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 Product Approval Information


DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448

October 16, 2002

Our STN: BL 103964/0

Hoffmann-La Roche, Incorporated
Attention: Candice Teuber, Pharm. D.
Program Director, Drug Regulatory Affairs
340 Kingsland Street
Nutley, NJ 07110-1199

Dear Dr. Teuber:

Your biologics license application for Peginterferon alfa-2a is approved effective this date. Hoffmann-La Roche, Nutley, New Jersey, is hereby authorized to introduce or deliver for introduction into interstate commerce, Peginterferon alfa-2a under Department of Health and Human Services U.S. License No. 0136.

Peginterferon alfa-2a is indicated for the treatment of adults with chronic hepatitis C who have compensated liver disease and who have not been previously treated with interferon alfa. Under this authorization, you are approved to manufacture Peginterferon alfa-2a drug substance and drug product, including filling and packaging, at your facility in Nutley, New Jersey, using bulk interferon alfa-2a drug substance manufactured at your facility in ----------------------------------. In accordance with approved labeling, your product will bear the proprietary name PEGASYS, and will be marketed in 180mg/1.0 mL single use vials.

The dating period for Peginterferon alfa-2a drug product shall be 12 months from the date of manufacture when stored at 2º to 8ºC. The date of manufacture shall be defined as the date of final sterile filtration of the formulated drug product. The dating period for Peginterferon alfa-2a drug substance and bulk interferon alfa-2a drug substance shall be 18 months when stored at -70ºC. 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 protocol in your license application is 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 Peginterferon alfa-2a 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 Peginterferon alfa-2a, 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.

All applications for new active ingredients, new dosage forms, new indications, new routes of administration, and new dosing regimens must contain an assessment of the safety and effectiveness of the product in pediatric patients unless this requirement is waived or deferred (21 CFR 601.27). We note that you have not fulfilled the requirements of 21 CFR 601.27. On the basis of your commitment described in item 1 below, we are deferring the submission of your pediatric studies, under 21 CFR 601.27(b), until September 2003. Please note that FDA may require additional pediatric studies to fulfill the pediatric requirements of 21 CFR 601.27.

We acknowledge your written commitments to provide additional information on ongoing studies and to conduct post-marketing studies as described in your letters of April 15, 2002, October 4, 2002, October 11, 2002, and October 15, 2002, as outlined below:

  1. To submit data from an ongoing study to evaluate the safety and pharmacokinetics of Peginterferon alfa-2a in pediatric patients 2 to 8 years of age. The protocol for study NR16141 entitled “The Safety, Viral Kinetics and Pharmacokinetics of Pegasys® After Multiple Doses in Young Children with Chronic Hepatitis C Infection” was submitted to BB-IND ------- on ---------------------. Patient accrual was completed on --------------------, the study will be completed by June 2003 and the final study report, data sets and modified labeling will be submitted by September 2003.

  2. To submit data from an ongoing study to evaluate the safety and efficacy of Peginterferon alfa-2a in African American genotype 1 patients versus Caucasian genotype 1 patients. The protocol for study NR16172 entitled “A Multicenter, Open-Label Study Investigating the Efficacy of Pegasys in Combination with Ribavirin as Initial Treatment of Chronic Hepatitis C in African American HCV Genotype 1 Patients as Compared to Caucasian HCV Genotype 1 Patients” was submitted to BB-IND ------ on ----------------. Patient accrual was completed on ---------------, the study will be completed by December 2002 and a final study report, data sets and modified labeling will be submitted by March 2003.

  3. To submit data from an ongoing study to evaluate the pharmacokinetics and pharmacodynamics effects of Peginterferon alfa-2a in patients receiving methadone. The protocol for study NP16048 entitled “The Pharmacokinetic and Pharmacodynamic Effects of the Concomitant Administration of Methadone and Peginterferon alfa-2a (PEG-IFN) in Chronic Hepatitis C (CHC) Patients Receiving Methadone Maintenance Therapy” was submitted to BB-IND ------- on ---------------. Patient accrual was completed on ----------------------, the study will be completed by January 2003, and a final study report, data sets, and modified labeling will be submitted by April 2003.

  4. To develop and evaluate improved immunogenicity screening assays for detecting binding and neutralizing antibodies using Peginterferon alfa-2a as the target molecule. These assays are to be validated for sensitivity, specificity and reproducibility. Approximately 300 patients will be enrolled in the study from ongoing or future clinical studies for hepatitis C indication. A clinical protocol including the intended cohort, study size and schedule for sampling will be submitted by February 2003. The methods and validation data for the assays will be submitted by June 2003. The results of the antibody evaluation will be submitted as part of an interim study report in May 2004, and the final study report by August 2004.

Protocols should be submitted to your BB-IND -------- with a cross-reference letter to the BLA.

Pursuant to 21 CFR Part 208, FDA has determined that this product poses a serious and significant public health concern requiring the distribution of a Medication Guide. Peginterferon alfa-2a is a product for which patient labeling could help prevent serious adverse effects and inform the patient of serious risks relative to benefit that could affect their decisions to use, or continue to use, the product. Therefore, a Medication Guide is necessary for safe and effective use of this product and FDA hereby approves the draft Medication Guide you submitted October 15, 2002. Please note that the final printed Medication Guide must conform to all conditions described in 21 CFR 208.20, including a minimum of 10 point text. Additionally, in accordance with 21 CFR 208, you are responsible for ensuring that this Medication Guide is available for distribution to every patient who is dispensed a prescription for this product. You are also responsible for ensuring that the label of each container or package includes a prominent and conspicuous instruction to authorized dispensers to provide a Medication Guide to each patient to whom the drug is dispensed, and states how the Medication Guide is provided.

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).

You may wish to submit two 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 ---

Jay P. Siegel, M.D., FACP
Director
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research


Last Updated: 10/17/2002

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Date created: September 25, 2003

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