DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
August 22, 1997
Our Reference No: 96-0372
Mr. Tim Surgenor
Genzyme Tissue Repair
74 Sidney Street
Cambridge, MA 02139-4136
Dear Mr. Surgenor:
This letter hereby issues Department of Health and Human Services Biologics License No. 1233 to Genzyme Tissue Repair, Cambridge, Massachusetts, in accordance with the provisions of Title III Part F of the Public Health Service Act of July 1, 1944 (58 Stat. 702) controlling the manufacture and sale of biological products. This license authorizes you to manufacture and ship for sale, barter, or exchange, in interstate and foreign commerce, those products for which your company has demonstrated compliance with establishment and product standards.
Under this license, you are authorized to manufacture Autologous Cultured Chondrocytes, for the repair of clinically significant, symptomatic cartilaginous defects of the femoral condyle (medial, lateral, or trochlear) caused by acute or repetitive trauma.
Under this authorization, you are approved to manufacture Autologous Cultured Chondrocytes at your facilities in Cambridge and Framingham, Massachusetts. Autologous Cultured Chondrocytes will be distributed under the tradename Cartiicel.
As per the May, 1996, Guidance on Applications for Products Comprised of Living Autologous Cells Manipulated Ex-vivo and Intended for Structural Repair or Reconstruction, you are not required to submit samples of future lots of Autologous Cultured Chondrocytes to the Center for Biologics Evaluation and Research (CBER) for release under 21 CFR 610.2. FDA will continue to monitor compliance with 21 CFR 610.1 requiring assay and release of only those lots that meet release specifications.
The dating period for the dosage formulation of this product shall be 72 hours from the date of manufacture when stored at 2-8°C. The date of manufacture shall be defined as the date of when the Autologous Cultured Chondrocytes are dispensed in the final container vial. Results of ongoing stability studies should be submitted as they become available.
At this time, we are also approving your requests to amend your biologics license application to utilize equivalent test methods under 21 CFR 610.9 to replace the rabbit pyrogen test with the limulus amebocyte lysate (LAL) test and the general safety test with a combination of assays for cell viability, cell morphology, and an adaptation of the MEM Elution Assay for cytotoxicity using the L929 murine cell line as product release tests.
Any changes in the manufacturing, testing, packaging or labeling of Autologous Cultured Chondrocytes, or in the manufacturing facilities will require the submission of information to your biologics license application for our review and written approval consistent with 21 CFR 601.12.
As requested in your letter of June 9, 1997, marketing approval of this product is granted under the accelerated approval for biological products regulations, 21 CFR 601.40-46. These regulations permit the use of certain surrogate endpoints or an effect on a clinical endpoint other than survival or irreversible morbidity as bases for approvals of products intended for serious or live-threatening illnesses or conditions.
Among other things, approval under these regulations requires that you conduct adequate and well-controlled studies to verify and describe clinical benefit as evidenced by durable favorable outcomes, and to verify the contribution of Autologous Cultured Chondrocytes to these outcomes, and that such studies be carried out with due diligence. If the postmarketing studies fail to verify clinical benefit observed with implantation of Autologous Cultured Chondrocytes, or are not conducted with due diligence, the Agency may, following a hearing, withdraw or modify approval.
Granting of this approval is contingent upon completion of clinical studies as outlined in your commitments of July 17 and August 22, 1997 designed to do the following:
- To establish the contribution of autologous cultured chondrocytes to structural and functional patient outcomes in a randomized, double-blind, placebo-controlled study of periosteal flap, with and without concomitant autologous cultured chondrocytes, in patients with femoral cartilage defects;
- To verify that the observed short-term functional, structural and histological outcomes will lead to durable clinical benefit by studying long-term clinical outcomes in a randomized, open-label controlled, three-arm comparative study of Carticel administration with periosteal flap versus abrasion arthroplasty versus microfracture.
Design, initiation, accrual, completion, and reporting of these studies is expected to occur within the framework described in your letter of July 17, 1997 and as further clarified in your facsimile of August 22, 1997. It is understood that, to fulfill the requirements of accelerated approval, both studies must be conducted with due diligence and both must demonstrate superiority of the Cartice1 therapy over the comparator on primary efficacy outcomes.
In addition, we acknowledge the following post-approval commitments concerning product manufacturing which are fully described in your letters of July 12, July 17, and August 6, 1997:
- To validate the chondrocyte morphology release test and to verify the identity of the various cell types seen in chondrocyte expansion cultures. Completion of all morphology testing is anticipated during the first Quarter of 1998;
- To validate sample storage for, and the interchangeability of, the gel clot and kinetic chromogenic LAL assays in the testing of Autologous Cultured Chondrocytes. Completion of this testing is anticipated by September, 1997;
- To develop a protocol and Standard Operating Procedure (SOP) for establishing and qualifying reference cell strains. Associated validation data and specifications are anticipated by January, 1998;
- To develop and validate an identity assay using molecular markers specific for chondrocytes. Progress reports on the development of this assay are anticipated at six month intervals;
- To establish objective criteria for expansion of previously frozen chondrocytes. Criteria and final manufacturing procedures are anticipated by January, 1998;
- To develop data demonstrating the inability of infectious virus to replicate in chondrocyte cell cultures. Completion of this study is anticipated by January, 1998;
- To validate product shelf life under a variety of shipping conditions. Progress reports are anticipated at six month intervals;
- To develop and evaluate a serum-free medium for chondrocyte expansion. The first progress report is anticipated in January, 1998;
- To perform routine monitoring of air flow in the production cleanroom and to set air change specifications based on these data;
- To conduct studies to demonstrate the effectiveness of disinfecting agents used in the product facility and on production equipment and containers.
Additionally, as committed in your facsimile of August 22, 1997 you will continue to follow all patients currently enrolled in the Carticel Patient Registry for a minimum of two years post-cell implantation and provide periodic reports of safety and clinical outcomes to the agency. All safety information obtained through the registry should be included in the periodic safety reports for Carticel as specified in 21 CFR 600.80.
It is requested that adverse experience reports be submitted in accordance with the adverse experience reporting requirements for licensed biological products (21 CFR 600.80) and that distribution reports be submitted as described (21 CFR 600.81). These requirements became effective on December 27, 1994. All adverse experience reports should be prominently identified according to 21 CFR 600.80 and be submitted to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockille Pike, Rockville, MD 20852-1448.
Please submit three copies of all final printed labeling at the time of use and include part II of the label transmittal form (FDA Form 2567) with completed implementation information. In addition, as specified in 21 CFR 601.45, any additional advertising and promotional labeling to be disseminated after 120 days following today's date should be submitted for review and approval using FDA Form 2567 to the Advertising and Promotional Labeling Staff, HFM-202, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448 at least 30 days prior to the initial publication of any advertisement or to the initial dissemination of any promotional labeling.
All promotional claims must be consistent with and not contrary to approved labeling. No comparative promotional claim or claim of superiority over other products should be made unless data to support such claims are submitted to and approved by the Center for Biologics Evaluation and Research.
Please acknowledge receipt of the enclosed biologics license to the Director, Division of Application Review and Policy (HFM-585), Center for Biologics Evaluation and Research
|--- signature ---||--- signature ---|
|Jay P. Siegel, M.D., FACP|
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
|Jerome A. Donlon, M.D., Ph.D.|
Office of Establishment Licensing and Product Surveillance
Center for Biologics Evaluation and Research