CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`
`214120Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`

`

`f;;!I U.S. FOOD & DRUG
`
`-
`
`ADM I N I STRATION
`
`Consult Memorandum
`
`
`Date:
`
`To:
`
`From:
`
`Through:
`
`Subject:
`
`Drug Name:
`
`Drug Sponsor
`
`
`Biomarker(s):
`
`Device Name:
`
`Device Sponsor:
`
`CDRH Tracking
`
`Number:
`
`Related
`
`Submissions:
`
`
`08/17/2020
`Emily Jen FDA/OC/CDER/OND/OOD/DHMI
`Jacqueline M Cleaiy CDRH/OPEQ/OHT7 /DIHD/IMFB
`Ying Katelin Mao (Branch chief) and Lea CaITington (Division Director)
`
`NDA 214120
`Azacitidine
`Celgene Corp
`
`Minimal Residual Disease (MRD)
`Laborato1y Developed Test
`
`(b)(.il}
`
`ICC2000416
`
`
`I. BACKGROUND and PURPOSE
`
`used to determine MRD.
`
`CDER requested CDRH to review the analytical validity of the assay
`
`The clinical trial (NCTOl 757535) was an international, multicenter, placebo-controlled, Phase 3 study
`with a double-blind, randomized, pai·allel-group design which evaluated the safety and efficacy of
`Azacitidine versus placebo as maintenance therapy in AML patients. Patients were em olled with de
`novo acute myelogenous leukemia {AML), AML secondaiy to prior diagnosis of myelodysplastic
`syndromes (MDS), or chronic myelomonocytic leukemia (CMML); the patients were aged 55 years or
`older, and had achieved first complete remission (CR) or complete remission with incomplete blood
`count recove1y (CRi) within 4 months+/- 7 days after intensive induction chemotherapy with or without
`consolidation therapy. The decision about induction and consolidation therapy regimens was an
`investigator choice prior to study emollment. Patients were not candidates for transplant at the time of
`randomization, which included patients who were not eligible for hematopoietic stem cell
`transplantation (HSCT), who did not have a transplant donor, or who chose not to proceed to HSCT.
`
`Patients who achieved a CR/CRi after completion of intensive induction therapy with or without
`consolidation were administered ONUREG 300 mg or placebo orally on Days 1 through 14 of each 28­
`day cycle. In the event of disease relapse (5% to 15% blasts in peripheral blood or bone maITow), the
`www.fda.gov
`
`Reference ID 4657779
`
`

`

`Interoffice Memorandum - (continued)
`
`Paee 2 of 6 paees
`
`dose schedule was extended to 21 days of repeated 28-day treatment cycles. Treatment continued until
`disease progression (more than 15% blasts were observed in peripheral blood or bone maITow) or until
`unacceptable toxicity.
`
`Specifically, the CDER seeks advice on:
`
`1. Please assess the analytical validity of the assay used to assess MRD in CC-486-AML-001. The
`(6) (4)
`document provided for review of the device is Module 5.3.1.4
`
`II. BIOMARKER/ANALYTE
`
`(6) (4)
`
`III.DEVICE USE IN THE TRIAL
`The assa applied for the anal ses has been desi ned
`
`(6)(41
`
`3 Pages have been Withheld in Full as B4 (CClffS) immediately following this page
`
`NDA214120_1CC2000416.ConsultMemo.Final.08172020.docx
`
`Reference ID 4657779
`
`

`

`Interoffice Memorandum - (continued)
`
`Paee 6 of 6 paees
`
`(b)(.il}
`
`VII. Final Recommendation from CDRH to CDER:
`
`We think it is important to note
`
`(b) (4)
`
`have been made to the original assay that was validated
`-----~--.,-~~~-----~~-.,---.,,----
`The cunent version of the assay used in the clinical trial has not been
`analytically validated. CDRH recommends that the sponsor provide the analytical validation
`perfonnance data to supp()rt the analytical validity of a reliable result being obtained
`CbJ<4J
`Cb><4l £ h MRD
`f
`.
`.
`.
`. h AML .
`.
`.---­
`or t e
`measurement m patients wit
`m rem1ss1on as paii o
`the AML 001 study.
`
`(b}(.ill
`
`Man modifications
`
`NDA214120_1CC2000416.ConsultMemo.Final.08172020.docx
`
`Reference ID 4657779
`
`

