Defying the FDA, Doctors in Colorado Offer Stem Cell Therapies for Joint Diseases

March 17, 2010 11:25 AM

The FDA has yet to approve stem cell therapies for general use in medicine, but that hasn’t stopped doctors in Colorado from providing them anyway.

Background
In 2007, Colorado-based Regenerative Sciences Inc., (RSI) began offering "Regenexx", to the public: an adult stem cell transplant that uses injected autologous mesenchymal stem cells to treat joint injuries and bone damage, as an alternative to traditional surgical techniques. Since then, they claim to have treated 348+ patients with 800+ injections and are reporting high success rates: 89% of their knee patients and 75% of their hip patients showed marked improvement. (Scroll to: "What is the success rate? How many people respond? What is the cure rate?")

Drug, or Surgical Procedure?
In 2008, the FDA sent RSI an untitled warning letter, which said the company could not use mesenchymal stem cells as an injectible on humans without a biologics license (BLA) or an investigational new drug application (IND). (See: "Will the FDA kill adult stem cell medicine?") More here (followup in first graph of this post) and here. The company responded, claiming Regenexx is a surgical procedure, (even though the cells are lab-cultured and used to treat disease conditions,) and thus not subject to FDA regulation. A response from the FDA is still pending.

posted by zarq (50 comments total)

I am personally not sure of what (if any) increased cancer risk might be associated with injected stem cells, but it’s worth noting that concerns have been raised in other procedures.
posted by zarq at 11:26 AM on March 17, 2010

Also....

I kept this out of the main post out of Pepsi Blue concerns. The company has extensive marketing online: Case Studies, promotional YouTube Videos and Journal Articles.
posted by zarq at 11:30 AM on March 17, 2010

The company responded, claiming Regenexx is a surgical procedure

The Regenexx™ Procedure is a breakthrough, non-surgical treatment option

Something is not right here!
posted by East Manitoba Regional Junior Kabaddi Champion '94 at 12:11 PM on March 17, 2010 [3 favorites]

Actually... I'm wrong When I put this FPP together, I came across this lengthy article from Men's Health on stem cell research and its potential applications to heart disease. I didn't read it thoroughly, or include it in the post because I thought it was only about heart therapies. Now that I'm reading it, it turns out the author did include some relevant info on page 6 about RSI and the FDA which I had missed:

The FDA is making the same argument against Regenerative Sciences, a for-profit stem-cell company (in the relatively low-risk arena of joint and disc repair) that treats its patients within U.S. borders. When in July 2008 the FDA informed the Denver-based clinic that it couldn't promote its stem-cell treatment like a drug treatment, Regenerative responded by filing a suit saying that what it was doing was out of the agency's jurisdiction. The case is now in early pretrial proceedings in U.S. District Court in Colorado.

Should be interesting to see how this pans out.
posted by zarq at 12:22 PM on March 17, 2010

So... anyone taking bets on cancer risks? I mean it seems like growing cells in a culture and then manually trying to get them to differentiate in to the cells you want could cause a lot of mutations along the way, although I don't really know. Is that an actual risk?

--

Anyway, these guys are using your own stem cells, so it's not like they're taking foreign substances and putting them in your body. So I'm not all that clear on why the procedure shouldn't be allowed, as long as people understand that it's experimental... although I don't know that that's necessarily the case.

Anyway, if the FDA really gets on his case, he can always just hop down to Mexico. Which makes me wonder what other countries are doing with stem cells today.

(Also, these are adult stem cells, which haven't been targeted by fundies)
posted by delmoi at 12:24 PM on March 17, 2010

During my conversation with Dr. Centeno, he pointed out that doctors and surgeons are developing new procedures all the time. Surgeons will often create new devices for their own use in surgery, doctors routinely try out new dosing regimes, or therapies on their patients. This is part of the medical profession.

Oh, Dr. Superman, you're so cute. You have a web page where you are *advertising* this new procedure as having benefits. Problem is, you have not tested these benefits. You have not published results in a peer-reviewed journal of these benefits*. Your site is not accredited by the widely-recognized accreditors for this kind of therapy. I can't imagine that insurance is paying for this, it's likely all out-of-pocket for the recipients.

I think he's just dumb and he doesn't understand the difference between and IND and an NDA (former is for research, latter is for marketing post-research). Sure, this qualifies as medicine, but this is research. He's colelcting data on the people that he injects, and he will likely use that data to prove benefits of the procedure to future patients. He's just not getting funded for it. He's not being held accountable by anyone for this research. I would bet that there's no IRB approval or informed consent form, either.

*I found one abstract in PubMed that he published regarding some safety surveillance on these patients, but no measurement of benefit. (They followed 227 patient for a year after therapy and saw only 1 instance of cancer that they claim was not related to therapy. However, only 45 of those 227 patients were followed with MRIs.)
posted by sarahnade at 12:47 PM on March 17, 2010 [2 favorites]

Oh, Dr. Superman, you're so cute.

It's pronounced "spa-CHEH-man".
posted by explosion at 12:54 PM on March 17, 2010 [7 favorites]

I'm actually about to go thaw out some of these mesenchymal stem cells (MSCs) in my lab for some experiments. My PhD research involves how their behavior (mostly mechanical behavior) is altered during that in vitro period where they are grown up from sparse cells from the bone marrow to a therapeutically relevant quantity in preparation for reimplantation. The experiments involve aiming dual lasers at suspended MSCs to deform them with photonic pressure alone.
posted by Mapes at 12:57 PM on March 17, 2010 [2 favorites]

Sarahnade, thanks very much for explaining, and for mentioning the article and flaws in their tracking/reporting. (Abstract is here if anyone else wants to see it.)

