Stem cell clinics like Nervana are spreading like wild-fire across the U.S.
A few months back the Sacramento area got a new stem cell clinic selling amniotic stem cell therapies for a variety of ills including most prominently arthritis and pain. This clinic is called Nervana Stem Cell Center.
I first noticed it via a huge ad in our local paper, The SacBee.
More recently, Nervana has advertised again in full-page spreads in the SacBee, but going by a different name: Lee Medical Group.
I saw another one of these ads for Lee Medical Group/Nervana (at left).
The SacBee must be collecting huge amounts of money for these ads, but should they even be running them? In my view, this stem cell clinic is selling unproven stem cell-based hope that could put patients at a variety of risks without published scientific data to back up that it works.
The clinic ads are making specific medical and regulatory claims too that seem dubious to me. For instance, if you look at the image at right of a specific part of the ad it says, “no known side effects”. 
Of course any treatment could have side effects and that includes something as simple as aspirin. Stem cell therapies are complicated and can have side effects that are serious.
It’s hard to even find out who the doctors are at this clinic even by calling them, looking at the ads, or going to their website. It seems most likely that the physicians are Drs. Tushar Goradia and Clarence Lee, but I’m not 100% sure. If this is not correct, I hope that Nervana will let me know and fill the community in on what is going on at the clinic in terms of the practitioners there. For instance, I have been trying to find out what experience and training these doctors have with stem cells.
Whoever heard of a medical clinic that won’t tell you who its doctors are?
Also, I have other questions. Is their amniotic stem cell therapy based on living cells or some extract?
I’m guessing it is the latter, but the ads seem to imply the former. In either case, what is the source of this amniotic material?
Their most recent ad also claims that the FDA is OK with their treatments, but is that right? In part it would depend on that question as to whether they are using living cells, the source of the cells, the question of homologous use (e.g. are amniotic stem cells similar enough to joint tissue to be considered not a drug requiring preapproval from the FDA before use), and much more.
It seems like at this point we have tons of questions about this stem cell clinic in the Northern California area and our community, but few answers.
An important additional question at another level is whether the SacBee should even be running these ads given this context and so many unknowns about this business. I’m trying to ask our local paper about this, but so far haven’t gotten very far.
See my new post on stem cell therapy side effects.
@Paul
You have good arguments, Dr. Centeno has good arguments. You criticise stem cell clinics and advise patients not to visit these clinics. Just to summarize: Dr. Centeno has supplied no evidence for the safety of stem cell therapies with his data, but Dr. Centeno has shown that his stem cell therapies have a high degree of security (not many significant side effects).
But what should patients do now?
Would you still advise not to visit stem cell clinics at all?
Or are there cases where you’d visit stem cell clinics?
Please give us patients a little feedback on this discussion.
@Paul,
I’m no expert on USA laws and regulations but I’d say that there is a case for the FTC taking an interest.
@Shinsakan
I haven’t analyzed every outfit that uses “amniotic stem cells” but I did put a bit of effort into working backwards from a couple of “stem cell clinics”, through the various product descriptions, until I ended up at official looking stuff that sure seemed to say it was both dead tissue and FDA approved (as containing growth factors but not approved as a stem cell).
I’m not a stem cell biologist so I can’t remember all the fancy terminology that I came across during the above exercise (too long ago). But I did put a bit of effort into cross-checking definitions of bio-techno-jargon at the time… Too bad I didn’t keep a record of my effort. Frankly, I thought the whole thing would go away as soon as a few clued in people exposed it. Silly me!
@stemcellfan – a “review” is not a controlled clinical trial – very different things.
“Is this study good enough to answer the questions concerning safety of stem cell application in the orthopedics?” Once again – not for the FDA – they need to see clinical trial data.
“Regenexx says it answers the question.…?” No they don’t – Centeno said it “adds to the data” that it is safe – so even he agrees that it’s not definitive.
Summary: safety and efficacy of a drug can only be approved in US by the FDA, not by Regenexx – the data needed comes from controlled clinical trials.
Sorry I can’t be any clearer than this but I leave it to you to decide from here.
… So the question is still. Is this study good enough to answer the questions concerning safety of stem cell application in the orthopedics?
Maybe only with a high likelihood?
Or not?
You say it does not answer the question. Regenexx says it answers the question. … ?
