November 19, 2010: Cellular, Tissue and Gene Therapies Advisory Committee Meeting Minutes
Meeting #49, November 19, 2010
Hilton Hotel, Gaithersburg, MD
Stanton L. Gerson, M.D.+
Matthew J. Allen, Vet. M.B., Ph.D.
Tabassum Ahsan, Ph.D.
Larry A. Couture, Ph.D.+
Linda A. Dahlgren, DVM, Ph.D., DACVS+
Steven M. Dubinett, M.D.
Evanthia Galanis, M.D.+
Steven A. Goldman, M.D., Ph.D.+
Mary Horowitz, M.D., M.S.
Francis John Hornicek, Jr., Ph.D., M.D.
Mei-Ling Ting Lee, Ph.D.
Mahendra S. Rao, M.D., Ph.D.**
Peter L. Saltonstall*+
Evan Y. Snyder, M.D., Ph.D.
TEMPORARY VOTING MEMBERS
Lung-Ji Chang, Ph.D.
John Coffin, Ph.D.
Steven H. Hughes, Ph.D.
Richard Mulligan, Ph.D.
Alan Rein, Ph.D.
Doris A. Taylor, Ph.D.
Gwendolyn K. Binder-Scholl, Ph.D.
Kenneth Cornetta, M.D.
Gianpietro G. Dotti, M.D.
Laurent M. Humeau, Ph.D.
Richard A. Morgan, Ph.D.
Xiaobin Victor Lu, Ph.D
Daniel Takefman, Ph.D.
Celia Witten, Ph.D., M.D.
* Consumer Representative
** Industry Representative
+ Not Attending
Designated Federal Officer
Committee Management Specialist
Sheryl Clark, M.B.A.
The summary minutes for the November 19, 2010 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee were approved on April 15, 2011.
I certify that I attended the November 19, 2010 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee and that this report accurately reflects what transpired.
Matthew J. Allen, Vet. M.B., Ph.D. Gail Dapolito
Acting Chair Designated Federal Official
Cellular, Tissue and Gene Therapies Cellular, Tissue and Gene Therapies
Advisory Committee Advisory Committee
The Cellular, Tissue and Gene Therapies Advisory Committee met in open session on November 19, 2010 at the Hilton Hotel, Gaithersburg, MD.
On November 19, the Chair called the meeting to order and introduced the members and consultants. The Designated Federal Official 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 in the meeting. No waivers were issued for the meeting.
In open session, the Committee discussed current FDA recommendations for testing of replication competent retrovirus (RCR)/lentivirus (RCL) in retroviral and lentiviral vector based gene therapy products.
The FDA provided an introduction to the topic of the meeting. Guest speakers provided information on 1) RCR/RCL testing at the Indiana University vector production facility; 2) RCL lot release testing for lentiviral vector transduced cells; 3) findings and challenges in product testing and patient monitoring for RCR/RCL in gene therapy clinical trials; 4) National Cancer Institute experience using engineered T cells for the treatment of cancer implications for RCR testing; and 5) clinical experience at Baylor College of Medicine with T lymphocytes genetically modified using retroviral vectors.
The Open Public Hearing followed the presentations. Two individuals made statements to the Committee related to a replication defective HIV vaccine and second generation lentiviral vector production systems.
Following the Open Public Hearing, the Committee addressed the following questions:
Based on the current vector systems being used for clinical production and supported by the data presented at this meeting regarding RCR/RCL testing results, please discuss the need for a cell culture based RCR/RCL assay as a lot release criterion for retroviral or lentiviral vector transduced cell products while keeping the RCR/RCL testing for all other prior steps in the manufacturing process.
Please consider the following in your discussions:
- Different vector designs and production systems may have different risk profiles with respect to RCR/RCL generation;
- Accumulated experience with gammaretroviral vector vs. less extensive experience with lentiviral vectors;
- Alternatives to the cell culture based RCR/RCL assay for the transduced cell products;
- PCR based RCR/RCL as a release test when feasible;
- Qualify the cell manufacturing process by testing the first few patient cell lots manufactured (how much data is needed);
- Qualify the cell manufacturing process and demonstrate the process will not amplify potential RCR/RCL with spiking experiments;
- Other possibilities.
The Committee discussed the general question of the need for, or an alternative to, the FDA required cell culture-based assay to detect replication competent retrovirus or lentivirus in retrovirus or lentivirus vector-based gene therapies.
