CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203085Orig1s000
`
`
`OTHER REVIEW(S)
`
`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Memorandum
`
`
`September 26, 2012
`
`Monica Hughes, M.S., Lead Regulatory Health Project Manager DOP2/OHOP
`
`NDA 203085: FDA Labeling Comments
`
`Date:
`From:
`Subject:
`
`___________________________________________________________________________
`Please find attached FDA’s counter proposal to your revised package insert (PI) and patient
`package insert (PPI) submitted via email communication on September 26, 2012.
`
`Please provide a response by 3:00 PM today, September 26, 2012. In addition to submitting
`your response to the NDA, please email me a copy of your responses as well as a clean and
`redlined version of the labeling.
`
`Please let me know if you have any questions.
`
`Regards,
`
`Monica Hughes, M.S.
`Lead Regulatory Health Project Manager
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`Phone: 301-796-9225, Fax: 301-796-9849
`
`
`
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`
`
`Reference ID: 3195292
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`18 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following
`this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MONICA L HUGHES
`09/26/2012
`
`Reference ID: 3195292
`
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`Attachment B: Sample PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`PMR/PMC Description: QT/QTc Interval Prolongation
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`Other:
`
`submitted
`10/31/2012
`11/30/2012
`MM/DD/YYYY
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`Regorafenib inhibited the hERG K+ current with an IC50 value of 12 micromolar, but demonstrated
`no effect on the cardiac action potential in rabbit Purkinje fibers and no effect on ECG intervals in
`Beagle dogs after oral and intravenous administration.
`In the NDA submission, the applicant included an interim analysis of the QT/QTc intervals
`completed on 25 patients with advanced solid tumors enrolled in Study 14814. The final study
`report for the dedicated cardiovascular safety study is to be submitted post marketing.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`The goal of the clinical trial is to assess the risk for regorafenib to potentially prolong the QT/QTc
`interval.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
`
`Page 1 of 3
`
`Reference ID: 3194115
`
`

`

`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`FDAAA required safety study/clinical trial
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`Complete a clinical trial evaluating the potential for a regorafenib to prolong the QT/QTc interval
`in an adequate number of patients administered repeated doses of 160 mg of regorafenib and
`submit the final study report, along with a thorough review of cardiac safety data.
`
`Required
`Observational pharmacoepidemiologic study
`Registry studies
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
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`Page 2 of 3
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`Reference ID: 3194115
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`Continuation of Question 4
`
`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`Other
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`(signature line for BLAs)
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
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`Page 3 of 3
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`Reference ID: 3194115
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`

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`Attachment B: Sample PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`PMR/PMC Description: Drug Interaction
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`Other:
`
`submitted
`10/31/2012
`11/30/2012
`MM/DD/YYYY
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`Regorafenib or the active metabolites M2 or M5 inhibited CYP2B6, CYP2C9, CYP2C8, CYP2C19,
`CYP2D6 and/or CYP3A4 in vitro. The R values suggest that a drug interaction trial is warranted
`with a sensitive substrate of CYP2B6, CYP2C19, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. A
`trial to assess the effects of regorafenib on the pharmacokinetics of a substrate of CYP2C8, CYP2C9,
`CYP2C19, and CYP3A4 is ongoing and the applicant proposes to submit the final study report in
`November 2012.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`The goal of the clinical trial is to assess the need to avoid coadministration of sensitive substrates of
`CYP2C8, CYP2C9, CYP2C19 and CYP3A4 with regorafenib.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
`
`Page 1 of 3
`
`Reference ID: 3194115
`
`

`

`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`FDAAA required safety study/clinical trial
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`Complete a clinical trial and submit the final study report to evaluate the effect of repeated doses of
`160 mg of regorafenib on the pharmacokinetics of a probe substrate of CYP2C8, CYP2C9,
`CYP3A4 and CYP2C19.
`
`Required
`Observational pharmacoepidemiologic study
`Registry studies
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
`
`Page 2 of 3
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`Reference ID: 3194115
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`Continuation of Question 4
`
`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`Other
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`(signature line for BLAs)
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/18/2012
`
`Page 3 of 3
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`Reference ID: 3194115
`
`

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`Attachment B: Sample PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`PMR/PMC Description:
`
`Impaired Renal Function
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`Other:
`
`12/31/2012
`12/31/2013
`06/30/2014
`MM/DD/YYYY
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`A pooled univariate analysis suggests that exposure of regorafenib increases with worsening renal
`function. The applicant is requested to conduct a multi-dose pharmacokinetic trial in patients with
`severe renal impairment.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`The goal of the clinical trial is to assess the need for a dose reduction or recommend avoidance of
`regorafenib for patients with severe renal impairment.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/25/2012
`
`Page 1 of 3
`
`Reference ID: 3194115
`
`

`

`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`FDAAA required safety study/clinical trial
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`Conduct a multiple dose trial to determine the appropriate regorafenib dose in patients with severe
`renal impairment. Submit the final protocol for FDA review before conducting the trial.
`
`Required
`Observational pharmacoepidemiologic study
`Registry studies
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/25/2012
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`Page 2 of 3
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`Reference ID: 3194115
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`Continuation of Question 4
`
`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`Other
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
`
`(signature line for BLAs)
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/25/2012
`
`Page 3 of 3
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`Reference ID: 3194115
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`