The FAQ says the therapies are not covered by insurance. Cost range: between $7,000 and $8,500.

It took me three hours to compile this FPP -- far more than usual. I spent a lot of that time looking for objective information about the procedures and couldn't find much. I found interesting conversations on kneeguru and fluther, but little else. As far as I could see, there have been no rigorous clinical trials and as you mention, no review oversight. But unless I missed something, they're not being marketed as experimental.
posted by zarq at 1:20 PM on March 17, 2010

delmoi, They are growing these cells in culture. They need to be tested for sterility, integrity, and dose/concentration prior to injection. (it's what Mapes said: they could change in culture.) They need to prove this for safety reasons (nobody wants bacteria or fungus injected directly into their joints, nobody wants an auto-immune disorder or cancer because they injected too many stem cells, or the wrong kind). All stem cell products are tested for infectious diseases prior to infusion. Or at least, the ones at accredited institutions are.

This is experimental because the cells have not been tested in humans for this indication, and because they haven't proven in a systematic way that they are able to grow cells in culture safely and inject them safely into humans. They haven't proven that this treatment is any better than other treatments in a controlled comparative trial. The benefits they do tout are suspect, because they have not been tested in such a trial. The FDA will want to see SOPs for collection and incubation and injection of the cells, and that those SOPs are being followed. And honestly, if I were a patient, I would want to know that the FDA is overseeing the study, because their job is to protect patients.

Searching on clinicaltrials.gov, there are at least 5 other studies being done using mesenchymal stem cells for orthopedic/cartilage problems; they take place in Egypt, Israel, Norway, and Korea.

Reading the blog, he states they have been approved by an accreditation board, ICMS. Funny, guess who's on that board? If you look into it, they also have an Institutional Review Board (!) and a template informed consent form which clearly states that stem cell use is an "investigational procedure" AND the patients have to pay $350 to be on the data registry to share data.

I need to leave this thread now because I can feel the GRAR growing inside me against this guy. Not that I don't think that stem cells hold many possibilities and could be a great treatment. It's just, like, why go through all the trouble of figuring out how to grow the cells in culture and injecting patients and following them and collecting data but NOT have it be in a standard, well-controlled clinical trial that you can publish in a well-respected peer reviewed journal? He's been doing this for 3 years and only published one paper on safety? Something's not right here.
posted by sarahnade at 1:35 PM on March 17, 2010 [3 favorites]

The experiments involve aiming dual lasers at suspended MSCs to deform them with photonic pressure alone... in bed.
posted by It's Raining Florence Henderson at 1:39 PM on March 17, 2010 [1 favorite]

I notice they don't have any comparison data, they only breathlessly state patient reports of satisfaction and pain reduction. No way to tell how this differs from other surgery, other medical treatment, or placebo. It's despicable that medical products companies want to promote their products without actually investing in proving their worth.
posted by Mental Wimp at 2:01 PM on March 17, 2010

So... anyone taking bets on cancer risks? I mean it seems like growing cells in a culture and then manually trying to get them to differentiate in to the cells you want could cause a lot of mutations along the way, although I don't really know. Is that an actual risk?

Several cancers result from mutations in stem cells in your body. Barrett's esophagus results from epithelial stem cells in your esophagus mutating and taking on the appearance of intestinal tissue, which carries a higher risk of esophageal cancer. Leukemias are cancers of precursor cells in your bone marrow. Normal precursor cells otherwise make blood and immune system cells. So putting stem cells in your body will likely carry several serious risks with it, including consequences from rejection by your immune system and cancer.
posted by Blazecock Pileon at 2:07 PM on March 17, 2010

Blazecock,

Your immune system might reject stem cells?

Why? Shouldn't they have all the right receptors for self-recognition?
posted by effugas at 3:04 AM on March 18, 2010

Your immune system might reject stem cells?

Unless those stem cells come from somewhere else in your own body, or from someone genetically identical, like an identical twin, you're probably likely to run into complications from your immune system rejecting the implanted cells, or vice versa.
posted by Blazecock Pileon at 4:31 AM on March 18, 2010

Blazecock,

They're re-injecting the patient's own stem cells, after cultivating them through a month's worth of generations. They're not sticking in someone else's tissue or anything.

That's why they can claim this is a surgical procedure. Time lapse not withstanding, it's like migrating bone from the hip to the spine.
posted by effugas at 6:12 AM on March 19, 2010

They're re-injecting the patient's own stem cells, after cultivating them through a month's worth of generations

I missed that part of it. Mea culpa.
posted by Blazecock Pileon at 12:23 PM on March 19, 2010

In other stem cell news: A 10-year-old British boy has become the first child to undergo a windpipe transplant with an organ crafted from his own stem cells.
posted by homunculus at 6:01 PM on March 19, 2010

