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`Food and Drug Administration
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` Silver Spring MD 20993
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` NDA APPROVAL
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 209884
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`Reference ID: 4409346
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`Novartis Pharmaceuticals Corporation
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`Attention: Mercy Abraham, Pharm.D.
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`Senior Global Program Regulatory Manager
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`One Health Plaza, Mailstop: # 310/2150F
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`East Hanover, NJ 07936-1080
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`Dear Dr. Abraham:
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`Please refer to your New Drug Application (NDA) dated and received July 26, 2018, and your
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`amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Mayzent (siponimod) tablets.
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`This new drug application provides for the use of Mayzent (siponimod) tablets for the treatment
`of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-
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`remitting disease, and active secondary progressive disease, in adults.
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved, effective on the
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`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the Prescribing Information and
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`Medication Guide) as well as annual reportable changes not included in the enclosed labeling.
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`Information on submitting SPL files using eLIST may be found in the guidance for industry SPL
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`Standard for Content of Labeling Technical Qs and As, available at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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`CM072392.pdf
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`The SPL will be accessible via publicly available labeling repositories.
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`Biogen Exhibit 2135
`Mylan v. Biogen
`IPR 2018-01403
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`Page 1 of 10
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` NDA 209884
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` Page 2
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` CARTON AND CONTAINER LABELING
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`Submit final printed carton and container labeling that are identical to the carton and container
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`labeling submitted on March 22, 2019, as soon as they are available, but no more than 30 days
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`after they are printed. Please submit these labeling electronically according to the guidance for
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`industry titled Providing Regulatory Submissions in Electronic Format — Certain Human
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`Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications
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`(April 2018, Revision 5). For administrative purposes, designate this submission “Final Printed
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`Carton and Container Labeling for approved NDA 209884.” Approval of this submission by
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`FDA is not required before the labeling is used.
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`ADVISORY COMMITTEE
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`Your application for Mayzent (siponimod) was not referred to an FDA advisory committee
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`because this drug is not the first in its class, the safety profile is similar to that of other drugs
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`approved for this indication, the clinical trial design was acceptable, the efficacy findings were
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`clear, and the safety profile was acceptable in light of the serious nature of the disease being
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`treated.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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`active ingredients (which includes new salts and new fixed combinations), new indications, new
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`dosage forms, new dosing regimens, or new routes of administration are required to contain an
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`assessment of the safety and effectiveness of the product for the claimed indication in pediatric
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`patients unless this requirement is waived, deferred, or inapplicable.
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`We are waiving the pediatric study requirement for ages birth up to 10 years because necessary
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`studies are impossible or highly impracticable. This is because of the small number of patients
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`in this age group with relapsing forms of multiple sclerosis.
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`We are deferring submission of your pediatric studies for ages 10 up to 17 years for this
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`application because this product is ready for approval for use in adults and the pediatric studies
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`have not been completed.
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`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
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`postmarketing studies. The status of this/these postmarketing studies must be reported annually
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`according to 21 CFR 314.81 and section 505B(a)(4)(C) of the FDCA. These required studies are
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`listed below.
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`3591-1
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`Juvenile rat toxicology study to evaluate effects of siponimod on growth,
`reproductive development, and neurological and neurobehavioral development.
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`Draft Protocol Submission: 07/18
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`Final Protocol Submission: 04/19
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`Reference ID: 4409346
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`Page 2 of 10
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` NDA 209884
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` Page 3
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`3591-2
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` Study/Trial Completion:
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` Final Report Submission:
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` 08/19
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` 02/20
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`Conduct a two-part study of siponimod in pediatric patients with relapsing forms
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`of multiple sclerosis (RMS) at least 10 years and less than 18 years of age. Part A
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`is an open-label study of the safety, tolerability, pharmacokinetics (PK), and
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`pharmacodynamics (PD) of siponimod in pediatric patients. Part A will include
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`two cohorts, one with body weights less than 40 kg and the other with body
`weights 40 kg or more. The objective of Part A is to determine titration and
`maintenance doses of siponimod that will result in PK and PD effects that are
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` comparable to those of the 5-day titration and the 1- or 2-mg genotype-based
`maintenance doses administered to adult patients. Part B is a randomized, double-
`blind, parallel-group study to evaluate the efficacy and safety of siponimod
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`compared to an appropriate control.
