CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`
`214120Orig1s000
`
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`

`

`IND 074618
`
`
`
`MEETING MINUTES
`
`
`Celgene Corporation
`Attention: Mary Vandekauter, M.S., RAC
`Director, Regulatory Affairs
`9225 Indian Creek Parkway, Suite 900
`Overland Park, KS 66210
`
`
`Dear Ms. Vandekauter:
`
`Please refer to your investigational new drug application (IND) submitted under section
`505(i) of the Federal Food, Drug, and Cosmetic Act for azacytidine.
`
`We also refer to the meeting between representatives of your firm and the FDA on
`November 21, 2019. The purpose of the meeting was to discuss a proposed marketing
`application for oral azacitidine.
`
` A
`
` copy of the official minutes of the meeting/telecon is enclosed for your information.
`Please notify us of any significant differences in understanding regarding the meeting
`outcomes.
`
`If you have any questions, call Rachel McMullen, Senior Regulatory Project Manager at
`(240) 402-4574.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Donna Przepiorka, MD, PhD
`Clinical Team Lead
`Division of Hematologic Malignancies 1
`Office of Oncologic Diseases
`Center for Drug Evaluation and Research
`
`
`
`
`Enclosure:
`• Meeting Minutes
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`/ ... -... ,~ Iii
`
`U.S. FOOD & DRUG
`
`ADMINISTRATION
`
`f
`
`.,,,./_/-
`
`(b) (4)
`
`MEMORANDUM OF MEETING MINUTES
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-NOA
`
`Meeting Date and Time:
`Meeting Location:
`
`November 21 , 2019; 10:00 AM to 11 :00 AM (ET)
`10903 New Hampshire Avenue
`White Oak Building 22, Conference Room: 1419
`Silver Spring, Maryland 20903
`
`Application Number:
`Product Name:
`Indication:
`
`IND 074618
`Azacitidine
`
`Sponsor Name:
`
`Celgene Corporation
`
`Meeting Chair:
`Meeting Recorder:
`
`Donna Przepiorka, MD, PhD
`Suria Yesmin, MS
`
`FDA ATTENDEES
`Division of Hematological Malignancies CDHM1 l
`R. Angelo de Claro, MD, Director (Acting)
`Donna Przepiorka, MD, PhD, Clinical Team Leader
`Emily Jen, MD, PhD Clinical Reviewer
`Patricia Dinndorf, MD, Clinical Reviewer
`Suria Yesmin, MS, Senior Regulatory Project Manager
`
`Office of Biostatistics. Division of Biometrics V
`Yute Wu, PhD, Acting Biometrics Team Leader
`Qing Xu, PhD, Biometrics Reviewer
`
`Office of Clinical Pharmacology
`Olanrewaju Okusanya, Pharm D, Clinical Pharmacology Team Lead
`Vicky Hsu, Pharm D, Clinical Pharmacology Reviewer
`
`Office of Pharmaceutical Quality
`Anamitro Banerjee, PhD, Branch Chief
`
`SPONSOR ATTENDEES
`Celgene Corporation
`Jay Backstrom, MD, Chief Medical Officer
`Paul Mclnulty, BS Vice President, Regulatory Affairs
`Mary Vandekauter, MS, Director, Regulatory Affairs
`
`Reference ID: 461!!398J
`
`

