CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`213801Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`MEETING PRELIMINARY COMMENTS
`
`IND 069416
`
`Astellas Pharma Global Development, Inc.
`Attention: Kristine Skjolaas, Ph.D.
`Associate Director, Regulatory Affairs
`1 Astellas Way
`Northbrook, IL 60062
`
`Dear Dr. Skjolaas:1
`
`Please refer to your investigational new drug application (IND) submitted under section
`505(i) of the Federal Food, Drug, and Cosmetic Act for YM178 (mirabegron) tablets and
`oral suspension.
`
`We also refer to your August 15, 2019, correspondence, received August 15, 2019,
`requesting a meeting to discuss your planned new drug application, specifically, the
`overall clinical development program, the pediatric data package to fulfill PREA
`requirements as well as the terms of the Written Request, and your submission plans
`for the pediatric and adult populations.
`
`Our preliminary responses to your meeting questions are enclosed.
`
`You should provide, to me, a hardcopy or electronic version of any materials (i.e.,
`slides or handouts) to be presented and/or discussed at the meeting.
`
`In accordance with 21 CFR 10.65(e) and FDA policy, you may not electronically record
`the discussion at this meeting. The official record of this meeting will be the FDA-
`generated minutes.
`
`1We 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: 4516358Reference ID: 4772718
`
`

`

`IND 69416
`Page 2
`
`If you have any questions, please call me at 301-796-0875.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Nenita Crisostomo
`Regulatory Health Project Manager
`Division of Bone, Reproductive and Urologic Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`ENCLOSURE:
`• Preliminary Meeting Comments
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PRELIMINARY MEETING COMMENTS
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-NDA
`
`Meeting Date and Time: November 14, 2019, at 1:00 PM – 2:00 PM, Eastern
`Meeting Location:
`10903 New Hampshire Avenue
`White Oak Building 22, Conference Room: 1315
`Silver Spring, Maryland 20903
`
`Application Number:
`IND 069416
`Product Name:
`YM178 (mirabegron) tablets and oral suspension
`
`Indication:
`Treatment of neurogenic detrusor overactivity in pediatric
`patients
`
`Sponsor Name:
`
`Astellas Pharma Global Development, Inc.
`
`Introduction:
`
`This material consists of our preliminary responses to your questions and any
`additional comments in preparation for the discussion at the meeting scheduled for
`November 14, 2019, at 1:00 PM – 2:00 PM, in 10903 New Hampshire Avenue,
`Silver Spring, Maryland 20903 between Astellas Pharma Global Development, Inc.
`and the Division of Bone, Reproductive and Urologic Products. We are sharing
`this material to promote a collaborative and successful discussion at the meeting.
`The meeting minutes will reflect agreements, important issues, and any action
`items discussed during the meeting and may not be identical to these preliminary
`comments following substantive discussion at the meeting. If you determine that
`discussion is needed for only some of the original questions, you have the option
`of reducing the agenda and/or changing the format of the meeting (e.g., from face
`to face to teleconference). Contact me, the Regulatory Project Manager (RPM), if
`there are any major changes to your development plan, the purpose of the
`meeting, or the questions based on our preliminary responses, as we may not be
`prepared to discuss or reach agreement on such changes at the meeting.
`
`1.0
`
`BACKGROUND
`
`Myrbetriq (mirabegron), 25mg and 50mg tablets, were approved for marketing in June
`2012 for treatment of overactive bladder (OAB) in adults. As required under the
`Pediatric Research Equity Act (PREA), postmarketing studies were conducted for the
`treatment of neurogenic detrusor overactivity (NDO) in pediatric patients aged 3 years
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 2
`
`to < 18 years of age. Also, a Written Request (WR) for pediatric studies was issued on
`March 18, 2016.
