`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`125387Orig1s000
`Eylea
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`aflibercept
`
`Regeneron Pharmaceuticals Inc.
`
`November 18, 2011
` Treatment of neovascular (wet) age-related macular
`degeneration.
`
`Novartis Exhibit 2286.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`125387Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`X
`X
`X
`
`X
`X
`
`Novartis Exhibit 2286.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`125387Orig1s000
`
`APPROVAL LETTER
`
`
`
`Novartis Exhibit 2286.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`~ , .... c,,
`
`( ~-t·"~ DEPARTMENTOFHEALTHANDHUMA SERVICES
`Y,, ~ +,>,, ...
`
`Our STN: BL 125387/0
`
`Regeneron Phaimaceuticals, Inc.
`Attention: Laura Pologe Ph.D.
`Associate Director, Regulat01y Affairs
`777 Old Saw Mill River Road
`Tanytown, New York 10591-6707
`
`Dea1· Dr. Pologe:
`
`Food and Drug Administl'ation
`Silver Sp1ing MD 20993
`
`BLA APPROVAL
`November 18, 2011
`
`Please refer to your Biologics License Application (BLA) dated Febmary 17, 2011 received
`Febrnaiy 18, 2011 , submitted under section 351 of the Public Health Se1vice Act for Eylea
`(aflibercept).
`
`We acknowledge receipt of your amendments dated Febma1y 28, March 10, 18, and 24, April 1,
`8, 11 (two), 13 (two), and 29 May 11 , 16 23, and 27, J1me 3, 7, 9, 16, 20, and 28, July 8 18, and
`19, August 1, 5, 10, 12, and 31 , September 1, 7, 12, 20, and 26, October 7, 21 , 24, and 27, and
`November 1, 9, 11 , and 17, 2011.
`
`We have approved your BLA for aflibercept effective this date. You are hereby authorized to
`intrnduce or deliver for introduction into interstate colilIIlerce, aflibercept under your existing
`Depaitment of Health and Human Se1vices U.S. License No. 1760. Aflibercept is indicated for
`treatment of neovascular (wet) age-related maculai· degeneration.
`
`Under this license, you are approved to manufacture aflibercept mug substance intermediate,
`(b)l4j
`mug substance, and f01mulated bulk at
`. The final
`formulated dru&9-roduct will be manufactured at
`Cb> <4>
`The final f01mulated mug pro uct will be labeled and packaged at
`l b 1
`(b) (4) y
`d
`. h th
`.
`. ou may a e your pro uct wit
`e propnetaiy name
`Eylea and mai· et 1t ma )~'11---s~m·-g~e---use vial containing 0.278 mL of 40 mg/mL aflibercept, as part
`of a final packaged product containing the aflibercept single-use vial, a 19-gauge x 1 ½-inch 5-
`micron filter needle, a 30-gauge x ½-inch needle and a 1-mL plastic syringe.
`
`The dating period for aflibercept shall be 15 months from the date of manufacture when stored at
`--,--,-. ----, !hl<4I
`2 - 8°C. The date of manufacture shall be defined as the
`The expiration date for the paclcaged product, afiibercept single-use
`needle ana filter needle) shall be de endent on the shortest expiration date of_any
`(b)(4J
`
`Novartis Exhibit 2286.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page2
`
`(6)(4!
`
`Results of ongoing stability should be submitted to the annual rep011.
`
`You are not currently required to submit samples of future lots of aflibercept to the Center for
`Dn1g 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 each lot.
`
`Any changes in the manufacturing, testing packaging, or labeling of aflibercept, or in the
`manufacturing facilities, will require the submission of inf01mation to your biologics license
`application for our review and written approval, consistent with 21 CFR 601 .12.
`
`We am approving this application for use as recormnended in the enclosed agreed-upon labeling
`text.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit, via the FDA
`automated drug registration and listing system (eLIST), the content of labeling [21 601.14(b)] in
`stmctured product labeling (SPL) format, as described at
`http://www.fda .gov/F orindusb.y/DataStandards/StrncturedProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package inse1i). Info1mation on submitting SPL
`files using eLIST may be found in the guidance for industry titled "SPL Standard for Content of
`Labeling Technical Qs and As" at
`http://ww.v.fda.gov/downloads/Dmgs/GuidanceComplianceRegulatoryinformation/Guidances/U
`CM072392.pdf. For adminisu-ative purposes, please designate this submission "Product
`Correspondence - Final SPL for approved BLA STN 125387."