`

`IND 074618
`Page 2
`
`Carrie Brownstein, MD, Vice President, Clinical R&D
`Charles Beach, PharmD, Executive Medical Director, Clinical R&D
`lgnazia La Torre, MD, Sr. Medical Director, Clinical R&D
`Keshava Kumar, PhD, Principal Clinical Research Scientist, Clinical R&D
`Qian Dong, PhD, Associate Director, Biostatistics
`Nanxiang Ge, PhD, Executive Director, Biostatisticas
`Allison Gaudy, PhD, Sr. Scientist, Pharmacokinetics
`Rochelle, Bailey, MD, Sr Director, Lead Global Safety Physician
`Christine Stuhlmiller, MBA, Sr Director, Global Project Leader
`Daniel Lopes de Menezes, PhD, Associate Director, Translational Development
`
`1.0 BACKGROUND
`
`CC-486, an oral formu lation of azacitidine, is being developed by Celgene Corporation,
`(b)(4~ The Sponsor is
`lanning to submit an
`the Sponsor, for treatment of AML
`4
`N DA for CC-486 in 1 Q 2020
`(bH
`1
`
`Aa vice on the con ent ana forma of ffie NOA was
`prov1 ea in ype C Written Responses issued on October 24, 2019.
`
`On September 27, 2019, the Sponsor requested a Type B meeting to obtain FDA's
`feedback on the adequacy of the results of Study CC-486-AML-001 to support
`submission of an NOA.
`
`FDA sent Preliminary Comments to Celgene on November 14, 2019.
`
`2.0
`
`DISCUSSION
`
`Question 1: Does the Agency agree that the efficacy results for the primary endpoint of
`OS in conjunction with the results of the key secondary endpoint of RFS demonstrate a
`statistically significant and meaningful clinical benefit of CC-486 in this patient
`population?
`
`FDA Response to Question 1: Your analysis demonstrates statistical significance
`according to the prespecified plan. Whether the efficacy results are clinically
`meaningful will be a review issue. We remind you that the data from CC-486-AML-001
`should be supported by data from treatment trials of AML (see response to Question 4,
`Type C WRO dated10/24/19).
`
`DISCUSSION: The Agency agreed that the Sponsor's plan to include three
`Phase 1 studies along with AZA-AML-001 in the SCE is acceptable. The
`Agency clarified that the ISE dataset should therefore include all 5 trials. The
`Agency also reminded the Sponsor that the maximum page limit of the Clinical
`Summary text (Modules 2.7.1 through 2.7.4) in total is 400 pages.
`
`Reference ID: 461!!398J
`
`

`

`IND 074618
`Page 3
`
`Question 2: Does the Agency agree that the safety profile of CC-486 observed in the
`ivotal Phase 3 study, Study CC-486-AML-001 is su ortive of an NDA for CC-486 ~i
`
`a) Does the Agency agree that the safety profile of CC-486 observed in the pivotal
`Phase 3 study, Study CC-486-AML-001 and consistent with the established safety
`profile for azacitidine is acceptable to enable filing of the proposed NOA?
`
`FDA Response to Question 2a: The safety data from CC-486-AML-001 alone are not
`sufficient for submission of an NOA; the submission should include safety data from
`other trials in your development program. See responses to Questions 5-8 in the Type
`C WRO dated 10/24/19. Whether the totality of the safety data is sufficient for filing the
`proposed NOA will be a review issue.
`
`DISCUSSION: There was no discussion.
`
`b) Despite relapse free survival being defined as the key secondary endpoint, per
`protocol, AML relapse and disease progression were reported as adverse events.
`Does the Agency agree with the Celgene proposal to present primary safety data
`for this study excluding AML relapse-associated events to allow for a more
`informative and clear interpretation of the safety profile of CC-486?
`
`FDA Response to Question 2b: We have no objection to your plan to exclude AML
`relapse/disease progression preferred terms as adverse events for the review of safety.
`In your submission, please provide a list of the preferred terms excluded from the
`analysis.
`
`DISCUSSION: There was no discussion.
`
`c) Does the Agency have any comments on the overall safety data package
`presented in this pre-NDA meeting package to support the review of the upcoming
`NOA?
`
`FDA Response to Question 2c: See response to 2a.
`
`DISCUSSION: There was no discussion.
`
`Question 3: Does the Agency agree that the efficacy and safety data from Study CC-
`486-AML-001, a Phase 3, Double-blind, Randomized, Placebo-Controlled Study to
`Compare the Efficacy and Safety of Oral Azacitidine (CC-486) Versus Placebo as
`Maintenance Therapy in Subjects with Acute Myeloid Leukemia are adequate for filing
`and review of the NDA for the proposed indication?
`
`Reference ID: 461!!398J
`
`

