CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`213051Orig1s000
`
`
`ADMINISTRATIVE and CORRESPONDENCE
`
`DOCUMENTS
`
`
`
`
`
`

`

`
`
` FOOD AND DRUG ADMINISTRATION
`
` CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`
`
`
`
` IND 114464
`
`
`
`MEETING MINUTES
`
`
`
`Novo Nordisk Inc.
`
`
`Attention: Stephanie DeChiaro
`
`
`Director, Regulatory Affairs
`
`800 Scudders Mill Rd.
`
`P.O. Box 846
`
`Plainsboro, NJ 08536
`
`
`Dear Ms. DeChiaro:
`
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`
`
`of the Federal Food, Drug, and Cosmetic Act for semaglutide tablets.
`
`
`
`We also refer to the meeting between representatives of your firm and the FDA on
`
`
`
`
`November 29, 2018. The purpose of the meeting was to discuss aspects of the oral semaglutide
`
`
`
`development program and the NDA submission.
`
`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, call Peter Franks, Regulatory Project Manager, at (240) 402-4197.
`
`
`
`
`
`Sincerely,
`
`
`
`{See appended electronic signature page}
`
`Lisa Yanoff, M.D.
`
`Director (Acting)
`
`Division of Metabolism and Endocrinology Products
`
`Office of Drug Evaluation II
`
`
`Center for Drug Evaluation and Research
`
`
`
`
`Enclosure:
`
`Meeting Minutes
`
`Sponsor Slides
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
` MEMORANDUM OF MEETING MINUTES
`
`
`
`
`
`B
`
`Pre-NDA
`
`
`IND 114464
`
`
`semaglutide tablets
`
`
`Type 2 diabetes mellitus
`
`Novo Nordisk, Inc.
`
`
`Lisa Yanoff
`
`Peter Franks
`
`
`
`
` IND 114464
` Page 1
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`
`Meeting Type:
`
`Meeting Category:
`
`
`Meeting Date and Time: November 29, 2018; 11:00 AM – 12:00 PM EST
`
`
`Meeting Location:
`White Oak Campus, Building 22, Room 1417
`
`
`Application Number:
`
`Product Name:
`
`
`Indication:
`
`Sponsor Name:
`
`
`Meeting Chair:
`
`Meeting Recorder:
`
`
`FDA ATTENDEES
`
`Division of Metabolism and Endocrinology Products
`
`Lisa Yanoff, M.D., Director (Acting)
`
`
`
`Mitra Rauschecker, M.D., Clinical Team Lead (Acting)
`
`
`Andreea Lungu, M.D., Clinical Reviewer
`
`
`
`Federica Basso, Ph.D., Nonclinical Team Lead (Acting)
`
`Elena Braithwaite, Ph.D., Nonclinical Reviewer
`
`Peter Franks, M.S., Regulatory Project Manager
`
`
`Allison Bean, Student Intern
`
`
`Office of Biostatistics
`
`
`Yun Wang, Ph.D., Statistical Team Lead
`
`
`Eugenio Andraca-Carrera, Ph.D., Statistical Team Lead
`
`Yoonhee Kim, Ph.D., Mathematical Statistician
`
`
`Ya-Hui (Catherine) Hsueh Ph.D., Mathematical Statistician
`
`
`
`Office of Biotechnology Products
`
`
`
`Daniela Verthelyi, M.D., Ph.D., Team Lead, Laboratory of Immunology
`
`
`Mohanraj Manangeeswaran, Ph.D., Reviewer, Laboratory of Immunology
`
`
`Office of Clinical Pharmacology
`
`
`Manoj Khurana, Ph.D., Clinical Pharmacology Team Lead
`
`
`Tao Liu, Ph.D., Clinical Pharmacology Reviewer
`
`
`Office of Surveillance and Epidemiology
`
`
`
`
`Nichelle Rashid, Safety Regulatory Project Management Team Lead (Acting)
`
`
`Ariane Conrad, Pharm.D., Safety Evaluator, DMEPA
`
`Terrolyn Thomas, MS, MBA; Senior Regulatory Project Manager
`
`

`

`
`
`
`
`
` IND 114464
` Page 2
`
`
`
` Office of Scientific Investigations
`
` Cynthia Kleppinger, M.D., Senior Medical Officer
`
`
`SPONSOR ATTENDEES
`
`Anders Hvelplund, Executive Director, US Clinical Development and Outcomes Research
`
`
