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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 021196/S-015
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Jazz Pharmaceuticals
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`Attention: Jennifer Ekelund
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`Vice President, US Regulatory Affairs
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`3180 Porter Drive
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`Palo Alto, CA 94304
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` Dear Ms. Ekelund:
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` Please refer to your Supplemental New Drug Application (sNDA) dated August 29, 2008,
` received September 2, 2008, submitted under section 505(b) of the Federal Food, Drug, and
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` Cosmetic Act (FD&C Act) and in accordance with section 909(b)(1) of the Food and Drug
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` Administration Amendments Act of 2007 (FDAAA) for Xyrem (sodium oxybate) 500 mg/ml
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` oral solution. Under section 909(b)(1) of FDAAA, we identified Xyrem as a product deemed to
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` have in effect an approved risk evaluation and mitigation strategy (REMS) because there were in
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` effect on the effective date of FDAAA, March 25, 2008, elements to assure safe use required
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` under 314.500 et seq. (Subpart H).
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` We also acknowledge receipt of your submissions dated November 13, 2008, August 25 and 31,
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`and October 7, 2009, February 3 and August 26, 2011, January 31, April 13, November 21, and
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` December 20, 2012, June 29, July 17, September 10, and October 8, 2013, and April 11 and 22,
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` and November 7, 2014.
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` This “Prior Approval” supplemental new drug application provides for a REMS that includes a
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` Medication Guide, 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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` RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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` In accordance with section 505-1 of the FD&C Act, we have determined that a REMS is
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` necessary for Xyrem to ensure that the benefits of the drug outweigh the risks of serious adverse
` outcomes resulting from inappropriate prescribing, misuse, and abuse of Xyrem.
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` In accordance with section 505-1 of the FD&C Act, as one element of a REMS, FDA may
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` require the development of a Medication Guide as provided for under 21 CFR 208. Pursuant to
` 21 CFR 208, FDA has determined that Xyrem poses a serious and significant public health
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`concern requiring the distribution of a Medication Guide. The Medication Guide is necessary for
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` patients’ safe and effective use of Xyrem. FDA has determined that Xyrem is a product for
` which patient labeling could help prevent serious adverse effects and that has serious risks
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` (relative to benefits) of which patients should be made aware because information concerning the
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`Reference ID: 3709011
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` NDA 021196/S-015
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` Page 2
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` risks could affect patients’ decisions to use, or continue to use, Xyrem. Under 21 CFR 208, you
` are responsible for ensuring that the Medication Guide is available for distribution to patients
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` who are dispensed Xyrem.
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`Pursuant to 505-1(f)(1), we have also determined that elements necessary to assure safe use are
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`required as part of a REMS to mitigate the risks of serious adverse outcomes resulting from
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`inappropriate prescribing, misuse, abuse, and diversion of Xyrem.1 The elements to assure safe
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`(ETASU) use will mitigate the aforementioned risks by ensuring that, prior to filling Xyrem
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`prescriptions, pharmacy controls exist that screen for concomitant use of sedative-hypnotics and
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`other potentially interacting agents, monitor for inappropriate prescribing, misuse, abuse, and
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`diversion, and notify prescribers when patients are receiving concomitant contraindicated
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`medications or there are signs of potential abuse or misuse. In addition, the ETASU will
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`mitigate the risks by informing prescribers, pharmacists, and patients of the risk of significant
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`central nervous system and respiratory depression associated with Xyrem, the contraindication of
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`use of Xyrem with sedative-hypnotics and alcohol, the potential for abuse, misuse, and overdose
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`associated with Xyrem, and the safe use, handling, and storage of Xyrem.
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`Your proposed REMS, submitted on November 7, 2014, and appended to this letter, is approved.
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`The REMS consists of a Medication Guide, ETASU, an implementation system, and a timetable
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`for submission of assessments of the REMS.
