CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209607Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`IND 70663
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`
`Molecular Insight Pharmaceuticals Inc.
`C/O Progenics Pharmaceuticals, Inc.
`Attention: Jouliana Jean Paul, J.D.
`Regulatory Affairs Manager
`1 World Trade Center, 47th Floor
`47th Floor, Suite J
`New York, NY 10007
`
`Dear Ms. Paul:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for 131I Iobenguane.
`
`We also refer to the meeting between representatives of your firm and the FDA on
`January 17, 2017. The purpose of the meeting was to discuss nonclinical, clinical pharmacology,
`clinical and statistical issues regarding the proposed NDA.
`
` 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, please call me at (301) 796-2320.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Sharon Sickafuse, M.S.
`Senior Regulatory Health Project Manager
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure:
`Meeting Minutes
`
`Reference ID: 4050193
`
`
`
`

`

`
`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`MEMORANDUM OF MEETING MINUTES
`
`
`Type B
`preNDA
`
`January 17, 2017
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date:
`
`Application Number:
`Product Name:
`Indication:
`
`Suzanne Demko
`Sharon Sickafuse
`
`IND 70663
`131I Iobenguane
`Treatment of iobenguane-avid metastatic or recurrent
`pheochromocytoma and paraganglioma
`Sponsor/Applicant Name: Molecular Insight Pharmaceuticals (MIP)
`
`Meeting Chair:
`Meeting Recorder:
`
`FDA ATTENDEES
`Office of Hematology and Oncology
`Division of Oncology Products 2
`Brendan Baggot
`Amy Barone, M.D.
`Diana Bradford, M.D.
`Suzanne, Demko, P.A.-C.
`Martha Donoghue, M.D.
`Patricia Keegan, M.D.
`Sharon Sickafuse, M.S.
`
`Division of Hematology Oncology Toxicology
`Whitney Helms, Ph.D.
`
`Office of Biostatistics
`Division V
`Huanyu (Jade) Chen, Ph.D.
`
`Office of Clinical Pharmacology
`Division V
`Brian Furmanksi, Ph.D.
`Hong Zhao, Ph.D.
`
`
`
`
`
`
`
`
`Reference ID: 4050193
`
`