This, you see how hard it is to decide for patients who is right?
… “This study is stronger evidence than post marketing surveillance, as that’s based on doctors and hospitals voluntarily reporting side effects, where this study constantly pinged patients about side effects (so it’s more likely to show what was going on).”
“I think for most physicians I’ve spoken to, there is little concern about the safety of BMC when injected into a knee or hip (i.e. orthopedic applications).”
“For autologous culture expanded bone marrow MSCs for use in orthopedic applications, given this long term safety data and the numerous clinical trials/published studies that have identified no safety issues (i.e no neoplasm)”
“This is our third safety paper on that same group.” …
@Gary sorry, but I can not agree, this paper is not presented as a review.
Take a look here:
http://www.regenexx.com/regenexx-publishes-worlds-largest-stem-cell-safety-paper/
Regenexx says: “With the publication of the world’s largest stem cell safety study by Regenexx in the Journal of International Orthopedics this week, 50% of those patients are ours.”
“Regenexx just published the world’s largest (2,372 patients) stem cell safety paper in any medical indication (not just orthopedics). This is the most in-depth analysis of safety available.” …
@stemcellfan – the study is not an approved controlled clinical trial – hence by definition it is not going to definitively answer the question of safety and efficacy from the point of view of regulators.
It is also unfair to expect this as the paper is presented as a review of a database not as a controlled trial. You’re asking the wrong question for this study and need to focus on the output of real controlled trials to get your answer.
Such clinical trials are ongoing – 43 listed in clinicaltrials.gov for orthopedic indications using stem cells.
So often stem cell therapies/clinics are discussed on this page, but at the end nobody is able to give a real answer because of missing trials/evidence. This should be changed.
… I ask myself: What can physicians learn from this study?
“but to show there is a likelihood of safety in various patients using his techniques.” Is that all?
“likelihood” What would you advise to a patient? Would you possibly recommend one of those stem cell therapies? Or would you never recommend it, because of missing evidence concerning safety? Is this likelihood maybe enough? (Of course you can’t give a real recommendation without knowing a special case/patient, but you could answer, if you would say “maybe” or “never” after knowing this study).
@Gary, thank you, but
“These studies are crucial and deliver very important information for late clinical studies …Hence, pre-clinical studies are valuable to some, but would also be “worthless” to you ”
But this study is in my opinion not a pre-clinical one. This study wanted to test the safety. But it hasn’t answered this crucial question.
“but that doesn’t mean it’s not a credible and honest study – it is – but it doesn’t move the therapy closer to approval.”
My first goal is not to evaluate a study, my special interest is to see a progress for stem cell therapy. So I don’t understand why nobody is doing a real clinical trial to answer the crucial question (see above), if this therapy is safe and working? …
(@Admin – my last post from yesterday didn’t appear so if it’s still in processing please ignore this one – if it didn’t arrive please post the one below – thanks)
@stemcellfan – you’re questions are very well formulated, so I hope I can answer them with equal clarity.
Why is study not worthless? There are many types of studies – such as pre-clinical animal studies that may indicate safety, but cannot be directly translated to patients. These studies are crucial and deliver very important information for late clinical studies. Clinical trials may then deliver definitive statements on the safety of a drug in humans (if results are compared to an untreated control group). Hence, pre-clinical studies are valuable to some, but would also be “worthless” to you.
Why does Centeno’s study not deliver the same statements as a controlled trial? The study falls short of a definitive clinical trial as there is no control group. Despite over 2000 patients, there are huge differences between them – from age to lifestyle, their illnesses are varied and some have previously taken medicines and others not – all this may have an effect on the results. In clinical trials the groups being compared are made as identical as possible so that the only difference in the drug.
But the results may provide insights for the planning of a real controlled clinical trial as Centeno identified many issues to be solved and some solutions. That is why is it not worthless to some, just like the pre-clincal studies.
Why did Centeno not include a control group? He did not present the study as a clinical trial but as results from work in his and other clinics over a number of years – and that’s fair enough. He didn’t set out to make definitive statements that the FDA need to approve the drug, but to show there is a likelihood of safety in various patients using his techniques.
And yes, he has a vested interest (Regenexx) in the safety of his techniques – so the study serves as marketing – but that doesn’t mean it’s not a credible and honest study – it is – but it doesn’t move the therapy closer to approval.
