CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`204553Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`IND 064892
`
`
`
`MEETING MINUTES
`
`
`Janssen Research & Development, LLC
`Attention: Huy Q. Truong, MS
`Associate Director, Global Regulatory Affairs
`920 U.S. Highway 202 South, PO Box 300
`Raritan, NJ 08869
`
`
`Dear Mr. Truong:1
`
`Please refer to your investigational new drug application (IND) submitted under section
`505(i) of the Federal Food, Drug, and Cosmetic Act for rivaroxaban.
`
`We also refer to the meeting between representatives of your firm and the FDA on August
`6, 2019. The purpose of the meeting was to discuss the planned New Drug Application
`submission for two proposed pediatric indications supported by the development program
`in the treatment and thromboprophylaxis of venous thromboembolism (VTE) and discuss
`the new pediatric formulation (granule for oral suspension).
`
` A
`
` copy of the official minutes of the meeting is enclosed for your information. Please
`notify us of any significant differences in understanding regarding the meeting
`outcomes.
`
`If you have any questions, contact Katie Chon, Regulatory Project Manager, at
`katie.chon@fda.hhs.gov or (240) 402-6578.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Tanya M. Wroblewski, MD
`Clinical Team Leader
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`• Meeting Minutes
`
`
`1 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`
`
`

`

`
`
`
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`B
`Pre-NDA
`
` IND 064892
` Rivaroxaban tablets
` Xarelto is indicated for the treatment of venous
`thromboembolism (VTE) and the reduction in the risk of
`recurrent VTE in children from birth to < 18 years of age
`following initiation of standard anticoagulation treatment.
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time: August 6, 2019 10:00 AM – 11:00 AM EST
`Meeting Location:
`10903 New Hampshire Avenue
`
`White Oak Building 22, Conference Room: 1315
`
`Silver Spring, Maryland 20903
`
`Application Number:
`Product Name:
`
`Indication:
`
` Xarelto is indicated for the thromboprophylaxis in children 2
`years to 8 years of age with congenital heart disease (CHD)
`who have undergone Fontan procedure.
` Janssen Research & Development, LLC (Janssen or JRD)
`
`Tanya Wroblewski, MD
`Katie Chon, PharmD, RPh
`
`Sponsor Name:
`
`Meeting Chair:
`Meeting Recorder:
`
`FDA ATTENDEES
`Office of Hematology and Oncology Products (OHOP)/Division of Hematology
`Products (DHP)
`Ann Farrell, MD, Director
`Tanya Wroblewski, MD, Clinical Team Leader
`Laurel Menapace, MD, Medical Officer
`Lori Ehrlich, MD, Medical Officer
`Katie Chon, PharmD, RPh, Regulatory Project Manager
`
`Office of Biostatistics/Division of Biometrics V
`Alexei Ionan, PhD, Statistical Reviewer
`
`Office of Clinical Pharmacology(OCP)/Division of Clinical Pharmacology I
`Venkateswaran Chithambaram-Pillai, PhD, Clinical Pharmacologist
`
`OCP/Division of Applied Regulatory Science
`Jeffry Florian, PhD, General Health Scientist
`
`
`
`
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 2
`
`
`OCP/Division of Pharmacometrics
`Xinyuan Zhang, PhD, Pharmacology reviewer
`
`Office of Pharmaceutical Quality
`Ramesh Raghavachari, PhD, Team Leader
`Sherita McLamore, PhD, Team Leader
`Emily Wu PhD, Product Quality Reviewer
`
`Office of Surveillance and Epidemiology/Division of Medication Error Prevention
`and Analysis
`Mishale Mistry, PharmD, MPH, Associate Director
`
`Office of Device Evaluation/Division of Anesthesiology, General Hospital,
`Respiratory, Infection Control, and Dental Devices
