Saving Stem Cells: How The Pharmaceutical Industry Can Help Regulate Rogue Clinics

Introduction

The proliferation of stem cell clinics offering unproven treatments to unsuspecting patients has astounded researchers and left regulators playing catch-up. The promise of stem cells has created a boom economy across the United States for an open and unregulated market, where snake oil salesmen sell hope and dubious cell-based therapy out of rogue clinics.

The Food and Drug Administration (FDA) which oversees regulation of human biologics, has not yet approved stem cell-based products for any use outside of clinical trials, with the exception of bone marrow transplants and similar procedures. (Reisman and Adams, 2010)

Although the FDA is responsible for regulating and approving medical products that are “intended to treat, cure or prevent disease” before they are available to a consumer market, there has been little to no such oversight of the hundreds of clinics operating in the US.

Stem cells are everywhere — and they are being marketed as a medical treatment for a plethora of ailments and as quick-fix cosmetic procedures.

As soon as stem cells became a possible cure for debilitating diseases that have long gone without breakthroughs in successful therapy, desperate patients began paying for unproven treatments with the hope that something would work. (Matthews and Iltis, 2015)

From an estimated 10 clinics in 2013 (Cryanoski, 2013) a recent paper put the number of unregulated clinics selling unapproved treatments at over 500 across the United States, spurred mostly by non-traditional marketing. (Turner and Knoepfler, 2016)

In this paper I will examine issues related to unregulated stem cells in the United States. I will show that without proper regulation, fraudulent clinics will continue to profit on unproven therapies, will almost certainly injure patients looking for miracle cures, and should be a particular concern for both the pharmaceutical industry, as well as federal health regulators.

I will argue that by continuing to turn a blind eye to the problem, the FDA and industry leaders both stand to be directly responsible for damaging the reputation of a medical advancement that could be a sincerely novel technology. The misuse and misrepresentation of stem cells in an unregulated market could result in the general population turning against them — just when real, proven applications are now within reach.

I believe it is in the best interests of the pharmaceutical industry to support federal oversight of stem cells, and lobby the FDA for more robust oversight of the hundreds of clinics around the country.

In this paper, I will explain the uses and dangers of stem cells, explore the various regulatory hurdles clinics are sidestepping, and consider what experts believe regulators and industry leaders can do to make accessing stem cell therapies safe for patients.

Legitimate therapies versus dangerous experiments

Stem cells first created in the early human embryo are known as human embryonic stem cells (hESC). They are remarkable because they are able to evolve to create many different kinds of human cells and tissue, as well as create more stem cells. Stem cells can also be found in and around the fetus (including the placenta and umbilical cord, which are particularly rich sources of stem cells) and throughout many different tissues of the adult human body. (Minger, 2013)

Three kinds of human stem cells have so far been identified: embryonic stem cells, adult stem cells, and induced pluripotent stem cells. All three kinds share key characteristics, including the ability to survive for long periods, to divide to make additional stem cells, to become any other kind of cell (a “blank slate”), and to develop into specific cell types (directed to do “specific work in the body”). (FDA, 2016)

In 2007, induced pluripotent stem cells (iPSC) were engineered in Japan, a process through which adult cells could be essentially reverse engineered to their original state, where they might develop into any other kind of cell. IPSCs were a significant advancement in stem cell technology, particularly because using them meant scientists could avoid the controversial practice of taking stem cells from human embryos. (Kramer, 2015)

No matter the origin of stem cells, “there are an ever-expanding number of ways in which they can be used in research, drug discovery and, potentially, in the clinic,” according to a paper by a researcher for General Electric Healthcare’s life sciences division, which partners with pharmaceutical companies to support stem cell research. (Minger, 2015) The possibilities afforded by stem cells has clearly not gone unnoticed by the international pharmaceutical industry.

One example of the ways stem cells can be particularly useful to the industry is as toxicology assays, a pre-trial testing ground for ways drugs might react with human tissue. For example, a 2014 article reported that “Pfizer now incorporates its own murine stem cell-based assay into its drug development pipeline to test for developmental toxicity,” and that the idea of using stem cells to replace animal testing is growing in popularity (Dove, 2014)

The global pharmaceutical giants are also making significant inroads on research for treatments for neurodegenerative diseases such as Parkinson’s, Alzheimer’s, multiple sclerosis, Huntington’s disease and others. (McFarling, 2016 and Kegal, 2017)

As research progresses, according to a paper in the journal Stem Cell Research & Therapy, “the advancement of these technologies is building [and] the number of stem cell clinical trials will increase tremendously and conceivably some will become standard treatments.” (Dantuma, Merchant, and Sugaya, 2010)

Big-name companies such as Novartis, Johnson & Johnson and Celgene, along with GE and Google’s Calico, are investing heavily in an astounding array of areas of stem cell research. And as major industry players look to partner with smaller firms on specific projects, it is clear that stem cells will play a crucial role in the booming fields of personalized and regenerative medicine. (Adeyanju, 2014 and Calico’s website, accessed 2017)

However, outside the legitimate clinics of the pharmaceutical industry and the labs of academia, rogue stem cell clinics claim to offer treatments and cures that simply don’t yet exist, and have not been tested or proven.

