Below we discuss the significance this carries for companies in the regenerative medicine space, and outline the potential risks of noncompliance. These risks go well beyond FDA enforcement, and include the possibility of FTC action, False Claims Act liability, product liability claims, and susceptibility to private lawsuits under the Lanham Act and similar state laws.
In 2017, FDA published a new regenerative medicine policy framework consisting of four guidance documents, which we previously discussed here. In this framework, FDA provided for a three-year period of risk-based enforcement discretion for certain human cell, tissue, or cellular- or tissue-based products (HCT/Ps) ending in November 2020. This “grace period,” initially planned to last three years, was meant to give certain manufacturers time to assess whether they need to file an investigational new drug application (IND) or marketing application with FDA, or whether they met the four regulatory criteria for continuing to market their products solely under the authority of section 361 of the Public Health Service Act (PHSA), which does not require pre-market review and approval. In July 2020, citing challenges presented by the COVID-19 pandemic, FDA extended this grace period by an additional six months until May 31, 2021, as we summarized here.
FDA’s growing frustration despite efforts to help industry achieve compliance
Aligned with its goals of helping regenerative medicine companies determine whether they needed to seek FDA approval, in June 2019, FDA implemented a temporary program called the “Tissue Reference Group Rapid Inquiry Program” (TRIP), aimed at assisting HCT/P manufacturers, as well as stakeholders that market HCT/Ps, to “obtain a rapid, preliminary, informal, non-binding assessment from the FDA regarding how specific HCT/Ps are regulated.” We summarized the opportunities available through this program here. TRIP was initially planned to last until December 31, 2019, and was extended through March 31, 2021.
TRIP’s end signaled at that time that FDA would not extend again the enforcement discretion period for HCT/P sponsors. That signaling was consistent with other public messages emanating from FDA, as well as from private communications, portending FDA’s likely stepped-up enforcement in the regenerative medicine space. For example, in the June 2020 JAMA article, Drs. Marks and Hahn cited an “increasing number of adverse events” following the use of unapproved regenerative medicine therapies as cause for FDA to act to prevent harm. They sternly admonished: “Companies involved in selling products that violate the regulations do so under the erroneous assertion that they are exempt from these FDA provisions.”
Since 2019, FDA has issued more than 350 Warning Letters and Untitled Letters to manufacturers, clinics, and health care providers related to unapproved regenerative medicine products. Indeed, a series of recent agency actions – including FDA citations, warning letters, product seizures, and even criminal charges – have demonstrated the government’s growing seriousness and commitment to policing stem cell therapies, which we summarized here.
FDA will not extend HCT/P enforcement discretion period
In an FDA “Voices” blog post on April 21, Dr. Marks wrote that the agency will not again extend the “grace period” for HCT/P companies to come into compliance with its regenerative medicine policy framework. In that article, Marks emphasized that FDA has taken – and will continue to take – action regarding unlawfully marketed HCT/Ps. Marks pointed out that, since December 2019, FDA “has issued more than 350 letters to manufacturers, clinics, and health care providers, noting that it has come to our attention that they may be offering unapproved regenerative medicine products and reiterating the FDA’s compliance and enforcement policy.”
Thus, before May 31, when FDA’s period of enforcement discretion ends and the agency begins cracking down on firms operating in the space that do not comply with its regenerative medicine policy framework, it is imperative that HCT/P manufacturers, as well as stakeholders that market HCT/Ps – including distributors, billing companies and consultants, health economics consultants, clinics, and health care providers – assure they are in compliance with FDA standards.
Companies still marketing regenerative medicine (including tissue) products under the framework of PHSA section 361 and 21 CFR Part 1271 must seriously evaluate whether their products can still meet the criteria of 361 HCT/Ps after the period of enforcement discretion ends. Those companies should also consider all the risks of marketing if those products are deemed not to qualify. Those risks extend beyond FDA enforcement, and include the potential for:
False Claims Act (FCA) liability based on FDA and CMS regulations, as well as marketing practices
Private Qui Tam actions to try to enforce FCA requirements
Private claims for false advertising and unfair competition under the Lanham Act
State law false advertising, unfair trade practices, and unfair competition claims
Claims for product liability under state common law
Audits by Medicare and Medicaid contractors
Companies currently marketing HCT/Ps that do not meet the criteria of PHSA section 361 are faced with limited options if they wish to lawfully commercialize those products in the future. Of course, FDA would like to see companies in this situation submit an IND, initiate controlled clinical studies, and ultimately submit a marketing application. However, for many companies in this situation, the prospect of opening an IND and initiating registrational-quality clinical studies is daunting.
A number of significant questions arise in the context of companies that pursue an FDA approval for their HCT/Ps. For example:
Will FDA require companies in this situation to conduct preclinical animal studies before initiating clinical trials in humans?
Will companies be able to persuade FDA to accept data from previous human experience with their products to support moving directly into later-stage clinical studies (rather than being required to start with conventional phase 1 trials)?
If companies previously conducted uncontrolled open-label studies with their products, will FDA be willing to accept data from those studies in support of a marketing application?
If a company lawfully markets an HCT/P in other countries, could the company submit patient data from those countries to FDA as real world evidence in support of a regulatory approval?
Will companies in this situation be able to qualify for any of FDA’s expedited programs for serious conditions, such as Fast Track, Breakthrough Therapy, Accelerated Approval, or Regenerative Medicine Advanced Therapy designation?
It remains to be seen how flexible FDA will be in working with companies that make a good faith effort to pursue regulatory approvals for their HCT/Ps.
Patient access concerns
The likelihood of impending enforcement action raises concern over patient access to products that have been relied upon for many years, as companies may decide to pull their products from the market rather than seek FDA approval. The question remains whether firms that decide to remove their products from the market should try to make other arrangements for patients in need, such as by pursuing clinical studies or making their products available under FDA’s expanded access regulations (sometimes referred to as “compassionate use”).