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October 9, 2009: Cellular, Tissue and Gene Therapies Advisory Committee Meeting Summary Minutes

Food and Drug Administration
Center for Biologics Evaluation and Research
Cellular, Tissue and Gene Therapies Advisory Committee 

SUMMARY MINUTES
Meeting #48, October 9, 2009
Hilton Hotel, Gaithersburg, MD  

COMMITTEE MEMBERS

Stanton L. Gerson, M.D.
Matthew J. Allen, Vet., M.B., Ph.D.
Richard J. Chappell, Ph.D.
Steven M. Dubinett, M.D.
Evanthia Galanis, M.D. +
Larry W. Kwak, M.D., Ph.D.
Mahendra S. Rao, M.D., Ph.D. **
Peter L. Saltonstall *+
Evan Y. Snyder, M.D., Ph.D.
Doris A. Taylor, Ph.D.
Savio L.C. Woo, Ph.D.

TEMPORARY VOTING MEMBERS

Karen E. Burke, M.D.
Lynn Drake, M.D.
Lloyd E. King, Jr., M.D.
Amy Newburger, M.D.
Michael J. Olding, M.D.
Karen R. Rue, R.N., M.B.A. *

FDA PARTICIPANTS

Terrig Thomas, Ph.D.
Agnes Lim, M.D.
Yao-Yao Zhu, M.D.
Shiowjen Lee, Ph.D.
Celia Witten, Ph.D., M.D.

* Consumer Representative
** Industry Representative

Designated Federal Officer
Gail Dapolito

Committee Management Specialist
Danielle Cubbage

The summary minutes for the October 9, 2009 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee were approved on March 23, 2010.

I certify that I attended the October 9, 2009 meeting of the Cellular, Tissue and Gene Therapies Advisory Committee and that this report accurately reflects what transpired.

_________/signature/_____________
Stanton L. Gerson, M.D., Chair

_________/signature/_____________
Gail Dapolito, Designated Federal Officer

FDA Cellular, Tissue and Gene Therapies Advisory Committee
Summary Minutes
Meeting #48, October 9, 2009 

The Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) met in open session on October 9, 2009 at the Pooks Hill Marriott, Bethesda, MD.

On October 9, the Chair called the meeting to order and introduced the members and consultants. The Designated Federal Officer 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 BLA 125348, Fibrocell Technologies, Inc. (formerly Isolagen Technologies, Inc) for moderate to severe nasolabial fold wrinkles.

Speakers representing Fibrocell Technologies, Inc. provided an introduction to the product and data on the manufacturing, safety and efficacy and clinical experience. FDA speakers presented information on the Agency’s product, safety and efficacy and statistical reviews.

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

Following the Open Public Hearing the Committee addressed the following discussion questions :

  1. Tumorigenicity: If approved, IT will be the first cellular product for this indication, and the first fibroblast product that is an injectable cell suspension. Uncontrolled cell growth and/or tumor formation could be potential risks of cultured fibroblasts due to their proliferative nature. In addition, there is a theoretical risk of the post-auricular biopsy transferring abnormal or malignant cells that may not be detected in the quality controls of product manufacturing. Long term follow-up data are limited. One case of basal cell cancer occurred near the site of injection; however, the relationship of IT to this case cannot be assessed.

    Based on the manufacturing and clinical data presented and your knowledge of the literature, please discuss any safety concerns relevant to tumor formation and the potential for longer term (beyond 12 months) risks with this product. If you believe there is potential risk, please discuss the basis for your opinion and your recommendations to address the risk(s).

There was general consensus among the Committee that as the product is derived from autologous cells, the risk of tumorgenicity from these cells is low. However, the committee was concerned that insufficient data had been presented on the characterization of the implanted cells to adequately assess the safety of the product. The Committee stated that more information is needed on; the survival and fate of the implanted cells; collagen production by implanted cells; the effect of passage number on the potential for tumorigenicity; the effect of growth-factors and other proteins secreted by implanted cells on the potential for tumorgenicity; and the effect of cell-mediated immune responses.

The Committee discussed the need for a greater than 12-month safety follow-up period for patients, including possible follow-up biopsies of implanted site(s). The Committee also briefly discussed other risk factors such as age (greater than 65); genetic predisposition to cancer; heavy smoking.

  1. Race and Ethnicity: An increase in safety events in non-Caucasian subjects in the trial was not observed; however, the sample size was small. Please discuss whether or not the data in the trial, and your knowledge of the literature, suggest that this product has the potential for causing risks such as hypertrophic scarring and keloid formation, or abnormal pigmentation in the non-Caucasian population. If you believe there is a potential increased risk, please provide your suggestions on how to minimize these adverse events.

The Committee agreed there were limited data available from the small number of non-Caucasian subjects to adequately assess risk in non-Caucasian populations and recommended “strong follow-up and reporting” in these populations.

  1. Other demographic characteristics: The proportions of subjects over 65 years of age and male subjects in the clinical trials were small. Please discuss whether or not the data from the trials, and your knowledge of the literature, suggest any potential safety concerns with use of this product in these groups.

