CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`205525Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`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.
`
`
`NDA #
`Product Name:
`
`PMR/PMC Description:
`
`205525
`Dronabinol oral solution
`
`3044-1
`Twenty-eight day, daily, repeat dose, oral gavage dose-range finding toxicity
`study in neonatal rats to provide rationale for dose selection for the 3 month
`neonatal rat toxicity study with Syndros (dronabinol oral solution).
`
` 08/2016
` 11/2016
` 01/2017
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`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
`
`
`
`This study is needed to inform dose selection in the pivotal 3-month oral toxicity study of dronabinol in
`neonatal rats, which is required to support the initiation of pediatric trials for all age groups. The Agency
`has agreed to allow the pediatric development program to begin after approval.
`
`
`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 6/30/2016
`
`Page 1 of 4
`
`Reference ID: 3953715
`
`

`

`This study will serve as the basis of dose selection for the pivotal 3-month oral toxicity study of dronabinol
`in neonatal rats.
`
`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.
`A 28-day oral dose-ranging toxicity study of dronabinol in neonatal rats.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 2 of 4
`
`Reference ID: 3953715
`
`

`

`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)
` 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
`Continuation of Question 4
`
`
` 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?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 3 of 4
`
`Reference ID: 3953715
`
`

`

`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 6/30/2016
`
`Page 4 of 4
`
`Reference ID: 3953715
`
`

`

`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.
`
`
`NDA #
`Product Name:
`
`PMR/PMC Description:
`
`205525
`Dronabinol oral solution
`
`3044-2
`Three-month repeat dose toxicity and toxicokinetic study in neonatal
`rats with a 28-day recovery period to provide safety assessment of
`Syndros (dronabinol oral solution) for pediatric clinical studies
`
` 01/2017
` 11/2017
` 06/2018
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`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
`
`
`
`The Agency has agreed to allow the pediatric development program to begin after approval. This study is
`required to support the initiation of pediatric trials for all age groups.
`
`
`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 6/30/2016
`
`Page 1 of 4
`
`Reference ID: 3953715
`
`

`

`

`

`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)
` 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
`Continuation of Question 4
`
`
` 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?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 3 of 4
`
`Reference ID: 3953715
`
`

`

`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 6/30/2016
`
`Page 4 of 4
`
`Reference ID: 3953715
`
`

`

`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.
`
`NDA/BLA #
`Product Name:
`
`205525
`dronabinol oral solution
`
`PMR/PMC Description:
`
`3044-3
`Deferred
`
`a” (4) under PREA to
`
`evaluate the phamracokinetics of Syndros (dronabinol oral solution) for the
`treatment of chemotherapy induced nausea and vomiting (CINW in pediatric
`cancer patients who failed to respond adequately to conventional antiemetic
`treatments from birth to 17 years of age.
`M"
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Trial Completion:
`Final Report Submission:
`Other:
`
`09/2018
`
`11/2021
`05/2022
`
`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.
`
`XI Unmet need
`I: Life-threatening condition
`[3 Long-term data needed
`l:l Only feasible to conduct post-approval
`[3 Prior clinical experience indicates safety
`E] Small subpopulation affected
`El Theoretical concern
`[X] Other
`
`This is a PREA PIVIR agreed upon during this review cycle. Under the regulations in place at the
`time of this NDA submission, an agreed iPSP was in place prior to NDA resubmission. Adult
`studies are completed and ready for approval, and nonclinical juvenile toxicity data need to be
`
`conducted to support initiation of pediatric clinical trials in children <17 years old.
`
`2. Describe the particular review issue and the goal of the study/clinical trial. Ifthe 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 6/30/2016
`
`Page 1 of 3
`
`Reference ID: 3953715
`
`

`

`This is a PREA PMR study to evaluate the PK of dronabinol oral solution in pediatric patients
`aged 0 to less than 17 years old.
`
`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.
`
` in pediatric chemotherapy
`induced nausea and vomiting (CINV) patients will be performed in children 0 to 17 years
`of age who have cancer and are undergoing treatment.
`
`
`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
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 2 of 3
`
`Reference ID: 3953715
`
`(b) (4)
`
`

`

` 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
`Continuation of Question 4
`
`
` 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?
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`
`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 6/30/2016
`
`Page 3 of 3
`
`Reference ID: 3953715
`
`

