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` NDA 203341/S-025
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`SUPPLEMENT APPROVAL
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` PF Prism C.V.
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` c/o Pfizer, Inc.
` Attention: Aparna Srirangam, MS, PhD
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` Senior Manager, Pfizer Global Regulatory Affairs
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` 10646 Science Center Drive
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` San Diego, CA 92121
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`Dear Dr. Srirangam:
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`Please refer to your supplemental new drug application (sNDA) dated March 30, 2023,
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`received March 30, 2023, and your amendments, submitted under section 505(b) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for BOSULIF (bosutinib) tablets.
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`This Prior Approval supplemental new drug application provides for a request for
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`pediatric exclusivity, along with a new pediatric indication for the treatment of pediatric
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`patients 1 year of age and older with chronic phase (CP) Philadelphia chromosome-
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`positive chronic myelogenous leukemia (Ph+ CML), newly-diagnosed or resistant or
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`intolerant to prior therapy.
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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 date of this letter, for use as recommended in the enclosed agreed-upon
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`labeling.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
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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, Patient Package Insert, and Instructions For Use), with the
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`addition of any labeling changes in pending “Changes Being Effected” (CBE)
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`Reference ID: 5251010
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` NDA 203341/S-025
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` Page 2
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` supplements, as well as annual reportable changes not included in the enclosed
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` 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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`Also within 14 days, amend all pending supplemental applications that include labeling
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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`annual reportable changes. To facilitate review of your submission(s), provide a
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`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
`Word version. The marked-up copy should provide appropriate annotations, including
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`supplement number(s) and annual report date(s).
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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
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`container labeling submitted on September 26, 2023, as soon as they are available, but
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`no more than 30 days after they are printed. Please submit these labeling electronically
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`according to the guidance for industry Providing Regulatory Submissions in Electronic
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`Format — Certain Human Pharmaceutical Product Applications and Related
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`Submissions Using the eCTD Specifications. For administrative purposes, designate
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`this submission “Final Printed Carton and Container Labeling for approved
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`NDA 203341/S-025.” Approval of this submission by FDA is not required before the
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`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
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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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`Because this drug product for this indication has an orphan drug designation, you are
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`exempt from this requirement.
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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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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 5251010
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` NDA 203341/S-025
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` Page 3
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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
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`unexpected serious risks of growth and developmental delay and of worsening of
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`serious adverse reactions including but not limited to gastrointestinal disorders,
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`hematologic toxicity, and infections, with prolonged exposure to bosutinib in pediatric
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`patients with CML.
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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 these serious risks.
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or
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`observational study) will be sufficient to identify these unexpected serious risks.
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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 trial:
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`4509-1 Conduct Study BCHILD (ITCC-054/COG AAML1921) to identify,
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`characterize, and determine the incidence of the serious potential risks of
`growth and developmental delay and worsening of serious adverse
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`reactions including but not limited to gastrointestinal disorders,
`hematologic toxicity, and infectious adverse events with prolonged
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`exposure (>12 months) to bosutinib in pediatric patients with chronic
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`phase chronic myeloid leukemia (CML). All patients enrolled in Study
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`BCHILD (ITCC-054/COG AAML1921) must be evaluated for growth and
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`development milestones and serious adverse events annually for at least
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`5 years from the initiation of bosutinib. Include assessments of growth
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`parameters, parameters of bone metabolism and growth, Tanner stage,
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`hormones associated with growth and pubertal development, and serious
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`adverse events. Include incidence rates, time to onset, and outcomes.
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`The timetable you submitted on September 12, 2023, states that you will conduct this
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`study according to the following schedule:
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`07/2028
`Study Completion:
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`Final Report Submission: 01/2029
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`Submit the datasets with the final report submission.
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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: 5251010
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` NDA 203341/S-025
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` Page 4
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` 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
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` revised as needed to meet the goal of the study or clinical trial.3
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` Submit clinical protocol(s) to your IND 068268 with a cross-reference letter to this NDA.
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` 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
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` bold capital letters at the top of the first page of the submission, as appropriate:
` Required Postmarketing Protocol Under 505(o), Required Postmarketing Final
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` Report Under 505(o), Required Postmarketing Correspondence Under 505(o).
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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(a)(1) 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(a)(1) 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.4
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` 3 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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`4 For the most recent version of a guidance, check the FDA guidance web page at
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`https://www.fda.gov/media/128163/download.
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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: 5251010
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` NDA 203341/S-025
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` Page 5
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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
` [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.5 Information and
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`Instructions for completing the form can be found at FDA.gov.6
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`All promotional materials that include representations about your drug product must be
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`promptly revised to be consistent with the labeling changes approved in this
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`supplement, including any new safety- related information [21 CFR 314.70(a)(4)]. The
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`revisions in your promotional materials should include prominent disclosure of the
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`important new safety-related information that appears in the revised labeling. Within 7
`days of receipt of this letter, submit your statement of intent to comply with
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`21 CFR 314.70(a)(4).
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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
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`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
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`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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`If you have any questions, email Brad McKenzie, Senior Regulatory Health Project
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`Manager, at bradley.mckenzie@fda.hhs.gov or call (301) 796-2583.
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`Sincerely,
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`{See appended electronic signature page}
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`R. Angelo de Claro, MD
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`Division Director
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`Division of Hematologic Malignancies I
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`Office of Oncologic Diseases
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`Center for Drug Evaluation and Research
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` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`6 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 5251010
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`NDA 203341/S-025
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`Page 6
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`ENCLOSURE(S):
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`• Content of Labeling
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`o Prescribing Information
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`o Patient Package Insert
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`Instructions For Use
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`o
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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: 5251010
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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/
`------------------------------------------------------------
`
`ROMEO A DE CLARO
`09/26/2023 01:49:41 PM
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`Reference ID: 5251010
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`(
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