`

`IND 70663
`Page 2
`
`SPONSOR ATTENDEES
`Stuart Apfel, M.D., Medical Monitor & Safety Officer
`Thomas Armor, B.S., CNMT Director, Clinical Imaging
`Mark R. Baker, Chief Executive Officer
`Ariane Cutulo, RAC, Senior Manager, Product Development
`Jouliana Jean-Paul, J.D., Manager, Regulatory Affairs
`Jessica Jensen, MPH, Vice President, Clinical Development
`, MPH, Clinical Consultant
`Yakov Rotshteyn, Ph.D., Executive Director, Product Development
`Nancy Stambler, Dr.P.H., Executive Director, Biometrics
`Vivien Wong, Ph.D., Executive Vice President, Development
`, Regulatory Consultant
`
`
`BACKGROUND
`
`On October 21, 2016, Molecular Insight Pharmaceuticals submitted a preNDA meeting request
`(SDN 224) to discuss the format and content of the clinical and nonclinical sections of a
`proposed NDA. The meeting package was submitted on December 19, 2016 (SDN 228).
`
`Regulatory
` MIP received orphan drug designation for 131I Iobenguane for the treatment of
`neuroendocrine tumors on January 18, 2006.
` Fast track designation was granted on March 8, 2006.
` On July 26, 2015, FDA granted a Breakthrough Therapy Designation for 131I Iobenguane
`for the treatment of patients with iobenguane-avid metastatic and/or recurrent
`pheochromocytoma and paraganglioma (PPGL) based on preliminary clinical evidence of
`efficacy obtained in Study MIP1B12B. An Initial Breakthrough Therapy meeting was
`held on January 22, 2016.
` MIP is proposing to submit a 505(b)(1) NDA in Q2 2017 for approval of this product in
`the United States. A preNDA CMC meeting occurred on October 6, 2016.
` A WRO letter was issued on September 9, 2016, regarding content and format of the
`Integrated Summary of Safety, datasets, and presentation of efficacy data.
`Nonclinical
`
`MIP plans to submit a series of nonclinical studies to evaluate the pharmacology, safety
`pharmacology, pharmacokinetics, and toxicity of 131I Iobenguane. MIP states that the
`pharmacology studies demonstrated the potential utility of 131I Iobenguane as a target for
`neuroendocrine tumors. An assessment of safety pharmacology consisted of an in vitro HERG
`assay and incorporating cardiovascular parameters into the repeated-dose toxicity study in dogs.
`MIP evaluated the toxicity of 127I Iobenguane in a 12-day repeated dose toxicity study in rats and
`in a 28-day repeated dose toxicity study in dogs. MIP states that they have also conducted a full
`battery of genotoxicity studies with unlabeled iobenguane (MIBG).
`
`
`
`
`
`Reference ID: 4050193
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 70663
`Page 3
`
`Clinical and Statistical
`
`Four clinical trials (MIP-IB11, MIP-IB12, MIP-IB12B, and MIP-IB13) will provide the
`supporting safety and efficacy data for 131I Iobenguane for the treatment of patients with
`iobenguane-avid malignant and/or recurrent pheochromocytoma and paraganglioma (PPGL).
`The patient populations of these trials include adult patients with PPGL (MIP-IB11, MIP-IB12
`and MIP-IB12B), adult patients with metastatic carcinoid tumors (MIP-IB11), and pediatric and
`adult patients with neuroblastoma (MIP-IB13). Dosing regimens differed across trials including
`dosimetry only (MIP-IB11), single-therapeutic dose and dose-ranging (MIP-IB12 and MIP-
`IB13), and two therapeutic doses (MIP-IB12B).
`
`MIP-IB12B, a multi-center, open-label, single arm study, is being conducted under a Special
`Protocol Assessment (SPA) agreement and will provide the efficacy data to support the NDA.
`Patients with malignant or recurrent PPGL enrolled in this study received one dosimetric dose
`and up to two 500 mCi therapeutic doses of 131I Iobenguane. Study MIP-IB12 was a single-dose
`dose-ranging study in patients with PPGL intended to provide supportive safety and efficacy data
`for the NDA. Study MIP-IB11, a dosimetry-only study without therapeutic dosing in patients
`with malignant or recurrent PPGL and metastatic only carcinoid, and Study MIP-IB13, a study
`conducted in patients with neuroblastoma, will provide safety data for the NDA. An expanded
`access program (EAP) is currently being established under an amendment to the MIP-IB12B
`protocol.
`
`The statistical analysis plan (SAP V4.0) for Study MIP-IB12B was submitted on May 27, 2016.
`The full analysis dataset (FAS) includes patients who received an imaging dose and at least one
`therapeutic dose. The per protocol dataset (PP) comprises patients who received an imaging dose
`and at least two therapeutic doses, were evaluated at Month-3 and Month-6 for efficacy, and did
`not have major protocol violations. The primary efficacy endpoint is the proportion of patients
`with a reduction (including discontinuation) of all anti-hypertensive medications by at least 50%
`for at least six months following treatment with at least one dose of 131I Iobenguane.
`
`The primary endpoint will be assessed at the time of study completion or discontinuation,
`whichever occurs first. The 50% reduction is determined separately for each baseline
`medication, based on the total daily dose of the antihypertensive medication(s) on the day of the
`first therapeutic dose.
`For the primary analysis of the primary endpoint, a point estimate (with a 95% confidence
`interval, calculated using the Agresti-Coull method) for the proportion of subjects in the FAS
`with a reduction (including discontinuation) of all antihypertensive medications by at least 50%
`for at least six months or two cycles will be calculated. This single-arm trial will be considered a
`success if the lower bound of this two-sided 95% confidence interval exceeds 0.10 (10%).
`In Appendix 1 of SAP V4.0, a detailed primary endpoint calculation clarifies the criteria and
`considerations for meeting the primary endpoint.
`Criteria for Meeting Primary Endpoint:
`1.
`Receive an imaging dose
`2.
`Receive at least one therapeutic dose
`
`
`
`Reference ID: 4050193
`
`