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`
`
`Attachment B: Sample PMR/PMC Development Template
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`PMR/PMC Description: Population Pharmacokinetic Analyses
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`Other:
`
`submitted
`not applicable
`11/30/2012
`MM/DD/YYYY
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
`
`The applicant proposes to conduct population pharmacokinntic analyses using the data collected in
`study 11650 and 14387 and submit the report post marketing due to the clinical safety and efficacy
`trial finished earlier than planned.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`The goal of population pharmacokinetic analyses is to assess the pharamcokinetics of regorafenib
`and the active M-2 and M-5 metabolites across all clinical trials which included pharmacokientic
`sampling and use a covariate model to determine the influence of intrinsic and extrinsic factors on
`the pharmacokinetic parameters. These analyses can support recommendations for dose
`modifications in specific populations.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/25/2012
`
`Page 1 of 3
`
`Reference ID: 3194115
`
`

`

`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
`Accelerated Approval (subpart H/E)
`Animal Efficacy Rule
`Pediatric Research Equity Act
`FDAAA required safety study/clinical trial
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`Assess a known serious risk related to the use of the drug?
`Assess signals of serious risk related to the use of the drug?
`Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
`Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
`Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`Submit an integrative population pharmacokinetic analysis report to evaluate the effect of intrinsic
`and extrinsic factors on the pharmacokinetics of regorafenib and its active metabolites M2 and M5.
`
`Required
`Observational pharmacoepidemiologic study
`Registry studies
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 9/25/2012
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`Page 2 of 3
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`Reference ID: 3194115
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`

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`Continuation of Question 4
`
`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`Other
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`5. Is the PMR/PMC clear, feasible, and appropriate?
`Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMR/PMC Development Coordinator:
`This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the
`safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality.
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`(signature line for BLAs)
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`Attachment B: Sample PMR/PMC Development Template
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`Last Updated 9/25/2012
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`Page 3 of 3
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`Reference ID: 3194115
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`Attachment B: Sample PMR/PMC Development Template
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`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
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`PMR/PMC Description: Exposure-Response Analyses
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`Study/Clinical trial Completion Date:
`Final Report Submission Date:
`Other:
`
`submitted
`not applicable
`11/30/2012
`MM/DD/YYYY
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`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
`Unmet need
`Life-threatening condition
`Long-term data needed
`Only feasible to conduct post-approval
`Prior clinical experience indicates safety
`Small subpopulation affected
`Theoretical concern
`Other
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`The applicant proposes to conduct an exposure-response analyses using the data collected during the
`registration trial and submit the report post marketing as the clincial trial trial finished earlier than
`expected.
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`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`The goal of these analyses is to explore the relationship between exposure of regorafenib and the
`active M-2 and M-5 metabolites and the safety and efficacy demonstrated in the reigstration trial.
`This analysis might help support the proposed dose modifications for adverse events listed in the
`labeling and potential dose modifications for organ impairment or drug interactions in which dose
`modifications are typically recommended based on identified exposure differences.
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`Attachment B: Sample PMR/PMC Development Template
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`Last Updated 9/18/2012
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`Page 1 of 3
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`Reference ID: 3194115
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`3.
`
`If the study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`- Which regulation?
`E] Accelerated Approval (subpart HIE)
`E] Animal Efficacy Rule
`E] Pediatric Research Equity Act
`E] FDAAA required safety study/clinical trial
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`-
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`-
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`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`E] Assess a known serious risk related to the use of the drug?
`[I Assess signals of serious risk related to the use of the drug?
`El Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
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`If the PMR is a FDAAA safety study/clinical trial, Will it be conducted as:
`E] Analysis of sp_ontaneous p_ostmarketing adverse events?
`Do not select the above shady/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`E] Analysis using pharmacovigjlance system?
`Do not select the above study/clinical trial Me if: the new phannacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not suflicient to assess this known serious risk, or has been established but is nevertheless not
`
`sufficient to assess or identify a serious risk
`
`[I Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g.. observational epidemiologic studies), animal studies. and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
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`[I Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? Ifthe
`study or trial will be performed in a subpopulation, list here.
`
`Submit an exposure-response analysis for regorafenib and its active metabolites M2 and M5 {'4’}
`using data collected from the CORRECT trial (Study
`14387) in patients with metastatic colorectal cancer (mCRC) who have progressed after standard
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`therapy.
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`Reguired
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`E] Observational pharmacoepidemiologic study
`El Registry studies
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`Attachment B: Sample PIVIR/PMC Development Template
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`Last Updated 91180012
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`Page 2 of 3
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`Reference ID: 3194115
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`Continuation of Question 4
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`Primary safety study or clinical trial
`Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
`Thorough Q-T clinical trial
`Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`Pharmacokinetic studies or clinical trials
`Drug interaction or bioavailability studies or clinical trials
`Dosing trials
`Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`E-R analyses of the data from the registration trial
`Meta-analysis or pooled analysis of previous studies/clinical trials
`Immunogenicity as a marker of safety
`Other (provide explanation)
`
`Agreed upon:
`Quality study without a safety endpoint (e.g., manufacturing, stability)
`Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
`Dose-response study or clinical trial performed for effectiveness
`Nonclinical study, not safety-related (specify)
`
`Other
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`Does the study/clinical trial meet criteria for PMRs or PMCs?
`Are the objectives clear from the description of the PMR/PMC?
`Has the applicant adequately justified the choice of schedule milestone dates?
`Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`PMR/PM