Food and Drug Administration

Center for Biologics Evaluation and Research

Cellular, Tissue and Gene Therapies Advisory Committee

SUMMARY MINUTES

Meeting #45,  April 10-11, 2008

Hilton Hotel, Gaithersburg, MD

COMMITTEE  MEMBERS TEMPORARY VOTING MEMBERS

April 10-11, 2008 April 10, 2008

Walter Urba, M.D., Ph.D., Chair                                                                                              Michéle P. Calos, Ph.D.          

Matthew J. Allen, Vet. M.B., Ph.D.                                                                                          Kenneth R. Chien, M.D., Ph.D.

Jeffrey S. Chamberlain, Ph.D.                                                                                                 Meri Firpo, Ph.D.

Richard J. Chappell, Ph.D.                                                                                                       Martin Friedlander, M.D., Ph.D.

Stanton L. Gerson, M.D. Steven A. Goldman, M.D., Ph.D.

Kurt C. Gunter, M.D.   *                                                                                                          John W. McDonald, M.D., Ph.D.

Farshid Guilak, Ph.D. ⁺                                                                                                           Daniel Salomon, M.D.

Larry W. Kwak, M.D., Ph.D.                                                                                                   Evan Y. Snyder, M.D., Ph.D.

Doris A. Taylor, Ph.D.                                                                                                             Sharon Terry, M.A.**⁺

Savio L.C. Woo, Ph.D.                                                                                                            William Tomford, M.D.

                                                                                                                                                Gordon C. Weir, M.D.

Guest Speakers – April 10 FDA PARTICIPANTS- April 10-11

Jeff W. Bulte, Ph.D.                                                                                                                Steven Bauer, Ph.D.

Melissa Carpenter, Ph.D.                                                                                                         Kimberly Benton, Ph.D.

Jonathan Dinsmore, Ph.D.                                                                                                       Theresa Chen, Ph.D.

Ole Isacson, M.D.                                                                                                                    Suzanne Epstein, Ph.D.

Jane Lebkowski, Ph.D.                                                                                                            Richard McFarland, Ph.D., M.D.

                                                                                                                                                Karen Midthun, M.D.

                                                                                                                                                Bruce Schneider, M.D.

                                                                                                                                                Celia Witten, M.D., Ph.D.

Executive Secretary Committee Management Specialist

Gail Dapolito                                                                                                                           Danielle Cubbage

*   Industry Representative

**Consumer Representative

⁺   Not Attending

The summary minutes for the April 10-11, 2008 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee were approved on July 24, 2008.

I certify that I attended the April 10-11, 2008 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee and that this report accurately reflects what transpired.

                        //s//                   __                         //s//__________

Gail Dapolito, Executive Secretary                  Walter Urba, M.D., Ph.D., Chair

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #45, April 10-11, 2008

The Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) met on April 10-11, 2008 at the Hilton Hotel, Gaithersburg, MD.  

On April 10, the Chair called the meeting to order and introduced the members and consultants.  The Executive Secretary read the conflict of interest statement into the public record.  In open session, the committee discussed scientific considerations for pre-clinical safety testing of cellular therapies derived from human embryonic stem cells (hESCs). 

The FDA speaker provided background information and described the goals and focus of the meeting.  Guest speakers presented data related to safety issues in the development of hESC cellular therapies, including data on pre-clinical models, cell and product characterization, cell dose, cell migration, imaging and tumorigenicity.

During the Open Public Hearing the Committee heard public comments related to the development and use of cellular therapies derived from hESCs.

Following the Open Public Hearing the Committee addressed discussion questions from the FDA related to the following issues:

Inappropriate Differentiation/Tumorigenicity:  Optimal study designs for preclinical assessment of inappropriate differentiation, including tumorigenic potential, of investigational cellular products derived from undifferentiated hESCs. 

In the discussion of the question the Committee considered the following: 

• Criteria for assay of undifferentiated hESCs, including their proliferative potential, their ability to differentiate and their capacity to form teratomas.
• Appropriate site of cell administration or placement in animals in order to obtain meaningful test results
• Appropriate study duration
• Most appropriate dosing method

The following were points of consensus among the Committee:

1) Undifferentiated cells should not be tolerated in hESC-derived cellular therapies for use in humans.

2) It is highly desirable to develop standardized tumorigencity assays.

