«RMIED
`oes
`
`
`
`Public Health Service
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`Food and Drug Administration
`Rockville, MD 20852
`
`Our STN: BL 125085/0
`
`FEB 2 6 2004
`
`Genentech, Incorporated
`Attention: Robert L. Garnick, Ph.D.
`Senior Vice President, Regulatory Affairs, Quality and Compliance
`1 DNA Way MS#48
`South San Francisco, CA 95080
`
`Dear Dr. Garnick:
`
`Wehave approved yourbiologics license application for Bevacizumabeffective this date.
`You are hereby authorized to introduce or deliver for introduction into interstate commerce,
`Bevacizumab under your existing Department of Health and Human Services U.S. License
`No. 1048. Bevacizumab, in combination with intravenous 5-fluorouracil-based chemotherapy,
`is indicated for the first-line treatment of patients with metastatic carcinoma of the colon and
`rectum.
`
`Underthis authorization, you are approved to manufacture Bevacizumabat yourfacility in
`South San Francisco, CA. You may label your product with the proprietary name AVASTIN
`and will market it as a 4 mL vial containing 100 mg (25 mg/mL) and as a 16 mL vial
`containing 400 mg (25 mg/mL).
`
`The dating period for Bevacizumab 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 your drug substance shall be 24 months
`whenstored at -20°C. We have approvedthe stability protocols in your license application for
`the purpose of extending the expiration dating period of your drug product and drug substance
`under 21 CFR 601.12.
`
`You currently are not required to submit samples of future lots of Bevacizumab to the Center
`for Drug Evaluation and Research (CDER)for release by the Director, CDER, under 21 CFR
`610.2. We will continue to monitor compliance with 21 CFR 610.1 requiring completion of
`tests for conformity with standards applicable to each product prior to release of eachlot.
`
`.
`
`You must submit information to your biologics license application for our review and written
`approval under 21 CFR 601.12 for any changes in the manufacturing, testing, packaging or
`labeling of Bevacizumab, or in the manufacturing facilities.
`
`All applications for new active ingredients, new dosage forms, new indications, new routes of
`administration, and new dosing regimens are required to contain an assessmentofthe safety
`and effectiveness of the product in pediatric patients unless this requirement is waived or
`
`IPR2023-00884
`Samsung et al. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2108
`Page1-—
`
`--
`
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2108 Page 2
`
`

`

`Page 3 ~ BL 125085/0
`
`evaluated in 2700 subjects, enrolled in the planned NSABP study, C-08, of whom 50
`percent will be randomized to receive Bevacizumab. Thefinal protocol will be
`submitted by June 30, 2004, patient accrual will be completed by December 29, 2006,
`this portion of the study will be completed by December 31, 2007, and the final report
`for this portion of the study submitted by June 30, 2008.
`
`To explore patient factors associated with the risk of development of proteinuria,
`characterize the clinical course of proteinuria, and assess screening strategies that more
`accurately identify patients at increased risk of high-grade proteinuria and nephrotic
`syndrome in 100 patients treated with Bevacizumab alone or in combination with
`FRE ion study AVF2938g. The data will be analyzed by overall study population
`and bytreatment arm. Thefinal protocol will be submitted by March 31, 2004, patient
`accrual will be completed by March 31, 2005, the study will be completed by
`March 31, 2006, and the final study report submitted by September 29, 2006.
`
`To conduct analyses to characterize the comparative incidence of hypertension in
`patients treated with Bevacizumab to those not receiving Bevacizumab, risk factors
`associated with hypertension, and the clinical course of hypertension (including time to
`resolution), using available data from studies AVF2107g, AVF2192g, and AVF2119¢.
`Collection of data under these studies will be completed by June 30, 2004, an analysis
`post-last patient observed will be submitted by December 31, 2004, the one year
`follow-up period will be completed by June 30, 2005, and an analysis post-one year
`follow-up will be submitted by December 30, 2005.
`
`To prospectively collect and analyze data characterizing the incidence andclinical
`course (including duration and medical management) of hypertension in patients during
`treatment and following the discontinuation of Bevacizumab and in concurrent control
`patients. This will be evaluated in 2700 subjects, enrolled in the planned NSABP
`study, C-08, of whom 50 percent will be randomized to receive Bevacizumab. The
`final protocol will be submitted by June 30, 2004, patient accrual will be completed by
`December 29, 2006, this portion of the study will be completed by December 31, 2007,
`and the final report for this portion of the study submitted by June 30, 2008.
`
`To provide narrative descriptions of each vascular adverse event (myocardial infarction,
`cerebrovascular accident, peripheral arterial event, vascular aneurysm or other vessel
`wall abnormalities, and venous thromboembolic events) for patients enrolled in study
`AVF2540g and to provide descriptive statistics of the incidence of vascular events
`(overall and each subtype). Patient accrual will be completed by June 30, 2004, the
`study will be completed by December 31, 2004, and the final study report submitted by
`June 30, 2005.
`
`To collect data and conduct analyses of the comparative incidence of delayed vascular
`events (myocardial infarction, cerebrovascular accident, peripheral arterial event,
`vascular aneurysm or other vessel wall abnormalities, and venous thromboembolic
`events) in Bevacizumab-treated patients following the discontinuation of Bevacizumab
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`IPR2023-00884
`Samsung et al.v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2108
`Page3
`
`

