In FY 2020, FDA issued nearly two dozen warning letters and untitled letters to human cell and tissue product (HCT/P) manufacturers marketing products they claim will treat various diseases and life-threatening conditions—including cancer, amyotrophic lateral sclerosis, Alzheimer’s, autism, arthritis, stroke, multiple sclerosis, macular degeneration, Parkinson’s disease, chronic obstructive pulmonary disease (COPD), and many others—without proof of the claims and agency approval.

At the PDA/FDA Joint Regulatory Conference held virtually in mid-September 2020, Biological Drug and Device Compliance Branch Chief, Division of Case Management in CBER’s Office of Compliance and Biologics Quality Maria Anderson provided a CBER compliance update focusing on compliance actions the agency has taken regarding HCT/P products this year.

She noted that in FY2020, CBER took 22 compliance actions, most of which pertain to HCT/Ps that did not meet the criteria set forth in 21 CFR1271 section 10a—products that the manufacturers believed did not require FDA approval to market, but the agency determined otherwise.

They also failed to qualify for the surgical procedure exception found in 21 CFR1271.15b. The products were not subjects of approved Biologic License Applications (BLAs). No INDs were in effect. And their actions violated the Food, Drug and Cosmetic Act (FD&C ACT) and Public Health Services Act (PHS Act).

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Patients were treated with these products by various routes of administration. These routes of administration were associated with higher risk so, if contaminated, the products could cause a range of adverse events from infection to death.

First, What are HCT/Ps?

FDA defines HCT/Ps in 21 CFR Part 1271 as “articles containing or consisting of human cells or tissue that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” There are two broad categories of HCT/Ps with quite different regulatory requirements, defined under sections 351 and 361 of the PHS Act.

Which section a product falls under can be a source of confusion, specifically regarding the interpretation of the terms “minimal manipulation” and “homologous use.” An HCT/P regulated solely under Sec. 361 has extremely specific properties and does not require an IND or premarket approval—the company or individual simply needs to declare that they meet the description of a 361 product.

There are those who think they meet the 361 requirements and market a product without agency approval but find out later that the agency disagrees. Anderson’s review focuses primarily on warning letters and untitled letters issued to firms that fall into this category.

COVID-19 Enters the Scene

The CBER branch chief explained that on January 31, the Department of Health and Human Services issued a declaration of a Public Health Emergency related to the novel Coronavirus (COVID-19), and mobilized the department’s operating divisions. On March 13, the U.S. President declared a National Emergency in response to COVID-19.

“As our agency diligently works with other regulatory bodies around the world to expedite the development and availability of safe and effective vaccines to address the COVID-19 pandemic, FDA is taking urgent measures to protect consumers from unlicensed, unapproved and unauthorized products claiming to treat, mitigate, prevent, diagnose, or cure COVID-19 in people,” Anderson stressed.

5 Warning Letters/4 Untitled Letters

During FY2020, CBER—sometimes jointly with other federal agencies—issued five warning letters and four untitled letters to firms marketing products that claimed to treat, cure, or vaccinate against COVID-19. In general, an untitled letter is issued after a review of a company’s website and/or Facebook page, whereas a warning letter results after a physical inspection. Figure 1 lists the date the letter was issued, the company, the product, and the disease(s) the product claims to cure or prevent, whether the firm received a warning letter or an untitled letter, and pertinent notes.

**FIGURE 1 | COVID-19 Warning Letters and Untitled Letters Issued in FY2020**

FDA Takes Compliance Actions

The products at issue in other compliance actions were intended to treat serious and life-threatening diseases and conditions other than COVID-19, Anderson explained. “And the non-homologous use of the product raised significant safety concerns because there is less basis on which to predict the product’s behavior in recipients. Use of these unapproved products could cause users to delay or discontinue medical treatments, and these treatments may have been found to be safe and effective through the New Drug Application (NDA) or BLA approval process.”

At the Food and Drug Law Institute (FDLI) Enforcement, Litigation, and Compliance Conference held in Washington, DC in December 2019, CBER Office of Compliance and Biologics Quality Deputy Office Director Melissa Mendoza reviewed the challenges her office was facing and the enforcement and litigation actions the center took the year before Anderson’s review—in FY2019—which also focused on companies marketing unapproved products with claims to treat a myriad of life-threatening illnesses.

[Author’s Note: Human Cell And Tissue Therapy Enforcement Actions Target Unapproved New Products Making Unsubstantiated Claims].

The intention, she said, is for compliance and enforcement efforts to be impactful. Enforcing the regulations against the bad actors is “critical to the legitimacy of the entire field. We want to encourage those who follow the rules to keep following them. And we want patients who are considering enrolling in a clinical trial to not be swayed by the allure of an unsubstantiated claim that they could be cured right now. We certainly want those clinical studies to be under FDA’s oversight.”

At the 2020 PDA/FDA Joint Regulatory Conference, Anderson said her office issued nine untitled letters and four warning letters to HCT/P manufacturers in FY2020 in addition to those issued to companies marketing COVID-19 treatments. Figure 2 lists the date the letter was issued, the company, the product, and disease claim, whether the firm received a warning letter or an untitled letter, and pertinent notes [Editor’s Note: Click table to enlarge].

**FIGURE 2 | Other HCT/P Warning Letters and Untitled Letters Issued in FY2020**

“It Has Come to Our Attention”

As part of FDA’s overall goal to support the responsible development of safe and effective products for patients, CBER continues to send “It Has Come to Our Attention” (IHCTOA) letters to reiterate the agency’s regenerative medicine policy framework and compliance and enforcement policy to a number of manufacturers, healthcare providers, and clinics throughout the country who might have been offering STEM cell treatments, Anderson explained.

“Based on our review, it appears that these establishments are marketing products without FDA approval. The letters are sent to companies that we have been made aware of through complaints, internet surveillance, and other means. They are intended to remind the recipients that the time is running out for enforcement discretion and that by May 2021, those firms who are required to do so would need to have redone the IND process if they intend to continue marketing their products.”

Over the past year, CBER has taken actions against firms after review of evidence collected at their establishments, which may have started as a complaint against the firm or routine surveillance by the agency.

“After we have acted, we have performed follow-up website review to ensure compliance. The agency announced in 2017 that for three years it would apply a risk-based regulatory approach to the oversight of regenerative medicine products taking into account how products are administered and the diseases and conditions for which they would be treated.”

“Though the period has been extended by six months, May 2021 will be here soon. We encourage firms to engage with the agency for appropriate development to explore the safety and potential benefits of these products. And of course, as always, public health is of paramount importance. We base our decisions and our actions on our public health mission, and we will continue to take appropriate steps to address those who jeopardize it.”

[Editor’s Note: Read the rest of the author’s series on cell and gene therapies.]

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