`

`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/
`------------------------------------------------------------
`
`RACHEL S MCMULLEN
`08/17/2020 04:50:39 PM
`
`Reference ID: 4657779
`
`

`

`DEPARTMENT OFHFALlH ANDIRJMAN SERVICES
`
`Center for Drug E"'llluation and Research
`Food and Drug Achninistration
`Silver Spring, MD, 20993
`
`CLINICAL OUTCOME ASSESSMENT (COA) REvlEW MEMORANDUM
`
`RE:
`
`NDA214120
`
`FROM:
`
`Julia Ju, PhannD., PhD.
`
`Clinical Outcome Assessment (COA) Reviewer
`
`Division of Clinical Outcome Assessment (DCOA)
`
`
`Elektra Papadopoulos, MD. MPH.
`
`Acting Division Director
`
`DCOA
`
`
`SUBJECT: Division of Hematologic Malignancies I consult to DCOA requesting review of
`the FACIT-Fatigue scale used in trial CC-486-AML-001
`
`DRUG SPONSOR: Celgene
`
`COA TRACKING NUMBER:
`
`C2020149
`
`Please check all that apply:
`
`D Rare Disease/Orphan Designation
`D Pediatric
`
`We are closing this consult request with this review !llemo since the review division and
`4
`sponsor have both agreed
`l for the FACIT-F and there was also no
`Cb><
`validity or reliability infonnation to review in the submission. The clinical outcome
`assessment (COA) consult request was filed in DARRTS by Division of Hematologic
`Malignancies 1 (DHMI) on April 10 2020 (DARRTS Reference ID: 4591366) for NDA ,
`. 'din
`214120 re ardin azacrt1
`(b)(4)
`e
`
`COA Tracking Number: C2020149
`
`Reference ID 4657616
`
`

`

`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/
`------------------------------------------------------------
`
`JING JU
`08/17/2020 02:16:02 PM
`
`ELEKTRA J PAPADOPOULOS
`08/17/2020 02:25:37 PM
`
`Reference ID: 4657616
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
`Date of This Memorandum:
`August 14, 2020
`Requesting Office or Division:
`Division of Hematologic Malignancies 1 (DHM 1)
`Application Type and Number: NDA 214120
`Product Name and Strength:
`Onureg (azacitidine) Tablets, 200 mg, 300 mg
`Applicant/Sponsor Name:
`Celgene Corporation, a wholly owned subsidiary of Bristol-
`Myers Squibb (Celgene)
`2020-419-2
`Nicole Iverson, PharmD, BCPS
`Hina Mehta, PharmD
`
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised container labels received on August 12, 2020 for Onureg. We
`review the revised container labels for Onureg (Appendix A) to determine if they are acceptable
`from a medication error perspective. The revisions are in response to recommendations that
`we made during a previous label and labeling review.a The revisions are also in response to the
`proprietary name request decision letter stating that the proprietary name, Onureg is
`conditionally acceptable.
`
`
`
`
`
` CONCLUSION
`2
`The Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Iverson N. Label and Labeling Review for Onureg (NDA 214120). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US);
`2020 JUN 29. RCM No.: 2020-419-2.
`
`1
`
`Reference ID: 4657047
`
`(b) (4)
`
`

`

`APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON AUGUST 12, 2020
`Container labels
`
`(b)(4l
`
`Reference ID 4657047
`
`
`2
`
`
`

`

`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/
`------------------------------------------------------------
`
`NICOLE F IVERSON
`08/14/2020 04:01:42 PM
`
`HINA S MEHTA
`08/17/2020 11:15:54 AM
`
`Reference ID: 4657047
`
`

