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` NDA 207924/S-007
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`SUPPLEMENT APPROVAL
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` Eli Lilly and Company
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` Attention: Jessie Lynn Bishop, MPH
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` Associate Director, Global Regulatory Affairs - US
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` Lilly Corporate Center / Drop Code 2543
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` Indianapolis, IN 46285
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`Dear Ms. Bishop:
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`Please refer to your supplemental new drug application (sNDA) dated and received
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`December 13, 2021, and your amendments, submitted under section 505(b) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for Olumiant (baricitinib) tablets.
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`This Prior Approval supplemental new drug application provides for the addition of the
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`indication for the treatment of adult patients with severe alopecia areata.
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved, effective
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`on the date of this letter, for use as recommended in the enclosed agreed-upon
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`labeling.
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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
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the FDA automated drug registration and listing system (eLIST), as described at
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`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`Prescribing Information and Medication Guide), with the addition of any labeling
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`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
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`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
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`industry SPL Standard for Content of Labeling Technical Qs and As.2
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`The SPL will be accessible from publicly available labeling repositories.
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`Reference ID: 4998371
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`

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` NDA 207924/S-007
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` Page 2
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` SENTINEL/ARIA NOTIFICATION
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` The Food and Drug Administration Amendments Act of 2007 (FDAAA) required FDA to
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` establish a national electronic system to monitor the safety of FDA-regulated medical
` products. In fulfillment of this mandate, FDA established the Sentinel System, which
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` enables FDA to proactively monitor drug safety using electronic health data from
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` multiple data sources that contribute to the Sentinel Distributed Database.
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`FDA plans to evaluate Olumiant (baricitinib) tablets in the Sentinel System. We have
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`determined that Sentinel’s Active Postmarket Risk Identification and Analysis System,
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`established under section 505(k)(3) of the FDCA, is sufficient to identify unexpected
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`serious risks (myocardial infarction, stroke, and thrombosis) possibly related to
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`baricitinib dose during long-term use for alopecia areata.
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`The ARIA safety assessment will be posted to the Sentinel website.3 Once there is
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`sufficient product uptake to support an analysis, an analysis plan will be posted online.
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`After the analysis is complete, FDA will also post the results on the Sentinel website.
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`FDA will notify you prior to posting the analysis plan.
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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
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`new active ingredients (which includes new salts and new fixed combinations), new
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`indications, new dosage forms, new dosing regimens, or new routes of administration
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`are required to contain an assessment of the safety and effectiveness of the product for
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`the claimed indication in pediatric patients unless this requirement is waived, deferred,
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`or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 to less than 6 years because
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`the studies are impossible or highly impractical.
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`We are deferring submission of your pediatric study for ages 6 years to less than 18
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`years for this application because this product is ready for approval for use in adults and
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`the pediatric study has not been completed.
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`Your deferred pediatric studies required by section 505B(a) of the Federal Food, Drug,
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`and Cosmetic Act are required postmarketing studies. The status of these
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`postmarketing studies must be reported annually according to 21 CFR 314.81 and
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`section 505B(a)(4)(C) of the Federal Food, Drug, and Cosmetic Act. These required
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`studies are listed below.
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` 4289-1 Conduct a randomized, controlled trial to evaluate the safety, efficacy, and
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` pharmacokinetics of baricitinib in the adolescent population (12 years to
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` 3 https://www.sentinelinitiative.org
`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4998371
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`

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` NDA 207924/S-007
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` Page 3
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` less than 18 years) with severe alopecia areata. Evaluate at least 300
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` subjects exposed to baricitinib for a minimum of 52 weeks.
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`Final Protocol Submission:
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`Study Completion:
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`Final Report Submission:
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`October 2022
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`January 2027
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`June 2027
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`4289-2 Conduct a randomized, controlled trial to evaluate the safety, efficacy, and
`pharmacokinetics of baricitinib in the pediatric population (6 years to less
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`than 12 years) with severe alopecia areata. Evaluate at least 100 subjects
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`exposed to baricitinib for a minimum of 52 weeks.
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`Final Protocol Submission:
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`Study Completion:
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`Final Report Submission:
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`December 2027
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`May 2031
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`November 2031
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`FDA considers the term final to mean that the applicant has submitted a protocol, the
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`FDA review team has sent comments to the applicant, and the protocol has been
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`revised as needed to meet the goal of the study or clinical trial.4
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`Submit the protocol(s) to your IND 112543, with a cross-reference letter to this NDA.
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`Reports of these required pediatric postmarketing studies must be submitted as an NDA
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`or as a supplement to your approved NDA with the proposed labeling changes you
`believe are warranted based on the data derived from these studies. When submitting
`the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
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`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover
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`letter of the submission.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA
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`to require holders of approved drug and biological product applications to conduct
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`postmarketing studies and clinical trials for certain purposes, if FDA makes certain
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`findings required by the statute.
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`We have determined that an analysis of spontaneous postmarketing adverse events
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`reported under subsection 505(k)(1) of the FDCA will not be sufficient to identify the
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`unexpected serious risk of adverse maternal, fetal, and infant outcomes of women
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`exposed to baricitinib during pregnancy.
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`Furthermore, the active postmarket risk identification and analysis system as available
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`under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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` 4 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
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` 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
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` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`U.S. Food and Drug Administration
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`
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4998371
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`

