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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
December 3, 2002
Our STN: BL 103964/5000
Jennifer Dudinak, Pharm. D.
Hoffmann-La Roche, Incorporated
340 Kingsland Street
Nutley, NJ 07110-1199
Dear Dr. Dudinak:
Your request to supplement your biologics license application (BLA) for Peginterferon alfa-2a (Pegasys) to include combination therapy with Ribavirin, USP (Copegus), for the treatment of chronic hepatitis C virus infection has been approved. Peginterferon alfa-2a, alone or in combination with Copegus, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha.
We acknowledge your written commitments to provide additional information from ongoing studies and to conduct post-marketing studies as described in your letters of November 27, 2002, December 2, 2002 and December 3, 2002 and as outlined below:
- To assess the safety and efficacy of Peginterferon alfa-2a alone or in combination with Ribavirin, USP in 112 pediatric patients infected with the hepatitis C virus. The protocol entitled “Pegylated Interferon +/- Ribavirin for Children with HCV” was submitted to BB-IND ----- on September 27, 2002. Patient accrual will begin in June 2003 and will be completed by June 2004. The study will be completed by June 2006 and a final study report, data sets and modified labeling will be submitted by December 2006.
- To submit data from an ongoing study to evaluate the safety and efficacy of Peginterferon alfa-2a and Ribavirin, USP in 400 African American and Caucasian genotype 1 patients. The protocol for the VIRAHEP-C study sponsored by NIDDK-NIH was submitted to BB-IND ----- on March 18, 2002. Patient accrual began in September 2002 and will be completed by August 2003. The study will be completed by March 2006 and a final study report, data sets and modified labeling will be submitted by September 2006. Upon completion of the study, you will submit by September 2006 a protocol and commitment (with schedule) to conduct an additional clinical study to optimize treatment response in the African American population. The factors associated with resistance to antiviral therapy in African Americans with chronic hepatitis C, which are selected for evaluation will be based upon the outcomes of the VIRAHEP-C study.
- To conduct a multicenter, randomized open-label trial in 1400 genotype 2/3, chronic hepatitis C patients to evaluate the safety and efficacy of Peginterferon alfa-2a and Ribavirin, USP. The protocol entitled “Randomized, Multicenter, Open-label Phase IIIb Study Evaluating the Efficacy and Safety of Pegylated Interferon alfa-2a (PEG-IFN) in Combination with Ribavirin Given for 16 vs. 24 weeks in Previously Untreated Patients with HCV (hepatitis C virus) Genotype 2/3 Infection” will be submitted to BB-IND ---- by March 2003. Patient accrual will begin in August 2003 and will be completed by August 2004. The study will be completed by September 2005 and the final study report, data sets and modified labeling will be submitted by December 2005.
- To conduct a substudy in 100 patients from the genotype 2/3 study to evaluate fasting triglyceride levels collected at baseline, end-of-treatment and follow-up. The study will be completed by September 2004 and data submitted by December 2004.
- To conduct a randomized, multi-center, open-label pilot study in 160 genotype-1, high viral load, chronic hepatitis C patients, who weigh > 85kg to evaluate the virologic response and safety of alternate dosing regimens of Peginterferon alfa-2a and Ribavirin, USP. The protocol will include a substudy evaluating the impact of Peginterferon alfa-2a and Ribavirin combination therapy on changes in specific lymphocyte phenotypes in approximately 80 patients (20 per arm). The study protocol entitled “A Randomized, Multicenter, Open Label Study to Evaluate the Effect of Peginterferon alfa-2a (Pegasys) Doses 180mg or 270mg in Combination with Ribavirin (Copegus) Doses of 1200 mg or 1600 mg on Viral Kinetics, Week 12 Virological Response, Safety, and Tolerability in CHC Patients Infected with HCV Genotype 1, Having High Viral Load and a Body Weight of Greater Than 85 Kilograms” will be submitted to BB-IND ---- by May 2003. Patient accrual will begin October 2003 and will be completed by June 2004. The study will be completed by October 2004 and a summary of the data will be submitted by December 2004. The results of this pilot study will be evaluated to determine whether an alternate dose of Peginterferon alfa-2a and/or Ribavirin, USP should be evaluated in a larger study.
- If the results of the pilot study suggest an acceptable risk benefit profile for any of the doses evaluated, a larger study will be conducted, in 900 evaluable patients equally randomized to two treatment arms [1:1] for 48 weeks, followed by a 24-week untreated follow-up period. The protocol for this study (or some other large study to be agreed upon with the FDA) will include a substudy to evaluate the potential association between lymphopenia, neutropenia and serious infections. The draft protocol will be submitted by December 2004. Patient enrollment will begin in March 2005 and will be completed by January 2006. The study will be completed by August 2007 and the final study reports, data sets and modified labeling will be submitted by November 2007.
- To better characterize the serious infections that were observed in studies NV 15801 and NV 15942 by following-up with each of the individual study sites to gather further information on the patients’ neutrophil count at the time of hospitalization for the infection. A final report of this data will be provided to the Agency by June 2003.
We also acknowledge the following agreement:
- In cases of serious infections reported in patients receiving Pegasys and Copegus combination therapy, a specific summary with details of each of the cases of serious infections reported in all clinical hepatitis C virus studies of Pegasys and spontaneous reports will be submitted in the annual report for BB-IND -----.
Pursuant to 21 CFR Part 208, FDA has determined that Peginterferon alfa-2a alone or in combination with Ribavirin, USP tablets 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 December 3, 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.
The text in italics below addresses the application of FDA's Pediatric Rule at 21 CFR 601.27 to this BLA. The Pediatric Rule has been challenged in court. On October 17, 2002, the court ruled that FDA did not have the authority to issue the Pediatric Rule and has barred FDA from enforcing it. The government has not yet decided whether to seek a stay of the court's order. In addition, the government has not yet decided whether to appeal the decision; an appeal must be filed within 60 days. Therefore, this letter contains a description of the pediatric studies that would be required under the Pediatric Rule, if the Pediatric Rule remained in effect and/or were upheld on appeal. Please be aware that whether or not these pediatric studies will be required will depend upon the resolution of the litigation. FDA will notify you as soon as possible as to whether this application will be subject to the requirements of the Pediatric Rule as described below. In any event, we hope you will decide to conduct these pediatric studies to provide important information on the safe and effective use of this drug in the relevant pediatric populations.
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). Based on information submitted, we are deferring submission of your pediatric studies until December 2006.
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-----------------------------------------------------------------------------------] supplement of the Peginterferon alfa-2a BLA (Our STN BL103964/5000). Please use this number on all future correspondence for this product, including all communications regarding post-marketing commitments.
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 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 an 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.
This information will be included in your biologics license application file.
Sincerely yours,
--- signature ---
Karen D. Weiss, M.D.
Director
Office of Therapeutics Research and Review
Center for Biologics Evaluation and Research
Last Updated: 12/10/2002
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Date created: September 25, 2003 |
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