`

`IND 074618
`Page 4
`
`
`
`FDA Response to Question 3: See responses to Questions 1 and 2.
`
`DISCUSSION: There was no discussion.
`
`Question 4: Celgene has updated the statistical analysis plan for Study CC-486-AML-
`001 based on feedback from the Agency provided on 29 Mar 2019. The SAP was
`finalized on 25 Jul 2019 and submitted to IND 074618 on 31 Jul 2019 (SN0465) prior to
`database lock and unblinding. However, based on the information presented in this
`meeting package, does the Agency have any additional statistical comments?
`
`FDA Response to Question 4: Without reviewing the data from the pivotal study CC-
`486-AML-001, we are unable to provide comment on the reliability of the estimates from
`the current statistical analyses. Whether additional statistical analyses would be
`needed to confirm the robustness of the efficacy results will be a review issue.
`
`DISCUSSION: There was no discussion.
`
`Question 5:
`a) Based on the efficacy and safety data presented, does the Agency foresee a
`potential need for an advisory committee for the proposed indication?
`
`
`FDA Response to Question 5a: Whether an advisory committee meeting will be
`needed will be a review issue.
`
`DISCUSSION: There was no discussion.
`
`b) Does the Agency foresee requesting an Applicant Orientation Meeting for CC-486?
`
`
`FDA Response to Question 5b: Yes.
`
`DISCUSSION: There was no discussion.
`
`Question 6: Celgene does not plan to prepare a Risk Evaluation and Mitigation
`Strategy (REMS) for oral azacitidine. Based on the data presented, does the Agency
`foresee a potential need for a REMS for the proposed indication?
`
`FDA Response to Question 6: Whether a REMS will be needed will be a review issue.
`
`DISCUSSION: There was no discussion.
`
`Question 7: Based on the efficacy and safety data presented, does the Agency support
`the Sponsor’s intention to request a Priority Review for this application?
`
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`IND 074618
`Page 5
`
`
`FDA Response to Question 7: You may request Priority Review, but whether the
`application is suitable for Priority Review will be determined during the filing review.
`
`DISCUSSION: There was no discussion.
`
`Question 8: Does the Agency have any other comments or advice that may aid in the
`preparation and submission of the NDA?
`
`FDA Response to Question 8: Yes, we have the following additional comments:
`
`a. Include an Analysis Data Reviewer’s Guide (ADRG) and Study Data Reviewer’s
`Guide (SDRG), an important part of a standards-compliant study and analysis data
`submission, be prepared and submitted for each data set in the NDA. Please refer to
`the “Study Data Technical Conformance Guide: Technical Specifications Document,”
`available at: https://www.fda.gov/media/131872/download.
`
`b. Ensure that the define file and/or Reviewer's Guide for the Analysis Data Sets
`identify the coding dictionary and version for controlled terminology (e.g., MedDRA
`version, WHO Drug Dictionary version, etc.).
`
`c. Provide sufficient comments, adequate bookmarks, and hyperlinks in the define
`file(s) to ensure efficient review.
`
`d. Submit SAS programs for Study CC-486-AML-001 and ISE. The Sponsors should
`provide the SAS programs (with adequate comments) used to create all ADaM
`datasets along with the tables and figures associated with primary and secondary
`efficacy analyses in order to help reviewers to better understand how the datasets,
`tables and figures were created. The main purpose of requesting the submission of
`these programs is to understand the process by which the variables for the
`respective analyses were created and to confirm the analysis algorithms.
`
`DISCUSSION: The Agency agreed to the Sponsor's proposal to submit the
`efficacy SAS programs only for the pivotal trial.
`
`e. Provide documentation of any correspondence (written documents or meeting
`minutes) with FDA regarding pivotal study of CC-486-AML-001.
`
`
`f. Provide the information on the important dates during the development (i.e.,
`database lock date, interim analyses or interim locked dates for the DMC, SAP sign-
`off dates, protocol sign-off dates, etc).
`
`g. To assist with the adjudication of efficacy, ensure that all granular results of marrow
`and peripheral blood testing are included an xpt data file. Please also include in xpt
`data file(s) with listings of a flag for relapse, date of relapse, flag for HSCT after
`study enrollment, date of HSCT after study enrollment, date of at least the 1st
