On February 3, 2014, the U.S. Court of Appeals for the District of Columbia Circuit upheld the U.S. Food and Drug Administration’s (FDA’s) position that Regenerative Sciences’ “Cultured Regenexx Procedure” was a biological drug subject to FDA approval through the biologics licensing application (BLA) process. U.S. v. Regenerative Sciences, LLC, 2014 WL 393602 (D.C.Cir. 2014). It also upheld the permanent injunction against the Company’s use of the drug without FDA approval. The Company asserted several alternate grounds for its position that the product was not FDA-regulated, including that: (1) the product is really a procedure governed by state “practice of medicine” rules rather than the Federal Food, Drug, and Cosmetic Act (FFDCA); (2) the product was not more than minimally manipulated, and, therefore, was included under an exemption from FDA approval; and (3) the product was a compounded product exempt from pre-approval. The court rejected all of these arguments.
The Cultured Regenexx Procedure involves extraction of mesenchymal stem cells (MSCs) from a patient, followed by cell expansion through cell culture techniques with or without added substances that aid in cell differentiation. The expanded MSCs are then combined with doxycycline (to control bacterial growth), and reinjected into the same patient (autologous use).
The case outcome was expected, given that the Cultured Regenexx Procedure involved significant processing of the cells. However, the court made several interesting conclusions.
First, the court made short work of the practice of medicine argument. Practice of medicine would apply to the actual injection/administration procedure in the patient, but the court said that procedure was not at issue. Instead, the court found that the manufacturing and distribution of the product were the steps that made the product a drug regulated by FDA and not a process under the practice of medicine. As a result, future arguments that a cell process is simply practice of medicine are probably not viable except in situations where there is very little or no processing of the cells.
Next, the court found that the product was more than minimally manipulated. Certain cell products that are not more than minimally manipulated are exempt from FDA approval requirements. The Company argued that FDA’s standard of minimal manipulation is too narrow and that its cell processing qualifies as minimal manipulation. The Company also stated that certain elements of FDA’s standards for minimal manipulation are invalid because they are found in a Federal Register preamble to the cell and tissue regulation and not in the actual regulation. The court rejected the Company’s arguments, stating that its finding was not based on FDA’s preamble statements that cell expansion is always more than minimal manipulation but, rather, based on the court record. As a result, the court did not address the validity of FDA’s minimal manipulation standard.
The court also noted that the Company admitted that its culturing process is designed to select cells for growth and biological characteristics. Thus, the process is more than minimal manipulation. By making this conclusion, the court did away with the Company’s legal argument that the preamble statement was invalid rulemaking.
Finally, the court rejected the Company’s position that its product was subject to pharmacy compounding rules and exempt from FDA approval. The court found that the ingredients in the product do not meet the statutory definition of “bulk drug substances,” and, therefore, cannot be used in compounded drugs.
The issue of whether the product was in interstate commerce (a requirement for FDA jurisdiction) was only briefly discussed, and the court held that FDA did in fact have jurisdiction.
The case outcome was not unexpected. The underlying District Court decision was well-reasoned, and the Regenexx product was not a good candidate for arguing an exemption to FDA preapproval requirements. Nevertheless, preapproval safe harbors and exemptions still exist.
FDA’s regulation of and policy for minimal manipulation still leave some room for cell therapy products that do not undergo the same level of processing as the Cultured Regenexx Procedure. Cells that do not use added components and that do not undergo cell culture expansion may avoid regulation. Additionally, the court left a narrow window open for expanded cell products if the Company could demonstrate that the processing does not alter the cells’ relevant biological characteristics. Nevertheless, sponsors of cell products that are cultured or expanded are likely to have a difficult time arguing that their products are only minimally manipulated.
The court devoted little time to the analysis of the compounding question, but there may be some room for compounded cell therapy products. The court only addressed drugs compounded from bulk pharmaceutical ingredients and noted that the Regenexx product did not meet that requirement. However, the FFDCA also permits compounding from non-bulk ingredients if certain requirements are met. It may, therefore, be possible for cell processing to meet those requirements.
The Regenerative Sciences case is, therefore, an important decision that continues to explore the boundaries of FDA’s jurisdiction over cell and tissue product regulation, as well as the interpretation of FDA’s regulations on these products. Further court challenges will undoubtedly continue.