( .I# I U.S. FOOD & DRUG
`
`,.,. .........
`•-..:::::i~
`
`ADMINISTRATION
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`
`
` NDA 203858/S-023
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`SUPPLEMENT APPROVAL
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`
` Amryt Pharmaceuticals, Inc.
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`
` US Agent for Amryt Pharmaceutical DAC
`
`
` Attention: Karla Werre
` REMS Manager
`
`
` 160 Federal Street, 21st floor
` Boston, MA 02110
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`
`
`
`
`Dear Ms. Werre:
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`
`
`
`Please refer to your supplemental new drug application (sNDA) dated and received
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`August 5, 2021, and your amendments, submitted under section 505(b) of the Federal
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`Food, Drug, and Cosmetic Act (FDCA) for Juxtapid (lomitapide) capsules.
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`This Prior Approval sNDA provides for proposed modifications to the approved Juxtapid
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`(lomitapide) risk evaluation and mitigation strategy (REMS).
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`We have completed our review of this supplemental application, as amended. It is
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`approved, effective on the date of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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`The REMS for Juxtapid (lomitapide) was originally approved on December 21, 2012,
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`and the most recent REMS modification was approved on May 27, 2021. The REMS
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`consists of elements to assure safe use, an implementation system, and a timetable for
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`submission of assessments of the REMS.
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`Your proposed modifications to the REMS consist of:
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`1. Updating the format of the REMS document in line with the recommendations in
`the Format and Content of a REMS Document- Guidance for Industry1
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`2. Changes to program materials secondary to findings of the completed Qualitative
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`Research (QR) around the deficit of prescriber knowledge on program
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`requirements around liver monitoring as demonstrated in recent poor KAB survey
`scores
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` 1 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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`Reference ID: 4930852
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`

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`NDA 203858/S-023
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`Page 2
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`3. Omitting obsolete materials (2017 Stakeholder letters) and
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`4. Editorial changes such as added demographic fields to Patient Guide, Patient
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`Prescriber Acknowledgement Form (PPAF) and Prescription Authorization Form
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`(PAF) and other editorial revisions related to punctuation, grammar, spelling,
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`defining acronyms, flow, font, simplification, and consistency to REMS appended
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`materials.
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`Your proposed modified REMS, submitted on August 5, 2021, amended and appended
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`to this letter, is approved.
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`The timetable for submission of assessments of the REMS must be revised. Submit
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`REMS assessments every two years beginning with the 11-year REMS assessment
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`due December 21, 2023.
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`The revised REMS assessment plan must include, but is not limited to, the following:
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`Program Implementation and Operations (per reporting period and cumulatively)
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`1. REMS Enrollment Statistics
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`a. Healthcare Provider Certification
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`The number of newly certified healthcare providers and the number of
`i.
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`active healthcare providers (prescribed at least once during the
`reporting period) in the Juxtapid REMS Program stratified by
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`healthcare provider credentials (e.g., Doctor of Medicine, Doctor of
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`Osteopathic Medicine, Nurse Practitioner, Physician Assistant) and
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`specialty (cardiology, endocrinology, internal medicine, other (and
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`include a full breakdown of prescribing specialties contained in the
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`“other” category)), and practice type (e.g., individual practice, group
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`practice, hospital, university (academic) center), and geographic region
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`(as defined by US Census).
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`Method of certification (i.e. through fax, or email).
`ii.
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`b. Pharmacy Enrollment
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`The number of pharmacies that were newly certified and the
`i.
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`number of pharmacies that were active (dispensed Juxtapid at least
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`once during the reporting period) in the REMS program, stratified
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`by geographic region (as defined by US Census)
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`Method of certification (e.g., through fax, or email).
`ii.
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`c. Wholesaler/Distributor Authorization
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`The number of wholesalers/distributors that were newly authorized
`i.
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`in the REMS program and the number that were active (shipped
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`Juxtapid at least once during the reporting period).
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`
`
`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`
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`Reference ID: 4930852
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`

