CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
`210259Orig1s000
`
`
` Calquence® capsule, 100 mg
`
`acalabrutinib
`
`
`
`Trade Name:
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`
`
`Approval Date:
`
`
`Indication:
`
`
`Acerta Pharma B.V.
`
`October 31, 2017
`
`For the treatment of adult patients with mantle cell
`lymphoma (MCL) who have received at least one prior
`therapy.
`
`

`

`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`210259Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Officer/Employee List
`Multidiscipline Review(s)
` Summary Review
` Office Director
` Cross Discipline Team Leader
` Clinical
` Non-Clinical
` Statistical
` Clinical Pharmacology
`Product Quality Review(s)
`Clinical Microbiology / Virology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`X
`
`X
`X
`X
`X
`
`

`

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`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`210259Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA 210259
`
`ACCELERATED APPROVAL
`
`
`Acerta Pharma B.V.
`Attention: Yasameen Qazen, PharmD
`Director, Regulatory Science
`2200 Bridge Parkway, Suite 101
`Redwood City, CA 94065
`
`
`Dear Dr. Qazen:
`
`Please refer to your New Drug Application (NDA) dated June 13, 2017, received June 13, 2017,
`and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
`Act (FDCA) for Calquence® (acalabrutinib) capsule, 100 mg.
`
`This new drug application provides for the use of Calquence® (acalabrutinib) capsule, 100 mg
`for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least
`one prior therapy.
`
`APPROVAL & LABELING
`
`We have completed our review of this application, as amended. It is approved under the
`provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
`letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug
`product and related activities must adhere to the substance and procedures of the referenced
`accelerated approval regulations.
`
`EXPIRATION DATING PERIOD
`
`°C, and a
`-month re-test period for the drug substance when stored at or below
`We grant a
`24-month drug product expiration period when stored at controlled room temperature conditions
`20°C-25°C (68°F-77°F); excursions permitted to 15°C-30°C (59°F-86°F) in the commercial
`packaging.
`
`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(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and text for the
`
`Reference ID: 4174988
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`NDA 210259
`Page 2
`
`
`patient package insert). 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 27, 2017, 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 — Certain
`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
`Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 210259.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`ADVISORY COMMITTEE
`
`Your application for acalabrutinib was not referred to an FDA advisory committee because the
`application did not raise significant safety or efficacy issues in the intended population
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled clinical trials to verify and describe clinical benefit. You are
`required to conduct such clinical trials with due diligence. If post-marketing clinical trials fail to
`verify clinical benefit or are not conducted with due diligence, we may, following a hearing in
`accordance with 21 CFR 314.530, withdraw this approval. We remind you of your post-
`marketing requirement specified in your submission dated October 30, 2017. This requirement,
`along with required completion dates, is listed below.
`
`PMR 3291-1 Submit the complete final report and datasets demonstrating clinical efficacy and
`safety from a randomized, double-blind, placebo-controlled, clinical trial of
`Calquence in combination with standard immunochemotherapy versus
`immunochemotherapy alone in patients with mantle cell lymphoma.
`
`
`
`Enrollment Completed Submission: 12/2020
`Trial Completion:
`
`
`10/2023
`Final Report Submission:
`
`11/2024
`
`
`Submit clinical protocols to your IND 118717 for this product. In addition, under
`21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary of each
`requirement in your annual report to this NDA. The status summary should include expected
`
`Reference ID: 4174988
`
`

`

`NDA 210259
`Page 3
`
`
`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.
`
`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
`submissions relating to this post-marketing requirement must be clearly designated “Subpart H
`Postmarketing Requirement(s).”
`
`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(s) 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 FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct post-marketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous post-marketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess 1) known risks of
`hemorrhage, infection, cytopenia, second primary malignancy, and atrial fibrillation, 2) a signal
`of tumor lysis syndrome, or 3) identify an unexpected serious risk of excessive drug toxicity
`from impaired hepatic function.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess 1) known risks of hemorrhage, infection, cytopenia, second
`primary malignancy, and atrial fibrillation, 2) a signal of tumor lysis syndrome, or 3) identify an
`unexpected serious risk of excessive drug toxicity from impaired hepatic function.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following trials:
`
`PMR 3291-2 Conduct a study to characterize the long-term safety of Calquence monotherapy.
`Submit interim and complete final reports showing long-term safety with a
`minimum of 24 months of follow-up from study ACE-LY-004 in patients with
`mantle cell lymphoma.
`
`
`
`Reference ID: 4174988
`
`

`

`NDA 210259
`Page 4
`
`
`The timetable you submitted on October 30, 2017, states that you will conduct this trial
`according to the following schedule:
`
`
`
`Trial Completion:
`Final Report Submission:
`
`02/2018
`12/2018
`
`
`PMR 3291-3 Conduct a clinical pharmacokinetic trial to determine an appropriate safe dose of
`acalabrutinib in patients with severe hepatic impairment. This trial should be
`designed and conducted in accordance with the FDA Guidance for Industry
`entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study
`Design, Data Analysis, and Impact on Dosing and Labeling.
`
`The timetable you submitted on October 30, 2017, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 06/2018
`Trial Completion:
`
`01/2020
`Final Report Submission:
`07/2020
`
`
`Submit clinical protocol(s) to your IND 118717 with a cross-reference letter to this NDA.
`Submit nonclinical and chemistry, manufacturing, and controls protocols and 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 post-marketing 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.
`
`
`Reference ID: 4174988
`
`

`

`NDA 210259
`Page 5
`
`
`PROMOTIONAL MATERIALS
`
`Under 21 CFR 314.550, you are required to submit, during the application pre-approval review
`period, all promotional materials, including promotional labeling and advertisements, that you
`intend to use in the first 120 days following marketing approval (i.e., your launch campaign). If
`you have not already met this requirement, you must immediately contact the Office of
`Prescription Drug Promotion (OPDP) at (301) 796-1200. Please ask to speak to a regulatory
`project manager or the appropriate reviewer to discuss this issue.
`
`As further required by 21 CFR 314.550, submit all promotional materials that you intend to use
`after the 120 days following marketing approval (i.e., your post-launch materials) at least 30
`days before the intended time of initial dissemination of labeling or initial publication of the
`advertisement. We ask that each submission include a detailed cover letter together with three
`copies each of the promotional materials, annotated references, and approved package insert
`(PI)/Medication Guide/patient PI (as applicable).
`
`Send each submission directly to:
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotions (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit promotional materials for accelerated approval products
`electronically in eCTD format. For more information about submitting promotional materials in
`eCTD format, see the draft Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with the 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.
`
`
`
`Reference ID: 4174988
`
`

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`NDA 210259
`Page 6
`
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`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval 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.
`
`If you have any questions, call Ashley Lucci Vaughn, Regulatory Project Manager, at
`(301) 796-5718.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Richard Pazdur, MD
`Director
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`Content of Labeling
`
`
`
`Reference ID: 4174988
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD PAZDUR
`10/31/2017
`
`Reference ID: 4174988
`
`