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND Th1MEDIATE CONTAINER LABELS
`
`Submit final printed carton and container labels that are identical to the enclosed ca1ion and
`immediate container labels submitted on November 17, 2011 , as soon as they are available, but
`no more than 30 days after tl1ey are printed. Please submit these labels electi·onically according
`to the guidance for industry titled "Providing Regulat01y Submissions in Elecb.·onic Format -
`Human Phaimaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (June 2008)" . Alternatively, you may submit 12 paper copies with 6 of the copies
`individually mounted on heavy-weight paper or similar material. For administrative purposes,
`designate this submission "Product Correspondence - Final Printed Carton and Container
`Labels for approved BLA STN 125387." Approval of this submission by FDA is not required
`before the labeling is used.
`
`Novartis Exhibit 2286.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 3
`
`Marketing the product(s) with final printed labeling (FPL) that is not identical to the approved
`labeling text may render the product misbranded and an unapproved new drug.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable. We are waiving the pediatric study requirement for this application
`because the product treats a disease that does not exist in pediatric age groups.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to
`require holders of approved drug and biological product applications to conduct postmarketing
`studies and clinical trials for certain purposes, if FDA makes certain findings required by the
`statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious
`risk of corneal endothelial cell decompensation following the intravitreal administration of Eylea
`(aflibercept).
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify an unexpected serious risk of corneal endothelial cell
`decompensation following the intravitreal administration of Eylea (aflibercept).
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`1. Provide clinical information from a 1-year (minimum) clinical trial evaluating the
`adverse effects, if any, on the corneal endothelium following administration of
`aflibercept.
`
`
`
`
`
`The timetable you submitted on October 24, 2011, states that you will conduct this trial
`according to the following schedule:
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`Submit the protocol to your IND 12462, with a cross-reference letter to this BLA. Submit all
`final report(s) to your BLA. Prominently identify the submission with the following wording in
`
`March 2012
`November 2015
`May 2016
`
`
`
`
`
`Novartis Exhibit 2286.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 4
`
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 601.70 requires you to report
`annually on the status of any postmarketing commitments or required studies or clinical trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR 601.70
`to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii) provided that you
`include the elements listed in 505(o) and 21 CFR 601.70. We remind you that to comply with
`505(o), your annual report must also include a report on the status of any study or clinical trial
`otherwise undertaken to investigate a safety issue. Failure to submit an annual report for studies
`or clinical trials required under 505(o) on the date required will be considered a violation of
`FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
`
`POSTMARKETING COMMITMENTS NOT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`
`2. To conduct three drug product hold time studies of the 40 mg/mL vial presentation filled
`at
` site. Material will be held at commercial scale, and
`microbiological samples (total viable count, bacterial endotoxin) will be taken at the end
`of the hold times. The completed validation report will be submitted as a CBE-0
`supplement.
`The timetable you submitted on November 11, 2011, states that you will conduct this
`study according to the following schedule:
`
`
`Final Report Submission: November 2012
`
`
`3. To conduct three drug product hold time studies for the 40 mg/mL vial presentation filled
`at the
` site. These studies will include t=0 and end of hold samples
`for product quality (pH, purity by size exclusion, purity by nrSDS-PAGE, charge variant
`distribution by IEF, isoaspartate, and potency of aflibercept) evaluation. The completed
`validation report will be provided as a CBE-0 supplement.
`
`
`
`
`
`The timetable you submitted on November 11 2011, states that you will conduct this
`study according to the following schedule:
`
`
`Final Report Submission: June 2012
`
`(b) (4)
`
`(b) (4)
`
`Novartis Exhibit 2286.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 5
`
`(b)(4)
`
`.
`process. The
`by the aflibercept
`4. To confirm
`(b)(4)
`.
`study will be perf 01mea under protocol on three ots o drng substance
`pro uced at the commercial scale.
`lllJ<:.tl will be measured with a validated analytical
`<bJ <41. The completed method
`test method for dete1mining
`validation and final rep011s w1ll 6e su6mittect m
`e 2012 annual report by January 2013.
`
`(bf(4)
`
`The timetable you submitted on November 11 , 2011, states that you will conduct this
`study according to the following schedule:
`
`Final Report Submission: Janua1y 2013
`
`5. To re-evaluate the release and shelf-life specifications for aflibercept drng product after
`30 commercial manufacturing runs to reflect increased manufacturing experience. The
`revisions to the quality control system, the corresponding data from the 30 commercial
`manufacturing runs, and the analysis and statistical plan used to evaluate the
`specifications and any changes to specifications will be provided in a PAS within 60 days
`after completion of the 30th lot manufactured using the commercial process or by
`December, 2014 whichever occurs first.
