Health Service Act], have been carved out of the regulations. When you get out of the criteria for simple tissue transfer and into regenerative medicine, the FDA views it as a potential drug product or biological product. There are four main criteria within this particular category. First, the tissue is minimally manipulated—basically, the same types of structure and function that the cell or tissue had when it was in the donor, it is still going to be in there when it is put into the recipient. Second, they are looking at homologous use. If you had a strength function or some sort of a membrane function in the donor, they want to see that type of use in the recipient. The third criterion for an HCT/P is that there are only certain additives that can be present—water, some simple preservatives, possibly some sugars. The addition of certain pharmaceuticals, etc., might be considered enough to make it more of a drug product. The fourth criterion is that the HCT/P tissue be not just for a medical effect, but that you have a biological effect or chemical effect with the drug product. FDA also has a very small section where you have HCT/P with tissue that has a biological effect, but involving a very close relationship between the donor and the recipient, probably some sort of family member. You can get away with not having that fall into the more highly regulated drug or biologic category.

There is one last definition of regenerative medicine: stem cells.

Meri Firpo: Stem cells are a reservoir of functional tissues that are regenerative in your body in normal physiological conditions and in degenerative diseases. They typically are very, very rare, in the range of one to 100,000 or one to one million cells in a tissue, and they do not usually have a function. They are there, instead, as a reservoir to make cells that do have functions. The best example is the bone marrow stem cell, which gives rise to blood. Bone marrow stem cells can proliferate and remain stem cells, or they can grow and divide and differentiate into functional cells. Some stem cells can only become one cell type, while others can become any cell type. Stem cells differ in their potential to become different cell types. Liver stem cells have a very limited capacity, whereas bone marrow stem cells have a big variety of cells that they can become. The only totally potent stem cells are the first few cell divisions after fertilization. After that, they lose their differentiation potential. These terms are not always used correctly, and I believe a lot of people confuse regenerative medicine as just working with stem cells. Stem cells are just one arm of this growing umbrella term of therapies.

Paul Orchard: Patients do not necessarily appreciate all those nuances. We need to identify the various populations of cells that we are potentially using or not using. I had a family call me and say, “My son has a neurologic disease. We previously transplanted him, and now we are going outside the country to get stem cells.” They could not tell me what kind of stem cells they meant, or how they were produced. Families latch on to the stem cell moniker, but do not necessary understand the implications.

Meri Firpo: People recognize the term and they think it is good. Whatever they hear about stem cells, they are good with it. It takes a level of scientific understanding to know what you are dealing with, but I think that is why they are told they are stem cells, because that gives them some sort of credibility with the public, which is potentially very dangerous.

Roger Hogue: I deal with autologous or patient-derived regenerative cell populations. I specifically do not refer to these as stem cells. I think it is too specific, and may denote false advertising. If you take that soup or bone marrow soup out of somebody and you transplant it into an area of injury, you are transplanting the array of regenerative cell populations into that area. Again, you are the catalyst—the patient does the work, not you. You are not doing anything more than what is allowed for processing, what is allowed for filtration. Sometimes it involves a combination of regenerative, rejuvenation, cosmetic, and aesthetic. We track adverse events, safety, efficacy, and outcomes, but it is still the patients healing themselves, and it does so even if I am not making a drug. I just take fat aspirate concentrate and deploy it somewhere that is injured.

Blake Johnson: You are not just transferring a single cell line in stem cells when you do these regenerative therapy treatments. You are getting a host of proteins, growth factor, cytokines, and some cells that help promote the natural healing process. All of us right now are losing millions of cells per second as we sit here. Why aren’t we falling to the ground? Because our bodies constantly replenish them. All we are doing is catalyzing the body’s ability to restore its innate capabilities, especially in areas where there is not a lot of blood flow to deliver those products in those cells. We are actually harvesting, concentrating, and putting them there. Stem cell therapy is not what we are doing. We are doing regenerative medicine.

