CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202570Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

` 09//2009
`(submitted)
` 12/2013
` 06//2014
`
`
`
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
`
`
`
`
`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
`
`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 Description:
`1789-1
`
`Clinical trial report and datasets from A8081007: Phase 3, Randomized,
`Open-label Study of the Efficacy and Safety of PF-02341066 vs. Standard of
`Care (Pemetrexed or Docetaxel) in Patients with Advanced Non-Small Cell
`Lung Cancer Harboring a Translocation or Inversion Event Involving the
`Anaplastic Lymphoma Kinase Gene Locus
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`
`
`This randomized trial will provide additional information on the safety and efficacy of crizotinib in
`a comparative setting.
`
`
`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.”
`
`Crizotinib was approved on the basis of single arm studies in a population with non-small cell lung
`cancer. To fully determine the safety profile of this drug in a population with substantial pre-
`existing disease, it will be necessary to compare the adverse event profile of crizotinib to that of
`other drugs. Further, the efficacy of crizotinib in comparison to other drugs is an important safety
`concern since this will impact the patient’s ultimate outcome.
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 1 of 43
`
`Reference ID: 3005826
`
`

`

`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.
`This is an ongoing randomized clinical trial in patients with non-small cell lung cancer who have
`received one prior therapy.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` 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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 2 of 43
`
`Reference ID: 3005826
`
`

`

`Continuation of Question 4
`
`
` 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)
`To ensure that the results of this study will be submitted regardless of the results of the primary
`analysis.
` 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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 3 of 43
`
`Reference ID: 3005826
`
`

`

` 06/2010
`(submitted)
` 12/2015
` 06/2016
`
`
`
`Trial Completion:
`Final Report Submission:
`Other:
`
`
`
`
`
`
`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
`
`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 Description:
`1789-2
`
`Clinical trial report and datasets from A8081014: Phase 3, Randomized,
`Open-label Study of the Efficacy and Safety of Crizotinib vs.
`Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously Untreated
`Patients with Non-Squamous Carcinoma of the Lung Harboring a
`Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase
`Gene Locus
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`
`
`This study will provide comparative information on the safety and efficacy of crizotinib in patients
`with non-small cell lung cancer who have received no prior treatment. Since this population has less
`comorbid disease, the adverse event profile of crizotinib, seen in this comparative setting, will be
`more clearly delineated.
`
`
`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.”
`
`Crizotinib was approved on the basis of a surrogate endpoint in two small, single-arm trials. This
`study will provide additional safety data as well as information of the efficacy of crizotinib in this
`setting. Information on the efficacy of crizotinib is ultimately a safety concern since it may impact
`overall survival.
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 4 of 43
`
`Reference ID: 3005826
`
`

`

`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.
`An ongoing clinical trial in patients with untreated non-small cell lung cancer
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` 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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 5 of 43
`
`Reference ID: 3005826
`
`

`

`Continuation of Question 4
`
`
` 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)
`Overall survival data from an ongoing clinical 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/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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 6 of 43
`
`Reference ID: 3005826
`
`

`

`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 Description:
`1789-3
`
`Submit the final report on the ongoing in vitro evaluations of induction
`potential of crizotinib on CYP2B and CYP2C enzymes.
`
`
`
`
`PMR/PMC Schedule Milestones:
`
`Final Protocol Submission: 12/2011
`Study Completion:
`
`12/2011
`Final Report Submission:
`12/2011
` Other:
`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
`
`
`As crizotinib induces CYP3A mRNA up to 23 fold, crizotinib may also induce CYP2B or
`CYP2C eneymes, which may subsequently decrease the drug concentrations of the substrates of
`these enzymes. The ongoing in vitro evaluations induction potential of crizotinib on CYP2B and
`CYP2C enzymes is therefore should be submitted for FDA’s review.
`
`
`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.”
`
`
`
`As crizotinib induces CYP3A mRNA up to 23 fold, crizotinib may also induce CYP2B or
`CYP2C eneymes, which may subsequently decrease the drug concentrations of the substrates of
`these enzymes. The ongoing in vitro evaluations induction potential of crizotinib on CYP2B and
`CYP2C enzymes may answer whether dose adjustments are needed for coadministration with
`CYP2B or CYP2C substrates with crizotinib.
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 7 of 43
`
`Reference ID: 3005826
`
`

`

`
`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.
`The study is in vitro screening study using biomaterials such as hepatocytes.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`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
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 8 of 43
`
`Reference ID: 3005826
`
`

`

` 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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 9 of 43
`
`Reference ID: 3005826
`
`