Nearly ten years ago, an international group of stem cell researchers foresaw this issue as a critical one, and through the International Society for Stem Cell Research (ISSCR) recommended guidelines for national regulatory agencies.

The ISSCR guidelines “include the use of experts in stem cell biology for peer review of research ranging from preclinical to clinical, emphasizing risks involved with stem cell-based therapies within the voluntary informed consent, new oversight criteria for medical innovative care that falls outside of the realm of a clinical trial, and the equality of benefits of stem cell treatments.” (Dantuma, Merchant, and Sugaya, 2010 and Lindvall et al, 2008)

To these experts, it was obvious that “the general public may not fully understand how many years of preclinical and clinical research will be required to bring novel stem-cell-based therapies to fruition,” and that “there are some clinics around the world already exploiting patients’ hopes by purporting to offer effective stem cell therapies for seriously ill patients, typically for large sums of money, but without credible scientific rationale, transparency, oversight, or patient protections.” (Lindvall et al, 2008)

This has not changed in the past decade, and the suggested regulatory processes have not been widely implemented.

In fact, the opposite has happened.

Instead of coming under the heavy hand of regulators, stem cell-derived treatments have fallen into the limelight. The media has seized on the promises of stem cell research, branding cell-based therapies as miracle cures that possess magical properties, a narrative that has enthralled the public — and snake oil salesmen masquerading as doctors.

Indeed, “hope, desperation, persuasive advertising, and trust in assurances provided by clinics are likely to be factors” resulting in the increased popularity of the treatments. (Turner, 2015) Hope is a powerful motivator, and polls show that patients are “not dissuaded by information about the lack of safety and efficacy data.” (Matthews and Iltis, 2015)

The market thus cannot hope to self-regulate.

Meanwhile, according to clinics and the media, stem cells can allegedly be used to cure anything. Some examples of purported uses include videos by National Geographic (2011) and Mashable (Nikolov, 2016) of a “stem cell gun” that heals burn victims by spraying their own cells back at them.

A popular US daytime television program, “The Doctors,” (2012) has featured adipose-derived stem cell (fat cells) “treatments” for everything from cosmetic procedures to relief from joint pain, and also highlighted the Regenexx procedure, which came under fire for offering unapproved bone marrow transplants to patients in Colorado in 2012 and ultimately lost in court to the FDA. (Cyranoski, 2012)

In Canada, a study that reversed some signs of multiple sclerosis in a handful of patients was met with an international media frenzy that incorrectly declared MS could be “cured with stem cells.” But the truth was much more complicated and included stem cells as just one piece of a robust treatment cocktail. (Kingston, 2016)

Some clinics also claim high-profile clients and spokespeople, including professional athletes and celebrity doctors. (Regalado, 2014)

A key paper from bioethicist Leigh Turner and stem cell expert Paul Knoepfler last year took stock of the unapproved stem cell industry in the US and found that the media and the internet were precisely responsible for the propagation of rogue clinics offering unapproved stem cell-derived “therapies.”

“Using rigorous Internet-based key word [sic] searches, [the authors] found 351 U.S. businesses engaged in direct-to-consumer marketing of stem cell interventions offered at 570 clinics,” many of which have been featured in the media mentioned above. (Turner and Knoepfler, 2016)

The majority of the clinics examined by the authors claim to use autologous adipose-derived stem-cell based interventions, and the authors also noted the “the relative abundance of US businesses marketing ‘amniotic’ and ‘placental’ stem cells.” (Turner and Knoepfler, 2016)

However, despite what clinic websites say, patients are often left in the dark about what kind of cells are being used, and that some treatments might render them incompatible with other, legitimate clinical trials. (Matthews and Iltis, 2015)

According to a further investigation by Stat News, “many [of the US clinics] charge $5,000 to $20,000 for injections of ‘stem cell’ solutions that may not contain the same kind of stem cells used in controlled experiments — and indeed may not contain stem cells at all.”