`

` Department of Health and Human Services
`
`
`Public Health Service
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Medical Policy
`
`
`
`
`PATIENT LABELING REVIEW
`
`
`
`August 3, 2020
`
`Rachel McMullen, MPH, MHA
`
`Senior Regulatory Project Manager
`
`Division of Hematologic Malignancies I (DHM1)
`
`
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`
`
`Division of Medical Policy Programs (DMPP)
`
`
`Sharon R. Mills, BSN, RN, CCRP
`Senior Patient Labeling Reviewer
`
`Division of Medical Policy Programs (DMPP)
`
`
`Susan Redwood, MPH, BSN, RN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`
`Rachel Conklin, MS, RN
`Regulatory Review Officer
`
`
`Office of Prescription Drug Promotion (OPDP)
`
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`Date:
`
`To:
`
`Through:
`
`From:
`
`Subject:
`
`Drug Name (established TRADENAME (azacitidine)
`name):
`Dosage Form and
`
`Route:
`Application
`Type/Number:
`Applicant:
`
`tablets, for oral use
`
`NDA 214120
`
`Celgene Corporation
`
`Reference ID: 4650937
`
`

`

`1
`
`INTRODUCTION
`On March 3, 2020, Celgene Corporation submitted for the Agency's review an
`original New Drng Application (NDA) 214120 for TRADENAME azaciditine ...
`4
`tablets. The proposed indication for TRADENAME (azaciditine) is
`(bH
`l
`
`This collaborative review is written by the Division of Medical Policy Programs
`(DMPP) and the Office of Prescription Drng Promotion (OPDP) in response to a
`request by the Division of Hematologic Malignancies I (DHMl) on April 14, 2020,
`for DMPP and OPDP to review the Applicant's proposed Patient Package Inse1i
`(PPI) for TRADENAME (azaciditine) tablets.
`
`2 MATERIAL REVIEWED
`
`• Draft TRADENAME (azaciditine) tablets PPI received on March 4, 2020,
`revised by the Review Division throughout the review cycle, and received by
`DMPP and OPDP on July 28, 2020.
`
`• Draft TRADENAME (azaciditine) tablets Prescribing Info1mation (Pl) received
`on March 3, 2020, revised by the Review Division throughout the review cycle,
`and received by DMPP and OPDP on July 28, 2020.
`
`3 REVIEW METHODS
`
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% coITesponds to an 8th grade reading level.
`
`Additionally, in 2008 the American Society of Consultant Phaimacists Foundation
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Presa;ption Labeling and Consumer Medication
`Information for People with Vision Loss. The ASCP and AFB recommended using
`fonts such as Verdana, Arial or APHont to make medical info1mation more
`accessible for patients with vision loss. We refo1matted the PPI document using the
`Arial font, size 10.
`
`In our collaborative review of the PPI we:
`
`•
`
`•
`
`•
`
`•
`
`simplified wording and clarified concepts where possible
`
`ensured that the PPI is consistent with the Prescribing Info1mation (Pl)
`
`removed unnecessa1y or redundant info1mation
`
`ensured that the PPI is free of promotional language or suggested revisions to
`ensure that it is free of promotional language
`
`Reference ID 4650937
`
`

`

`x
`
` ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`
`
` Useful Written Consumer Medication Information (published July 2006)
`
`4 CONCLUSIONS
`
` The PPI is acceptable with our recommended changes.
`
`5 RECOMMENDATIONS
`Please send these comments to the Applicant and copy DMPP and OPDP on the
`x
`correspondence.
`x Our collaborative review of the PPI is appended to this memorandum. Consult
`DMPP and OPDP regarding any additional revisions made to the PI to
`
`
`
`determine if corresponding revisions need to be made to the PPI.
`Please let us know if you have any questions.
`
`Reference ID: 4650937
`
`5 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`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/
`------------------------------------------------------------
`
`SUSAN W REDWOOD
`08/03/2020 02:32:24 PM
`
`RACHAEL E CONKLIN
`08/03/2020 03:05:10 PM
`
`SHARON R MILLS
`08/03/2020 03:14:23 PM
`
`LASHAWN M GRIFFITHS
`08/03/2020 03:35:29 PM
`
`Reference ID: 4650937
`
`

`

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`
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`
`Reference ID: 4649583
`
`
`
`
`

