FDA Takes Aim At Regenerative Medicine Compliance With New Rapid Inquiry Program

By Melissa A. Greenwald, M.D.

Regenerative medicine holds a lot of promise for patients, while many current therapies being used have an underwhelming amount of evidence to back claims being made. A June 2019 FDA announcement for a time-limited program, the Tissue Reference Group (TRG) Rapid Inquiry Program (TRIP), focuses attention once again on the FDA’s comprehensive regenerative medicine policy framework. Through Dec. 31, 2019, the TRIP aims to provide a three-day turnaround on responses to manufacturers who wish to obtain a “gut check” on the regulatory pathway of their product.

Background

On Nov. 15, 2017, the FDA announced a comprehensive regenerative medicine policy framework to aid the development of regenerative medicine products. As part of the announcement, the FDA acknowledged that product development was occurring at a rapid pace and that the application of the human cells, tissues, and cellular and tissue-based products (HCT/Ps) regulatory framework, specifically 21 CFR Part 1271.10(a) requirements indicating what products are solely regulated as “361 HCT/Ps,”¹ was challenging for product developers to understand how they apply to their products. As such, a 36-month period of enforcement discretion was also announced, allowing manufacturers of certain products subject to the FDA’s premarket review time to determine if their products require premarket review and approval and then to meet those requirements. The FDA stated that it did not intend to exercise enforcement discretion for those products that pose what it called a “significant safety concern.” The agency posted a warning to consumers about cell therapies on Nov. 16, 2017 and has issued warning letters since that time — including some high-profile letters that have garnered media attention.

At the time, the FDA hoped that manufacturers would review the guidance documents provided — which had been under development for several years, including draft guidance for public comment — and come to the agency early on to develop a plan to comply with requirements for premarket review. By all appearances, the response has been tepid at best.

The TRIP was announced in June 2019, likely hoping to:

• raise more awareness of the November 2020 deadline for 351 HCT/Ps to be in compliance with premarket review requirements,
• entice some manufacturers to begin dialogue with the FDA, and
• provide an incentive for manufacturers that otherwise may be reluctant to ask questions of the TRG due to the lengthy time frames involved in receiving a response.

An Overview Description

The TRIP, effective until Dec. 31, 2019, is intended to provide manufacturers of human cells, tissues, and cellular and tissue-based products a way to obtain a rapid, preliminary, informal and nonbinding assessment from the FDA regarding how specific HCT/Ps appear to be appropriately regulated. The goal is to provide responses within three days of submission, and additional information may be requested if the information provided is insufficiently detailed to make an assessment.

To submit a TRIP inquiry, the FDA requests the following information:

1. The manufacturer of the product, if other than requester.
2. The source of the product, including whether it is autologous or allogeneic.
3. A clear, step by step description of how the product is processed from the time of recovery to the point of use.
4. The specific way(s) the product is to be used and route of administration.
5. Description of any device or apparatus (e.g., syringe) required to deliver the HCT/P to the recipient.

TRIP submissions are limited to a single HCT/P with an single intended use – if an HCT/P has more than one intended use or if a manufacturer wishes to learn about more than one HCT/P, separate inquiries should be submitted for each HCT/P-intended use pair.

TRIP requests should be submitted electronically to the following email address: industry.biologics@fda.hhs.gov, with “TRIP Inquiry” in the subject line of the email.

With the limited information collected and the rapid turnaround time for response, the nonbinding written feedback is limited to the following four responses:

1. the HCT/P appears to be appropriately regulated solely under section 361 of the Public Health Service (PHS) Act and the regulations in 21 CFR Part 1271,
2. the HCT/P appears to be appropriately regulated under section 351 of the PHS Act and/or Federal Food, Drug, and Cosmetic Act, and applicable regulations, as a drug, device, or biologic,
3. the product does not appear to be an HCT/P, or
4. a recommendation cannot be made through the TRIP program because further discussion between the inquirer and the FDA would be needed.

Discussion

Multiple mechanisms are available for manufacturers to seek feedback from the FDA regarding the regulatory status of their product, as summarized in the following table.

