,,--... 111
`
`(
`
`U.S. FOOD & DRUG
`
`-.,- : / -
`
`ADMIN ISTRATION
`
`NOA 217003
`
`Pharmacyclics LLC
`Attention: Xi Tian, PhD
`Senior Manager, Regulatory Affairs
`1000 Gateway Boulevard
`South San Francisco, CA 94080
`
`Dear Dr. Tian:
`
`NDAAPPROVAL
`
`Please refer to your new drug application (NOA) dated February 24, 2022, received
`February 24, 2022, and your amendments, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for IMBRUVICA (ibrutinib) oral
`suspension.
`
`This NOA provides for the use of IMBRUVICA (ibrutinib) oral suspension for the
`treatment of adult and pediatric patients age 1 year and older with chronic graft versus
`host disease (cGVHD) after failure of one or more lines of systemic therapy.
`
`APPROVAL & LABELING
`
`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.
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`We are waiving the req uirements of 21 CFR 201.57(d)(8) regard ing the length of
`Highlights of Prescribing Information. This waiver applies to all future supplements
`containing revised labeling unless we notify you otherwise.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the
`content of labeling [21 CFR 314.50(1)] in structured product labeling (SPL) format using
`the FDA automated drug reg istration and listing system (eLIST), as described at
`FDA.gov. 1 Content of labeling must be identical to the enclosed labeling (text for the
`Prescribing Information, Patient Package Insert, Instructions for Use) as well as annual
`reportab le changes not included in the enclosed labeling. Information on submitting SPL
`
`1 http://www. fda. gov /F orl ndustry/DataStandards/Structu red Prod uctlabelinq/defau It.htm
`
`Reference ID 5035070
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` NDA 217003
`
`Page 2
`
`
` files using eLIST may be found in the guidance for industry SPL Standard for Content of
`
`
`
` Labeling Technical Qs and As.2
`
`
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`CARTON AND CONTAINER LABELING
`
`
`
`We acknowledge your August 22, 2022, submission containing final printed carton and
`
`container labeling.
`
`
`DATING PERIOD
`
`
`
`
`Based on the stability data submitted to date, the expiry dating period for IMBRUVICA
`
`
`
`(ibrutinib) oral suspension shall be 24 months from the date of manufacture when stored
`
`
`at 2-25°C (36-77°F).
`
`
`ADVISORY COMMITTEE
`
`
`
`
`Your application for IMBRUVICA was not referred to an FDA advisory committee
`
`
`
`
`because outside expertise was not necessary and there were no controversial issues
`
`that would benefit from advisory committee discussion.
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for
`
`
`
`new active ingredients (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 assessment of the safety and effectiveness of the product for
`
`
`the claimed indication in pediatric patients unless this requirement is waived, deferred,
`
`or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are
`
`
`exempt from this requirement.
`
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`
`
`
`Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA
`
`
`to require holders of approved drug and biological product applications to conduct
`
`
`
`
`postmarketing studies and clinical trials for certain purposes, if FDA makes certain
`
`
`findings required by the statute.
`
`
`
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`
`
`
`
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`
`Reference ID: 5035070
`
`

`

`
`
`
`
`
` NDA 217003
`
`Page 3
`
`
` We have determined that an analysis of spontaneous postmarketing adverse events
`
`
`
`
`
`
`
` reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal
` of a serious risk of the impact on growth and development, of ibrutinib in pediatric
`
`
`
`
` patients with cGVHD.
`
`
`
`Furthermore, the active postmarket risk identification and analysis system as available
`
`
`
`
`under section 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
`
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or
`
`
`observational study) will be sufficient to assess a signal of a serious risk.
`
`
`
`
`Therefore, based on appropriate scientific data, FDA has determined that you are
`
`required to conduct the following trial:
`
`
`
`
`
`4328-1 Conduct analyses to characterize long-term safety of ibrutinib in terms of
`
`growth and development in pediatric patients. Patients enrolled in Study
`
`
`PCYC-1146-IM should be evaluated for growth and development
`
`
`milestones annually for at least 5 years from the initiation of ibrutinib. Data
`
`
`
`should include growth parameters as measured by height and weight,
`
`
`sexual maturation by Tanner stage, performance status, immune
`
`
`reconstitution, adverse events, and patient-reported outcomes measures.
`
`
`
`
`The timetable you submitted on August 19, 2022, states that you will conduct this trial
`
`according to the following schedule:
`
`
`
`
`
`Submit the datasets with the final report submission.
`
`
`
`
`FDA considers the term final to mean that the applicant has submitted a protocol, the
`
`
`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.3
`
`
` Submit clinical protocol(s) to your IND 147315 with a cross-reference letter to this NDA.
`
`
`
`
`
`
` Submit nonclinical and chemistry, manufacturing, and controls protocols and all final
` report(s) to your NDA. Prominently identify the submission with the following wording in
`
`
`
`
`
`
` bold capital letters at the top of the first page of the submission, as appropriate:
` Required Postmarketing Protocol Under 505(o), Required Postmarketing Final
`
`
`
`
` Report Under 505(o), Required Postmarketing Correspondence Under 505(o).
`
`
`
`
`
`
`
`Trial Completion:
`01/2026
`
`
`
`Final Report Submission:
`07/2026
`
`
`
`
`3 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section
`
`
`505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019).
`
`
`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 5035070
`
`

`

`
`
`
`
`
` NDA 217003
`
`Page 4
`
`
` 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.
`
`
`
`FDA will consider the submission of your annual report under section 506B and
`
`
`21 CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and
`
`
`
`21 CFR 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report
`
`
`
`
`must also include a report on the status of any study or clinical trial otherwise
`
`
`undertaken to investigate a safety issue. Failure to submit an annual report for studies
`
`
`or clinical trials required under 505(o) on the date required will be considered a violation
`
`
`of FDCA section 505(o)(3)(E)(ii) and could result in enforcement action.
`
`
`PROMOTIONAL MATERIALS
`
`
`
`You may request advisory comments on proposed introductory advertising and
`
`
`promotional labeling. For information about submitting promotional materials, see the
`
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`
`Electronic Format—Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.4
`
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials,
`
`
`
`and the Prescribing Information, at the time of initial dissemination or publication,
`
`
`
`accompanied by a Form FDA 2253. Form FDA 2253 is available at FDA.gov.5
`
`
`Information and Instructions for completing the form can be found at FDA.gov.6
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`4 For the most recent version of a guidance, check the FDA guidance web page at
`
`
`
`https://www.fda.gov/media/128163/download.
`
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
`6 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
`
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 5035070
`
`

`

`
`
`
`
`
` NDA 217003
`
`Page 5
`
`
`
`
` If you have any questions, contact Rosa Lee-Alonzo, Senior Regulatory Health Project
` Manager, at rosa.lee-alonzo@fda.hhs.gov or (301) 348-3004.
`
`
`
`
`
`
`
`Sincerely,
`
`
`
`{See appended electronic signature page}
`
`
`R. Angelo de Claro, MD
`
`
`Division Director
`
`Division of Hematologic Malignancies I
`
`Office of Oncologic Diseases
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Patient Package Insert
`
`
`Instructions for Use
`o
`
`
`
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 5035070
`
`

`

`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/
`------------------------------------------------------------
`
`ROMEO A DE CLARO
`08/24/2022 10:03:01 AM
`
`Reference ID: 5035070
`
`(
`
`
`
`