Historically, FDA has stated in various contexts that it does not intend to regulate the practice of medicine. Indeed, the Federal Food, Drug, and Cosmetic Act contains an express provision to this effect applicable to medical devices,[1] and FDA frequently applies the same concept to drug and biologic regulation. Although FDA’s abstention from regulating the practice of medicine typically refers to the matter of off-label use of approved or cleared drugs or devices, the area of FDA discretion may have a broader scope. The relatively new emergence of stem cell therapy represents an interesting case that requires the agency to determine whether and under what circumstances it will exercise its enforcement authority over the practice of medicine. Today FDA issued long-awaited new guidance on its enforcement approach to stem cell therapy and related forms of medical treatment.
Background
Stem cell therapy is under exploration for a wide range of potential applications. While FDA established regulations[2] in 2001 governing certain uses of human cells, tissues, and cellular and tissue-based products (“HCT/Ps”) – including stem cells – and defining the circumstances under which such materials would or would not require FDA premarket approval, FDA’s affirmative approval of stem cells for specific indications has thus far been limited.
FDA is clearly concerned about potential abuse of the “practice of medicine” concept with respect to stem cell therapy. In enforcement actions taken in August of this year against StemImmune, Inc., California Stem Cell Treatment Centers, and US Stem Cell Clinic, LLC., FDA took the position that the product administered to patients did not qualify for the exemption from premarket approval established in 21 CFR Part 1271. In its Warning Letter to US Stem Cell Clinic, FDA explained that this was primarily because the clinic’s product, derived from adipose structural tissue, was more than “minimally manipulated”[3] and was intended for treatment of a variety of diseases, rather than for “homologous use” (i.e., use of cells or tissues that perform one or more of the same basic functions in the recipient as they performed in the donor). [4] In an August statement, FDA Commissioner Scott Gottlieb, MD, noted “one of the most promising new fields of science and medicine is the area of cell therapies and their use in regenerative medicine.” Dr. Gottlieb went on, however, to say that “[t]here are a small number of unscrupulous actors who have seized on the clinical promise of regenerative medicine, while exploiting the uncertainty, in order to make deceptive, and sometimes corrupt, assurances to patients based on unproven and, in some cases, dangerously dubious products.”
As stated by Dr. Gottlieb, it is FDA’s task to define when stem cell treatments are medical products subject to FDA’s regulation and when they are therapies individualized by practitioners in such a way that they are not subject to FDA regulation. Under current regulations at 21 CFR Part 1271, certain medical uses of cells and tissues (e.g., homologous use of minimally manipulated material) may generally occur without FDA premarket review.
However, where FDA premarket review is indicated, there is also the risk that FDA regulation will impede innovation in the stem cell therapy area. The agency has committed to establishing policy to more clearly define the forms of stem cell treatment that do not require premarket review (the practice of medicine) and, for those that do require premarket review, to develop an approval process that is minimally burdensome and facilitates innovation.
In essence, FDA regulatory and enforcement guidelines, in the context of stem cell therapy, would define when the practice of medicine becomes the creation of a new drug, biologic or device in interstate commerce, and hence subject to FDA premarket approval. As indicated by FDA’s new proposed policy on direct-to-consumer genetic tests, for example, the agency in the current climate appears to be committed to adopting flexible approaches to regulations.[5] The policy on regulation of stem cell therapy and premarket approval procedures ideally would also adopt a flexible regulatory framework.
New FDA Guidelines
On November 16, 2017, FDA announced issuance of a comprehensive framework for the development of regenerative medicine products, including novel stem cell therapies. In two Final Guidance documents, FDA clarified certain provisions of 21 CFR Part 1271 that bear on whether and how HCT/Ps will be regulated by the agency. In its Final Guidance entitled “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception,” FDA stated its view that autologous cells or tissues that are removed from an individual and implanted into the same individual without intervening processing steps beyond rinsing, cleansing, sizing, or shaping, raise no additional risks of contamination and communicable disease transmission beyond that typically associated with surgery. Medical practitioners providing stem cell or other cell or tissue-based therapy falling within the “same surgical procedure” exception are not required to register the establishment (if not otherwise required to register), list the product, or obtain FDA premarket clearance. The guidance clarified that removal and implantation procedures occurring a number of days apart at the same establishment may be considered the “same surgical procedure” under certain limited circumstances and gives several examples of medical procedures that may qualify.
In a second Final Guidance entitled “Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use,” FDA clarifies how these terms will be applied for purposes of Part 1271. These criteria are key to determining whether an entity offering a cell or tissue-based treatment will be required only to register their establishment and list the treatment product or also be required to obtain premarket approval from FDA. In applying the “minimal manipulation” definition, the guidance explains the different criteria that must be considered depending on whether the product is structural tissue or cellular/nonstructural. The guidance also expands on the requirement that the cell or tissue be for “homologous use” in order to be exempt from premarket approval under Part 1271. Finally, the guidance states FDA’s intent to temporarily exercise enforcement discretion for cell or tissue-based treatments that are not exempt from IND or premarket approval requirements under Part 1271. To give manufacturers time to determine if they need to submit an IND or marketing application in light of the new guidance and, if such an application is needed, to prepare the IND or marketing application, FDA generally intends to exercise enforcement discretion for the next 36 months, provided that the HCT/P is intended for autologous use and its use does not raise significant safety concerns.
In two separate draft guidances entitled “Evaluation of Devices Used with Regenerative Medicine Advanced Therapies” and “Expedited Programs for Regenerative Medicine therapies for Serious Conditions,” FDA proposes streamlined requirements for devices used in the recovery, isolation, and delivery of regenerative medicine advanced therapies (RMATs) established under the 21st Century Cures Act[6] and describes the expedited review programs that may be available to sponsors of regenerative medicine therapies. Both draft guidances have a 90-day comment period.
Conclusion
By virtue of adding needed clarity to key definitions and criteria – and by exercising enforcement discretion in the implementation of the new guidance – FDA’s new policies are welcome and expected to encourage innovation in the exciting new world of stem cell therapy. We would be happy to assist affected companies, institutions, and other entities in evaluating the new guidelines and their potential impact on operations and practices.
[1] 21 U.S.C. § 396 (“Nothing in this chapter shall be construed to limit or interfere with the authority of a health care practitioner to prescribe or administer any legally marketed device to a patient for any condition or disease within a legitimate health care practitioner-patient relationship. This section shall not limit any existing authority of the Secretary to establish and enforce restrictions on the sale or distribution, or in the labeling, of a device that are part of a determination of substantial equivalence, established as a condition of approval, or promulgated through regulations. Further, this section shall not change any existing prohibition on the promotion of unapproved uses of legally marketed devices.”).
[2] 21 CFR Part 1271; 66 Fed. Reg. 5447 (January 19, 2001).
[3] 21 CFR §1271.3(f)
[4] 21 CFR §1271.3(c)
[5] 82 Fed. Reg. 51633 (November 7, 2017).
[6] Under Section 3033 of the 21st Century Cures Act, RMAT is a regenerative medicine therapy (cell therapy, therapeutic tissue engineering product, human cell and tissue product, or combination, except those regulated solely under 21 CFR Part 1271) which (a) is intended to treat a serious or life-threatening disease, and (b) is supported by preliminary clinical evidence that the drug has the potential to address unmet medical needs.