CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`204063Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`MEMORANDUM
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
` Public Health Service
`
`
` Food and Drug Administration
`
`
`
`
`
`________________________________________________________________________
`
`Division of Neurology Products (HFD-120)
`Center for Drug Evaluation and Research
`
`Date: March 20, 2013
`
`From: Lois M. Freed, Ph.D.
`
`Supervisory Pharmacologist
`
`Subject: NDA 204-063 (BG-00012, dimethyl fumarate, TECFIDERA), labeling
`recommendations.
`________________________________________________________________________
`
`Recommendations for labeling are provided in this memo; the sponsor’s proposed
`labeling was used as the base document. These labeling recommendations take into
`account those provided by Dr. Banks-Muckenfuss (cf. Pharmacology/Toxicology NDA
`Review and Evaluation, NDA 204063, Melissa K. Banks-Muckenfuss, Ph.D., 1/28/2013)
`and some, but not all, of the additional comments provided by the sponsor. Plasma
`exposure (AUC) margins were calculated using values in humans from repeat-dose
`studies (# 109HV103 and 109HV104): Cmax: 2.24-2.4 µg/mL; AUC: 10-11.3 µg*hr/mL.
`
`
`
`Reference ID: 3279692
`
`1
`
`

`

`
`
`
`SPONSOR
`
`
`RECOMMENDED
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`-----INDICATIONS AND USAGE-----
`-----INDICATIONS AND USAGE-----
`TECFIDERA is indicated for the treatment of
`patients with relapsing forms of multiple sclerosis.
`(1)
`
`----USE IN SPECIFIC POPULATIONS-----
`Pregnancy: based on animal data, may cause fetal
`harm. (8.1)
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`Pregnancy Category C
`
`There are no adequate and well-controlled studies in
`pregnant women. In animals, adverse effects on
`offspring survival, growth, sexual maturation, and
`neurobehavioral function were observed when
`dimethyl fumarate (DMF) was administered during
`pregnancy and lactation at clinical relevant doses.
`TECFIDERA should be used during pregnancy only
`if the potential benefit justifies the potential risk to
`the fetus.
`
`In rats administered DMF orally (25, 100, 250
`mg/kg/day) throughout organogenesis, embryofetal
`toxicity (reduced fetal body weight and delayed
`ossification) were observed at the highest dose
`tested. This dose also produced evidence of
`maternal toxicity (reduced body weight). Plasma
`exposure (AUC) for monomethyl fumarate (MMF),
`the major circulating metabolite, at the no-effect
`dose is approximately three times that in humans at
`the recommended human dose (RHD) of 480
`mg/day. In rabbits administered DMF orally (25, 75,
`and 150 mg/kg/day) throughout organogenesis,
`embryolethality and decreased maternal body
`weight were observed at the highest dose tested.
`The plasma AUC for MMF at the no-effect dose is
`approximately 5 times that in humans at the RHD.
`
`Oral administration of DMF (25, 100, and 250
`mg/kg/day) to rats throughout organogenesis and
`lactation resulted in increased lethality, persistent
`reductions in body weight, delayed sexual
`maturation (male and female pups), and reduced
`testicular weight in offspring at the highest dose
`tested. Neurobehavioral impairment was observed at
`all doses. A no-effect dose for developmental
`
`2
`
`
`
`Reference ID: 3279692
`
`(b) (4)
`
`