`

`IND 70663
`Page 4
`
`3.
`
`2.
`
`3.
`
`4.
`
`Have a reduction of each pre-therapeutic dose (baseline) of anti-hypertensive medication
`by ≥50% for a minimum of six consecutive months beginning during the 12-month
`Efficacy Phase of the study, during which no new, long-term antihypertensive medication
`is introduced.
`Considerations:
`1.
`The introduction of a new, transient (i.e., duration ≤ 14 days) antihypertensive medication
`regimen at any point during the study will not disqualify a patient from being able to
`achieve the primary efficacy endpoint.
`Conversely, the introduction of a new, long-term (i.e., duration > 14 days)
`antihypertensive medication regimen after receiving a therapeutic dose will disqualify a
`patient from being able to achieve the primary endpoint. New long-term antihypertensive
`medications introduced before Therapeutic Dose #1 is administered are considered part
`of the baseline antihypertensive medication regimen that must be reduced by at least 50%
`for achieving primary endpoint.
`A transient (i.e., duration ≤ 14 days) dose increase of an existing antihypertensive
`medication regimen at any point during the study will not disqualify a patient from being
`able to achieve the primary endpoint.
`Conversely, a long-term (i.e., duration > 14 days) increase in dose of an existing
`antihypertensive medication regimen after receiving a therapeutic dose will disqualify a
`patient from being able to achieve the primary endpoint.
`The introduction of an antihypertensive medication regimen or increase in existing
`antihypertensive medication regimen that occurs after the patient has already met the
`primary endpoint (i.e., had a ≥50% reduction of all antihypertensive medications for at
`least six consecutive months) will not disqualify the patient from achieving the primary
`endpoint.
`Only antihypertensive medication prescribed for hypertension should be included for the
`primary endpoint (e.g. propranolol prescribed for atrial fibrillation will not be included).
`A month is defined as a 28-days period.
`A patient must begin the 6-month responder period during the 12-month efficacy
`evaluation phase and may extend into the long term follow up phase.
`The secondary efficacy endpoints include 1) overall response rate, 2) tumor response of complete
`response, partial response, and mixed response, 3) status of bone lesions using Soloway Scale,
`and 4) tumor marker responses. Tumors will be measured at baseline and at 3, 6, 9 and 12
`months after the first Therapeutic Dose. Overall tumor response at 3, 6, 9 and 12 months per
`RECIST criteria will be assessed centrally by independent, blinded readers.
`Recruitment for study MIP-IB12B ended on December 31, 2015. As of July 2016, 74 patients
`received at least an imaging dose, 68 patients received at least one therapeutic dose (FAS) and 49
`patients received two therapeutic doses. As specified in the analysis plan and in the protocol
`accepted under the SPA, there are at least 58 evaluable patients in the FAS population. Although
`58 patients was the goal, an additional 10 patients were granted approval to participate in the trial
`because an Expanded Access Protocol (EAP) was not yet available. As a result, the last (68th)
`patient received the first therapeutic dose in February 2016. A total of 41 patients have
`
`5.
`
`6.
`
`7.
`8.
`
`
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`Reference ID: 4050193
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`