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`FDA initially approved Xyrem in July 2002 under the restricted distribution provisions in 21
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`CFR Part 314 Subpart H. Sodium oxybate, which is a Schedule III controlled substance under
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`the Controlled Substances Act (CSA), is associated with the risks of abuse and misuse. Sodium
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`oxybate, the active ingredient of Xyrem, is the sodium salt of gamma-hydroxybutyrate (GHB),
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`which is a Schedule I controlled substance under the CSA. Abuse of GHB either alone or in
`combination with other CNS depressants is associated with adverse reactions including seizure,
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`respiratory depression, decreases in the level of consciousness, coma, and death. The rapid onset
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`of sedation, coupled with amnesia, particularly when combined with alcohol, has proven to be
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`dangerous for voluntary and involuntary users (e.g., assault victims).
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`When Congress passed FDAAA in 2007, it set forth a comprehensive statutory framework that
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`requires a careful balance between the need to evaluate and mitigate risk of a drug to ensure that
`its benefits outweigh its risks, and the potential burdens of REMS elements on patient access and
`the health care delivery system. In addition, Congress expressly prohibited the use of ETASU to
`“block or delay approval” of applications under sections 505(b)(2) and 505(j) of the FD&C Act.2
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`For drugs previously approved under Subpart H with restricted distribution, like Xyrem, FDAAA
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`established that they were “deemed to have in effect an approved [REMS] under Section 505-1
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` 1 The goal of mitigating diversion in this REMS refers to preventing the sale or transfer of the drug outside the
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` framework of the REMS in order to mitigate the risks of central nervous system depression, respiratory depression,
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` abuse, and misuse.
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`2 FD&C Act Section 505-1(f)(8).
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`Reference ID: 3709011
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` Page 3
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` of the [FD&C] Act,” and required the submission of a proposed REMS within 180 days for
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` FDA’s review and approval.3
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`FDA is mindful of the statutory requirement under the FD&C Act that ETASU be
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`“commensurate with the specific serious risk[s] listed in the labeling” of the drug, that ETASU
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`“not be unduly burdensome on patient access to the drug,” and “to the extent practicable,” that
`ETASU be structured “so as to minimize their burden on the health care delivery system.”4 We
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`also note that it is part of FDA’s statutory mandate to approve generic drugs that meet the
`standard for approval.5
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`Pursuant to these statutory provisions, FDA has sought to finalize and approve the REMS for
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`Xyrem since 2008. In doing so, we have faced repeated, lengthy delays. The REMS you
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`submitted on November 7, 2014, which we are now approving, contains a requirement that
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`Xyrem be distributed only by a single pharmacy. Jazz’s position that a single pharmacy is
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`critical to the safe use of Xyrem has not been a consistent one. In 2009, Jazz submitted a
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`supplemental NDA for a new indication for Xyrem for treatment of fibromyalgia in which it
`proposed to include multiple certified pharmacies.6
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`However, by early 2011, after FDA declined to approve the fibromyalgia indication, Jazz
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`changed its position. By that time, Jazz had been granted several patents related to its single
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`pharmacy distribution system. In its 2013 SEC filings, Jazz noted that it expected FDA
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`modifications to the Xyrem REMS and stated that, “depending on the extent to which certain
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`provisions of our Xyrem deemed REMS which are currently protected by our method of use
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`patents covering the distribution of Xyrem are changed as part of updating our REMS
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`documents, the ability of our existing patents to protect our Xyrem distribution system from
`generic competitors may be reduced.” 7 This statement, in conjunction with Jazz’s change in
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`position regarding the necessity of the single pharmacy requirement, suggests Jazz’s awareness
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`that the Xyrem REMS could have the effect of blocking or delaying approval of generic versions
`of Xyrem. Such an outcome would reflect the use of REMS to block or delay generic
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`competition in a manner inconsistent with section 505-1(f)(8). It would also place an unjustified
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`burden on patient access and on the healthcare delivery system.
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`FDA is approving the REMS Jazz submitted on November 7, 2014, closing a chapter on a REMS
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`that has been pending for 7 years -- far longer than could have been reasonably anticipated when
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`FDAAA was enacted. Our action approving the REMS submitted by Jazz should not be
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`construed or understood as agreement with Jazz that limiting dispensing to a single pharmacy is
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` 3 FDAAA Section 909(b)(1).
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`4 FD&C Act Section 505-1(f)(2)(A), (C), and (D).
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`5 FD&C Act Section 505(j).
