CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`021825Orig1s000
`
`
`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 Description:
`
`NDA 021825/ Ferriprox (Deferiprone)
`
`Conduct a trial to determine the efficacy and safety of the use of
`deferiprone to treat iron overload in patients with sickle cell disease and
`transfusional hemosiderosis who have not been adequately treated with
`available chelating agents. Submit the protocol for review and
`concurrence prior to commencing. The trial will enroll a sufficient
`number of patients with sickle cell disease as described above, to
`provide sufficient evidence to assess the efficacy and safety in the
`sickle cell disease population described. The trial may enroll patients
`with other conditions who have developed transfusional iron overload.
`The trial will stratify for hematologic diagnosis for the randomization.
`The primary and secondary endpoints will measure changes in cardiac
`iron concentration and liver iron concentration.
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
` February 2012
`
`January 2016
`
`July 2016
` MM/DD/YYYY
`
`
`PMR 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
`
`
`
`The evidence of drug benefit comes from a thalassemic population with an unmet need. The
`benefit/risk in patients with SCD has not been evaluated as yet.
`
`
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 1 of 4
`
`Reference ID: 3029011
`
`

`

`
`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 trials that support the sponsor’s application for approval of deferiprone for the indication were
`performed almost entirely in subjects with thalassemia. In the US, the thalassemia population is
`approximately 1,000 individuals. In the US, it is very likely that the main population that will be
`treated will be the sickle cell anemia population. In the clinical trials, there were only five persons
`with sickle cell disease who were treated (and all were treated in the Compassionate Use Treatment
`Program), so data for the efficacy and safety in that population are not available.
`
`
`
`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.
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 2 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`
`
`Single arm prospective trial in patients with sickle cell disease who iron overloaded.
`
`Drug exposure for at least 12 months; follow-up of an additional month.
`
`Endpoints to be studied: Liver iron concentration; serum ferritin; cardiac MRI T2*; safety;
`discontinuations
`
`Entry criteria: (LIC > 7 mg Fe/g dw, serum ferritin > 2500 µg/L, MRI T2* < 20 ms) after adequate
`trial of other chelators
`
`
`
`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)
`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)
`New patient population
`
`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 Template
`
`Last Updated 10/14/2011
`
`Page 3 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`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 10/14/2011
`
`Page 4 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`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 Description:
`
`NDA 021825 Ferriprox (deferiprone)
`
`
`Establish a registry in order to perform an enhanced
`pharmacovigilance study of agranulocytosis. Submit a protocol to
`establish the registry and describe procedures for this enhanced
`pharmacovigilance prior to commencing the study. Procedures
`should include: Creation of marketing materials to inform and
`encourage clinicians to report agranulocytosis events to the
`sponsor; monitoring of all reported cases and active follow-up to
`characterize the demographics, recent prior blood counts,
`concomitant medications, co-existing conditions, duration of drug
`exposure prior to onset, outcomes of the event, and other factors
`that may help to characterize the agranulocytosis event. Sponsor
`also will institute procedures to obtain blood samples from patients
`with reported cases of agranulocytosis to store for later analysis of
`possible genetic underlying factors that may predict the risk of
`agranulocytosis. Submit interim reports annually describing the
`above results.
`
`
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
` April 2012
` October 2018
` April 2019
` MM/DD/YYYY
`
`
`PMR 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
`
`
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 1 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`Agranulocytosis occurs in 1-2% of treated patients. Risk factors and characteristics are not well
`known.
`
`
`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.”
`
`Agranulocytosis is fatal in a proportion of cases. For this drug, some cases are reversible. Possible
`mitigating factors or risk factors are not known.
`
`
`
`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
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 2 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`
`
` 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.
`Registry of cases of agranulocytosis with enhanced PV.
`
`
`
`
`
`
`
`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)
`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?
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 3 of 4
`
`Reference ID: 3029011
`
`

`

`
`
` 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 10/14/2011
`
`Page 4 of 4
`
`Reference ID: 3029011
`
`

