On the same day that FDA’s Commissioner, Dr. Scott Gottlieb, announced new policy initiatives regarding stem cell therapies and regenerative medicine, FDA announced stepped up enforcement in this area and posted a warning letter issued to U.S. Stem Cell Clinic located in Sunrise, FL. FDA issued the warning letter following an inspection beginning in April 2017, for marketing stem cell products without a valid license and deviations from current Good Manufacturing Practice (cGMP) for the cell-based products.
On the heels of the agency’s seizure action of StemImmune Inc. (reported in our prior post), the warning letter further signals the agency’s priority for enforcement against “unscrupulous clinics” that mislead vulnerable patients into believing that such treatments are safe and effective.
FDA observed the following deviations during the U.S. Stem Cell Clinic inspection:
361 HCT/P criteria – The agency determined that the product did not meet the criteria to be regulated solely under section 361 of the Public Health Service Act (PHSA) (42 USC 264) and 21 CFR part 1271.10(a) (the “361 HCT/P criteria”). Specifically, it failed the minimal manipulation and homologous use requirements – in other words, the product was more than minimally manipulated. The clinic processed adipose tissue (body fat) into stromal vascular fraction (stem cells derived from body fat), altering original relevant characteristics of the structural adipose tissue (see applicable draft guidance). The clinic then administered the product intravenously or directly into the spinal cord of patients to treat a variety of serious diseases or conditions. Those diseases included amyotrophic lateral sclerosis (ALS), Parkinson’s disease, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and heart disease. FDA stated that treating those diseases are not among the same basic functions of adipose tissue, such cushioning the body, and therefore not a homologous use. As a result, the company was marketing the product without the required biologics license.
cGMP deviations – FDA investigators identified several significant deviations from cGMP, including, among others, failing to establish adequate procedures to prevent microbiological contamination, validate aseptic and sterilization processes, and complete appropriate laboratory testing, such as sterility and endotoxin testing, which put patients at risk of infections.
Delaying inspection – FDA indicated that the company impaired the agency’s ability to conduct the inspection, including by refusing entry except by appointment. Such a refusal is a prohibited act under section 301(f) the Federal Food, Drug and Cosmetic Act (FDCA) (21 USC 331(f)). In addition, under section 501(j) of the FDCA (21 USC 351(j)), a drug is deemed adulterated if the inspection is delayed, denied, limited, or refused (see FDA guidance for details on what constitutes such actions).
Apparently one day after FDA posted the Warning Letter, U.S. Stem Cell Clinic submitted a response to FDA, which is also posted on the clinic’s website. Similar to its response to the Form FDA 483 issued following inspection, the clinic did not directly address any of the observations. Instead, the clinic claimed that the 361 HCT/P criteria and cGMP regulations are not applicable because it is not manufacturing a drug. The clinic also called the agency’s claim that it impaired the ability to conduct the inspection “blatantly false” and requested removal of the statement from the record. The clinic asserted that the activity is a medical procedure – the tissue is removed from the patient and re-implanted in the patient during the same surgical procedure – thus, is regulated by state medical boards and agencies with authority to regulate the practice of medicine. The clinic questioned FDA’s authority to regulate an individual’s ability to utilize his/her own cells for medical treatment, and requested that the agency respond to specific questions relating to its interpretation of the laws.
While FDA recognizes the potential for stem-cell therapy to improve patient outcomes, in an article published last November in the New England Journal of Medicine, former FDA Commissioner Robert Califf, M.D. and other scientists outlined the agency’s concerns arising from clinics marketing regenerative therapies derived from patients’ fat cells without compelling evidence from adequate, well-controlled clinical trials and without FDA approval. In addition some of these therapies, according to the article, have been associated with significant adverse events, including paraplegia and tumors leading to nephrectomy. In a March 2017 report, researchers presented cases of three patients who suffered permanent bilateral vision loss after fat tissue-derived stem cells were injected into their eyes at a Florida clinic (identified as U.S. Stem Cell Clinic in an article published by The New York Times and other media sources). The patients, ages 72 to 88, allegedly sought treatment based on an announcement of a study on ClinicalTrials.gov.
In the coming months, FDA anticipates implementing a comprehensive policy interpreting the applicable regulatory framework and defining a streamlined process to obtain the agency’s approval. And, in the meantime, FDA indicated that it will continue to take additional action against a “pool of actors who are clearly stepping over the line” and putting patient health at risk. FDA has not publicly responded to the clinic’s response, but we anticipate the agency will expect corrective action, based on FDA’s statements discussed above, as well as the 2014 D.C. Circuit decision in U.S. v. Regenerative Sciences, affirming FDA’s authority to regulate autologous stem cell procedures as drugs and biologics, and rejecting the practice of medicine defense.
We will continue to closely monitor and report on any developments on this. More (is promised) to come, so stay tuned.