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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 203858/S-013, S-016
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`Food and Drug Administration
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` Silver Spring MD 20993
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` SUPPLEMENT APPROVAL
` REMS ASSESSMENT PLAN REVISION
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` Aegerion Pharmaceuticals
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` Attention: Sheryl Raukete
` Global Regulatory Lead, Regulatory Affairs
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` One Main Street, 8th Floor
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` Cambridge, MA 02142
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`Dear Ms. Raukete:
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`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received
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`October 5, 2015 (S-013) and July 7, 2016 (S-016), and your amendments, submitted under
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`section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Juxtapid (lomitapide)
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`capsules, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, and 60 mg.
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`Supplement -013, submitted as a Prior Approval supplemental new drug application, proposes
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`modifications of the REMS to expand the number of certified pharmacies.
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`Supplement -016, submitted as a Prior Approval supplemental new drug application, was
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`submitted in response to and proposes modifications described in our Safety Labeling Change
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`Notification/REMS Modification Notification letter dated March 11, 2016. The labeling changes
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`to comply with this notification were approved in supplement-015 on May 23, 2016.
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`We also refer to our REMS Assessment Acknowledgement letter dated June 17, 2016.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Juxtapid (lomitapide) was originally approved on December 21, 2012, and the
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`most recent modification was approved on August 13, 2013. The REMS consists of elements to
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`assure safe use, an implementation system, and a timetable for submission of assessments of the
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`REMS. In order to ensure that the benefits of Juxtapid (lomitapide) outweigh its risks, we
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`determined that you were required to modify the REMS for Juxtpaid. The required
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`modifications were outlined in our Safety Labeling Change Notification/REMS Modification
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`Notification letter issued on March 11, 2016, and included modifications to the REMS
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`document, changes to the existing REMS materials, and the following new REMS materials:
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`Patient Guide and Patient-Prescriber Acknowledgement Form.
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`Reference ID: 4036116
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` NDA 203858/S-013, S-016
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` Page 2
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` Your proposed modified REMS, submitted on October 5, 2015 (S-013), and July 7, 2016
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` (S-016), as amended and appended to this letter, is approved.
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`You must implement the modifications to the REMS program within 60 calendar days from the
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`date of this letter. Prescribers and pharmacies have 180 calendar days from the date of this letter
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`to complete the recertification process.
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`The timetable for submission of assessments of the REMS remains the same as that approved on
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`December 21, 2012.
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`In order to align with the modified REMS, the REMS assessment plan is being revised. The
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`revised REMS assessment plan must include, but is not limited to, the following:
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`1. Knowledge, Attitudes, and Behavior (KAB) Surveys of Prescribers
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`A KAB Survey will be conducted with a random sample of certified prescribers to assess
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`their awareness and understanding of the indication for use, the risk of hepatotoxicity,
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`including appropriate evaluation, monitoring and counseling to minimize this risk, as
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`described in the Prescribing Information (PI), Fact Sheet, and the Prescriber Training
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`Module. The survey will also assess prescribers’ awareness of the JUXTAPID REMS
`Program materials and knowledge of requirements of the JUXTAPID REMS Program.
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`In the event of substantive changes to the methodology and protocol for the KAB Survey,
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`or the survey instrument, these documents will be provided to the FDA at least 90 days
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`before the survey is administered.
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`The protocol will include:
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`a.
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`the target sample size and precision estimates associated with that sample size
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`b. a description of the methodology for recruitment and selection of the prescriber
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`sample
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`c.
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`the specific criteria that will be used to select participants in the survey
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`d. a description of how and when the surveys will be administered
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`Reference ID: 4036116
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`e. an explanation of the design features and controls that will be included to
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`minimize bias and compensate for limitations in the methodology
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`f. a copy of the survey questionnaire
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`The KAB assessment will be included in your next assessment report and will be
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`repeated annually thereafter. Survey results will be provided in each annual REMS
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`Assessment Report.
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` NDA 203858/S-013, S-016
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` Page 3
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` 2. Survey to Evaluate Patient Knowledge
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`A survey to evaluate the understanding of patients on their understanding of the REMS
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`goal about the risk of hepatotoxicity and the need for baseline and periodic monitoring
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`will be performed and the data included in the second assessment report following the
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`approval of the modification to the JUXTAPID REMS Program, due to be submitted on
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`or before 12/21/2018. The protocol or survey instrument will be provided to the FDA at
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`least 90 days before the survey is implemented.
