Dear FDA Dockets Manager:
AABB is an international, not-for-profit association representing individuals and institutions involved in the field of transfusion medicine and cellular therapies. The association is committed to improving health by developing and delivering standards, accreditation and educational programs that focus on optimizing patient and donor care and safety. AABB membership consists of nearly 2,000 institutions and 8,000 individuals, including physicians, nurses, scientists, researchers, administrators, medical technologists and other health care providers. Members are located in more than 80 countries.
AABB appreciates the opportunity to provide comments on this draft guidance document titled "Draft Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products." In developing the comments, AABB collected feedback from member cellular therapy experts. In general, we commend FDA on this comprehensive draft guidance, which takes into consideration the unique product-specific characteristics of cellular and gene therapies, and highlights how different approaches may be useful in planning and conducting preclinical studies for such products. We also acknowledge that the considerations and recommendations throughout the document are aligned with feedback received on preclinical investigational cellular therapy studies in recent years.
We appreciate the Agency's recognition of the potential difficulty for all toxicology assessments to fully comply with the Good Laboratory Practice (GLP) regulations in 21 CFR 58. The allowance for use of toxicology data collected in proof of concept studies or studies that incorporate some endpoints included in the toxicology study (e.g. vector biodistribution, cell fate, or specific immunological endpoints), which may require unique animal care issues and/or technical expertise that may not be available at a GLP facility is important. The instructions and references for use when toxicology studies are noncompliant to GLP regulations are a helpful resource.
Listed below are several areas that we feel would benefit from some wording modification or additional clarification. Comments are arranged in the following format:
Section – language from draft guidance reprinted with page # and other identifying information.
Recommendation – recommendation or clarification request.
Background – rationale with information supporting the recommendation.
Section – I: INTRODUCTION. Page 2, paragraph 2. When finalized, this guidance will not apply to those human cells, tissues, and cellular and tissue-based products (HCT/P's) regulated under section 361 of the PHS Act (42 U.S.C. 264) as described under 21 CFR Part 1271 or to products regulated as medical devices under 21 CFR Part 820.
Recommendation – We recommend revising the sentence to read, "When finalized, this guidance will not apply to those human cells, tissues, and cellular and tissue-based products (HCT/P's) regulated solely under section 361 of the PHS Act (42 U.S.C. 264) as described under 21 CFR Part 1271 or to products regulated as medical devices under 21 CFR Part 820."
Background – We recommend including the word "solely" to acknowledge the fact there may be certain instances when a cellular or gene therapy product is subject to overlapping regulatory requirements (i.e. the product may be subject to specific requirements in 21 CFR 1271, but is formally regulated as a 351 product).
Section – II: BACKGROUND. Page 3, paragraph 3. Inherent in such an approach to regulation is the need for communication between the sponsor and the review office. Given the significant pace at which information pertaining to novel CGT products is accumulating as a consequence of basic research, we recommend early and ongoing communication with OCTGT pharmacology/toxicology staff during product development.
Recommendation – We recommend including a footnote to read: "See 21 CFR 312.82 (pre-IND meetings and certain end of Phase 1 meetings), 21 CFR 312.47 (end of Phase 2/pre-Phase 3 meetings and pre-NDA/BLA meetings, and "Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products," February 2000."
Background – We believe including the aforementioned regulatory references would be beneficial for a sponsor naïve to formal communications with FDA. These references will direct the reader to specific regulations and Guidance for Industry documents which further describe the types, goals, and mechanisms for requesting formal meetings with FDA.
Section – III: PRECLINICAL STUDY CONSIDERATIONS. B: Recommendations for general preclinical program design. 3: Selection of animal models of disease/injury. Page 5, paragraph 4. Examples of animal model limitations include:
- Inherent variability of the model.
- Limited historical/baseline data for the model.
- Technical limitations with the physiological and anatomical constraints of the model
- Animal care issues.
- Limited fidelity in modeling human pathophysiology of the disease/injury of interest.
Recommendation – We recommend an addition to the list of examples of animal model limitations (which would be continued on page 6) to include, "f. the use of young animal models in diseases associated with aging in humans."
Background – Many novel cellular and gene therapy clinical trials are focused on age-associated diseases. Independent of disease, the aged microenvironment is characterized by oxidant stress and inflammation, which cannot be reflected in young animal models.
Section – IV: RECOMMENDATIONS FOR INVESTIGATIONAL CELL THERAPY (CT) PRODUCTS. D: Safety. Page 17, paragraph 2. Potential safety concerns of investigational CT products include all of the following:
- Administration site reactions.
- Potential inflammatory response in target and/or non-target tissues.
- Host immune response to the cells.
- Migration from the site of administration.
- Potential to differentiate into an unintended/inappropriate cell type (ectopic tissue formation).
- Unregulated/dysregulated proliferation of the cells within the host.
- Potential tumorigenicity.
Recommendation – We recommend the addition of an item to the list to include, "8. Toxicity due to cell carrier or scaffold (not exclusively limited to an immune response)."
Background – Many cells, when injected as suspensions, will undergo rapid cell death (anoikis) if they do not attach to an extracellular matrix. For this reason, pre-attachment of cells on artificial matrices is an important strategy for survival of cellular grafts and their presentation (e.g. polarization, alignment).
Section – IV: RECOMMENDATIONS FOR INVESTIGATIONAL CELL THERAPY (CT) PRODUCTS. F: CT products with implantable scaffolds. 2: Scaffolds. Page 20, paragraph 4. Any scaffold construct (synthetic or non-synthetic polymers) used should be identical to the intended clinical scaffold.
Recommendation – We recommend revising the parenthetical reference to read "(polymers or other scaffolds)."
Background – The original sentence implies a scaffold can only be a constructed of a polymer material. The suggested revision is more inclusive of other types of materials (i.e. a biological material such as amniotic membrane or a hydrogel).
Section – IV: RECOMMENDATIONS FOR INVESTIGATIONAL CELL THERAPY (CT) PRODUCTS. F: CT products with implantable scaffolds. 8: Safety. Page 22, paragraph 1. Local toxicities (e.g., tumorigenicity, altered tissue function at the injection site, inappropriate cellular differentiation) may be due to interactions of the product components with the tissue or to the degradation of product components at the site of administration.
Recommendation – We recommend revising the sentence to read, "Local toxicities (e.g., tumorigenicity, altered tissue function at the injection site, inappropriate cellular differentiation, inflammatory infiltrate) may be due to interactions of the product components with the tissue or to the degradation of product components at the site of administration."
Background – We recommend including "inflammatory infiltrate" in the list of examples because localized inflammation is a common response to foreign epitopes on cells, and also to synthetic materials.
AABB appreciates the opportunity to comment on the draft guidance. Should you have any questions regarding these comments or would like additional information, please contact Rafael Cassata at email@example.com.
Rafael Cassata, MS, RAC (US, EU)
Deputy Director, Regulatory Affairs – Cellular Therapies