`
`Astellas has developed mirabegron extended-release granules which, when
`reconstituted in water, result in an oral suspension of 8 mg/mL. The suspension is
`intended for administration to pediatric patients with NDO below a specified cutoff
`weight and to patients above that cutoff weight who cannot swallow tablets.
`
`Astellas requested this meeting to discuss the 1) pediatric package intended to fulfill
`PREA and WR, 2) submission plans for sNDA 202611 for mirabegron tablets and NDA
`213801 for mirabegron granules for oral suspension for the treatment of pediatric NDO
`patients, and 3)
`
`
`The Meeting Information Package was received on September 24, 2019.
`
`2.0
`
`2.1.
`
`DISCUSSION
`
`Regulatory
`
`Question 1 (Phase 3 Study 178-CL-206A): Does the Agency agree that the
`pediatric clinical development program as already conducted for mirabegron is
`sufficient to support the submission of an efficacy and safety supplement and
`new NDA for the proposed indication for mirabegron tablets and granules for
`treatment of NDO in pediatric patients aged 3 to < 18 years?
`
`FDA Response:
`A determination as to whether your program is sufficient to support the filing of a
`supplemental NDA and a new NDA for mirabegron tablets and granules for oral
`suspension, respectively, for the treatment of NDO in pediatric patients cannot be made
`prior to our preliminary review of the submissions. However, in general, your
`development program appears reasonable.
`
`Question 2 (Compliance with Written Request): Does the Agency agree that the
`pediatric clinical development program as already conducted for mirabegron is
`consistent with the requirements under PREA and is sufficient to support a
`Request for Pediatric Exclusivity for mirabegron?
`
`FDA Response:
`A determination as to whether your pediatric clinical development program meets the
`PREA requirements and the terms of the WR cannot be made prior to our review of the
`submissions and presentation of the data before FDA’s Pediatric Exclusivity Board.
`However, your pediatric development program appears to be sufficient to provide
`information to determine whether the PREA and Written Request requirements have
`been met.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b) (4)
`
`

`

`IND 069416
`Page 3
`
`Question 3
`
`FDA Response:
`
`
`
`
`
`
`
`
`
`
`
`2.2.
`
`Clinical
`
`Question 4 (Integrated Summary of Efficacy): Does the Agency agree with
`Astellas’ request to present the efficacy data as described above but not to
`provide an Integrated Summary of Efficacy?
`
`FDA Response:
`Yes.
`
`Question 5 (Integrated Summary of Safety): Does the Agency agree with Astellas’
`proposed presentation of the safety analyses for use of mirabegron in the
`treatment of NDO in pediatric patients?
`
`FDA Response:
`Yes. In addition, we have the following requests for safety information in your NDA
`submission:
`
`1. Submit case report forms (CRFs) and case narratives for all deaths, SAEs, and
`discontinuations due to AEs.
`
`2. Provide a summary table, including all deaths, SAEs, and discontinuations due to
`AEs, categorized by system organ class (SOC) and preferred term (PT), with
`hyperlinks to the case narratives.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 069416
`Page 4
`
`3. Provide case narratives for all 5 reported hypersensitivity AEs and for both
`reported cardiovascular AEs (mild QT prolongation and mild bradycardia).
`
`4. Provide a detailed analysis of shifts from normal to abnormal vital signs, including
`categorical shifts upward in blood pressure and in heart rate, based on age-
`related normative reference values.
`
`5. Given the open label nature of the study 178-CL-206A, provide the individual
`patient-level blood pressure and heart rate data along with information on
`potentially confounding factors that have been previously communicated to you.
`These factors include, but are not limited to, the timing of vital sign
`measurements relative to other study visit interventions (e.g., phlebotomy) and
`the patient demeanor during vital sign measurements. This information will
`assist in the clinical interpretation of changes from baseline in blood pressure
`and heart rate category.
`
`Question 6 (Clinical Datasets): Does the Agency agree with the proposed plan for
`submission of electronic datasets in the planned sNDA to NDA 202611 and the
`new NDA 213801 for mirabegron?