Paul Orchard: Some groups are very interested in specific stem cell therapies. The neural stem cell groups, for instance, are potentially growing cells that might be oligodendrocyte precursors and they are going to implant them in the brain, where you hope to get myelination in a patient that has previously been demyelinated. So that is a much different approach because you have a defined population of cells that was created in a very specific way under an IMD [inherited metabolic disorder], and is likely going to be company-sponsored in terms of a clinical trial. So that is still regenerative medicine and using stem cells, but it is not a heterogeneous population of cells that we are talking about in some of the other contexts.

Amy Fowler: In the past, these types of therapies were very much focused around individual physicians, and now we are starting to see more and more commercial entities coming into this space, then creating a product that is mass produced. You start getting into new types of FDA regulations, not just the practice of medicine and the physician therapy. It is really a health care product that is on the market.

Now that we have those definitions in place, let’s discuss some examples of how regenerative medicine is being used today.

Paul Orchard: My practice includes blood stem cell transplantation for a variety of diseases. I think of it primarily as therapy and not necessarily regenerative therapy, but there are things that we would like to use that would fit more into the latter category. For instance, we have a patient with leukemia who is unlikely to be cured by standard chemotherapy. We would do an allogeneic bone marrow transplant. We get marrow from a sibling or from a compatible unrelated donor, for instance, give some chemotherapy to the patient, and reinfuse marrow. It is primarily to allow them to recover their hemopoietic function, but there are some immunologic pieces that might help eradicate leukemia. Now, if we were developing a mesenchymal stromal cell population, for instance, that has the capacity to be immunologically important and we give cells like that to patients that have graft versus host disease to calm down a process that is immunologically active, then maybe that could be termed in a different light.

Blake Johnson: We are using autologous cell products, biocellular products—specifically bone marrow concentrate and PRP [platelet-rich plasma] harvested from whole blood—to treat musculoskeletal disorders, soft tissues, tendons, ligament injuries, joints, intravertebral discs, and more.

Where have you seen the greatest success?

Blake Johnson: Patient reports, discussions with practitioners around the country, and the peer-reviewed published literature have all shown restoration of the physiologic tissue function and appearance microscopically and even on imaging and also clinical function for patients.

Meri Firpo: My lab works with pluripotent stem cells, primarily taken from a little piece of skin. We culture out the missing column of cells, and reprogram them with either genes or proteins or other factors into pluripotent stem cells. So they were not stem cells, but we reprogrammed them into stem cells in the laboratory. These cells are like embryonic cells, which can give rise to any tissue, and we encourage them to become insulin-producing cells that can be transplanted to replace cells lost in patients who have diabetes. We have proof of concept that this works, and we are working out all of the issues that the FDA would like us to describe: what are the cells, what are the contaminating cells, what do the cells do in the recipient, and whether there are any other types of cells that pose risks to the patient.

Let’s talk about the challenges facing regenerative medicine. We can break them into three large categories: regulatory, reimbursement, and integration. New FDA guidelines came out on November 16, 2017, specifically trying to protect the public from clinics that were offering dangerous or improving versions of stem cell therapies. Let’s talk about these guidelines.

Roger Hogue: What is most interesting to me is that an adipocyte-derived stem cell has now been categorized as a drug, which means that the specific regenerative cell population within your body is now under the jurisdiction of the FDA. I find that to be an amazing declaration. I certainly do not agree with it, but it is an FDA guidance. It has not been ratified or passed by Congress yet.

Amy Fowler: Two of the two new November guidances are out for a 90-day public comment period. This is everyone’s chance to be on the record and give feedback to FDA and guide FDA in putting out something that is more appropriate. I encourage everyone to look at those.

Blake Johnson: It all falls under the definition of HCT/Ps and what you do with those harvested tissues. If you do anything beyond some limited organic water, etc., then they are going to classify it as a drug. The FDA is overseeing a physician process, something that should be under the purview of physicians. The FDA claims that it falls under its purview because it is now a drug harvested from that patient because of that manipulation, under the interpretation of that guideline of minimum manipulation.