“Is the stem cell therapy (in this case the orthopedic applications) safe?” A paper cannot definitively and legally make such a statement – only the FDA can.
There is a new interesting statement by Dr. Centeno
http://www.regenexx.com/regenexx-publishes-worlds-largest-stem-cell-safety-paper/
He distinguishes between same day bone marrow stem cell procedures (aka bone marrow concentrate or BMC)
and
autologous culture expanded bone marrow MSCs for use in orthopedic applications
and he cites another study
http://www.ncbi.nlm.nih.gov/pubmed/?term=Safety+of+intra-articular+cell-therapy+with+culture-expanded+stem+cells+in+humans%3A+a+systematic+literature+review#
which should support his point of view?
Difficult to judge?
@stemcellfan good questions
@Gary Jennings
what do you think about? I don’t understand what you mean, too. Could you please explain us?
corrected version
@Gary
Thanks, it is really difficult for me to understand, but in this case I see no sense in the discussed study. A scientific research study should answer questions. But I don’t see just one question which is answered by this study. We all would like to get answers especially to the following questions:
– is the stem cell therapy (in this case the orthopedic applications) safe?
– is the stem cell therapy efficacy?
None of this questions is answered, so in my opinion this research paper is only diappointing and worthless.
You said the study is not worthless: “no, it supports accumulating evidence that MSC are safe for use.” Sorry, but I do not understand what you mean. Which question concerning stem cell therapy is answered by this study? Do you see any?
@stemcellfan – I disagree strongly with your conclusions as you’re coupling statements together that are not related.
“patients learn from this study that the safety of these kind of stem cell applications is likely safe.”
If you’re Centeno yes, but he has a vested interest as he profits from his patients. I don’t have a vested interest and I would not take such a therapy until it has been proven safe in a controlled clinical trial.
“this study supports all stem cell clinics who offer similar treatments.”
Certainly not – it would support independent data obtained in controlled clinical trials. But this has nothing to do with the quality of clinics or doctors (Centeno said in an interview on this blog).
“it certainly shows that the number of serious sight effects is very low”
Low – compared to what? There is no control group.
“an elevated likelihood for safety not enough for the FDA but probably for many patients, and a good reason for stem cell clinics.Would you agree?”
Absolutely not – there should be no difference between safety of a therapy from one clinic to the next – or are you saying it’s OK for some patients to accept less safety?
@Gary,
thank you for explaining.
“no, it supports accumulating evidence that MSC are safe for use.”
So, all patients can learn from this study that the safety of these kind of stem cell applications is likely safe.
And so this study supports all stem cell clinics who offer similar treatments.
So my recommended conclusion from above seems to be right?:
“but it certainly shows that the number of serious sight effects is very low, or not?” (no evidence for zero, but low)
I would summarize: No evidence but an elevated likelihood for the safety of stem cell application – not enough for the FDA but problably for many, many patients, and a good reason for stem cell clinics.
Would you agree?
@Roger,
good question, I always thought PRP could only work in the joint where it is injected. But I don’t know. Hope anyone could answer.
@Paul,
thanks, looking forward to read it.
@stemcellfan – I’m acutely aware how frustrating this must be for anyone with no background in clinical trials or approval processes. Two thousand patients and still no conclusion?! Let me try to explain the value of the study and its limitations.
If I’m a normal guy (not a rich dude) and a patient for a stem cell therapy, I can’t afford to go to a clinic and pay $10,000, so I rely on my health insurer to pay – e.g. Obamacare in US, NHS in UK, or many private companies – but these insurers aren’t going to pay for something that doesn’t work or may give you a cardiac – so for their own security, they only insure treatments with FDA approved products.
So why can’t FDA approve MSC therapy now that Centeno has published? Because they need to make sure they approve products with statistically significant safety and efficacy data between the treatment group and a control group without treatment. Here we come to the missing control group that Paul and Jeff spoke about – it is essential for FDA approval.
So is the Centeno study totally worthless – no, it supports accumulating evidence that MSC are safe for use. Is it worthless to a patient expecting an MSC therapy to be paid by his insurers – probably because it won’t be considered by FDA.
If Paul, Jeff and others think this is incorrect please step in.