There was consensus from the Committee that the available data suggest there are questions concerning effectiveness in the over 65 population. The Committee stated that assessment of the therapy could be more difficult in elderly patients using the existing measurement scales. Deep nasolabial wrinkle folds on a background of increased facial wrinkles may interfere with interpretation of the filling effect. Some Committee members also questioned whether altered immune responses and photo-damaged skin in older populations could pose additional safety concerns. However, the Committee stated that patients over 65 years of age should not be excluded.

For the most part, the Committee felt there were no particular concerns regarding male patients with one caution that males have an increased incidence of cancer as they age and this could be an added risk for this demographic.

  1. Physician Training: The available safety data demonstrate a high incidence (up to 2/3 of subjects) of injection-site reactions. Those events tended to last longer in IT-treated subjects than in the vehicle-control group. About 6% of events in the IT-treated group lasted beyond 30 days. Such events may present cosmetic concerns. The applicant notes that proper injection technique can play a role in the frequency and severity of these reactions. The applicant is proposing a physician training program as a requirement for use of the product.
    • Do you have specific recommendations for the content of a practitioner training program?
    • Do you have any other recommendations on how to minimize these adverse events?

The Committee stated that short term injection site reactions are not unusual with injectable fillers. Consequently, short term reactions should be considered separately from long term reactions that pose both a cosmetic and safety concern. Such long term reactions could be unrelated to practitioner training. In general, the Committee agreed there was insufficient data presented to evaluate the risk of long term safety of the product.

The Committee supported a practitioner training program that would include all medical personnel involved in the preparation and administration of the product. The Committee recommended that the following elements be included in a training program: appropriate selection and screening of patients, appropriate techniques for performing biopsies, preparation of cells and product handling; instruction in injection technique; appropriate training for evaluators; adequate documentation of completion of training; reference video in addition to on-site training; screening, documentation and follow-up of adverse events.

There were several comments from the Committee expressing concern that, if licensed, the product will inevitably be used off-label to treat other facial wrinkles. There was a suggestion that the Sponsor require confirmation from practitioners that the product will be used only as intended, for the indication of nasolabial fold wrinkles.

  1. 21 CFR 601.25(d)(1) states that safety of a licensed biological product means the relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time. Proof of safety shall consist of adequate tests by methods reasonably applicable to show the biological product is safe under the prescribed conditions of use, including results of significant human experience during use.
    • Do the data presented demonstrate safety for the proposed indication? 
    • If no, what additional studies should be performed?
    • If yes, do you have any specific recommendations for the labeling?

In a general discussion of this question prior to voting, the Committee commented on the lack of sufficient data related to the processing, characterization and collagen production of the injected cells. Some Committee members expressed concern that due to a lack of data on the mechanism of action, there was insufficient information to assess the safety of the product and recommended collection of long-term follow-up data. Other Committee members commented that safety might be less of a concern as this is an autologous product and that the available clinical data did not suggest the product was unsafe. There was general consensus that as this is a novel cellular therapy for a non life- threatening condition, safety standards should be set at a high level.

In a discussion of additional studies that could be performed to increase safety assurance, the Committee commented on the need to determine if efficacy is derived from normal collagen production versus scar formation. Longer-term studies (greater than 1 year) may be necessary to determine whether implanted cells remain productive. Some safety concerns could also be addressed by further product characterization, such as karyotyping, and analysis for tumor markers. Additional safety and mechanistic data could be obtained by conducting a clinical study in which cells are injected into a less visible area on the body followed by taking serial biopsies for analysis. Some Committee members stated it may be possible to obtain safety and efficacy data from previous commercial use of the product in Europe.

The Committee voted on the following:

Do the data presented demonstrate safety for the proposed indication?

Voting Results:

Yes = 6
No = 8
Abstain = 0
Total = 14 voting members

(Please see transcripts for poll of individual votes)

  1. 21 CFR 601.25(d)(2) states that effectiveness means a reasonable expectation that, in a significant proportion of the target population, the pharmacological or other effect of the biological product, when used under adequate directions, for use and warnings against unsafe use, will serve a clinically significant function in the diagnosis, cure, mitigation, treatment, or prevention of disease in man.
    • Do the data presented demonstrate effectiveness for the proposed indication?
    • If no, what additional studies should be performed?
    • If yes, do you have any specific recommendations for the labeling?

A majority of the Committee agreed that the available data demonstrated efficacy in the narrowly defined application: nasolabial fold wrinkles. Dissenting members voiced concern about the lack of objective and long-term efficacy data. The Committee suggested additional studies are needed to evaluate the product in elderly, non-Caucasian and male populations and recommended a registry be created and maintained to gather information on ethnicity, race, age and sex.

The Committee voted on the following:
Do the data presented demonstrate effectiveness for the proposed indication?
Voting Results:

Yes = 11
No = 3
Abstain = 0
Total = 14 voting members

(Please see transcripts for poll of individual votes)

Following this discussion and vote 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/AdvisoryCommittees/CommitteesMeetingMaterials/default.htm