David Brown: This is a problem with the FDA itself, because its mandate is strictly drug oriented. It’s the same in my field in gene editing. If you were able to genetically manipulate a cell, the end result, that gene sequence, is considered a drug if it is inserted into a human. It is obviously ridiculous, because the definitions, regulations, quality control, and everything that goes into that is so much more complex than a drug. We are being forced to accept regulations that are not compatible with biologic reality and are, in essence, very unscientific. Some things in my field that involve genome manipulation fall under the Department of Agriculture’s jurisdiction, which has completely different definitions than the FDA. This is just an arbitrary designation as to whom you submit for approval to do the work or to get approval to take the work clinically. So the federal government has a major problem. It is inconsistent with science.

Amy Fowler: I think one thing that the FDA clearly needs to do is to distinguish physician practice of medicine from more of a commercial practice where something is being manufactured and then sold.

Blake Johnson: Any time you can make money, the companies are going to get into it. When a physician performs a procedure on a patient with autologous tissue harvested from that same patient, there is no chance of rejection, there is no chance of transmission of another disease. If they have a disease, you are going to give it back to them, but you are not giving it to another person. Harvesting amniotic cellular products and selling them might sound pretty enticing to a 75-year-old guy with osteoarthritis in his knees, who might say, “Those young cells are going to be better than my own cells, so I want that amniotic stuff, Doc.” I’m not making this up, I have heard this from patients. It is a very easy sell to take these products and make them sound like they have credibility, and the public has to be aware of that. That is what should be regulated in those products that are potentially dangerous. Many of these procedures are performed by non-physicians who do not even have specialized training.

Is the FDA dictating the practice of medicine?

Amy Fowler: That is where the definition of the HCT/P in the regulations is key. There are also a number of rulings from the Tissue Reference Group that essentially are guidance for companies and for practitioners. It is very specific. Sometimes we get into a gray area and we produce our best opinion. Sometimes we go to FDA to talk about it.

David Brown: When I started practice, I specialized in pediatric endocrinology. Almost every product we had was a biologic-derived product, from animal-derived insulin to human growth hormone derived from ground-up pituitary glands. Ninety percent of these were basically crude cellular preparations, which, it is astounding, had FDA approval. When I went to work for one of the early biotechnology companies, we did sophisticated genome editing with isolated individual genes for insulin and growth hormone. We produced highly purified products, and it took us 11 years to get the approval for growth hormone and seven for insulin. It was the opposite paradigm with the FDA when we had something that was pure biologically, produced from a single gene source and pure culture using standardized good manufacturing procedures. I think we have the same argument in reverse going on now. Back then, we never had a single meeting during any of our clinical trials or introduced any idea without having a representative from the FDA present. We will have to go through that same process here.

Amy Fowler: There is a lot of innovation out there, a lot of startup companies that have great ideas and great products. They want to go through a regulated process, but it is not economically feasible for a lot of these companies. There has been a lot of investment in this area recently and there is definitely more to come, but there is a big jump to actually taking a drug or a biologic through the agency.

David Brown: It costs about $100 million per year for a company to take a pharmaceutical product for approval, and the average time is 7–8 years. In today’s dollars, it is pretty close to $1 billion per drug. That is really exceeding the capacity for what even large industry can do. But $1 billion per drug is why you have seen so few drugs come to market and why you have the problem with regard to efficacy. Almost none of us respond identically to any of these products. They represent the best decision for the common denominator. It is a statistical, population-based approach, whereas the kinds of therapies we are talking about here are much more individual-based. The FDA has to reeducate itself, or we need to have a new federal agency that understands the science. The FDA clearly does not.

Isn’t it a significant challenge to say that the drug we bring for approval is made from one patient’s stem cells, which are different from another patient’s stem cells? How can we apply the same testing mechanisms to stem cells derived from your body to stem cells derived from my body?

David Brown: We are in an area of reactive medicine. We react and apply things when a disease circumstance presents itself. What we really have to do is define ourselves biologically. What is wellness? What are the transitions into disease? Under P4, or Precision Medicine, we define each individual in terms of a multiplicity of factors. We literally have to construct data clouds on each of us to define who we are biologically, and then attempt to take those therapies and match them as closely as possible to that information. That is a very expensive thing to do.