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`6 Transcript of the Joint Meeting of the Arthritis Advisory Committee and the Drug Safety and Risk Management
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`Advisory Committee (Aug. 20, 2010) at 99 (“NDA 22-531, sodium oxybate for fibromyalgia indication, was
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`submitted to the agency on December 11, 2009”) available at
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`http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommi
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`ttee/UCM225445.pdf.
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` 7 Form 10-Q, September 30, 2013, at 54.
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`Reference ID: 3709011
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` NDA 021196/S-015
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` Page 4
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` the only way to ensure that the benefits of Xyrem outweigh the risks under section 505-1 of the
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` FD&C Act. We continue to be concerned that limiting the distribution of Xyrem to one
` pharmacy imposes burdens on patient access and the healthcare delivery system. No other
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`currently approved REMS requires a sponsor to limit dispensing to a single pharmacy.
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`At this time, FDA finds that the REMS approved today meets the applicable statutory standards.
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` As with all REMS, FDA intends to evaluate the Xyrem REMS, including the burdens it imposes,
` on an ongoing basis and will require modifications as appropriate.
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`The REMS assessment plan should include, but is not limited to, the following:
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`For the 6-month assessment and all subsequent REMS assessments submitted thereafter:
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`1. Program statistics (totals for the current REMS assessment reporting period and cumulative
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`totals from approval of the finalized REMS, if feasible)
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`Jazz Pharmaceuticals will report to FDA the following:
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`• Patients:
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`o Number of patients enrolled
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`o Number of patients enrolled who received at least one shipment of XYREM
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`o Number of duplicate patients detected by the Certified Pharmacy
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`o Number of patients associated with more than one prescriber during their therapy
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`o Number of patients who were disenrolled from the program and reasons for
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`disenrollment
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`o Number of patients who have discontinued XYREM after receiving at least one
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`shipment of XYREM
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` Proportion of discontinued patients who were associated with a report of a serious
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`adverse event, including death
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`o Age and gender of enrolled patients.
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`• Prescribers:
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`o Number of prescribers certified
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`o Number of certified prescribers who have written at least one prescription for
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`XYREM
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`o Number of certified prescribers by specialty
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`o Number of certified prescribers who were disenrolled during the reporting period and
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`reasons for disenrollment
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`o Number of disenrolled prescribers who were associated with a XYREM prescription
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`and number of disenrolled prescribers associated with a XYREM shipment
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`o Number of patients by current enrolled prescriber.
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`• Certified Pharmacy
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`o If the Certified Pharmacy was decertified during the reporting period and reasons for
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`decertification.
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`2. Dispensing and compliance data (totals for the current REMS assessment reporting period
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`and cumulative totals from approval of the finalized REMS)
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`Reference ID: 3709011
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` Page 5
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` Jazz Pharmaceuticals will monitor and track shipping and handling of XYREM and report to
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` FDA the following:
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`Reference ID: 3709011
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` • Total number of prescriptions
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` • Total number of bottles and shipments sent
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` • Total number of first-time fills and refills
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` • Number of shipments lost in delivery (and unrecovered) with number of DEA 106 Forms
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` and RMRs completed
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` • Number of patients prescribed a daily dose >9 g
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` • Number of prescriptions filled from a prescriber who was not enrolled
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` • Number of prescriptions for more than a 30 days’ supply (first fill) or more than a 90
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` days’ supply (refills) and reasons
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` • Number of Risk Management Reports submitted to the Sponsor
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`o Number of patients with an RMR
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`o Number of patients with multiple RMRs
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`o Number of alerts generated from RMRs
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`o Number of RMRs generated from early refill requests
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`o Number of RMRs generated for other reasons (list reasons)
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`o Number of prescriber-related RMRs
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` • Number of patients with overlapping prescriptions (more than one active prescription)
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` • Number of duplicate patients who were shipped XYREM under more than one name or
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` identifier
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` • Number of patients who were shipped XYREM after being disenrolled
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` • Number of patients who requested an early refill and reason for the request
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`o Number of requests approved
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`o Number of requests denied by the prescriber
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`o Number of requests denied by the Certified Pharmacy
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`o Number of patients with multiple requests for early refills