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`IND 074618
`Page 6
`
`
`
`poststudy therapy, identity of regimen name or drug(s) used for at least the 1st
`poststudy therapy, date of last CBC showing continuing remission, and date last
`known alive.
`
`h. Regarding the MRD assay used for CC-486-AML-001, please include the following
`in your submission:
`
`i. Justification that MRD cutpoint as used is clinically valid for the context of the use.
`
`ii. An xpt data file with results of MRD testing. For each result, specify the sample
`type, date of sample, assay used, input quantity, assay sensitivity, and assay
`result.
`iii. The following technical information about the assay:
`• A statement of intended use;
`• The specific test method (including instruments, reagents, and specimen
`handling);
`• Confirmation that the lab has a process in place for reagent control;
`• A brief discussion of how the test method was validated analytically for each
`specimen type; and
`• A summary of the performance obtained for accuracy, precision, specificity, and
`sensitivity
`
`
`
`DISCUSSION: The Sponsor noted that they intend to submit the requested
`information regarding MRD. They stated that additional information on the
`durability of MRD response may be available after the time of submission. The
`Agency agreed that it would be useful to receive updated MRD data when
`available.
`
`
`i. To assist with the adjudication of causality of fatal adverse events, the submission
`should include an xpt data file with the date of death, study day of death, proximate
`cause of death (usually as reported by the investigator) and the root cause of death
`as determined by the sponsor for patients in the ISS. The root cause is generally
`categorized as a) direct effect of active AML, b) an adverse drug reaction or c) an
`unrelated intercurrent event (such as car accident).
`
`DISCUSSION: The Sponsor proposed to submit cause of death only for
`patients in the maintenance pool. The Agency indicated that the data for
`adjudication of on-treatment deaths should include for all subjects in the ISS.
`
`
`j.
`
`In the ISS, please include an analysis to determine the incidence of prolonged
`thrombocytopenia (platelets < 50 Gi/L) or neutropenia (ANC < 0.5 Gi/L) past cycle
`day 42 of therapy in the absence of active leukemia.
`
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`IND 074618
`Page 7
`
`
`
`DISCUSSION: The Agency agreed that these analyses could be included for
`the AML maintenance pool only. The Agency will leave a postmeeting note
`regarding the proposed approach to these analyses.
`
`Postmeeting Note:
`Algorithm steps 1 and 2 are reasonable. In step 3, prolonged
`thrombocytopenia or neutropenia need not be defined from Day 28 onwards.
`The analysis should determine the incidence of each cytopenia lasting past
`Cycle Day 42 regardless of start date of the cytopenia.
`
`
`k. In your submission, please also address the standard clinical pharmacology pre-
`NDA comments and other requests/advice sent in the WRO on 10/24/19.
`
`
`ADDTITIONAL CMC DISCUSISON:
`
`The proposed plan as conveyed by the email dated November 19, 2019, appears
`reasonable. The Sponsor should point out any updates or amendments to the
`cross-reference information.
`
`
`3.0 OTHER IMPORTANT MEETING INFORMATION
`
`DISCUSSION OF THE CONTENT OF A COMPLETE APPLICATION
`
`
`• The content of a complete application was discussed.
`
`
`The contents were discussed. The Agency and Sponsor reached
`agreement on the content of a complete application.
`
` •
`
` •
`
` •
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
` All applications are expected to include a comprehensive and readily
`located list of all clinical sites and manufacturing facilities included or
`referenced in the application.
`
` A preliminary discussion was held on the need for a REMS, other risk
`management actions and, where applicable, the development of a Formal
`Communication Plan
`
`The Agency indicated that at the present time they were unaware of
`any safety issues that would require a REMS or special risk
`management action. The final determination will be a review issue.
`
` Major components of the application are expected to be submitted with the
`original application and are not subject to agreement for late submission.
`You stated you intend to submit a complete application and therefore, there
`are no agreements for late submission of application components.
`
`