There are clear benefits to regenerative medicine procedures that are helping patients in many ways, but they are not covered by health insurance. What needs to happen for health plans to pay for these procedures?

Ron Hanson: I don’t know of any individual insurance companies and HMOs that are paying for this, other than one in Louisiana. The real answer is, as soon as the AMA makes a CPT [Current Procedural Terminology] code for it, that’s when it is going to get covered. That’s when everybody is going to get trained and become regenerative medicine experts. I’m betting that in 2019 some AMA codes will be created. The tracking code for platelet-rich plasma was created in 2012, and the average from a tracking code to a new code is five years, so they are already taking longer than usual.

Paul Orchard: Is there an accreditation process for a group that would want to do a specific type of delivery of a specific cell population process in a specific way? What kind of guidelines can you use to ensure that one person is doing this in a reasonable way and somebody else is a fly-by-night person doing it in their garage?

Ron Hanson: I know of two. The International Cellular Medical Society wrote the guidelines for platelet-rich plasma, bone marrow, and adipose: how to prepare a patient, extract and process the tissue, and reintroduce it into the patient, as well as aftercare. These were kind of best practice guidelines, just a bunch of people who have been doing this for a while getting together and saying this is what you should do. I have gone around the country four or five times to testify where there was malpractice involved in a regenerative clinic. The other one is the American Association of Orthopaedic Medicine [AAOM]. That was the original regenerative medicine group, that and Hackett Hemwall Patterson Foundation, that essentially started using about seven different agents to cause either irritation or induction of the person’s own healing responses in the body from a variety of mechanisms. Very few individuals now have the AAOM’s IROM [Interventional and Regenerative Orthopaedic Medicine] certification.

Another element of insurance coverage will be FDA approval, and FDA approval isn’t going to come without randomized clinical trials. How do you conduct randomized clinical trials on your own stem cells?

Amy Fowler: Clinical trials are FDA’s favorite. Well-controlled, randomized clinical trials are also a favorite of CMS, because they give you such great scientific information. A lot of very cutting-edge drugs and other therapies are able to get on the market with maybe a smaller section of clinical information, under the understanding that there is some sort of phase for commitment for further study. We may be able to use that as a bargaining point in some negotiations with FDA.

Ron Hanson: I’ll give you an example of how difficult this is. A leading physical therapist recently asked what I did for Achilles tendinosis. I asked if she meant Achilles tendinosis in the middle part of the tendon, at the insertional part, if there were calcifications in the insertion or in the midbody, adherence to the sheath, hypervascularization, increased neural tissue around the sheath, peripheral nerve entrapment, radicular symptoms, or impingement of the nerve root that were causing this? This is why it would be extraordinarily difficult for us to randomize multicenter-trailed placebo control. No one individual is exactly the same as another individual. As materials, methods, protocols, experience, and understanding of all of the different facets end up being somewhat standardized, it will be easier to understand what works and what doesn’t work and under what circumstances.

What sorts of challenges are there in getting providers to refer patients to regenerative medicine procedures?

Blake Johnson: Right now, this is primarily patient driven. Some patients are motivated to get better, and they want to use minimally invasive modalities rather than surgery as their first line for treatment. Professional athletes are starting to look at regenerative medicine as the first line of therapy for injuries, before they start going in and getting steroid injections. The second part is education. You have to educate physicians about what we are doing and make sure that they know that you are using sound medical practice. Like anything in medicine, when something is new, not everybody who has been out in practice and out of training for several years is going to know about it. They need to learn about it, just as practicing radiologists had to learn about MR [magnetic resonance] when that came out in the 1980s.