`
`The timetable you submitted on November 11 , 2011 , states that you will conduct this
`study according to the following schedule:
`
`Final Repo1i Submission: December 2014
`
`6. To re-evaluate the release and shelf-life specifications for aflibercept drug substance after
`30 commercial manufacturing 111I1s to reflect increased manufacturing experience. The
`revisions to the quality control system, the corresponding data from the 30 commercial
`manufacturing 111I1s, and the analysis and statistical plan used to evaluate the
`specifications and any changes to specifications will be provided in a PAS by within 60
`days after completion of the 30th lot manufactured using the commercial process or by
`June, 2013, whichever occurs fast.
`
`The timetable you submitted on November 11 , 2011, states that you will conduct this
`study according to the following schedule:
`
`Final Repo1t Submission: June 2013
`
`7. To re-evaluate the release and shelf-life specifications for aflibercept dmg substance
`inte1mediate after 30 commercial manufacturing 111I1s to reflect increased manufacturing
`experience. The revisions to the quality control system, the corresponding data from the
`30 commercial manufacturing mns, and the analysis and statistical plan used to evaluate
`the specifications and any changes to specifications will be provided in a PAS within 60
`days after completion of the 30th lot manufactured using the commercial process or by
`June, 2014, whichever occurs first.
`
`Novartis Exhibit 2286.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 6
`
`
`The timetable you submitted on November 11, 2011, states that you will conduct this
`study according to the following schedule:
`
`Final Report Submission: June 2014
`
`
`
`
`
`
`
`
`
`8. To re-evaluate the release and shelf-life specifications for aflibercept formulated bulk
`after 30 commercial manufacturing runs to reflect increased manufacturing experience.
`The revisions to the quality control system, the corresponding data from the 30
`commercial manufacturing runs, and the analysis and statistical plan used to evaluate the
`specifications and any changes to specifications will be provided in a PAS within 60 days
`after completion of the 30th lot manufactured using the commercial process or by June,
`2013, whichever occurs first.
`
`The timetable you submitted on November 11, 2011, states that you will conduct this
`study according to the following schedule:
`
`Final Report Submission: June 2013
`
`
`Submit clinical protocols to your IND 12462 for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all final reports to this BLA. In addition, under 21
`CFR 601.70 you should include a status summary of each commitment in your annual progress
`report of postmarketing studies and clinical trials to this BLA. The status summary should
`include expected summary completion and final report submission dates, any changes in plans
`since the last annual report, and, for clinical studies/trials, number of patients entered into each
`study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`REPORTING REQUIREMENTS
`
`You must submit adverse experience reports under the adverse experience reporting
`requirements for licensed biological products (21 CFR 600.80). You should submit
`postmarketing adverse experience reports to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Central Document Room
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Prominently identify all adverse experience reports as described in 21 CFR 600.80.
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`
`Novartis Exhibit 2286.009
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 7
`
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`You must submit distribution reports under the distribution reporting requirements for licensed
`biological products (21 CFR 600.81).
`
`You must submit reports of biological product deviations under 21 CFR 600.14. You should
`promptly identify and investigate all manufacturing deviations, including those associated with
`processing, testing, packing, labeling, storage, holding and distribution. 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, you must submit a report on Form FDA-3486 to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Compliance Risk Management and Surveillance
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`Biological product deviations, sent by courier or overnight mail, should be addressed to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Compliance Risk Management and Surveillance
`10903 New Hampshire Avenue, Bldg. 51, Room 4206
`Silver Spring, MD 20903
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials, and the package insert, at the time of initial
`dissemination or publication, accompanied by a Form FDA 2253. For instruction on completing
`the Form FDA 2253, see page 2 of the Form. For more information about submission of
`promotional materials to the Division of Drug Marketing, Advertising, and Communications
`(DDMAC), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`Novartis Exhibit 2286.0010
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`BL 125387/0
`Page 8
`
`All promotional claims 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
`unless you have substantial evidence to support that claim.
`
`POST-ACTION FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post-action feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`If you have any questions, call Michael Puglisi, Regulatory Project Manager, at
`(301) 796-0791.
`
`
`Sincerely,
`
`
`
` /
`
` Edward Cox, M.D., M.P.H./
`Edward Cox, M.D., M.P.H.
`Director
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`Content of Labeling
`Carton and Container Labeling
`
`Novartis Exhibit 2286.0011
`Regeneron v. Novartis, IPR2021-00816
`
`