`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`
`Trade Name:
`
`
`
`
`Generic Name:
`
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`APPLICATION NUMBER:
`
`207620Orig1s000
`
`ENTRESTO Tablets, 24 mg/26 mg, 49 mg/51 mg, and
`97 mg/103 mg.
`
`sacubitril/valsartan
`
`Novartis Pharmaceuticals Corp.
`
`July 7, 2015
`
`Indicated to reduce the risk of cardiovascular death and
`hospitalization for heart failure in patients with chronic
`heart failure (NYHA Class II-IV) and reduced ejection
`fraction.
`ENTRESTO is usually administered in conjunction
`with other heart failure therapies, in place of an
`angiotensin converting enzyme (ACE) inhibitor or
`other angiotensin II receptor blocker (ARB).
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`207620Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`X
`
`X
`
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`X
`X
`X
`
`
`
`
`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 / Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`

`

`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`207620Orig1s000
`APPROVAL LETTER
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 207620
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Novartis Pharmaceuticals Corp.
`Attention: Masha Berkhin, PharmD
`Global Program Regulatory Director
`One Health Plaza
`Building 100
`East Hanover, NJ 07936
`
`
`Dear Dr. Berkhin:
`
`Please refer to your New Drug Application (NDA) dated December 17, 2014, submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for ENTRESTO
`(sacubitril/valsartan) Tablets, 24 mg/26 mg, 49 mg/51 mg, and 97 mg/103 mg.
`
`We acknowledge receipt of your amendments dated January 15, 16 (two), 20, 22, 28 (two), 30,
`February 2, 5, 11, 18, 20, 24, 26, March 3, 10, 12, 13, 17, April 2, 3, 8, 15 (two), 16, 20, 21, 24,
`29, May 1, 4, 6, 7, 13, 15 (two), 22, 26, June 2, 3, 4, 11, 12, 15, 19, 25, 26, and July 1, 2, and 6,
`2015.
`This new drug application provides for the use of ENTRESTO (sacubitril/valsartan) Tablets,
`indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in
`patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.
`ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of
`an angiotensin converting enzyme (ACE) inhibitor or other angiotensin II receptor blocker
`(ARB).
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`In addition, the revised comparability protocols for 1) drug product manufacturing site, control,
`batch size, and process and 2)
` intermediate manufacturing site, control, batch size,
`and process as included in Submission 0000 dated September 30, 2014 are approved. Regulatory
`notification of changes to the approved protocols must be made via a prior approval supplement.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`
`Reference ID: 3788834
`
`(b) (4)
`
`

`

`NDA 207620
`Page 2
`
`
`of labeling must be identical to the enclosed labeling (text for the package insert and text for the
`patient package insert). Information on submitting SPL files using eLIST may be found in the
`guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`We acknowledge your June 11, 2015, submission containing final printed carton and container
`labels.
`
`ADVISORY COMMITTEE
`
`Your application for ENTRESTO was not referred to an FDA advisory committee because:
` The safety profile is acceptable for ENTRESTO to reduce the risk of cardiovascular
`death and hospitalization for heart failure in patients with chronic heart failure (NYHA
`Class II-IV) and reduced ejection fraction.
`ENTRESTO is usually administered in conjunction with other heart failure therapies, in
`place of an ACE inhibitor or other ARB.
` The application did not raise significant safety or efficacy issues that were unexpected for
`a drug of these classes
` The application did not raise significant public health questions on the role of the drug in
`the diagnosis, cure, mitigation, treatment, or prevention of a disease
` Outside expertise was not necessary; there were no controversial issues that would
`benefit from advisory committee discussion.
`
`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 in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable. The causes and mechanisms of heart failure are different in
`children compared to adults. Heart failure in children is most commonly caused by congenital
`heart malformations and cardiomyopathy whereas the primary etiology of adult heart failure is
`ischemic heart disease due to atherosclerotic coronary artery disease. The form of heart failure
`seen in adults is rare in children; hence conducting a trial is highly impractical.
`
`
`Reference ID: 3788834
`
`