`

`IND 074618
`Page 8
`
`
`
`In addition, we note the chemistry pre-submission meeting on October 17, 2018, and
`refer you to the minutes of that meeting for any additional agreements that may have
`been reached.
`
`PREA REQUIREMENTS
`
`Under the Pediatric Research Equity Act (PREA) (codified at section 505B of the
`Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 355c), all applications for
`new active ingredients (which includes new salts and new fixed combinations), new
`indications, new dosage forms, new dosing regimens, or new routes of administration
`are required to contain an assessment of the safety and effectiveness of the product for
`the claimed indication(s) in pediatric patients unless this requirement is waived or
`deferred (see section 505B(a)(1)(A) of the FD&C Act). Applications for drugs or
`biological products for which orphan designation has been granted that otherwise would
`be subject to the requirements of section 505B(a)(1)(A) are exempt pursuant to section
`505B(k)(1) from the PREA requirement to conduct pediatric assessments.
`
`Title V of the FDA Reauthorization Act of 2017 (FDARA) amended the statute to create
`section 505B(a)(1)(B), which requires that any original marketing application for certain
`adult oncology drugs (i.e., those intended for treatment of an adult cancer and with
`molecular targets that FDA has determined to be substantially relevant to the growth or
`progression of a pediatric cancer) that are submitted on or after August 18, 2020,
`contain reports of molecularly targeted pediatric cancer investigations. See link to list of
`relevant molecular targets below. These molecularly targeted pediatric cancer
`investigations must be “designed to yield clinically meaningful pediatric study data,
`gathered using appropriate formulations for each age group for which the study is
`required, regarding dosing, safety, and preliminary efficacy to inform potential pediatric
`labeling” (section 505B(a)(3)). Applications for drugs or biological products for which
`orphan designation has been granted and which are subject to the requirements of
`section 505B(a)(1)(B), however, will not be exempt from PREA (see section 505B(k)(2))
`and will be required to include plans to conduct the molecularly targeted pediatric
`investigations as required, unless such investigations are waived or deferred.
`
`Under section 505B(e)(2)(A)(i) of the FD&C Act, you must submit an Initial Pediatric
`Study Plan (iPSP) within 60 days of an End of Phase 2 (EOP2) meeting, or such other
`time as agreed upon with FDA. (In the absence of an EOP2 meeting, refer to the draft
`guidance below.) The iPSP must contain an outline of the pediatric assessment(s) or
`molecularly targeted pediatric cancer investigation(s) that you plan to conduct
`(including, to the extent practicable study objectives and design, age groups, relevant
`endpoints, and statistical approach); any request for a deferral, partial waiver, or waiver,
`if applicable, along with any supporting documentation; and any previously negotiated
`pediatric plans with other regulatory authorities. The iPSP should be submitted in PDF
`and Word format. Failure to include an Agreed iPSP with a marketing application could
`result in a refuse to file action.
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`IND 074618
`Page 9
`
`
`
`For additional guidance on the timing, content, and submission of the iPSP, including an
`iPSP Template, please refer to the draft guidance for industry Pediatric Study Plans:
`Content of and Process for Submitting Initial Pediatric Study Plans and Amended
`Pediatric Study Plans.
`
`For the latest version of the molecular target list, please refer to FDA.gov.1
`
`FDARA REQUIREMENTS
`
`Sponsors planning to submit original applications on or after August 18, 2020 or
`sponsors who are uncertain of their submission date may request a meeting with the
`Oncology Center of Excellence Pediatric Oncology Program to discuss preparation of
`the sponsor’s initial pediatric study plan (iPSP) for a drug/biologic that is intended to
`treat a serious or life-threatening disease/ condition which includes addressing the
`amendments to PREA (Sec. 505B of the FD &C Act) for early evaluation in the pediatric
`population of new drugs directed at a target that the FDA deems substantively relevant
`to the growth or progression of one or more types of cancer in children. The purpose of
`these meetings will be to discuss the Agency’s current thinking about the relevance of a
`specific target and the specific expectations for early assessment in the pediatric
`population unless substantive justification for a waiver or deferral can be provided.
`Meetings requests should be sent to the appropriate review division with the cover letter
`clearly stating “MEETING REQUEST FOR PREPARATION OF iPSP MEETING
`UNDER FDARA.” These meetings will be scheduled within 30 days of meeting request
`receipt. The Agency strongly advises the complete meeting package be submitted at
`the same time as the meeting request. Sponsors should consult FDA’s Guidance on
`Formal Meetings Between the FDA and Sponsors or Applicants2 to ensure open lines of
`dialogue before and during their drug development process.
`
`In addition, you may contact the OCE Subcommittee of PeRC Regulatory Project
`Manager by email at OCEPERC@fda.hhs.gov. For further guidance on pediatric
`product development, please refer to FDA.gov.3
`
`PRESCRIBING INFORMATION
`
`In your application, you must submit proposed prescribing information (PI) that
`conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and
`201.57 including the Pregnancy and Lactation Labeling Rule (PLLR) (for applications
`submitted on or after June 30, 2015). As you develop your proposed PI, we encourage
`you to review the labeling review resources on the PLR Requirements for Prescribing
`
`
`1 https://www.fda.gov/about-fda/oncology-center-excellence/pediatric-oncology
`2 See the guidance for industry “Formal Meetings Between the FDA and Sponsors or Applicants.”
`3 https://www.fda.gov/drugs/development-resources/pediatric-and-maternal-health-
`product-development
`
`
`
`
`
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`
`