`Anne Phillips, Senior Vice President, Clinical Medical and Regulatory Affairs
`
`
`Birgitte Lysgaard-Jensen, Senior Regulatory Professional, HQ Regulatory Affairs
`
`Jan Vanggaard Andersen, Nonclinical Project Director, Nonclinical Project Management
`
`Jeppe Juul, Statistical Programming Specialist, Biostatistics
`
`
`Jeppe Zacho, Senior Director, Medical and Science
`
`
`
`
`Mads Frederik Rasmussen, Corporate Project VP, Semaglutide Diabetes & Diabetes Outcomes
`
`
`Mette Thomsen, International Medical Director, Medical and Science
`
`Premlata Gunapu, Manager, US Regulatory Affairs
`
`
`Robert Clark, Vice President, US Regulatory Affairs
`
`
`
`Stephanie DeChiaro, Senior Director, US Regulatory Affairs
`
`
`Stephen Gough, Senior Vice President, Global Chief Medical Officer
`
`
`Trine Saugstrup, Statistical Director, Biostatistics
`
`Vibeke Hatorp, Senior Director, HQ Regulatory Affairs
`
`1.0
`
`
`Novo Nordisk has requested a Type B Pre-NDA meeting under IND 114464 to discuss aspects
`
`
`
`
`of the oral semaglutide development program and the requirements for NDA submission.
`Semaglutide is a long acting glucagon-like peptide-1 (GLP-1) analogue that is being developed
`
`as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes
`
`
`mellitus (T2DM). Semaglutide is also being investigated in a subcutaneous injection for T2DM
`
`
`under IND 079754.
`
`
`BACKGROUND
`
`
`
`
`
`
`
`The peptide backbone of semaglutide has an acylation in position 26 with a fatty-acid derivative,
`
`
`which binds to albumin and thereby stabilizes the peptide backbone in plasma and decreases the
`
`renal clearance of the compound. The IND for semaglutide tablet, co-formulated with sodium N­
`[8-(2-hydroxybenzoyl) amino] caprylate (SNAC), was submitted on September 26, 2013, for
`
`
`
`once-daily oral administration as an adjunct to diet and exercise to improve glycemic control in
`
`patients with T2DM. SNAC is an excipient that intends to increase the bioavailability of orally
`
`administered semaglutide.
`
`
`On September 22, 2014, FDA provided Type C written responses. The responses included
`
`recommendations and feedback on the oral semaglutide Phase 3 program.
`
`
`On March 27, 2015, FDA provided Type C written responses. The responses included advice on
`the oral semaglutide development program in pediatric subjects aged 10 to less than 18 years.
`
`
`On July 10, 2015, FDA provided Type B meeting minutes for the End-of-Phase 2 Meeting,
`
`
`
`which occurred on June 11, 2015. During this meeting, the Agency provided comments on
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`(b) (4)
`
`

`

`
`
`
`
`
` IND 114464
`
` Page 3
`
`
`
`
` chemistry, manufacturing and controls (CMC), preclinical, and clinical topics related to the
`
` initiation of the Phase 3 program.
`
`
`
`Novo Nordisk initiated a Phase 3 clinical development program in 2016 that is currently
`
`
`ongoing. The program includes a cardiovascular safety study (PIONEER 6).
`
`
`On March 24, 2017, FDA provided Type C written responses. The responses included
`recommendations and feedback on the quality development of the drug product.
`
`
`
`NDA 209637 for Ozempic (semaglutide) injection 0.5 mg and 1 mg was approved on
`
`December 5, 2017, for once-weekly (OW) subcutaneous (s.c.) administration, as adjunct to diet
`
`and exercise to improve glycemic control in adults with T2DM.