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`NDA 203858/S-023
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`Page 3
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`2. REMS Compliance
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`a. Provide a summary of non-compliance identified, including but not limited
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`to:
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`i.
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`ii.
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`iii.
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`iv.
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`Provide a copy of the non-compliance plan used during that reporting
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`period, including the criteria for non-compliance for each stakeholder,
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`actions taken to address non-compliance for each case, and which
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`events lead to de-certification from the REMS
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`Detailed description of root cause of noncompliance with REMS
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`program required dispensing and any corrective and/or preventive
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`actions taken to address noncompliance during the reporting period
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`and cumulatively.
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`Provide a copy of the audit plan for each stakeholder (i.e. certified
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`pharmacies, wholesalers/distributors, or other entities) including any
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`auditing surveys or protocols used
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`Report of audit findings for each stakeholder
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`1. The number of audits expected, and the number of audits
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`conducted
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`2. The number and types of deficiencies noted for each group of
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`audited stakeholders
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`3. For those with deficiencies noted, report the number that
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`successfully completed a corrective and preventive action (CAPA)
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`within one month of audit
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`Include a unique ID for each stakeholder that had deviations to
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`track deviations by stakeholder over time
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`4.
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`b. Healthcare Provider
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`Number of healthcare providers who that had their certification
`i.
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`revoked during the reporting period and cumulatively and the reason
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`for the revocation
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`Information on the number of prescribers who have submitted an
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`altered Juxtapid REMS Program Prescription Authorization Form
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`(and what alterations were made).
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`ii.
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`c. Pharmacies
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`Number of pharmacies that had their certification revoked during the
`i.
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`reporting period and cumulatively and the reason for the revocation.
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`The number of instances certified pharmacies dispensed Juxtapid
`using a prescription that was not accompanied by a Juxtapid REMS
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`
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`U.S. Food and Drug Administration
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`
`Silver Spring, MD 20993
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`www.fda.gov
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`ii.
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`Reference ID: 4930852
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`NDA 203858/S-023
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`Page 4
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`iii.
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`iv.
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`Program Patient-Prescriber Acknowledgement Form.
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`Number of instances certified pharmacies dispensed Juxtapid in
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`response to a prescription received on an altered Juxtapid REMS
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`Program Prescription Authorization Form.
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`The number of new prescriptions received, and the number that
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`were not accompanied by the Juxtapid REMS Program Prescription
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`Authorization Form.
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`d. Wholesalers/Distributors
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`Number of wholesalers/distributors that had their authorization
`i.
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`revoked during the reporting period and cumulatively and the reason
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`for the revocation.
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`Number of Juxtapid orders shipped to non-certified pharmacies.
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`ii.
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`3. REMS Call Center
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`a. Summary of issues and complaints received by Juxtapid REMS Program Call
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`Center; summary of resolution of the issues and complaints.
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`b. Summary of the reasons (and numbers per reason) for calls into the Juxtapid
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`REMS Program Call Center.
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`4. Juxtapid Utilization Data
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`a. The number of prescriptions dispensed for Juxtapid, including quantity of
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`capsules (mean, minimum, maximum) and dosage strength, overall and
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`subset by compliance with the Juxtapid REMS Program requirements (e.g.,
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`received from Juxtapid certified vs. non-certified healthcare providers, number
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`of initial prescriptions dispensed without a signed attestation on the Juxtapid
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`REMS Program Prescription Authorization Form). Dispensing details are to
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`be obtained from the pharmacies.
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`b. Volume of prescriptions for each prescriber stratified by specialty, including a
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`full breakdown of prescribing specialties contained in the “other” category.
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`c. Specialties of the “high volume” prescribers, i.e., those who write more than
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`four prescriptions in an assessment period and cumulatively, including a full
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`breakdown of prescribing specialties contained in the “other” category.
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`d. The number of Juxtapid orders shipped to pharmacies during the reporting
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`period and cumulatively, including number of bottles, bottle size and dosage
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`strength.
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`e. The number and demographics (e.g., including gender, age, geographic
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`location) of unique patients who received Juxtapid during the reporting period
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`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`Reference ID: 4930852
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`