`
`FDA Response:
`Yes, we agree with your proposed plan. In addition, submit the analysis programs.
`
`Question 7 (Dosing and Administration): Does the Agency agree with the model-
`based approach for the development of the dosing recommendations for
`mirabegron (extended-release tablets and granules for oral suspension) in the
`pediatric population?
`
`FDA Response:
`Your model-based approach for dosing selection and recommendation appears
`generally acceptable. In your planned sNDA and NDA submissions, update your
`population PK modeling and simulations with all available pediatric data, including data
`from dosing with tablets and granules for oral suspension, to support the recommended
`dosing regimen in labeling.
`
`Question 8 (Proposed Labeling Format)
`
`Question 8a: Does the Agency agree with the proposal of a single mirabegron
`label inclusive of both the tablet and granules for oral suspension formulations
`and both the adult OAB and pediatric NDO indications?
`
`FDA Response:
`A single label covering multiple formulations may be acceptable. However, a detailed
`discussion of labeling, including whether a single mirabegron label inclusive of both
`tablet and granule for oral suspension formulations, is premature at this time.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 5
`
`We have the following additional comments:
`
`1. We do not agree with your proposal to
`
`See our response to Question 3.
`
`2.
`
`3.
`
`.
`
`
`
`
`It appears that the new granules for oral suspension formulation may not be
`bioequivalent to the currently marketed tablet formulation and thus, not
`interchangeable on a mg to mg or 1:1 conversion basis. If both formulations are
`approved under a single label, specific information may be needed in labeling to
`reduce the risk of over- or under-dose medication errors.
`
`Question 8b: Does the Agency agree with the proposed patient “Instructions for
`Use” for oral suspension in the “Pediatric Patient Information”?
`
`FDA Response:
`A detailed discussion of labeling, including the proposed “Instructions for Use” in the
`proposed PPI, is premature. The acceptability of the patient labeling will be a review
`issue.
`
`Question 8c: Does the Agency agree with the proposed pharmacist instructions
`for reconstitution of the granules and supply of appropriate dosing device in the
`
`
` subsection of the full “Prescribing Information”?
`
`FDA Response:
`A detailed discussion of labeling, including the proposed “
`
`
`” in the
`proposed PI, is premature. The acceptability of the labeling will be a review issue.
`
`Question 9 (Submission Content)
`Question 9a: Does the Agency agree with the proposed submission plan of the
`sNDA to NDA 202611 mirabegron tablets?
`
`FDA Response:
`Yes.
`
`We have the following technical comments:
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 069416
`Page 6
`
`1. Follow the CTD heading and hierarchy guidance at
`https://www.fda.gov/media/76444/download to place each document in the
`proper eCTD sub heading.
`
`2. Because your application is in eCTD format, cross referencing has to be done in
`the leaf level of the xml backbone.
`
`3. To use cross application link, both applications would need to be in eCTD
`format. The applications need to include the appropriate prefix in the href links
`(e.g. xlink:href="../../indXXXXXX/0009/m2/24-nonclin-
`over/nonclinical-overview.pdf"). In the leaf titles of the documents, it is
`recommended that the leaf title indicate the words “cross reference to” and the
`application number (e.g. Cross Ref to indXXXXXX). The cross reference
`information in the leaf title allows the reviewer to know that the document resides
`in another application.
`
`4. Prior to using cross application linking in an application and to ensure successful
`use of cross application links, it is recommended that you submit an "eCTD cross
`application links" sample. However, if you have used cross application linking
`prior, there is no need for a cross application sample.
`
`5. To submit an eCTD cross application links sample, you would need to
`request two sample application numbers from the ESUB team -
`esub@fda.hhs.gov. For more information on eCTD sample, please refer to the
`Sample Process web page which is located at
`http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmi
`ssionRequirements/ElectronicSubmissions/UCM315023.pdf
`
`Question 9b: Does the Agency agree with the proposed submission plan of the
`new NDA 213801 for mirabegron granules for oral suspension?