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` NDA 207924/S-007
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` Page 4
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` Therefore, based on appropriate scientific data, FDA has determined that you are
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` required to conduct the following:
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`4289-3 Conduct a Pregnancy Exposure Registry, a prospective, registry based
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`observational exposure cohort study that compares the maternal, fetal,
`and infant outcomes of women exposed to baricitinib during pregnancy to
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` an unexposed control population. The registry should be designed to
` detect and record major and minor congenital malformations, spontaneous
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` abortions, stillbirths, elective terminations, small for gestational age,
` preterm birth, and any other adverse pregnancy outcomes. These
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` outcomes will be assessed throughout pregnancy. Infant outcomes,
`including effects on postnatal growth and development, will be assessed
`through at least the first year of life.
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`For more information, see the May 2019 FDA draft guidance for industry
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`Post approval Pregnancy Safety Studies.
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`https://www.fda.gov/regulatory-information/search-fda-guidance-
`documents/postapproval-pregnancy-safety-studies-guidance-industry
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`The timetable you submitted on June 9, 2022 states that you will conduct
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`this study according to the following schedule:
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Interim/Other:
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`Study/Trial Completion:
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`Final Report Submission:
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`December 2022
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`June 2023
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`June 2028
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`June 2033
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`June 2034
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`4289-4 Conduct a pregnancy study that uses a different design from the
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`Pregnancy Registry (for example, a retrospective cohort study using
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`claims or electronic medical record data or a case control study) to assess
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`major congenital malformations, spontaneous abortions, stillbirths, and
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`small for gestational age and preterm birth in women exposed to baricitinib
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`during pregnancy compared to an unexposed control population.
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`The timetable you submitted on June 9, 2022 states that you will conduct
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`this study according to the following schedule:
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`Draft Protocol Submission:
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`Final Protocol Submission:
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`Interim/Other:
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`Study/Trial Completion:
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`Final Report Submission:
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`December 2022
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`June 2023
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`June 2026
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`June 2029
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`June 2030
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4998371
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`

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` NDA 207924/S-007
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` Page 5
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` FDA considers the term final to mean that the applicant has submitted a protocol, the
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` FDA review team has sent comments to the applicant, and the protocol has been
` revised as needed to meet the goal of the study or clinical trial.5
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`Submission of the protocols for required postmarketing observational studies to your
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`IND is for purposes of administrative tracking only. These studies do not constitute
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`clinical investigations pursuant to 21 CFR 312.3(b) and therefore are not subject to the
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`IND requirements under 21 CFR part 312.
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of
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`any study or clinical trial required under this section. This section also requires you to
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`periodically report to FDA on the status of any study or clinical trial otherwise
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`undertaken to investigate a safety issue. Section 506B of the FDCA, as well as
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`21 CFR 314.81(b)(2)(vii) requires you to report annually on the status of any
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`postmarketing commitments or required studies or clinical 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
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`must also include a report on the status of any study or clinical trial otherwise
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`undertaken to investigate a safety issue. Failure to submit an annual report for studies
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`or clinical trials required under 505(o) on the date required will be considered a violation
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`of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and
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`promotional labeling. For information about submitting promotional materials, see the
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`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
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`Electronic Format-Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.6
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`You must submit final promotional materials and Prescribing Information, accompanied
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`by a Form FDA 2253, at the time of initial dissemination or publication
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`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.7 Information and
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`Instructions for completing the form can be found at FDA.gov.8
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` 5 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
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` 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
` https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`
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` 6 For the most recent version of a guidance, check the FDA guidance web page at
` https://www.fda.gov/media/128163/download.
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` 7 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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` 8 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
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`
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4998371
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`

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` NDA 207924/S-007
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` Page 6
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`PATENT LISTING REQUIREMENTS
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` Pursuant to 21 CFR 314.53(d)(2) and 314.70(f), certain changes to an approved NDA
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` submitted in a supplement require you to submit patent information for listing in the
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` Orange Book upon approval of the supplement. You must submit the patent information
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` required by 21 CFR 314.53(d)(2)(i)(A) through (C) and 314.53(d)(2)(ii)(A) and (C), as
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` applicable, to FDA on Form FDA 3542 within 30 days after the date of approval of the
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` supplement for the patent information to be timely filed (see 21 CFR
` 314.53(c)(2)(ii)). You also must ensure that any changes to your approved NDA that
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` require the submission of a request to remove patent information from the Orange Book
` are submitted to FDA at the time of approval of the supplement pursuant to 21 CFR
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` 314.53(d)(2)(ii)(B) and 314.53(f)(2)(iv).
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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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`As required under 21 CFR 314.80, report each adverse drug experience that is both
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`serious and unexpected within 15 days from initial receipt of the information.
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`If you have any questions, call Strother D. Dixon, Senior Regulatory Project Manager, at
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`(301) 796-1015.
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`Sincerely,
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`{See appended electronic signature page}
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`
`
`Gordana Diglisic, MD
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`Associate Director for Therapeutic Review
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`
`Division of Dermatology and Dentistry
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`Office of Immunology and Inflammation
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`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`• Content of Labeling
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`
`o Prescribing Information
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`o Medication Guide
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`
`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`
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`Reference ID: 4998371
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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/
`------------------------------------------------------------
`
`GORDANA DIGLISIC
`06/13/2022 01:58:30 PM
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`Reference ID: 4998371
`
`(
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