`

`Section
`
`6.1 Clinical Trials
`Experience
`
`Statement from Draft
`(if applicable)
`
`OPDP Comment
`
`14 CLINICAL
`STUDIES
`
`14 CLINCIAL
`STUDIES
`
`"A subgroup analysis
`showed consistency in
`the OS benefit for
`patients in either CR or
`CRi."
`
`(b)(~l
`
`Is it standard to include
`OPDP is concerned that inclusion
`(b) (4J
`
`(b)(~l
`
`and we
`suggest considering deletion of this information.
`
`--~~~---..,~-....,..-~--~......,...~-~~....,.-,.-;
`
`However, we defer to the review team as to whether
`this information is considered informative for
`prescribers and should be retained.
`OPDP would like to confirm that the study was
`adequately powered to show consistency of effect in
`these subgroups.
`
`(b)(4)
`
`We defer to the review division regarding the
`appropriateness of inclusion of this information in the
`labeling.
`
`25 Pages n.ave oeen WillilielCi in Full as B4 (CCUTS) immeiliately following lliis page
`
`Reference ID 4649583
`
`2
`
`

`

`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/
`------------------------------------------------------------
`
`RACHAEL E CONKLIN
`07/30/2020 04:23:13 PM
`
`Reference ID: 4649583
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
`Date of This Memorandum:
`June 29, 2020
`Requesting Office or Division:
`Division of Hematologic Malignancies 1 (DHM 1)
`Application Type and Number: NDA 214120
`Product Name and Strength:
`azacitidine* Tablets, 200 mg, 300 mg
`Applicant/Sponsor Name:
`Celgene Corporation, a wholly owned subsidiary of Bristol-
`Myers Squibb (Celgene)
`2020-419-1
`Nicole Iverson, PharmD, BCPS
`Hina Mehta, PharmD
`
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`
`1
`The Applicant submitted revised container labels,
`
`received on June 15, 2020 for azacitidine. We reviewed the revised container labels,
`
` for azacitidine (Appendix A) to determine if they are
`
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a In addition, we
`
`note the Applicant
`
`
`
`
`
`
`
` CONCLUSION
`
`2
`The revised container labels,
`a medication error perspective. We acknowledge revisions
`
`are unacceptable from
`
`
`
`
`
`* The proposed proprietary name, Onureg was withdrawn by the Applicant and the proposed proprietary name
`
`submission is currently under review.
`
`a Iverson N. Label and Labeling Review for azacitidine (NDA 214120). Silver Spring (MD): FDA, CDER, OSE, DMEPA
`
`(US); 2020 May 27. RCM No.: 2020-419.
`
`
`1
`
`Reference ID: 4633227
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

` We note the
` which is inconsistent with current
`labels and labeling contain the word,
`terminology recommended in labeling for hazardous drugs. We also note
`
`
`
`
`3 RECOMMENDATIONS FOR CELGENE CORPORATION, A WHOLLY OWNED SUBSIDIARY OF
`BRISTOL-MYERS SQUIBB (CELGENE)
`We recommend the following be implemented prior to approval of this NDA:
`A. General Comments (Container Labels & Carton Labeling)
`1. We acknowledge that you have reviewed approved product labeling. However,
` to “hazardous” on the labels and
`we recommend revising the word,
`labeling to reflect alignment with current terminology recommended in labeling
`
`to “CAUTION:
`for hazardous drug. Revise
`
`Hazardous Agent”.
`B. Container labels
`1. We note revisions to the product codes in the National Drug Code (NDC) number
`
`
`C.
`
`1.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4633227
`
`2
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`APPENDIX A. IMAGES OF LABEL AND LABELING RECEIVED ON JUNE 15, 2020
`Container labels
`
`(6)(4j
`
`4 Pages have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`Reference ID 4633227
`
`
`3
`
`
`

`

`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/
`------------------------------------------------------------
`
`NICOLE F IVERSON
`06/29/2020 03:22:10 PM
`
`HINA S MEHTA
`06/30/2020 01:14:34 PM
`
`Reference ID: 4633227
`
`