A handful of lawsuits of have cropped up over the years, with plaintiffs claiming a multitude of injuries, from the development of malignant tumors to going blind. (Hiltzik, 2017; Mole, 2017; Servick, 2014; and Cyranoski, 2012)

Skyrocketing costs, limited reported successes and a distinct possibility that the treatments can actually harm patients has not resulted in clinics expecting any downturn in demand. (Turner, 2015)

Ultimately, it seems profitability for the clinics offering treatments outweighs concerns of falling by the wayside of regulators, even if cells and procedures used fall under what the FDA would consider a human biologic under the purview of federal regulation. (Turner and Knoepfler, 2016)

While the FDA looks the other way and pharmaceutical companies stay out the the fray, clinics are uninterested in taking on the “costs of performing carefully designed and properly conducted safety and efficacy studies that are cleared by the FDA.” (Turner, 2015)

Regulatory hurdles

It is not uncommon for new and novel treatments to face some significant regulatory challenges before being approved for routine procedures, and as human biologic material, stem cells are no different.

Before they can be introduced onto the market responsibly, “routine cell therapy will require… development of robust, reproducible and standardised protocols and workflows for manufacturing and quality control.” (Minger, 2013)

According to the FDA, it is this process specifically — ensuring safety and efficacy of the products and the procedures and technology created to utilize them — that presents obstacles.

“Stem cells are immensely complex, the FDA cautions — far more so than many other FDA-regulated products — and they bring with them unique considerations for meeting regulatory standards.” (Reisman and Adams, 2014)

For example, in some cases it is possible that stem cells which are grown outside a human body can develop dangerous side effects, such as tumors and other adverse reactions, when introduced into a patient. In other cases, it may be possible that stem cells become impotent and fail to perform their function, even when taken from the person using them. (Reisman and Adams, 2014)

It is still difficult to know how stem cells will react in certain environments because there have not been a large body of clinical trials to show in what ways cell therapies can be repeatedly successful.

If one takes the FDA at its own rules, the fact that a handful of clinics have been shut down or received letters compelling them to cease treating patients with unapproved cell-based therapies, as well as the lawsuits brought against companies in Colorado and Texas (Cyranoski, 2013 and Matthews and Iltis, 2015), it seems the FDA certainly considers stem cells the responsibility of federal regulators.

However, the clinics claim that their procedures fall under a somewhat vague section of the Code of Federal Regulations, 21 CFR 1271, which relates to human cells, tissues, and cell and tissue-based products (HCT/Ps).

The clinics insist that they are compliant with regulations because of a section referred to as the “same surgical exemption,” which reads:

“You are not required to comply with the requirements of this part if you are an establishment that removes HCT/P’s from an individual and implants such HCT/P’s into the same individual during the same surgical procedure.”

However, the study conducted by Turner and Knoepfler, as well as an earlier paper by Turner, showed that many clinics do not fall under the exemption the way they claim to, and that it is clear from the FDA’s warning letters to at least five clinics that the agency considers the treatments offered as including an extra “manufacturing or processing step” which means HCT/Ps “are not returned to the patient in the ‘same’ surgical procedure.” (Turner, 2015)

A 2014 draft guidance from the agency, although not legally enforceable, clarifies the government’s position and points to two other criteria that must also be met to make HCT/P treatments exempt from regulation: the HCT/P must be only “minimally manipulated,” and must be for “intended for homologous use only.” This guidance was updated in 2016 to be even more clear. (Kux, 2016)

Despite assertions that the clinics meet the criteria, the majority of processes in question wherein US clinics treat patients with HCT/Ps through their marketed adipose-derived stem cell treatments “do not appear to be congruent with how the FDA interprets the standard of…use,” according to Turner.

It doesn’t help that the legally unenforceable federal guidance may also fall out of step with the federal regulations officially on the books, or local and state regulations, which can be markedly different from federal rules.

These differences are known as hard law (on the books) and soft law (guidelines and suggestions) (Sleeboom-Faulkner et al, 2015), and the US clinics are a prime example of the various ways different jurisdictions view regulation and the “same surgical exemption,”rule — and the ways they flout it.

