DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`NDA 022527
`
`Novartis Pharmaceutical Corporation
`Attention: Mara Stiles
`Regional Branch Regulatory Manager
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Dear Ms. Stiles:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`Please refer to your new drug application (NDA) dated December 18, 2009, received December
`21, 2009, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act, for
`GILENYA® (fingolimod) 0.5 mg Capsules.
`
`We acknowledge receipt of your submissions dated June 15, 2009, July 24, 2009, October 5,
`2009, January 20, 2010, January 28, 2010, February 3, 2010, February 8, 2010, February 9,
`2010, February 11, 2010, February 15, 2010, February 16, 2010 (2), February 18, 2010, February
`22, 2010, March 1, 2010, March 4, 2010 (2), March 9, 2010, March 10, 2010, March 11, 2010,
`March 12, 2010 (3), March 13, 2010, March 15, 2010, March 16, 2010, March 18, 2010 (4),
`March 19, 2010, March 23, 2010, March 29, 2010 (2), March 30, 2010 (2), March 31, 2010,
`April 1, 2010, April 2, 2010 (2), April 7, 2010, April 8, 2010 (3), April 20, 2010 (2), April 21,
`2010 (3), April 22, 2010, April 23, 2010, April 27, 2010, April 28, 2010 (4), April 29, 2010 (2),
`May 3, 2010 (3), May 4, 2010, May 11, 2010, May 12, 2010 (4), May 13, 2010 (2), May 17,
`2010, May 18, 2010 (2), May 19, 2010, May 20, 2010, May 21, 2010, May 24, 2010 (2), May
`25, 2010, May 26, 2010, May 28, 2010 (3), June 1, 2010 (2), June 3, 2010, June 4, 2010, June 8,
`2010 (2), June 14, 2010, June 16, 2010 (2), June 17, 2010, June 18, 2010, June 21, 2010, June
`22, 2010, June 28, 2010, June 29, 2010 (2), June 30, 2010, July 1, 2010 (2), July 6, 2010, July 7,
`2010 (2), July 8, 2010, July 9, 2010, July 20, 2010, July 27, 2010, July 30, 2010 (3), August 6,
`2010, August 10, 2010, August 11, 2010, August 13, 2010, August 16, 2010, August 18, 2010,
`August 25, 2010 (2), August 31, 2010, September 1, 2010, September 3, 2010, September 8,
`2010 (2), September 10, 2010, September 13, 2010, September 14, 2010 (2), September 16,
`2010, September 17, 2010 (2), September 18, 2010, September 20, 2010 (2), and September 21,
`2010.
`
`This new drug application provides for the use of GILENYA® (fingolimod) 0.5 mg Capsules for
`the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of
`relapses and to delay the accumulation of physical disability.
`
`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.
`
`Apotex v. Novartis
`IPR2017-00854
`NOVARTIS 2037
`
`1
`
`

`

`NDA 022527
`Page 2
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`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 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert, Medication Guide). Information 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://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
`
`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on September 17, 2010, as soon as they are available, but no more
`than 30 days after they are printed. Please submit these labels electronically according to the
`guidance for industry titled “Providing Regulatory Submissions in Electronic Format – Human
`Pharmaceutical 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 “Final Printed Carton and Container Labels for approved NDA 022527.”
`Approval of this submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with 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 in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for ages birth through nine years of age because
`necessary studies are impossible or highly impracticable. This is because the number of
`pediatric patients less than 10 years of age with multiple sclerosis is too small.
`
`2
`
`