What about injecting possible unwanted cancer T cells along with the so called “stem cell material” where they could migrate and start a neoplasm else were in the body? Anyone know anything about this?
@Muggles,
yes, this is really diappointing. I really don’t understand, why researchers are doing such a big and encouraging study without a proper control group. The additional cost won’t have been too big, I think.
Hernigou P, Homma Y, Flouzat-Lachaniette C-H, Poignard A,
Chevallier N, Rouard H (2013) have done their study without a special control group, too. I don’t understand why?
Hope, one day someone will do a study with a suitable control group to give us a valid answer concerning these stem cell therapies. Until this will happen in my opinion nobody could really know, if theses therapies will work.
@Richie,
I think I know why they aren’t including control groups and will discuss this as part of my upcoming post on the Centeno paper, which I think will go up on Monday most likely.
Paul
@Gary,
if this study allows no conclusions concerning stem cell therapies, in my opinion it is worthless.
but what do you think we could conclude for stem cell therapies because of this study?
I am not sure, I think (see above), maybe the study certainly shows that the number of serious sight effects is very low, or not? But there is still no evidence that there is no risk for serious sight effects including cancer.
But what do you think?
@stemcellfan – as far as I can see, nobody has said the study is worthless, nor that is is not very good. If that’s what you’re reading, then read again carefully.
Richie asked if the report was a game-changer – I don’t believe so, because there is nothing in the conclusions that hasn’t been reported before. You said, “the study is a big milestone” – but you don’t say what that milestone is – please define the milestone.
The discussion regarding controls is important because this determines whether regulators and insurers consider the data sufficient to approve and pay for the therapy. In this case, the report will not convince them to do so.
@Bernadette,
all people are interested in stem cells are looking for valid data and so of course discussing all published data ist very important.
@Muggles
So many data should be worthless? Maybe the study is not very good but it certainly shows that the number of serious sight effects is very low, or not?
If Dr. Centeno himself stated, “The main weaknesses of the current research are that it is based on data accessed from a treatment registry. Thus, there is no control group with which the frequency and type of observed illnesses could be compared.”…WHAT exactly was the purpose of this discussion?
@Bernadette,
The study isn’t perfect for a number of reasons including the lack of controls, but that doesn’t mean it has no meaning. It is worth discussing and thinking about. I’m also going to do a post on it.
Paul
@Richie – you say, “I really don’t understand, why is the chosen control group worthless?”
Once again – there is NO chosen control group in Centeno’s study – he compares adverse event rates to the general population, but this doesn’t make them a control group in any clinical sense (see Paul’s comment above and the reference I posted about what a control group is).
I can understand why this is disappointing when you see such a lot of data that apparently shows safety – but it is exactly that – “apparent safety”. The paper is a retrospective study of n=1 cases that cannot provide an homogenous treatment group nor any control group – after all, it isn’t a clinical trial.
Btw, Centeno agrees about the lack of control group and writes, “The main weaknesses of the current research are that it is based on data accessed from a treatment registry. Thus, there is no control group with which the frequency and type of observed illnesses could be compared.”
The paper of Hernigou P, Homma Y, Flouzat-Lachaniette C-H, Poignard A,
Chevallier N, Rouard H (2013) is No. 15 in the References of Centenos paper
… ” No tumor formation was found at the treatment sites on the 7306 magnetic resonance images and 52,430 radiographs among the 1873 patients. Fifty-three cancers were diagnosed in areas other than the treatment site. On the basis of cancer incidence in the general population during the same period, the expected number of cancers was between ninety-seven and 108 for the same age and sex distribution. The range of the standardized incidence ratio for the follow-up period was between 0.49 and 0.54 (95% confidence interval, 0.30 to 0.80)”.”
It is very difficult for me and many other people, too. But both conclusions sound logical to me. I have understand, it would be better to choose another control group, but why it is not possible to use the data of all people for comparison at all? Hernigou P et al have done the same in their own study and as far as I know the don’t belong to Regenexx.
… According to the National Cancer
Institute, the annual incidence of cancer in the U.S. population
in 2011 was 0.44 % (438 cases per 100,000 individuals), and
0.78 % in adults 50–64 years [27]. In contrast, we observed a
lower annual cancer rate (0.14 %) among our registry participants.