`Rita Lin, MS, RAC, Human Factors Engineer
`
`SPONSOR ATTENDEES
`James Buckley, MS, Director, JRD Global CMC Regulatory Affairs
`Angela Falzone, PhD, Scientific Director, JRD CMC Leader
`Kimberly Nessel, MS, Scientific Director, JRD Cardiovascular and Metabolism
`L Miriam Pina, MD, Senior Director, JRD Project Physician
`Branden Reid, PhD, Associate Director, JRD Global CMC Regulatory Affairs, Medical
`Devices and Combination Products
`Huy Q Truong, MS, Associate Director, JRD Global Regulatory Affairs
`
`Bayer Pharmaceuticals (Sponsor’s collaborator)
`Matthew Gale, PhD, Statistical and Programming Lead
`Artur Lutfullin, MD, Senior Global Regulatory Strategist
`Miriam Tamm, PhD, Senior Statistician, Integrated Analysis Statistics
`
`(Via teleconference):
`Penny Zhu, PhD, Associate Scientist Director, JRD Pharmacometrics, Global Clinical
`Pharmacology
`
`Bayer Pharmaceuticals (Sponsor collaborator):
`Dagmar Kubitza, MD, Head Pharmacodynamics Cardiovascular, Clinical Pharmacology
`Cardiovascular/Hematology
`Akos F Pap, PhD, Project Statistician
`William Smith, MD, Global Clinical Lead
`Thomas Uhlich, PhD, CMC Technical Development Team Leader, Global Chemical and
`Pharmaceutical Development
`Katrin Coboeken, PhD, Scientist Systems Pharmacology (Modelling)
`Madhurima Maajumder, PhD, Study Statistician for Einstein Jr Phase 3 study
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 3
`
`
`1.0 BACKGROUND
`
`Rivaroxaban is an oral Factor Xa inhibitor indicated:
`•
`to reduce the risk of stroke and systemic embolism in patients with nonvalvular
`atrial fibrillation
`for the treatment of deep vein thrombosis (DVT)
`for the treatment of pulmonary embolism (PE)
`for the reduction in the risk of recurrence of DVT and/or PE in patients at
`continued risk for recurrent DVT and/or PE after completion of initial treatment
`lasting at least 6 months
`for the prophylaxis of DVT, which may lead to PE in patients undergoing knee or
`hip replacement surgery
`in combination with aspirin, to reduce the risk of major cardiovascular events
`(cardiovascular (CV) death, myocardial infarction (MI) and stroke) in patients with
`chronic coronary artery disease (CAD) or peripheral artery disease (PAD)
`
`•
`•
`•
`
`•
`
`•
`
`
`The proposed indications the Sponsor is seeking are the following:
`• Xarelto is indicated for the treatment of venous thromboembolism (VTE) and the
`reduction in the risk of recurrent VTE in children from birth to < 18 years of age
`following initiation of standard anticoagulation treatment.
`• Xarelto is indicated for the thromboprophylaxis in children 2 years to
` with congenital heart disease (CHD) who have undergone Fontan
`procedure.
`
`
`
`
`On May 29, 2015, Janssen submitted a Proposed Pediatric Study Request (PPSR) for
`rivaroxaban and on June 8, 2017, the Agency issued a formal Written Request (WR).
`On March 23, 2018, the Agency issued a WR – Amendment 1.
`
`On May 22, 2019, the Sponsor requested a meeting to discuss their planned New Drug
`Application (NDA) for two proposed pediatric indications supported by the development
`program in the treatment and thromboprophylaxis of venous thromboembolism (VTE)
`and discuss the new pediatric formulation (granule for oral suspension). In addition, the
`Sponsor seeks guidance on the proposed stability package and testing including the
`planned assessment in the support of the filing for registration of the commercial
`product and the oral dosing device, the planned timing and contents of the NDA
`submission.
`
`FDA sent Preliminary Comments to Janssen on July 31, 2019.
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`(b) (4)
`
`