`

`8.3 Nursing Mothers
`
`It is not known whether this drug is excreted in
`human milk. Because many drugs are excreted in
`human milk, caution should be exercised when
`TRADENAME is administered to a nursing woman.
`
`12 CLINICAL PHARMACOLOGY
`
`toxicity was not identified. The lowest dose tested
`was associated with plasma AUC for MMF lower
`than that in humans at the RHD.
`
`Pregnancy Registry
`
`[No comment on PR wording; defer to clinical
`team.]
`
`This section should be omitted.
`
`8.3 Nursing Mothers
`
`It is not known whether this drug is excreted in
`human milk. Because many drugs are excreted in
`human milk, caution should be exercised when
`TECFIDERA is administered to a nursing woman.
`8.4 Pediatric Use
`
`Safety and effectiveness in pediatric patients not
`been established.
`
`12.1 Mechanism of Action
`
`The mechanism by which dimethyl fumarate (DMF)
`exerts its therapeutic effect in multiple sclerosis is
`unknown. DMF and the metabolite, monomethyl
`fumarate (MMF), have been shown to activate the
`Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)
`pathway in vitro and in vivo in animals and humans.
`The Nrf2 pathway is involved in the cellular
`response to oxidative stress. MMF has been
`identified as a nicotinic acid receptor agonist in
`vitro.
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`Reference ID: 3279692
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`13.1 Carcinogenesis, Mutagenesis, Impairment of
`Fertility
`
`Carcinogenesis
`Carcinogenicity studies of dimethyl fumarate
`(DMF) were conducted in mouse and rat. In mouse,
`oral administration of DMF (25, 75, 200 and 400
`mg/kg/day) for up to two years resulted in an
`increase in nonglandular stomach (forestomach) and
`kidney tumors: squamous cell carcinomas and
`papillomas of the forestomach in males and females
`at 200 and 400 mg/kg/day; leiomyosarcomas of the
`forestomach at 400 mg/kg/day in males and
`females; renal tubular adenomas and carcinoma at
`200 and 400 mg/kg/day in males; and renal tubule
`adenomas at 400 mg/kg/day in females. Plasma
`MMF exposure (AUC) at the highest dose not
`associated with tumors in mouse (75 mg/kg/day)
`was similar to that in humans at the recommended
`human dose (RHD) of 480 mg/day.
`
`In rat, oral administration of DMF (25, 50, 100, and
`150 mg/kg/day) for up to two years resulted in
`increases in squamous cell carcinomas and
`papillomas of the forestomach at all doses tested in
`males and females, and in testicular interstitial
`(Leydig) cell adenomas at 100 and 150 mg/kg/day.
`Plasma MMF AUC at the lowest dose tested was
`lower than that in humans at the RHD.
`
`Mutagenesis
`Dimethyl fumarate and monomethyl fumarate
`(MMF) were not mutagenic in the in vitro bacterial
`reverse mutation (Ames) assay. DMF and MMF
`were clastogenic in the in vitro chromosomal
`aberration assay in human peripheral blood
`lymphocytes in the absence of metabolic activation.
`DMF was not clastogenic in the in vivo
`micronucleus assay in rat.
`
`Impairment of Fertility
`In male rat, oral administration of DMF (75, 250,
`and 375 mg/kg/day) prior to and throughout the
`mating period had no effect on fertility; however,
`increases in non-motile sperm were observed at the
`mid and high doses. The no-effect dose for adverse
`effects on sperm is similar to the recommended
`human dose (RHD) of 480 mg/day on a body
`surface area (mg/m2) basis.
`
`In female rat, oral administration of DMF (20, 100,
`and 250 mg/kg/day) prior to and during mating and
`continuing to gestation day 7 caused disruption of
`the estrus cycle and increases in embryolethality at
`the highest dose tested. The highest dose not
`associated with adverse effects (100 mg/kg/day) is
`
`4
`
`
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`Reference ID: 3279692
`
`(b) (4)
`
`

`

`twice the RHD on a mg/m2 basis.
`
`Testicular toxicity (germinal epithelial
`degeneration, atrophy, hypospermia, and/or
`hyperplasia) was observed at clinically relevant
`doses in mouse, rat, and dog in subchronic and
`chronic oral toxicity studies of DMF, and in a
`chronic oral toxicity study of fumaric acid esters
`(including DMF) in rat.
`13.2 Animal Toxicology and/or Pharmacology
`
`Kidney toxicity was observed after repeated oral
`administration of dimethyl fumarate (DMF) in
`mouse, rat, dog, and monkey. Renal tubule epithelia
`regeneration, suggestive of tubule epithelial injury,
`was observed in all species. Renal tubular
`hyperplasia was observed in rats with dosing for up
`to two years. Cortical atrophy and interstitial
`fibrosis were observed in dog and monkey at doses
`above 5 mg/kg/day. In monkey, the highest dose
`tested (75 mg/kg/day) was associated with single
`cell necrosis and multifocal and diffuse interstitial
`fibrosis, indicating irreversible loss of renal tissue
`and function. In dog and monkey, the 5-mg/kg/day
`dose was associated with plasma MMF exposures
`less than or similar to that in humans at the
`recommended human dose (RHD).
`
` dose-related increase in incidence and severity of
`retinal degeneration was observed in mouse
`following oral administration of DMF for up to two
`years at doses above 75 mg/kg/day, a dose
`associated with plasma MMF exposure (AUC)
`similar to that in humans at the RHD.
`
`
` A
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`
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`Reference ID: 3279692
`
`5
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LOIS M FREED
`03/20/2013
`
`Reference ID: 3279692
`
`