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`• Number of initial shipments sent to patients without completion of the XYREM REMS
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` Program Patient Counseling Checklist
` • Summary table from XYREM REMS Program Patient Counseling Checklists of the
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` number of patients taking the following concomitant medications and who subsequently
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` received at least one shipment of XYREM:
`o Sedative hypnotics
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`o Alcohol
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`o Other potentially interacting agents:
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`  Sedating antidepressants, antipsychotics, or anti-epileptics
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`  General anesthetics
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`  Muscle relaxants
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`  Opioid analgesics
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`  Divalproex sodium or other valproate drug (e.g., valproic acid)
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` Illicit CNS depressants (e.g., heroin or gamma-hydroxybutyrate [GHB])
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` • Summary table from XYREM REMS Program Patient Counseling Checklists of the
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` number of patients who have been diagnosed with the following conditions and who
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` subsequently received at least one shipment of XYREM:
`o Sleep apnea
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`o Asthma, COPD, or other conditions affecting the respiratory system
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` • Number of notifications by pharmacists to prescribers for the following situations and the
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` outcome of the notification (dispensed XYREM, counseled patient, and summary of
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` other actions):
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`o Use with contraindicated medications (concomitant sedative hypnotics)
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`o Use with other concomitant CNS-depressant medications (sedating antidepressants or
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` antipsychotics, sedating anti-epileptics, general anesthetics, muscle relaxants, opioid
` analgesics, or illicit CNS depressants)
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`o Patient report of alcohol use
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`o Patient report of diagnosis of sleep apnea
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`o Patient report of diagnosis of asthma, COPD, or other conditions affecting breathing
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`o Suspected abuse, misuse, or diversion
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`o Alerts regarding potential abuse, misuse, or diversion on the patient profiles
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`o Prescription error
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`o Early refill requests.
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` 3. Pharmacovigilance/surveillance (totals for the current REMS assessment reporting period
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` and cumulative totals from start of program, if feasible)
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` Jazz Pharmaceuticals will provide to FDA the following:
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` Summary tables of the number of reports of serious adverse events to include all outcomes of
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` death, emergency department visits (when admitted to hospital), or hospitalizations resulting
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` • Use with concurrent sedative hypnotics and alcohol
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` Intentional misuse
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` • Abuse
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` • Overdose
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` • Medication error.
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` The summary tables will include the following data fields (CIOMS II line listings): date, report
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`ID, report type, notifier, age, gender, start and stop date, dose, frequency, onset date, system
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` organ class, outcome, and causality.
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` 4. Program infrastructure and performance surveillance (information for the current REMS
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` assessment reporting period)
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` Jazz Pharmaceuticals will provide to FDA the following:
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` • Call center report with number of calls received
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` • Summary of frequently asked questions
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` • Summary of any REMS-related problems identified
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` • Summary of program or system problems and a description of any corrective actions
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` taken.
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`5. A report on periodic assessments of the dispensing of the Medication Guide in accordance
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`with 21 CFR 208.24
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`Jazz Pharmaceuticals will report to FDA on the dispensing of the Medication Guide as part of the
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`REMS assessments.
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`6. With respect to REMS goals, an assessment of the extent to which the Elements to Assure
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`Safe Use are meeting the goals or whether the goals or such elements should be modified
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`Reference ID: 3709011
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` Page 7
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` Jazz Pharmaceuticals will institute a system of oversight and review to evaluate whether the
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` REMS is meeting its goals. If Jazz Pharmaceuticals determines, based on the results of the
` assessments, surveillance, and knowledge assessments, that modifications to the XYREM REMS
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` program are needed (or that an element is no longer needed) to continue to ensure that the
`benefits of XYREM outweigh the risks and that the REMS is not unduly burdensome to patient
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` access or the healthcare system the company will submit a prior approval supplement to FDA
` proposing a revised REMS prior to implementing any changes to the approved REMS.
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` For the 12-month assessment after approval of the finalized REMS and all subsequent
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` REMS assessments submitted thereafter:
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` 7. Assessment of patients’ and prescribers’ understanding of the following:
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`• The risk of significant CNS and respiratory depression associated with XYREM even at
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` recommended doses
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` • The contraindicated uses of XYREM
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` • The potential for abuse, misuse, and overdose associated with XYREM
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` • The safe use, handling, and storage of XYREM
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` • The XYREM REMS Program requirements.