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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2108 Page 4
`
`

`

`Page 5 - BL 125085/0
`
`16.
`
`17.
`
`18.
`
`19.
`
`20.
`
`June 30, 2008, and the population pharmacokinetics final study report submitted by
`December 31, 2008.
`
`To develop a standardized approachto the collection of data and generation of narrative
`descriptions of selected adverse events (gastrointestinal perforation, intra-abdominal
`abscess, fistula, wound dehiscence) that will include description of the event, surgical
`operative and pathology reports, and outcome/resolution information, for all such
`patients enrolled in studies NO16966 and NSABP study C-08. The summary report for
`this data will be submitted by June 30, 2008.
`
`To provide the final study report for study E3200, examining the comparative safety
`and effectiveness of single agent Bevacizumab, Bevacizumab in combination with the
`FEE cceimen, and AWARE alone. The study will be completed by
`September 30, 2005 and the final study report submitted by March 31, 2006.
`
`To provide the study report for study AVF2192g examining the comparative efficacy
`and safety of 5-fluorouracil and leucovorin with and without Bevacizumabin patients
`with newly diagnosed metastatic colorectal cancer who are unable to tolerate inmotecan-
`based therapy. The final study report will be submitted by September 30, 2004.
`
`To develop a validated, sensitive and accurate assay for the detection of an immune
`response (binding and neutralizing antibodies) to Bevacizumab, including procedures
`for accurate detection of antibodies to Bevacizumab in the presence of serum containing
`Bevacizumab and vascular endothelial growth factor. The assay methodology and
`validation report will be submitted by September 30, 2004.
`
`To more accurately characterize the immune response to Bevacizumab in NSABPstudy
`C-08 using the more sensitive, validated assay described above. The final protocol will
`be submitted by June 30, 2004, patient accrual will be completed by
`December 29, 2006, the study will be completed by June 30, 2008, and the final study
`report submitted by December 31, 2008.
`
`Postmarketing Studies not subject to reporting requirements of 21 CFR 601.70:
`
`21.
`
`22.
`
`To re-evaluate the release and shelf-life specifications for Bevacizumab Drug Substance
`and Drug Product based upon tolerance intervals on a yearly basis to reflect increased
`manufacturing experience. The cumulative data and analysis for product manufactured
`up to and including 2004 will be provided in the February 2004 to February 2005
`Annual Report to be submitted by April 30, 2005.
`
`To perform fn vitro and in vivo viral and adventitious agent testing on a current
`
`RPA<cac production lot of Bevacizumabata ceil age ofof
`the master cell bank to validate the [SWAMI limit ofin vizro age that wasestablished in
`small-scale studies. The testing will be completed by June 30, 2004, and thefinal study
`
`IPR2023-00884
`Samsung et al.v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2108
`Page5
`
`

