I have interviewed two folks on the very important US vs. Regenerative Sciences legal case: Dr. Chris Centeno and Doug Sipp. More background on the case can be found at the FDA Law Blog.
I thank them both for their time and for sharing their unique perspectives.
I have specific rules for these interviews and how I have posted the answers to ensure fairness. Also I’m not providing any commentary of my own in this article. The opinions expressed here are strictly those of Sipp and Centeno. Bolded questions are from me, Paul Knoepfler, and answers are listed below from each. I have posted the answers verbatim and for fairness neither party saw the other party’s answers in advance. The questions to both Centeno and Sipp were identical except where indicated at the end with a question just for Centeno as a party to the case. I have also alternated between whose answer comes first, starting with Centeno. The only rules I requested of the two was that their answers conform to the rules of this blog (e.g. no personal attacks) and that they try to be brief.
Here we go….
What is your perspective on the US v Regenerative Sciences lawsuit?
Centeno: The FDA derives its authority from congress to regulate human tissue through the Public Health Service Act (PHSA). This case will eventually decide whether FDA had the legal authority under the PHSA to classify autologous human tissue as a drug. Another question is whether FDA can regulate any part of the practice of medicine. Rather than give you my own perspective, let me let others speak from their testimony to FDA during the public hearings on the changes to 1271 that permitted this classification:
- American Red Cross opposed on the grounds that FDA had no authority over tissue as a drug (see link)
- The American Society of Clinical Oncology (30,000 oncologists) opposed because these rules would infringe on medical practice and saw no justification for the initiative (see link)
- Others opposing (hyperlinked): Northwestern Organ Transplant Program, Osiris Therapeutics, Biotechnology Association
Sipp: It appears to me that this is going to be a key legal decision that will impact not only the marketing of autologous “stem cell” products and procedures, but potentially that of human cell and tissue products in general.
Can you see convincing points being made on both sides or are you mainly in support of one side or the other?
Sipp: My main desire is to see stem cells introduced into the clinic only via responsible, rigorous and ethical scientific testing. To ensure that this happens, there is a clear need for strong, clear and independently enforced regulations. This case will in large part determine whether the United States is able to protect the integrity of its the emerging regenerative medicine industry through appropriate regulations ensuring that cell-based interventions are demonstrably safe and effective before they are sold to patients en masse. The uncertainties introduced by the self-serving litigation brought by this company have already had widesspead consequences in that they seem to have emboldened many others by suggesting that highly profitable stem cell applications can be marketed without the need for rigorous testing or appropriate oversight, and without fear of prosecution.
Centeno: I see this case as a key test of how society wants medical innovation to occur and the balance between the two types of regulatory errors.
Practicing physicians generally support the continued need for dual new therapy discovery pathways to protect patients and advance medicine-“FDA/Pharma” and “Physician Innovation”. While all of our advances in drug therapy have occurred through the FDA/Pharma pathway, almost all of our innovations in medical procedures have developed through physicians treating patients and outside of the RCT process. Without both, we would have none of the modern medical miracles we all take for granted.
Type 1 regulatory error occurs when we allow a harmful therapy to be widely used-FDA excels in preventing this type of error. Type 2 regulatory error occurs when a beneficial therapy is disallowed-this is mitigated through the Physician Innovation pathway. For example, FDA’s current process is hampered by a glacially slow adoption of new therapies in exchange for obtaining high quality data supporting safety and efficacy, while the physician pathway for innovation allows much quicker access to therapies but is hampered by lower quality data. The FDA approach uses regulatory assurances to expose patients to mass unconsented risk (i.e. patients don’t sign a consent to take the newest Cholesterol drug; they assume certain safety and efficacy parameters). On the other hand, medical procedures require an individual consented risk (ICR). No matter how you slice it, applying a mass manufacture public health model to an individually consented risk makes little sense. For example, patients are consented for significant medical procedure risks every day where it’s often impossible to fully quantify the risk or verify the likelihood of success-just as in an autologous stem cell procedure. So to answer your question, I see the need for both points of view and believe FDA has just lost focus in this instance. I believe when cells are mass manufactured and distributed they should be regulated as drugs because there is mass unconsented risk and that preventing type 2 error has a societal benefit. The flip side of that coin is that applying mass distribution principles to autologous cells magnifies type 1 error and ignores the ICR concept-which hampers innovation. Has FDA made a good decision when pursuing this case? As former FDA commissioner Dr. von Eschenbach recently said in the Wall Street Journal Op Ed, he believed that this case has “cast a pall over the future of regenerative medicine”.
If Regenerative Sciences wins the case, what do you believe will be the impact of the case more broadly for stem cell treatments in the U.S. and globally?
