The FDA and Its New Guidance on Regenerative Medicine Drugs
by Barbara Unger, GMP Quality Expert, and GMP Regulatory Intelligence Editor-in-Chief
The four guidance we address here are part of the FDA’s announced ‘comprehensive regenerative medicine policy framework’ and support implementation of provisions in the 21st Century Cures Act. The FDA is actively supporting the development of stem cell and other types of regenerative therapies and attempting to differentiate them from the hundreds of stem cell clinics that make broad and unfounded claims of safety and efficacy. The FDA has issued several warning letters in the past year to clinics that deliver services and products of this type where the FDA determined they posed an immediate safety risk to the public. At issue regarding enforcement appears to be the definitions of “minimal manipulation” and “homologous use” — both of which are defined in the guidance. The NYT also reports the story with their perspective. Below, we address each of the four recent guidance, beginning with the two that are final and following with the two that are drafts available for comment:
#1. The FR announced availability of a 24-page final guidance, ‘Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use.’ This guidance was issued from CBER, CDRH, and the Office of Combination Products. It finalizes the content of two draft guidance on similar topics published December 2014 and October 2015. It also incorporates and, thus, finalizes certain aspects of the draft guidance from December 2014 addressing ‘Adipose Tissue.’ The guidance includes a discussion of relevant definitions, particularly ‘minimal manipulation’ and ‘homologous use,’ along with 27 questions and answers.
The guidance defines ‘minimal manipulation’ — often a misinterpreted requirement and one for which the industry requested additional explanation. Minimal manipulation means:
- For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
- For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.
The FDA further states, “If an HCT/P does not meet the criteria set out in 21 CFR1271.10(a), and the establishment that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.15.”
The FDA defines the other important definition, ‘homologous use’, used to determine whether products may be regulated solely under 21 CFR 1271 as: “…homologous use means 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.” To make this determination, the FDA will consider both the intended use of the product as identified in labeling, advertising, and “other indications of a manufacturer’s objective intent.” A flowchart on page 5 of the guidance is useful to determine how to apply criteria in 21CFR 1271(a).
Following the flowchart, the FDA provides 27 questions and answers on a variety of topics classified as follows:
- Questions and Answers Regarding Minimal Manipulation
- General Concepts (5 questions)
- Structural Tissue (9 questions)
- Cells or Nonstructural Tissues (2 questions)
- Questions and Answers Regarding Homologous Use
- 6 questions
- Additional Information
- 5 questions
The FDA also includes a section on their compliance policy for these product types. The FDA will give manufacturers 36 months to prepare either an IND or a marketing application. During that time, the FDA will ‘generally’ exercise enforcement discretion for products that do not meet all criteria identified in 21 CFR 1271.10(a) if the HCT/P is “intended for autologous use and its use does not raise reported safety concerns or potential significant safety concerns.” Personally, 36 months seems excessive, and it will be interesting to see how many INDs and BLAs they receive during this time. A shorter time frame may have focused firms reaching a decision in a timely manner and ensuring they take the appropriate action. The FDA will focus their enforcement on high risk products considering their route of administration and whether the products are allogenic (non-autologous).
#2. The FR announced availability of a 10-page final guidance, Same Surgical Procedure Exception under 21CFR1271.15(b): Questions and Answers Regarding the Scope of the Exception. This guidance is published by CBER with cooperation from CDRH and the Office of Combination Products. This guidance is provided in a question and answer format, 7 in total. The Introduction and Background sections provide a detailed background on related guidance and regulations. The Q&A “includes examples based on inquiries received by the Agency since the final rule, ‘Human Cells, Tissues, and Cellular and Tissue Based Products; Establishment Registration and Listing’ (Establishment Registration and Listing final rule) was published on January 19, 2001 (66 FR 5447).”
The seven questions address the following:
- The relationship between the exception in 21 CFR 1271.15(b) and the four criteria described in 21 CFR 1271.10(a)
- When the exception in 21 CFR 1271.15(b) applies
- Section 1271.15(b) refers to implanting “such HCT/P.” What is meant by “such HCT/P?”
- What is autologous use? (This seems to be a frequent question also addressed in the preceding guidance).
- What types of procedures are considered the same surgical procedures?
- Are there any types of procedures consisting of more than a single operation that are considered same surgical procedure for purposes of the exception in 21 CFR 1271.15(b)?
- Can an establishment that processes an autologous HCT/P after removal and prior to implantation still qualify for the exception in 21 CFR 1271.15(b)?
