FDA Regulation of HCT/Ps: What Wound Care Practitioners Need to Know

Editor’s Note: The following article discusses products characterized as “cellular and/or tissue-based products” (CTPs) by ASTM International. For purposes of this article, the legal and regulatory definition “human cells, tissues, and cellular- and tissue-based products” (HCT/Ps) – is used.

Chronic wound care is a field with increasing importance as the incidence of diabetes rises dramatically in the United States. The last 10 years have seen significant increase in the number of human allograft products marketed for the treatment of chronic wounds. Four draft guidance documents relating to the U.S. Food & Drug Administration’s (FDA’s) regulation of human cells, tissues, and cellular and tissue-based products (HCT/Ps) for skin wounds will, when finalized, have significant implications for the industry. In September, the FDA held a high-profile meeting that sought to collect stakeholder feedback before finalizing the guidance. This article will discuss what providers in the wound clinic need to know.

What Are HCT/Ps?

HCT/Ps are biological products that are “intended for implantation, transplantation, infusion, or transfer into a human recipient.” There are many types of HCT/Ps that are appropriately marketed for use in repairing, replacing, reconstructing, or supplementing a patient’s own damaged or diseased tissues and organs. Some HCT/Ps are also intended for therapeutic indications that fall outside these traditional HCT/P uses. 

One increasingly common area where HCT/Ps are used is the treatment of chronic wounds, including diabetic foot ulcers and venous leg ulcers. Today, there are dozens of HCT/Ps on the market for these indications.

Why Is Guidance Needed Concerning HCT/P Regulation?

In 2001, the FDA established a tiered, risk-based approach to the regulation of HCT/Ps. Under this approach, some human tissue products (those that meet certain criteria set forth in the FDA’s regulations) are regulated pursuant only to Section 361 of the Public Health Service Act (PHSA) and are essentially “fast tracked” to market. These criteria include, primarily, that a product is minimally manipulated, intended for homologous use, and does not depend on the metabolic activity of living cells to achieve its primary function. 

HCT/Ps that meet the regulatory criteria are subject to controls intended to minimize infectious disease risks, but there is no requirement to obtain premarket approval from the FDA. By contrast, HCT/Ps that do not meet regulatory criteria are subject to regulation under Section 361 of the PHSA and regulation as biological products under the Federal Food, Drug, and Cosmetic Act (FFDCA). As biological products, they must have FDA premarket approval, typically in the form of a biologics license application. These products are rigorously reviewed by the FDA and must undergo large-scale prospective, randomized clinical trials demonstrating safety and efficacy.  The regulatory burden is thus significantly greater for HCT/Ps regulated as biologics than it is for HCT/Ps that may be marketed as Section 361 HCT/Ps. Perhaps the most striking aspect of the HCT/P regulatory framework is that it’s left to a product’s distributor to make the determination as to whether the product satisfies the criteria for marketing as a Section 361 HCT/P, thus escaping the necessity for premarket approval, as well as post-market advertising and promotion oversight and comprehensive adverse event-reporting requirements. Over the last 5-8 years, there has been growing concern among some regulators, clinicians, biological product distributors, and patient communities that some HCT/Ps are being marketed under Section 361 of the PHSA when they do not actually meet the requirements for marketing under this simplified pathway. These stakeholders believe the Section 361 pathway is appropriate for traditional allograft products, but does not provide adequate oversight when applied to cell and tissue-based products (CTPs) that interact with, or are claimed to interact with, the body in complex ways. In the context of wound care, for example, there’s little argument that the Section 361 framework is appropriate for allografts intended as simple wound-covering products because the primary concern with those products is to ensure they don’t transmit disease from donor to recipient. But many believe it’s poorly suited for products that are intended to mediate the wound healing cascade to overcome stalled healing because those products require more rigorous oversight to ensure their safety and efficacy. These stakeholders also believe it may be difficult for busy clinicians who are treating patients with hard-to-heal wounds to distinguish FDA-reviewed products from those that are not. As a result, there’s concern that patients may not be receiving evidence-based care. Regulators and other stakeholders believe the four draft guidances, when finalized, will help ensure that only products that genuinely satisfy the existing regulatory criteria will be marketed under the Section 361 pathway in the future, while those that do not will be appropriately subjected to the additional patient safeguards found in the FFDCA and the FDA’s implementing regulations. On the other hand, the allograft industry and allied stakeholders argue that, because their products have so little in the way of regulatory oversight, they are more cost effective for patients. They also argue there is no evidence that patients have been harmed by the absence of premarket review of these products. However, proponents of additional regulation claim that, because the only adverse events that must be reported to the FDA for Section 361 are incidents involving disease transmission, the lack of evidence of patient harm is illusory.

What Happens Next?

FDA’s draft guidance is intended to bring clarity to the industry as to the appropriate application of the existing regulatory criteria for marketing a HCT/P under the Section 361 pathway — clarity that is particularly necessary in light of the fact that HCT/P distributors are the arbiters, in the first instance, of whether their products meet those criteria. The guidance has not yet progressed beyond the proposal stage and won’t do so in the immediate future. Most analysts believe the updated documents will not be released before President-elect Donald Trump enters office early in 2017. A pessimistic view suggests an official issuance will not make its way through the pipeline until fall 2017. Nevertheless, it’s unlikely that action on the draft guidance will be abandoned entirely. For the reasons discussed in this article, finalizing the draft guidance will put to rest many of the questions surrounding the regulatory status of CTPs, particularly those intended for complex wound healing functions. In more general terms, finalizing the guidance is critical to ensure consistent, predictable, even-handed regulation that fosters the innovation needed among patients living with chronic wounds that are unresponsive to existing therapies. 

James R. Ravitz leads the food, drug, medical device, and agriculture practice at Arent Fox LLP,  Washington, DC. Naomi J.L. Halpern is a counsel at Arent Fox and advises clients on regulatory issues involving the FDA.