Centeno: This case will be appealed by both sides and likely end up in the Supreme Court (or not and be settled at the Appellate court level). Therefore its impact won’t be felt for several years. If FDA loses this case, it could lose in many ways and in many different areas. As one specific example, a federal judge could delete parts of 1271 as “ultra vires” (beyond the powers authorized by congress). In that case, I expect the FDA will issue a Compliance Policy Guide (CPG). The CPG must more clearly define what is the practice of medicine and what is the manufacture of a drug. If this future comes to pass, I suspect you’ll see physicians using autologous stem cells alongside any “stem cell drugs” being produced for mass distribution. In the short run this competition will lower prices for consumers and perhaps expand the number of doctors offering questionable therapies. In the long-term, the systems already in place to regulate physicians will respond and autologous stem cells will be regulated the same as the culture of human embryos for fertility treatments (5 day blastocyst procedure). There will be physician regulations through individual states with professional societies jumping in to provide guidelines and accreditation (like the College of American Pathologist’s IVF Accreditation program) as well as a civil court system to address malpractice claims. The physician side won’t be under regulated, as physicians are already regulated through a bevy of entities including medical boards, public health departments, Medicare, hospitals, specialty boards, and the civil court system.
Sipp: In the best-case scenario, it will be a complete disaster for the field. By eroding the ability of the government to exert control over stem cell marketing, a decision in favor of Regenerative Sciences would result in an accelelration of the race to the bottom mentality that already characterizes the industry. The United States has a well-deserved reputation for being at the forefront of biomedical research and science-based regulation, so what happens here will definitely ripple very quickly into other countries. The worst case scenario, I don’t even want to think about.
Do you have a prediction on the outcome of the case?
Sipp: I am not a lawyer and do not have insight into the current status of the proceedings, so I really couldn’t speculate. The company will no doubt try to turn even a loss into a win by claiming government oppression, if it turns out the court rules in favor of the FDA. Either way, watch for it to be used in marketing materials for years to come
Centeno: I don’t see how FDA can prevail. Congress and the courts have always told the agency that it has no regulatory authority over physicians.
In the United States, we have two very separate systems of medical regulation: federal and local. On the federal level, an example is the FDA, whosejobitistoregulatedrugsandmedicaldevicesthataresoldin interstate commerce. On the local level, examples include statemedicalboards as well as the local departments of health. Your doctor is not regulated by the federal government, but by the state in which he or she practices medicine. These separate regulatory systems have always been kept apart by a “Great Wall” that literally prevents physicians from being regulated by the federal government or FDA. An apt example is a physician’s right to use medicationsoff–label. While the FDA can approve a new drug to treat a certain disease, it cannot tell physicians how to prescribe that drug. Physicians are free to use the drug for any disease and in any dose, even if that dose is not the one that’s approved by the FDA. This separation of regulation acts as a system of checks and balances, much like the separation of the executive, judicial and congressional branches of government serves to keep power in check. Why is that important? The bottom line is that your physician is charged with doing whatever it takes to save your life — whether or not the federal government approves of it. The judge in US v. Evers put it best (United States v. Evers, 453 F. Supp. 1141 (M.D. Ala. 1978))- “A free, progressive society has an enormous stake in recognizing and protecting this right of the physician.”
Does this case in any way connect with the recent Texas Medical Board decision?
Centeno: I’m not sure. I have had no discussions with TMB. However, what happened in Texas in inevitable as the FDA doesn’t have the resources to monitor physicians and so state medical boards will have to jump in.
As an example, there are almost 1 MM US physicians. There is one FDA which is overburdened and underfunded. There are 50 state medical boards charged with overseeing physicians while FDA is strictly prohibited from having authority over physicians. Even if congress decided tomorrow to grant FDA regulatory authority over physicians, it would have to dramatically increase the size of the agency just to keep up. For example, FDA performs about 1,000 annual drug manufacture factory inspections and finds cGMP violations in 54% of these plants. To police physicians, it would need to increase that number 10x just to have a very poor surveillance program (inspecting about 1% of physicians per anum). In addition, the efficiency of these inspections would drop off a cliff. Right now FDA can safeguard the health of millions of patient drug doses by inspecting one large drug factory. If they were inspecting physician offices for autologous stem cell “manufacture”, that efficiency would drop to at best tens to hundreds of “doses” per year per inspection. So the numbers above would need to increase by at least 1,000X to monitor 1 million US physicians using stem cells at a similar level of surveillance as exists now. That overall 10,000X increase in FDA size would take it from about 12,000 employees to somewhere north of ten million, making it by far largest federal agency and much larger than the rest of the federal government. Therefore, the only place physicians using stem cells could be regulated is by the states which are already funded to police physicians.
Sipp: I don’t know of any direct connection between the main actors, other than various associations with a group calling itself the International Cellular Medicine Society, which was founded by Regenerative Sciences’ owner. Both cases do seem to represent sinister challenges to the authority of the FDA, while offering no alternative of equivalent legal, scientific and moral authority to replace it.
