CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`214324Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`IND 134582
`
`United Therapeutics Corporation
`Attention: Sarah Gemberling, PhD, RAC
`Associate Manager, Regulatory Affairs
`P.O. Box 14186
`55 T.W. Alexander Drive
`Research Triangle Park, NC 27709
`
`Dear Dr. Gemberling:
`
`MEETING REQUEST-
`WRITTEN RESPONSES
`
`Please refer to your investigational new drug application (IND) submitted under section
`505(i) of the Federal Food, Drug, and Cosmetic Act for Tyvaso DPI.
`
`We also refer to your submission dated October 2, 2020, containing a meeting request.
`The purpose of the requested meeting was to discuss your proposal for the filing of a
`new NDA (Pre-Assigned application number NDA 214324) for Treprostinil Inhalation
`Powder for the treatment of pulmonary arterial hypertension (PAH) and the treatment of
`pulmonary hypertension associated with interstitial lung disease (PH-ILD).
`
`Further reference is made to our Meeting Granted letter dated October 20, 2020,
`wherein we stated that written responses to your questions would be provided in lieu of
`a meeting.
`
`The enclosed document constitutes our written responses to the questions contained in
`your October 30, 2020 background package.
`
`If you have any questions, call Wayne Amchin, MPA, MIA, RAC, Regulatory Project
`Manager at 301-796-0421.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Norman Stockbridge, MD, PhD
`Director
`Division of Cardiology and Nephrology
`Office of Cardiology, Hematology, Endocrinology
`and Nephrology
`Center for Drug Evaluation and Research
`
`Enclosure:
` Written Responses
`
`
`Reference ID: 4704205
`
`

