Food and Drug Administration

Center for Biologics Evaluation and Research

Cellular, Tissue and Gene Therapies Advisory Committee

 

SUMMARY MINUTES

Meeting #43,  March 29-30, 2007

Hilton Hotel, Gaithersburg, MD

 

 

COMMITTEE  MEMBERS                       TEMPORARY VOTING MEMBERS     

March 29-30, 2007                                        March 29, 2007

James J. Mulé, Ph.D., Chair                            Richard B. Alexander, M.D.

Matthew J. Allen, Vet. M.B., Ph.D.               Glenn Dranoff, M.D.

Michéle P. Calos, Ph.D.                                  Steven M. Dubinett, M.D.

Jeffrey S. Chamberlain, Ph.D.                        Maha Hussain, M.D. FACP

Richard J. Chappell, Ph.D.                             Francesco Marincola, M.D.

Stanton L. Gerson, M.D.++                              Robert J. Samuels+

Kurt C. Gunter, M.D. *                                  Howard I. Scher, M.D.

Farshid Guilak, Ph.D.                                    

Larry W. Kwak, M.D., Ph.D.                                     March 30, 2007

Doris A. Taylor, Ph.D.                                    Mary Horowitz, M.D.

Sharon F. Terry, M.S.**                                    Joanne Kurtzberg, M.D.

William W. Tomford, M.D.                            Mary J. Laughlin, M.D.

Walter Urba, M.D., Ph.D.++                            J. Jeffrey McCullough, M.D.

Savio L.C. Woo, Ph.D.                                   Donna M. Regan, MT(ASCP)SBB

 

FDA PARTICIPANTS- March 29             FDA PARTICIPANTS – March 30

Steven Bauer, Ph.D.                                       Ellen Lazarus, M.D., CAPT USPHS

Kathryn Carbone, M.D.                                  Celia Witten, M.D., Ph.D.

Jesse L. Goodman, M.D., M.P.H.

Ke Liu, M.D., Ph.D.                                       Committee Management Specialist

Raj Puri, M.D., Ph.D.                                     Rosanna Harvey

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

Keith Wonnacott, Ph.D.                                 Executive Secretary

Bo-Guang Zhen, Ph.D.                                   Gail Dapolito

 

*   Industry Representative

**Consumer Representative

+     Patient Representative

++   Not Participating 3/29

 

The summary minutes for the March 29-30, 2007 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee were approved on October 31, 2007.

 

I certify that I attended the March 29-30, 2007 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee and that this report accurately reflects what transpired.

 

 

_________//s//__________________ ___________//s//___________________

Gail Dapolito, Executive Secretary                James J. Mulé Ph.D., Chair


FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #43, March 29-30, 2007

 

 

The Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) met on March 29-30, 2007 at the Hilton Hotel, Gaithersburg, MD.  

 

On March 29, 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.  This statement identified members and consultants of the Committee with an appearance of a financial conflict of interest, for whom FDA issued waivers to participate.  Copies of the waivers are available from the FDA Freedom of Information Office.

 

In open session, the committee discussed Sipuleucel-T, Dendreon (BLA-STN 125197) indicated for the treatment of men with asymptomatic metastatic hormone refractory prostate cancer. 

 

The Sponsor presented data related to clinical and product development, efficacy and safety, clinical practice and the benefits and risks of the product.  The FDA provided regulatory perspectives related to product manufacturing, clinical and statistical reviews of the product. 

 

During the Open Public Hearing the Committee heard public comments related to the safety, effectiveness and availability of the product.

 

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

 

Effect of variability in product dose on product quality, safety and effectiveness:

 

The Committee acknowledged variability in each product dose.  The Committee suggested this variability could not be completely overcome in the manufacturing process as the autologous product dose and composition are inherent to each individual patient.

 

The Committee discussed the possibility that cell types other than CD54 cells may contribute to the purported action of the product.   Contributions by T cells in the product could influence the product’s activity, but that was hard to determine because during manufacturing antigen uptake by the product occurs in the presence of all the cells types collected from the patient’s peripheral blood.


FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #43, March 29-30, 2007

 

Primary mode of action:

 

In a brief discussion of the primary mode of action and potency of the final product, the Committee generally agreed that CD54 upregulation was a good indication of antigen presenting cell activation and that the therapy has the potential to improve antigen presentation to tumor-specific T cells.  The Committee suggested that more information was needed to determine the role of other cell types present in the product, such as NK, B, and T cells.