 

Mechanism	Process/Feedback	Type of Feedback Provided	Time frame
Tissue Reference Group	Informal/Nonbinding	Application of the criteria in 21 CFR 1271.10(a) to human cells, tissues and cellular and tissue-based products (HCT/Ps); whether exceptions from the requirements in Part 1271 apply (see 21 CFR 1271.15); which regulations apply when the HCT/P does not meet the criteria in 21 CFR 1271.10(a), and when an exception in 21 CFR 1271.15 is not applicable (see 21 CFR 1271.20)	Goal of 60 days
Request for Designation	Formal/Binding	Determination of a combination product’s primary mode of action; assignment of the lead agency center for the product’s premarket review and regulation; the agency component that will have jurisdiction for any drug, device, or biological product	60 days
Pre-RFD process	Formal/nonbinding	(1) the regulatory identity or classification of a product as a drug, device, biological product, or combination product, and/or (2) whether CBER, CDER, or CDRH will regulate the product if it is a non-combination product, or which of those agency centers will have primary jurisdiction for the premarket review and regulation if it is a combination product	Goal of 60 days
TRIP	Informal/Nonbinding	Interpretation of applicable regulatory framework, especially related to applicability of 1271.10(a), limited to basic responses	Goal: three days Ends 12/31/2019

 

Given the multiple pathways already available to obtain both binding and nonbinding feedback from the FDA regarding the regulatory status of products, it appears that the main advantage to the TRIP is the short turnaround time. This could certainly be a low-stakes way for manufacturers that are not accustomed to interacting with the FDA to initiate their first contact.

Those most likely to benefit from the TRIP include manufacturers that are:

1. currently marketing a product that feel confident of their regulatory approach and wish to receive written confirmation from the agency that their pathway appears correct, or
2. developing new products and wish to seek more regulatory clarity before deciding to embark on further development.

There is ample evidence that the FDA intends to follow through on enforcement of the comprehensive regenerative medicine regulatory framework. Since the framework was announced, multiple warning letters have been issued to cell and gene therapy manufacturers, with at least two cases being litigated. While I have heard various assertions being made that the FDA doesn’t have the authority to regulate these products (or at the very least they shouldn’t be concerned about “my” particular product), there has been a recent court decision in Florida upholding the FDA’s right to a permanent injunction against U.S. Stem Cell. Furthermore, changes to the electronic Human Cell and Tissue Establishment Registration System (eHCTERS) (intended for 361 HCT/P product registration) were rolled out in November 2018 (just ahead of the yearly registration cycle). Those changes essentially removed the ability to register many products — signaling that the FDA likely does not consider those products are appropriately regulated as 361 HCT/Ps. Even after receiving letters that the FDA would no longer allow registration of products previously registered in eHCTERs, it is clear the FDA is concerned about the number of manufacturers coming into compliance, as noted in the webpage announcing the TRIP in June 2019.

It is unclear why there has been such a tepid response from manufacturers addressing the regulatory requirements for their products, and thus it remains to be seen how things will play out after the enforcement discretion period ends in December 2020. Developing a regulatory submission takes time, and some may well be in the process of sorting out what needs to be done. Perhaps there are procrastinators out there waiting until the deadline, creating a surge of IND submissions in late 2020. It is possible there are businesses out there that have not heard about the FDA regulation of stem cells, in spite of efforts to get the word out. Perhaps others are burying their head in the sand, intending to continue with business as usual until the regulator comes knocking on their door.

Regardless of whether you take advantage of the TRIP or other FDA mechanisms, seek outside advice, or make your own determination, it is prudent to be prepared with a written analysis explaining how you came to the conclusion you have regarding your regulatory status when the FDA does come knocking on your door. The FDA/CBER encourages early interaction with sponsors in order to head off potential problems as early as possible. In this case, it is most likely the prepared sponsors who speak to FDA before the deadline that will enjoy shorter time frames for obtaining responses and increase the odds of obtaining a favorable plan for coming into compliance.

Notes:

1. HCT/Ps meeting all the criteria under 1271.10(a) are regulated under 361 of the Public Health Service Act to prevent communicable disease transmission and do not require premarket review — all HCT/Ps not meeting these criteria require premarket review as a biologic, drug, device, or combination product.

About The Author:

Melissa Greenwald, M.D., is an internationally recognized expert in cell, organ, and tissue safety and policy. She is a graduate of the Uniformed Services University School of Medicine who spent 25 years on active duty in the U.S. Public Health Service with over 14 years at the FDA, regulating human tissues for transplantation. Greenwald also spent four years at the Health Resources and Services Administration, where she retired as the director of the Division of Transplantation. Greenwald now directs her own consulting business specializing on safety management and regulatory affairs for cell, organ, and tissue products. She can be reached at magreenwaldconsulting@gmail.com or on LinkedIn.