Hello all, this is the "Dr. Centeno" that has sparked so much spirited discussion on this board. Let me clarify a few things, as there are lots of inaccuracies cropping up here:
1. We spent two years going through an HHS registered IRB on this procedure. During that time, other doctors, healthcare professionals, and community members looked at safety issues.
2. The FDA never sent us a warning letter, but an "untitled letter". The difference is that the agency sends untitled letters when they are unsure of their regulatory authority. Such letters have no weight. I would encourage you to Google "untitled letter", as it has a very specific connotation that's quite different from a "Warning Letter". The whole "Warning Letter" thing was cooked up by a big pharma blogger who seems to be very threatened by what we're doing.
3. We do extensive testing on the cells and follow the lab and clinical guidelines posted here: http://www.cellmedicinesociety.org/component/content/category/48?layout=blog. These tests include those performed at the University of Colorado genetics lab for clonal analysis with strict release criteria on the cells. This also includes periodic flow cytometry to ensure that we are in fact producing cells with markers c/w MSC's as well as safety checks on infectious cross contamination (remember, these are autologous cells).
4. Our lab is audited by Reglera, an independent 3rd party best practices organization (not affiliated with us), see http://www.reglera.com/biomed/fs_biomed.asp.
5. Each patient pays a $350 fee to ICMS so that this 501c3 non-profit will track outcomes and complications. While our clinic was instrumental in helping set up ICMS, it now counts more than 200 members from the US and abroad and has a life of its own. It's third party non-profit complications registry should have about 500 patients per month being entered (the minority from our clinic) by year's end. We will have our 2nd ICMS conference in November if anyone wants to attend (see www.cellmedicinesociety.org). The guidelines I reference are now controlled by committees within ICMS that made up of physicians and researchers.
6. While I know many of you are only comfortable with FDA's process, it is demonstrably not perfect. As an example, many, many drugs have gone to market that had to be pulled for serious safety issues. While I'm personally FDA agnostic (I can also see its successes and that it has many hard working scientists doing their best), the practice of medicine has never been regulated by FDA as there is simply no public health risk to warrant such federal regulation. As an example, an infection acquired in your local hospital or a medical mistake is not a federal public health issue. Neither is the processing of autologous cells. The best analog would be the 3-5 day blastocyst IVF procedure used by my OB/GYN colleagues for fertility treatments. This is not FDA regulated, but involves up to a 100X culture expansion of embryonic stem cells (in this case called a blastocyst). These labs are regulated via the practice of medicine by professional societies (two major ones) and accredited through the College of American Pathologist's CAP program.
7. This is all autologous work, right down to the growth media (autologous platelet lysate). This work is allogeneic, doesn't involve embryonic cells, another person's adult stem cells, cord cells, or IPS cells.
8. We just published the world's biggest complications tracking papers for human stem cell work at http://www.ncbi.nlm.nih.gov/pubmed/19951252 (n=227). We are not aware of a bigger dataset of stem cell therapy complications anywhere (this includes FDA trials for BLA's for stem cells that will be sold in interstate commerce (a federal public health issue). We will publish larger hip/knee and other area datasets this year and publish an n=approx 450 dataset as well.
9. While you may not know this, about half of what your doctor does on a day to day basis has no level I evidence support. If you've even had low back surgery, knee surgery, ankle surgery, or known someone that has, none of these have level I evidence support (or anything approaching it). This long list includes (to name a few): spinal laminectomy, knee arthroscopy, knee micro fracture, arthroscopic ankle ligament repair, lumbar fusion.
In summary, we never set out to circumvent anybody's regulations. We are practicing medicine the way your doctor practices medicine. While you may not have thought about it, you don't want your doctor's medical practice to be regulated by the FDA. As a concrete example, if you're suffering from a serious disease in the ICU and your doctor knows of several studies that show that drug X plus drug Y may help, you don't want your doctor applying for a 10 year IND to try and save your life. Your doctor has the ability to call down to the hospital pharmacy and have them compound these drugs this way (whether or not they have ever been conceived as part of an IND) or whether or not one or more of them has ever been FDA approved. The triple safety checks on this are at the hospital level (local), at the state medical board level, and at the malpractice level.
Happy to answer any other questions you may have. However, let's keep it professional.
Chris Centeno, M.D.
posted by Dr. Centeno at 8:41 AM on March 22, 2010 [5 favorites]

Typo above, under #7 meant to say "not" allogeneic...
posted by Dr. Centeno at 9:01 AM on March 22, 2010

9. While you may not know this, about half of what your doctor does on a day to day basis has no level I evidence support. If you've even had low back surgery, knee surgery, ankle surgery, or known someone that has, none of these have level I evidence support (or anything approaching it). This long list includes (to name a few): spinal laminectomy, knee arthroscopy, knee micro fracture, arthroscopic ankle ligament repair, lumbar fusion.

This. As a health researcher, I am keenly aware of this. This is a huge problem with medical care today. It wastes money, diverts research from useful tracks, and harms people. In large numbers. Daily. Using the existence of this practice as an excuse to make some money while you can is unconscionable.
posted by Mental Wimp at 11:43 AM on March 22, 2010 [2 favorites]

Again, let's keep it professional. Will reply after patient care...
posted by Dr. Centeno at 1:03 PM on March 22, 2010

This will likely be a multi-part answer as I'm still seeing patients and fitting this in-between patient care responsibilities.