`

`IND 064892
`Page 4
`
`
`2. DISCUSSION
`
`Preamble: Per the Guidance for Industry – Submitting Separate Marketing Applications
`and Clinical Data for Purpose of Assessing User Fee2, you will need to submit a
`separate NDA for the pediatric formulation, Granule for Oral Suspension.
`
`Discussion: See Question 2 response.
`
`2.1. Clinical Pharmacology
`
`Question 1: Technical details of the 2 alternatives for an electronic data package of the
`PBPK model are provided. Does the Agency consider the proposed plan adequate and
`acceptable?
`
`FDA Response to Question 1: We recommend you submit your package option B
`under module 5.3.3. Please convert software specific file extensions (i.e., mat, .pksim,
`.mbp, etc.) to .txt files. Also provide a script and instruction on converting the files back
`to the original formats. Submit the figures in .pdf format.
`
`Discussion: Clinical Pharmacology offered several options to the Sponsor
`depending on the size of the submission. The submission as a physical media is
`only an option if size is greater than 10GB and would still need to follow eCTD
`specifications. The Agency recommends submission via Gateway. To facilitate
`submission, it is not necessary to change file names. To preserve folder
`hierarchy, we recommend submission of the picture of the structure under
`Module 5 datasets folder.
`
`It is acceptable to provide .pdf file as part of the report for the submission.
`
`Post meeting note:
`The example of the folder hierarchy is provided below.
`Example folder hierarchy, where ‘Package’ is the beginning of the sponsor’s
`proposed project folder hierarchy
`
`Adopted from the Data Standards Technical Conformance Guide.3
`
`The FDA clarified during the meeting that the report and materials should be
`linked under Module 5.3.3.5 in the submission.
`
`
`
`
`
`2 https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submitting-separate-
`marketing-applications-and-clinical-data-purposes-assessing-user-fees
`3 https://www.fda.gov/media/122913/download
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 5
`
`2.2.|Chemistry, Manufacturing, and Controls
`
`Question 2: Sponsor's position that these data constitute a suitable basis for the
`Agency to assess the NDA shelf-life proposal. Does the Agency agree with the
`Sponsor's proposal?
`
`FDA Response to Question 2: We recommend you submit a minimum of twelve
`months and six monthsof stability data for the long term and accelerated storage
`conditions, respectively, for three primary stability batches packaged in the commercial
`container closure system intended for the U.S. market, since this is a new formulation
`and dosage form. You mayinclude the stability data generated by your partnerin the
`submission as supporting information. The drug product expiry will be determined by the
`stability results for the three primary stability batches.
`
`Discussion: The Agencystated the Sponsorwill need to submit a separate NDA
`to support the pediatric formulation complete withall clinical data (efficacy and
`safety) to support the proposed indication(s). The NDA will need to include
`appropriate cross-reference to existing NDAs.
`
`The Sponsorproposed 6 month long term andstability data and the Agencydid
`not agree. The Sponsor can submit an alternative proposal. The Agency
`proposed that the Sponsorcould provide 9 monthstability data with the
`application and 12 month data within 30 days after NDA submission.
`
`Question 3: Does the Agency agreethatit is acceptable for the Sponsorto provide 1
`representative executed batch record from a primary stability batch that fully represents
`the proposed commercialformulation,fill, and container closure system (CCS)?
`
`FDA Response to Question 3: We recommendyou provide the executed batch
`recordsforall three primary stability batches.
`
`Discussion: There was no discussion.
`
`Question 4: The Sponsor proposes
`
`FDA Response to Question 4:
`
`ore
`
`(o)(4)
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4976086
`
`

`

`IND 064892
`Page 6
`
`Human Factors
`
`Wenote you intend
`
`With regards to your planned HF efforts, the comprehensive use-related risk analysis
`should include a comprehensive and systematic evaluation ofall the steps involved in
`using your product(e.g., based on a task analysis) the errors that users might commit or
`the tasks they mightfail to perform and the potential negative clinical consequencesof
`use errors and taskfailures. Below are examplesof risks and potential errors for your
`consideration as you develop your product. Please note that these are examples and
`therefore, are not inclusive ofall risks associated with your proposed product:
`
`a. Evaluate the color of the plunger with respect to the readability of the dose
`markings.
`will support accurate measurementof
`It is unclear whether your proposed
`all potential doses(i.e., will some patients require more than 5 mL).
`It is not clear if the user needs to consider what volume of drug to draw up for a
`range of patients of different weights within each color
`
`b.
`
`c.
`
`group. You state that
`
`you state that
`
`
`Itis not clear if you have considered confusion by your intended users who are
`color vision deficient (color blind) and not color vision deficient and how that user
`characteristic may influence user interaction with the proposed product.
`In your summary
`of product risk assessmentin Table 13
`(pg. 33),
`
`.
`
`.
`
`If models of the sameor similar combination products exist, your use-related risk
`analysis should incorporate applicable information on known use-related problems with
`those products. Useful information can be obtained from your own experience as well
`as from public sources such asliterature, adverse event reports, and product safety
`communications (see draft guidance for industry Human Factors Studies and Related
`Clinical Study Considerations in Combination Product Design and Development).
`
`Your risk analysis should also discussrisk-mitigation strategies you employed to reduce
`risks you haveidentified and the methods you intend to use for validating the risk-
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4976086
`
`