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`3. Additional REMS Metrics
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`The REMS Assessment will also include evaluation of the following program metrics:
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`a. Communications with certified prescribers and certified pharmacies:
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`i. The date of mailing and number of recipients of the REMS Letter for
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`Healthcare Providers and REMS Letter for Pharmacists
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`ii. The number of mailings returned; and
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`iii. A copy of all documents included in each mailing.
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`iv. Summary of issues and complaints received by JUXTAPID REMS
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`Program Call Center; summary of resolution of the issues and complaints.
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`v. Summary of the reasons (and numbers per reason) for calls into the
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`JUXTAPID REMS Program Call Center.
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`b. Prescriber Certification:
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`i. The number of Healthcare Prescribers certified (and the number of
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`prescribers that were certified at the time of a requirement for
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`re-certification was instituted) in the JUXTAPID REMS Program (during
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`the reporting period and cumulatively) and stratified by prescriber degree,
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`practice setting (i.e., type of practice and geographic location) including a
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`full breakdown of prescribing specialties contained in the “other”
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`category.
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`ii. Volume of prescriptions for each prescriber and each specialty, including
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`a full breakdown of prescribing specialties contained in the “other”
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`category.
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`iii. Specialties of the “high volume” prescribers, i.e., those who write more
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`than 4 prescriptions in an assessment period and cumulatively, including a
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`full breakdown of prescribing specialties contained in the “other”
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`category.
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`iv. A summary of the method prescribers used to enroll (fax, email) (during
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`the reporting period and cumulatively).
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`v. Number of healthcare providers that had their certification revoked during
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`the reporting period and cumulatively and the reason for the revocation.
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`Reference ID: 4036116
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` NDA 203858/S-013, S-016
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` Page 4
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`c.
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`d.
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`e.
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`Reference ID: 4036116
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` Wholesaler/Distributor Authorization:
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`i. The number of wholesalers/distributors that were authorized in the REMS
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`program (during the reporting period and cumulatively).
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`ii. Number of wholesalers/distributors that had their authorization revoked
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`during the reporting period and cumulatively and the reason for the
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`revocation.
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`iii. The number of JUXTAPID orders shipped to pharmacies during the
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`reporting period and cumulatively, including number of bottles, bottle size
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`and dosage strength.
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`iv. Number of JUXTAPID orders shipped to non-certified pharmacies.
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`Pharmacy Enrollment:
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`i. The number of pharmacies that were certified (and the number of
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`pharmacies that were certified at the time of a requirement for
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`re-certification was instituted that recertified) in the REMS program
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`(during the reporting period and cumulatively).
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`ii. Number of pharmacies that had their certification revoked during the
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`reporting period and cumulatively and the reason for the revocation.
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`Pharmacy Metrics:
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`i. The number of new prescriptions received, and the number that were not
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`accompanied by the JUXTAPID REMS Program Prescription
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`Authorization Form.
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`ii. The number of prescriptions dispensed for JUXTAPID, including quantity
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`of capsules (mean, minimum, maximum) and dosage strength during the
`reporting period and cumulatively, overall and subset by compliance with
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`the JUXTAPID REMS Program requirements (e.g., received from
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`JUXTAPID certified vs. non-certified healthcare providers, number of
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`initial prescriptions dispensed without a signed attestation on the
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`JUXTAPID REMS Program Prescription Authorization Form).
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`Dispensing details are to be obtained from the pharmacies.
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`iii. The number of instances certified pharmacies dispensed JUXTAPID using
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`a prescription that was not accompanied by a JUXTAPID REMS Program
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`Patient-Prescriber Acknowledgement Form.
`iv. Information on the number of prescribers who have submitted an altered
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`JUXTAPID REMS Program Prescription Authorization Form (and what
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`alterations were made).
`v. 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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`vi. The number and demographics (e.g., including gender, age, geographic
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`location) of unique patients who received JUXTAPID during the reporting
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` NDA 203858/S-013, S-016
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` Page 5
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` period and annually. The number is to be calculated by reconciling orders
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` dispensed to unique patients.
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` vii. Duration of therapy for patients (mean, median, range).
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` viii. The number of prescriptions pending and canceled, as well as the reason
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` for prescriptions pending and canceled.
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` ix. Specific criterion used to classify a prescription as canceled.
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` x. 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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` xi. Percentage of fill delays that involve new prescriptions versus refills.
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`xii. Detailed description of root cause of noncompliance with REMS program-
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` required dispensing and any corrective and/or preventive actions taken to
` address noncompliance during the reporting period and cumulatively.