`

`NDA 207620
`Page 3
`
`
`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 assess a signal of a serious risk
`of angioedema in Black patients or to identify an unexpected serious risk of cognitive
`dysfunction with the use of Entresto (sacubitril/valsartan).
`
`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 or identify these serious risks.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`2924-1
`
`Conduct an epidemiologic study using claims or electronic health records data to
`evaluate the incidence of angioedema in Black patients treated with Entresto
`compared to a control drug. A target sample size, supported by sample size
`calculation, should be included in the protocol.
`
`The timetable you submitted on June 19, 2015, states that you will conduct this study
`according to the following schedule:
`
`
`
`
`
`
`
`Draft Protocol Submission December 2015
`Final Protocol submission
`July 2016
`Interim Report #1
`
`July 2017
`Interim Report #2
`
`July 2018
`Final Report Submission:
`July 2019
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify the unexpected serious risks of cognitive dysfunction with the
`use of Entresto (sacubitril/valsartan).
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`2924-2 A multicenter, randomized, double-blind, active-controlled trial to evaluate the
`effects of Entresto compared to valsartan on cognitive function as assessed by
`comprehensive neurocognitive battery and PET imaging in patients with chronic
`heart failure with preserved ejection fraction.
`
`Reference ID: 3788834
`
`

`

`NDA 207620
`
`Page 4
`
`The timetable you submitted on July 6, 2015, states that you will conduct this trial
`according to the following schedule:
`
`Draft Protocol Submission November 2015
`
`Final Protocol submission
`Trial Completion
`Final Report Submission:
`
`April 2016
`October 2021
`March 2022
`
`Submit the protocols to your 1ND 104628, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(0)”, “Required Postmarketing Final Report Under
`505(0)”, “Required Postmarketing Correspondence Under 505(0)”.
`
`Section 505(0)(3)OE)(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 314.81(b)(2)(vii) 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 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(0)(3)OE)(ii) provided that you include the elements listed in 505(0) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(0), 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(0)
`on the date required will be considered a violation of FDCA section 505(0)(3)(E)(ii) and could
`result in enforcement action.
`
`POSTMARKETING CONINIITNIENTS NOT SUBJECT TO REPORTING
`
`REQUIRENIENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`2924-3
`
`Development of a new dissolution method for all the strengths with demonstrated
`discriminating ability,
`"’""
`, and setting of
`the final dissolution acceptance criterion for EntrestoTM (sacubitril/valsartan)
`Tablets, 97/ 103, 49/51, and 24/26 mg using the new dissolution method and data
`from the overall multipoint dissolution profile from a minimum of 12 commercial
`batches per strength, manufactured under the same conditions as those used for
`the manufacture of the batches used in pivotal clinical trials. The FDA will be
`open to providing feedback during the method’s development process as needed.
`
`Reference ID: 3788834
`
`

`

`NDA 207620
`Page 5
`
`
`The timetable you submitted on June 25, 2015, states that you will conduct this study according
`to the following schedule:
`
`
`Dissolution Method Development Report Submission:
`Final Report Submission:
`
`
`
`
`
`February 2016
`July 2016
`
`
`Submit clinical protocols to your IND 104628 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. 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.”
`
`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
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. Form FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`Reference ID: 3788834
`
`

`

`NDA 207620
`Page 6
`
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`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
`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.
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval 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.
`
`PDUFA V APPLICANT INTERVIEW
`
`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
`and final assessment of the Program for Enhanced Review Transparency and Communication for
`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
`Letter states that these assessments will include interviews with applicants following FDA action
`on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
`complete responses, and withdrawals after filing. The purpose of the interview is to better
`understand applicant experiences with the Program and its ability to improve transparency and
`communication during FDA review.
`
`ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
`the interview process. Your responses during the interview will be confidential with respect to
`the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
`identifying information to anyone outside their project team. They will report only anonymized
`results and findings in the interim and final assessments. Members of the FDA review team will
`be interviewed by ERG separately. While your participation in the interview is voluntary, your
`feedback will be helpful to these assessments.
`
`Reference ID: 3788834
`
`

`

`Sincerely,
`
`{See appended electronic signature page}
`
`Ellis F. Unger, MD
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`NDA 207620
`Page 7
`
`
`
`If you have any questions, please call:
`
`
`Alexis Childers, RAC
`Senior Regulatory Project Manager
`(301) 796-0442
`
`
`
`
`
`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`
`Reference ID: 3788834
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ELLIS F UNGER
`07/07/2015
`
`Reference ID: 3788834
`
`