`

`Clinical Inspection Summary
`NDA 214120 (azacitidine)
`
`CLINICAL INSPECTION SUMMARY
`
`Date
`From
`
`To
`
`NDA
`Applicant
`Drue
`NME
`
`Division Classification
`
`Proposed Indication
`
`June 30, 2020
`Anthony Orencia M.D., F.A.C.P., Medical Officer
`Min Lu, M.D., M.P.H., Team Leader
`Kassa Ayalew, M.D., M.P.H., Branch Chief
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
`Office of Scientific Investigations
`Emily Jen, M.D., Medical Officer
`Donna Przepiorka, M.D., Ph.D., Clinical Team Leader (Acting)
`R. Angelo de Claro, M.D., Director
`Rachel McMullen, MPH, MHA, Regulato1y Project Manager
`Division of Hematolo!ZV Mali!Illancv 1 (DHMI/OOD)
`214120
`Celgene Corporation
`Onureg™ (azacitidine)
`No (505b2)
`Cytotoxic cytosine nucleoside analogue, via induction of
`antineoplastic activi!Y
`
`(b)(4J­
`
`Consultation Request Date
`Summary Goal Date
`Action Goal Date
`PDUFADate
`
`I
`March 16, 2020 (Priority Review)
`July 6, 2020
`September 3, 2020
`September 3, 2020
`
`I. OVERALL ASSESSMENT OF FINDINGS AND REC01\1MENDATIONS
`The sponsor, Celgene Corporation, was inspected in suppo1i ofNDA 214120. The sponsor
`appeared to maintain adequate oversight of the clinical trials. Based on the results of the
`inspection, Study CC-486-AML-001 appears to have adequate oversight by the sponsor.
`An inspection assignment was issued and plans to conduct these GCP inspections were
`scheduled by the Office ofRegulato1y Affairs (ORA). The COVID-19 global pandemic has
`significantly limited our ability to conduct on-site GCP inspections. As a result, inspections of
`Andrew Wei, M.D. (Australia Site 500) and Christopher Pocock, M.D. (UK Site 902) were not
`conducted. Remote data investigation ofsource records from Drs. Wei and Pocock by ORA was
`not feasible due to local restriction, to obtain remote access at source records. Therefore, OSI is
`unable to determine if Study CC-486-AML-001 at both Dr. Andrew Wei and Dr. Christopher
`Pocock sites was conducted adequately, and whether the study data from those sites are reliable
`in suppo1i of the proposed indication.
`
`Reference ID 4633602
`
`

`

`Page 2 Clinical Inspection Summary NDA 214 120 (azacitidine)
`
`II.
`
`BACKGROUND
`
`Azacitidine (5-azacytidine, CC-486), primarily excreted by the kidneys, is a chemical analogue of the
`cytosine nucleoside used in DNA and RNA. Azacitidine may induce antineoplastic activity by
`inhibition of DNA methyltransferase at low doses and cytotoxicity through incorporation into RNA
`and DNA at high doses.
`
`A single study, Study CC-486-AML-001, will fo1m the basis for the regulato1y decision-making
`process for this application.
`
`Study CC-486-AML-001
`Study CC-486-AML-001 was a multicenter, placebo-controlled, Phase 3 study with a double-blind,
`randomized, parallel-group design in subjects with de novo AML or AML secondaiy to prior
`diagnosis of myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). The
`study consisted of 3 phases: the Pre-randomization Phase (Screening Phase), the Treatment Phase, and
`the Follow-up Phase. The study was am ended to include an Extension Phase (EP).
`
`Best suppo1i ive care may have been used in combination with study treatment as deemed necessaiy in
`both treatment groups. These supportive treatments may have included the following: red blood cell
`(RBC) and platelet transfusions, use of e1ythropoiesis stimulating agents (ESAs), antibiotic, antiviral,
`and antifungal therapy, nutritional suppo1i, and granulocyte colony stimulating factors (G-CSFs) for
`subjects experiencing neutropenic infections.
`
`The prima1y study objective was to evaluate whether maintenance therapy with CC-486 improved
`overall survival (OS) compared with placebo in subjects with acute myeloid leukemia (AML), over 55
`years of age, who had achieved first complete remission (CR) or complete remission with incomplete
`blood count recove1y (CRi) after induction with intensive chemotherapy with or without consolidation
`chemotherapy.
`
`The prima1y efficacy endpoint was overall survival. This endpoint was defined as time from
`randomization to death from any cause.
`
`Study CC-486-AML-001 was conducted at 147 investigational sites in Europe, No1i h America, Asia,
`and South America. The first subject first visit date was May 10, 2013. The data cutoff date was July
`15, 2019.
`
`Reference ID 4633602
`
`

