CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`201023
`201023
`
`
`
`APPLICA TION NUMBER:
`
`OTHER REVIEW(S)
`OTHER REVIEW! S!
`
`
`
`
`
`

`

`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: PMR 1649-1: To evaluate the potential for a serious risk of intravenous
`infusion of particulate matter into the blood stream, it is necessary to better
`understand and characterize the supersaturated pre-mix. Conduct a study to
`provide data which address particulate nucleation and kinetic factors of
`precipitation in the pre-mix. Conduct this study using multiple samples drawn
`from multiple batches so as to more fully support an in-use life of the pre-mix.
`Study considerations include (but are not necessarily limited to); interior
`surface properties of the container closure (e.g., treatments, roughness,
`scratches, etc.), initial mixing agitation force (vigorous shaking), physical
`shock on standing (e.g., vigorous shaking during in-use storage), needle
`sticks, syringe use, temperature (and temperature changes during in-use
`storage), and additional time point sampling beyond the proposed duration of
`in-use storage of the pre-mix solution (e.g., 1 to 4 hours).
`Collect and provide photographs of the precipitate as it appears in the
`container and isolated photomicrographs of the particles, as feasible, in the
`final report.
`Provide by mass balance, the mass of precipitated drug as precipitated mass
`and as mass percent of the total cabazitaxel content, in the final report.
`
` September 2010
` March 2011
`
`June 2011
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`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
`
`
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 1 of 4
`
`

`

`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 concentration of cabazitaxel in the first dilution pre-mix solution (e.g., 10 mg/mL) is super
`
` exceeding the solubility in the pre-mix vehicle by
`saturated
`. Nucleation and kinetic factors are critical in that they will largely determine the duration that
`this desired but thermodynamically unstable pre-mix solution will persist. The database you have
`provided to support the one-hour physical in-use stability (i.e., no precipitation) is inadequate.
`
`
`
`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?
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 2 of 4
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`

`

`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.
`
`
`
`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)
`
`
`
`
`
`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?
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 3 of 4
`
`

`

`
`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 6/17/2010
`
`Page 4 of 4
`
`

`

`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: PMR 1649-2: To evaluate the potential for a serious risk of intravenous
`infusion of particulate matter into the blood stream, it is necessary to better
`understand and characterize the supersaturated infusion solution. Conduct a
`study which addresses particulate nucleation and kinetic factors of
`precipitation from the infusion solution. Conduct this study using multiple
`samples drawn for at least three additional batches in the containers (bags and
`sets) which you propose to label for this use so as to more fully support an in-
`use life of the infusion solution.
`Study factors include (but are not necessarily limited to); interior surface
`properties of the container (e.g.., treatments, roughness, plasticizers, etc.),
`initial mixing agitation force (vigorous shaking), physical shock on standing
`(e.g., vigorous shaking during in-use storage), needle sticks, temperature (and
`temperature changes during in-use storage), and additional time point
`sampling beyond the proposed duration of in-use storage of the infusion
`solution.
`Collect and provide photographs of the precipitate as it appears in the
`container and isolated photomicrographs of the particles, as feasible, for each
`observed precipitation or evidence of precipitation (e.g., clogged filters,
`impeded infusion flow, etc.), in the final report.
`Provide by mass balance, the mass of precipitated drug as precipitated mass
`and as mass percent of the total cabazitaxel content in the final report.
`
`
` September 2010
` March 2011
`
`June 2011
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`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
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 1 of 4
`
`

`

`
`
`
`
`
`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 concentration of cabazitaxel in the infusion solution (0.10 mg/mL to 0.26 mg/mL) is also super
`saturated
` exceeding the solubility by up to
`
`Nucleation and kinetic factors are critical in that they will largely determine the duration that the
`desired but thermodynamically unstable infusion solution will persist. The database you have
`provided to support the in-use shelf life is inadequate.
`
`
`
`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
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 2 of 4
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` 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.
`
`
`
`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)
`
`
`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
`
`
`
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 3 of 4
`
`

`

`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 6/17/2010
`
`Page 4 of 4
`
`

`

`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: PMR 1649-3: Conduct a Phase 3 randomized controlled trial in patients with
`hormone-refractory metastatic prostate cancer comparing 75 mg/m2 docetaxel
`with prednisone with cabazitaxel 25 mg/m2 with prednisone and cabazitaxel
`20 mg/m2 with prednisone as first-line therapy. The primary endpoint should
`be overall survival to evaluate the incidence of drug-related death as well as
`efficacy. The trial should be powered to detect a 25% difference in overall
`survival. The trial will include interim analyses for evaluation of efficacy
`based on overall survival and safety of the 25 mg/m2 with prednisone arm
`versus the 20 mg/m2 with prednisone arm to potentially drop one of the
`cabazitaxel arms. Submit the protocol for agency review prior to
`commencing the trial.
`
` November 2010
` December 2017
`
`June 2018
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`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
`
`
`
`Cabazitaxel has demonstrated a survival advantage for patients with metastatic hormone-refractory
`prostate cancer (mHRPC) who already have received docetaxel. Although the dose studied in the
`Phase 3 trial demonstrated a survival advantage, there was significant toxicity, and some Phase 1
`data indicates that a lower dose could have been studied. Therefore, we are asking the applicant to
`study a lwoer dose; however, we do not want deny patients the potential ebenfit of this treatment
`while the study is ongoing.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 1 of 4
`
`

