Targeting the spread of unregulated Stem Cell and regenerative therapies

By: Kellsye Fabian, PhD

Image by Darko Stojanovic from Pixabay

Advances in regenerative medicine research have generated significant public interest in therapies that have the potential to restore the normal function of cells, tissues and organs that have been damaged by age, disease, or trauma. Investment and enthusiasm in this field have propelled the development of regenerative therapies such as cell therapy, bioengineered tissue products, and gene therapy. While several hundreds of these treatments have progressed to clinical trials, the Food and Drug Administration (FDA) has approved only a few regenerative therapies. Of these, most are stem cell-based products derived from umbilical cord blood used to treat blood cancers and immune disorders, and three are gene therapies to treat cancer or blindness. 

Alarmingly, an increasing number of businesses and for-profit clinics have been marketing regenerative therapies, mostly stem cell products, that have not been reviewed by the FDA. In 2016, there were 351 stem cell businesses offering interventions that could be administered in 570 clinics. That number was estimated to have doubled in 2018. Most of these establishments tout that their products can treat or cure serious illnesses and/or provide a wide range of benefits. These claims are often unsubstantiated. Moreover, these unapproved interventions pose a great danger to patients and have resulted in serious complications including blindness, infections, cardiovascular complications, cancer and death.

 Some patients remain willing to take the risks, especially those with serious diseases who have exhausted all possible conventional treatment or those that may be searching for alternative therapies. These individuals often fall prey to the overly optimistic portrayals of stem cell products in the media advertisements from stem cell companies. 

For years, these unscrupulous businesses have avoided heavy regulations. Physicians, researchers and ethicists, have urged for stricter monitoring of regenerative therapies as the commercial activity related to these interventions expanded. In response, the FDA has increased its oversight of the field and has issued guidance relating to the regulation of human cells, tissues and cellular or tissue-based products (HCT/Ps) to ensure that commercialized regenerative therapies are safe and are founded on scientific evidence.

FDA increased oversight 

Since 2017, the FDA has increased oversight and enforcement of regulations against unscrupulous providers of stem cell products. In 2018, the FDA sought permanent injunctions against two stem cell clinics, California Stem Cell Treatment Center Inc and Florida-based US Stem Cell Clinic LLC, for selling unapproved stem cell products and for significantly deviating from current good manufacturing practice requirements that ensure the sterility of biological products. 

The case against California Stem Cell Treatment Centers began in August 2017, when the US Marshals Service, on behalf of the FDA, seized five vials of smallpox virus vaccine from a clinic affiliated with California Stem Cell Treatment Centers. The vaccine was provided by a company called StemImmune and was being combined with stromal vascular fraction (SVF), which are cells derived from patient adipose (fat) tissues that consists of a variety of cells, including a small number of mesenchymal stem cells. This combined product was then administered to cancer patients in California Stem Cell Treatment Centers intravenously or through direct injection into patients’ tumors. 

Cancer patients have potentially compromised immune systems and the use of a vaccine in this manner could pose great risks, such as inflammation and swelling of the heart and surrounding tissues, to the patients. In addition, California Stem Cell Treatment Center provided unapproved treatments to patients with arthritis, stroke, ALS, multiple sclerosis, macular degeneration, Parkinson’s disease, COPD, and diabetes. The injunction case against California Stem Cell Treatment Center is still pending.

US Stem Cell Clinic also marketed SVF to patients seeking for treatment for conditions such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis. Three women with macular degeneration, an eye disease that causes vision loss, went blind after receiving eye injections of SVF products from US Stem Cell Clinic. Following these events, in June 2019 a Florida judge ruled that the FDA is entitled to an injunction against US Stem Cell Clinic, meaning that the FDA has the authority to regulate them and stop them from providing potentially harmful products.

While this decision strengthened the position of the FDA as a regulatory body for regenerative medicine, businesses have found different tactics to continue selling unapproved products. After the court ruling, US Stem Cell Clinic stopped selling the fat-based procedure. However, it said that it would continue to offer other stem cell treatments. Instead of stem cells derived from fat, which was the topic of the injunction, the company would now harvest cells from patients’ bone marrow and other tissues to “treat” different conditions. Another company, Liveyon, was given a warning by the FDA in December of 2019 for selling unapproved umbilical-cord blood-based products that were tied to life-threatening bacterial infections. Liveyon has since halted the distribution of its products in the US but has opened a clinic in Cancun, Mexico where it has continues “treating” patients outside the scope of the FDA. Other companies have changed their terminology and marketing language to escape the FDA crackdown against stem cell clinics. Instead of using the phrase “stem cells” in their websites and advertising, they now use “cellular therapy” and “allografts.”

The FDA’s Regulatory Framework for Regenerative Medicine

The warnings and injunctions filed by the FDA against the aforementioned stem cell businesses were in conjunction with the comprehensive policy framework for regenerative medicine that the agency announced in November 2017. The policy framework aims to clarify which medical products are subject to the agency’s approval requirements and to streamline the review process for new regenerative therapies. 

In the case of cellular and tissue products/procedure, there is often a gray area concerning what should be considered medical products, which are under FDA oversight, and what should be considered an individualized treatment being performed by a doctor within their medical practice, which is not regulated by the FDA. Stem cell clinics have often used this ambiguity as justification to sell products without FDA approval. According to the new guidelines, for cells and tissue to be exempt from FDA regulation, several criteria should be met: 1) they must be taken from and given back to the same individual during the same surgery, 2) they must not undergo significant manufacturing (minimal manipulation), 3) they must perform the same basic function (homologous use) when re-introduced to the patient, 4) they must not be combined with another drug or device, and 5) the benefits and risks must be well understood. If any of these criteria are not met, the cell or tissue is considered a drug or biologic and is subject to pre-market review of the FDA. Some ambiguities still persist in the current form of the policy, such as what constitutes “minimal manipulation” and how to address nonhomologous use (i.e. the cells or tissues are used in ways other than its original function). The guidelines are an important starting point in determining which therapies are under the FDA’s purview and continued dialogue between the FDA and stakeholders involved in product development will provide more clarity about how products will be classified.

The policy framework also addresses how the FDA aims to implement the regenerative medicine provisions of the 21^st Century Cures Act. Signed into law in 2016, the Cures Act is designed to expedite the development and review of innovative medical products. One of the new programs under this law is the Regenerative Medicine Advanced Therapy (RMAT) designation. A product is only eligible for RMAT designation if 1) it is a cell therapy, therapeutic tissue-engineering product, HCT/P, gene therapy, or combination product using any such therapy; 2) it is intended to treat, modify, reverse, or cure a serious condition; and 3) preliminary clinical evidence indicates that the therapy has the potential to address unmet medical needs for such condition. Stakeholders involved in product development strongly support the creation of this expedited review program. Meanwhile, others are concerned that the RMAT designation will lead to the approval of therapies based on fewer or smaller studies and, hence, treatment-related adverse events would emerge only after a product is on the market. But since RMAT therapies are intended to treat serious conditions, the risks may be acceptable and may be outweighed by the benefits to the patients. Nevertheless, postmarket studies would be essential and must be required to ensure the safety and efficacy of RMAT therapies. 

The establishment of these policy frameworks are definitely a step towards better regulation of the unbridled regenerative therapies. The increased enforcement of these new guidelines will hopefully dissuade unscrupulous businesses from taking shortcuts while encouraging legitimate companies to develop novel treatments. This will ensure that regenerative medicine will continue to be an exciting field that has the potential to provide innovative treatments that will improve human health. 

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