Ron Hanson: I sometimes use the example of carpal tunnel syndrome. Eyebrows go up a little when I say that the most common pathology in carpal tunnel syndrome is adhesions at the median nerve, at or just before the carpal tunnel, and those adhesions mean that the nerve can’t move appropriately, so it is getting squished in the tissue. Three-quarters of those individuals also have significant neck neural impingement, brachial plexus neural impingement. It’s so much more complex, with so many more moving parts, to educate an average practitioner on this completely different paradigm. It is completely different than just cutting the flexor retinaculum. I’ve seen hundreds of patients after their flexor retinaculum was cut, and their adhesions are now worse than before, because they didn’t deal with the underlying cause of why that nerve was entrapped and symptomatic in the first place.

David Brown: I think it is cost. I worry about the real procedures when we get into things that are going to cost millions of dollars, because the problem is that this is front-loaded, and the insurance industry doesn’t like that. With Parkinson’s disease, there may eventually be some technology to induce dopaminergic neurons and have a legitimate effect in regeneration, and it is going to cost a million and a half dollars. The patient has the procedure done in September, Blue Cross will pay for it, and then they are going to be on Medica in January. Medica is the beneficiary of that and that model is known. Blue Cross and any of the companies are going to say we’re not going to front-load on this. We have to have a model that disseminates these costs.

What are the biggest misperceptions about regenerative medicine?

Meri Firpo: My perspective is that of the potential patient. A lot of patients are confused when they hear “stem cell.” One woman called me and said that there is a doctor in the Ukraine who will “cure my son’s dyslexia by injecting stem cells into his brain”—for $45,000. When you are desperate or thinking about a loved one, you want to do whatever you can, and some people are vulnerable to being ripped off. It would be helpful to understand what’s real and what is snake oil. There should be some sort of independent oversight or confirmation. Is this something that I’m not providing to my child that could cure him, or is this something that is potentially incredibly harmful? If some kind of cells from somewhere, somebody, some animal, is going to be injected into my son’s brain, there has to be a way for people to tell the difference between what is potentially helpful, whether the data they see on the website is real, versus something that is completely fabricated, or cells taken from someone who potentially has a communicable disease.

Roger Hogue: There need to be standards, but understand that physicians who are practicing regenerative medicine are already heavily regulated by the Minnesota Board of Medical Practice—and by malpractice attorneys. If a physician harms someone, does something that transmits disease or causes death, it’s ludicrous to think that isn’t going to be investigated or reviewed. Of course it will be. There are a lot of things that need to be done. One of the things that physicians are not doing appropriately is calling it some type of specific treatment like stem cell treatment. That needs to be abandoned because this is really just autologous biocellular treatment.

What should patients ask if they are pursuing regenerative medicine-based treatment?

David Brown: The patient has to be intimately involved in the process and in the conversation and dialogue. It’s not so much what they should ask, it’s how open they are to understanding and asking the right questions regarding outcomes and implications and being an integral part of the decision to proceed with these procedures and any followup. It’s much more of a science and practice that requires active patient engagement. The more educated and more sophisticated the patient is, the better the outcomes.

Blake Johnson: A lot of these procedures are now done by non-physicians. Do those boards regulate and oversee the practitioners in their field as much as the medical doctors are overseen? If you’re operating under the oversight of a board that will come down hard on anyone who gets out of line and practices any kind of non-safe medical practice, you have a layer of protection. The second thing is to talk to the physician about their experience with what they’re doing. If somebody is just doing this because they can bill for it and they have zero experience in their procedures, you can find that out. What is your experience? Do you have any patient testimonials? Registries are going to be a very important part of that going forward. Patients really do need to educate themselves on this, because it’s not going through the approval of an insurance company, so they’ve lost that layer of vetting.

Doctors are not getting taught regenerative medicine in medical school. How does someone go about learning to become a practitioner of regenerative medicine?

Paul Orchard: From the patient’s standpoint, it’s hard to ask what the rationale is, to try to get a better sense of the purpose of using a specific type of cell for a specific indication. Down the road, there is going to be some sort of threshold that people would have to reach in terms of becoming certified or having some sort of shingle to hang out and say, “Yes, I’ve done enough of these that I’ve met the accreditation standards.” Say that the guy down the street who is mixing the cells up in his bathtub hasn’t done this. I don’t know exactly how those things are going to end up getting vetted and regulated, but I can well imagine that those things are going to be important to separate out the wheat from the chaff, especially if you get to a point where insurance starts paying for these things and you just don’t know who is going to start doing it and in what circumstances.