These findings are consistent with previous reports
indicating no increased risk of tumor formation following
BMC injections or treatment with culture-expanded MSCs
[9, 11, 13, 15].
Hernigou P, Homma Y, Flouzat-Lachaniette C-H, Poignard A,
Chevallier N, Rouard H (2013) have made a similar conclusion with a comparable control group: … see next comment
@Richie,
The proper controls are crucial.
For instance, the types of patients treated at the specific clinics providing the stem cell transplants reported in this paper (I’m reading it now) might normally have much lower (or higher) rates of cancer, immune or other problems even without any stem cell intervention versus those reports in other patient populations in other papers or in the US population at large.
Paul
@Muggles,
thank for your answer. I understand the study design could be better and it would be better, if there were another control group.
But I really don’t understand, why is the choosen control group worthless?: And why it is not possible to make the following conclusion:
“Of the seven reported cases of neoplasm among the registry
patients, none occurred at the site of implantation despite all
injections being confirmed with imaging guidance. Given the
number and age of the patients followed in the registry, and
the amount of time that the patients were followed, some cases
of cancer were expected. … see next comment
@Paul, that’s great, thank you, looking forward to read it .
@Richie – no control group means it was not a controlled clinical investigation and cannot make any definitive claims about clinical safety and efficacy. https://en.wikipedia.org/wiki/Clinical_control_group
For regulatory approval and cost coverage by insurers, real controls are what counts as the general public is not a control group in any scientific or clinical sense. It’s just an unrelated comparison.
For Centeno this is not relevant as he’s not trying to get the therapy approved or covered by insurers – he will rely on patients paying for it themselves. For Regenexx the publication is just great marketing.
@Paul @all other experts,
you are always asking for data of stem cell cinics. Now there is big data. So, we would like to know, what do you think about this data? Is this enough evidence? – a game changer? or are you still sceptic about this kind of therapy?
Many patients / potential patients are readers of your blog and are very interested in especially your opinion. So please let us know and give us a short statement.
@Richie,
I’m swamped right now, but reading this paper and doing a blog post review of it are on my list of stuff to do. As Muggles pointed out, inclusion of controls is really important to give clinical data meaning. Paul
@Jeff,
no control group? – Yes, no special control group, but:”… a lower rate than in the general population…” So I think the control group is the general population…, because of this for me this study seems to be enough evidence, or do I make a mistake?
@stemcellfan – you don’t agree that there’s no control group?
@Richie – a therapy can only be said to be safe with respect to a control group that is identical except for the therapy itself (one variable).
No therapy has zero side-effects and it might be that most of the 325 observed adverse events (including cancer) in Centeno’s paper were also seen in a control group – and not related to MSC therapy. But Centeno didn’t have a control group so he cannot definitively make that statement.
@jeff,
just take a look, someone asked already your question about the efficacy. Hope we could read a significant answer…
http://www.regenexx.com/regenexx-publishes-worlds-largest-stem-cell-safety-paper/
This study includes a variety of data that substantiate a good compatibility. Even if the data could be better, I think the study shows, that the applied stem cell therapies are well tolerated.
@Jeff Muggles,
I don’t agree with you, in my opinion this study is a big milestone.
@Richie – unfortunately there is no control group with which the frequency of observed adverse events (including cancer) can be compared so the safety conclusions are speculative and not definitive (in clinical terms).
Nevertheless, an interesting collection of n=1 cases, which doubtless contributes some circumstantial evidence to the safety profile of MSC. I’d be interested to see the efficacy data on the 2372 patients.
But what do you think about this study?
http://link.springer.com/article/10.1007/s00264-016-3162-y
This study could maybe a game changer and evidence for the safety of stem cell applications?
What do you think?
@Brian, not sure if this is what they are doing here, but amniotic stem cells that are similar to mesenchymal stem cells can actually be isolated from both the amniotic fluid and the amniotic membrane. What you are talking about is the amniotic membrane itself, which can be processed in ways such as freeze-drying to kill cells and then used as a biomaterial (perhaps most notably for corneal regeneration). There has been talk that amniotic stem cells are minimally immunogenic (i.e., less immunogenic than allogeneic mesenchymal stem cells) through secretion of immunoregulatory factors and also that they have greater differentiation capability than mesenchymal stem cells (although these types of claims usually abound whenever anyone isolates mesenchymal stem cells from a new source). As far as I know, they have actually been applied in some clinical trials without any reports of tumor formation, and amniotic stem cell banks exist.