 

Immune Monitoring Data

 

The Committee stated the proposed mechanism of action was plausible, but that the data were insufficient to determine the specificity of the product.  Data are needed related to the immunogenicity of different components of the recombinant antigen. In general, more information is needed in order to  1) determine the function of antigen presenting cells in the product in stimulating T and B cell responses, 2) determine the role of PAP antigen in eliciting an immune response, and 3)  evaluate host T cell activation and suppression in product function, and how that will or will not correlate with survival.

 

Product Safety Related to Cerebrovascular Events

 

The Committee recognized that the sponsor’s study results appeared to indicate that an increased number of cerebrovascular accidents (CVA) were observed in subjects who received Sipuleucel T compared to APC-placebo (antigen presenting cell-placebo) subjects in all three completed Phase 3 trials and one on-going Phase 3 trial. However, the Committee stated that the  significance of this observation was difficult to determine due to the small sample size of the studies, and the observed increase of CVA rate in androgen dependent prostate cancer subjects who received APC-placebo.  The Committee agreed with the sponsor’s plan to include monitoring of CVAs, particularly to obtain more data on the risk of CVA in androgen-independent patients.  The sponsor was encouraged to also prospectively obtain patient data on cardiovascular histories, concurrent medications and other co-morbidities.

 

Efficacy Data (Primary and Secondary Endpoints)

 

There was general consensus from the Committee that the data showed a survival difference in patients who received the therapy in study D9901.  Some Committee members stated the survival data were not persuasive of the efficacy of the product.  They stated it was difficult to determine if the survival difference was related to the effect of the therapy because the sponsor’s trials were not designed with overall survival as a pre-defined endpoint.  They were also concerned that a survival difference was not supported by other anti-tumor activity or treatment effects on other disease manifestations.  Other Committee members stated the survival data and methodology were persuasive in considering the product to be effective and making the product available would be a positive step in moving forward the field of cellular immunotherapies.  A number of members on the committee stated and agreed that the results of the sponsor’s on-going Phase 3 clinical trial designed with overall survival as the primary endpoint were critical in establishing the effectiveness of the product.

 

Applicability of study results to minority populations

 

The Committee recognized that the lack of minority recruitment in clinical trials in the U.S. was an issue that, in general, needs to be addressed.  The Committee strongly encouraged increased accrual and additional data from minority populations be obtained in the sponsor’s on-going Phase 3 trial.  The Committee did not believe that data already obtained from the 2 clinical trials under discussion could be generalized to patients of all ethnic backgrounds.

 

Following the general discussion questions, the Committee was asked to discuss and  vote on the following questions:

 

  1. Does the submitted data establish that sipuleucel-T (APC-8015) is reasonably safe for the intended population?

 

The Committee voted 17 –yes, 0-no, 0-abstain that the data establish that sipuleucel-T is reasonably safe for the intended population.

 

Committee members stated due to the small patient population in the clinical studies, more data on the risk of cerebrovascular accidents and vigilant patient follow-up are essential.

 

  1. Does the submitted data establish the efficacy of sipuleucel-T (APC-8015) in the intended population?

 

The Committee asked for clarification from the FDA and the question was clarified to mean does the submitted data provide substantial evidence of the efficacy of the product in the intended population.

 

The Committee voted 13-yes, 4-no, 0 abstain that there was substantial evidence that the product is efficacious.

 

Of those voting in the majority, many Committee members felt that while there was substantial evidence of effectiveness, the data did not definitively establish the efficacy of the product.  Other Committee members stated there was sufficient evidence of effectiveness to make the product available at this time and that it was an important step in moving the field of immunotherapy forward.  In general, the Committee agreed that  results of the on-going Phase 3 clinical trial were critical in definitively assessing  efficacy of the product.

 

The discussion of this topic concluded.  In the next session, the Committee received overviews of laboratory research programs in the Tumor Vaccine and Biotechnology Branch and the Cellular and Tissue Therapy Branch, Center for Biologics Evaluation and Research, FDA. 

Following the laboratory research overviews the open session was adjourned.  The meeting was reconvened in open session on March 30.


FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #43, March 29-30, 2007

 

On March 30, 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.  This statement identified members and consultants of the Committee with an appearance of a financial conflict of interest, for whom FDA issued waivers to participate.  Copies of the waivers are available from the FDA Freedom of Information Office.

 

In open session, the Committee discussed 1) the FDA Draft Guidance to Industry:  Minimally manipulated, unrelated, allogeneic placental/umbilical cord blood intended for hematopoietic reconstitution in patients with hematological malignancies and 2) scientific issues related to minimally manipulated, unrelated, allogeneic, peripheral blood stem cells.

 

The FDA provided an overview of the Draft Guidance, describing the proposed license application procedure, the contents of the application, and applicable regulatory requirements.

A guest speaker from the New York Blood Center (NYBC), presented current and historical data on cord blood manufacturing, processing and utilization as well as the NYBC extensive experience with cord blood transplants.