`

`
`
`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 Description:
`
`NDA 021825/ Ferriprox (Deferiprone)
`Conduct a clinical trial per ICH E14 to assess the potential for deferiprone to
`prolong the QT interval. Submit the protocol for IRT review and concurrence
`prior to commencing.
`
`Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`
`July 2012
`
`July 2013
`
` December 2013
`
`
`
`
`PMR 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
`
`
`
`In clinical trials with deferiprone, one patient developed torsades de pointes and there is anecdotal
`evidence of a small prolongation in the QT interval. Sudden unexplained deaths do not appear to
`have occurred. A consultation from the CDER DCRP QT Interdisciplinary Review Team (June 17,
`2011) states that ECGs collected in clinical trials with deferiprone are inconclusive and that the pro-
`arrhythmic liability of deferiprone has not been excluded. The Team recommends that a thorough
`QT assessment be performed.
`
`
`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 arrhythmogenic potential of deferiprone.
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 1 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`
`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 clinical trial evaluating the potential for deferiprone to prolong the QT interval.
`
`
`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 10/14/2011
`
`Page 2 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`
`
`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?
` 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 10/14/2011
`
`Page 3 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`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 Description:
`
`NDA 021825/ Ferriprox (Deferiprone)
`Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-
`glucuronide metabolite in subjects with hepatic impairment. This
`pharmacokinetic trial should be conducted in a population with mild to
`severe hepatic insufficiency and the number of patients enrolled in the
`trial should be sufficient to detect PK differences. The subjects enrolled in
`this trial should have demographics that are representative of the indicated
`population (e.g., age, weight, gender, race). Submit the protocol for
`review and concurrence prior to commencing.
`
`
`
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`Other:
`
`
` September 2012
` February 2014
`
`July 2014
` MM/DD/YYYY
`
`
`PMR 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
`
`
`
`Serious condition / unmet needs / Limited to patients with mild, moderate, and severe hepatic
`impairment.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 1 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`Deferiprone is extensively metabolized to deferiprone glucuronide (on average > 90%) in the liver
`and possibly extrahepatically (e.g., kidney). The effect of hepatic impairment on deferiprone
`exposure was not assessed. Increased exposure due hepatic dysfunction may increase the risk of
`severe adverse events (e.g., agranulocytosis) that have resulted in fatalities.
`
`
`
`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 multicenter, open-label, sequential design trial in both healthy subjects with normal hepatic
`function, and otherwise healthy subjects with mild, moderate, or severe hepatic impairment (using
`Child Pugh Classification) to compare the pharmacokinetics (PK) of both deferiprone and its
`primary 3-O-glucuronide metabolite.
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 2 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`
`
`
`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)
`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?
` 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.
`
`
`_____________RCK__________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 3 of 3
`
`Reference ID: 3029011
`
`

`

`
`
`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 Description:
`
`NDA 021825/ Ferriprox (Deferiprone)
`Conduct a pharmacokinetic trial of both deferiprone and its primary 3-O-
`glucuronide metabolite in subjects with renal impairment. This
`pharmacokinetic trial should be conducted in a population with mild to
`severe renal insufficiency and the number of patients enrolled in the trial
`should be sufficient to detect PK differences. The subjects enrolled in this
`trial should have demographics that represent the indicated population
`(e.g., age, weight, gender, race) to the extent possible. Submit the
`protocol for review and concurrence prior to commencing.
`
`
`
`Final Protocol Submission:
`Trial Completion:
`Final Report Submission:
`Other:
`
`
` September 2012
` February 2014
`
`July 2014
` MM/DD/YYYY
`
`
`PMR 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
`
`
`
`Serious condition; affects patients with mild, moderate, and severe renal impairment.
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
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`Page 1 of 3
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`Reference ID: 3029011
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`The majority (about 95%) of deferiprone is excreted in the urine as the glucuronide with 5%
`excreted as the parent. The effect of renal impairment on deferiprone exposure has not been
`assessed. The potential for accumulation and toxicity of the glucuronide metabolite is unknown and
`the contribution of renal UGT1A6 to the metabolism of deferiprone, is unknown. In patients with
`renal impairment these factors may increase the risk of severe adverse events (e.g., agranulocytosis)
`that have resulted in fatalities.
`
`
`
`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 multicenter, open-label, sequential design trial in both healthy subjects with normal renal
`function, and otherwise healthy subjects with mild, moderate, or severe renal impairment (using
`Creatinine Clearance) to compare the pharmacokinetics (PK) of both deferiprone and its primary
`3-O-glucuronide metabolite.
`
`PMR/PMC Development Template
`
`Last Updated 10/14/2011
`
`Page 2 of 3
`
`Reference ID: 3029011
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`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)
`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 tri