Ron Hanson: I started the first fellowship in the country that was all regenerative medicine. For that group, I would only train somebody who had a musculoskeletal background already, and they had to be trained in either ultrasound or fluoroscopic guidance before they came into the fellowship, because I was going to train them in at least two more forms of guidance, and there is no way to do three right from the get-go. The reservoir of information that you have to draw from to do this effectively is tremendous. You need to erase everything that you know, because what we are doing in regenerative medicine is completely different. First, your mindset, is it already in a regenerative medicine standpoint, or can we get it there? I have a bias towards DOs [doctors of osteopathic medicine], who must be trained in prolotherapy. That will probably end up being the reservoir from which most regenerative medicine doctors are going to be cut.

Paul Orchard: Registries for patients treated for rare disease tend to be company-sponsored, because the company has a stake in a product. If orthopedics or radiology or some governing body, or maybe the insurance company, is sufficiently interested in developing this, that would mean that we really need this data and we’re going to fund it. It’s much better if you have some sort of mandated system where somebody collects the data on every patient at various time points. If it’s left open to people to self-report, then you introduce bias. It’s probably better than no information, but it’s tougher to know what to deal with.

What is a therapeutic dose of stem cells? How do we measure how much we give and how often do we give it?

Paul Orchard: We can look at all the various cell populations that we administer to patients and know exactly what the doses are of each different cell population, so that’s very useful information in the big picture. There’s no reason that couldn’t happen here, too. If we think that a lot of nuclear cell population with platelet-rich plasma is important, are there specific cells in there that are more important than others? Is there some mix of cells that ends up being optimal?

Roger Hogue: There are a lot of different FDA-cleared closed loop systems for isolating platelet-rich plasma from whole blood. Some of them use lasers to sort cells and other ones have different systems. You can control the neutrophil or the monocyte percentage and amount, and so whenever you put white blood cells into PRP, it becomes more inflammatory. The monocytes sometimes differentiate into macrophages, and there is some paracrine immune-mediated potential in an inflamed area. So there is a benefit in being able to optimize either the amount of platelet-rich plasma, the percentage above baseline, the different cell populations, and there is technology out there to be able to do that. Not everybody is going to be able to take a hemocytometer and assess exactly what they have when they’re injecting it. Sometimes I see people just draw a tube of blood, spin it, and then the plasma, which is just plasma, they will say it’s PRP, and then they’ll inject it into the patient and it’s completely bogus. There are going to be folks that will cut corners and maybe sell near beer. It’s not as effective.

How do we know if a regenerative medicine procedure is working? How can we tell whether it is creating a therapeutic benefit?

Roger Hogue: If you’re talking about platelet-rich plasma, the results will be apparent within a few weeks. If you’re talking about a biocellular treatment using autologous bone marrow or fat that contains mesenchymal stem cells or a host of regenerative cell populations that have the ability to help regenerate and rejuvenate damaged tissue, it’s different. We know that the gestational period for humans is about nine months, and, surprisingly, it does take several months for patients to usually see benefit. I believe the benefits will last 1–2 years out. When someone does an autologous or a microfollicular grafting, the hair transplant specialists usually evaluate at two years whether this graft is successful. There is a lot of regenerative medicine being done out there, and I think that hair grafts is a good example. If they have to wait two years to see the full effect of the graft, it isn’t unreasonable that if we are taking fat or bone marrow, then months to a year is not unreasonable.

Blake Johnson: That’s not to say that nothing happens for a year, but it’s not like putting an anti-inflammatory corticosteroid in, where in a day or two the effect will be perceived by the patient, because you’re rebuilding and repairing. If you sprain an ankle, you don’t expect to be better by this weekend. It takes weeks for that to happen. So we definitely tell patients that for the first eight weeks or so, you may not experience any improvement at all, and then after that it’s a gradual healing and regenerative process, and we track it out a year and even beyond. But that doesn’t mean they’re not going to have any perceived improvement for a full year.