`

`Page 6 - BL 125085/0
`
`23.
`
`24.
`
`25.
`
`26.
`
`report submitted as part of the February 2004 to February 2005 annual report to be
`submitted by April 30, 2005.
`
`To perform genetic stability testing on a current PYMscale production lot of
`Bevacizumab at a cell age ofFREE of the master cell bank to validate the
`FW limit of in vitro age that was established in small-scale studies. The nucleotide
`sequenceofthe integrated bevacizumab expression construct coding for the correct
`amino acid sequence in the aged cells will be verified by peptide mapping with 100%
`sequence coverage. The testing will be completed by June 30, 2004, and thefinal
`study report submitted as part of the February 2004 to February 2005 annual report to
`be submitted by April 30, 2005.
`
`To perform and submit a formalized assessment ofthe overall risk of cross-
`contamination betweenEn derived products that could result from sharing
`product-contacting equipment and parts by June 30, 2004.
`
`To modify your practices in accordance with the risk assessmentas stated in
`commitment 24 by providing an implementation plan for any modifications and a
`justification for any continued sharing of minor process equipmentand parts by
`September 30, 2004.
`
`To develop control measures (e.g., equipment, procedures and training) to ensure that
`hoses that are exposed to process fluids are dedicated to eitherFYprocess
`areas. These measures will be implemented by December 31, 2004.
`
`Werequest that you submitclinical protocols to your IND, with a cross-reference letter to this
`biologics license application (BLA), STN BL 125085. Submit nonclinical and chemistry,
`manufacturing, and coatrols protocols and all study final reports to your BLA, STN BLA
`125085. If the information in the final study report supports a change in the labeling, the final
`study report should be submitted as a supplement. We may also request a supplementif we
`think labeling changes are needed. Please use the following designators to label prominently
`all submissions, including supplements, relating to these postmarketing study commitments as
`appropriate:
`e Postmarketing Study Protocol
`e Postmarketing Study Final Report
`* Postmarketing Study Correspondence
`* Aunual Report on Postmarketing Studies
`
`For each postmarketing study subject to the reporting requirements of 21 CPR 601.70, you
`must describe the status in an annual report on postmarketing studies for this product. The
`status report for each study should include:
`
`*
`»
`
`information to identify and describe the postmarketing commitment,
`the original schedule for the commitment,
`
`IPR2023-00884
`Samsung et al.v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2108
`Page6
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`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2108 Page 7
`
`

`

`Page 8 - BL 125085/0
`
`Compliance Risk Managementand Surveillance, HFD-330, Montrose Metro 2, 11919
`Rockville Pike, Rockville, MD 20852.
`
`Please submit all final printed labeling at the time of use and include implementation
`information on FDA Form 356h. Please provide a PDF-formatelectronic 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 a
`cover letter requesting advisory comments to the Division of Drug Marketing, Advertising and
`Communications (HFD-42), Center for Drug Evaluation and Research, Food and Drug
`Administration, 5600 Fishers Lane/Room 8B45, Rockville, MD 20857. Final printed
`advertising and promotional labeling should be submitted at the time of initial dissemination,
`accompanied by a FDA Form 2253.
`
`All promotional claums must be consistent with and not contrary to approved labeling. You
`should not make a comparative promotional claim or claim of superiority over other products
`umless you have substantial evidence to support that claim.
`
`The regulatory responsibility for review and continuing oversightfor this product transferred
`from the Center for Biologics Evaluation and Research to the Center for Drug Evaluation and
`Research effective June 30, 2003. For further information about the transfer, please see
`http://www .fda.gov/cder/biologics/default.htm. Until further notice, however, all
`correspondence, except as provided elsewherein this letter, should continue to be addressed
`to:
`
`CBER Document Control Center
`Attn: Office of Therapeutics Research and Review
`Suite 200N (HFM-99)
`1401 Rockville Pike
`Rockville, Maryland 20852-1448
`
`Sincerely, Karen D. Weiss, M.D.
`
`Director
`Office of Drug Evaluation VI
`Office of New Drugs
`Center for Drug Evaluation and Research
`
`Enclosure: Labeling
`
`IPR2023-00884
`Samsung etal. v. Regeneron
`Regeneron Pharmaceuticals, Inc. Exhibit2108
`Page 8
`
`