`

`IND 70663
`Page 5
`
`completed their four-year long-term follow-up (LTFU) and, as of July 2016, eight patients are
`being followed currently. The projected timing for 68 patients to complete the 12-month
`efficacy evaluation (12 months from first therapeutic dose) is March 2017, at which point a
`database lock will occur and a clinical study report will be prepared in support of a NDA
`submission.
`
`In MIP’s November 18, 2016, response to FDA’s WRO letter of September 9, 2016, they
`proposed to provide ADaM datasets for studies MIP-IB12B and MIP-IB13, but not for MIP-
`IB11 and MIP-IB12 as these studies were started in 2006 and 2007, respectively, and were
`previously completed and submitted to the IND in legacy format. FDA recommended that the
`Sponsor contact cder-edata@fda.hhs.gov to request a waiver to the proposed partial non-CDISC
`submission for studies MIP-IB11 and MIP-IB12 that are unsupported or retired by
`December 17, 2016. The request for the waiver was submitted on December 7, 2016.
`
`FDA emailed preliminary comments to MIP on January 12, 2017. MIP responded via email on
`January 13, 2017, stating that they wished to discuss items #4, 16, 17, 18a, 18b, and 18d.
`
`SPONSOR QUESTIONS AND FDA RESPONSES
`
`Regulatory
`
`1.
`
`Due to the high, unmet medical need for patients with metastatic and/or recurrent
`pheochromocytoma and paraganglioma (PPGL), and assuming the registrational study
`MIP-IB12B meets the primary endpoint specified in the SPA, Progenics intends to
`request Priority Review for NDA 209607. Beyond a summary of the MIP-IB12B data
`and a summary of AZEDRA benefit-risk considerations, can the Agency identify any
`additional items to provide that would support the Priority Review request?
`
`FDA Response:
`FDA does not anticipate that additional items will be required to support the Priority
`Review Request based on unmet medical need, Breakthrough Therapy Designation and
`clinical data provided.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Progenics proposes to submit the complete NDA in eCTD format on or about June 30,
`2017. However, the Nonclinical Study Reports (Module 4) and the Nonclinical
`Summaries (Modules 2.4 and 2.6) will be completed and available for submission in
`January 2017. Is the Agency amenable to receiving the nonclinical sections of the NDA,
`on a rolling basis, in advance of the complete NDA filing?
`
`FDA Response:
`Yes.
`
`
`2.
`
`
`
`Reference ID: 4050193
`
`

`

`IND 70663
`Page 6
`
`
`Discussion:
`MIP did not have any questions or comments.
`
`
`3.
`
`Based on the well-known mechanism of action of MIBG in neuroendocrine tumors and
`the use of the required dosimetry step as a safety check, as well as the strict in-hospital
`radiation safety regulations and guidelines governing radiotherapeutics administration,
`the Sponsor does not plan to include a REMS in the AZEDRA NDA submission. Does the
`Agency agree?
`
`FDA Response:
`The need for a REMS is not anticipated, however, FDA expects MIP to submit a detailed
`risk-benefit profile assessment with the original NDA.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Safety and Efficacy Assessments
`
`4.
`
`The statistical analysis plan (SAP) for study MIP-IB12B was submitted to the Agency for
`review on May 27, 2016 (SN0207). For the assessment of primary efficacy endpoint
`responders, the SAP incorporates important data definitions not detailed in the protocol.
`Does the Agency agree with the data definitions related to the primary efficacy analysis
`described in the SAP and highlighted in the Information Package?
`
`FDA Response:
`FDA acknowledges MIP’s modifications to the primary efficacy analysis population and
`the data definitions. A final determination of the most appropriate analysis population
`and description of clinical benefit will be made during review of the NDA where all data
`are available. Provide all time to event data, including the duration of response, in weeks
`instead of “months” defined as a 28 day period.
`
`Discussion:
`MIP acknowledged FDA’s comments and agreed to provide all time to event data in
`weeks. MIP will submit the final SAP in February 2017.
`
`MIP proposed the following change to the definition of primary outcome responder (new
`language is underlined):
`
`
`
`Reference ID: 4050193
`
`(b) (4)
`
`