`

`IND 064892
`Page 7
`
`
`mitigation strategies. This information is needed to ensure that all potential risks
`involved in using your product have been considered and adequately mitigated and the
`residual risks are acceptable.
`
`Based on the aforementioned information and data, you should determine whether you
`need to submit the results of a HF validation study conducted under simulated use
`conditions with representative users performing necessary tasks to demonstrate safe
`and effective use of the product.
`
`If you determine you need to submit the results of a HF validation study, the risk
`analysis can be used to inform the design of a human factors validation study protocol
`for your product. We recommend you submit your study protocol for feedback from the
`Agency before commencing your study. Please note we will need 60 days to review
`and provide comments on the HF validation study protocol. Plan your development
`program timeline accordingly. Note that submission of a protocol for review is not a
`requirement. If you decide not to submit a protocol, this approach carries some risk to
`you because prospective Agency review is not possible, but this is a decision for your
`company.
`
`Please refer to our draft guidance titled “Contents of a Complete Submission for
`Threshold Analyses and Human Factors Submissions to Drug and Biologic
`Applications” for the content of a human factors validation study protocol submission.
`The guidance is available online at
`https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
`ances/UCM621902.pdf
`
`Once complete, the requested information should be submitted to IND 064892 in eCTD
`Section 5.3.5.4 – Other Study reports and related information.
`
`Guidance on human factors procedures to follow can be found in Applying Human
`Factors and Usability Engineering to Medical Devices, available online at:
`http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Guidanc
`eDocuments/ucm259760.pdf
`
`Guidance on Safety Considerations for Product Design to Minimize Medication Errors
`can be found online at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guida
`nces/UCM331810.pdf
`
`Note that we recently published two draft guidance documents that, while not yet
`finalized, might also be useful in understanding our current thinking and our approach to
`human factors for combination products, product design, and labeling:
`
`Human Factors Studies and Related Clinical Study Considerations in Combination
`Product Design and Development can be found online at:
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 8
`
`http://www.fda.gov/downloads/Regulatory|nformation/Guidances/UCM484345 pdf
`
`Safety Considerations for Container Labels and Carton Labeling Design to Minimize
`Medication Errors can be found online at:
`http://www.fda.gov/downloads/drugs/quidancecomplianceregulatoryinformation/quidanc
`es/ucm349009.pdf
`
`Device Engineering
`In addition to the humanfactors considerations stated above,
`
`
`you have stated that /™
`
`provide dose (syringe) accuracyverification testing to
`gency agreesthat you should
`verify that the markings are applied correctly and remain accurate. The Agency also
`recommendsthatin addition, drug-device compatibility studies should be conductedto
`confirm that short contact times do not adversely impact drug quality. Please ensure
`that you conduct a thoroughrisk analysis based on the materials, design, and
`packaging comparison. Please reference design considerations referenced in guidance
`Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with
`Drugs andBiological Products.4
`
`
`
`Discussion: The Agency agrees with the Sponsor’s proposal on attached slides
`12, 14, 15.
`
`2.3.
`
`Clinical and Statistical
`
`Question 5:
`a)
`Does the Agency agree with the plans for the statistical analyses and
`presentation of results as outlined in the Statistical Analysis Plan, submitted on 21 May
`2019 (IND 064892, eCTD Seq.2845) for the Phase 3 clinical study (Study 14372) in
`EINSTEIN Junior?
`
`Does the Agency agree with the plansfor the statistical analyses and
`b)
`presentation of results as outlined in the Statistical Analysis Plan, Amendment1,
`submitted on 21 May 2019 (IND 064892, eCTD Seq.2845) for the UNIVERSE study?
`
`FDA Responseto Question 5:
`a) The plans appearacceptable.
`b) The plans appear acceptable.
`
`Please ensure that statistical analyses plans and presentations of results are consistent
`with description and specifications in the Written Request.
`
`4 https://www.fda.gov/media/76403/download
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4976086
`
`