`

`
`
` Page 3 Clinical Inspection Summary NDA 214120 (azacitidine)
`
`Of the 555 study patients screened, a total of 472 subjects were randomized to treatment. There were
`238 subjects randomized in the CC-486 group and 234 study patients in the placebo group.
`
`Compared to placebo, randomized patients on azacitidine (CC-486) most frequently reported the
`following treatment-emergent adverse events: nausea, vomiting, diarrhea, neutropenia, constipation,
`thrombocytopenia, and fatigue.
`
`The most frequently reported serious adverse events for azacytidine (CC-486) relative to placebo were
`febrile neutropenia, pneumonia, sepsis, and fever.
`
`III. RESULTS
`
`Celgene Corporation [Sponsor]
`86 Morris Avenue
`
`Summit, NJ 07901
`
`
`Inspection dates: May 26 to June 3, 2020
`
`This inspection evaluated compliance with the sponsor’s responsibilities concerning the conduct
`of Study CC-486-AML-001 which had 472 enrolled study subjects.
`
`The inspection included review of organizational charts, vendor oversight, transfer of
`obligations, investigator agreements, financial disclosures, monitoring plans, monitoring reports,
`monitor qualifications, safety reports, adverse events, protocol deviations, and standard operating
`procedures. Monitoring files for the following study sites were evaluated and found to be
`adequate: 401, 902, 972, 252, 530, 652, 860, and 500. Monitoring was conducted frequently,
`and 100% source data verification was performed. Underreporting of significant adverse events
`to the Agency was not found in this sponsor audit. A noncompliant site, Site 401 (e.g., delay in
`timely sign offs of laboratory documents), was eventually brought into compliance.
`
`A Form FDA 483 was not issued at the end of the study inspection. In general, the sponsor
`appeared to be in compliance with Good Clinical Practice. Clinical trial oversight and monitoring
`by the sponsor appeared to be adequate.
`
`{See appended electronic signature page}
`Anthony Orencia, M.D.
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
`Office of Scientific Investigations
`
`Reference ID: 4633602
`
`

`

`
`
` Page 4 Clinical Inspection Summary NDA 214120 (azacitidine)
`
`CONCURRENCE:
`
`CONCURRENCE:
`
`{See appended electronic signature page}
`Min Lu, M.D., M.P.H.
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
` Office of Scientific Investigations
`
`{See appended electronic signature page}
`Kassa Ayalew, M.D., M.P.H.
`Branch Chief
`Good Clinical Practice Assessment Branch
`Division of Clinical Compliance Evaluation
` Office of Scientific Investigations
`
`Reference ID: 4633602
`
`

`

`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/
`------------------------------------------------------------
`
`ANTHONY J ORENCIA
`06/30/2020 01:00:35 PM
`
`MIN LU
`06/30/2020 01:02:35 PM
`
`KASSA AYALEW
`06/30/2020 01:06:01 PM
`
`Reference ID: 4633602
`
`

`

`LABEL AND LABELING REVIEW
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
`*** This document contains proprietary information that cannot be released to the public***
`
`Date of This Review:
`May 27, 2020
`Requesting Office or Division:
`Division of Hematologic Malignancies 1 (DHM 1)
`Application Type and Number: NDA 214120
`Product Name, Dosage Form,
`azacitidine* Tablets, 200 mg, 300 mg
`and Strength:
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`
`Single Ingredient Product
`Prescription (Rx)
`Celgene Corporation, a wholly owned subsidiary of Bristol-
`Myers Squibb (Celgene)
`March 3, 2020, March 20, 2020, and May 14, 2020
`2020-419
`Nicole Iverson, PharmD, BCPS
`Hina Mehta, PharmD
`
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`* The proposed proprietary name, Onureg was withdrawn by the Applicant and the proposed proprietary name
`submission is currently under review.
`
`1
`
`Reference ID: 4615192
`
`