`

`IND 70663
`Page 7
`
`
`FDA stated that they are not comfortable with the revised definition at this time because
`of the possibility that it could result in classification of some patients as responders who
`would not be appropriate.
`
`FDA noted that changes in tumor size and catecholamine levels as evidence of an
`antitumor response to 131I Iobenguane will also be considered during review of the NDA.
`
`FDA requested that MIP include definition of the primary endpoint in the SAP instead of
`in an appendix to SAP. MIP agreed to do so.
`
`At the recommendation of the Agency, Progenics plans to provide an assessment of the
`extent to which AZEDRA provides a significant advance over alternative (i.e., off-label)
`therapy of PPGL, along with a summary of the natural history of the diseases. Does the
`Agency agree that the information to be included, as outlined below is a reasonable plan
`to provide adequate supportive efficacy information for full NDA (i.e., non-accelerated)
`approval?
`
`FDA Response:
`The proposed plan appears acceptable to provide adequate supportive efficacy
`information for the NDA; however, a final determination will be made during review of
`the NDA.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Based on agreement and feedback from the Agency in a WRO Type C meeting on
`September 9, 2016, the Sponsor has prepared the ISS SAP accordingly. Does the Agency
`agree with the ISS SAP as presented in the Information package?
`
`FDA Response:
`Yes, the ISS SAP appears acceptable.
`
`Discussion:
`MIP did not have any questions or comments.
`
`At the recommendation of the Agency, Progenics plans to support the AZEDRA safety
`database with a thorough literature review addressing the reported toxicity of
`conventional I-131 iobenguane. Does the Agency agree that the content outline
`presented below sufficiently encompasses the supplemental safety information in support
`of NDA submission?
`
`
`
`
`
`5.
`
`
`
`6.
`
`
`7.
`
`
`
`Reference ID: 4050193
`
`(b) (4)
`
`

`

`IND 70663
`Page 8
`
`
`FDA Response:
`The content outline appears acceptable; however, a final determination will be made on
`review of the information officially submitted to the NDA.
`
`
`
`
`
`
`Nonclinical
`
`8.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Does the Agency agree with the proposed content of Module 4 as outlined in the
`Information Package?
`
`FDA Response:
`In general, the proposed content of Module 4 appears acceptable.
`
`
`Clinical and Statistical
`
`9.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Does the Agency agree with the proposed content of Module 5 as outlined in the
`Information Package?
`
`FDA Response:  
`The content outline appears acceptable; however, a final determination will be made on
`review of the information officially submitted to the NDA.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Progenics plans to submit narratives and case report forms (CRF) for subjects in the
`clinical program who experienced serious adverse events, discontinuations due to
`adverse events and deaths. We also plan to submit CRFs for subjects who experienced an
`adverse event of special interest (AESI), as defined in the individual study reports and in
`the ISS SAP. CRFs for all other patients will be available upon request. Does the
`Agency agree with this plan for submission of narratives and CRFs?
`
`FDA Response:  
`Yes, the plan appears acceptable.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Progenics plans to submit one study report (pivotal study MIP-IB12B) in granular eCTD
`format and three study reports (MIP-IB11, MIP-IB12, and MIP-IB13) in legacy
`electronic format. Does the Agency agree with this approach?
`
`
`
`
`
`
`10.
`
`
`11.
`
`
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`

`

`IND 70663
`Page 9
`
`
`
`12.
`
`
`13.
`
`FDA Response:  
`Yes, the plan appears acceptable; however the request for waiver is under review.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Does the Agency agree with the proposed content of the Summary of Clinical Efficacy
`(Module 2.7.3) as outlined in Appendix A?
`
`FDA Response:  
`The proposed content of the Summary of Clinical Efficacy appears acceptable; however,
`a final determination will be made on review of the information officially submitted to
`the NDA.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Does the Agency agree with the proposed content of the Summary of Clinical Safety
`(Module 2.7.4) as outlined in Appendix A?
`
`FDA Response:  
`The proposed content of the Summary of Clinical Safety appears acceptable; however, a
`final determination will be made on review of the information officially submitted to the
`NDA.
`
`Discussion:
`MIP did not have any questions or comments.
`
`14.
`
`Clinical Pharmacology
`
`Does the Agency agree with the proposed content of the Clinical Pharmacology Summary
`(Module 2.7.2) as described below?
`
`FDA Response:
`Yes. In the Summary of Clinical Pharmacology, address the following:
`
` 
`
` What is the basis for selecting the dose(s) and dosing regimen used in the registration
`trial(s)?
`
` How was the potential for 131I Iobenguane to prolong the QT/QTc interval assessed?
`What are the conclusions and proposed labeling description?
`
` What are the characteristics of distribution, metabolism and elimination of
`131I Iobenguane?
`
`
`
`
`
`Reference ID: 4050193
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`

