Product Approval Information
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
April 30, 2003
Our STN: BL 125058/0
Biomarin Pharmaceutical Inc
Attention: Matthew Patterson
371 Bel Marin Keys Boulevard
Novato, California 94949
Dear Mr. Patterson:
This letter hereby issues Department of Health and Human Services U.S. License No. 1649 to Biomarin Pharmaceutical Inc., Novato, California, in accordance with the provisions of Section 351(a) of the Public Health Service Act controlling the manufacture and sale of biological products. This license authorizes you to introduce or deliver for introduction into interstate commerce, those products for which your company has demonstrated compliance with establishment and product standards.
Under this license you are authorized to manufacture the product Laronidase. Laronidase is indicated for patients with Hurler and Hurler-Scheie forms of Mucopolysaccharidosis I (MPS I) and for patients with the Scheie form who have moderate to severe symptoms. The risks and benefits of treating mildly affected patients with the Scheie form have not been established. Laronidase has been shown to improve pulmonary function and walking capacity. Laronidase has not been evaluated for effects on the central nervous system manifestations of the disorder.
Under this authorization, you are approved to manufacture Laronidase at your facility in Novato, CA. Final formulated drug product may be filled at --------------------------------------------------------------------------------------. Labeling, packaging and distribution of unlabeled vials of drug product will occur at Genzyme Corporation, Allston, MA. In accordance with approved labeling, your product will bear the proprietary name Aldurazyme, and will be marketed in 5 mL single-use vials containing 2.9 mg Laronidase per 5 mL of solution.
The dating period for Laronidase shall be 24 months from the date of manufacture when stored at 2° to 8°C. The date of manufacture shall be defined as the date of final sterile filtration of the final formulated product. The dating period for drug substance shall be 12 months when stored at 2° to 8°C. Results of ongoing stability studies should be submitted throughout the dating period, as they become available, including the results of stability studies from the first three production lots. The stability protocols in your license application are considered approved for the purpose of extending the expiration dating period of your drug substance and drug product as specified in 21 CFR 601.12.
You are not currently required to submit samples of future lots of Laronidase to the Center for Biologics Evaluation and Research (CBER) for release by the Director, CBER, 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 specification.
Any changes in the manufacturing, testing, packaging or labeling of Laronidase, 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.
We acknowledge your written commitments to provide additional information on ongoing studies and to conduct postmarketing studies as described in your letters of January 27, 2003 and April 25, 2003 as outlined below:
Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70
- To re-evaluate drug substance and drug product specifications after a minimum of 30 additional lots of Laronidase are produced. A report of the results will be submitted to the FDA by February 28, 2005.
- To submit product quality data from a worst-case scenario study at laboratory scale to support hold times for intermediates in the drug substance manufacture. Results, including all tests required by the usual Certificate of Analysis, will be submitted to the FDA by December 31, 2003.
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70
- To further develop the IgE and Neutralizing Antibody assays to achieve greater sensitivity and to use the more sensitive assays for monitoring antibody responses in postmarketing studies. Assay validation reports from the revised assays will be submitted by September 30, 2003.
- To conduct a randomized study of the effect of different doses and schedules of Laronidase on clinical response. The final protocol of this study will be submitted to FDA by June 30, 2003, patient accrual will be completed by June 30, 2004, the last patient visit in November 30, 2004, and a final study report will be submitted to FDA by May 31, 2005. In addition, a follow-up study will be conducted if warranted based on the results of this study.
- To evaluate long-term safety and activity data in a registry study of patients being treated with Laronidase. Among other things, the registry data will be used to evaluate the effect of Laronidase on pregnancy and lactation, and potential effects of antibody formation and urinary GAG levels on clinical outcomes. The registry protocol will be submitted by May 31, 2003 and will be initiated by July 31, 2003. Major adverse events among patients receiving long-term treatment will be collected and submitted through the periodic safety update reports as specified by the regulations (21 CFR 600.80). The registry data will be analyzed at yearly intervals and the results will be submitted in annual reports for BB-IND ----. A final study report will be submitted to the FDA by December 31, 2020.
- To assess urinary GAG and antibody levels in approximately 50 patients (not including subjects of prior and ongoing clinical trials) quarterly for two years and then annually for the subsequent two years. This program, as an additional sub-study of the registry, will be initiated by October 31, 2003, completed by October 31, 2007 and a final report will be submitted to FDA by April 30, 2008.
- To evaluate data from studies ALID-003-99 and ALID-006-01 to determine if a correlation exists between endogenous enzyme activity and patient antibody responses and infusion reactions. A final study report will be submitted by June 30, 2003. If this report fails to provide an adequate sampling of endogenous enzyme, BioMarin will submit by October 31, 2003 a plan to conduct an additional study.
- To evaluate the treatment of patients younger than six years of age. The protocol for the study in patients under five years of age being conducted in Europe was submitted to the FDA on February 27, 2003 to BB-IND ----. Patient accrual will be completed by August 31, 2003, the study will be completed by August 31, 2004, and a final study report will be submitted by February 28, 2005.
You should submit clinical protocols to your BB-IND ---- with a cross-reference letter to the BLA. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to this BLA. In addition, under 21 CFR 601.70, you must submit an annual postmarketing status report to this BLA. For each reportable commitment, you must provide a description, the original schedule, the status, and an explanation of the status including the number of patients or subjects enrolled to date and the total planned enrollment. We may publicly disclose information regarding postmarketing studies subject to the reporting requirements of 21 CFR 601.70. You should label prominently all submissions, including supplements, relating to postmarketing study commitments, for example, as follows “Postmarketing Study Protocol,” “Postmarketing Study Final Report,” “Postmarketing Study Correspondence,” or “Annual Report on Postmarketing Studies.” You may refer to the April 2001 Draft Guidance for Industry: Reports on the Status of Postmarketing Studies - Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 for further information.
It is required 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 in accordance with 21 CFR 600.81. Postmarketing adverse experience reports and distribution reports should be submitted to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Rockville, MD 20852-1448. All adverse experience reports should be prominently identified according to 21 CFR 600.80.
You are required to submit reports of biological product deviations in accordance with 21 CFR 600.14. All manufacturing deviations, including those associated with processing, testing, packing, labeling, storage, holding and distribution, should be promptly identified and investigated. If the deviation involves a distributed product, may affect the safety, purity, or potency of the product, and meets the other criteria in the regulation, a report must be submitted on Form FDA-3486 to the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.
Please submit all final printed labeling at the time of use and include implementation information on FDA Form 356h. Please provide a PDF-format electronic copy as well as original paper copies (ten for circulars and five for other labels). In addition, you may wish to submit three draft copies of the proposed introductory advertising and promotional labeling with FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. Final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by FDA Form 2253.
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.
--- signature ---
Steven A. Masiello
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
--- signature ---
Sharon T. Risso, M.A.
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
Last Updated: 5/1/2003
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Date created: September 25, 2003