`
`
`On April 23, 2018, FDA provided recommendations and feedback for an amendment dated
`
`March 23, 2018, which contained a cardiovascular “bridging” strategy involving cardiovascular
`
`data from both the semaglutide injection and the semaglutide tablet trials.
`
`
`
`FDA sent Preliminary Comments to Novo Nordisk on November 27, 2018.
`
`
`
`2. DISCUSSION
`
`The sponsor’s questions are followed by our bolded response. Any meeting discussion is in
`
`
`
`italicized text. Any post-meeting comments are underlined.
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`
`
`2.1.
`
`
`
`Clinical
`
`
`Question 1: Does the Agency agree to the proposed approach for presentation of the
`
`
`efficacy evaluations in the SCE?
`
`FDA Response to Question 1:
`
`
`
`
`
`You propose to present the full evaluation of efficacy in the Summary of Clinical
`
`Efficacy (SCE) trial-by-trial, with no pooling of data across trials, and that the SCE will
`
`serve as Integrated Summary of Effectiveness (ISE). Your proposed approach seems
`
`reasonable. We agree with the use of the treatment policy estimand as a primary
`estimand for presentations of study results and potential claims of superiority, and non-
`
`inferiority.
`
`Discussion: No further discussion.
`
`
`
`Question 2: Does the Agency agree to 05 November 2018 as the cut-off date for the NDA?
`
`
`
`
`FDA Response to Question 2:
`
`
`Your proposal to included blinded safety data from 3 trials (PIONEER 7 extension, and
`
`clinical pharmacology trials 4248, and 4427) as of the NDA cut-off date of
`
`
`
`

`

`
`
`
` IND 114464
`
` Page 4
`
`
`
`
`
`
`
`
`
`
` November 5, 2018, is acceptable. If safety issues are identified that require an
`
` assessment of unblinded data from these trials, unblinding may be requested.
` Additionally, for PIONEER 6, we recommend you include all adjudicated events in the
`
`
` primary analysis between the cut-off date and the trial termination visit.
`
`
`Discussion: The sponsor referred to slide 2 of their presentation. The sponsor clarified that
`
`subjects’ last visits in PIONEER 6 occurred between July and September 2018. All events
`
`that occurred up to the last study visit were adjudicated and will be included in the clinical
`
`study report and the corresponding datasets in the NDA submission. The sponsor also
`mentioned that they underwent adjudications for all clinical events occurred between last
`
`subject last visit and database lock for PIONEER 6 and describe the cases in the clinical
`
`
`
`study report. The database lock for PIONEER 6 occurred in November 2018. FDA had no
`
`further comments.
`
`Question 3: Does the Agency agree with the proposal of waiving the submission of a
`
`
`
`4-month safety update to the NDA for oral semaglutide?
`
`FDA Response to Question 3:
`
`
`No, we do not agree. You should submit the 4-month safety update with any available
`
`new data.
`
`
`Discussion: No further discussion.
`
`
`
`Question 4: Does the Agency agree to only include data from oral semaglutide clinical trials
`
`
`
`
`in the ISS?
`
`
`FDA Response to Question 4:
`
`
`Your proposal is acceptable.
`
`
`Discussion: No further discussion.
`
`
`
`Question 5: Does the Agency agree to the proposed pooling strategy to be used in the ISS?
`
`
`
`
`FDA Response to Question 5:
`
`
`You are proposing to evaluate safety based on the following pools: Phase 3a pool
`
`(PIONEER 1-5, and 7-10), placebo pool (PIONEER 1, 4, 5, 8, and 9), and placebo dose
`
`pool (where all three doses of semaglutide were evaluated, PIONEER 1, 8, and 9). You
`
`
`also propose to present data from the cardiovascular outcome trial (PIONEER 6)
`
`
`separately from the Phase 3 pool.
`
`
`We agree that data from the cardiovascular outcomes trial can be presented separately.