`
`FDA Response:
`Yes. However, Pharmacology written and tabulated summaries should be included in
`Module 2.6.
`
`In addition, we remind you to follow the CTD heading and hierarchy guidance at
`https://www.fda.gov/media/76444/download to place each document in the proper
`eCTD sub heading.
`
`Question 9c: Regarding PREA and pediatric exclusivity requirements for
`submission of associated reports to the original NDA 202611(tablets), does the
`Agency agree that the CSRs can be incorporated into NDA 202611 by a cross-
`reference to the new NDA 213801 (granules) and that this is acceptable for FDA
`review of pediatric exclusivity?
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 7
`
`FDA Response:
`Yes.
`
`2.3.
`
`Chemistry, Manufacturing and Controls
`
`Question 10 (Drug Substance): Does the Agency agree with the proposal to
`cross-reference to Myrbetriq NDA 202611 for drug substance information for
`mirabegron in the planned new NDA 213801 for mirabegron granules for oral
`suspension?
`
`FDA Response:
`Yes, drug substance information may be incorporated into the NDA by cross-reference
`to NDA 202611. However, the new NDA should include complete drug substance
`manufacturing site information in 3.2.S.2.1 and in the Form 356h. Identify any pending
`drug substance-related supplements to NDA 202611 when the new NDA is submitted.
`
`Question 11 (Stability Data in the NDA Submission): Does the Agency agree with
`the proposal to submit 9-month long-term primary stability data at the time of
`filing with 12-month long-term stability data and the corresponding in-use
`reconstitution data provided 30 days after the initial submission?
`
`FDA Response:
`Yes, we agree with the proposal to submit 9-months long-term stability data, along with
`6-months accelerated stability data, for three registration batches at the time of initial
`submission, with 12-month long-term data and in-use stability data for the reconstituted
`product within 30 days of the initial submission. We note that the registration stability
`batches were manufactured in October and November 2018. If submission of the new
`NDA is delayed until 2020, we request that the 12-month data and the in-use stability
`data be submitted in the initial submission.
`
`To ensure the adequacy of the drug product stability protocol and the reconstituted
`suspension in-use stability protocol, we recommend that you submit these protocols to
`the IND.
`
`Question 12 (Prior Approval Inspection): Does the Agency agree with the
`proposal that the
` process validation is not required before
`the Prior Approval Inspection?
`
`FDA Response:
`Process Performance Qualification (PPQ) batch production, as discussed in FDA
`Guidance for Industry - Process Validation: General Principles and Practices, January
`2011, is not required to be completed prior to a pre-approval inspection. However, PPQ
`must be successfully completed prior to commercial launch. We recommend that PPQ
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b) (4)
`
`

`

`IND 069416
`Page 8
`
`production is carried out based on the FDA-approved manufacturing process and
`control strategies.
`
` is critical to product
`If the
`stability (i.e., is ‘functional’), the initial NDA submission should include data
`demonstrating the adequacy of the
` process at APEBV Meppel (e.g., 3 months
`accelerated stability data on three batches). Full validation
` of
`the
` process should be performed as described in the process validation
`guidance.
`
` have no impact on
`If stability data demonstrate that the
`process can be waived as long as
`protection of the drug product, the PPQ for
`the equipment for
` process is qualified and demonstrated suitable for its
`intended purpose.
`
`ADDITIONAL COMMENTS
`
`Chemistry, Manufacturing and Controls (CMC)
`
`Product Quality
`1.
`Include a test for suspendability of the granules and a test for pH of the oral
`suspension when it is reconstituted as directed in the labeling to the drug product
`specification.
`
`Biopharmaceutics
`
`Dissolution Data Presentation:
`
`In the dissolution method development report, and/or batch analysis section, present
`detailed experimental dissolution data as follows:
`
`1.
