CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`
`
`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.
`
`NDA203284
`Ravicti
`
` A
`
` milk-only lactation trial in lactating female patients with Urea Cycle
`Disorders receiving Ravicti (glycerol phenylbutyrate) to assess the
`pharmacokinetics of Ravicti (glycerol phenylbutyrate) and its active
`metabolites in breast milk using an assay that has been validated in
`milk.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
` December 2013
`
`June 2015
` December 2015
`
`
`
`
`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
`
`
`
`A rat carcinogenicity study showed an increased incidence of malignancies. In addition,
`phenylacetic acid (PAA), the main metabolite of Ravicti, has been shown to cause neurotoxicity in
`clinical studies where it was given IV to cancer patients. A pre-approval study in lactating women
`was not possible due to the rarity (low prevalence) of Urea Cycle Disorders and the scarcity of
`lactating patients. However Ravicti is expected to be used by women of reproductive age and data
`on exposure of the drug via breast milk is needed.
`
`
`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 1/30/2013
`
`Page 1 of 3
`
`Reference ID: 3252923
`
`

`

`Because a rat carcinogenicity study showed an increased incidence of malignancies and because
`FAA has been shown to be neurotoxic. it is important to assess the presence of drug in breast milk.
`Milk only studies can provide information regarding timing of maternal dose relative to breast-
`feeding. the duration recommended to discard milk relative to maternal dose, and when to resume
`
`breast-feeding relative to maternal dose or drug exposure.
`
`3.
`
`If the study/clinical trial is a PMR, check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart H/E)
`E] Animal Eflicacy Rule
`E] Pediatric Research Equity Act
`IX] 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?
`[2 Assess signals of serious risk related to the use of the drug?
`E] 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:
`E] Analysis of spontaneous postrnarketing adverse events?
`Do not select the above stator/clinical trial type if. such an analysis will not be sufficient to
`assess or identify a serious risk
`
`stem?
`' ance
`harmacovi
`E] Anal sis usin
`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
`
`E] Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidenriologic studies), animal studies. and laboratory
`experiments?
`Do not select the above study Me if: a study will not be sufficient to identify or assess a
`serious risk
`
`[Z 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 hmnan
`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.
`
`(D) (4)
`
`PMRI‘PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 2 of 3
`
`Reference ID: 3252923
`
`

`

`
`
`
`
`
`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.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 3 of 3
`
`Reference ID: 3252923
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NANCY C SNOW
`01/30/2013
`
`MELANIE J BLANK
`01/31/2013
`
`Reference ID: 3252923
`
`

`

`
`
`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.
`
`NDA203284
`Ravicti (glycerol phenylbutyrate)
`
` A
`
` clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti
`(glycerol phenylbutyrate) and its metabolites (PBA, PAA, and PAGN) during
`Ravicti (glycerol phenylbutyrate) treatment in pediatric patients with Urea
`Cycle Disorders who are ages 2 months to less than 2 years.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`July 2013
`
`July 2016
`
` December 2016
`
`
`
`
`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
`
`
`
`Very few data on patients in the age category of 2 months to 2 years were included in the NDA. The
`numbers of patients in this age range (4) and the timing of assessments were insufficient to conduct
`an adequate exploration of an effective dosing algorithm (by mg/kg vs. mg/m2) and the association
`between adverse events and Ravicti metabolite (in particular, PAA) levels. Two of the four patients
`in this age-range had PAA levels ~ 500 μg/mL when on buphenyl or HPN-100.
`
`
`PAA toxicity, with neurological and gastrointestinal manifestations has been demonstrated
`with IV administration of PAA. The symptoms at PPA levels of ~500 μg/mL were
`somnolence, emesis and lethargy in patients with cancer who received IV PAA. More
`severe toxicity (confusion and psychomotor depression) occurred in patients with mean
`peak PAA level of 682 μg/mL1. Overdose of IV PAA in children has been reported to cause
`death and coma.2 Levels of PAA in these children were > 1000 μg/mL.
`
`
`1 Thibault A et al, Phase I study of phenylacetate administered twice daily to patients with cancer. Cancer
`1995;75:2932-8.
`2 Parphanphoj et al (2000), Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring
`the treatment of acute hyperammonemia, J. Inherit. Metab. Dis 23: 129-36.
`
`
`PMR/PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 1 of 4
`
`Reference ID: 3252919
`
`