What is your view of where stem cell-based treatments are heading more globally? Are there countries of particular concern to you? How does the U.S. fit into that spectrum?
Sipp: Stem cell pseudomedicine has failed to show its safety and efficacy in any rigorous scientific tests of which I am aware, but it has clearly shown itself to be immensely profitable, which is why it continues to grow despite warnings by government, medical and scientific groups from around the world. The country I worry most about, hands down, is the US, because it will set the tone for the rest of the world, and also because it is seeing the most rapid expansion of the industry in recent years – growth that is fueled in large part by the efforts of profiteers to undermine the already under-funded system that is all that stands in the way of their ability to exploit even more patients for financial gain.
Centeno: I’m concerned by the proliferation of clinics who operate in a vacuum and offer treatments for every known disease. In fact, I support clinics who work through an IRB for novel or potentially risky therapies, track all patients in a formalized registry, and publish their data in the peer reviewed literature.
Over the past few years we’ve seen a few ex-US clinics move towards these standards and I’m confident that this will have a domino effect so that more clinics follow these guidelines. This doesn’t mean that the clinics offering silly therapies are going to go completely away, just like alternative health clinics offering dubious alternative therapies to cancer patients aren’t going to cease. However, as more high quality physician directed care is offered, the sites offering cells for every known condition will reduce in number.
Any country that allows the use of stem cells outside of the “IRB/ registry/publication” framework I discussed is a concern. I don’t approve of clinics offering therapies with little prima facie evidence of efficacy.
Over the past year or so, the US has arguably become the world’s biggest purveyor of stem cell treatments. If one includes the use of stem cells isolated from bone marrow to promote spinal fusion, there are literally thousands of applications of stem cells every day that have no level 1 evidence of efficacy. These 510k cleared bedside “stem cell concentrator” systems are being used with at best level 2-3 evidence or anecdotal experience that stem cells may help reduce the likelihood of a bony non-union. On the more concerning side, the US has seen a recent explosion of clinics offering mostly IV adipose Stromal Vascular Fraction based therapies for every known disease (from Alzheimer’s to ALS to anti-aging/cosmetic use). The FDA’s efforts (they have now classified SVF as a biologic drug) have had little impact on this phenomenon, as there are simply too many physicians.
I don’t support this explosion of clinics that operate outside of the framework I’ve described. I think we’ll eventually see more Texas type interventions from state medical boards to curb these clinics and apply standards.
(Question just for Centeno) As a party directly involved can you give us a concise history of how the case developed?
Centeno: In 2005 we ported an established equine model of cultured MSC use to orthopedic patients. At that time, we received a consensus of three legal opinions that culturing cells for our own patient’s use was the practice of medicine. We received IRB approval and treated a small number of patients initially (knee, hip, low back OA) using imaging guided joint injections and research grade MRI. We also followed these patients in a registry and no patient paid for care. Our goal wasn’t to perform an RCT, but to get a sense as clinicians what worked and didn’t work. By the end of 2007, we began treating our usual patients with cells. All of this data has been published or is still in submission for publication.
In early 2008 we received an “Untitled Letter” from FDA questioning whether we were producing a biologic drug. We responded to the letter, but the agency refused to meet to discuss why they took this position. In 2009 they arrived at our clinic and issued 482/483 forms (notices of a drug factory inspection). Since FDA maintained that we were a drug factory, deficient in many ways as any physician office, hospital, or O.R. would be, and this made no common sense to us, we sued in Denver District court. The court eventually ruled that since an “Untitled Letter” wasn’t final agency action, the court couldn’t review our case.
The FDA inspected our clinic as a drug factory again in 2010. At this time, we filed for simultaneous TRO’s in Denver and DC Federal courts-the goal being to force the agency to take an action. The DC docket moved faster and we presented oral arguments to Judge Collier. Before the judge could rule, the FDA filed for an injunction to prevent us from culturing cells. As part of a stipulation between the parties, we rolled all suits and countersuits into one case, stopped culturing MSCs at our Colorado facility until the case was resolved, and continued our same day isolation procedures which were 21 CFR 1271.15(b) compliant.
Both sides hired experts. FDA’s experts stated we were producing a drug while our experts disagreed and confirmed that the standards we were following for autologous cell culture exceeded those used for medical grade IVF cell culture (expert 1 andexpert 2). An interesting exchange that explains some of the basic issues in the case is illustrated in Dr. Freeman’s response to one FDA’s expert’s criticisms of our research.
In August of 2011, the judge issued a “Show Cause” order. In her order, she brought forth new issues. The judge asked the FDA to show how congress authorized the agency to classify a cell as a drug and how a cell had “chemical action”. Both parties have responded and the judge has yet to rule on her order. In the meantime, many legal watchers have chimed in with their opinions/predictions: