FDA Logo links to FDA home page
Center for Drug Evaluation and Research, U.S. Food and Drug AdministrationU.S. Food and Drug AdministrationCenter for Drug Evaluation and Research
 HHS Logo links to Department of Health and Human Services website

FDA Home Page | CDER Home Page | CDER Site Info | Contact CDER | What's New @ CDER

horizonal rule
CDER Home About CDER Drug Information Regulatory Guidance CDER Calendar Specific Audiences CDER Archives
 
Powered by Google
 

 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

January 30, 2003

Our STN: BL 125036 / 0

Biogen, Inc.
Attention: Nadine D. Cohen, Ph.D.
Vice President, Regulatory Affairs
14 Cambridge Center
Cambridge, MA 02142

Dear Dr. Cohen:

Your biologics license application for Alefacept is approved effective this date. Biogen, Inc., Cambridge, Massachusetts, is hereby authorized to introduce or deliver for introduction into interstate commerce, Alefacept, under Department of Health and Human Services U.S. License No. 1204.

Alefacept is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. Under this authorization, you are approved to manufacture Alefacept at your facilities in Cambridge, Massachusetts and Research Triangle Park, North Carolina. Final formulated drug product will be filled at ----------------------------------------------------------------------------
---------------------. Unlabeled vials of drug product will be shipped to -------------------------------------------------------- for labeling and packaging. In accordance with approved labeling, your product will bear the proprietary name Amevive, and will be marketed in 7.5 mg and 15 mg single-use vials.

The dating period for Alefacept shall be 24 months from the date of manufacture when stored at controlled room temperature (15-30°C, 59-86°F). 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 24 months from the date of manufacture when stored at -70° + 10°C. The expiration date for the packaged product, Alefacept plus Sterile Water for Injection, USP shall be dependent on the earliest expiration date of either component. 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 Alefacept 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 601.1 requiring assay and release of only those lots that meet release specification. Any changes in the manufacturing, testing, packaging or labeling of Alefacept, 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 letter of January 27, 2003 as outlined below:

Chemistry, Manufacturing, and Controls

  1. To make the following changes in all package labeling in the next printing and submit these changes in the form of a "Special Labeling Supplement-Changes Being Effected" as described under 21 CFR 601.12(f)(2) by September 30, 2003:

    • Revise the statement, "Store at room temperature (15-30°C, 59-86°F)" to read "Store at controlled room temperature (15-30°C, 59-86°F)".

    • Include the following statement, "Protect from light. Retain in carton until time of use."

  2. To conduct a validation study of container/closure integrity of ------- bottles used to store bulk drug substance and to submit the protocol and final study report to the BLA by September 30, 2003.

Clinical

  1. To develop a dual-specificity immunogenicity assay for anti-LFA3TIP antibodies that is capable of distinguishing between anti-LFA3 and anti-Fc antibodies by June 30, 2003. Validation of the assay will be completed by September 30, 2003 and the final validation report will be submitted to FDA by December 31, 2003.

  2. To test archival patient samples from all patients who tested positive for anti-LFA3TIP antibodies and a sampling of patients who tested negative for a total of approximately 1200 patient samples in the new dual-specificity immunogenicity assay. Results of the analysis and any applicable, revised labeling will be submitted to the FDA by August 31, 2004.

  3. To further assess the effect of body weight on the safety and efficacy of Alefacept in a multicenter, randomized, blinded, parallel group study of approximately 390 patients. The final protocol for this study will be submitted to FDA by March 31, 2003. Patient accrual will be completed by June 30, 2004, the study completed by December 31, 2004, and the final study report, and applicable, revised labeling will be submitted to FDA by June 30, 2005.

  4. To further evaluate the safety and efficacy of Alefacept when administered over multiple cycles. The study will include 400 patients treated with up to three courses of Alefacept. The final protocol for this study was submitted on October 1, 2002. The study protocol will be amended to include sampling of approximately 50-100 patients for the assessment of immunogenicity to Alefacept. Collected serum samples will be archived for subsequent analysis by the dual-specificity immunogenicity assay. Patient accrual will be completed by June 30, 2003, the study completed by June 30, 2006, and the final study report, immunogenicity data, and applicable, revised labeling will be submitted to FDA by December 31, 2006.

  5. To further evaluate the risk of infections and malignancies in patients treated with Alefacept in a single cohort of 5000 patients followed for 5 years. The final protocol will be submitted to FDA by March 31, 2003. Patient accrual will be completed by December 31, 2004, the results of the study will be reported to the BLA annually with applicable, revised labeling beginning September 30, 2005, the study will be completed by December 31, 2009, and the final study report, and applicable, revised labeling will be submitted to FDA by July 31, 2010.