#3. The FR announced availability of a 13-page draft guidance ‘Evaluation of Devices Used with Regenerative Medicine Advanced Therapies.’ This draft guidance is issued by CBER, CDRH, and the Office of Combination Products. This guidance was written to “…provide you, device manufacturers, applicants, and sponsors engaged in the development of regenerative medicine therapies, with our current thinking regarding evaluation of devices used in the recovery, isolation or delivery of regenerative medicine advanced therapies.” Applicable to this guidance, the FDA defines the terms ‘recovery,’ ‘isolation,’ and ‘delivery.’
The FDA clearly identifies that a range of devices could be used in such processes including those of very low risk and others in a higher risk category. Other equipment such as centrifuges and chromatography columns are often used in the preparation of these products but are far removed from direct patient care and are outside the scope of this guidance. The FDA is going to apply the ‘least burdensome principle’ to the regulation of these medical devices to ensure safety and effectiveness.
The guidance addresses existing premarket pathways for approval of these devices. This includes, as appropriate for the intended use:
- Premarket notifications (510(k))
- De Novo Classification Request for devices which have not previously been classified
- Premarket Approval Application (PMA), and
- Humanitarian Device Exemption
The FDA recognizes that these new product types may include combination products. These will generally be reviewed as a single application, consistent with the FDA’s practice for combination products in general.
Section V of the guidance identifies factors to consider when a device is limited to use with a unique cell-based RMAT product or, alternatively, when it may be used with more than one type of cell-based RMAT. Again, there is not a one size fits all, and it will depend on the specific product/device. This guidance, however, appears to cover many options and provides a reasonable basis for beginning to address devices in this important new therapeutic entity.
#4. The FR announced availability of a 15-page draft guidance, Expedited Programs for Regenerative Medicine Therapies for Serious Conditions. This guidance identifies the various options for expedited development and reviews regenerative medicine advanced therapies for serious or life-threatening diseases. The beginning of section III provides a historical review of how the FDA has supported expedited review and approval along with relevant definitions of term used for these pathways.
Five different options are provided for expedited programs for these product types including:
- Fast Track Designation may be assigned to IND compounds and offer sponsors the opportunity to facilitate development/expedite review. Drugs may be granted fast track designation by CBER if the new drug is “…intended to treat a serious condition and for which nonclinical or clinical data demonstrate the potential [emphasis added] to address an unmet medical need in those with such condition.”
- Breakthrough Therapy Designation is granted to “…an investigational new drug that is intended to treat a serious condition, and for which preliminary clinical evidence [emphasis added] indicates that the product may demonstrate substantial improvement over available therapies on one or more clinically significant endpoints.” This burden of proof is harder to achieve than fast track designation. CBER provides specific examples of therapies that may be considered for breakthrough therapy designation in this section.
- Regenerative Medicine Advanced Therapy Designation may be granted to an investigational compound and provides all the advantages of both fast track and breakthrough designation programs. These product types include cell therapies, therapeutic tissue engineering products, human cell and tissue products, gene therapies, and some combination products when the biological component provides the greatest contribution to the intended therapeutic effect. Early meetings with the FDA are among the most valuable of these advantages in development of these new product types. The guidance provides additional details regarding the type of products who might merit this designation along with a tabulation of the key aspects of RMAT designation as compared to breakthrough therapy designation.
- Priority Review Designation may be given to RMAT designated compounds if “supported by clinical data at the time the marketing application is submitted [emphasis added].” CBER will make this decision within 60 calendar days of receipt of the application or supplement. Priority review products have a 6-month goal to complete review.
- Accelerated Approval is generally used for cases where it would require an extended timeframe to measure the intended clinical benefit of a drug. For drugs that are approved under this process, the FDA may withdraw it’s marketing approval if the sponsor fails to comply with confirmatory clinical trials to be conducted post approval. CBER encourages firms that wish to seek accelerated approval designation to meet with them early in the development process. This gives the FDA the opportunity to provide feedback on clinical trial design, surrogate endpoints, and the number of clinical sites that contribute data to the trial supporting registration.
CBER will work with sponsors to design clinical trial designs that will support approval based on either surrogate or novel endpoints. Many of these products have a limited patient base so the ‘usual’ clinical trial patient population may simply not be possible. Finally, CBER encourages sponsors of RMAT products to begin discussions with the FDA early in development. The novelty and complexity of these products, limitation in patient numbers, and potential use of surrogate or alternate endpoints require ongoing discussions with CBER to ensure a rapid FDA approval.
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