`

`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.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`205525
`dronabinol oral solution
`
`3044-4
`Deferred pediatric study under PREA to evaluate the tolerability and efficacy
`of dronabinol oral solution for the treatment of chemotherapy induced nausea
`and vomiting (CINV) in pediatric patients who failed to respond adequately to
`conventional antiemetic treatments aged birth to 17 years.
`
` 07/2022
` 09/2025
` 03/2026
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`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
`
`
`
`This is a PREA PMR agreed upon during this review cycle. Under the regulations in place at the
`time of this NDA submission, an agreed iPSP was in place prior to NDA resubmission. Adult
`studies are completed and ready for approval, and nonclinical juvenile toxicity data need to be
`conducted to support initiation of pediatric clinical trials in children <17 years old.
`
`
`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.”
`
`This is a PREA PMR study to evaluate the efficacy and safety of dronabinol oral solution in
`pediatric patients aged 0 to less than 17 years olds receiving
` emetogenic
`chemotherapy.
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 1 of 3
`
`Reference ID: 3953715
`
`(b) (4)
`
`

`

`3.
`
`Ifthe study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`
`l:l Accelerated Approval (subpart HIE)
`E] Animal Efficacy Rule
`[XI Pediatric Research Equity Act
`[:I FDAAA required safety study/clinical trial
`
`—
`
`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?
`l:| Assess signals of serious risk related to the use of the drug?
`l:| 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 pgstmarketing 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
`
`El Analysis using pharmacovigjlance system?
`Do not select the above study/clinical trial (me 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
`
`[: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
`
`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)? If the study
`or trial will be performed in a subpopulation. list here.
`
`(m4) tolerability and efficacy study in pediatric cancer patients
`This is a pivotal
`age 0-17 years old receiving
`M“) emetogenic chemotherapy. The primary
`endpoint will be
`(me)
`
`
`
`Required
`
`:l Observational phannacoepidemiologic study
`:1 Registry studies
`XI Primary safety study or clinical trial
`:I Phannacogenetic or phannacogenonric study or clinical trial if required to further assess safety
`:I Thorough Q-T clinical trial
`:I Nonclinical (animal) safety study (e.g.. carcinogenicity. reproductive toxicology)
`:l Nonclinical study (laboratory resistance. receptor affinity. quality study related to safety)
`:I Pharmacokinetic studies or clinical trials
`:l Drug interaction or bioavailability studies or clinical trials
`:l Dosing trials
`
`
`
`PMR/PMC Development Template
`
`Last Updated 6r’30r’2016
`
`Page 2 of 3
`
`Reference ID: 3953715
`
`

`

`Continuation of Question 4
`
`
` 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?
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`
`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 6/30/2016
`
`Page 3 of 3
`
`Reference ID: 3953715
`
`

`

`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.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`205525
`Dronabinol oral solution
`
`3044-5
`Pre-/postnatal developmental toxicology study in rats exposed to
`Syndros (dronabinol oral solution) to assess the risk of neurotoxicity.
`
`
` 10/2016
` 10/2017
` 07/2018
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`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
`
`
`
`
`Recent publications indicate a potential for neurocognitive impairment following prenatal
`exposure to delta-9-THC (dronabinol). Although the label for the reference product (Marinol)
`does not indicate that postnatal developmental effects were observed, it is likely that the pre-
`/postnatal developmental study that supported approval of Marinol used methods that were
`inadequate for assessing neurocognitive impairment or other subtle signs of developmental
`neurotoxicity.
`
`
`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 6/30/2016
`
`Page 1 of 4
`
`Reference ID: 3953715
`
`

`

`This study is needed to provide adequate information about the risk of developmental
`neurotoxicity following prenatal exposure to dronabinol. The study results should be included in
`subsection 8.1 (Pregnancy) of 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?
`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.
`Pre-/postnatal developmental toxicology study in rats
`
`
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 2 of 4
`
`Reference ID: 3953715
`
`

`

`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)
` 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
`Continuation of Question 4
`
`
` 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
`Pre-/postnatal developmental toxicology study in rats
`
`
`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?
`
`
`
`
`
`
`
`
`
` Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial
`
`If so, does the clinical trial meet the following criteria?
`
` There is a significant question about the public health risks of an approved drug
` There is not enough existing information to assess these risks
` Information cannot be gained through a different kind of investigation
` The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and
` The trial will emphasize risk minimization for participants as the protocol is developed
`
`PMR/PMC Development Template
`
`Last Updated 6/30/2016
`
`Page 3 of 4
`
`Reference ID: 3953715
`
`

`

`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 6/30/2016
`
`Page 4 of 4
`
`Reference ID: 3953715
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MAUREEN D DEWEY
`06