I think the kind of pathway directed or guideline directed care you're discussing (i.e. only allowing physicians to use care that has level I evidence) will never work in the real world and is again highlighted above in the scenario discussed (ICU). While from an academic standpoint this seems to make allot of sense, like many purely academic points of view, it sometimes doesn't hold water in pragmatic terms. Some examples:
1. From the ICU scenario above, is it best for the physician who has no level I evidence available to A. let the patient perish because level 1 evidence isn't available B. use best available evidence
2. Since only about 1/2 of medical care (some estimates as low as 30% to as high as 80%, depending on specialty and types of care being discussed-office based vs. hospital, clinic vs. university setting) has level 1 evidence support, should physicians: A. drop all medical decisions except for level 1 evidence B. use best evidence available
3. In developing new therapies, should a physician: A. only be limited to those therapies that have a strong enough business model to pay for the 100 million or so that an FDA trial would run B. use observation of patient response to available therapies to determine which might work best and then test those hypotheses with more rigorous research C. none of the above and stay paralyzed by the need to have level 1 research backing every decision
Listen, not a day goes by in clinical practice where you see patients that don't fit neatly into a level 1 decision protocol. Should you pat these patients on the head and say "get lost, you don't fit the decision matrix"? What if you were one of these patients? Striving for level 1 evidence is generally a good thing, but on the flip side it also pushes us toward heavy handed, side effect heavy medical care solutions that may be the best business plan (to support the cost of the trials), but not the best medicine. This is an age old town vs. gown discussion, so I think we'll have to agree to disagree. However, FDA's track record of dangerous drug approvals reads like a top 40 chart, so we'll have to agree that the current EBM paradigm needs some work. Also please note the clinical guidelines posted at www.cellmedicinesociety.org, as they an attempt at balancing safety with access and efficacy, written by doctors seeing patients.
.
posted by Dr. Centeno at 2:09 PM on March 22, 2010

Dr. Centano, it's nice to meet you. Thank you for joining Metafilter and responding.

It's probably going to take me a day or two to respond to your points, but as the person who constructed this post I'm responsible for the accuracy of its content (not comments made by other users of course, just the initial post itself,) so I should clarify something immediately: You are correct that your company received an "untitled" letter and not a warning letter. I mislabeled it as an "untitled warning letter" above. They are two separate entities. What's more, I shouldn't have made that mistake. I actually do know the difference between them. Over the years I've had different clients who received warning or untitled letters from the FDA. My apologies.

2. The FDA never sent us a warning letter, but an "untitled letter". The difference is that the agency sends untitled letters when they are unsure of their regulatory authority. Such letters have no weight.

Respectfully, I do not believe this is entirely accurate.

The FDA sends both untitled letters and warning letters for the same purpose: to cite regulatory violations. Both types of letters present evidence, then request a written response (typically within 30 days,) from the addressee explaining how the violation has been corrected. The difference between an untitled letter and a warning letter is the degree of perceived violation, not that the FDA is unsure of their regulatory authority.

An Untitled Letter is an initial correspondence with regulated industry that cites violations that do not meet the threshold of regulatory significance for a Warning Letter. Examples when CBER has issued an Untitled Letter include after its review of a manufacturer's advertising and promotional labeling, after an inspection under CBER's bioresearch monitoring program or by Team Biologics, and as a result of internet website surveillance.

I do realize that your disagreement with the FDA hinged to a large extent on whether or not they had the authority to regulate your use of autologous stem cells in Regenexx treatments. However, untitled letters are often used to address advertising and promotional labeling violations for drugs / biologics that the FDA has already approved for specified use(s). I believe that fits your situation, no?
posted by zarq at 4:57 PM on March 22, 2010

Zarq,

Nice to meet you as well. I appreciate the professional discussion. The way I discussed it above is how it was explained to me, but maybe this sheds more light on the topic, see:
http://druganddevicelaw.blogspot.com/2007/08/untitled-as-in-untitled-letters.html and particular this quote:
"But courts should be sensitive to two things: (1) the regulatory insignificance of "Untitled Letters," and (2) the undue weight a lay jury might accord an untitled letter if it were admitted into evidence.
"Untitled Letters" should almost never be admitted into evidence. If relevant to any issue at all, their prejudicial effect surely outweigh their probative value."
At the end of the day, there's a very simple and critical piece here that's easy to miss. The FDCA applies only to food, products, drugs, devices sold in interstate commerce. We practice medicine here in Colorado and do not advertise, sell, or otherwise promote stem cells for order to be sold between the states. This is a very important distinction. As an example, your doctor (as stated above) can call a compounding pharmacy and get compound X (never FDA approved) sent over on prescription. That's the practice of medicine and pharmacy. There are reasons (as stated above), we want it that way. The FDA has challenged this and lost at the supreme court level, resulting in the following CPG: http://www.pharmwatch.org/comp/cpg.shtml. Your local restaurant, hospital, barber, and doctor are all regulated at the state/local level and not the federal level. The public health risk of these one on one risk scenarios do not warrant federal regulation (nor has congress authorized it). However, if the restaurant starts selling a secret sauce to all 50 states, your barber sells a hair crème to all 50 states, or your doctor sells stem cells in a vial to all 50 states, these are federal public health issues as one bad batch of any of these can make hundreds of thousands to millions of people ill in potentially all 50 states.

Chris Centeno, M.D.
posted by Dr. Centeno at 6:43 AM on March 23, 2010

Listen, not a day goes by in clinical practice where you see patients that don't fit neatly into a level 1 decision protocol. Should you pat these patients on the head and say "get lost, you don't fit the decision matrix"? What if you were one of these patients?

