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` DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` Food and Drug Administration
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` Silver Spring MD 20993
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`ACCELERATED APPROVAL
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` NDA 210259
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` Acerta Pharma B.V.
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` Attention: Yasameen Qazen, PharmD
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` Director, Regulatory Science
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` 2200 Bridge Parkway, Suite 101
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` Redwood City, CA 94065
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` Dear Dr. Qazen:
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` Please refer to your New Drug Application (NDA) dated June 13, 2017, received June 13, 2017,
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` and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic
` Act (FDCA) for Calquence® (acalabrutinib) capsule, 100 mg.
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` This new drug application provides for the use of Calquence® (acalabrutinib) capsule, 100 mg
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`for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least
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` one 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 under the
` provisions of accelerated approval regulations (21 CFR 314.500), effective on the date of this
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` letter, for use as recommended in the enclosed agreed-upon labeling text. Marketing of this drug
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`product and related activities must adhere to the substance and procedures of the referenced
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`accelerated approval regulations.
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` EXPIRATION DATING PERIOD
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`°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.
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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 content of
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` 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
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`of labeling must be identical to the enclosed labeling (text for the package insert and text for the
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`Reference ID: 4174988
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`(b)
`(4)
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`(b)
`(4)
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` NDA 210259
` Page 2
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` patient package insert). Information on submitting SPL files using eLIST may be found in the
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` guidance for industry titled “SPL Standard for Content of Labeling Technical Qs and As” at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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` CM072392.pdf.
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` The SPL will be accessible via publicly available labeling repositories.
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` CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the carton and immediate
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` container labels submitted on September 27, 2017, as soon as they are available, but no more
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` than 30 days after they are printed. Please submit these labels electronically according to the
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`guidance for industry titled Providing Regulatory Submissions in Electronic Format — Certain
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`Human Pharmaceutical Product Applications and Related Submissions Using the eCTD
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` Specifications (May 2015, Revision 3). For administrative purposes, designate this submission
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`“Final Printed Carton and Container Labels for approved NDA 210259.” Approval of this
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` submission by FDA is not required before the labeling is used.
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` ADVISORY COMMITTEE
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` Your application for acalabrutinib was not referred to an FDA advisory committee because the
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` application did not raise significant safety or efficacy issues in the intended population
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` ACCELERATED APPROVAL REQUIREMENTS
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` Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
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` 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-
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` marketing requirement specified in your submission dated October 30, 2017. This requirement,
` along with required completion dates, is listed below.
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`PMR 3291-1 Submit the complete final report and datasets demonstrating clinical efficacy and
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`safety from a randomized, double-blind, placebo-controlled, clinical trial of
`Calquence in combination with standard immunochemotherapy versus
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`immunochemotherapy alone in patients with mantle cell lymphoma.
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`Enrollment Completed Submission: 12/2020
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`10/2023
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` Trial Completion:
`11/2024
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` Final Report Submission:
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` Submit clinical protocols to your IND 118717 for this product. In addition, under
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` 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
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`Reference ID: 4174988
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` NDA 210259
` Page 3
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` summary completion and final report submission dates, any changes in plans since the last
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`annual report, and, for clinical studies/trials, number of patients entered into each study/trial.
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` Submit final reports to this NDA as a supplemental application. For administrative purposes, all
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`submissions relating to this post-marketing requirement must be clearly designated “Subpart H
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` Postmarketing Requirement(s).”
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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 new
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` 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
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` product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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` deferred, or inapplicable.
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` Because this drug product for this indication has an orphan drug designation, you are exempt
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` from this requirement.
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` POSTMARKETING REQUIREMENTS UNDER 505(o)
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` Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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` biological product applications to conduct post-marketing studies and clinical trials for certain
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` purposes, if FDA makes certain findings required by the statute.
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` We have determined that an analysis of spontaneous post-marketing adverse events reported
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`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
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` of tumor lysis syndrome, or 3) identify an unexpected serious risk of excessive drug toxicity
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` from impaired hepatic function.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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` 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 observational
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`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
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` unexpected serious risk of excessive drug toxicity from impaired hepatic function.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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` conduct the following trials:
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` 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
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`mantle cell lymphoma.
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`Reference ID: 4174988
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` NDA 210259
` Page 4
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`The timetable you submitted on October 30, 2017, states that you will conduct this trial
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` according to the following schedule:
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` Trial Completion:
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` Final Report Submission:
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`02/2018
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`12/2018
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`PMR 3291-3 Conduct a clinical pharmacokinetic trial to determine an appropriate safe dose of
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` acalabrutinib in patients with severe hepatic impairment. This trial should be
` designed and conducted in accordance with the FDA Guidance for Industry
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` entitled “Pharmacokinetics in Patients with Impaired Hepatic Function: Study
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` Design, Data Analysis, and Impact on Dosing and Labeling.
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`The timetable you submitted on October 30, 2017, states that you will conduct this trial
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` according to the following schedule:
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`Final Protocol Submission: 06/2018
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`01/2020
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` Trial Completion:
`07/2020
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` Final Report Submission:
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`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
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` 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
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` Protocol Under 505(o), Required Postmarketing Final Report Under 505(o), Required
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` 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 any
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` 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
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` 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
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` 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
`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 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
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` 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.
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`Reference ID: 4174988
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` NDA 210259
` Page 5
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` PROMOTIONAL MATERIALS
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` Under 21 CFR 314.550, you are required to submit, during the application pre-approval review
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`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
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` 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.
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` As further required by 21 CFR 314.550, submit all promotional materials that you intend to use
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` 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
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`copies each of the promotional materials, annotated references, and approved package insert
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`(PI)/Medication Guide/patient PI (as applicable).
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` Send each submission directly to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotions (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit promotional materials for accelerated approval products
`electronically in eCTD format. For more information about submitting promotional materials in
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` eCTD format, see the draft Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
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` CM443702.pdf ).
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` REPORTING REQUIREMENTS
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` We remind you that you must comply with the reporting requirements for an approved NDA
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` (21 CFR 314.80 and 314.81).
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` MEDWATCH-TO-MANUFACTURER PROGRAM
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` The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
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` 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
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`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.
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`Reference ID: 4174988
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` NDA 210259
` Page 6
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` POST APPROVAL FEEDBACK MEETING
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` New molecular entities and new biologics qualify for a post approval feedback meeting. Such
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` 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
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` 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
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` Manager for this application.
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` If you have any questions, call Ashley Lucci Vaughn, Regulatory Project Manager, at
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` (301) 796-5718.
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` Sincerely,
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` {See appended electronic signature page}
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` Richard Pazdur, MD
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` Director
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` Office of Hematology and Oncology Products
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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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`Reference ID: 4174988
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`RICHARD PAZDUR
`10/31/2017
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`Reference ID: 4174988
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