We have been writing about dubious stem cell therapies for over a decade. At first the phenomenon was mostly in countries with poor regulations, such as China, but the practice has spread to the West, including the US. Just two weeks ago David Weinberg wrote here about stem cells therapies causing blindness.
The science of stem cell therapies has progressed at a predictably slow pace. This is a complex technology involving living cells, and is the kind of thing that typically takes about 20 years or longer to go from concept to clinic. For many potential applications the science is simply not ready yet for medical applications, but the hype has been around for almost two decades. This is a situation ripe for exploitation.
Similar to the eye clinics David wrote about, The New York Times did an investigative piece about Regenexx, a company selling stem cell therapies for arthritis, such as knee arthritis. There are a few details in the story that will be interesting and familiar to SBM readers.
First – The science
A recent overview of the science of using mesenchymal stromal cells (MSCs – a type of stem cell) for arthritis and bone repair captures the state of the science.
Despite these efforts, the effectiveness of MSCs as a treatment modality for these conditions is still uncertain and market authorisations have been limited. In addition, critical and clear phenotypic parameters for defining MSCs are uncertain and a coherent biological framework surrounding the therapeutic mechanism of action is not yet available. Added to this, cell manufacturing protocols are complex and costly and present substantial challenges in terms of regulatory oversight and standardisation.
Essentially, the science is not yet ready for clinical applications. Isolating the correct cells is complicated and expensive, and still an uncertain area of regulation. We are still not sure of the potential mechanism of action. But most importantly, rigorous clinical trials have not clearly shown benefit for specific conditions. Such therapies are promising, but we need to do more research.
The most recently published systematic review of clinical trials concluded:
Intra-articular MSCs provide improvements in pain and function in knee osteoarthritis at short-term follow-up (<28 months) in many cases. Some efficacy has been shown of MSCs for cartilage repair in osteoarthritis; however, the evidence of efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited.
The treatments show promise, but the data is limited. I say “treatments” plural because:
Among 17 studies, 8 studies used bone marrow-derived MSCs, 6 used adipose tissue-derived stromal vascular fraction, 2 used adipose tissue-derived MSCs, and 1 used umbilical cord blood-derived MSCs.
That’s very few studies for each treatment type. The same preliminary data is available for a related treatment, platelet-rich plasma:
At present, results from these RCTs seem to favor PRP use over other intra-articular treatments to improve pain scales in the short and medium term (6-12 months), but the overall level of evidence is low. As a result, clinical effectiveness of PRP for knee osteoarthritis treatment is still under debate. This is, prominently, the result of a lack of standardization of PRP products, scarceness of high quality RCTs not showing high risks of bias, and poor patient stratification for inclusion in the RCTs.
In other words – these types of stem cell treatments for knee arthritis and related conditions show promise but are still in a preliminary stage of research preventing confident conclusions about their clinical risks and benefits. We are still working out some basic issues as well, such as which cell types are best, from which source, and in what numbers. We also need more information about mechanism of action.
This is a point in the arc of research where many treatments may still fail. We may get to large rigorous trials and discover the treatment is worthless, or that we simply have not been doing it correctly. Arthritis is a particularly difficult outcome to study because the symptoms do tend to wax and wane. Also, most clinical trials will involve some physical therapy which may be producing any observed improvement. Procedures also tend to have a large placebo effect.
A failure of regulation
Unfortunately we are at the perfect stage in the path of research for clinics or practitioners to emerge and start using the “cutting edge” treatments. They can point to all this preliminary evidence and it will sound convincing to many people. Experts may sound a note of caution, but they may also be hopeful for the treatment and conducting research themselves.
This is exactly where we need effective regulation. There should be a threshold of evidence of safety and efficacy before we can charge patients thousands of dollars for a treatment, rather than offering treatments in the context of clinical research.
In the US, the FDA has chosen so far to take a very hands-off approach, while they wait and see where the industry goes. They have also carved out an interesting space for dubious clinics to operate. The situation seems identical to what David wrote about with eye stem cell treatments. One practitioner actually wrote their PhD dissertation on: “How to treat patients with adult stem cells without FDA approval and without the necessity of conducting any prior clinical trial“. This sounds like a handbook of how to commit stem cell fraud.
Regenexx has taken a similar approach. According to the FDA, you can take a patient’s own cells and inject them somewhere else and this does not constitute a “drug” or biological product that they would need to regulate. However, if you manipulate the cells significantly, it becomes a target for regulation. So – you can drive through this massive loop hole by simply not manipulating the cells you are injecting. Take bone marrow, or fat cells, or platelets, and inject them directly. (“Minimal” manipulation such as concentrating cells is apparently allowed.)
Because this is allowed, that is exactly what Regenexx and other stem cell clinics are doing. But that is also the rub – it means that all of the research I just reviewed above is irrelevant. Those studies mostly involve identifying and purifying specific cell types, even estimating their numbers. So there is extreme quality and dose control in those clinical trials. What Regenexx is doing has no such controls. They basically don’t know exactly what kinds of cells and in what numbers their doctors are injecting.
By going around FDA regulations, they have also gone around the existing published scientific evidence. They claim they are doing their own studies, but as The NYT reports:
As for clinical trials, Regenexx says it is conducting them now. But only one small controlled study has been published, in December. Patients with arthritic knees got either exercise therapy, or stem cell treatment. After three months, the patients given stem cells were doing better. But all the patients in the exercise group later got stem cells, too, so the results are hard to interpret.
Most of the other studies Regenexx has listed on clinicaltrials.gov have either been abandoned or will not be completed until 2021 or later.
I have to wonder why they abandoned many of the studies they listed on clinicaltrials.gov.
The failure of regulation at this stage is also highly problematic because it allows for the development of an industry dedicated to using a treatment that has not been proven effective. This can hamper clinical research, as patients can already get the treatment, so why risk a clinical trial where they may get randomized to the placebo group? Also, doctors who know how to do the procedure, which generates a tremendous revenue stream, may be reluctant to perform the kind of clinical trials that can prove it doesn’t work. History also shows that practitioners will be slow to abandon a lucrative treatment if later studies show it does not work. They will simply cherry pick the studies that show what they want.
The end result is that we can have 20-30 years of an industry of expensive treatments that ultimately are not effective, that sucked up a lot of resources, and even slowed clinical research. They may also confuse the scientific literature by publishing in-house studies with a massive bias toward their treatment. We also know from prior historical reviews that many treatments adopted in this preliminary phase are later reversed because they don’t work.
All of this should concern anyone interested in the problem of rising health care costs. This is a massive inefficiency in the system.
And of course – many individual patients may be harmed by prematurely adopting ineffective treatments. They may be financially harmed, and their ultimate clinical outcomes may also be worse than if they stuck with proven therapies.
I certainly hope that the science of using autologous stem cells for the treatment of arthritis and other bone and tendon related problems pans out, and is ultimately highly effective and cost-efficient. But the premature commercialization of such treatments is likely to harm, not help, such hopes.