Please note that I and my family, as well as everyone on this blog, are these patients. And, yes, often therapies are prescribed to a patient in lieu of a pat on the head, when the physician knows they are equivalent. And, yes, you can concoct emergent conditions where a physician needs to just use her best judgment regarding treatment in the face of inadequate information about therapeutic efficacy. There is no other choice.

But to use these as an excuse to begin using unproven, costly therapies in non-emergent situations is intellectually dishonest. The appeal to "business models" is laughably misdirected. I'm at the American Society for Preventive Oncology today, and I just heard a talk regarding OncoType Dx, a genetic test purportedly to determine recurrence risk that has caught on with oncologists and pathologists with zero evidence of its efficacy at changing recurrence probability, mortality, or quality of life for the population. Yet it is widely, and in some places universally, used for the class of node-negative, ER-positive breast cancer cases and it costs $3600/pop per the presenter. Somebody's business model is making $100Ms without going through the the "trouble" of a carefully done study of the intervention's impact on health. Why is that? Why hasn't your therapy gone through such testing before being adopted? How can you be so confident of its value when the history of medical practice is littered with such confidently applied therapies that when tested turned out to be harmful? The burden is on you to justify not testing it, not for the rest of us to justify testing it.
posted by Mental Wimp at 7:35 AM on March 23, 2010 [1 favorite]

Again, let's keep it professional, if you can't post without losing it or resorting to name calling, don't post. Let's break these arguments down.
1. Untested-We spent two years looking at pre/post MRI's to ensure that this procedure met our guidelines as being effective or at least a better alternative to traditional surgery (which by the way has no level 1 evidence support). We have published and will continue to do so. You bring up a chicken or the egg scenario that while sounding intellectually attractive doesn't work in the real world. Let's say in your world, doctors must prove level 1 evidence before they can use a certain type of care and that this is codified into every state practice act for all healthcare professionals. In this world, medical innovation comes to a screeching halt. While this would be a financial boon to CRO's, universities, and big pharma, it would not serve the public interest. In this world, the funding to test the efficacy of virtually all surgical or non-medication based procedures, would never exist or would take decades to procure from government. In the meantime, 50% of routine medical care would stop while the decades and trillions in funding needed to rigorously test every part of medical care was carried out. The surgeon who wants to try something new to enhance his surgery would be unable to do so. Medicine would go from multiple small speed boats testing new hypotheses to a huge aircraft carrier that could only change course by committee. Again, the public interest wouldn't be served.
2. Funding-You and others have brought up this concept of an issue with wasting money. When the funding is public (i.e. we all pay for it whether through private for government insurance), I agree that high levels of evidence should exist. However, this procedure is paid for by the patient. When it comes to patient choice to spend their dollars on elective healthcare, I disagree. To use a car analogy, some people like Toyotas and some decide to spend the extra money on a Lexus. This is a personal choice issue. There are consumer reports that tell us that the Lexus may not be worth the extra money, but if the guy down the street wants to buy a Lexus, more power to him. If we apply this model to healthcare, IVF is a good example. The conception rate with IVF for women 40 or older is dismal (40%?). IVF is largely not covered by insurance and in women over 40, for the public as a whole, that's likely a good thing. Until recently, we didn't know the long-term risks of IVF. However, if a woman wants IVF (as opposed to adoption), who am I (or you, or anyone) to tell her she can't try? Are the fertility specialists selling false hope because some of these over 40 women will never get pregnant despite spending tens of thousands? No, these women are informed of the risks/benefits. They are informed that while only 40% of them may get pregnant, this number doesn't apply to them as an individual (i.e. they may have problems that make it impossible to get pregnant). We inform our patients in the same way. They sign a form that says this procedure is experimental and as such there is a strict requirement that they enter into a long-term, non-profit, tracking registry. They know what data exists at that point in time or doesn't exist. Should I have the right to chose Lasik surgery? Chiropractic? Acupuncture? Nutritional supplements? Where does this line get drawn and who exactly draws this line? Universities? healthcare practitioners? Governments?
posted by Dr. Centeno at 8:53 AM on March 23, 2010

Missed the harm issue, as above, see http://www.ncbi.nlm.nih.gov/pubmed/19951252

If we apply the standard surgical care to this same cohort, we would have seen much more significant and serious complications. For example, a recent retrospective study of more than 17,000 total knee arthroplasties (TKA) demonstrated that serious surgical complications were between 7.7%-10% (primary vs. revision; p=0.007). 90 day complication rates for death were 0.3% and 0.6% (p=0.1) and for pulmonary embolism 0.5% and 0.4% (p=0.6). 90 day re-admission rates for primary and revision TKA including infection were 0.5% and 4.2% (p<0.001).[1] Applying these surgical complication rates to our published knee knee procedures to date would yield the following complications:
1. 17-23 patients with serious surgical complications
2. Approximately 1 patient mortality as a result of the surgery
3. Approximately 1-2 patients with pulmonary emboli
4. Approximately 2-9 patients with a hospital readmission for serious infection (IV antibiotics)
1. Khatod, M., et al., Knee replacement: epidemiology, outcomes, and trends in Southern California: 17,080 replacements from 1995 through 2004. Acta Orthop, 2008. 79(6): p. 812-9.
posted by Dr. Centeno at 10:20 AM on March 23, 2010

...resorting to name calling...

If I actually call you a name, feel free to call me out on it. Until that time, please refrain from accusing me of beating my wife.