`
`2.
`
`In the narrative portion of the dissolution report, include individual vessel data, in
`particular, investigation of selected equipment, media, agitation speed, etc.
`
`In addition to the mean dissolution data presented in graphical and tabular
`formats, submit in the “Batch Analysis” section 3.2.P.5.4 of your NDA the
`individual vessel dissolution data for the batches of the proposed product used in
`the pivotal clinical/PK and registration/stability studies in Microsoft Excel “.xls or
`.xlsx” format. If available, include data at release, time zero stability time point,
`and over the duration of stability testing under long-term storage conditions.
`
`3. Provide the dissolution data as described in the example below.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 069416
`Page 9
`
`Example - Reporting of individual vessel dissolution data
`
`4. Follow the instructions provided in “Specifications for File Format Types Using
`eCTD Specifications” – updated March 2, 2017 (link below).
`https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSub
`missionRequirements/ElectronicSubmissions/UCM347471.pdf.
`
`Dissolution Acceptance Criterion:
`
`For the selection of the dissolution acceptance criterion of the proposed drug product,
`consider the following:
`
`1. Use the multi-point dissolution data (n=12, sampling every 2 hours) from the
`pivotal clinical/PK drug product-batches and primary registration batches for the
`setting of the dissolution acceptance criterion of the proposed drug product (i.e.,
`sampling time points and limits) to cover the beginning, intermediate and later
`stages of the dissolution profile. The recommended range at any dissolution time
`point specification is ± 10% deviation from the mean dissolution profile obtained
`from the clinical/bioavailability lots. When applicable, include the dissolution
`profile data to support in-process dissolution acceptance criteria. Select the last
`sampling time point where Q =
` % dissolution occurs.
`
`2. Ensure that the in vitro dissolution profile is complete and that the plateau of drug
`dissolved is reached (i.e., no increase over 3 consecutive time-points).
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`(b)
`(4)
`
`

`

`IND 069416
`Page 10
`
`3. Base the dissolution acceptance criterion on the average in vitro dissolution data
`of each batch/lot under study, equivalent to USP Stage 2 testing (n = 12).
`
`4.
`
`Include a detailed discussion of the justification of the proposed dissolution
`acceptance criterion in the appropriate section of the eCTD.
`
`Dissolution Acceptance Criterion/Criteria Recommendation:
`
`We remind you that our recommendation on the adequacy of the proposed dissolution
`acceptance criterion/criteria for the proposed drug product will be made during the
`review based on the totality of the provided dissolution data.
`
`IN SILICO PBPK MODELING SUPPORTING DS and/or DP ATTRIBUTES
`
`To aid in the regulatory-decision making in terms of setting the appropriate acceptance
`criterion(a) for drug substance (DS) or drug product (DP) attributes (e.g., drug
`substance particle size, drug product hardness, drug product dissolution) based on in
`silico physiologically-based pharmacokinetics (PBPK) modeling, provide the following
`information/data (if available):
`
`1. Relevant in vivo data (e.g., BA/BE, PK data) to demonstrate that drug product-
`batches with your proposed acceptance criterion(a) for drug substance or drug
`product attributes have a similar systemic exposure compared to that of the
`pivotal bio-study drug product-batch.
`
`2. Available supportive data from in silico physiologically-based pharmacokinetics
`(PBPK) modeling and simulation demonstrating the in vivo impact at the
`extremes of the proposed drug substance and/or drug product attributes. For this
`purpose, submit the following information:
`
`a. A modeling summary report, that provides an overview of the modeling
`strategy and details the modeling procedures, including model development,
`verification/validation, and application in a step-wise manner. Inclusion of a
`flow chart, decision tree, or other similar representation is preferred for clarity.