As for what this particular clinic is doing, though, it is difficult to believe that they would have the expertise or facilities to extract, culture, and store amniotic stem cells. My guess would be that if they are actually using amniotic stem cells that they would be procuring them from a bank, but even that is hard to believe. Alternatively, as you suggested they might simply be processing the amniotic membrane and passing it off as “stem cell” material without really including any stem cells. The clinic’s website suggests that they use either lipoaspirate-derived stem cells or amniotic stem cells depending on the need, which to me suggests that they are probably mostly doing the standard lipoaspirate treatment, anyway.
Growl, they’re not stem cells. Yep, there are companies that take amniotic fluid and pulverize it and process it to pieces to make an FDA-approved product that may have growth factors and mushed-up bio-matrix-type material that may be useful in some circumstances but which has been totally oversold (as is the habit for the drug-peddling industry — Indeed, another reason why I totally object to calling a cell a drug!). Anyone can find out about this guff with a little internet effort. I’ve posted links before and won’t bother repeating myself.
Call it “extra-cellular guff and long-dead, now deceased, formerly maybe cells” — not stem cells.
@Brian, I think you are right, but many of the clinics market this kind of product as living cells because presumably of the positive buzz over stem cells that frankly sounds a lot cooler and more powerful than “extracellular guff”. As someone mentioned earlier, should the FTC be getting involved? I think it was a year or two ago at a meeting some FTC person claimed they had never received complaints about stem cells.
Paul
Are you aware UCDavis put a full page advertisement in Sacramento Magazine stating “Stem cells got me back on my feet” which suggests the institution is giving stem cell treatments, although the patient is actually involved in “an innovative study”?
My experience has been that T Cells are aspirated along with the belly fat from your stomach area and separated with a centrifuge. These would be living cells
that are supposed to be mostly undamaged. Some “secret” chemical is added to the T Cells and they are injected back into “diseased” parts of your body. My question is what about the damaged T Cells introduced also? Is the idea that with enough good T Cells numbering in the millions, they will overcome the bad ones? Millions of undamaged T Cells are stored in your belly fat as opposed to those from bone marrow indicating a good source. However, the “shot gun” injection method used looks like “junk science” to me. I know the theory is that living T Cells can change into almost any cell, but this leaves a lot of unanswered questions about safety and any good results.
What I found out about how these clinics tend to operate from a legal standpoint,
is that some are connected to a stem cell clinical trial registered with Clinicaltrials.gov using a documented study. One study being used is registered to Elliot Lander of Cell Surgical Network Inc. trial Number: NCT01953523 were no results have been published at this time. Go to http://www.clinicaltrials.gov to check this out using the name or number above. The FDA part of the equation is that they are using guidelines for standard surgical procedures.
Dr. Knoepfler,
Please keep us updated if you find anything more regarding whether these amniotic stem cell injections actually contain living cells.
The FDA has made its case on several occasions that an amniotic tissue-derived product containing living cells is not a 361 HCT/P, but a 351 drug or biological product. Please correct me if I am wrong, but I’m not aware of any amniotic 351’s currently on the market.
@Dustin,
Yes, that is my understanding on amniotics as well. If the product in question has living cells in it, then it is going to be a 351 in this kind of case with only rare exceptions that don’t immediately come to mind and I’m not sure there are any 351s of this kind on the market. It’s hard to know if there are some with INDs out there. If on the other hand, the amniotic product has no living cells in it then clinics in my opinion should inform prospective customers of that in a clear, direct way.
Paul
I think you’re onto something here with, “…new ad claims…”
These clinics operate in an unclear area of regulatory guidance, and it’s a difficult area to police. But advertising standards isn’t difficult, and misleading the public is easier to get at through Federal Trade Commission rules to protect consumers.
In the past, FTC have fined Kellogs $5 million for falsely advertising a breakfast cereal that purportedly improved children’s health and diet pill makers are regularly called up by the FTC.
(editor’s note: comment slightly edited for content)
My experience with these stem cell clinics, is that they use a “shot gun” method to inject the adipose stem cells into your veins, muscles or joints. The theory is that if enough are injected, something may work to repair cell damage.