The potential use of stem cells for the treatment of human disease finds its roots in the 1961 when two scientists, Drs. James Till and Ernest McColluch serendipitously found that the intravenous injection of bone marrow cells in mice previously treated with radiation led to the growth and proliferation of cells in the spleen of the animals, leading to the clinical application of bone marrow transplant.  Since then, use of peripheral blood or bone marrow have built a long history in the medical community, especially in the oncology space.  Much academic research has also been done on using pluripotent stem cells for a variety of potential applications.

Most recently, we’ve seen the proliferation of “regenerative” medicine uses for stem cells derived from adult, amniotic, fat-derived bone marrow and other tissues.  According to a study published in August of 2016, there were already 351 US businesses engaged in direct-to-consumer marketing of stem cell therapies in 570 clinics, no doubt a fraction of the number today.  Due to the regulatory framework that has lagged behind this trend, many raise alarm that these represent expensive, unproven, scientifically dubious treatments being marketed as cures for a wide variety of diseases and disorders.

The Regulatory Landscape

When regenerative stem cell products began to be developed, these products derived from human donors initially followed regulations designed to protect the public from transmissible disease (Public Health Service [PHS] Act Sections 351 and 361).

In 2005, FDA exerted regulatory oversight of human cell, tissues and tissue-based products (HCT/Ps) that are minimally manipulated and intended for homologous use only (21 CFR 1271). The manufacture of these products must not involve the combination of cells or tissues with another article and must not have a systemic effect unless designated for autologous transplantation, first- or second-degree-related allogenic transplantation, or reproductive use. These products do not require pre-market approval and initially included tissues such as corneas and heart valves.  Any tissue products outside of these parameters is subject to the familiar requirements for pre-market approval of drugs, biologics, and devices.

The limits of “minimally manipulated” and “homologous use” have been tested by the introduction and use of regenerative stem cell therapies, such as mesenchymal tissues which are removed, processed, and reinfused/injected into the patient. The FDA responded with a guidance document in November 2017 that clarifies “minimal manipulation” and “homologous use.” This guidance also revealed that many of the products previously assumed to qualify for these characteristics in fact do not, and are thus subject to premarket regulations governing drugs, biologics and devices.

Additionally, an exception found in 21 CFR 1271.15(b) which includes “an establishment that removes HCT/Ps from an individual and implants such HCT/Ps into the same individual during the same procedure” was applied by product manufacturers to regenerative stem cell therapies. However, FDA’s guidance clarified that many of the products being sold and used under this exception do not actually qualify and are thus subject to pre-market approval requirements.

The 21st Century Cures Act of 2016 established the Regenerative Medicine Advanced Therapy (RMAT) designation for cell and tissue products, though the RMAT criteria admittedly encompass only a fraction of the regenerative stem cell therapies. And though this pathway provides a potentially less burdensome and expensive approval process, of the 97 RMAT applications received since December 2016, only 31 have been granted, while 53 were denied.

The sheer volume of potentially noncompliant products and their uses has become so great that the FDA granted a 3 year “discretionary enforcement” period that ends in December 2020. During this period, all manufacturers of these products are expected to re-evaluate their products in light of the guidance and re-justify their classification.

Exerting Oversight

In the meantime, a gap in guidance and oversight to assist those developing and employing HCT/P products has developed in the landscape of regenerative stem cell therapies. As reports of serious injuries related to the use of stem cell products mounts, state governments, professional governance organizations, and others have stepped in to bring order to the scene.

  • The Federation of State Medical Boards created a Workgroup to Study Regenerative and Stem Cell Therapy Practices which resulted in the adoption and publication of a policy on Regenerative and Stem Cell Therapy Practices in April of 2018.
  • The International Society for Stem Cell Research (ISSR), in existence since 2002, published a series of articles and guidances to advise clinicians, researchers and IRBs on the conduct of clinical trials to assure the ethical and scientifically responsible use of these products.
  • State governments have also stepped in to protect the public from what was seen to represent unproven, risky and costly treatments. To date, laws have been enacted in California, Washington, Florida, Texas, and others that impose controls over the use of these products.

Discretionary Enforcement

The “grace period” offered by the FDA in its discretionary enforcement statement did not indicate that the federal agencies would leave the public and medical community unprotected and uniformed. In addition to the guidances previously mentioned, successive FDA commissioners Robert Califf, MD, and Scott Gottlieb, MD, published articles in the New England Journal of Medicine in March of 2017 and March of 2018 respectively. Dr. Califf’s article focused on the unproven nature of many of these products and warned of the risks related to their use. He also assured the medical community that the FDA would address the challenges related to these products and provide guidelines for their development and pathway for approval. Dr. Gottlieb’s article clearly laid out the current regulatory construct imposed on these products and proposed a pathway to assure that these therapies are safe and effective. The FDA has also issued warnings to the public advising them of the “illegal and potentially harmful” stem cell treatment offered by “dishonest and unscrupulous stem cell clinics”.

Addressing the Bad Actors

The FDA and FTC have both stepped in to crack down on the more egregious offenders in this scene. The FDA has issued 483s and warning letters to stem cell clinics finding that their products do not meet the criteria of “minimally manipulated” and exception under “same surgical procedure” criteria. They also fault clinics on good manufacturing practices. In October of 2018, the FTC imposed a $3.31 million judgment against a California-based physician and his stem cell clinics which also mandates refunds to consumers harmed by “the defendants’ allegedly deceptive conduct”. These events can only be perceived as a taste of what is to come as the agencies bring the situation under control.

The Challenge to Physicians, Institutions, and IRBs

The tenuous situation surrounding stem cell therapies presents many challenges for institutions, physicians, and IRBs. During this period of uncertainty and risk, institutions balk at permitting their clinicians to pursue the use of these products, while consumers, convinced of their worth by abundant but anecdotal “evidence” clamor for access, even at great expense. Clinicians interested in safe and ethical use of these products are stymied by the costs and regulatory burden of pursuing approval within the premarket approval process. Stem cell product manufacturers, already profiting from the sale of their products during this period of “discretionary enforcement,” will soon be scrambling to meet the regulatory criteria for continued distribution and sale of their products with the December 2020 deadline fast approaching.

Where Do We Go From Here?

All of the players in this landscape agree on one thing: valid clinical safety and effectiveness data is essential for continued safe and ethical use. All are aware of the huge expense and burden of mounting phase I-III clinical trials common to the drug industry and are paralyzed into inaction. In the 2018 NEJM article, Marks and Gottleib propose a novel and possibly workable approach: encourage individual or small groups of physicians to collaborate in the development of regenerative stem cell products for use in each respective clinic under one Biologics License Application (BLA). They also propose the use of “real-world data” in support of such BLAs. The proposal calls upon IRBs to assure that any clinical research done in pursuit of approval for these products are ethical and scientifically sound. Fortunately, the International Society for Stem Cell Research advice for IRBs offers a comprehensive framework for the review of stem cell trials.

And then there are the research practitioners, each of us in our various roles in the medical and clinical research community who are often identified by family and friends as the one who can advise and guide them through this labyrinth. The grandmother or aunt who reads the anecdotal reports on social media claiming dramatic cures for arthritis or other problems common to aging.  The niece or nephew who learns of a dire diagnosis and in their desperate internet search finds a clinic in a distant location offering treatments and cures using stem cells.  Each of these ready to take on great, out-of-pocket expense for what is likely untested treatment.  If nothing else, being well informed will serve us best.

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