Roger Hogue: Usually when I do either a bone marrow or fat-derived autologous treatment for osteoarthritis of the knee or hip or ankle or hand, I will, one month or two months post-procedure, do platelet-rich plasma, which is known to help the regenerative cell population by establishing differentiation, division, angiogenesis, and growth factors so there is a continuum of promotion of wound repair.

Should the Federal Trade Commission regulate what can be called stem cell treatments?

Ron Hanson: Medical boards and physician societies are the best way to regulate, and the spectrum of malpractice lawsuits is the best way for physicians to be monitored. It’s more or less what the Practice of Medicine Act wanted, which was for us to be as independent as possible, to be able to provide the care needed at that moment for that person the way it needed to be done. The more that these autonomous agencies get involved in different things, the more difficult it’s going to be for any of us to provide the care that a person sitting right in front of us needs. I was at the clinic that the FDA took on in 2007, and that clinic was using a single-cell source of mesenchymal stromal cells for treatment of arthritis, tendons, and ligaments. The FTC was a secondary, behind the FDA, to get involved in what was actually said on the website, what was being said to people calling in to the clinic. They would have fake patients call in and ask, “What are they telling you?” The more arms of the octopus that get involved in this, the more difficult it’s going to be. I believe that trusting the individuals who have been trained to do this, allowing them to do what they were trained to do for the best benefit of the patient, is the way to go.

In terms of the professional liability issues that regenerative medicine poses, is this limiting quicker physician buy-in?

Paul Orchard: Anybody can sue anybody for pretty much anything, so a lot of it ends up being what was said to the patient prior to the procedure. We have patients sign extensive consent forms. Some of these are 20 pages long and nobody reads them, which defeats the purpose, but understanding the relative risks and benefits of any procedure still ends up being key. We have a fair amount of data for a lot of the things that we’ve been treating for a long period of time. We can say that the peritransplant mortality is 10–15 percent in this circumstance, and the chance that your leukemia will come back is 20 percent. There is a lot of variation in terms of how patients present and the range of regenerative interventions we’re talking about here. If somebody injures their Achilles tendon, there are 50 different ways to assess where they are. Can we unify that enough to ask a specific question in a longitudinal study on specific outcomes? Those studies should be feasible, but they probably aren’t going to be easy, and they will be very expensive. I haven’t heard that there is somebody willing to put together a huge study like that.

Blake Johnson: It’s important to put it in context historically. You heard earlier how human growth hormone got started by putting cadaver pituitary tissue in a little mortar and pestle environment and making a slurry, then injecting it in kids. Only a minority of orthopedic surgical procedures performed today went through any kind of trial at all. Aspirin today would not make it through the FDA’s approval process. You would not be able to buy an aspirin if it was brought today for a trial, because of the side effects. We are holding this to a standard that most of medicine has never been held to. It’s great to have controlled blind trials, getting people to be the controls who don’t get the actual cellular biologics and then going through the same process as those that did, but those are really tough trials to do.

Life saving and life enhancing advances related to regenerative medicine stand to drastically change the playing field for several areas of health care. What challenges does this pose?

Ron Hanson: A paradigm shift is coming. One study looked at 600 patients with knee OA [osteoarthritis] and were candidates for total knee arthroplasty. Two years after a regenerative medicine procedure, 94 percent of them still had not gone on to total knee. We surmised that Medicare alone would save about $10 billion per year, just on total knee arthroplasty. Before you pull out your horns and start to cheer, ask whose pockets lost out on that $10 billion? That’s partly what we’re up against. We’re also partly up against the dogma that tends to stay adhered in medicine much longer than changes happen. We have a fantastic opportunity to save time, energy, and resources. These are big changes, not just in dollars, but also in how all of us look at something. Going from a reactive to a proactive medical model is going to be transformative. That’s a different paradigm than what allopathic medicine was born on. Likewise, it’s a much more integrated care model. The more articulate, careful, and understanding that we can be going forward with these changes, the more successful we will be.