`

`IND 074618
`Page 10
`
`
`Information4 and Pregnancy and Lactation Labeling Final Rule5 websites, which include:
`
`
`• The Final Rule (Physician Labeling Rule) on the content and format of the PI for
`human drug and biological products.
`
`• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and
`format of information related to pregnancy, lactation, and females and males of
`reproductive potential.
`
`• Regulations and related guidance documents.
`
`• A sample tool illustrating the format for Highlights and Contents, and
`
`• The Selected Requirements for Prescribing Information (SRPI) − a checklist of
`important format items from labeling regulations and guidances.
`
`• FDA’s established pharmacologic class (EPC) text phrases for inclusion in the
`Highlights Indications and Usage heading.
`
`Pursuant to the PLLR, you should include the following information with your application
`to support the changes in the Pregnancy, Lactation, and Females and Males of
`Reproductive Potential subsections of labeling. The application should include a review
`and summary of the available published literature regarding the drug’s use in pregnant
`and lactating women and the effects of the drug on male and female fertility (include
`search parameters and a copy of each reference publication), a cumulative review and
`summary of relevant cases reported in your pharmacovigilance database (from the time
`of product development to present), a summary of drug utilization rates amongst
`females of reproductive potential (e.g., aged 15 to 44 years) calculated cumulatively
`since initial approval, and an interim report of an ongoing pregnancy registry or a final
`report on a closed pregnancy registry. If you believe the information is not applicable,
`provide justification. Otherwise, this information should be located in Module 1. Refer to
`the draft guidance for industry Pregnancy, Lactation, and Reproductive Potential:
`Labeling for Human Prescription Drug and Biological Products – Content and Format.
`
`Prior to submission of your proposed PI, use the SRPI checklist to ensure conformance
`with the format items in regulations and guidances.
`
`After initiation of all trials planned for the phase 3 program, you should consider
`requesting a Type C meeting to gain agreement on the safety analysis strategy for the
`
`
`4 https://www.fda.gov/drugs/laws-acts-and-rules/plr-requirements-prescribing-
`information
`5 https://www.fda.gov/drugs/labeling/pregnancy-and-lactation-labeling-drugs-final-rule
`
`
`
`
`
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`
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`

`IND 074618
`Page 11
`
`
`Integrated Summary of Safety (ISS) and related data requirements. Topics of
`discussion at this meeting would include pooling strategy (i.e., specific studies to be
`pooled and analytic methodology intended to manage between-study design
`differences, if applicable), specific queries including use of specific standardized
`MedDRA queries (SMQs), and other important analyses intended to support safety. The
`meeting should be held after you have drafted an analytic plan for the ISS, and prior to
`programming work for pooled or other safety analyses planned for inclusion in the ISS.
`This meeting, if held, would precede the Pre-NDA meeting. Note that this meeting is
`optional; the issues can instead be addressed at the pre-NDA meeting.
`
`To optimize the output of this meeting, submit the following documents for review as
`part of the briefing package:
`• Description of all trials to be included in the ISS. Please provide a tabular listing
`of clinical trials including appropriate details.
`
`•
`
`ISS statistical analysis plan, including proposed pooling strategy, rationale for
`inclusion or exclusion of trials from the pooled population(s), and planned
`analytic strategies to manage differences in trial designs (e.g., in length,
`randomization ratio imbalances, study populations, etc.).
`
`• For a phase 3 program that includes trial(s) with multiple periods (e.g., double-
`blind randomized period, long-term extension period, etc.), submit planned
`criteria for analyses across the program for determination of start / end of trial
`period (i.e., method of assignment of study events to a specific study period).
`
`• Prioritized list of previously observed and anticipated safety issues to be
`evaluated, and planned analytic strategy including any SMQs, modifications to
`specific SMQs, or sponsor-created groupings of Preferred Terms. A rationale
`supporting any proposed modifications to an SMQ or sponsor-created groupings
`should be provided.
`
`When requesting this meeting, clearly mark your submission “DISCUSS SAFETY
`ANALYSIS STRATEGY FOR THE ISS” in large font, bolded type at the beginning of
`the cover letter for the Type C meeting request.
`
`SUBMISSION FORMAT REQUIREMENTS
`
`The Electronic Common Technical Document (eCTD) is CDER and CBER’s standard
`format for electronic regulatory submissions. The following submission types: NDA,
`ANDA, BLA, Master File (except Type III) and Commercial INDs must be submitted in
`eCTD format. Submissions that do not adhere to the requirements stated in the eCTD
`
`
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
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`