All I ask is that you do a randomized study to find out if you're having a positive impact. It's so easy to fool the public with medical procedures, because outcomes are so variable that they obscure the counterfactual outcomes, so your car analogy does not fit. I'm not asking that you prove the value of standard surgery (which, as you point out, is questionable, but let's not go there). If you're popping in (and getting paid for) X procedures, randomize X/2 to standard surgery and rest to the cellular therapy. It doesn't seem like that would cost a whole lot. Hell, I'm a statistician, I'll create the randomization list for you, all you have to do is follow it. Sample size an issue? Go here to find out how big a study you'd need to do. And then for everyone's sake, do the study.
posted by Mental Wimp at 10:37 AM on March 23, 2010 [1 favorite]

As I said, we'll keep publishing. Our "grand design" will be to meet your expectations and exceed those with a national tracking registry controlled by a non-profit (see www.cellmedicinesociety.org). However, let's look at some patients in the real world. Saw a 45 ish male this am who has a large hole in the cartilage in the knee (OCD). He has tried and failed all surgical approaches, so he's been told that the next step is a knee replacement. At 45 years old and being an ex-tri-athlete, he's not too excited about having someone saw out his knee. He can no longer climb stairs without pain, compared to two years ago when he ran and completed the Death Valley Marathon. He's put on 50 pounds because he can't run. He is also concerned that he would need several knee replacements in his lifetime. These are 60-90 minute first surgeries and 4 hour second and subsequent surgeries (read markedly increased patient risk for complications on later surgeries). He's too young for a knee replacement, so the doctors he has seen have told him to "live with it". We have 3.0 T MRI evidence that our procedure can help to fill in these holes. We lack large scale generalizability data, but will publish some of that this year (n= approx 100, 1 year follow-up). Should this patient have the right to pay out of his own pocket to get a procedure that is far safer than the surgical alternative? He's intelligent, has studied the risks, we have discussed with him that we don't have all of the data yet.
posted by Dr. Centeno at 10:54 AM on March 23, 2010

I missed the wife beating comment, LOL...
posted by Dr. Centeno at 10:55 AM on March 23, 2010 [1 favorite]

Hey Chris, welcome to MetaFilter, hope you enjoy it here. As you can see, some of the members here disagree with you. If you keep punctuating every comment with exhortations that others should not comment "without losing it or resorting to name calling," when in fact no such name-calling has taken place, and certainly no one has "lost it," people are going to see it as (a) an attempt by you to distract from real disagreement and the real issues that underlie the same and (b) a willingness to imply that things have happened when they haven't. I think the latter especially would be counterproductive to an effort to gain trust by discussing your methods here.

If you want to discuss other users' behavior there is a a thread in the MetaTalk area of the site where it is appropriate to do that.
posted by grouse at 8:04 AM on March 28, 2010 [6 favorites]

FWIW -- I found the similar discussions to which the MetaTalk post links to be interesting and informative:

Anyone have objective data on the effectiveness of the Regenexx stem cell procedure?

Does anyone know anything about the newly patented injections of Regenexx?

posted by ericb at 8:17 AM on March 28, 2010 [1 favorite]

Reading the blog, he states they have been approved by an accreditation board, ICMS. Funny, guess who's on that board?

The 'ICMS Board of Directors' webpage comes up blank for me.
posted by ericb at 8:39 AM on March 28, 2010

The 'ICMS Board of Directors' webpage comes up blank for me.

Weird, it works for me:

The ICMS Board of Directors are:

Christopher J. Centeno, M.D. - Medical Director
George A. Leimbach, M.D.
John Schultz, M.D.
Michael D. Freeman, Ph.D., M.P.H., D.C. - Board President
Sean S. Kohles, PhD
Steven A. Shapiro, Esq.

David B. Audley (Ex Officio) - Executive Director, ICMS

Also note the members of the ICMS Institutional Review Board:

Christopher J. Centeno, M.D.
George Leimbach, M.D.
Mark Reilly, M.S., P.T.
Mary Cirillo, R.H.I.T., L.P.N.
Michael Freeman, Ph.D., M.P.H., D.C.
Millicent Purdy
Robert Schalks
Steve Shapiro, Esq.
John Schultz
Evan Katz
Chris West
Gary Ghiselli, MD
Sean Kohles, PhD
David Harshfleid, MD
C. Turner, MD
Henry Young, MD
Richard Gracer
David Audley (Ex Officio)

Note that Centeno, Schultz, and Reilly are all listed as staff of the Centeno-Schultz clinic.
posted by grouse at 8:48 AM on March 28, 2010

I read some of those links ericb posted, and one of them linked to this paper, which discussed the procedure in one patient (Centeno et al., 2008).

I'm not sure if this is publicly available (I'm on a university network), but I quote a piece from the conclusion.

"Although no conclusion can be made from one case report, if similar findings are published from pilot studies and then larger well-designed trials, the results may have implications for interventional pain management."

Comparing this conclusion to a statement on their site "The Regenexx Stem Cell Expansion Procedure has been studied extensively for several years and continues to prove to be safe and reliable."

There is a big difference between the two claims.
posted by a womble is an active kind of sloth at 10:18 AM on March 28, 2010 [1 favorite]

This is why, after my recent accident, I drink a whole cup of stem cells every night.
posted by klangklangston at 10:21 AM on March 28, 2010 [4 favorites]

The ICMS Board of Directors, Freeman, is a co-author on all of the papers on the Regenexx site.