`

`NDA 022527
`Page 3
`
`Additionally, we are deferring submission of your pediatric study for ages 10 through 17 years
`for this application because this product is ready for approval for use in adults and the pediatric
`study has not been completed.
`
`Your deferred pediatric study required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act is a required postmarketing study. The status of this postmarketing study must be
`reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the Federal Food,
`Drug, and Cosmetic Act. This required study is listed below.
`
`1679-1: Deferred pediatric study under PREA: a 24-month, randomized, active-controlled,
`parallel group study to evaluate the single and multiple dose pharmacokinetics of
`fingolimod, and the safety and efficacy of multiple doses of fingolimod compared
`to interferon beta 1-a-intramuscular (Avonex) for the treatment of relapsing-
`remitting multiple sclerosis. The efficacy portion of this trial should be designed
`to show superiority of fingolimod over active control.
`
`Final Protocol Submission Date:
`Study Completion Date:
`Final Report Submission:
`
`December 1, 2011
`August 6, 2015
`January 1, 2016
`
`Submit the protocol for the study to your IND as a special protocol assessment (SPA), with a
`cross-reference letter to this NDA. Submit final study reports to this NDA. For administrative
`purposes, all submissions related to this required pediatric postmarketing study must be clearly
`designated “Required Pediatric Assessment”.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o) 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
`[section 505(o)(3)(A)].
`
`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 unexpected serious
`risks of adverse effects including eye toxicity, cardiac and vascular toxicity, pulmonary toxicity,
`seizures, serious and opportunistic infection, malignancies, liver toxicity, adverse maternal, fetal,
`and infant outcomes in women exposed to fingolimod during pregnancy, and effects on postnatal
`growth and development in exposed fetuses. In addition, analysis of spontaneous postmarketing
`adverse events will not be sufficient to identify unexpected serious risks related to the potential for
`fingolimod to inhibit CYP2C8, and for fingolimod-P to inhibit CYP2B6, or induce CYP450
`isoenzymes, and the potential for statins to induce the metabolism of fingolimod by CYP4F2.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`3
`
`

`

`NDA 022527
`Page 4
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`1679-2: A postmarketing observational prospective, parallel cohort study in relapsing
`multiple sclerosis patients to assess the potentially serious risk of: eye toxicity,
`cardiac and vascular toxicity, pulmonary toxicity, seizures, serious and
`opportunistic infections, malignancies, liver toxicity and atypical multiple
`sclerosis relapse. Specific outcomes examined should include, but not be limited
`to, macular edema, symptomatic bradycardia, second and third degree
`atrioventricular block, and lymphoma. The two observed cohorts should consist of
`1) patients newly prescribed fingolimod and 2) patients receiving another disease
`modifying therapy. The study population should be representative of patients with
`relapsing multiple sclerosis who take disease modifying therapies and should
`include patients with a history of diabetes or other cardiovascular risk factors. The
`study design should minimize differences between the cohorts by defining the
`populations in both cohorts so that they will be similar, by ensuring that both
`cohorts have similar clinical assessments, and by ensuring that patients who
`discontinue treatment have continued follow-up. In addition, the study protocol
`should account for duration of exposure, treatment changes, and loss to follow-up.
`Sample size should be supported by estimates of the rates of the events of interest.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`January 31, 2011
`Final Protocol Submission:
`May 15, 2020
`Study Completion:
`Final Report Submission: December 15, 2020
`
`1679-3: Develop and maintain a prospective, observational pregnancy exposure registry
`study conducted in the United States that compares the maternal, fetal, and infant
`outcomes of women exposed to fingolimod during pregnancy to an unexposed
`control population. The registry will detect and record major and minor congenital
`malformations, spontaneous abortions, stillbirths, elective terminations, adverse
`effects on immune system development, and any other adverse pregnancy
`outcomes. These outcomes will be assessed throughout pregnancy. Infant
`outcomes will be assessed through at least the first year of life.
`
`In addition, for guidance on how to establish a pregnancy exposure registry,
`please review the Guidance for Industry on Establishing Pregnancy Exposure
`Registries available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
`n/Guidances/UCM071639.pdf.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`4
`
`