In general the Committee agreed that an immunocompromised rodent model would be appropriate to test for tumorgenicity in many cases. To the extent possible, investigators and sponsors should develop preclinical experimental systems capable of predicting safety and efficacy in the intended clinical situation. In many cases, large animals will be needed for this purpose. The Committee recommended that toxicity studies in preclinical models include the same route of administration anticipated for clinical trials.

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #45, April 10-11, 2008

3) Pre-clinical models should be determined by the disease target and cell type of interest and differentiation stage of implanted cells.

This will not be a “one size fits all” approach; it will be important to match the disease target to the characteristics of the implanted cells.   Studies should define the expansion, cell cycle kinetics of the cell population over time, and other aspects of pharmacologic disposition in animal models that replicate the target disease as closely as possible.   

The Committee also discussed the appropriateness of allogeneic and xenotranplantation models. There were varying views on the Committee of the usefulness of allogeneic and xenotransplantation animal models.  Some Committee members stated allogeneic animal studies might be useful in answering specific safety questions and that xenotransplantation studies might be required for safety and efficacy studies.  In general, the Committee did not encourage requiring sponsors to 1) develop expensive allogeneic models that might not translate well to the clinical situation or 2) develop complicated xenotransplantation models to answer safety questions that might best be answered in simpler pre-clinical models in a step-by-step fashion.  The Committee also recommended development of preclinical models to study the safety of various delivery systems. 

In a discussion of cell dosing, the Committee stated that it was important that the maximal dose/number of cells administered to humans should not exceed the number of cells that will form tumors in animal models.  Therefore, it is critical that sponsors evaluate the number of cells tolerable in an appropriate animal.  The human dose should not be scaled from animal models but should be based on the absolute number used in animals.  The proportion of differentiated/undifferentiated ESCs should not vary from what is planned for clinical use.  Cell dose will be product specific and dose escalation studies should be very conservative in design. 

There was no consensus among the Committee on appropriate follow-up of preclinical studies.  Follow-up studies may be determined by the disease, cell type, and ability of differentiated derivatives to form tumors.

Characterization of hESC-Derived Cellular Preparations

In the discussion, the Committee considered the following: 

• Product characteristics predictive of  adverse events
• Specificity and sensitivity of specific assays to distinguish undifferentiated, appropriately, or inappropriately differentiated derivatives

The Committee discussion began with a brief overview of some characteristics that would be important to assess in hESC-derived cell preparations.  These include:

• Characterization of cells by STR analysis and genetic studies.

The Committee emphasized prior comments that functional (teratoma) assays need to correlate with specific cell characteristics or sets of characteristics.

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

                                                Meeting #45, April 10-11, 2008

• Cell viability before and after cell transfer

Transferred hESC-derived cells may have a therapeutic effect (positive or negative) without long term survival of the cells.

• Cell purity/quality - detection of contaminating and inert cells

Methods to accomplish this could include cell surface markers (immunostaining and flow cytometry); reporter genes; PCR analysis; in-vitro and in-vivo assays

The Committee generally agreed that heterogeneity in hESC-derived cell preparations may be tolerated.  In some instances, heterogeneity may be required for successful engraftment and functionality.  The Committee recommended that sponsors be able to document the absence of undifferentiated cells, and batch-to-batch consistency of the cell populations. 

Patient Monitoring

In the discussion of the question the Committee considered the following:

• Features of early phase clinical trial design that will facilitate monitoring of patient safety following administration of hESC-derived cellular products
• Other trial design features that can help to increase the probability of obtaining a measurable therapeutic benefit while ensure maximum safety

In a broad discussion of this question, the Committee suggested there might be a need for general and case-by-case monitoring.  General approaches might be useful to detect certain toxicities (e.g., tumorigenicity), but more targeted approaches might be needed to detect potential problems determined by the specific disease.  There was general acceptance by the Committee that patient surveillance needs to be broad and long-term, potentially for the life of the patient, to monitor for tumorigenicity (including formation of teratomas) and potential neurologic, immunologic, and other problems that might occur long-term.

The Committee discussed appropriate features of clinical trial design.  There was no consensus among the Committee on this issue.  There was a suggestion, that until sufficient data are generated by the field, long-term follow-up of short-term Phase I dose escalation studies may be needed before enrolling successive patients.  While the Committee made no specific recommendation for follow-up in early Phase I dose escalation studies, there was a general opinion that waiting 6-12 months for follow-up in a Phase I study was impractical and would not allow progress to be made.