`IND 074618
`Page 12
`
`
`Guidance will be subject to rejection. For more information please visit FDA.gov.6
`
`The FDA Electronic Submissions Gateway (ESG) is the central transmission point for
`sending information electronically to the FDA and enables the secure submission of
`regulatory information for review. Submissions less than 10 GB must be submitted via
`the ESG. For submissions that are greater than 10 GB, refer to the FDA technical
`specification Specification for Transmitting Electronic Submissions using eCTD
`Specifications. For additional information, see FDA.gov.7
`
`OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS
`
`The Office of Scientific Investigations (OSI) requests that the items described in the
`draft guidance for industry Standardized Format for Electronic Submission of NDA and
`BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER
`Submissions (February 2018) and the associated Bioresearch Monitoring Technical
`Conformance Guide Containing Technical Specifications be provided to facilitate
`development of clinical investigator and sponsor/monitor/CRO inspection assignments,
`and the background packages that are sent with those assignments to the FDA ORA
`investigators who conduct those inspections. This information is requested for all major
`trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials).
`Please note that if the requested items are provided elsewhere in submission in the
`format described, the Applicant can describe location or provide a link to the requested
`information.
`
`Please refer to the draft guidance for industry Standardized Format for Electronic
`Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring
`(BIMO) Inspections for CDER Submissions (February 2018) and the associated
`Bioresearch Monitoring Technical Conformance Guide Containing Technical
`Specifications.8
`
`ISSUES REQUIRING FURTHER DISCUSSION
`4.0
`There were no issues requiring further discussion.
`
`5.0 ACTION ITEMS
`NA
`
`6.0 ATTACHMENTS AND HANDOUTS
`A copy of the Sponsor’s responses is attached for reference.
`
`
`
`
`6 http://www.fda.gov/ectd
`7 http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway
`8 https://www.fda.gov/media/85061/download
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`18 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/
`------------------------------------------------------------
`
`DONNA PRZEPIORKA
`11/25/2019 11:35:35 AM
`
`
`
`Reference ID: 4524903Reference ID: 4666382
`
`

`

`~siaVJc).
`
`( ~ FOODANDDRUGADMINISTRATION
`
`~ ~~ CENTER FOR DRUG EVALUATION AND RESEARCH
`"'.v~.fllydlO (J.
`
`MEMORANDUM OF MEETING MINUTES (Sponsor)
`
`Meeting Type:
`Meeting Category:
`
`Type B
`End of Phase 112
`
`Meeting Date and Time:
`Meeting Location:
`
`September 6, 2011 ; 1 :OOPM, EST
`Bldg. #22, Room 1415
`
`Application Number:
`Product Name:
`Indication:
`
`074618
`Oral Azacitidine
`
`(6)(4j
`
`Sponsor/Applicant Name: Celgene
`June 23, 2011
`Meeting Request Date:
`Meeting BGP date:
`August 9, 2011
`
`Meeting Chair:
`Meeting Recorder:
`
`Edvardas Kaminskas, M.D.
`Kim J. Robe1ison
`
`FDA ATTENDEES:
`Edvardas Kaminskas, M.D., Acting Deputy Director DHP
`Albe1i Deisseroth, M.D., Ph.D., Medical Officer, DHP
`Bahm Habtemariam, Phann.D., Reviewer, Office of Clinical Phannacology, DCP5
`Julie Bullock, Phann.D., Team Leader, Office of Clinical Phaimacology, DCP5
`Mai·k Rothmann, Ph.D., Statistical Team Leader, DBV
`Kyung Y. Lee, Ph.D., Statistical Reviewer, DBV
`Kim J. Robe1ison, Regulato1y Project Manager, DDOP
`
`SPONSOR ATTENDEES:
`Jay Backstrom, MD, MPH- Corporate Vice President, Clinical Reseai·ch and
`Development
`Benton Brown, MD - Senior Director, Drng Safety
`Adrienne Farid, PhD - Executive Director, Project Leadership
`Eric Laille, MS - Senior Scientist, Clinical Phaimacology
`Lela Lucy, MS - Principal Statistician, Biostatistics
`Paul Mclnulty - Director, Regulato1y Affairs
`Penny Ng, MSc, MBA, RAC - Senior Manager, Regulato1y Affairs
`Kaushik Datta, PhD, DABT - Senior Principal Scientist, Toxicology
`
`Reference ID: 3012462
`Reference ID 4666382
`
`

`

`Meeting Minutes OODP
`Type B, EOP 1/2
`
`
`
`
`
` DDOP
`September 6, 2011
`
`
`
`Barry Skikne, MD, FACP, FCP (SA) – Execu