I don't understand how these things work, I suppose. Seems like Regenexx has a very strong presence in the ICMS, which makes sense at one level, but might also raise questions about how impartial they are.

"The International Cellular Medicine Society is an independent nonprofit organization dedicated to the advancement of safe and effective adult stem cell therapies through research, education and oversight"
posted by a womble is an active kind of sloth at 10:33 AM on March 28, 2010

Final observation:

"Regenexx has Cell Lines and Lab Certified by International Credentialing Body". This article states "we had no part in the analysis or decision of ICMS to certify our clinic". That may be true, but the people who develop Regenexx, sit on the ICMS board.

I realize this information is all public, but maybe a statement like this should have some disclaimers about Regenexx doctors being board members of this credentialing body.
posted by a womble is an active kind of sloth at 11:01 AM on March 28, 2010

The ICMS Board of Directors are:

Christopher J. Centeno, M.D. - Medical Director
George A. Leimbach, M.D.
John Schultz, M.D.
Michael D. Freeman, Ph.D., M.P.H., D.C. - Board President
Sean S. Kohles, PhD
Steven A. Shapiro, Esq....

Well, done, sir. Well done.
posted by Mental Wimp at 11:01 AM on March 28, 2010

The president of ICMS is a chiropractor?
posted by grouse at 11:20 AM on March 28, 2010

The FDA has reviewed the summary of the clinical data from the pivotal trial that formed the
base for the European marketing authorization for ChondroCelect which was approved in
Europe in October 2009 as the first and still only product approved under the new Advanced
Therapy Medicinal Product (ATMP) regulation.
posted by Akeem at 12:38 PM on March 28, 2010

Dr. Centeno, I would be interested in seeing the HHS IRB approval. When did you apply and what date was it approved? Do you have documentation of it available online?
posted by stoneweaver at 2:52 PM on March 28, 2010

Dr. Centeno said this about ICMS:

5. Each patient pays a $350 fee to ICMS so that this 501c3 non-profit will track outcomes and complications. While our clinic was instrumental in helping set up ICMS, it now counts more than 200 members from the US and abroad and has a life of its own. It's third party non-profit complications registry should have about 500 patients per month being entered (the minority from our clinic) by year's end. We will have our 2nd ICMS conference in November if anyone wants to attend (see www.cellmedicinesociety.org). The guidelines I reference are now controlled by committees within ICMS that made up of physicians and researchers.

So he acknowledges, at least here on MetaFilter, that there is a connection. In light of that fact, all this analysis of the board of directors and stuff seems a little overzealous.
Are they less open about the connection off MetaFilter? If so, the finger pointing makes more sense..
posted by Chuckles at 3:05 PM on March 28, 2010

I agree with Chuckles on this issue. While relevant, the board membership connection was mentioned by Dr. Centeno, so I don't think its a smoking gun issue.

MentalWimp, I agree with your argument about the need to provide valid statistical evidence to back up the use of medical procedures. But I have little to no knowledge of statistics. Keeping my lack of knowledge in mind, could you explain to me what type of testing has been done by this company, why you think it is lacking, and what type of testing could remedy this? (Basically, all I've been able to take away from your discussion is that the company is not using randomized testing to justify its procedures...is this correctly framing your argument?)

Dr. Centeno: What is Level 1 research, a level 1 decision protocol, level 1 evidence? I'm not a medical professional, so I don't really have the ability to follow the discussion you are having with MentalWimp, though I am interested in this dispute. Could you explain to me what these classifications are, and also why your companies studies support the use of these procedures?


Sorry that I need the Idiot's Guide...
posted by HabeasCorpus at 3:27 PM on March 28, 2010

The whole "Warning Letter" thing was cooked up by a big pharma blogger who seems to be very threatened by what we're doing.

Is that blogger Lee Buckler, the attorney linked in the post?
If so, I thought he raised good questions:

• If a person is marketing a product via Twitter, a Wordpress blog, etc., is this considered interstate commerce?

• If a company is growing stem cells, are they manufacturing a biologic?

• Is the US comfortable with this type of thing going completely without regulation or oversight, to ensure that it without harm to patients?

I saw Centeno's response, but would be interested in hearing more from those who practice law.

Below the article are some other interesting comments:

• "Not settling with organizing doctors against the FDA with his "American Stem Cell Therapy Association (ASCTA)" (see my previous blog comments), Dr. Christopher Centeno is now inciting patients to oppose the "FDA's position that the patient's own adult stem cells are drugs and should be regulated as such." To facilitate patient activism he has launched a patient web-site, www.safestemcells.org, to drive the activities and opinions of patients in what he's calling the Safe Stem Cells NOW! movement."

• "Did you see that Centeno tried to keep all FDA proceedings confidential? link And it got denied! link"

posted by Houstonian at 3:32 PM on March 28, 2010

Are they less open about the connection off MetaFilter? If so, the finger pointing makes more sense..

I confess I was a little overzealous earlier, but from looking at the sites there was no link made between the two (and it was only after I re-read his points I saw point #5).

However, the ICMS certifying Regenexx, seeing as they helped set it up lacks credibility; secondly it is not clear where the ICMS IRB is registered.
posted by a womble is an active kind of sloth at 3:33 PM on March 28, 2010

Keeping my lack of knowledge in mind, could you explain to me what type of testing has been done by this company, why you think it is lacking, and what type of testing could remedy this?