There was no consensus from the Committee on appropriate patient enrollment for Phase I studies.  Ideally, dose escalation studies would enroll a large number of patients (50-100) or have appropriate surrogate endpoints to address safety questions with some level of statistical confidence. However, it was pointed out that such large numbers are likely to be impractical and that it is customary to use much smaller numbers in initial trials, which typically are designed to identify serious safety issues not predicted by animal data. A more realistic enrollment might be 3-50 patients/cohort.   A dose staggering trial was also discussed as a clinical design to help determine what relevant outcomes that can be confirmed in short term studies. 

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #45, April 10-11, 2008

Some Committee members suggested that clinical study design, with appropriate informed consent, include collection and biopsy of abnormal cells as well as recovery and evaluation of tissue at autopsy.   Local and systemic imaging would be helpful in evaluating cell migration and other aspects of disposition in vivo.  Available genetic markers should be used, if possible, to determine whether abnormal cells arose from implanted hESC-derived cells. Committee members suggested that each batch of implanted hESC-derived cells have a documented DNA profile, in order to distinguish if late occurring tumors can be shown to result from the hESC-derived cell preparation (vs. other tumors).  Sponsors should be encouraged to develop real-time imaging/labeling methods for tracking cells.

This ended the Committee discussion and the meeting was adjourned until the following morning.

On April 11, the Chair, called the meeting to order and introduced the Committee Members.  There were no Temporary Voting Members for this session.  The Executive Secretary read the conflict of interest statement into the public record.  Copies of the waivers are available from the FDA Freedom of Information Office. 

In open session, the FDA provided updates on the following:

· Office of Cellular, Tissue and Gene Therapies (OCTGT) response to the September 2005 External Review of OCTGT research program

· FDA Somatic Cell Therapy Letter

· OCTGT Guidance Development Program

There were no requests to address the Committee during the Open Public Hearing.

Office of Cellular, Tissue and Gene Therapies (OCTGT) response to the September 2005 External Review of OCTGT research program

FDA provided the Committee information on the following:

• Research programs in the Center for Biologics Evaluation and Research (CBER) including CBER’s and OCTGT’s mission, products regulated, and management of its research programs. 
• Actions implemented by the Office of Cellular, Tissue and Gene Therapies (OCTGT), CBER in response to an external review (September 2005) of the overall OCTGT research program:

OCTGT management initiatives will address CBER priorities in the development of 1) an horizon scanning system for product trends, 2) communications tools such as work-in-progress talks and annual reporting, 3) collaborations, 4) recruitment efforts, and 5) an automated regulatory workload system.

OCTGT priorities are 1) “the development and evaluation of methods and standards” for improved product characterization, 2) the “development and evaluation of non-clinical methods informative about the safety and efficacy” of OCTGT products, 3) “participation in CBER, FDA and Department-wide initiatives including risk assessment, clinical trial design and monitoring, development of biomarkers, counter-terrorism, pandemic influenza preparedness and HIV/AIDS programs as well as Office-specific initiatives in these areas,” 4) “improvement of microbial safety of human tissues products.”

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #45, April 10-11, 2008

FDA Somatic Cell Therapy Letter

The FDA previously issued to sponsors of cell therapy INDs the FDA Somatic Cell Therapy Letter.  Sponsors were asked to respond to the Letter within 60 days of the anniversary date of the IND.  Sponsors were asked to provide in their response CMC (chemistry, manufacturing and controls) and clinical trial data.

Based on the outcome of the OCTGT review of sponsors’ responses to the FDA Somatic Cell Therapy Letter, the FDA will discontinue both issuing the Somatic Cell Therapy Letter to sponsors of new INDs and requesting yearly updates in this format.   IND Sponsors may provide updates and information in amendments or annual reports, as appropriate. 

OCTGT Guidance Development Program

FDA described the process for developing, publishing and implementing FDA Guidances to Industry and Staff.  OCTGT publishes annually in the Federal Register a list of topics OCTGT anticipates developing Guidances for in the coming two year period.  The FDA briefly outlined several Guidances that OCTGT recently published and implemented. One Guidance was described in detail (Preparation of IDEs and INDs for Products Intended to Repair and Replace Knee Cartilage) as an example of cross-center guidance development for cross-cutting product areas, and of areas in which the CTGTAC has provided valued advice.

Following the FDA updates the meeting was adjourned.

For more detailed information concerning this session presentation and committee discussion summarized above, please refer to the meeting transcripts available on the FDA website at http://www.fda.gov/ohrms/dockets.