Blake Johnson: One of the main reasons we do pain management is to reduce the amount of analgesics they take. We want to do anything we can do to decrease their level of pain and decrease the net dose of medications, because the cycle is really vicious with opioids and is now being recognized as a crisis—denied by some, but more and more practitioners are realizing that it really is a crisis. We are trying to not just modulate the pain but the source of the pain by canalizing the body’s natural healing process. As you do so, those nociceptors that are firing that pain message to the brain start to settle down so that patients can start weaning off the medications.

Roger Hogue: It’s a little humbling for a physician used to healing somebody to now be the mere catalyst and having patients do it themselves. The thing that happens is that patients might be on multiple anti-inflammatories, sometimes steroids, sometimes taking one drug to treat the side effect of another drug. When I tell them I want them to get off anti-inflammatories two weeks before their procedure, they ask if they will be all right. When they come back a month later, they say that they never knew what it was like when they were overusing, and that they are now listening to their bodies. Our culture is so used to a knee-jerk response: I’ve got a symptom, so I’ve got to take something. That’s partly what led to the opioid crisis. People don’t know what it’s like to just be healthy and to have general feedback from their bodies. In our haste to make something go away quickly, sometimes it doesn’t work well. It’s hard to argue against regenerative medicine when you see the actual dynamic effects of how it can change lives.

What is the most important thing to understand about regenerative medicine?

Paul Orchard: There are a number of different types of regenerative medicine. Some are autologous cells, some are allogeneic cells, and some are genetically derived cells. If we’re primarily talking about cell products, what exactly are we talking about using, and for what indication? What works for one particular type of injury may not work for another type of injury, or one location may be different from another. We’re talking about it in generic terms here, but I think being specific about what we’re doing for what indication ends up being fundamentally important in figuring out the best paths forward for regenerative medicine.

Roger Hogue: Endogenous regenerative medicine, which deals with autologous, patient-derived biocellular treatments, is under the purview of the practitioners and state medical boards, and outside the purview of the FDA, because this is taking parts of the patient at the point of care, same day surgery, and putting it back in to help them. Exogenous regenerative medicine, which means that you are doing gene splicing, gene editing, growing an organ somewhere, or you’re taking foreign stuff and you’re putting it back in, is a very, very big difference. On this panel, some of us are doing endogenous regenerative medicine using autologous treatments, while others are using more exogenous, where it comes from another patient, comes from an animal, or gets doctored in some way. That’s the big distinction.

Blake Johnson: Regenerative medicine encompasses a big arena, a big field, and so what one person does in their practice doesn’t encompass the entire field. There is a lot of exciting research being done in neurologic disease, cardiac disease, and endocrine disease. The term does not refer to just one thing. There are a number of different ways of employing that and you really have to know, if you’re a patient looking at a practice and considering it, what materials they’re using, how they’re harvesting it, how they’re delivering it or employing it. There will be a huge amount of variability in terms of what there is on the landscape.

Ron Hanson: One of my favorite physical therapists had a plaque on his wall that said, “efficacy.” From a medical standpoint it is the ability to induce meaningful change in another individual. Long ago, I used to think that my injection was the most important piece of the equation. Over time I’ve found that regenerative medicine is far more than this. It is all the way from what somebody eats to many other practices, including their sleep and their mindset. I like to tell patients that there are 100 things I could do to make them feel better, but “feeling better” does not equal healing. Healing is a very personalized, individualized process for the person that is sitting right in front of you. It’s going to be difficult for that to gain steam because of the way that we are traditionally taught, in kind of a “lowest common denominator,” “this works for everybody” approach, but as we think about healing and efficacy and we go forward to see and work with our patients, it will be obvious what the best choices are going forward.

David Brown: Regenerative medicine has the potential to create living functional cells and tissues that can be used to repair or replace those that have been damaged irreparably due to a whole spectrum of causalities. It encompasses the vast totality of medicine. They have just begun to scratch the surface with the things that they’re doing, and it’s only going to be better, it’s only going to be validated and become more credible and universal.

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