`

`
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`The goal of the clinical trial is to gain data on the safety, efficacy and dosing in pediatric patients
`between the age of 2 months and 2 years in order to dose patients in this age group properly. Dosing
`for this age group for trials conducted under the NDA was not explored since all patients were
`converted from one medication, to Ravicti. The numbers of patients in this age group was too small
`to draw any meaningful conclusions. In addition PK data of the active drug/active metabolite were
`not regularly monitored in association with adverse events. Therefore the trials submitted with the
`NDA did not rule out a safety risk associated with the active metabolite.
`
`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 1/30/2013
`
`Page 2 of 4
`
`Reference ID: 3252919
`
`

`

`(b) (4)
`
`Required
`
`E] Observational phannacoepidemiologic study
`[:1 Registry studies
`[Z Primary safety study or clinical trial
`[I Pharmacogenetic or pharmacogenomic study or clinical trial ifrequired to further assess safety
`E] Thorough Q-T clinical trial
`El Nonclinical (animal) safety study (e.g., carcinogenicity. reproductive toxicology)
`Continuation 0
`tion 4
`
`D Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
`[Z Pharmacokinetic studies or clinical trials
`El Drug interaction or bioavailability studies or clinical trials
`E] Dosing trials
`E] Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
`E] Meta-analysis or pooled analysis of previous studies/clinical trials
`El Immunogenicity as a marker of safety
`C] Other (provide explanation)
`
`Agreed upon:
`
`E] Quality study without a safety endpoint (e.g., manufacturing. stability)
`El Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
`E] 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
`E] Dose-response study or clinical trial performed for effectiveness
`E] Nonclinical study. not safety-related (specify)
`
`[3 Other
`
`5.
`
`Is the PMR/PMC clear, feasible. and appropriate?
`
`I] Does the study/clinical trial meet criteria for PMRs or PMCs?
`[I Are the objectives clear from the description of the PMR/PMC?
`I: Has the applicant adequately justified the choice of schedule milestone dates?
`El 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:
`
`PMRI‘PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 3 of 4
`
`Reference ID: 3252919
`
`

`

`
`
` 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 1/30/2013
`
`Page 4 of 4
`
`Reference ID: 3252919
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NANCY C SNOW
`01/30/2013
`
`MELANIE J BLANK
`01/31/2013
`
`Reference ID: 3252919
`
`

`

`
`
`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.
`
`NDA203284
`Ravicti (glycerol phenylbutyrate)
`
` A
`
` randomized, controlled clinical trial to assess the safety and efficacy of
`Ravicti (glycerol phenylbutyrate) in patients with Urea Cycle Disorders who
`are treatment naïve to phenylbutyrate.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`
`
`
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`
`
`
`August 2013
`
`June 2016
`
`March 2017
`
`
`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
`
`
`
`In clinical studies in support of NDA203284 most patients were on an established dose of Buphenyl
`(sodium phenylbutyrate) prior to enrolling in the trial. The dose of Ravicti administered to most
`patients was based on the dose of Buphenyl the patient was receiving. Therefore there is limited
`experience with dosing of Ravicti in treatment naïve patients. A concerning safety signal was that 2
`of the 6 patients who were started on Ravicti without first attaining a stable dose of Buphenyl had
`neurological TEAEs that lead to dose reduction and discontinuation. Ravicti has the same active
`moiety as Buphenyl. Therefore, it is considered safe for the purpose of approval to initiate dosing
`with Ravicti. However, the signal of neurotoxicity that was seen in the 2 patients who were not
`already stabilized on Buphenyl raises the concern that treatment naïve patients may not tolerate de
`novo dosing with this product as well as they do with Buphenyl.
`
`
`
`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 1/30/2013
`
`Page 1 of 3
`
`Reference ID: 3252909
`
`