Most researchers in medical areas agree that before a therapy, diagnostic procedure, or prevention or screening method ("intervention") is recommended for use in the general community, it needs to undergo rigorous testing to determine its effectiveness at improving clinical outcomes for some defined set of patients (if it is a therapy or diagnostic) or subjects (if it is a prevention or screen). If possible, randomized trials against some control, either existing standard therapy or placebo if no such therapy exists, should be done, because randomization assures that the comparison is unconfounded by differences between patients or subjects who receive the experimental intervention and those who get the control. In some instances, it may be hard to implement randomized trials or they may be unethical, and they can be expensive if a large number of centers must be involved or if third-party reimbursement isn't available for the cost of an expensive intervention. Well designed and analyzed observational studies where a group who has received the intervention is compared to another group who happened to get something else can be acceptable, but they can leave uncertainty about whether the intervention or the differences between groups is responsible for the differences in outcomes. These studies are submitted for publication to peer-reviewed journals so that the community can judge the validity of the studies and whether they on average show clinical or health benefit to those who received the intervention. Often times it is necessary to replicate the studies, especially if they are observational and potentially confounded.

The company seems to have skipped these crucial steps and gone straight to the selling of the intervention to the public. They are "collecting data" but it's not even clear that these data will allow the direct estimation of benefit and harm. By the way, this has happened many, many times in medical practice, as Chris Centeno notes in one of his comments, and many therapies that have not undergone rigorous study are currently paid for by the health care system. This, in my opinion, is not a good thing, because it means we are paying for interventions that may not only be doing no good, but may also be doing harm. A good example is PSA screening for prostate cancer, where the harms outweigh the benefits in randomized trials. Other examples where harm was found after use had become accepted by physicians are antiarrhythmics following myocardial infarction, early versions of carotid endarterectomies, and bone marrow transplants for breast cancer. The number of high-cost interventions besides the one Chris mentioned for which we don't have solid evidence is astounding: cardiac by-pass surgery or angioplasty & stenting for coronary artery disease, solid organ transplants, and cardiac pacing for mild bradycardia, to name a few.

So to me, this is not only an ethical issue of potential harm without knowing it, but also it affects the cost of medical care. To be clear, this therapy may be the greatest thing since penicillin, but without rigorous study it is impossible to know with any certainty. We should require such evidence before we pay for any such interventions.
posted by Mental Wimp at 11:11 AM on March 29, 2010 [2 favorites]

I have to chime if only to say that I wish I could favorite Mental Wimp's comments many times over (though I would differ on his interpretation regarding the data on solid organ transplantation).

Dr. Centeno notes accurately that a fair bit of the treatments used in medical practice do not have level I evidence. While this is true, it is a) not necessarily a good thing, and b) a much smaller fraction of therapies in frequent use have less than level III evidence to support their use (level III being defined as based on opinions of respected authorities, clinical experience, descriptive studies, or reports of expert committees). This intervention barely even scratches that level of evidence in terms of the support it has. One can not help but question how well informed patients who choose to spend nearly $7-8k on such a treatment are in that context, though Dr. Centeno takes it as a given that despite his central role in developing, researching, and financially benefiting from the therapy, he is capable of providing a fair and balanced assessment of the risks and benefits of it to his patients.

"What your doctor does on a day to day basis" is held to a different standard than what your researcher does on a day to day basis. Physicians who also wear the hat of researcher must do so with great caution. There is a long and well published history relating to professional research ethics and while I appreciate the fact that this is IRB-approved work (a private board, I am guessing?), I remain concerned about the research ethics of this case. The criticism this group's approach receives on a regular basis is an unsurprising result of the clear conflict of interest that exists in prescribing a potentially lucrative therapy at the bedside while at the same time publishing research on the subject. This therapy may well be an incredible innovation, but rather than popping into internet forums to provide hand-waving defenses about the challenges of doing things by the book and limitations of the FDA, I would urge Dr. Centeno and his colleagues to recuse themselves of the scientific analysis of this modality, and hand it over to 3rd party researchers who recognize a state of equipoise on the subject (something currently lacking), and can be monitored and reviewed by IRBs and DSMBs with an extra layer of distance from personal incentive.
posted by drpynchon at 1:11 PM on March 29, 2010

Yes, the IRB is of a private group, which has Centeno, Schultz, and Reilly (all staff of the Centeno-Schultz of the clinic), and Freeman (co-author on all Regenexx publications) as members. Half of the board of directors of this group are intimately connected with this research (Centeno, Schultz, Freeman), so even if they recuse themselves from decisions involving their own work, they will still be picking the other IRB members are in the first place.

Chuckles and HabeasCorpus say that Centeno and others haven't concealed this information, but concealment is not the problem. This arrangement, where the principal researchers and staff on a particular project are all members of the IRB, and where they have a great deal of influence over the appointment of the other IRB members are, is incredibly unusual and hardly provides the unswayed operation at arm's length that the IRB system is supposed to provide. (Those of you who are unfamiliar with this system should know that for most research projects, the relevant IRB will usually contain zero people otherwise directly involved in the project, and will be appointed by someone who has no direct involvement with the project). The fact that this IRB does not seem to be registered with the usual federal body is even more concerning, calling into question the procedures they follow and whether they meet common standards.

In short, I'll echo a womble is an active kind of sloth that the IRB approval process here appears to lack credibility, and I wonder how well it is protecting the research subjects.
posted by grouse at 1:41 PM on March 29, 2010