CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203858Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #
`Product Name:
`
`PMR/PMC Description:
`
`203858
`Juxtapid (lomitapide)
`A juvenile animal toxicology study to evaluate the effects of lomitapide on
`learning, memory, behavior, coordination, growth, and long bone
`development with and without vitamin and essential fatty acid
`supplementation to determine whether any observed effects are due directly to
`lomitapide or secondarily to the inhibition of absorption of fat soluble
`vitamins and/or essential fatty acids. This study should be completed before
`any formal pediatric studies are initiated.
`
` 07/15/2013
` 12/30/2013
` 06/15/2014
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other:
`
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`The intended pharmacodynamic activity of lomitapide is to reduce LDL-cholesterol and
`triglycerides in patients with homozygous familial hypercholesterolemia (HoFH). HoFH is a life-
`threatening condition with unmet medical need. A specific safety signal has not been identified
`indicating that pediatric patients will be more susceptible to drug-induced injury, but there are
`theoretical concerns regarding the inhibition of cholesterol synthesis and/or the absorption of fat
`soluble vitamins and essential fatty acids during childhood, which is an important age for
`neurological development as well as overall growth.
`
`
`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 11/28/2012
`
`
`
`Page 1 of
`
`Reference ID: 3235079
`
`

`

`
`
`Lomitapide inhibits the activity of microsomal triglyceride transfer protein (MTP), which prevents
`very low density lipoprotein (VLDL)-cholesterol and chylomicrons from being synthesized in the
`liver and small intestine, respectively. Chylomicrons are important for the absorption of fat soluble
`vitamins and essential fatty acids from the diet. Individuals with abetalipoproteinemia, a rare
`autosomal recessive disease that results from an inactivating mutation of the MTP gene, develop
`several neurological disorders including mental retardation, developmental delay, dyspraxia, muscle
`weakness, slurred speech, progressive decreased vision, and balance and coordination problems. It
`is suspected that the neurological deficits derive from deficiencies in fat soluble vitamins and
`essential fatty acids; however, the effect of MTP inactivation on cholesterol synthesis could also
`have a contributing effect on neurological development. The goal of the required juvenile
`toxicology study is to evaluate whether the use of lomitapide during early childhood years has a
`negative impact on neurological function, including learning, memory, behavior, and coordination.
`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 11/28/2012
`
`
`
`Page 2 of
`
`Reference ID: 3235079
`
`

`

`
`
`
`
`
`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 Template
`
`Last Updated 11/28/2012
`
`
`
`Page 3 of
`
`Reference ID: 3235079
`
`(b) (4)
`
`

`

`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`
`_______________________________________
`(signature line for BLAs)
`
`PMR/PMC Development Template
`
`Last Updated 11/28/2012
`
`
`
`Page 4 of
`
`Reference ID: 3235079
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`203858
`Juxtapid (lomitapide)
`An assessment and analysis of spontaneous reports of malignancy,
`teratogenicity, and hepatic abnormalities in patients treated with Juxtapid
`(lomitapide). Specialized follow-up should be obtained on these cases to
`collect additional information on the events.
`
` 11/30/2013
` 12/31/2014
` 12/31/2015
` 12/31/2016
` 12/31/2017
` 12/31/2018
` 12/31/2019
` 12/31/2020
` 12/31/2021
` 12/31/2022
` 12/01/2023
` 06/01/2024
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Interim Report Submissions:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused by
`mutations in the low-density lipoprotein (LDL) receptor gene and characterized by elevated
`plasma levels of LDL cholesterol (LDL-C) with normal triglycerides, tendon xanthomas,
`and premature coronary atherosclerosis. Juxtapid (lomitapide) was granted an orphan drug
`designation for the treatment of HoFH. Known and potential safety concerns include small
`bowel and hepatic malignancies, teratogenicity, hepatic transaminase elevations, hepatic
`steatosis, and potentially hepatic fibrosis. Given the small population affected by this
`disorder (~1 in a million), the small number of patients studied, and the short duration of
`clinical trials, enhanced pharmacovigilance is required to generate additional data to better
`assess risks related to the long-term use of the drug.
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 1 of 4
`
`Reference ID: 3235079
`
`

