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Product Approval
Information - Licensing Action
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448
June 20, 2003
Our STN: BL 103976 / 0
Genentech, Incorporated
Attention: Robert L. Garnick, Ph.D.
Senior Vice President, Regulatory Affairs
Quality and Compliance
1 DNA Way
South San Francisco, CA 94080-4990
Dear Dr. Garnick:
Your biologics license application for Omalizumab is approved effective this date. Genentech, Incorporated, South San Francisco, California is hereby authorized to introduce or deliver for introduction into interstate commerce, Omalizumab under Department of Health and Human Services U.S. License No. 1048.
Omalizumab is indicated for adults and adolescents (12 years of age and above) with moderate to severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids. Under this authorization, you are approved to manufacture Omalizumab at your facilities in South San Francisco, California and --------------------. Final formulated drug product will be manufactured, filled, labeled and packaged at South San Francisco. In accordance with approved labeling, your product will bear the proprietary name Xolair, and will be marketed in single-use vials containing 202.5 mg of lyophilized product designed to deliver 150 mg Omalizumab/1.2 mL upon reconstitution with 1.4 mL Sterile Water for Injection.
The dating period for Omalizumab shall be 18 months from the date of manufacture when stored at 2-8° C. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for drug substance shall be -------- when stored at ---- °C or ---------- when stored at ---- °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.
You are not currently required to submit samples of future lots of Omalizumab 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 Omalizumab, 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.
FDA's Pediatric Rule at 21 CFR 314.55 and 21 CFR 601.27 was challenged in court. On October 17, 2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and barred FDA from enforcing it. Although the government decided not to pursue an appeal in the courts, it will work with Congress in an effort to enact legislation requiring pharmaceutical manufacturers to conduct appropriate pediatric clinical trials. In addition, third party intervenors have decided to appeal the court's decision striking down the rule. Therefore, we encourage you to submit a pediatric plan that describes development of your product in the pediatric population where it may be used. Please be aware that whether or not this pediatric plan and subsequent submission of pediatric data will be required depends upon passage and specific requirements of legislation or the success of the third party appeal. In any event, we hope you will decide to submit a pediatric plan and conduct the appropriate pediatric studies to provide important information on the safe and effective use of this drug in the relevant pediatric populations.
We acknowledge your written commitments to conduct postmarketing studies as described in your letters of May 5, 2003, and June 18, and 19, 2003, as outlined below:
Postmarketing Studies subject to reporting requirements of 21 CFR 601.70.
- To conduct a multicenter, randomized, double-blind, parallel-group, placebo-controlled study with a 28-week treatment phase, to determine the effect of subcutaneous administration of Omalizumab compared with placebo, on rates of clinically significant asthma exacerbations in adolescents and adults with asthma and skin test or in vitro reactivity to an aeroallergen who have reduced lung function and inadequate asthma symptom control despite treatment with oral corticosteroids. The final protocol of the study will be submitted to FDA by June 30, 2004, patient accrual will be completed by September 30, 2006, the study will be completed by February 28, 2007, and a final study report will be submitted to the FDA by August 31, 2007.
- To conduct a parallel group, double blind, randomized and placebo controlled study, to assess the efficacy of Omalizumab for the reduction of clinically significant exacerbations in asthma patients with an FEV1>80% predicted who are receiving inhaled corticosteroids with or without concomitant long acting beta agonist use. These patients will have skin test or in vitro reactivity to an aeroallergen. The final protocol of the study will be submitted to FDA by November 30, 2003, patient accrual will be completed by October 31, 2004, the study will be completed by June 30, 2005, and a final study report will be submitted to the FDA by November 30, 2005.
- To conduct a prospective, observational cohort study of 5,000 Omalizumab-treated and 2,500 untreated patients that assess the clinical safety of Omalizumab by determining the incidence of malignancy and other serious adverse events (SAEs) in Omalizumab-treated patients with moderate to severe persistent asthma and skin test or in vitro reactivity to an aeroallergen compared with patients not treated with Omalizumab. Study subjects will be followed for at least 5 years, and Omalizumab-treated patients will be matched at enrollment to untreated patients by age, gender and race/ethnicity. Interim reports will be filed yearly. The final protocol of the study will be submitted to FDA by December 31, 2003, patient accrual will be completed by March 31, 2006, the study will be completed by March 31, 2011, and a final study report will be submitted to the FDA by September 30, 2011.
- To conduct a study that will assess the stability of IgE levels in 250 adolescent and adult asthma patients with skin test or in vitro reactivity to an aeroallergen who are not exposed to Omalizumab. The study will assess patients longitudinally. In addition, the study will include an assessment comparing pre-treatment IgE levels with steady-state post-Omalizumab treatment levels in patients treated with Omalizumab for at least several months, and who then discontinue Omalizumab treatment. The final protocol of the study will be submitted to FDA by December 31, 2003, patient accrual will be completed by March 31, 2006, the study will be completed by March 31, 2011, and a final study report will be submitted to the FDA by September 30, 2011.
- To conduct a prospective, observational study of 250 pregnant women with asthma exposed to Omalizumab that will assess the outcomes in the offspring born to those women who were exposed to Omalizumab during pregnancy and breastfeeding relative to background risk in similar patients not exposed to Omalizumab. These outcomes will include adverse effects on immune system development, neonatal thrombocytopenia, major birth defects (congenital anomalies), minor birth defects, and spontaneous abortion. The final protocol of the study will be submitted to FDA by
December 31, 2003, patient accrual will be completed by March 31, 2009, the study will be completed by March 31, 2010, and a final study report will be submitted to the FDA by September 30, 2010.
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You should submit clinical protocols to your BB-IND ---- with a cross-reference letter to STN 103976/0. Submit nonclinical and chemistry, manufacturing, and controls protocols and all study final reports to STN 103976/0. In addition, under 21 CFR 601.70, you must submit an annual postmarketing status report to STN 103976/0. 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 an 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 a 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.
Sincerely yours,
--- signature ---
Sharon T. Risso, M.A.
Acting Director
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
Last Updated: 6/23/2003
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Date created: September 25, 2003 |
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