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`Draft Protocol Submission: 03/20
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`Final Protocol Submission: 09/20
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`09/25
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`Study/Trial Completion:
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`Final Report Submission:
`03/26
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`Submit the protocols to your IND 76122 with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as a new drug
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`application (NDA) or as a supplement to your approved NDA with the proposed labeling
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`changes you believe are warranted based on the data derived from these studies. When
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`submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
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`the submission.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
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`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 known serious risk of
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`pulmonary toxicity or identify an unexpected serious risk of teratogenicity.
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`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 these serious risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following studies:
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`Reference ID: 4409346
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`Page 3 of 10
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` NDA 209884
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` Page 4
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` 3591-3 A prospective, parallel cohort study in patients with relapsing forms of multiple
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`sclerosis to assess the potentially serious risk of pulmonary toxicity. The two
`cohorts should consist of patients newly prescribed siponimod and patients
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`receiving another drug used to treat relapsing forms of multiple sclerosis. The
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`study design should minimize differences between the cohorts by defining the
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`populations in both cohorts so that they will be similar, by ensuring that both
`cohorts have similar clinical assessments (specifically FEV1, FVC, and DLCO),
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`and by ensuring that patients who discontinue treatment have continued follow-
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`up. In addition, the study protocol should account for duration of exposure,
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`treatment changes, and loss to follow-up. Sample size should be supported by
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`estimates of the rates of the events of interest.
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`The timetable you submitted on March 19, 2019, states that you will conduct this study
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`according to the following schedule:
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Study Completion:
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`Final Report Submission:
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`06/20
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`12/20
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`12/26
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`12/27
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`Conduct prospective pregnancy exposure registry cohort analyses in the United
`States that compare the maternal, fetal, and infant outcomes of women
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`with multiple sclerosis exposed to siponimod during pregnancy with two
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`unexposed control populations: one consisting of women with multiple sclerosis
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`who have not been exposed to siponimod before or during pregnancy, and the
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`other consisting of women without multiple sclerosis. The registry will identify
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`and record pregnancy complications, major and minor congenital malformations,
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`spontaneous abortions, stillbirths, elective terminations, preterm births, small for
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`gestational-age births, and any other adverse outcomes, including postnatal
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`growth and development. Outcomes will be assessed throughout pregnancy.
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`3591-4
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`Reference ID: 4409346
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`Page 4 of 10
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` NDA 209884
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` Page 5
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` Infant outcomes, including effects on postnatal growth and development, will be
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` assessed through at least the first year of life.
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`The timetable you submitted on March 21, 2019, states that you will conduct this study
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`according to the following schedule:
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`03/20
`Draft Protocol Submission:
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`09/20
`Final Protocol Submission:
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`Annual Interim Report Submissions: 09/21
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`09/22
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`09/23
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`09/24
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`09/25
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`09/26
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`09/27
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`09/28
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`09/29
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`09/30
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`Study Completion:
`09/31
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`Final Report Submission:
`09/32
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`3591-5
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`Conduct a pregnancy outcomes study using a different study design than provided
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`for in PMR 3591-4 (for example, a retrospective cohort study using claims or
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`electronic medical record data or a case control study) to assess major congenital
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`malformations, spontaneous abortions, stillbirths, and small-for-gestational-age
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`births in women exposed to siponimod during pregnancy compared to an
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`unexposed control population.
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`Reference ID: 4409346
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`Page 5 of 10
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` NDA 209884
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` Page 6
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` The timetable you submitted on March 19, 2019, states that you will conduct this study
` according to the following schedule:
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`03/20
`Draft Protocol Submission:
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`09/20
`Final Protocol Submission:
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`Annual Interim Report Submissions: 05/21
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`05/22
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`05/23
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`05/24
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`05/25
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`05/26
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`05/27
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`05/28
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`05/29
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`05/30
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`05/31
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`Study Completion:
`09/31
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`Final Report Submission:
`09/32
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`Submit clinical protocols to your IND 76122 with a cross-reference letter to this NDA. Submit
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`nonclinical and chemistry, manufacturing, and controls protocols and all final reports to your
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`NDA. Prominently identify the submission with the following wording in bold capital letters at
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`the top of the first page of the submission, as appropriate: Required Postmarketing Protocol
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`Under 505(o), Required Postmarketing Final Report Under 505(o), Required
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`Postmarketing Correspondence Under 505(o).