`

`
`
`
`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 paucity of long-term safety data on Juxtapid (lomitapide) remains a concern. Because
`of the rarity of HoFH, the availability of patients and person-years of exposure that
`contribute to our current understanding of the safety of Juxtapid (lomitapide) is limited.
`The pre-clinical and clinical development programs revealed known and potential serious
`risks associated with Juxtapid (lomitapide) including small bowel and hepatic
`malignancies, teratogenicity, hepatic transaminase elevations, hepatic steatosis, and
`potentially hepatic fibrosis.
`
`The goal of the enhanced pharmacovigilance study is to gather additional data to better
`assess risks related to the long-term use of the drug. The study will continue for a period of
`10 years from the date of approval.
`
`The enhanced pharmacovigilance program will include the following:
`
`a) Active query of reporters to obtain additional clinical information related to reports of
`malignancy, teratogenicity, and hepatic abnormalities. The sponsor should actively query
`reporters for the following information:
` (i) For reports of malignancy: cancer site, timing and duration of Juxtapid (lomitapide)
`exposure in relation to diagnosis, and other risk factors for the specific cancer.
` (ii) For reports of teratogenicity: nature of the defect, timing and duration of Juxtapid
`(lomitapide) exposure during pregnancy, and other risk factors for congenital malformations
` (iii) For reports of hepatic abnormalities: liver-related laboratory, imaging and
`pathology results, duration of Juxtapid (lomitapide) exposure, and other risk factors for
`hepatic abnormalities
`
`b) Expedited reporting to FDA of all initial and follow-up reports of malignancies,
`teratogenicity, fatty liver, hepatic steatosis, and hepatic abnormalities with a serious
`outcome.
`
`Interim analyses and summaries of new and cumulative safety information must be
`submitted annually, followed by the final report at the conclusion of the monitoring period.
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 2 of 4
`
`Reference ID: 3235079
`
`

`

`
`
`
`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.
`Enhanced pharmacovigilance program for reports of malignancy, teratogenicity, and
`hepatic abnormalities in patients treated with Juxtapid (lomitapide) for a period of 10 years
`from the date of approval to collect data that will be analyzed to better define these risks.
`The enhanced pharmacovigilance program includes the following: a) active query of
`reporters to obtain additional clinical information related to reports of malignancy,
`teratogenicity, and hepatic abnormalities; b) expedited reporting to FDA of all initial and
`follow-up reports of malignancies, teratogenicity, fatty liver, hepatic steatosis, and hepatic
`abnormalities with a serious outcome. Interim analyses and summaries of new and
`cumulative safety information must be submitted annually, followed by the final report at
`the conclusion of the monitoring period.
`
`
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 3 of 4
`
`Reference ID: 3235079
`
`

`

`
`
`
`
`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)
`Enhanced pharmacovigilance
`
`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 12/20/2012
`
`Page 4 of 4
`
`Reference ID: 3235079
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA/BLA #
`Product Name:
`
`PMR/PMC Description:
`
`203858
`Juxtapid (lomitapide)
`A long-term prospective observational study (product exposure registry) of
`patients with homozygous familial hypercholesterolemia (HoFH) treated with
`Juxtapid (lomitapide) to evaluate known and potential serious risks related to
`the use of Juxtapid (lomitapide).
`
` 11/30/2013
` 12/31/2014
` 12/31/2015
` 12/31/2016
` 12/31/2017
` 12/31/2018
` 12/31/2019
` 12/31/2020
` 12/31/2021
` 12/31/2022
` 12/31/2023
` 12/31/2024
` 12/31/2025
` 12/31/2026
` 12/31/2027
` 03/01/2028
` 09/01/2028
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Interim Report 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
`
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 1 of 5
`
`Reference ID: 3235079
`
`

