FDA Extends Enforcement Discretion Period For Regenerative Medicine Products, But This Isn't A Green Light For Bad Actors

By Chad Landmon, partner and chair, Axinn’s Intellectual Property and Food and Drug Administration practice groups, and Michelle Divelbiss, associate, Axinn’s Intellectual Property practice group

Human cells, tissues, and cellular and tissue-based products (HCT/Ps) have emerged as an exciting and lucrative area of regenerative medicine, and the regenerative medicine industry has paid close attention to FDA and its regulatory practices. Cutting edge scientific advances often do not fit into narrowly tailored regulatory schemes, but FDA has worked to “adapt [its] regulatory model to meet the revolutionary nature of the products [FDA is] being asked to evaluate.”[1]

In another win for advocates of a flexible and workable approach to the regulation of HCT/Ps, FDA recently extended its discretionary enforcement period by six months due to challenges presented by the COVID-19 pandemic. FDA will continue to focus enforcement efforts on HCT/Ps that pose a higher risk to patients and will focus less on products deemed to pose a lower risk.  With this extension, many in the industry can breathe a sigh of relief that there appear to be no major changes to HCT/P guidance or enforcement objectives, at least until May 2021.

I. HCT/Ps Are Important for the Continued Development of Regenerative Medicine

HCT/Ps are “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.”[2]  For example, an individual with a ruptured ACL may have undergone surgery to replace it with an ACL from a cadaver, and someone with severe burns might receive skin grafts with skin from a cadaver.  Both the cadaver ACL and skin are considered HCT/Ps. These products are not necessarily drugs, devices, or biologics, and instead often require a slightly different approach to regulation.

II. Regulation of HCT/Ps

FDA’s latest guidance applies to products regulated under 21 C.F.R. Part 1271, which “create[s] an electronic registration and listing system for establishments that manufacture . . . [HCT/Ps] and . . . establish[s] donor-eligibility, current good tissue practice, and other procedures to prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps.”[3] 

HCT/Ps are not all subject to the same approval and safety regulations. If an HCT/P is minimally manipulated and for homologous use only, among other requirements, the product is regulated under section 361 of the Public Health Service Act (PHS Act).  Section 361 is principally concerned with safety and preventing the spread of communicable diseases.  If the product does not meet these specific criteria, however, it is subject to premarket approval because it is regulated as a drug, device, or biological product under the Federal Food, Drug, and Cosmetic Act (drugs and devices) and/or section 351 of the PHS Act (biological products).  As many in the industry know, premarket approval can be a long and expensive process, and it is often advantageous to avoid it, if possible.

III. HCT/Ps Are Regulated Based on Presumed Risk and Safety Concerns

To determine whether an HCT/P is subject to section 361, it must be determined whether the product is “minimally manipulated” and intended for “homologous use.”  The definition of minimal manipulation depends on whether the tissue is considered structural or not.  Structural tissues, such as bone, skin, blood vessels, articular cartilage, adipose tissue, and tendons, are minimally manipulated if there is “processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement.”[4]  In contrast, non-structural tissues, such as reproductive cells, pancreatic tissue, and peripheral nerves, are minimally manipulated if there is “processing that does not alter the relevant biological characteristics of cells or tissues.”[5]  FDA has found that “[p]rocessing that alters the original characteristics of the HCT/P raises increased safety and effectiveness concerns for the HCT/P because there would be less basis on which to predict the product’s function after transplantation.”[6]  Methods for shaping the product are often considered to be a minimal manipulation of the product.  For example, “shap[ing] bone into dowels, screws, and pins” involves minimal manipulation “because the processing does not alter the bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.”[7]

In addition to being minimally manipulated, a product must also be intended for homologous use to be subject to section 261.  Homologous use refers to “the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor.”[8]  FDA believes that products intended for non-homologous use are “more likely to raise significant safety concerns than HCT/Ps intended for homologous use because there is less basis on which to predict the product’s behavior in the recipient . . . .”[9]  To determine intent, FDA looks only to “the labeling, advertising, or other indications of the manufacturer’s objective intent.”[10]