`

`NDA 202570 (Crizotinib)
`PMR/PMC Ophthalmology
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR Description:
`1789-4
`
`Clinical trial (existing trial or new clinical trial) in which at least 30
`patients are studied. The following examinations should be performed
`in these patients at baseline, 2 and 6 weeks after drug administration
`and 2-8 weeks after discontinuation of the therapy (single visit post
`therapy).
`
`
`1. Best corrected distance visual acuity
`2. Refractive error associated with best corrected distance visual
`acuity
`3. Pupil size under standardized lighting conditions
`4. Slit lamp biomicroscopy of the anterior segment
`5. Intraocular pressure
`6. Ocular coherence tomography of the macula
`7. Dilated fundus photography of the retina
`
`
`
` 10/2011
` 12/2013
` 06/2014
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`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
`X Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`Additional ophthalmology examinations and tests will further clarify the significance and long term
`effects of these visual symptoms.
`
`
`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.”
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 10 of 43
`
`Reference ID: 3005826
`
`

`

`Visual disturbances associated with the use of crizotinib occurred in the majority of patients taking
`the drug product. These events have not been well characterized and included diplopia,
`photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous
`floaters, visual brightness, and visual acuity reduced.
`
`
`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
`X FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`X Assess a known serious risk related to the use of the drug?
`X 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
`
` X
`
` 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.
`Clinical trial (existing trial or new clinical trial) in which at least 30 patients are studied.
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 11 of 43
`
`Reference ID: 3005826
`
`

`

`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`X 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)
`Continuation of Question 4
`
`
` 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?
`X Does the study/clinical trial meet criteria for PMRs or PMCs?
`X 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)
`
`PMR/PMC Development Template
`
`Last Updated 8/24/2011
`
`Page 12 of 43
`
`Reference ID: 3005826
`
`

`

`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 Description:
`1789-5
`
`Complete the ECG sub-study in trial A8081007 and submit the final study
`report, along with a thorough review of cardiac safety data to address any
`potential impact of crizotinib on QTc interval prolongation in patients.
`
`
`
`Final Protocol Submission
`Trial Completion Date:
`Final Report Submission Date:
`Other:
`
`
`09/2009 (submitted)
`12/2013
`06/2014
`MM/DD/YYYY
`
`
`
`
`PMR/PMC Schedule Milestones:
`
`
`
`
`
`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
`
`
`
`Crizotinib appears to prolong the QTC interval. However, the QTc evalaution of crizotinib
`in trials A8081001 and A8081005 is inconclusive, due to ECG acquisition and
`interpretation issues. Large increases in QT interval (i.e., ~20 ms) can not be reliably
`excluded. The IRT-QTc review team recommends this PMR, based on previous agreement
`with the sponsor, to complete and submit a ongoing dedicated QTc assessment at 250 mg
`BID in the ECG sub-study in trial A8081007 to gain reliable estimation of QT effect size,
`especially if indications other than NSCLC with different benefit-risk balances are being
`pursued.
`
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`PMR/PMC Development Template
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`Last Updated 8/24/2011
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`Page 13 of 43
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`Reference ID: 3005826
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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.”
`
`
`
`Based on the QTc evalaution of crizotinib in trials A8081001 and A8081005, crizotinib
`appears to be associated with concentration-dependent QT interval prolongation (P <
`0.001).
`The QT-IRT recommends a PMR to complete and submit an ongoing dedicated QTc
`assessment at 250 mg BID in the ECG-substudy in trial A8081007 to gain reliable
`estimation of QT effect size.
`
`
`
`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?
`
`PMR/PMC Development Template
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`Last Updated 8/24/2011
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`Page 14 of 43
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`Reference ID: 3005826
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`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.
`
`Time-matched PK/ECGs samples will be collected in 40 patients in the treatment Arm A (250 mg
`crizotinib BID) of Phase 3 trial 1007. In this ECG sub-study, all post-screening ECGs will be read
`in a blinded fashion by a central reader. The ECG recordings will be transferred digitally to a
`central reader where they will be stripped of any information which could permit identification of
`the patient, site, date or time. The ECGs will be evaluated for interval assessments including PR,
`QT, RR and QRS.
`Based upon the standard deviation of change from baseline of QTc of 16 ms (Study A8081001), a
`total sample size of 40 patients from both Studies A8081007 (Arm A) and A8081005 should be
`sufficient for greater than 90% probability that all five boundaries of upper one-sided 95%
`confidence intervals for the change from baseline of QTc at all five QTc sampling time points on
`Cycle 2 Day 1 are under 20 ms, assuming the true change from baseline in QTc is 10 ms.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`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)
`QT prolongation assessment using open-label, non-thorough QT study design.
`
`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 Subpa