`
`
`To facilitate the safety review, we ask that you present the following additional pools:
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
` IND 114464
`
` Page 5
`
`
`
`
`
`
`
` 1. A pool of placebo-controlled studies (PIONEER 1, 4, 5, and 8)
`
`
` 2. A pool of the multi-national Phase 3 studies (PIONEER 1-5, and 7, 8)
`
` 3. A pool of the Japanese safety studies (PIONEER 9 and 10)
`
`
`
`
`
`
`
`When presenting the safety findings, we request that you present the findings by
`
`individual dose of semaglutide, pooled semaglutide, compared to placebo, compared to
`
`active comparator, and compared to all comparators (as applicable).
`
`Discussion: As an alternative to the pooling strategy that FDA recommended, the sponsor
`
`
`proposed a revised pooling strategy with 3 pools, including a Phase 3a pool, a placebo pool,
`and a placebo-dose pool. The sponsor referred to slide 3 of their presentation. FDA agreed
`with this pooling strategy. FDA would like to have the ability to separate out the Japanese
`
`studies (PIONEER 9 and 10), and the sponsor stated that these studies would be flagged in
`
`datasets, and easily separated for analysis.
`
`Question 6: Does the Agency agree with the proposed strategy for presentation of the safety
`
`
`evaluation in the Integrated Summary of Safety?
`
`
`FDA Response to Question 6:
`
`
`You propose to assess safety in the ISS via an integrated approach based on the data
`collected across the oral semaglutide clinical program, based on the safety analysis set,
`and the on-treatment observation period (with the exception of death, and adverse
`
`events with potential long latency between onset and diagnosis, for which the in-trial
`
`observation period will be used). Safety data from clinical pharmacology trials will also
`
`
`be presented in the ISS in a pool separate from the Phase 3 studies (exposure, and AEs).
`
`Safety data from the dose finding study 3790 will be presented separately as it includes
`
`doses not studied in the Phase 3 program. The evaluation of cardiovascular safety will
`
`be based on the cardiovascular outcomes trial PIONEER 6.
`
`
`Your proposed strategy for presenting safety appears generally adequate, with the
`exception of the proposed pools for the Phase 3 studies (see our response to Question 5
`
`above).
`
`At the time of the NDA submission, please submit a document listing the source of the
`
`data for each of the safety tables.
`
`Discussion: No further discussion.
`
`
`
`Question 7: Does the Agency agree to the above proposal [regarding immunogenicity
`
`
`
`
`assays]?
`
`
`FDA Response to Question 7:
`
`
`No, we do not agree. For the oral semiglutide program, you will need to submit a
`
`
`complete immunogenicity dataset from the oral semaglutide program that includes data
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
` IND 114464
` Page 6
`
`
`
`
`from screening, confirmatory and titering ADA assays, as well as a neutralizing assay.
`Although your screening assay is not isotype specific, you should provide data
`supporting that your assay would detect anti-semaglutide antibodies of IgA isotype, if
`
`present in the serum. If there is clinical evidence of hypersensitivity, an assessment of
`
`
`IgE antibodies using an assay that can detect clinically relevant levels of IgE may be
`
`
`required. Please submit the preferred terms used to evaluate for hypersensitivity in the
`
`clinical program with the NDA submission and clarify if these terms were pre-specified.
`
`
`
`Regarding the neutralizing assay, submitting a cross-reference for the validation would
`
`
`be acceptable. We recommend that the immunogenicity part of the submission be
`
`
`
`arranged into distinct sections (1) Immunogenicity Risk Assessment, including a risk
`
`
`assessment for the novel excipients used in your product (2) Tiered Bioanalytical
`
`Strategy and Assay Validation Summaries, (3) Clinical Study Design and Detailed
`
`
`Immunogenicity Sampling Plans, (4) Clinical Immunogenicity Data Analysis, and (5)
`
`Conclusions and Risk Evaluation and Mitigation Strategies if needed (REMS).