`

`IND 70663
`Page 10
`
`
`
`15.
`
` What influence do intrinsic factors (such as sex, race, weight, disease, organ
`impairment) have on 131I Iobenguane exposure, efficacy and safety? What dose
`modifications are recommended?
`
` What influence do extrinsic factors (such as drug interactions) have on
`131I Iobenguane exposure, efficacy, and safety? What dose modifications are
`recommended?
`
`Discussion:
`MIP did not have any questions or comments.
`
`Dosimetry data generated in each clinical study will be provided in their respective
`Clinical Study Reports. A discussion of dosimetry data will also be included in the
`Summary of Clinical Pharmacology (Module 2.7.2). Dosimetry raw data and whole body
`planar images will not be included in the NDA. Does the Agency agree with this
`approach?
`
`FDA Response:
`The proposal appears acceptable; however, ensure that all datasets are in the SAS
`transport files (*.xpt) format and description of each data item is provided in a define.pdf
`file.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Safety Update
`
`16.
`
`
`
`Does the Agency agree with the proposed timing and content of the post-submission
`safety update?
`
`FDA Response:
`FDA agrees with MIP’s plan to submit the 120-Day post submission safety update to
`include safety data from the long-term follow-up period of Study MIP-IB12B, as well as
`safety from the ongoing Expanded Access Study.
`
`Discussion:
`MIP stated that the 120-day safety update would be submitted in October with a data cut-
`off of August 30, 2017. FDA agreed and asked MIP to consider whether a Day 90
`submission would be feasible.
`
`MIP asked if FDA wanted to receive topline data after the database lock in March 2017.
`FDA stated that this is not necessary, unless these topline results are dramatically
`different from the preliminary data previously discussed.
`
`
`
`
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`