`

`NDA 022527
`Page 5
`
`Final Protocol Submission: December 21, 2010
`Study Completion:
`March 31, 2017
`Final Report Submission: October 31, 2017
`
`1679-4: An in vitro study to evaluate the potential for fingolimod-P to induce CYP450
`isoenzymes.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`Final Protocol Submission: February 1, 2011
`Study Completion:
`September 1, 2011
`Final Report Submission: December 1, 2011
`
`1679-5: An in vitro study to evaluate the potential for fingolimod to inhibit CYP2C8 and
`for fingolimod-P to inhibit CYP2B6.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`July 15, 2010
`Study Completion:
`Final Report Submission: October 15, 2010
`
`1679-6: An in vitro study to evaluate the potential for statins (e.g. simvastatin, lovastatin)
`to induce CYP4F2, an enzyme that metabolizes fingolimod.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`Final Protocol Submission: February 1, 2011
`Study Completion:
`September 1, 2011
`Final Report Submission: December 1, 2011
`
`1679-7: An integrated summary of safety for Studies FTY720D2301, FTY720D2302, and
`FTY720D2309 (upon completion of Study FTY720D2309). The summary should
`include updated exposure and analyses of safety following the format of a 4-
`month NDA safety update report, for the double-blind portion of the studies (Pool
`D + FTY7202309) and all studies (Pool E + 2309 double blind and extension).
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`Final Protocol Submission: December 21, 2010
`Study Completion:
`June 30, 2011
`Final Report Submission:
`January 30, 2012
`
`5
`
`

`

`NDA 022527
`Page 6
`
`1679-8: A juvenile rat toxicology study. The study should utilize animals of an age range
`and stage(s) of development that are comparable to the intended pediatric
`population; the duration of dosing should cover the intended length of treatment
`in the pediatric population. In addition to the usual toxicological parameters, this
`study should evaluate effects of fingolimod on growth, reproductive development,
`and neurological and neurobehavioral development.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this study according to the following schedule:
`
`January 31, 2011
`Final Protocol Submission:
`October 29, 2011
`Study Completion Date:
`Final Report Submission: March 31, 2012
`
`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 the potential for the
`pharmacokinetic interaction of fingolimod with carbamazepine.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required, to
`conduct the following:
`
`1679-9 A drug interaction clinical trial to evaluate the effect of carbamazepine on
`fingolimod pharmacokinetics.
`
`The timetable you submitted on September 17, 2010 states that you will
`conduct this trial according to the following schedule:
`
`Final Protocol Submission: February 1, 2011
`April 1, 2012
`Trial Completion:
`Final Report Submission:
`July 1, 2012
`
`Submit all protocols to your IND, with a cross-reference letter to this NDA. Submit all final
`reports 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(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 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`6
`
`

`

`NDA 022527
`Page 7
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to have satisfied the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii)
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitment in your submission dated September 8, 2010.
`This commitment is listed below.
`
`1679-10 A prospective, randomized, controlled study of fingolimod 0.5 mg, fingolimod
`0.25 mg, and an appropriate control, of at least one year duration, to evaluate the
`efficacy and safety of the drug.
`
`Final Protocol Submission: September 30, 2011
`Study Completion:
`March 30, 2015
`Final Report Submission:
`July 30, 2015
`
`Submit the clinical protocol to your IND for this product and all study 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 this postmarketing commitment
`should be prominently labeled “Postmarketing Commitment Protocol,” “Postmarketing
`Commitment Final Report,” or “Postmarketing Commitment Correspondence.”
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`Section 505-1 of the FDCA authorizes FDA to require the submission of a Risk Evaluation and
`Mitigation Strategy (REMS) if FDA determines that such a strategy is necessary to ensure that
`the benefits of the drug outweigh the risks (section 505-1(a)).
`
`In accordance with section 505-1 of FDCA, we have determined that a REMS is necessary for
`GILENYA (fingolimod) to ensure that the benefits of the drug outweigh the risk of
`bradyarrhythmia and atrioventricular block at treatment initiation, infections, macular edema,
`respiratory effects, hepatic effects, and fetal risk.
`
`In accordance with section 505-1 of FDCA, as one element of a REMS, FDA may require the
`development of a Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR
`Part 208, FDA has determined that GILENYA (fingolimod) poses a serious and significant
`public health concern requiring the distribution of a Medication Guide. The Medication Guide is
`necessary for patients’ safe and effective use of GILENYA (fingolimod). FDA has
`determined that GILENYA (fingolimod) is a product for which patient labeling could help
`
`7
`
`