`
`b. Detailed information on the inputs used in the development, optimization and
`verification/validation of the model(s). All physiological and physicochemical
`parameters, as well as their sources should be clearly specified. While we
`acknowledge that some input parameters are estimated (optimized), when the
`parameters are optimized, the initial value selection, the estimation method,
`the justification for the optimization algorithm, and the assumption(s) used
`should be provided. For simulation, provide the input values/ranges of
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 11
`
`parameters, single or population simulation (number of simulated subjects)
`and the output report.
`
`c. The definition file(s) listing all input and output files, and the use or purpose of
`each of these files, in an appropriate format (e.g., .pdf, .xpt,.xls).
`
`d. Although we do not request the use of a specific software, due to substantive
`differences in software/versions, clear identification of software parameters is
`critical, which should include: name and version of the software, and (for
`custom modeling software) schematics of model structure and differential
`equations.
`
`e. The methodological approach for model verification/validation, results
`verification/validation, and sensitivity analyses to interrogate the robustness of
`the model should be clearly presented. We expect that PK data may
`contribute to establish confidence in model appropriateness when addressing
`the study question(s).
`
`f. The generated data from the verified/validated model to address the study
`question(s) should be presented using tables, figures and text where
`appropriate.
`
`g. The complete PBPK modeling and simulation report, definition files, and
`datasets in module 5.3.1.3 of the eCTD.
`
`3. Our final decision regarding the acceptability of the acceptance criterion(a) of the
`drug substance and/or drug product attributes will be made during the review of
`your submission based on the totality of the supportive data and relevant
`information, including quality demonstration of submitted PBPK modeling and
`simulation work.
`
`3.0
`
`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.
`
`We acknowledge your agreed Initial Pediatric Study Plan (iPSP) dated December 11,
`2013.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 12
`
`4.0
`
`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
`Information2 and Pregnancy and Lactation Labeling Final Rule3 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,
`
`2 https://www.fda.gov/drugs/laws-acts-and-rules/plr-requirements-prescribing-
`information
`3 https://www.fda.gov/drugs/labeling/pregnancy-and-lactation-labeling-drugs-final-rule
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 13
`
`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.
`
`5.0 MANUFACTURING FACILITIES
`
`To facilitate our inspectional process, we request that you clearly identify in a single
`location, either on the Form FDA 356h, or an attachment to the form, all manufacturing
`facilities associated with your application. Include the full corporate name of the facility
`and address where the manufacturing function is performed, with the FEI number, and
`specific manufacturing responsibilities for each facility.
`
`Also provide the name and title of an onsite contact person, including their phone
`number, fax number, and email address. Provide a brief description of the
`manufacturing operation conducted at each facility, including the type of testing and
`DMF number (if applicable). Each facility should be ready for GMP inspection at the
`time of submission.
`
`Consider using a table similar to the one below as an attachment to Form FDA 356h.
`Indicate under Establishment Information on page 1 of Form FDA 356h that the
`information is provided in the attachment titled, “Product name, NDA/BLA 012345,
`Establishment Information for Form 356h.”
`
`Federal
`Establishment
`Indicator
`(FEI) or
`Registration
`Number
`(CFN)
`
`Drug
`Master
`File
`Number
`(if
`applicable
`)
`
`Manufacturing
`Step(s)
`or Type of Testing
`[Establishment
`function]
`
`Site Name
`
`Site
`Address
`
`(1)
`(2)
`
`Corresponding names and titles of onsite contact:
`
`Site Name
`
`Site
`Address
`
`Onsite Contact
`(Person, Title)
`
`Phone
`and Fax
`number
`
`Email address
`
`(1)
`(2)
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`IND 069416
`Page 14
`
`6.0
`
`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.4
`
`4 https://www.fda.gov/media/85061/download
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`

`

`Signature Page 1 of 1
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`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/
`------------------------------------------------------------
`
`NENITA I CRISOSTOMO
`11/06/2019 12:40:35 AM
`
`
`
`Reference ID: 4516358Reference ID: 4772718
`
`