`

`
`
`Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder caused by
`mutations in the low-density lipoprotein (LDL) receptor gene and characterized by elevated
`plasma levels of LDL cholesterol (LDL-C) with normal triglycerides, tendon xanthomas,
`and premature coronary atherosclerosis. Juxtapid (lomitapide) was granted an orphan drug
`designation for the treatment of HoFH. Known and potential safety concerns include small
`bowel and hepatic malignancies, hepatic transaminase elevations, hepatic steatosis, and
`hepatic fibrosis, teratogenicity, and major adverse cardiovascular events. Given the small
`population affected by this disorder (~1 in a million), the small number of patients studied,
`and the short duration of clinical trials, a postmarketing registry is required to generate
`additional person-years of exposure to assess risks related to the long-term use of the drug.
`
`
`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 paucity of long-term safety data on Juxtapid (lomitapide) remains a concern. Because of the
`rarity of HoFH, the availability of patients and person-years of exposure that contribute to our current
`understanding of the safety of Juxtapid (lomitapide) is limited. The pre-clinical and clinical
`development programs revealed known and potential serious risks associated with Juxtapid
`(lomitapide) including hepatic transaminase elevations, hepatic steatosis, hepatic fibrosis, small
`bowel and hepatic malignancies, teratogenicity, and major adverse cardiovascular events. The goal of
`the registry is to generate additional person-years of exposure to assess these and other serious risks
`related to Juxtapid (lomitapide) use.
`
`The registry will include a sample of patients prescribed Juxtapid (lomitapide) and followed for 10
`years.
`
`
`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?
`
`
`
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 2 of 5
`
`Reference ID: 3235079
`
`

`

`
`
`
`
`- 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 12/20/2012
`
`Page 3 of 5
`
`Reference ID: 3235079
`
`

`

`
`
`The paucity of long-term safety data on Juxtapid (lomitapide) remains a concern. Because of the
`rarity of HoFH, the availability of patients and person-years of exposure that contribute to our
`current understanding of the safety of Juxtapid (lomitapide) is limited. The pre-clinical and
`clinical development programs revealed known and potential serious risks associated with Juxtapid
`(lomitapide) including hepatic transaminase elevations, hepatic steatosis, small bowel and hepatic
`malignancies, teratogenicity, and major adverse cardiovascular events. The goal of the registry is
`to generate additional person-years of exposure to assess these and other serious risk related to
`Juxtapid (lomitapide) use.
`
`The registry will include a sample of patients prescribed Juxtapid (lomitapide) and followed for
`10 years to describe the following:
`• Patient age, sex, and race
`• Country of treatment
`• Cardiovascular history
`• History of apheresis
`• Other medical history
`• Concomitant medications, including start and stop dates
`• Use of dietary and vitamin supplements
`• Use of contraception by females receiving Juxtapid (lomitapide) , including type
`Juxtapid (lomitapide) dose, duration of use, start date, discontinuation date,
`•
`reasons for discontinuation, person-years of exposure
`• Liver enzyme monitoring frequency
`• Serum lipid levels
`
`
`Data to be provided should include incidence rates for the following outcomes of interest:
`• Death and causes of death
`• Major adverse cardiovascular events (cardiovascular death, non-fatal MI, non-fatal
`stroke, unstable angina, and revascularization procedures)
`• Malignancies, including small bowel and hepatic neoplasms
`• Hepatic adverse events including hepatic transaminase elevations with and without
`bilirubin elevations, hepatic steatosis, non-alcoholic fatty liver (NAFL), non-alcoholic
`steatohepatitis (NASH), hepatic fibrosis
`• Exposed pregnancies and outcomes of exposed pregnancies
`
`
`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)
`
`
`PMR/PMC Development Template
`
`Last Updated 12/20/2012
`
`Page 4 of 5
`
`Reference ID: 3235079
`
`