`
`
`
`Discussion: The sponsor stated that they would implement the recommendations as set forth
`in the FDA preliminary comments document. The sponsor referenced a November 14, 2018,
`submission to the IND which includes validated methods for antibody assays. The sponsor is
`
`awaiting feedback from FDA on these methods, and plans to reanalyze samples once the
`
`feedback is received. The sponsor inquired on the timeframe to provide feedback, and FDA
`stated that the review would be provided as soon as possible, since this is needed prior to the
`
`NDA submission which is planned for March 2019.
`
`2.1.
`
`
`Statistics
`
`
`Question 8: Does the Agency agree to the planned ADaM domains that will be included in
`the NDA?
`
`
`
`FDA Response to Question 8:
`
`
`Yes, we agree with your proposal to submit electronic data sets for all Phase 2, Phase 3,
`
`and clinical pharmacology studies.
`
`Discussion: No further discussion.
`
`
`
`Question 9: Does the Agency have any comments to the format of the sample datasets
`
`
`provided?
`
`
`FDA Response to Question 9:
`
`
`In addition to analysis results metadata in define-xml, please provide analysis programs
`
`with adequate annotations that are used for key efficacy analysis including pre­
`
`specified sensitivity analysis, as well as post-hoc analyses included in the planned
`clinical study report, if any. Provide a separate tabular listing (see below example) in
`
`
`pdf format to describe the key efficacy analysis you have done, the list should include
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
` IND 114464
` Page 7
`
`
`
`
` the output file name, analysis program name, the title of results with table/figure
`
`number, datasets utilized, and macros used. All macros inside the actual program for
`running should also be submitted.
`
`
`
`
`
`Example of tabular listing:
`
` Output file
` Program Name Title/Description
`
`
`
` name
` Eff_output Eff_anal1.sas
`
`
`
`
`
`
`
`
` Primary Efficacy
`
` analysis
`
` in Table XX.X in the
`
` clinical study report
`
`
` Datasets
`
` Utilized
` ADLB, ADSL
`
`
`
`
` Macro’s Used
`
`
`
` %macro1
`
`
`
` Please clarify a definition of “period 30” in the Table 4 Core Variables from the
`
`
` submitted Analysis Data Reviewer’s Guide Trial ID NN9924-4233. Please clarify the
` meaning of “period 30” for each trial. Also, clarify the difference between variables
`
`named TRT30P and TRTP. We prefer the same core variable names (for example, core
`
` variable indicating treatment arm as TRTP or etc.) across ADaM domains and across
`
` trials used in the key efficacy analyses.
`
`Discussion: The sponsor referred to slide 5 of their presentation and the sponsor will clarify
`
`
`the definition of variable names in the analysis data reviewer’s guide. FDA had no further
`
`comments.
`
`Question 10: Does the Agency have any comment to the excerpts from the Reviewer’s
`
`
`
`
`
`Guide?
`
`
`
`FDA Response to Question 10:
`
`
`
`
`See response to Question 9.
`
`
`Discussion: No further discussion.
`
`
`
`
`
`
`2.2.
`
`
`Regulatory
`
`
`Question 11: Does the Agency have any input to the approach outlined above [regarding
`
`
`
`use of a priority review voucher]?
`
`
`FDA Response to Question 11:
`
`
`
`
`We do not have any comments.
`
`
`Discussion: No further discussion. See below discussion on Cardiovascular Strategy, which
`
`
`
`includes reference to the priority review voucher.
`
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
`
`
`
`
`
`
` IND 114464
` Page 8
`
`
`
` 2.3. Additional Discussion Topics
`
`
` The sponsor included two additional topics with their slide presentation to discuss, if time
`
`
`
`permitted, which were not included in the meeting package. These topics included the
`
`
`cardiovascular strategy for oral semaglutide
`
`
`Cardiovascular Strategy
`
`
`The sponsor stated at the meeting that they intend to include a CV indication with the oral
`
`semaglutide NDA. FDA encouraged the sponsor to request a Type C meeting, in teleconference
`
`
`format, to review the topline safety and MACE results of the CVOT study. FDA stated that this
`teleconference should occur prior to the submission of the NDA, which is planned for March
`2019.