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`NDA 203858/S-023
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`Page 5
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`and annually. The number is to be calculated by reconciling orders dispensed
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`to unique patients.
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`f. Duration of therapy for patients (mean, median, range).
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`g. The number of prescriptions pending and canceled, as well as the reason for
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`prescriptions pending and canceled.
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`h. Specific criterion used to classify a prescription as canceled.
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`i. Report of number, length, and reasons for shipment delays to patients and
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`whether or not these reasons were related to the REMS, and any additional
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`information from insurance payers as to what they are stating as the reason
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`for delay/non-payment.
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`j. Percentage of fill delays that involve new prescriptions versus refills.
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`Knowledge (per reporting period and cumulatively)
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`5. Knowledge, Attitudes, and Behavior (KAB) Surveys of Prescribers to assess
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`understanding of:
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`a. The approved indication of Juxtapid
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`b. The risk of hepatoxicity associated with Juxtapid use
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`c. The need to monitor patients during treatment with Juxtapid as per product
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`labeling
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`6. Survey to Evaluate Patient Knowledge of:
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`a. the risk of hepatoxicity
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`b. the need for baseline and periodic monitoring
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`7. Specification of measures that would be taken to increase awareness if surveys
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`indicate that awareness of the risks associated to Juxtapid is not adequate.
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`Safe Use Conditions (per reporting period and cumulatively)
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`8. Prescription Authorization Form (PAF)
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`a. Number of patients with completed PAFs who have not received a dispensed
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`prescription for Juxtapid.
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`b. Time between receipt of PAF and prescription dispensing and analysis and
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`summary of reasons for delays
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`c. Proportion of prescriptions that were associated with the updated PAF from
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`the February 2022 REMS modification.
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`9. Patient-Prescriber Acknowledgement Form (PPAF)
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`a. Proportion of dispensed prescriptions associated with an updated PPAF from
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`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4930852
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`

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`NDA 203858/S-023
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`Page 6
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`the February 2022 REMS modification.
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`Health Outcomes and/or Surrogates of Health Outcomes (per reporting period and
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`cumulatively)
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`10.With regard to the risk of hepatotoxicity associated with Juxtapid, provide an
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`analysis of the post-marketing cases of specific hepatic adverse events reported in
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`association with Juxtapid, including outcome.
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`11.The requirements for assessments of an approved REMS under section 505-1(g)(3)
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`include with respect to each goal included in the strategy, an assessment of the
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`extent to which the approved strategy, including each element of the strategy, is
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`meeting the goal or whether one or more such goals or such elements should be
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`modified.
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`We remind you that in addition to the REMS assessments submitted according to the
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`timetable in the approved REMS, you must include an adequate rationale to support a
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`proposed REMS modification for the addition, modification, or removal of any goal or
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`element of the REMS, as described in section 505-1(g)(4) of the FDCA.
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`We also remind you that you must submit a REMS assessment when you submit a
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`supplemental application for a new indication for use, as described in section 505-
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`1(g)(2)(A) of the FDCA. This assessment should include:
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`a) An evaluation of how the benefit-risk profile will or will not change with the new
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`indication;
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`b) A determination of the implications of a change in the benefit-risk profile for the
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`current REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those
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`risks and an evaluation of whether those risks can be appropriately managed
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`with the currently approved REMS.
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`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether
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`the REMS was meeting its goals at the time of that last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`e) If a REMS assessment has not been submitted in the 18 months prior to
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`submission of the supplemental application for a new indication for use: Provision
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`of as many of the currently listed assessment plan items as is feasible.
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`f)
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`If you propose a REMS modification based on a change in the benefit-risk profile
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`or because of the new indication of use, submit an adequate rationale to support
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`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`Reference ID: 4930852
`
`