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` 8. Certified Pharmacy knowledge assessments
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` • Assessment of the understanding of all Certified Pharmacy staff involved in the XYREM
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` REMS Program of the following:
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`o The approved indications for XYREM
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`o The abuse potential of XYREM
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`o The contraindication of use of XYREM with sedative hypnotics and alcohol
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`o The risk of significant CNS and respiratory depression associated with XYREM even
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` at recommended doses
`o The XYREM REMS Program requirements
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`o The types of information in the Central Database
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`o Monitoring patients for signs of inappropriate prescribing, abuse, misuse, and
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` diversion
`o The requirement to report all potential adverse events
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` • Assessment of pharmacists’ understanding of the following:
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`o Requirements for limiting the first prescription to a one-month supply and subsequent
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` prescriptions to no more than a three-month supply
`o Prescriber notification requirements
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`o Requirements for validating the prescriber’s and patient’s enrollment
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`o The ability to disenroll a prescriber or patient for noncompliance with the XYREM
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` REMS Program
`o Requirements for validating a XYREM prescription
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`o Requirement for completing the XYREM REMS Program Patient Checklist
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`o Actions taken if the patient is using a contraindicated medication or other potentially
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` interacting agent
`o Patient counseling information
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`o Requirements to consult with the prescriber when clarification is needed for a
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` prescription and/or for an early refill request
`o Requirements for completing XYREM REMS Program Risk Management Reports
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`o Requirements for shipment of XYREM to the patient
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`Reference ID: 3709011
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` 9. A summary report of audits of the Certified Pharmacy conducted during the assessment
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` period
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` Jazz Pharmaceuticals will provide a summary of the audits of the Certified Pharmacy that were
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` conducted during the assessment period, including the topics covered during the audit and the
` numbers of significant observations.
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` 10. Patient knowledge survey
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` A representative sample of patients will be surveyed using a structured questionnaire annually
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` following the first formal XYREM REMS Program assessment. The objective is to assess their
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` knowledge of the key risk information and REMS requirements, including the serious risks
` associated with XYREM. The knowledge survey will be conducted according to industry
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` standards and will assess patients who have received XYREM for at least one month.
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`The protocol includes details on the sample size and associated confidence intervals for various
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` response rates: selection criteria for defining the sample, the expected number of patients or
` caregivers to be surveyed, recruitment strategies, how and when the surveys will be
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`administered, an explanation of controls used to minimize bias, an explanation of the controls
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`used to compensate for the limitations associated with the methodology, the survey instruments
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` (questionnaires and/or moderator’s guide), and any available background information on testing
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`of survey questions and correlation to the information of the Medication Guide and the XYREM
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` REMS Program Patient Quick Start Guide.
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` Survey data collection will be completed approximately 10 months after implementation of the
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` REMS, thus enabling XYREM knowledge assessments to be submitted to the FDA at the 12­
` month REMS assessment, at all subsequent REMS assessments, and as needed following
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` substantive changes to the REMS-related educational materials. The protocol for the patient
` survey and the survey instrument are provided in Appendix 2 of the Supporting Document.
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` Data from the patient survey will be reported as descriptive statistics for the survey
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`administration, study population, and survey questions. Results will include numbers of patients,
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` patient contacts by the Certified Pharmacy, patient demographics, and response data showing
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` level of patient understanding of the risks associated with XYREM use.
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` 11. Prescriber knowledge survey
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`
`A representative sample of prescribers will be surveyed annually following the first formal
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`XYREM REMS Program assessment. The objective is to assess their knowledge of the XYREM
`
`REMS key risk information and program requirements. The goal of this survey initiative will be
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`
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`to determine whether the XYREM REMS Elements to Assure Safe Use are effective in
`
`educating prescribers about the key risk information and the procedures to be followed in the
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`
`XYREM REMS. The survey will be conducted according to industry standards and will assess
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`prescribers who have prescribed XYREM.