`

`
`
`
`
` 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 12/20/2012
`
`Page 5 of 5
`
`Reference ID: 3235079
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`12/20/2012
`
`Reference ID: 3235079
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`Division of Professional Drug Promotion (DPDP)
`Division of Consumer Drug Promotion (DCDP)
`
`****Pre-decisional Agency Information****
`
`
`
`
`
`Memorandum
`
`Date:
`December 12, 2012
`
`
`To:
`
`Kati Johnson, Regulatory Project Manager
`
` Division of Metabolism and Endoc
`rinology Products (DMEP)
`
`From:
`
`
`
`
`
`
`
`
`Subject:
`
`Samuel M. Skariah, Regulatory Review Officer
`Division of Professional Drug Promotion (DCDP)
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`
`Kendra Y. Jones, Regulatory Review Officer, DCDP
`Division of Consumer Drug Promotion (DPDP), OPDP
`
`NDA 203858
`OPDP labeling lomitapide mesylate, capsules for oral use
`
`
`
`
`
`
`
`
`
`In response to DMEP’s November 27, 2012, consult request, OPDP has
`reviewed the proposed draft package insert (PI) and medication guide for
`lomitapide mesylate, capsules for oral use.
`
`OPDP comments on the proposed draft PI are based on the version sent via
`from Kati Johnson (RPM) email on December 6, 2012. OPDP’s comments on
`the proposed draft medication guide are based on the version sent via email from
`Sharon Williams (DMPP) on December 11, 2012.
`
`Comments regarding the proposed draft PI and medication guide are provided in
`the marked versions below.
`
`Thank you for the opportunity to comment on these proposed materials.
`
`If you have any questions on the proposed draft PI, please contact Samuel
`Skariah at 301. 796. 2774 or Sam.Skariah@fda.hhs.gov.
`
`If you have any questions on the proposed draft medication guide, please contact
`Kendra Jones at 301.796.3917 or Kendra.Jones@fda.hhs.gov.
`
`
`
`Reference ID: 3229972
`
`1
`
`43 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KENDRA Y JONES
`12/12/2012
`
`Reference ID: 3229972
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Medical Policy Initiatives
`Division of Medical Policy Programs
`
`PATIENT LABELING REVIEW
`
`November 14, 2012
`Mary Parks, MD, Director
`Division of Metabolism and Endocrinology Products
`(DMEP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Melissa Hulett, RN, BSN, MSBA
`Team Leader, Patient Labeling Team
`Division of Medical Policy Programs (DMPP)
`
`Sharon W. Williams, MSN, BSN, RN
`Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`DMPP Review of Patient Labeling (Medication Guide)
`
`Date:
`To:
`
`Through:
`
`From:
`
`Subject:
`Drug Name (established
`name):
`
`(lomitapide mesylate)
`
`Dosage Form and Route: Capsules
`
`
`203858
`
`
`Application
`Type/Number:
`
`
`Applicant:
`
`
`
`Aegerion Pharmaceuticals
`
`
`
`
`
`
`
`Reference ID: 3216156
`
`1
`
`

`

` 1
`
`
`
`INTRODUCTION
`On February 29, 2012 Aegerion Pharmaceuticals submitted an original New Drug
`Application (NDA) indicated for the treatment of homozygous familial
`hypercholesterolemia (HoFH) when used as adjunct to a low-fat diet and other lipid-
`lowering therapies (LLT).
`This review is written in response to a request by the Division of Metabolism and
`Endocrinology Products (DMEP) for the Division of Medical Policy Programs
`(DMPP) to review the Applicant’s proposed Medication Guide (MG) for lomitapide
`mesylate capsules.
`The Risk Mitigation and Evaluation Strategy (REMS) is being reviewed by the
`Division of Risk Management (DRISK) and will be provided to DMEP by DRISK
`under separate cover. The MG for lomitapide mesylate capsules is outside of the
`REMS.
`
`2 MATERIAL REVIEWED
` Draft lomitapide mesylate Medication Guide received on February 29, 2012 and
`received by DMPP on November 1, 2012.
` Draft lomitapide mesylate Prescribing Information (PI) received on February 29,
`2012, revised by the Review Division throughout the current review cycle and
`received by DMPP on November 1, 2012.
`
`
`3 REVIEW METHODS
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`reading level, and have a reading ease score of at least 60%. A reading ease score of
`60% corresponds to an 8th grade reading level. In our review of the MG the target
`reading level is at or below an 8th gr