`IND 70663
`Page 11
`
`
`MIP asked if FDA anticipated the need for an advisory committee. FDA stated that an
`advisory committee meeting is not currently anticipated, but that a decision will be made
`after receiving the NDA.
`
`FDA recommended that MIP submit a request for an application orientation meeting at
`least one month before the planned NDA submission. MIP stated that they would do so.
`
`ADDITIONAL FDA CLINICAL PHARMACOLOGY COMMENTS
`
`17.
`
`In the NDA submission, provide the specific activity for 131I Iobenguane and convert the
`proposed dose from mCi to GBq.
`
`Discussion:
`MIP stated that specific activity information at time of calibration (TOC) for all batches
`used in 131I Iobenguane clinical studies will be provided in Module 2.7.1. FDA stated
`that this was acceptable.
`
`MIP stated that doses will be indicated in both mCi and GBq in clinical pharmacology
`related documents where feasible. Conversion to SI units may not be done in documents
`such as legacy documents and previously submitted reports, etc. FDA provided
`concurrence with this plan and requested that MIP provide the dose in mass units and in
`GBq in the clinical pharmacology datasets. MIP agreed to do so.
`
`In addition, apply the following advice in preparing the clinical pharmacology sections of
`the original NDA submission:
`
`a.
`
`Submit bioanalytical methods and validation reports for all clinical pharmacology
`and biopharmaceutics studies.
`
`Discussion:
`Validation reports for LC/MS/MS bioanalytical methods will be provided, but not
`for direct gamma counting using an automated well gamma counter. FDA stated
`that this was acceptable and requested that MIP provide the following information
`regarding the gamma counter at each clinical site: make and model, limit of
`quantitation, linear range, and information on the reference standard. MIP agreed
`to do so and clarified that the dosing solution was used as the reference standard
`for converting the raw counts to units of radioactivity concentration.
`
`b.
`
`
`
`Provide complete datasets for all clinical pharmacology and biopharmaceutics
`studies. The subject’s unique ID in the pharmacokinetic datasets should be
`consistent with those in datasets submitted for clinical review.
`
`Discussion:
`MIP stated that datasets will be provided as SAS transport files (*.xpt).
`
`
`
`
`18.
`
`
`
`
`
`
`
`
`
`
`
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`IND 70663
`Page 12
`
`
`c.
`
`
`
`
`
`
`
`d.
`
`e.
`
`
`
`Provide all concentration-time and derived pharmacokinetic parameter datasets as
`SAS transport files (*.xpt). A description of each data item should be provided in
`a define.pdf file. Any concentrations or patients that have been excluded from the
`analysis should be flagged and maintained in the datasets.
`
`Discussion:
`MIP did not have any questions or comments.
`
`Present the pharmacokinetic parameter data as geometric mean with coefficient of
`variation (and mean ± standard deviation) and median with range as appropriate
`in the study reports.
`
`Discussion:
`MIP stated that geometric means for the PK parameter data will be provided in
`Modules 2.7.1 and 2.7.2, but will not be available in the previously submitted
`MIP-IB11 report. FDA stated that this was acceptable.
`
`Identify individual patients with dose modifications; the time to the first dose
`modification; and the reasons for dose modification. Provide the relevant
`descriptive statistics for each of these variables in support of the proposed dose in
`the Summary of Clinical Pharmacology.
`
`Discussion.:
`MIP did not have any questions or comments.
`
`
`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.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from these requirements. Please include a statement that confirms this finding, along with a
`reference to this communication, as part of the pediatric section (1.9 for eCTD submissions) of
`your application. If there are any changes to your development plans that would cause your
`application to trigger PREA, your exempt status would change.
`
`
`
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`Reference ID: 4050193
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`IND 70663
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`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.
`
`
`The application should include a review and summary of the available published literature
`regarding drug use in pregnant and lactating women, a review and summary of reports from your
`pharmacovigilance database, and an interim or final report of an ongoing or closed pregnancy
`registry (if applicable), which 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.
`
`Office of Scientific Investigations (OSI) Requests
`
`The Office of Scientific Investigations (OSI) requests that the following items 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 field investigators
`who conduct those inspections (Item I and II). 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.
`
`The dataset that is requested in Item III below is for use in a clinical site selection model that is
`being piloted in CDER. Electronic submission of the site level dataset is voluntary and is
`
`
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`Reference ID: 4050193
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`

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`IND 70663
`Page 14
`
`intended to facilitate the timely selection of appropriate clinical sites for FDA inspection as part
`of the application and/or supplement review process.
`This request also provides instructions for where OSI requested items should be placed within an
`eCTD submission (Attachment 1, Technical Instructions: Submitting Bioresearch Monitoring
`(BIMO) Clinical Data in eCTD Format).
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4050193
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`

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`IND 70663
`Page 15
`
`I. Request for general study related information and comprehensive clinical investigator
`information (if items are provided elsewhere in submission, describe location or provide
`link to requested information).
`
`1. Please include the following information in a tabular format in the original NDA for each
`of the completed pivotal clinical trials:
`a. Site number
`b. Principal investigator
`c. Site Location: Address (e.g., Street, City, State, Country) and contact information
`(i.e., phone, fax, email)
`d. Location of Principal Investigator: Address (e.g., Street, City, State, and Country) and
`contact information (i.e., phone, fax, email). If the Applicant is aware of changes to a
`clinical investigator’s site address or contact information since the time of the clinical
`investigator’s participation in the study, we request that this updated information also
`be provided.
`
`
`2. Please include the following information in a tabular format, by site, in the original NDA
`for each of the completed pivotal clinical trials:
`a. Number of subjects screened at each site
`b. Number of subjects randomized at each site
`c. Number of subjects treated who prematurely discontinued for each site by site
`
`
`3. Please include the following information in a tabular fo