`

`IND 064892
`Page 9
`
`
`
`Discussion: There was no discussion.
`
`Question 6: The Sponsor plans to provide specific pooled analyses of clinical trials in
`the EINSTEIN Junior program, i.e., treatment of VTE and the reduction in the risk of
`recurrent VTE in children from birth to <18 years of age as explained. Does the Agency
`agree with the Sponsor’s Plan for pooled analyses?
`
`FDA Response to Question 6: Yes, the Agency agrees with the presentation of pooled
`analyses as described in the meeting package.
`
`Discussion: There was no discussion.
`
`Question 7: Post-marketing exposure and cumulative adverse events reports received
`from worldwide post-marketing surveillance, including spontaneous reports, will also be
`provided. Does the Agency agree with this proposal?
`
`FDA Response to Question 7: Yes, the Agency agrees with the proposal.
`
`Discussion: There was no discussion.
`
`Question 8: Each study will provide both the SDTM package for source data and the
`ADaM package for analysis data. In addition, the Sponsor proposes to submit the
`ADaM package for the pooled analyses of clinical trials in the EINSTEIN Junior
`program, i.e., treatment of VTE and the reduction in the risk of recurrent VTE in children
`from birth to <18 years of age. Datasets of individual studies with the exception of the
`Phase 3 study 14372 as noted will not be provided with the submission. Does the
`Agency agree with this proposal?
`
`FDA Response to Question 8: Yes, the Agency agrees with this proposal.
`
`Discussion: There was no discussion.
`
`Question 9: Executable SAS codes will be provided for primary efficacy and principal
`safety outputs for the 2 Phase 3 studies EINSTEIN Junior (Study 14372) and
`UNIVERSE.
`
`Non-executable SAS codes will be provided for the generation of analysis data sets for
`the 2 Phase 3 studies EINSTEIN Junior (Study 14372) and UNIVERSE. These are
`intended to provide reviewers an understanding of analysis algorithms and creation.
`
`Non-executable SAS codes will also be provided for selected key outputs in the 2
`Phase 3 studies EINSTEIN Junior (Study 14372) and UNIVERSE. The “table of tables”
`document in Module 5 in eCTD will be provided to link outputs and corresponding SAS
`codes.
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 10
`
`
`Executable SAS codes will also be provided for the pooled bleeding event analyses of
`clinical trials in the EINSTEIN Junior program as described in Section 11.3.2 For all
`other pooled analyses (ie, adverse events) of clinical trials in the EINSTEIN Junior
`program as described in Section 11.3.2 non-executable SAS codes will be provided. A
`“table of tables” document in Module 5 in eCTD will be provided to link pooled analyses
`of clinical trials in the EINSTEIN Junior program as described in Section 11.3.2 and
`corresponding SAS codes.
`
`Non-executable SAS codes will be provided for the generation of the pooled analysis
`data sets (for pool 1, pool 2, pool 3) of clinical trials in the EINSTEIN Junior program as
`described in Section 11.3.2 These are intended to provide reviewers an understanding
`of analysis algorithms and creation. Does the Agency agree with this proposal?
`
`FDA Response to Question 9: The approach is acceptable. Please ensure
`compliance with Study Data Standards and the latest version of the STUDY DATA
`TECHNICAL CONFORMANCE GUIDE: Technical Specifications Document
`https://www.fda.gov/industry/fda-resources-data-standards/study-data-standards-
`resources
`
`Please provide the following in the submission:
`
`
`• Executable, clearly commented, non-macro programs in ASCII format used to
`create tables and figures for primary and key secondary efficacy analyses and
`any additional information included in Section 14 CLINICAL STUDIES of the
`Prescribing Information, if applicable. Ensure that programs call only data
`submitted to the Agency and can be easily used to reproduce the results in the
`CSR. Ensure that variables used in the programs for generating results in the
`CSR are described clearly in the define file.
`• To facilitate the analysis, please include code in programs that explicitly converts
`submitted .xpt files into the data format used by programs.
`• A clear index with descriptions of the programs
`• Annotations for each figure and table in the CSR with a list of datasets and
`variables, as well as a link to the program used to generate results.
`
`
`Discussion: The Agency agreed to the code in .sas file format, guidance for the
`executable code and example table of table would be provided in reviewer’s guide
`(ADRG). All results in the USPI Section 14 Clinical Studies including baseline
`characteristics among others would be provided.
`
`The StatXact 10 procedures compatible with the latest version would be
`acceptable.
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 11
`
`
`Question 10: Does the Agency agree with the proposal for providing the narratives in
`the sNDA?
`
`FDA Response to Question 10: Yes, the Agency agrees with the proposal for
`providing narratives in your submissions.
`
`Please see the preamble regarding the need for a separate NDA for pediatric
`formulation (granule for oral suspension).
`
`Discussion: There was no discussion.
`
`Question 11a: In accordance with the 2006 FDA guidance document entitled “Adverse
`Reactions Section of Labeling for Human Prescription Drug and Biological Products –
`Content and Format”, the Sponsor proposes to include only adverse drug reactions in
`the United States Prescribing Information (USPI) and not all adverse events (AEs)
`collected during the use of a drug in clinical trial. Does the Agency agree with this
`approach?
`
`FDA Response to Question 11a: Your proposed labeling approach for the application
`is reasonable; however, we cannot agree until review of the adverse event datasets.
`Please note that we cannot agree to labeling at this time and that labeling negotiations
`will occur after the filing decision and review of application.
`
`Discussion: There was no discussion.
`
`Question 11b: Does the Agency agree with the following information proposed to be
`included in the Adverse Reactions Section (Section 6) of the USPI?
`
`The Adverse Reactions Section of the USPI will include:
`
`
`FDA Response to Question 11b: The content proposed in the Adverse Reactions
`Section of the USPI will be a review issue once the application is submitted. Labeling
`negotiations will occur during the review of the supplemental application.
`
`Discussion: There was no discussion.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`(b) (4)
`
`