`

`The ability of treatment naive patients to tolerate Ravicti is an important safety issue. To ensure safe
`dosing of Ravicti when starting patients de novo. it is important to study an initial dosing and
`maintenance dosing algorithm based on protein intake. underlying disorder and catabolic/anabolic
`
`state in a controlled trial.
`
`3.
`
`If the study/clinical trial is a PMR. check the applicable regulation.
`Ifnot a PMR, skip to 4.
`
`— Which regulation?
`El Accelerated Approval (subpart HIE)
`E] Animal Efficacy Rule
`E] Pediatric Research Equity Act
`X] FDAAA required safety study/clinical trial
`
`—
`
`—
`
`If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
`I] Assess a known serious risk related to the use of the drug?
`[Z Assess signals of serious risk related to the use of the drug?
`E] 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:
`E] Analysis of spontaneous postmarketing adverse events?
`Do not select the above stator/clinical trial type if. such an analysis will not be sufficient to
`assess or identify a serious risk
`
`E] Analysis using pharmacovigilance ystem?
`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
`
`E] 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 We if: a study will not be sufficient to identify or assess a
`serious risk
`
`[Z 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.
`(b) (4)
`
`PMR/‘PMC Development Template
`
`Last Updated 1/30f2013
`
`Page 2 of 3
`
`Reference ID: 3252909
`
`

`

`
`
`
`
`
`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.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 3 of 3
`
`Reference ID: 3252909
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NANCY C SNOW
`01/30/2013
`
`MELANIE J BLANK
`01/31/2013
`
`Reference ID: 3252909
`
`

`

`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:
`
`203-284
`Ravicti
`
`To conduct an in vivo drug interaction study to evaluate the effect of
`_
`_
`PMR/PMC DCSCUPUOHI Ravicti (glycerol phenylbutyrate) on the pharmacokinetics of a drug
`that is a sensitive substrate of CYP3A4/5 (e.g., midazolam).
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`Study/Trial Completion:
`Final Report Submission:
`Other:
`
`September 2013
`March 2014
`July 2014
`
`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.
`
`[I Unmet need
`D Life-threatening condition
`El Long-term data needed
`El Only feasible to conduct post-approval
`E] Prior clinical experience indicates safety
`E] Small subpopulation affected
`[Z Theoretical concern
`C] Other
`
`In vitro studies suggested that phenylbutyrate, a metabolite of Ravicti, can
`potentially inhibit the metabolism of concomitant medications that are
`substrates of CYP3A4/5, CYP2D6 and/or CYP2C19. Since chronic
`
`potential in vivo drug interaction with concomitant medications is warranted.
`
`administration of Ravicti is expected for UCD patients and the available
`alternative i.e. Buphenyl® also contains phenylbutyrate, the evaluation of the
`
`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 Ifthe FDAAA PMR is created post-approval. describe the “new
`safety information.”
`
`In vitro studies suggested drug interaction potential with substrates of three CYP
`enzymes, we are requesting one in vivo study with a substrate of CYP3A to adequately
`communicate the drug interaction potential to the prescribers by improving the labeling for
`drug interactions. The results of the study in combination of in vitro studies may be used to
`
`(b) (6)
`
`PMR/‘PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 1 of 3
`
`Reference ID: 3252899
`
`

`

`
`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 1/30/2013
`
`Page 2 of 3
`
`Reference ID: 3252899
`
`(b) (4)
`
`

`

`
`
`
`
`
`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.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 1/30/2013
`
`Page 3 of 3
`
`Reference ID: 3252899
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`INSOOK KIM
`01/30/2013
`
`EDWARD D BASHAW
`01/30/2013
`
`Reference ID: 3252899
`
`

`

`
`
`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.
`
`NDA203284
`Ravicti (glycerol phenylbutyrate )
`
` A
`
` clinical trial to assess the safety, efficacy, and pharmacokinetics of
`Ravicti (glycerol phenylbutyrate) and its metabolites (PBA, PAA and
`PAGN) during Ravicti (glycerol phenylbutyrate) treatment in pediatric
`patients with Urea Cycle Disorders who are under 2 months of age.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
` August 2013
` August 2017
` March 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
`
`
`
` Absence of completely developed pancreatic exocrine function could increase the risk of
`malabsorption of Ravicti and subsequent loss of ammonia level control in patients less than 2
`months of age. There will need to be a sufficient number of patients under age 29 days to make a
`complete assessment o f the safety and efficacy of Ravicti in this population.
`
`
`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 1/30/2013
`
`Page 1 of 4
`
`Reference ID: 3252905
`
`

`

`
`
`The goal of the clinical trial is to establish PK/PD of the Ravicti metabolites, dosing algorithm,
`safety and efficacy in patients with UCDs under 2 months of age where there is theoretical concern
`of an inability to absorb the drug because of absence of fully developed pancreatic exocrine function
`with the subsequent loss of ammonia control.
`
`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/clinic