`

`WRITTEN RESPONSES
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-NDA
`
`Application Number:
`
`IND 134582
`
`Product Name:
`Indication:
`
`Sponsor Name:
`Regulatory Pathway:
`
`Tyvaso DPI
`Pulmonary arterial hypertension and pulmonary
`hypertension due to interstitial lung disease
`United Therapeutics Corporation
`505(b)(1) of the Federal Food, Drug, and Cosmetic Act
`
`1.0
`
`BACKGROUND
`
`Treprostinil is a prostacyclin vasodilator and has been approved in inhalation(Tyvaso),
`injection (Remodulin), and oral (Orenitram) formulations. A pre-IND meeting was held
`with the previous sponsor, and meeting minutes were issued on July 28, 2017. The IND
`was submitted on January 29, 2018, and a safe-to-proceed letter with non-hold
`comments was issued on March 1, 2018. A type C guidance meeting was also held on
`January 11, 2018, following the sponsor’s acquisition of this product to discuss the
`intended product development pathway and to gain agreement on the content of a
`marketing application.
`
`The proposed product is being developed as a combination drug/device product for oral
`inhalation consisting of cartridges containing Treprostinil Inhalation Powder for use in a
`reusable breath-powered dry powder inhaler. The drug/device combination will be used
`for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve
`exercise ability. The previous sponsor was developing the proposed product under the
`505(b)(2) regulatory pathway, but United Therapeutics is developing it under the
`505(b)(1) pathway.
`
`2.0
`
`2.1.
`
`QUESTIONS AND RESPONSES
`
`Clinical
`
`Question 1: Study TIP-PH-101: An Open-label, Clinical Study to Evaluate the Safety
`and Tolerability of Treprostinil Inhalation Powder (TreT) in Subjects with Pulmonary
`Arterial Hypertension Currently Using Tyvaso is currently ongoing and open to
`enrollment. During the pre-IND meeting on 28 June 2017 held with the previous
`sponsor, it was agreed that a sample size of approximately 45 subjects dosed for 3
`weeks (i.e., 2.5 treatment years) would be sufficient to demonstrate safety and
`tolerability. In response to the ongoing COVID-19 pandemic, UTC re-examined the
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 2
`
`sample size needed to demonstrate safety and tolerability of TreT. Since the TIP-PH-
`101 study has an Optional Extension Phase, 17.4 treatment years of TreT exposure has
`already accumulated for all enrolled subjects. The PAH patient population has little
`margin to tolerate the respiratory compromise caused by COVID-19 pneumonitis,
`therefore UTC would like to minimize the risk of exposing these patients to SARS-Cov-2
`(while in clinic and travelling to clinic) by limiting enrollment to no more than absolutely
`necessary to meet the study objectives. UTC proposes to decrease the total sample
`size of TIP-PH-101 to at least 38 subjects and use existing clinical data in support of the
`NDA. Does the Agency agree?
`
`Note: This question was withdrawn by a November 17, 2020 email from Dr. Sarah
`Gemberling, PhD, RAC, Associate Manager, Regulatory Affairs, United Therapeutics,
`informing the Division that enrollment for the study is now complete and it met the
`protocol specified sample size. Therefore, UTC no longer requires a response for
`question 1.
`
`Question 2: Three clinical studies were conducted to support the filing of the NDA. 1) a
`single ascending dose (SAD) study in healthy volunteers (MKC-475-001), 2) an open-
`label study to evaluate the short-term safety and tolerability following repeat doses of
`TreT (TIP-PH-101) in PAH patients currently treated with Tyvaso, and 3) a relative
`bioavailability study of TreT compared to Tyvaso (TIP-PH-102). Since none of these
`studies are major, pivotal studies, UTC does not plan to include Bioresearch Monitoring
`(BIMO) datasets with the NDA submission. Does the Agency agree that BIMO datasets
`are not required to support this application?
`
`FDA Response to Question 2: Yes, we agree that BIMO datasets will not be needed.
`
`Question 3: Study TIP-PH-101: An Open-label, Clinical Study to Evaluate the Safety
`and Tolerability of Treprostinil Inhalation Powder (TreT) in Subjects with Pulmonary
`Arterial Hypertension Currently Using Tyvaso, consists of a three-week Treatment
`Phase followed by an Optional Extension Phase. As described in the Statistical Analysis
`Plan, after all subjects complete the Treatment Phase, the Treatment Phase database
`will be locked and analysis of the data from the Treatment Phase will be carried out.
`Available data from the Optional Extension Phase will also be analyzed at this time.
`Therefore, the primary TIP-PH-101 Clinical Study Report that will be submitted in the
`original NDA will contain all data from the Treatment Phase and any available data at
`the time of data cut from the Optional Extension Phase. Does the Agency agree with
`this approach?
`
`FDA Response to Question 3: Yes, we agree.
`
`Question 4: UTC plans to rely on existing treprostinil evidence of safety and
`effectiveness from approved treprostinil products, Tyvaso (NDA 022387), Remodulin
`(NDA 021272), and Orenitram (NDA 203496), in addition to the three agreed clinical
`studies for Treprostinil Inhalation Powder. Within the Integrated Summaries of Safety
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 3
`
`and Effectiveness, UTC plans to cross reference evidence in the approved NDAs in
`addition to summaries of the new clinical studies. Sections 2.7.3 and 2.7.4 will be
`sufficiently detailed to serve as the narrative portion of the ISE and ISS, respectively,
`while concise enough to meet the suggested size limitations for Module 2. Therefore,
`UTC proposes to split the ISE and ISS across Module 2 and Module 5, with the
`narrative portion located in Sections 2.7.3 or 2.7.4 and the appendices of tables, figures,
`and datasets located in Section 5.3.5.3. Does the Agency agree with this approach?
`
`FDA Response to Question 4: Yes, we agree.
`
`2.2.
`
`Format and Administrative Questions
`
`Question 5 (multi-discipline): Is the planned Table of Contents for the NDA, Section
`15.2.2, sufficient for review?
`
`FDA Response to Question 5: Include the appropriate Regional Information and
`Appendices in your drug product quality submission, and include the “Summary of
`Biopharmaceutic studies and associated analytical methods” and “Summary of Clinical
`Pharmacology Studies” under Module 2.7. From a clinical perspective and
`pharmacology/toxicology perspective your planned NDA Table of Contents is
`acceptable.
`
`Question 6 (Clinical): The clinical development plan, as agreed with the Agency during
`a pre-IND meeting on 28 June 2017, and subsequent Type C meetings under IND
`134,582 (06 January 2019 (preliminary meeting comments accepted as final minutes)
`and 04 December 2019), included clinical studies to establish safety/tolerability,
`characterize pharmacokinetics of the drug product, and assess relative bioavailability of
`treprostinil between Tyvaso and TreT. UTC currently has an efficacy supplement (S-
`017; NDA 022387) under review for Tyvaso (treprostinil) Inhalation Solution to add the
`PH-ILD indication. If the data support the approval of the Tyvaso label extension to
`include treatment of PH-ILD, UTC intends to include the same indication for the
`Treprostinil Inhalation Powder NDA. Demonstrated relative bioavailability of treprostinil
`between Tyvaso and TreT should support the use of TreT in all approved Tyvaso
`indications. Does the Agency agree?
`
`FDA Response to Question 6: Yes, we agree with your plan.
`
`Question 7 (CMC): UTC intends to cross reference DMF
` for all information
`related to the quality of the Treprostinil Inhalation Powder drug product and the dry
`powder inhaler. All future manufacturing changes will be reflected in the DMF and cross
`referenced in the Treprostinil Inhalation Powder NDA. Notifications of DMF updates will
`be submitted to the NDA as annual reports, CBE, or PAS, as appropriate. Does the
`Agency have any concerns?
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`(b) (4)
`
`