The following points were considered:
Different vector designs and production systems may have different risk profiles with respect to RCR/RCL generation
There was consensus from the Committee that different vector designs and production systems do have different risk profiles with respect to RCR/RCL generation.
Accumulated experience with gammaretroviral vector vs. less extensive experience with lentiviral vectors
The Committee agreed that there is more accumulated experience with gammaretroviral vector systems. There were varying viewpoints on the impact of this difference as a consideration for lot release testing of transduced cells. Some members stated that the difference in accumulated experience between the two vector systems would not necessarily impact on the broader question of policy for lot release testing of transduced cells. Other members stated that the lesser experience with replication competence of lentiviral vector systems would be a consideration. Another viewpoint expressed was that given the current depth of knowledge of lentiviral vector manufacturing processes there is no indication that lentiviral vector systems would have a higher risk of replication competence in final transduced cells.
Alternatives to the cell culture based RCR/RCL assay for the transduced cell products:
- PCR based RCR/RCL as a release test when feasible
There was no consensus from the Committee on the issue of replacing a cell culture-based assay with a PCR-based assay for lot release of gammaretroviral vector or lentiviral vector based transduced cells. In general, the Committee did not support eliminating lot release testing on transduced cells. The Committee recognized there are difficulties attributed to both types of assays: Cell-based lot release assays take too long to complete and PCR-based lot release assays may not be sensitive enough. There was general support for work to progress on two fronts – to develop a quicker lot release cell-based assay and to develop more sensitive PCR-based assays.
Some Committee members supported a PCR-based lot release assay, provided the assay was validated for sensitivity and specificity vs. the biological assay. Other members stated PCR-based assays are currently less sensitive than cell-based assays and are prone to false positives. Some members felt that the manufacturing processes (vs. PCR assay itself) was the major factor in creating false positives. Some Committee members would support a two-step strategy with validation by a cell-based assay of PCR-positive lots. However, the rate of false positives from PCR-based assays might be too high to employ a two-step strategy at this time.
- Qualify the cell manufacturing process by testing the first few patient cell lots manufactured (how much data is needed)
There was consensus from the Committee that testing of the first few patient cell lots was not a sufficient way to qualify the manufacturing process.
- Qualify the cell manufacturing process and demonstrate the process will not amplify potential RCR/RCL with spiking experiments
The Committee agreed that spiking experiments should be done. However, there was no consensus as to whether the spiking experiments would be sufficient to qualify a cell manufacturing process to replace the RCR/RCL release testing.
At several points in the discussion, Committee members remarked that target/recipient cells are a major safety consideration and that there are not sufficient clinical data available on the risk of RCR/RCL in different patient populations treated with gammaretroviral vector-based or lentiviral vector-based gene therapies.
The Committee supported the redundancy of testing, (during manufacturing) recommended by the FDA. The Committee supported a case-by-case evaluation by FDA of testing requirements depending on the product and manufacturing process submitted by a sponsor. The FDA Guidance does allow for this flexibility.
Do you recommend additional modifications to other aspects of the current FDA recommendations for RCR/RCL testing or patient monitoring?
The Committee agreed with current process testing requirements for master cell banks, working cell banks, vector lot release and lot release of transduced cells. Recommendations were made for improvement in sampling and testing of RCR/RCL methodology. For PCR-based RCR/RCL assays, appropriate primer and probe sets must be carefully designed to maximize the chance of detection of a potential RCR/RCL. This will probably depend on the specific vector and transduced cell product.
In a discussion of patient monitoring the Committee stressed that special attention should be paid to situations where HIV-1-based lentiviral-based vectors are used to transduce HIV-1 infected cells which are reinfused into patients. Conversely, if a patient becomes HIV-1 positive after infused with cells transduced with an HIV-1-based lentiviral vector, close monitoring, and analyses of potential novel HIV-1 variants should be undertaken. In theory, novel variants of HIV could be generated through mobilization and recombination events between the vector and wild-type HIV-1 present in patients. The unknown characteristic of these novel variants of HIV could pose safety concerns.
Additionally, the Committee stated that attention should be paid to novel stem cells or progenitor cells other than hematopoietic stem/progenitor cells which may have very different properties with respect to RCR/RCL generation and dynamics.
Following this discussion the meeting was adjourned.