For example, Rick Perry, a one-time presidential candidate and current US Secretary of Energy has reportedly undergone treatments in his home state of Texas, and as governor loosened laws around the clinics to “bolster the stem cell industry”. (Cyranoski, 2013)

Another notable example is the 2012 case of Regenexx, in which the DC Circuit Court of Appeals ruled the procedure offered by the clinic “violated federal laws.” (Matthews and Iltis, 2015 and Cyranoski, 2012)

However, these cases did not make a dent in curbing similar violations by the other hundreds of clinics, likely because with such significant revenue, “clinics engaging in such commercial activity are unlikely to cease operating simply because the FDA has released [three] new draft guidances.” (Turner, 2015)

Last year, the FDA began to take the situation more seriously, and called for a series of hearings and an open comment period, indicating an openness to increased scrutiny on stem cell clinics. (FDA Hearing Part 15, 2016, McFarling, 2016)

However, the political wind has since shifted.

There are obviously concerns for the future of the FDA in the President Trump era. The agency is perpetually understaffed, and a look at the President’s 2018 draft budget shows it will likely also be underfunded, as well as headed by leadership that has less of a mandate to regulate cell-based therapies that are already active on the open market. (Achenbach and Sun, 2017)

In fact, according to recent news items, the future of the FDA may be funded almost entirely by industry user fees. (Humer, 2017) But this development may have a silver lining, in that if pharma giants wholly control the finances of the FDA, a push from the industry may be the way to crack down on untested treatments and rogue clinics.

The industry needs to step in

It is up to the pharmaceutical industry to put pressure on the FDA before stem cell clinics offering untested therapies damage the fragile reputation of cell-based therapies and responsible clinical trials, losing the trust of the public once and for all — and costing the industry millions in lost profits in the process.

There is already a bad feeling from the general public that the government and the pharma giants are “in cahoots” (Cyranoski, 2013) and that regulation is actually too strict (Howard, 2016). Patients and clinics believe “the FDA is being pressured into taking a tough line by academics and pharmaceutical giants who want to control, and profit from, the stem cell industry.” (McFarling, 2016). There is no evidence that this is true, yet it has driven patients into the waiting arms of the clinics.

In fact, the FDA has accelerated the routes for pharmaceutical uses of stem cells to enter the market, including allowing post-marketing trials and surrogate endpoints. (Sleeboom- Faulkner et al, 2016).

Scientists, including those researchers who work within pharmaceutical companies that are compelled to abide by tried and true safety standards and standardized methods for clinical trials, worry that “fraudulent clinics will negatively impact the reputation of the field” and threaten funding into further research. (Matthews and Iltis, 2015 and Cyranoski, 2013)

Experts believe there is a possibility to move forward, but the solution to saving stem cells must be a pragmatic one that recognizes the need for wide collaboration between all stakeholders, not only the federal government and industry leaders. (Matthews and Iltis, 2015)

This is obviously difficult, as “academic researchers will be left to walk a delicate line: Acknowledge the progress they’ve made in developing stem cell therapies — and then make the case that such treatments aren’t yet ready for prime time, and especially not in for-profit clinics.” (McFarling, 2016)

But to maintain support of research that abides by federal laws while curbing dangerous clinics, pharmaceutical companies will need to show leadership and encourage policies that will “connect, acknowledge and recognize the interests of stakeholders — the patients, the researchers, the regulators, and the investors.” (Matthews and Iltis, 2015)

And for the FDA’s part, a compelling case was made by Nature’s editorial board, suggesting regulators should endeavor to be open to creating a more efficient system with partners in the private sector and continue to contribute standards for safety and efficacy. (2016)

The FDA has committed to moving in that direction, and to work closely with investigators, sponsors and developers of stem cell therapies. (Marks et al, 2017).

Conclusion

Stem cells offer the remarkable possibility to revolutionize our conception of human disease, create new treatments, and save lives. However, outstanding safety issues must be at the forefront of any discussion regarding the creation of new policies to advance cell-based therapies.

Experts agree that the fact that researchers are beginning to see positive results in clinical trials for stem cell treatments of patients with MS, for example, have only been possible “because of decades of tedious work to establish safety protocols, test concepts and learn how to grow, produce and manipulate stem cells.” (McFarling, 2016)

The FDA must continue to insist on its role as gatekeeper for safety and efficacy, and make it clear to the public that the idea that regulation is too strict is a misunderstanding. (Turner, 2015 and Nature, 2016)

If the FDA and pharmaceutical industry continue to rest on their laurels when it comes to ferreting out the legitimate from the herd of rogue clinics, patient lives may be at stake, as well as the reputation of stem cells themselves.

The pharmaceutical industry is already on the right path, by partnering with smaller stem cell research bodies both at home and abroad. (Minger, 2013) By utilizing their role as industry lobbyists, pharmaceutical leaders may be able to bring stakeholders together and create meaningful policy that will suit a contemporary stem cell marketplace that prioritizes patient safety.

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