`

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`NDA 203858/S-023
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`Page 7
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`the modification, including: Provision of the reason(s) why the proposed REMS
`modification is necessary, the potential effect on the serious risk(s) for which the
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` REMS was required, on patient access to the drug, and/or on the burden on the
` health care delivery system; and other appropriate evidence or data to support
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`
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` the proposed change. Additionally, include any changes to the assessment plan
` necessary to assess the proposed modified REMS. If you are not proposing
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` REMS modifications, provide a rationale for why the REMS does not need to be
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` modified.
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` If the assessment instruments and methodology for your REMS assessments are not
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` included in the REMS supporting document, or if you propose changes to the submitted
`assessment instruments or methodology, you should update the REMS supporting
`document to include specific assessment instrument and methodology information at
`
`
`least 90 days before the assessments will be conducted. Updates to the REMS
`
`supporting document may be included in a new document that references previous
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`REMS supporting document submission(s) for unchanged portions. Alternatively,
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`updates may be made by modifying the complete previous REMS supporting document,
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`with all changes marked and highlighted.
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`Prominently identify the submission containing the assessment instruments and
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`methodology with the following wording in bold capital letters at the top of the first page
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`of the submission:
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`NDA 203858 REMS ASSESSMENT METHODOLOGY
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`(insert concise description of content in bold capital letters, e.g.,
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`ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
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`AUDIT PLAN, DRUG USE STUDY)
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`An authorized generic drug under this NDA must have an approved REMS prior to
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`marketing. Should you decide to market, sell, or distribute an authorized generic drug
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`under this NDA, contact us to discuss what will be required in the authorized generic
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`drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
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`covered application with elements to assure safe use from using any element to block
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`or delay approval of an application under section 505(b)(2) or (j). A violation of this
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`provision in 505-1(f) could result in enforcement action.
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`Prominently identify any submission containing the REMS assessments or proposed
`modifications of the REMS with the following wording in bold capital letters at the top of
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`the first page of the submission as appropriate:
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`
`
`
`
`NDA 203858 REMS ASSESSMENT
`
`
`
`
`or
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4930852
`
`

`

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` NDA 203858/S-023
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` Page 8
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` NEW SUPPLEMENT FOR NDA 203858/S-000
`
`
`
` CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
`
`
`
`
` or
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`
`NEW SUPPLEMENT FOR NDA 203858/S-000/
`
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED MAJOR REMS MODIFICATION
`
`
`or
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`NEW SUPPLEMENT FOR NDA 203858/S-000/
`
`PRIOR APPROVAL SUPPLEMENT
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`
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
`
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`CHANGES SUBMITTED IN SUPPLEMENT XXX
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`
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`
`
`FOR NDA 203858/S-000
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`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA 203858
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`
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`Should you choose to submit a REMS revision, prominently identify the submission
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`containing the REMS revisions with the following wording in bold capital letters at the
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`top of the first page of the submission:
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`
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`To facilitate review of your submission, we request that you submit your proposed
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`modified REMS and other REMS-related materials in Microsoft Word format. If certain
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`documents, such as enrollment forms, or website screenshots are only in PDF format,
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`
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`they may be submitted as such, but Word format is preferred.
`
`
`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
`
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`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
`
`you intend to submit the REMS document in SPL format, as soon as possible, but no
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`
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`later than 14 days from the date of this letter, submit the REMS document in SPL format
`
`using the FDA automated drug registration and listing system (eLIST).
`
`
`
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`For more information on submitting REMS in SPL format, please email
`
`FDAREMSwebsite@fda.hhs.gov.
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4930852
`
`

`

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` NDA 203858/S-023
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` Page 9
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` REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`
`If you have any questions, call Ron Picking, Regulatory Project Manager, at
`
`240-402-3211.
`
`
`
`Sincerely,
`
`
`
`{See appended electronic signature page}
`
`
`Monika Houstoun, Pharm.D., M.P.H.
`
`Deputy Director for Safety (Acting)
`
`
`Division of Diabetes, Lipid Disorders, and
`
`Obesity
`
`Office of Cardiology, Hematology,
`
`Endocrinology, and Nephrology
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURES:
`
`Juxtapid REMS Document
`
`Juxtapid REMS Materials:
`
`• Prescriber Enrollment Form
`
`• Patient Guide
`
`• Patient-Prescriber Acknowledgement Form
`
`• Prescription Authorization Form
`
`
`• Pharmacy Enrollment Form
`
`• Prescriber Training Module and Knowledge Assessment
`
`• Pharmacy Training Module and Knowledge Assessment
`
`• Fact Sheet
`
`• Website
`
`
`
`U.S. Food and Drug Administration
`
`Silver Spring, MD 20993
`
`www.fda.gov
`
`
`
`Reference ID: 4930852
`
`

`

`-
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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MONIKA A HOUSTOUN
`02/01/2022 10:25:47 PM
`
`Reference ID: 4930852
`
`(b)
`
`