 

During the Open Public Hearing, the Committee heard comments from representatives of the cord blood industry on the implementation of the Draft Guidance. 

 

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

 

  • Types of data that could be submitted to demonstrate comparability between previously manufactured HPC-C (hematopoietic stem/progenitor cells –cord blood) and HPC-C manufactured currently
  • Clinical indication described in the Draft Guidance and additional indications
  • Recommendations to assist cord blood manufacturers in preparing information to be submitted in a Biologics License Application for HPC-C
  • Data adequate to demonstrate safety and efficacy of HPC-A (hematopoietic stem/progenitor cells – apheresis) and approach to licensure of HPC-A similar to the one proposed for cord blood

 

Types of data that could be submitted to demonstrate comparability between previously manufactured HPC-C (hematopoietic stem/progenitor cells –cord blood) and HPC-C manufactured currently

 

In general, the Committee had no objection to the approach to demonstration of comparability described in the Draft Guidance, which includes submission of nonclinical laboratory and clinical data, where available. The Committee stated that stability studies could provide data on the comparability of previously and newly manufactured HPC-C units and provide comparison information on transplanted units.  For example, post-thaw cell recovery assays (total nucleated cell count (TNC), viable CD34+ cell content and colony forming unit (CFU)) performed on units of HPC-C used for stability testing could also be used to assess comparability.


 

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #43, March 29-30, 2007

 

 

Some Committee members suggested that comparability is best measured clinically by engraftment outcomes and engraftment measures need to be determined. The Committee discussed the correlation of TNC, viable CD34+ cell content and CFU content with successful engraftment of HPC-C to treat hematological malignancies.  The Committee generally agreed that successful engraftment outcomes correlate best with TNC and CFU vs.  viable CD34+  cell content.  However, there are many confounding clinical factors that affect engraftment and other transplant outcomes.

 

The Committee discussed the limitations of CD34+ cell enumeration and CFU assays; however, most felt that these assays are useful despite the limitations.  They stated that there are alternate test methods (not discussed in the Draft Guidance) for determining comparability but these are unique to individual laboratories and, at this time, should not be included in the Guidance.  Efforts should be focused on standardization of the widely used functional assays (CFU, viable CD34+ cells).

 

In a discussion of accreditation standards, the Committee agreed there is a need to standardize accreditation of cord blood banks and other processing facilities.  The Committee suggested that existing standards of FACT, NetCord and AABB could be accepted for licensure.  FDA stated these voluntary standards were considered in writing the Draft Guidance where they related to manufacturing and establishment controls covered by the applicable regulations.

 

The Committee discussed implementation of Current Good Manufacturing Practice (CGMP) in the manufacture of cord blood and generally encouraged the FDA to allow flexibility in the Guidance in how cord blood banks comply with CGMPs.  The Committee stated it might be a challenge for cord blood banks to implement and comply with CGMPs. For example, cord banks may not understand how to implement CGMPs for buildings and facilities, or they may not have documented conformance with these requirements in the past.  It was also stated that CGMP compliance could significantly increase the cost of processing cord blood for transplantation.

 

Clinical indication described in the Draft Guidance and additional indications

 

There was consensus from the Committee that the Draft Guidance should be expanded to include non-hematologic malignancies and non-malignant indications that are normally considered for bone marrow transplantation. 

 


 

 

FDA Cellular, Tissue and Gene Therapies Advisory Committee

Summary Minutes

Meeting #43, March 29-30, 2007

 

Recommendations to assist cord blood manufacturers in preparing information to be submitted in Biologics License Application for HPC-C

 

The Committee stated the Draft Guidance was well written and encouraged 1) the FDA to make efforts to publicize the document and 2) cord blood banks to communicate with

FDA as soon as they begin the licensing application process.  The FDA was also encouraged, as much as possible, to align requirements in the Guidance with existing voluntary (ex. FACT) accreditation requirements.

 

The Committee discussed the licensure of HPC-C manufactured in non-US cord blood banks, and said that licensure of HPC-C at all foreign banks that list their products in international registries was not feasible. 

 

Data adequate to demonstrate safety and efficacy of HPC-A (hematopoietic stem/progenitor cells – apheresis) and approach to licensure of HPC-A similar to the one proposed for cord blood

 

The Committee stated there are many differences between HPC-C and HPC-A in collecting, processing and release criteria that would need to be taken into consideration. Donor safety issues should be addressed. Some members expressed concern about the regulatory burden associated with implementation of licensure requirements. Any approach should balance the regulatory issues with the need to assure continued operation of the many collection centers to assure donor access.

 

Following this discussion 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.