`

`IND 134582
`Page 4
`
`FDA Response to Question 7: From a CMC perspective, the proposed approach
`appears reasonable.
`
`Question 8 (multi-discipline): The draft Treprostinil Inhalation Powder Package Insert
`was based on the Package Insert for Tyvaso (NDA 022387). Adverse events from the
`completed TreT clinical studies are summarized in Section 6 Adverse Reactions of the
`draft Package Insert. Study TIP-PH-102 is further summarized in Section 12 Clinical
`Pharmacology
` Does
`the Agency agree with the placement of these studies in the draft Package Insert?
`
`FDA Response to Question 8:
` Otherwise your approach seems reasonable.
`
`
`
`Question 9 (Clincial, Labeling): The NDA submission will include Instructions for Use
`of the combination product. In the Acknowledgement letter dated 13 June 2020 for
`UTC’s Tyvaso (NDA 022387) Supplement 017, the Agency noted that the Patient
`Package Insert would be removed from the approved labeling because it is duplicative
`of the Instructions for Use. Does the Agency agree that a separate Patient Package
`Insert is not required in addition to the Instructions for Use and Package Insert for
`Treprostinil Inhalation Powder?
`
`FDA Response to Question 9: We agree this approach is reasonable.
`
`ADDITIONAL COMMENTS:
`
`COMMENTS ABOUT ACCEPTABILITY OF THE DEVICE FOR THE MARKETING
`APPLICATION:
`
`1. You stated that you have minor changes to the device. However, it is not clear
`exactly where these changes are made.
`a. To allow the Agency to evaluate whether the proposed changes may
`affect safety or effectiveness, please provide drawings and description on
`the changes.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 134582
`Page 5
`
`3.0
`
`ADDITIONAL 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.1 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.2
`
`1 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.
`2 https://www.fda.gov/drugs/development-resources/pediatric-and-maternal-health-
`product-development
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`(b) (4)
`
`

`

`IND 134582
`Page 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
`Information3 and Pregnancy and Lactation Labeling Final Rule4 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:
`
`3 https://www.fda.gov/drugs/laws-acts-and-rules/plr-requirements-prescribing-
`information
`4 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: 4704205
`
`