FDA’s guidance provides some illuminating examples.  For obvious reasons, FDA considers the use of “a heart valve . . . transplanted to replace a dysfunctional heart valve” to be homologous use “because the donor heart value performs the same basic function in the donor as in the recipient of ensuring unidirectional blood flow within the heart.”[11]  FDA also finds that pericardium “used as a wound covering for dura mater defects . . . is homologous use because the pericardium is intended to serve as a covering in the recipient . . . .”[12]  Even though the pericardium, a membrane enclosing the heart, is being used to cover the dura mater, a membrane enclosing the brain and spinal cord, the basic function is the same. 

When determining whether a product is intended for homologous use, this “same function test” provides ample opportunity for creative thinking and advocacy.  For example, FDA guidance describes the basic functions of amniotic membrane, which “include serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero.”[13]  FDA states that “[a]n amniotic membrane product [that] is used for wound healing . . . is not homologous use because wound healing . . . [is] not [a] basic function[] of amniotic membrane.”[14]  Nevertheless, an amniotic membrane could also be described as having the basic function of serving as a cover and protecting the growth and development of new cells.  Presented in this way, an amniotic membrane product used for wound healing might be considered homologous use because the product is serving as a cover to the wound and protecting the growth and development of new cells.

Because FDA looks to a manufacturer’s subjective intent, it is important to have a cohesive plan to advocate for the designation of minimally manipulated and intended for homologous use.  This advocacy plan should be coordinated among R&D, labeling, marketing, and the regulatory team for the best chance of regulation under section 361 of the PHS Act.

IV. FDA Will Continue Its Risk-Based Approach to Enforcement Until May 2021

In FDA’s 2017 guidance for HCT/Ps, FDA announced it would exercise enforcement discretion until November 2020.  This period was intended to provide additional time for manufacturers to work with FDA to determine whether their regenerative medicine products will be subject to section 361 of the PHS Act with a focus on safety or subject to other sections requiring regulatory approval. 

During this time of exercising its enforcement discretion, FDA stated that it will focus its enforcement activities on products that are higher risk.  FDA describes minimally manipulated and homologous use products as well as those administered by “intradermal, subcutaneous, or intra-articular injection” as lower-risk products.[15]  Higher risk products, however, are those that are not both minimally manipulated and intended for homologous use.  Additionally, “products with routes of administration associated with a higher risk . . . [include] those administered by intravenous injection or infusion, aerosol inhalation, intraocular injection, or injection or infusion into the central nervous system.”[16] 

On July 20, 2020, however, FDA announced that it will extend this enforcement discretion period until May 31, 2021.  FDA has been taxed dealing with the COVID-19 pandemic, and this extension will relieve some of the pressure on both FDA and manufacturers.  HCT/P manufacturers will now have additional time to evaluate whether their products are subject to regulation as a drug, device, or biological product and to prepare and submit documentation for approval, if needed. 

Peter Marks, M.D., Ph.D., director of FDA’s Center for Biologics Evaluation and Research, has cautioned, however, that FDA’s enforcement discretion policy “was never intended to provide a cover for bad actors, and [FDA] intend[s] to continue to take action against manufacturers and health care providers who are offering unapproved regenerative medicine products that have the potential to put patients at significant risk.”[17]  Thus, it is imperative that regenerative medicine companies continue to evaluate their products to determine the appropriate regulatory paradigm.

In addition, this extension of FDA’s enforcement discretion provides a unique opportunity for companies to properly align their regulatory strategy. Manufacturers of HCT/Ps may now have some additional time to advocate before FDA for a determination that their products be considered minimally manipulated and homologous. On the other hand, if a company has determined that its regenerative medicine products are more akin to a drug, medical device, or biologic, this additional time period can be used to navigate any required FDA approval regimen. At the end of the day, regenerative medicines are playing an increasingly important role in our healthcare system, and companies need to remain mindful of FDA’s increased focus in this area.