  6. To further evaluate the time course of recovery of lymphocyte counts (total lymphocytes and important lymphocyte subsets) to within 75% of baseline. The study will include 400 patients treated with up to three courses of Alefacept. The final protocol for this study was submitted to FDA on October 1, 2002. Patient accrual will be completed by June 30, 2003, the study completed by June 30, 2006, the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2006.

  7. To evaluate the safety and efficacy of Alefacept in patients with erythrodermic and pustular psoriasis. The final protocol for this study was submitted to FDA on October 1, 2002. The protocol will be amended to allow inclusion of patients with stable erythrodermic and pustular psoriasis. Patient accrual will be completed by June 30, 2003, the study completed by June 30, 2006, and the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2006.

  8. To report the results of study C-715 evaluating the safety and efficacy of Alefacept in patients with concomitant psoriasis and psoriatic arthritis. The final study report and applicable, revised labeling will be submitted to FDA by March 21, 2003.

  9. To provide an assessment of the potential need to study Alefacept in the HIV population when more data on the long-term safety in the non-HIV-infected population becomes available. This assessment, to be submitted to the FDA by March 31, 2004, should reflect factors such as the unmet need for such therapy in the HIV-infected patient population and further information with regard to long-term safety in the non-HIV-infected patient population. If FDA then determines that a study is needed, a draft protocol and commitment with schedule will be submitted within two months of written notification of that determination.

  10. To obtain additional safety data in populations with advanced age, diabetes mellitus and major trauma (accidental or surgical). This will be addressed in two clinical studies:

    1. The first study will include 400 patients treated with up to three courses of Alefacept. The final protocol for this study was submitted to FDA on October 1, 2002. Patient accrual will be completed by June 30, 2003, the study will be completed by June 30, 2006, and the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2006.

    2. The second study will include 5000 patients. The final protocol for this study will be submitted to FDA by March 31, 2003. Patient accrual will be completed by December 31, 2004, the results of the study will be reported to the BLA annually with applicable, revised labeling beginning September 30, 2005, the study will be completed by December 31, 2009, and the final study report, and applicable, revised labeling will be submitted to FDA by July 31, 2010.

  11. To evaluate the safety of Alefacept administered concomitantly with UVB and major systemic antipsoriatic therapies. The final protocol for this study was submitted to FDA on October 1, 2002, for approximately 400 patients treated with up to three courses of Alefacept. Patient accrual will be completed by June 30, 2003, the study completed by June 30, 2006, and the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2006.

  12. To evaluate the safety of Alefacept administered concomitantly with Methotrexate in a randomized, double blind study of approximately 60 patients. The final protocol will be submitted to FDA by June 30, 2003. Patient accrual will be completed by December 31, 2003, the study completed by June 30, 2004, and the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2004.

  13. To evaluate the safety of Alefacept administered concomitantly with Cyclosporin in a double blind randomized study, of approximately 60 patients. The final protocol will be submitted to FDA by September 30, 2003. Patient accrual will be completed by March 31, 2004, the study completed by September 30, 2004, and the final study report, and applicable, revised labeling will be submitted to FDA by March 31, 2005.

  14. To evaluate the ability of patients to mount an immune response to standard vaccinations, such as influenza or pneumococcal vaccines, while receiving Alefacept. The study will include approximately 40 patients. The final protocol will be submitted to FDA by June 30, 2004. Patient accrual will be completed by December 31, 2004, the study completed by June 30, 2005, and the final study report, and applicable, revised labeling will be submitted to FDA by December 31, 2005.

  15. To establish and maintain a pregnancy registry of women with psoriasis who were exposed to Alefacept at any point within an 8-week time period prior to conception, or at any point during the pregnancy. The final protocol will be submitted to FDA by June 30, 2003. Patient accrual will be completed by June 30, 2005, the study completed by June 30, 2007, and the final study report and applicable, revised lableing will be submitted to FDA by January 31, 2008. An interim analysis will be conducted and submitted to the BLA with applicable, revised labeling after the initial evaluation of 125 exposed pregnancies is known.

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

We also acknowledge your agreements to:

  1. Sample each filled bulk drug substance bottle for endotoxin and bioburden.

  2. Monitor rouging of the microfiltration system and report any failures and corrective actions to the FDA.

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: 1/31/2003

 

Back to Top     Back to Index

Date created: September 25, 2003
horizonal rule

CDER Home Page | CDER Site Info | Contact CDER | What's New @ CDER
FDA Home Page | Search FDA Site | FDA A-Z Index | Contact FDA | HHS Home Page

FDA/Center for Drug Evaluation and Research