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`Submission of the protocols for required postmarketing observational studies to your IND is for
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`purposes of administrative tracking only. These studies do not constitute clinical investigations
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`pursuant to 21 CFR 312.3(b) and therefore are not subject to the IND requirements under
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`21 CFR part 312 or FDA’s regulations under 21 CFR parts 50 (Protection of Human Subjects)
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`and 56 (Institutional Review Boards).
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
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`study or clinical trial required under this section. This section also requires you to periodically
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`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
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`report annually on the status of any postmarketing commitments or required studies or clinical
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`trials.
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`FDA will consider the submission of your annual report under section 506B and
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`21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
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`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
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`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must
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`also include a report on the status of any study or clinical trial otherwise undertaken to
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`investigate a safety issue. Failure to submit an annual report for studies or clinical trials required
`
`Reference ID: 4409346
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`Page 6 of 10
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`3591-6
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`Establish an in-vitro diagnostic device to guide the use of siponimod in patients
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`
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`with relapsing forms of multiple sclerosis. The device should detect, at a
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`minimum, the presence of the *2 and *3 alleles in cytochrome P450 2C9
`(CYP2C9). The device should detect patients homozygous for the CYP2C9 *3/*3
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` genotype with statistical confidence.
`
` NDA 209884
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` Page 7
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` under 505(o) on the date required will be considered a violation of FDCA section
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` 505(o)(3)(E)(ii) and could result in enforcement action.
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` We remind you of your postmarketing commitments:
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`The timetable you submitted on March 20, 2019, states that you will conduct this study
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`according to the following schedule:
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` Draft Protocol Submission: 12/20
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` Final Protocol Submission: 12/21
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` 12/22
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` Study/Trial Completion:
`
` Final Report Submission:
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` 12/23
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` A final submitted protocol is one that the FDA has reviewed and commented upon, and you have
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` revised as needed to meet the goal of the study or clinical trial.
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` Submit clinical protocols to your IND 76122 for this product. Submit nonclinical and chemistry,
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` manufacturing, and controls protocols and all postmarketing final reports to this NDA. In
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` addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status
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`summary of each commitment in your annual report to this NDA. The status summary should
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` 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
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` study/trial. All submissions, including supplements, relating to these postmarketing
` commitments should be prominently labeled “Postmarketing Commitment Protocol,”
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` “Postmarketing Commitment Final Report,” or “Postmarketing Commitment Correspondence.”
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`Reference ID: 4409346
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`Page 7 of 10
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` NDA 209884
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` Page 8
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` REQUESTED PHARMACOVIGILANCE
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`We request that you perform postmarketing surveillance for malignancies, life-threatening or
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`fatal infections, and thromboembolic vascular events. We request that you provide expedited
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`reports directly to the Division of Neurology Products and that you include comprehensive
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`summaries and analyses of these events quarterly as part of your required postmarketing safety
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`reports [e.g., periodic safety update reports (PSURs)].
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`
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`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
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`proposed materials in draft or mock-up form with annotated references, and the Prescribing
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`Information, Medication Guide, and Patient Package Insert (as applicable) to:
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`
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
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`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
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`Prescribing Information, at the time of initial dissemination or publication, accompanied by a
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`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
`
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` 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
`
`
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` (21 CFR 314.80 and 314.81).
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`Reference ID: 4409346
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`Page 8 of 10
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` NDA 209884
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` Page 9
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` MEDWATCH-TO-MANUFACTURER PROGRAM
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`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
`
`
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`New molecular entities and new biological products qualify for a post approval feedback
`
`
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`meeting. Such meetings are used to discuss the quality of the application and to evaluate the
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`
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`communication process during drug development and marketing application review. The
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`purpose is to learn from successful aspects of the review process and to identify areas that could
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`
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`benefit from improvement. If you would like to have such a meeting with us, call the Regulatory
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`Project Manager for this application.
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`
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`If you have any questions, call LCDR Nahleen Lopez, Regulatory Project Manager, at (240)
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`
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`402-2659.
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`Sincerely,
`
`
` {See appended electronic signature page}
`
` Ellis Unger, MD
`
` Director
` Office of Drug Evaluation I
`
` Office of New Drugs
` Center for Drug Evaluation and Research
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`
`
` ENCLOSURE(S):
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` Content of Labeling
` Prescribing Information
`
` Medication Guide
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`
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`
`
`Reference ID: 4409346
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`Page 9 of 10
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`

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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`ELLIS F UNGER
`03/26/2019 06:06:07 PM
`
`Reference ID: 4409346
`
`(
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`Page 10 of 10
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