`

`NDA 204063
`Tecfidera
`
`PMR/PMC Development Template for TECFIDERA (dimethyl fumarate)
`
`PMR # 2014-1
`
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: Deferred pediatric trial under PREA: A randomized, controlled, parallel
`group superiority trial in pediatric patients ages 10 through 17 years to
`evaluate the pharmacokinetics of dimethyl fumarate, and the safety and
`efficacy of dimethyl fumarate compared to an appropriate control for
`the treatment of relapsing forms of multiple sclerosis.
`
` 11/30/2016
` 10/31/2019
` 02/28/2020
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`This is a PREA requirement. A waiver has been given for children under from birth to nine
`years of age because necessary studies are impossible or highly impracticable due to the small
`number of patients less than 10 years old with multiple sclerosis. A deferral has been given for
`those ages 10 up to 17; it is appropriate for a PMR because the drug is about to be approved and
`the pediatric study has not been completed.
`
`
`
`
`PMR/PMC Development Template
`
`Last Updated 3/7/2013
`
`Page 1 of 4
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`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 this study is to evaluate the pharmacokinetics, safety, and efficacy of dimethyl fumarate
`in pediatric patients ages 10 to up to 17 compared to an appropriate control for treatment of
`relapsing forms of multiple sclerosis.
`
`
`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
`
`
`
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`
`PMR/PMC Development Template
`
`Last Updated 3/7/2013
`
`Page 2 of 4
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`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.
`Deferred pediatric trial under PREA: A randomized, controlled, parallel group superiority
`trial in pediatric patients ages 10 through 17 years to evaluate the pharmacokinetics of
`dimethyl fumarate, and the safety and efficacy of dimethyl fumarate compared to an
`appropriate control for the treatment of relapsing forms of multiple sclerosis.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`Continuation of Question 4
`
`
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`PREA pediatric clinical trial
`
`
`
`
`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 3/7/2013
`
`Page 3 of 4
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`
`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 3/7/2013
`
`Page 4 of 4
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`
`PMR/PMC Development Template for TECFIDERA (dimethyl fumarate)
`PMR # 2014-2
`
` 6/30/12
` 8/30/13
` 10/30/13
` MM/DD/YYYY
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: Receptor binding study for abuse potential assessment
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`The clinical data collected so far does not indicate major problems with respect to abuse
`potential.
`
`
`
`
`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 NDA for dimethyl fumarate does not contain all of the information necessary for a
`complete evaluation of its abuse potential. The goal of this study is to provide
`information about the abuse potential of dimethyl fumarate. Although activation of the
`nuclear factor (erythroid-derived 2)-like 2 (NFE2L2 or Nrf2) transcriptional pathway is
`not a pharmacological mechanism of action traditionally recognized to be associated with
`known drugs of abuse, comprehensive receptor binding studies with dimethyl fumarate
`would establish whether activity at receptor sites associated with abused drugs exists.
`
`
`Tecfidera PMR/PMC Development Template Last Updated 2/7/13
`
`
`
` Page 1 of 3
`
`Reference ID: 3272669
`
`