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` f. 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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` cumulatively), including outcome.
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` g. Specification of measures that would be taken to increase awareness if prescriber
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` surveys indicate that prescriber awareness of the risks associated to JUXTAPID is
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` not adequate.
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`4. 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 extent to
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`which the approved strategy, including each element of the strategy, is meeting the goal
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`or whether one or more such goals or such elements should be modified.
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`We remind you that in addition to the REMS assessments submitted according to the timetable in
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`the approved REMS, you must include an adequate rationale to support a proposed REMS
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`modification for the addition, modification, or removal of any of goal or element of the REMS,
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`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 supplemental
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`application for a new indication for use as described in section 505-1(g)(2)(A) of the FDCA.
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`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 current
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`REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those risks
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`and an evaluation of whether those risks can be appropriately managed with the currently
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`approved REMS.
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`Reference ID: 4036116
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` NDA 203858/S-013, S-016
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` Page 6
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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 the
` REMS was meeting its goals at the time of that the 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 submission of the
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` supplemental application for a new indication for use: Provision of as many of the
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` currently listed assessment plan items as is feasible.
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`f) If you propose a REMS modification based on a change in the benefit-risk profile or
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` because of the new indication of use, submit an adequate rationale to support the
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` modification, including: Provision of the reason(s) why the proposed REMS
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` modification is necessary, the potential effect on the serious risk(s) for which the REMS
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` 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 the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing REMS modifications, provide a
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`rationale for why the REMS does not need to be modified.
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`If the assessment instruments and methodology for your REMS assessments are not included in
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`the REMS supporting document, or if you propose changes to the submitted assessment
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`instruments or methodology, you should update the REMS supporting document to include
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`specific assessment instrument and methodology information at least 90 days before the
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`assessments will be conducted. Updates to the REMS supporting document may be included in a
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`new document that references previous REMS supporting document submission(s) for
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`unchanged portions. Alternatively, updates may be made by modifying the complete previous
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`REMS supporting document, with all changes marked and highlighted. Prominently identify the
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`submission containing the assessment instruments and methodology with the following wording
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`in bold capital letters at the top of the first page of the submission:
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`NDA 203858 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY)
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
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`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
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`application with elements to assure safe use from using any element to block or delay approval
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`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
`result in enforcement action.
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`Prominently identify any submission containing the REMS assessments or proposed
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`modifications of the REMS with the following wording in bold capital letters at the top of the
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`first page of the submission as appropriate:
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`Reference ID: 4036116
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` NDA 203858/S-013, S-016
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` Page 7
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` NDA 203858 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 203858/S-000
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`CHANGES BEING EFFECTED IN 30 DAYS
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`PROPOSED MINOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 203858/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 203858/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
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`SUBMITTED IN SUPPLEMENT XXX
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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
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`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA 203858
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`Should you choose to submit a REMS revision, prominently identify the submission containing
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`the REMS revisions 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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`To facilitate review of your submission, we request that you submit your proposed modified
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`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
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`as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
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`is to include as many as possible in Word format.
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`Reference ID: 4036116
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`

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` NDA 203858/S-013, S-016
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` Page 8
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` If you have any questions, call Kati Johnson, Senior Regulatory Project Manager, at
` (301) 796-1234.
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`Sincerely,
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`{See appended electronic signature page}
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`
`Jennifer Rodriguez Pippins, M.D., M.P.H.
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`Deputy Director for Safety
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`Division of Metabolism and Endocrinology Products
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`Office of Drug Evaluation II
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`Center for Drug Evaluation and Research
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`ENCLOSURES:
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`JUXTAPID REMS Document
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`JUXTAPID REMS Program Prescriber Enrollment Form
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`JUXTAPID REMS Program Prescriber Training Module and Knowledge Assessment
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`JUXTAPID REMS Program Fact Sheet
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`JUXTAPID REMS Program Patient Guide
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`JUXTAPID REMS Program Patient-Prescriber Acknowledgement Form
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`JUXTAPID REMS Program Prescription Authorization Form
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`JUXTAPID REMS Letter for Healthcare Providers
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`JUXTAPID REMS Program Website Landing Page
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`JUXTAPID REMS Program Pharmacy Training Module and Knowledge Assessment
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`JUXTAPID REMS Program Pharmacy Enrollment Form
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`JUXTAPID REMS Letter for Pharmacists
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`Reference ID: 4036116
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JENNIFER R PIPPINS
`01/03/2017
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`Reference ID: 4036116
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`