`

`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 dose of cabazitaxel studied in the Phase 3 trial as a second-line therapy for patients with
`mHRPC demonstrated a survival advantage but also had an extensive adverse event profile. The
`goal of the trial in this PMR is to determine whether a lower dose will increase the saftey but
`preserve the efficacy of the dose that will be in the labeling.
`
`
`
`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?
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 2 of 4
`
`

`

`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.
`A Phase 3 randomized controlled trial in patients with hormone-refractory metastatic prostate
`cancer comparing 75 mg/m2 docetaxel with prednisone with cabazitaxel 25 mg/m2 with prednisone
`and cabazitaxel 20 mg/m2 with prednisone as first-line therapy. The primary endpoint should be
`overall survival to evaluate the incidence of drug-related death as well as efficacy. The trial should
`be powered to detect a 25% difference in overall survival. The trial will include interim analyses
`for evaluation of efficacy based on overall survival and safety of the 25 mg/m2 with prednisone
`arm versus the 20 mg/m2 with prednisone arm to potentially drop one of the cabazitaxel arms.
`Submit the protocol for agency review prior to commencing the trial.
`
`
`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)
`
`
`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
`
`
`
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 3 of 4
`
`

`

`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 6/17/2010
`
`Page 4 of 4
`
`

`

`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:
`
`1649-4: Conduct a Phase 3 randomized controlled trial in 1222 patients with
`hormone-refractory metastatic prostate cancer previously treated with
`docetaxel comparing cabazitaxel 20 mg/m2 with prednisone versus
`cabazitaxel 25 mg/m2 with prednisone and powered to preserve 50% of the
`treatment effect of cabazitaxel 25 mg/m2. The study will include interim
`analyses for evaluation of drug-related deaths as well as efficacy based on the
`safety and overall survival of the cabazitaxel 25 mg/m2 with prednisone arm
`versus the cabazitaxel 20 mg/m2 with prednisone arm to potentially
`discontinue the trial. Submit the protocol for agency review prior to
`commencing the trial.
`
` November 2010
`
` 2017
`
`June 2018
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`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
`
`
`
`Cabazitaxel has demonstrated a survival advantage for patients with metastatic hormone-refractory
`prostate cancer (mHRPC) who already have received docetaxel. Although the dose studied in the
`Phase 3 trial demonstrated a survival advantage, there was significant toxicity, and some Phase 1
`data indicates that a lower dose could have been studied. Therefore, we are asking the applicant to
`study a lwoer dose; however, we do not want deny patients the potential ebenfit of this treatment
`while the study is ongoing.
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 1 of 4
`
`(b) (4)
`
`

`

`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 dose of cabazitaxel studied in the Phase 3 trial as a second-line therapy for patients with
`mHRPC demonstrated a survival advantage but also had an extensive adverse event profile. The
`goal of the trial in this PMR is to determine whether a lower dose will increase the saftey but
`preserve the efficacy of the dose that will be in the labeling.
`
`
`
`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?
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 2 of 4
`
`

`

`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.
`A Phase 3 randomized controlled trial in 1222 patients with hormone-refractory metastatic prostate
`cancer previously treated with docetaxel comparing cabazitaxel 20 mg/m2 with prednisone versus
`cabazitaxel 25 mg/m2 with prednisone and powered to preserve 50% of the treatment effect of
`cabazitaxel 25mg/m2. The study will include interim analyses for evaluation of drug-related deaths
`and safety as well as overall survival of the cabazitaxel 25 mg/m2 with prednisone arm versus the
`cabazitaxel 20 mg/m2 with prednisone arm to potentially discontinue the trial. The sponsor will
`submit the protocol for agency review prior to commencing the trial.
`
`
`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)
`
`
`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
`
`
`
`
`
`
`
`
`Attachment B: Sample PMR/PMC Development Template
`
`Last Updated 6/17/2010
`
`Page 3 of 4
`
`

`

`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 6/17/2010
`
`Page 4 of 4
`
`

`

`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: PMR 1649-5: Complete and submit the final report of trial TES10884,
`along with a thorough review of cardiac safety data, for the potential of
`cabazitaxel on QTc interval prolongation in patients.
`
`Final Analysis Plan Submission:
`Trial Completion Date:
`Final Report Submission Date:
`Other:
`
`January 2010
`December 2011
`June 2012
`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
`
`
`
`No QT interval data were collected in the clinical studies conducted to date. A dedicated QT clinical
`trial (TES10884) has been proposed by the applicant and reviewed by QT-IRT. The applicant’s
`response to QT-IRT comments is under Agency’s review. The applicant will be required to conduct
`and complete trial TES10884 to evalute the the influence of cabazitaxel on QT intervals
`prolongation.
`
`
`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.”
`
`
`
`In the pivotal trial EFC6193 supporting the efficacy and safety of cabazitaxel, cases of sudden
`death/cardiac arrest were reported only in the cabazitaxel arm. The number of cardiac arrhythmias
`AEs was higher in the cabazitaxel arm, including grade ≥ 3 cases than in the mitoxantrone control
`arm. With no QT interval data collected in the clinical studies to date, the applicant poposed
`dedicated clinical trial TES10884 in cancer patients to determine whether cabazitaxel has a
`po