`

`IND 064892
`Page 12
`
`
`
`Question 12: A submission of a sNDA in 4Q 2020, which will comprise the EINSTEIN
`Junior study data and analyses package for the proposed indication of treatment of VTE
`and the reduction in the risk of recurrent VTE in pediatric subjects from birth to <18
`years of age AND inclusion of the combined registration stability data package as
`proposed in Question 2 to assess the market product’s shelf-life. A submission of the
`UNIVERSE study sNDA for the CHD indication in 1Q 2021. Does the Agency concur
`with the Sponsor’s proposed timelines and planned submission of the respective
`sNDA(s)?
`
`FDA Response to Question 12: Yes, the Agency agrees with your timelines.
`
`Please see the preamble regarding the need for a separate NDA for pediatric
`formulation (granule for oral suspension).
`
`Discussion: See response to question 2 regarding submission of separate NDA.
`
`OTHER ADDITIONAL COMMENTS:
`
`
`1. Please ensure that the application submissions address all the specifics and
`details in the Written Request.
`
`
`Discussion: There was no discussion.
`
`Additional Post meeting addendum notes:
`For the NDA submission, the Sponsor proposed a cross reference document in
`m1.4.4 in tabular format containing the application number, date of submission,
`file name(s), etc. of the cross referenced application (e.g., NDA 022406 and NDA
`202439), where applicable, without cross-application hyperlinks to support the
`pediatric formulation of rivaroxaban.
`
`The Agency agrees with this proposal.
`
`3.0 OTHER IMPORTANT INFORMATION
`
`PREA REQUIREMENTS
`
`Under the Pediatric Research Equity Act (PREA) (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,
`deferred, or inapplicable.
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
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`IND 064892
`Page 13
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`Please be advised that under the Food and Drug Administration Safety and Innovation
`Act (FDASIA), you must submit an Initial Pediatric Study Plan (iPSP) within 60 days of
`an End-of-Phase-2 (EOP2) meeting. In the absence of an EOP2 meeting, refer to the
`draft guidance below. The iPSP must contain an outline of the pediatric study or studies
`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.
`
`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.5 In addition, you may contact the Division of Pediatric and
`Maternal Health at 301-796-2200 or email Pedsdrugs@fda.hhs.gov. For further
`guidance on pediatric product development, please refer to FDA.gov.6
`
`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
`Information7 and Pregnancy and Lactation Labeling Final Rule8 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
`
`
`5 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent
`version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`6 https://www.fda.gov/drugs/development-resources/pediatric-and-maternal-health-product-development
`7 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08
`4159.htm
`8 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09
`3307.htm
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4475085Reference ID: 4910036
`
`

`

`IND 064892
`Page 14
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`• 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.
`
`DISCUSSION OF SAFETY ANALYSIS STRATEGY FOR THE ISS
`
`After initiation of all tr