`
`
`Post Meeting Comment: The sponsor submitted a formal meeting request on
`December 11, 2018, to discuss the CVOT study. In lieu of a type C meeting, the sponsor and
`FDA held an informal teleconference on December 20, 2018, for the sponsor to present the
`
`topline safety and MACE results from the PIONEER-6 study. Based on the presentation at this
`
`
`teleconference and lack of clarity on the data that will be relied upon for the sought-after
`
`
`
`indication, FDA recommended that the sponsor submit a pre-NDA meeting request to discuss the
`
`cardiovascular indication, for which the sponsor indicated that they may submit a separate
`
`NDA.
`
`In addition to the CV indication, the sponsor stated that they intend to submit a priority review
`
`voucher for the oral semaglutide NDA, which would entail a 6-month review clock. FDA
`
`recommended that if they do intend to use the voucher, that they may submit any finalized study
`
`
`reports to the IND as soon as possible, prior to the NDA submission. These would include
`
`clinical study reports, nonclinical reports, and/or clinical pharmacology reports. The sponsor
`
`inquired on if FDA had a preferred format for clinical pharmacology data, and FDA agreed to
`
`provide an example table with this information as soon as possible. Additionally, FDA
`
`
`
`recommended that a data walkthrough meeting should occur shortly after the NDA is submitted.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
` IND 114464
` Page 9
`
`
`
` 3.0 OTHER IMPORTANT MEETING 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.
`
` 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 at:
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM360507.pdf. 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:
`
`
`http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht
`m.
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
`
` IND 114464
`
`
` Page 10
`
`
` 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 Information and Pregnancy and Lactation
`
`
`Labeling Final Rule 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
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM425398.pdf).
`
`
`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 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 Integrated Summary of
`
`
`
`
`
`
`Safety (ISS) and related data requirements. Topics of discussion at this meeting would include
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
`•
`
` IND 114464
`
`
` Page 11
`
`
`
`
` 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.
`
`
`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
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
`
`
`
`
`
` IND 114464
`
`
` Page 12
`
`
` in the attachment titled, “Product name, NDA/BLA 012345, Establishment Information for Form
`
` 356h.”
`
`
` Federal
`
`
` Establishment
`Indicator
`
`(FEI) or
`
`Registration
`
`Number
`
`(CFN)
`
`
`
`
` Site Name
`
`
`
` Site Address
`
`
`
`
`
`
`
`
` 1.
`
` 2.
`
`
`Corresponding names and titles of onsite contact:
`
`
` Drug
`
` Master
`
`
` File
`Number
`
`(if
`applicable)
`
`
`
`
`Manufacturing Step(s)
`
`or Type of Testing
`
`[Establishment
`function]
`
`
`
`
`
`
`
` Email address
`
`Phone and
`
` Fax
` number
`
`
`
`
`
`
`
`
`
` 1.
`
` 2.
`
`
` FDA has made a preliminary determination that the application for this product would not be
` reviewed as a new molecular entity (NME) and would not be subject to the Program under
`
`
`
`
` PDUFA VI. Please note that this is a preliminary determination, based on information available
`
` to FDA at this time, and will be re-evaluated at the time your application is submitted. This
`
`
`
` determination is based on our understanding of the active moiety (21 CFR 314.108(a)) and
`
` whether another marketing application containing the same active moiety is approved or
`
` marketed. Please also note that the NME determination for an application is distinct from and
`
`
`
` independent of the new chemical entity (NCE) determination and any related exclusivity
` determinations, which are made after approval of an NDA
`
`
`
`
`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.
`
`
`
`
` Site Name
`
`
`
` Site Address
`
`
`
`
`Onsite Contact
`
`(Person, Title)
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`

`

`
`
`
`
` IND 114464
`
`
` Page 13
`
`
`
`
` 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:
`
`
`
`https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire
`ments/UCM332466.pdf
`
`
`https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire
`ments/UCM332468.pdf.
`
`
`4.0
`
`Sponsor’s slides presented at the meeting
`
`ATTACHMENTS AND HANDOUTS
`
`
`
`
`
`
`Reference ID: 4369068Reference ID: 4497378
`
`6 Page(s) hav