How is Regenerative Medicine Regulated?
Promotion of regenerative medicine has a prominent place in the newly minted 21st Century Cures Act. Still, existing authority is not fundamentally altered, including the conditions of approval of such products.
Let’s posit autologous platelet rich plasma (PRP) as a test case. In reviewing protocols involving autologous PRP, IRBs often hear a common refrain: Investigators urge that preparation of the PRP with a cleared device covers the subsequent use or that the use falls within the practice of medicine unregulated by the FDA. The latter may well be true in the clinical context, which allows clinicians to use approved test articles off label, but research involving administration of autologous PRP is another matter.
If prospectively studying the safety and effectiveness of directly injected autologous PRP (such that the protocol dictates the procedure), prior FDA submission is likely necessary. A recent article relays a similar conclusion: “…for clinician researchers who intend to use PRP in an investigational manner to determine safety and efficacy, a formal review including IND or IDE and IRB approval is required.” How, then, is autologous PRP regulated? Let’s review the options.
At first blush, it may seem that PRP should be regulated as Human Cells, Tissues, and Cellular and Tissue-based Products (HCT/Ps). The FDA defines HCT/Ps as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” However, whole blood or blood components or blood derivative products subject to listing as biologics or drugs are not considered HCT/Ps.
Second, the FDA, in announcing a public hearing held in September 2016, explicitly recommended “…that comments exclude discussion of products that do not meet the definition of an HCT/P, such as platelet rich plasma and other blood products.”
Last, the 21st Century Cures Act specifically excludes HCT/Ps regulated solely under 21 CFR Part 1271 from the definition of regenerative medicine therapy. As a result, the inapplicability of premarket submission for homologous use of minimally manipulated cells does not apply.
It might then seem logical that PRP is regulated as a drug, or more specifically as a biologic; after all, PRP falls under the definition of a biologic. Yet, the question remains as to whether clinical investigations involving autologous uses of PRP may yet require an IND.1 There is, however, little to no explicit guidance on point.
The regulations in Part 312 generally require that human subject research be conducted under an IND if it is a clinical investigation involving a biologic, which is not otherwise exempt. An experiment in which a biologic is administered to one or more human subjects, where the biologic was not already lawfully marketed, would require an IND.
Still, it is not clear that an IND—and subsequent BLA—fits the situation, because autologous PRP cannot be marketed as a stand-alone product, since the product is derived from and administered to the same individual after processing with a device.
Many platelet separator systems are 510(k) cleared devices, with an intended use that includes preparation of PRP. This can include post-preparation uses for diagnostic tests and for mixing the preparation with autograft and/or allograft bone prior to application to an orthopedic site. At least in one instance, these uses were added as part of a modified 510(k). The fact that some indications include post-processing uses demonstrates that the mere clearance of the preparation device does not enable any subsequent use of the product.
The FDA supports this interpretation. In a 2009 warning letter, the FDA specifically required that a platelet separator system’s label declare: “The [PRP] prepared by this device has not been evaluated for any clinical indications.” Furthermore, the FDA rebuked the manufacturer for advertising that the device output has been evaluated for clinical indications in the area of sports medicine, signaling this represented a major change to the cleared intended use for the device that could significantly affect its safety or effectiveness. Finally, the FDA found the product adulterated and misbranded for failure to obtain premarket approval, clearance (510(k)), or an investigational device exemption (IDE).
Notably, the FDA did not cite statutes governing drugs and biologics (apart from one regarding misbranding, 21 U.S.C. § 352, that contains elements applicable to both drugs and devices).
How to Conduct Research Utilizing Regenerative Medicine Therapies
The research use of regenerative medicine therapies in which products are derived from and delivered back to the participant’s own body should be framed according to the indication for the device necessary to create the product. 2
The first consideration, then, is:
- Whether the proposed use of the product described in the protocol falls within the intended use, as identified in the 510(k) summary or other labeling.
If so, the clinical investigation is exempted from IDE requirements. Beitzel, et al. summarize the FDA’s stance on PRP as follows: “Per the FDA, PRP’s intended use is in an operative setting to mix with bone graft materials to enhance bone graft handling properties. Use outside this setting is considered to be off label.”
An FDA employee, presenting examples of “PRP devices” reviewed by CBER, appears to corroborate this: “Intended to be used to mix with bone graft materials to enhance bone graft handling properties in orthopedic practices; not intended for direct patient application such as injection or implant without prior mixing with the bone graft materials.”
Consequently, if finding the proposed use to exceed the intended use, which is likely to be the case for autologous PRP, the second hurdle is:
- Whether the proposed use of the device output does not pose a significant risk.
Potentially depending on the site of injection and available literature, conclusions may vary. Injection of a product into intervertebral discs would likely be viewed by the FDA as having potential for serious risk to the health, safety, or welfare of a research participant. Thus, an IDE would be required for such a study involving autologous use of a regenerative medicine therapy, such as PRP.
As always, early engagement with the FDA, the IRB, and/or a regulatory consultant is advised to streamline the envisioned research and avoid unexpected delay.
1 See generally U.S. v. Regenerative Sciences, 741 F.3d 1314 (2014) (holding that a mixture containing mesenchymal stem cells was a biologic regulated under part 1271 governing HCT/Ps and that the autologous use did not constitute the practice of medicine outside the FDA’s jurisdiction).
2 In further support, the following PMA was issued for a hematopoietic stem cell concentration device with an intended use that expressly includes administering the output to patients via infusion. See http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/PremarketApprovalsPMAs/UCM091901.pdf.