`

`1 REASON FOR REVIEW
`As part of the approval process for NDA 214120 azacitidine tablets this review evaluates the
`proposed container label,
`Prescribing Information (PI)
`and Patient Information for areas that may lead to medication errors.
`
`2 MATERIALS REVIEWED
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`Table 1. Materials Considered for this Review
`Material Reviewed
`
`Product Information/Prescribing Information
`Previous DMEPA Reviews
`Human Factors Study
`ISMP Newsletters*
`FDA Adverse Event Reporting System (FAERS)*
`Other
`Labels and Labeling
`N/A=not applicable for this review
`
`*We do not typically search FAERS or ISMP Newsletters for our label and labeling reviews
`
`unless we are aware of medication errors through our routine postmarket safety surveillance
`
`
`Appendix Section
`(for Methods and Results)
`A
`B
`C- N/A
`D – N/A
`E – N/A
`F- N/A
`G
`
`3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED
`Celgene submitted a 505(b)(1) application to obtain marketing approval of azacitidine tablets.
`
`Azacitidine is proposed
`
`
`
`
`
`
`
`
`We performed a risk assessment of the proposed container labels,
`
` Prescribing Information (PI) and Patient Information for azacitidine tablets
`to determine whether there are significant concerns in terms of safety related to preventable
`
`medication errors. We note
`
`
`
`
`
`2
`
`
`Reference ID: 4615192
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`We identified areas of the proposed labels and labeling that could be revised to improve clarity
`and readability of important information. For the Division, we note that the PI and Patient
`Information lacks clarity on the recommended dosage, administration, and storage instructions.
`We also noted the use of sequential product codes in the National Drug Code (NDC) numbers.
`For the Applicant, we note the labels and labeling lack clarity in the package type, dosage form,
`product codes in the NDC numbers, strength, and special handling precautions. We also note
`lack of clarity of the administration instructions, a graphic in front of the proprietary name,
`prominence of the Rx only statement, and inconsistency in the terminology used for the
`recommended dosage. These factors may confuse the user and inadvertently lead to
`medication errors. We provide recommendations for the Division in Section 4.1 and the
`Applicant in Section 4.2 to address these deficiencies.
`
`CONCLUSION & RECOMMENDATIONS
`4
`We have identified areas in the proposed PI that can be improved to increase readability and
`prominence of important information and promote the safe use of the product. We provide
`recommendations in Section 4.1 for the Division and Section 4.2 for Celgene to address our
`concerns.
`
`4.1 RECOMMENDATIONS FOR DIVISION OF HEMATOLOGIC MALIGNANCIES 1 (DHM 1)
`A. Highlights of Prescribing Information
`
`a McMullen R. FDA Communication: Information Request for Azacitidine (NDA 214120). Silver Spring (MD): FDA,
`CDER, OOD, DHM1 (US); 2020 MAY 05. \\cdsesub1\evsprod\nda214120\0008\m1\us\resp-to-fda-req-dated-
`05may2020.pdf
`
`3
`
`
`Reference ID: 4615192
`
`(b) (4)
`
`

`

`1. We note your submission received April 30, 2020 requesting a withdrawal for the
`proposed proprietary name “Onureg”. Replace the proprietary name “Onureg”
`in the Prescribing Information with “Tradename” as a placeholder until a
`proprietary name is found conditionally acceptable.
`2. Revise the statement,
`
`
`to
`
`“Recommended dosage: 300 mg taken orally once daily on Days 1 to14 of
`each28-day cycles.”
`3. ONUREG should not be split or cut. To prevent administration errors, consider
`including the statement, “Swallow tablets whole. Do not cut, crush, or chew the
`tablets.”
`B. Prescribing Information
`1. Dosage and Administration Section
`a. Section 2.1 Recommended Dosage
`i. Revise the statement,
`
`
`
`
`
`to “The recommended
` dosage of ONUREG is 300 mg orally once daily on Days 1 to 14 of
`
`each 28-day cycles.”
`b. Section 2.2 Administration
`i. Onureg should not be split or cut and the statement lacks clarity.
`
`To prevent administration errors, revise the statement,
`
` to “Swallow tablets whole. Do
`not cut, crush, or chew the tablets.”
`It is not clear within how many hours after a dose is missed that a
`patient can still take the dose. It is recommended to clarify this
`instruction to avoid potential overdoses.
`iii. Since this statement is in the Prescribing Information,
`
`ii.
`
`
`
`
` it would be important to indicate if Onureg
`can be substituted for other Azacitidine products to help mitigate
`
`
`
`
`
`4
`
`
`Reference ID: 4615192
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` the risk of substitution errors. Thus, we recommend including a
`statement to indicate if Onureg is substitutable.
`iv. ONUREG is a hazardous