`

`IND 134582
`Page 7
`
`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.
`
`DATA STANDARDS FOR STUDIES
`
`Under section 745A(a) of the FD&C Act, electronic submissions “shall be submitted in
`such electronic format as specified by [FDA].” FDA has determined that study data
`contained in electronic submissions (i.e., NDAs, BLAs, ANDAs and INDs) must be in a
`format that the Agency can process, review, and archive. Currently, the Agency can
`process, review, and archive electronic submissions of clinical and nonclinical study
`data that use the standards specified in the Data Standards Catalog.5
`
`On December 17, 2014, FDA issued the guidance for industry Providing Electronic
`Submissions in Electronic Format - Standardized Study Data. This guidance describes
`the submission types, the standardized study data requirements, and when
`standardized study data are required. Further, it describes the availability of
`implementation support in the form of a technical specifications document, Study Data
`Technical Conformance Guide, as well as email access to the eData Team (cder-
`edata@fda.hhs.gov) for specific questions related to study data standards.
`Standardized study data are required in marketing application submissions for clinical
`and nonclinical studies that started after December 17, 2016. Standardized study data
`are required in commercial IND application submissions for clinical and nonclinical
`studies that started after December 17, 2017. CDER has produced a Study Data
`Standards Resources web page6 that provides specifications for sponsors regarding
`implementation and submission of clinical and nonclinical study data in a standardized
`format. This web page will be updated regularly to reflect CDER's growing experience in
`order to meet the needs of its reviewers.
`
`For commercial INDs and NDAs, Standard for Exchange of Nonclinical Data (SEND)
`datasets are required to be submitted along with nonclinical study reports for study
`types that are modeled in an FDA-supported SEND Implementation Guide version. The
`FDA Data Standards Catalog, which can be found on the Study Data Standards
`Resources web page noted above, lists the supported SEND Implementation Guide
`versions and associated implementation dates.
`
`Although the submission of study data in conformance to the standards listed in the
`FDA Data Standards Catalog will not be required in studies that started on or before
`December 17, 2016, CDER strongly encourages IND sponsors to use the FDA
`supported data standards for the submission of IND applications and marketing
`applications. The implementation of data standards should occur as early as possible in
`
`5 http://www.fda.gov/forindustry/datastandards/studydatastandards/default.htm
`6 http://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 8
`
`the product development lifecycle, so that data standards are accounted for in the
`design, conduct, and analysis of clinical and nonclinical studies. For clinical and
`nonclinical studies, IND sponsors should include a plan (e.g., in the IND) describing the
`submission of standardized study data to FDA. This study data standardization plan
`(see the FDA Study Data Technical Conformance Guide) will assist FDA in identifying
`potential data standardization issues early in the development program.
`
`If you have not previously submitted an eCTD submission or standardized study data,
`we encourage you to send us samples for validation following the instructions at
`FDA.gov. For general toxicology, supporting nonclinical toxicokinetic, and
`carcinogenicity studies, submit data in the Standards for the Exchange of Nonclinical
`Data (SEND) format. The validation of sample submissions tests conformance to FDA
`supported electronic submission and data standards; there is no scientific review of
`content.
`
`The Agency encourages submission of sample data for review before submission of the
`marketing application. These datasets will be reviewed only for conformance to
`standards, structure, and format. They will not be reviewed as a part of an application
`review. These datasets should represent datasets used for the phase 3 trials. The FDA
`Study Data Technical Conformance Guide (Section 7.2 eCTD Sample Submission pg.
`30) includes the link to the instructions for submitting eCTD and sample data to the
`Agency. The Agency strongly encourages Sponsors to submit standardized sample
`data using the standards listed in the Data Standards Catalog referenced on the FDA
`Study Data Standards Resources web site. When submitting sample data sets, clearly
`identify them as such with SAMPLE STANDARDIZED DATASETS on the cover letter
`of your submission.
`
`Additional information can be found at FDA.gov.7
`
`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 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.
`
`7 https://www.fda.gov/industry/study-data-standards-resources/study-data-submission-
`cder-and-cber
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 9
`
`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 in the attachment titled, “Product name, NDA/BLA 012345,
`Establishment Information for Form 356h.”
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 10
`
`Site Name
`
`Site
`Address
`
`(1)
`(2)
`
`Federal
`Establishment
`Indicator
`(FEI) or
`Registration
`Number
`(CFN)
`
`Drug
`Master
`File
`Number
`(if
`applicable
`)
`
`Manufacturing
`Step(s)
`or Type of Testing
`[Establishment
`function]
`
`Corresponding names and titles of onsite contact:
`
`Site Name
`
`Site
`Address
`
`Onsite Contact
`(Person, Title)
`
`Phone
`and Fax
`number
`
`Email address
`
`(1)
`(2)
`
`To facilitate our facility assessment and inspectional process for your marketing
`application, we refer you to the instructional supplement for filling out Form FDA 356h8
`and the guidance for industry, Identification of Manufacturing Establishments in
`Applications Submitted to CBER and CDER Questions and Answers9. Submit all related
`manufacturing and testing facilities in eCTD Module 3, including those proposed for
`commercial production and those used for product and manufacturing process
`development.
`
`8 https://www.fda.gov/media/84223/download
`9 https://www.fda.gov/regulatory-information/search-fda-guidance-
`documents/identification-manufacturing-establishments-applications-submitted-cber-
`and-cder-questions-and
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`IND 134582
`Page 11
`
`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, and the associated conformance guide, 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.10
`
`10 https://www.fda.gov/media/85061/download
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4704205
`
`

`

`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.
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`WAYNE S AMCHIN
`11/19/2020 10:30:54 AM
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`NORMAN L STOCKBRIDGE
`11/19/2020 11:49:54 AM
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`Reference ID: 4704205
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