`

`
`
`NDA 204063
`Tecfidera
`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 comprehensive in vitro receptor binding study with dimethyl fumarate and with its
`metabolite monomethyl fumarate. This includes characterizing the affinity of dimethyl
`fumarate and monomethyl fumarate on dopamine, serotonin, GABA (gamma-amino-
`butyric-acid), opioid, NMDA, monoamine, sodium channel, calcium channel, and
`cannabinoid receptor sites, as well as the interaction of dimethyl fumarate and of
`monomethyl fumarate with nitric oxide synthase.
`
`
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`
`Tecfidera PMR/PMC Development Template Last Updated 2/7/13
`
`
`
` Page 2 of 3
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`Continuation of Question 4
`
`
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`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)
`
`Tecfidera PMR/PMC Development Template Last Updated 2/7/13
`
`
`
` Page 3 of 3
`
`Reference ID: 3272669
`
`

`

`NDA 204063
`Tecfidera
`
`PMR/PMC Development Template for Tecfidera (dimethyl fumarate)
` PMR # 2014-3
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: A nonclinical self-administration study to assess abuse potential using
`dimethyl fumarate in animals trained to discriminate the known drug of
`abuse from saline.
`
` 10/30/2013
` 02/28/2014
` 03/30/2014
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`The clinical data collected so far does not indicate major problems with respect to abuse
`potential.
`
`
`
`
`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 NDA for dimethyl fumarate does not contain all of the information necessary for a
`complete evaluation of its abuse potential. The goal of this study is to provide
`information about the abuse potential of dimethyl fumarate. The ability of dimethyl
`fumarate to produce self-administration is unknown. Among preclinical behavioral
`models used to evaluate the abuse potential of a drug, self-administration is often cited as
`the standard preclinical abuse potential assessment because of its face validity and
`predictive validity. Data from self-administration studies will provide information about
`the likelihood that dimethyl fumarate will function as a reinforcer and be abused.
`
`
`Tecfidera PMR/PMC Development Template Last Updated 3/7/13
`
` Page 1 of 3
`
`Reference ID: 3272669
`
`

`

`
`
`NDA 204063
`Tecfidera
`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 nonclinical self-administration study to assess abuse potential using dimethyl fumarate
`in animals trained to discriminate the known drug of abuse from saline. The animals
`chosen must demonstrate similar metabolism of dimethyl fumarate and monomethyl
`fumarate as observed in humans.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
`
`Tecfidera PMR/PMC Development Template Last Updated 3/7/13
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` Page 2 of 3
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`NDA 204063
`Tecfidera
`Continuation of Question 4
`
`
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
`
` Does the study/clinical trial meet criteria for PMRs or PMCs?
` Are the objectives clear from the description of the PMR/PMC?
` Has the applicant adequately justified the choice of schedule milestone dates?
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process?
`
`
`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)
`
`Tecfidera PMR/PMC Development Template Last Updated 3/7/13
`
` Page 3 of 3
`
`Reference ID: 3272669
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`

`NDA 204063
`Tecfidera
`
`PMR/PMC Development Template for TECFIDERA (dimethyl fumarate)
`PMR # 2014-4
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`PMR/PMC Description: A nonclinical discrimination study to assess abuse potential using
`dimethyl fumarate in animals trained to discriminate the known drug of
`abuse from saline.
`
`
` 3/30/2014
` 7/30/2014
` 8/30/2014
` MM/DD/YYYY
`
`
`PMR/PMC Schedule Milestones: Final protocol Submission Date:
`
`Study/Clinical trial Completion Date:
`
`Final Report Submission Date:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`The clinical data collected so far does not indicate major problems with respect to abuse
`potential.
`
`
`
`
`
`Tecfidera PMR/PMC Development Template Last Updated 3/7/2013
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` Page 1 of 4
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`NDA 204063
`Tecfidera
`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 NDA for dimethyl fumarate does not contain all of the information necessary for a
`complete evaluation of its abuse potential. The goal of this study is to provide
`information about the abuse potential of dimethyl fumarate. The similarity of dimethyl
`fumarate to other drugs of abuse as evaluated in the drug discrimination study is
`unknown. Among preclinical behavioral models used to evaluate the abuse potential of a
`drug, the discrimination study is often cited as one of the most important standard
`preclinical abuse potential evaluations because of its face validity and predictive validity.
`Data from discrimination studies will provide information about the similarity of
`dimethyl fumarate to other drugs of abuse and serve as a predictor of its potential for
`abuse
`
`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 sufficien