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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 22561
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`Reference ID: 4410993
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`EMD Serono, Inc.
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`Attention: Tammy Sarnelli, MPA
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`Head of Global Regulatory Affairs-Immunology and Neurology
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`45A Middlesex Turnpike
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`Billerica, MA 01821
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`Dear Ms. Sarnelli:
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`Please refer to your New Drug Application (NDA) dated May 30, 2018, received May 31, 2018,
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`and your amendments, submitted under section 505(b)(1) Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Mavenclad (cladribine) tablets, 10 mg.
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`We also refer to your NDA originally submitted September 30, 2009; to our Complete Response
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`letter dated February 28, 2011; and to your NDA withdrawal request dated August 19, 2011.
`Your NDA submission dated May 31, 2018, is considered a “resubmission after withdrawal” and
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`responds to all of the items listed in our February 28, 2011, Complete Response letter.
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`This NDA provides for the use of Mavenclad (cladribine) tablets, 10 mg, for the treatment of
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`relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active
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`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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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 7
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`

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` NDA 22561
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`Page 2
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` The SPL will be accessible via publicly available labeling repositories.
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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 January 30, 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 22561.” Approval of this submission by
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`FDA is not required before the labeling is used.
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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
`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 this application because there is evidence
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`strongly suggesting that the drug product would be unsafe in all pediatric age groups. The long­
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`term risk of malignancies in adult subjects treated with cladribine is an unacceptable risk in
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`pediatric patients.
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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
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`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
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`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk of
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`malignancy or assess a known serious risk of teratogenicity.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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`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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`3592-1
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`Conduct an observational study to assess the long-term risk of malignancy for
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`Mavenclad compared to other therapies used in the treatment of adults with
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`relapsing forms of multiple sclerosis. Describe and justify the choice of
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`appropriate comparator population(s) and estimated background rate(s) relative to
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`Reference ID: 4410993
`
`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 2 of 7
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` cladribine-exposed patients; clearly define the primary comparator
` population. Design the study around a testable hypothesis to assess, with sufficient
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` sample size and power, a clinically meaningful increase in malignancy risk above
` the comparator background rate(s), with a pre-specified statistical analysis method.
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` Specify concise case definitions and validation algorithms. For the Mavenclad­
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` exposed and comparator(s) cohorts, clearly define the study drug initiation period
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` and any exclusion and inclusion criteria. Enroll patients over an initial 4-year
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` period and follow for a minimum of 8 years from the time of enrollment.
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`Draft Protocol Submission: 08/2019
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`Final Protocol Submission: 09/2020
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`02/2033
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`Study Completion:
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`Final Report Submission:
`02/2034
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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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` NDA 22561
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`Page 3
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`3592-2
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`Establish a worldwide Pregnancy Surveillance Program to collect and analyze
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`information for a minimum of 10 years on pregnancy complications and birth
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`outcomes in women exposed to Mavenclad during pregnancy. Provide a complete
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`protocol which includes details regarding how you plan to encourage patients and
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`providers to report pregnancy exposures (e.g., telephone contact number and/or
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`website in prescribing information), measures to ensure complete data capture
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`regarding pregnancy outcomes, and any adverse effects in offspring and plans for
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`comprehensive data analysis and yearly reporting.
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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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`Draft Protocol Submission: 08/2019
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`Final Protocol Submission: 09/2020
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`09/2021
`Annual Interim Report:
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`09/2022
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`09/2023
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`09/2024
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`09/2025
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`09/2026
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`09/2027
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`09/2028
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`09/2029
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`09/2030
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`02/2031
`Study Completion:
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`Final Report Submission:
`02/2032
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`Reference ID: 4410993
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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 3 of 7
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`

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` NDA 22561
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`Page 4
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` Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
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` study) will be sufficient to identify an unexpected serious risk of a drug-drug interaction between
` Mavenclad and oral contraceptives.
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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 trials:
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`3592-3
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`Conduct a clinical drug-drug interaction trial to evaluate the effect of cladribine on
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`the pharmacokinetics (PK) of oral contraceptives. Include an evaluation of the
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`effect on the components ethinyl estradiol (EE) and norelgestromin (NGMN).
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`The timetable you submitted on March 19, 2019, states that you will conduct this trial according
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`to the following schedule:
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`Draft Protocol Submission: 06/2019
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`Final Protocol Submission: 06/2020
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`08/2023
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`Trial Completion:
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`Final Report Submission:
`08/2024
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`Submit clinical protocols to your IND 74634, 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
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`Reference ID: 4410993
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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 4 of 7
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`

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` NDA 22561
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`Page 5
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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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`REQUESTED PHARMACOVIGILANCE
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`We request that you perform postmarketing surveillance for malignancies, opportunistic
`infections, graft-versus-host disease with blood transfusion, liver injury, serious skin reactions,
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`and acute cardiac failure after exposure to Mavenclad. We request that you provide expedited
`reports directly to the Division of Neurology Products. Include comprehensive summaries and
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` analyses of these events quarterly as part of your required postmarketing safety 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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`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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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`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.
`For more information about submitting promotional materials in eCTD format, see the draft
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`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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` CM443702.pdf ).
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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.
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`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`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.
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`Reference ID: 4410993
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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 5 of 7
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`Sincerely,
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` {See appended electronic signature page}
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`Eric Bastings, MD
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`Deputy Director
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`Division of Neurology Products
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`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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` NDA 22561
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`Page 6
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` REPORTING REQUIREMENTS
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`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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`If you have any questions, please call Sandra Folkendt, Senior Regulatory Project Manager,
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`at (240) 402-2804.
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`ENCLOSURE(S):
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`Content of Labeling
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`Prescribing Information
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`Medication Guide
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`Reference ID: 4410993
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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 6 of 7
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`

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`Signature Page 1 of 1
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`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/
`------------------------------------------------------------
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`ERIC P BASTINGS
`03/29/2019 04:27:10 PM
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`Reference ID: 4410993
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`Biogen Exhibit 2136
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 7 of 7
`
`