`

`NDA 022527
`Page 8
`
`prevent serious adverse effects and that has a serious risk (relative to benefits) of which patients
`should be made aware because information concerning the risk could affect patients’ decisions to
`use, or continue to use GILENYA (fingolimod). Under 21 CFR 208, you are responsible for
`ensuring that the Medication Guide is available for distribution to patients who are dispensed
`GILENYA (fingolimod).
`
`We have also determined that a communication plan is necessary to support implementation of
`the REMS.
`
`Your proposed REMS, submitted on September 17, 2010 and appended to this letter, is
`approved. The REMS consists of a Medication Guide, a communication plan, and a timetable for
`submission of assessments of the REMS.
`
`The REMS assessment plan should include but is not limited to the following:
`a. An evaluation of healthcare providers’ (HCPs) and patients’ understanding of the
`serious risks of GILENYA (fingolimod)
`b. A report on periodic assessments of the distribution and dispensing of the
`Medication Guide in accordance with 21 CFR 208.24
`c. A report on failures to adhere to distribution and dispensing requirements of the
`Medication Guide, and corrective actions taken to address noncompliance with 21
`CFR 208.24
`d. With regard to assessment of the communication plan:
`i. The date of product launch and the launch of the communication plan
`ii. The date(s) of mailing and number of recipients of the Dear Healthcare
`Professional (DHCP) letter and the Guide to Important Safety
`Information; Using Gilenya in Patients with Relapsing Forms of Multiple
`Sclerosis.
`iii. The number of mailings returned.
`iv. The sources of the recipient lists
`v. Periodic summaries of serious adverse event reports of symptomatic and
`asymptomatic bradyarrhythmia and atrioventricular blocks, infections,
`macular edema, respiratory effects, hepatic effects, and fetal risk.
`vi. Periodic summaries of pregnancies in women exposed to fingolimod and
`maternal and fetal outcomes, including updates from fingolimod
`pregnancy exposure registry.
`e. Based on the information submitted, an assessment of and conclusion regarding
`whether the REMS is meeting its goals, and whether modifications to the REMS
`are needed.
`f. Specification of measures that would be taken to increase awareness if surveys of
`HCPs indicate that provider awareness is not adequate.
`
`Assessments of an approved REMS must include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. With respect to any such postapproval
`study, you must include the status of such study, including whether any difficulties completing
`the study have been encountered. With respect to any such postapproval clinical trial, you must
`
`8
`
`

`

`NDA 022527
`Page 9
`
`include the status of such clinical trial, including whether enrollment has begun, the number of
`participants enrolled, the expected completion date, whether any difficulties completing the
`clinical trial have been encountered, and registration information with respect to requirements
`under subsections (i) and (j) of section 402 of the Public Health Service Act. You can satisfy
`these requirements in your REMS assessments by referring to relevant information included in
`the most recent annual report required under section 506B and 21 CFR 314.81(b)(2)(vii) and
`including any updates to the status information since the annual report was prepared. Failure to
`comply with the REMS assessments provisions in section 505-1(g) could result in enforcement
`action.
`
`We remind you that in addition to the assessments submitted according to the timetable included
`in the approved REMS, you must submit a REMS assessment and may propose a modification to
`the approved REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of FDCA.
`
`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission:
`
`NDA 022527 REMS ASSESSMENT
`NEW SUPPLEMENT FOR NDA 022527
`PROPOSED REMS MODIFICATION
` REMS ASSESSMENT
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE) FOR NDA 022527
`
` REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
`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
`
`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
`
`9
`
`

`

`NDA 022527
`Page 10
`
`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.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, to
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and to the following address:
`
`MedWatch Program
`Office of Special Health Issues
`Food and Drug Administration
`10903 New Hampshire Ave
`Building 32, Mail Stop 5353
`Silver Spring, MD 20993
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`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-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.
`
`10
`
`

`

`NDA 022527
`Page 11
`
`If you have any questions, call LT Hamet Touré, Pharm.D. MPH, Regulatory Project Manager,
`at (301) 796-7534.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Robert Temple, MD
`Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`ENCLOSURE(S):
`Content of Labeling
`REMS
`
`11
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`ROBERT TEMPLE
`09/21/2010
`
`Reference ID: 2838731
`
`12
`
`