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`The protocol includes details on the sample size and the associated confidence intervals for
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`response rates, selection criteria for defining the sample, the expected number of prescribers to
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`be surveyed, recruitment strategies, how and when the surveys will be administered, an
`explanation of the controls used to minimize bias, an explanation of the controls used to
`compensate for the limitations associated with the methodology, the survey instruments
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`Reference ID: 3709011
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`

`

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` NDA 021196/S-015
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` Page 9
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` (questionnaires and/or moderator’s guide), and any available background information on testing
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`
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`of survey questions and correlation to the messages of the prescribing information and XYREM
`
` REMS Program Prescriber Brochure.
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` Survey data collection will be completed approximately 10 months following implementation of
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`
` the REMS, thus enabling XYREM knowledge assessments to be submitted to the FDA at the 12­
` month REMS assessment, at all subsequent assessments, and as needed following substantive
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`changes to the REMS-related educational materials. The protocol for the prescriber survey and
`the survey instrument are provided in Appendix 2 of the Supporting Document. Results will
`
`
` include numbers of prescribers, prescriber contacts by the Certified Pharmacy, prescriber
` demographics, and response data showing level of prescriber understanding of safe use of
`
` XYREM, including approved indications; contraindications; risk of severe CNS/respiratory
`
`
` depression; abuse, misuse, and diversion; and death.
`
` 12. Certified Pharmacy training knowledge assessments
`
`
`All Certified Pharmacy staff involved in the XYREM REMS Program will be required to
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`complete Module A of the XYREM REMS Program Certified Pharmacy Training at least
`annually. In addition, all pharmacists involved in dispensing XYREM under the XYREM REMS
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`Program will be required to complete Module B of the XYREM REMS Program Certified
` Pharmacy Training at least annually. A knowledge assessment must be successfully completed
`
`
` for each module as part of the training requirement. Successful completion of the knowledge
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`
`
` assessments requires an 80% accuracy level. The Module A and Module B Knowledge
` Assessments are provided in Appendix 1 of the Supporting Document.
`
`
`
`13. Surveillance and monitoring
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`
`
`Jazz Pharmaceuticals will periodically monitor available safety databases, such as those
`
`established by the Drug Abuse Warning Network (DAWN), the American Association of Poison
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`Control Centers (AAPCC) National Poison Data System (NPDS), The National Forensic
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`Laboratory Information System, the National Drug Threat Assessment, and the Society for
`
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`Forensic Toxicologists (SOFT) for any information regarding abuse, misuse, or diversion of
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`
`
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`sodium oxybate. Any relevant information will be included in the REMS assessments.
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`
`
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`In addition to the assessments submitted according to the timetable included in the approved
`
`REMS, you must submit a REMS assessment when you submit a supplemental application for a
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`
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`new indication for use as described in section 505-1(g)(2)(A) of the FD&C Act.
`
`
`Under section 505-1(g)(2)(C), FDA may require the submission of a REMS assessment if FDA
`
`determines that that an assessment is needed to evaluate whether the approved strategy should be
`modified to ensure the benefits of the drug outweigh the risks of the drug or minimize the burden
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`
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`on the health care delivery system of complying with the strategy.
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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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`
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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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`Reference ID: 3709011
`
`

`

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` NDA 021196/S-015
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` Page 10
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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
`
`
` REMS supporting document, with all changes marked and highlighted. Prominently identify the
`
` submission containing the assessment instruments and methodology with the following wording
`
`
` in bold capital letters at the top of the first page of the submission:
`
`
`
`
`NDA 021196 REMS CORRESPONDENCE
`
`
`(insert concise description of content in bold capital letters, e.g.,
`
`
`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
`
`
`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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`
`
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`Prominently identify the submission containing the REMS assessments or proposed
`
`
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`modifications with the following wording in bold capital letters at the top of the first page of the
`
`submission:
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`
`
`NDA 021196 REMS ASSESSMENT
`
`
`NEW SUPPLEMENT FOR NDA 021196
`
`
`PROPOSED REMS MODIFICATION
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`
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021196
`
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
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`
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`
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
`
` REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
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`
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`(21 CFR 314.80 and 314.81).
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`
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`Reference ID: 3709011
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`

`

` NDA 021196/S-015
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` Page 11
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` If you have any questions, call Vandna Kishore, Regulatory Project Manager, at (301) 796-4193.
`
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Billy Dunn, M.D.
`
`Director
`
`Division of Neurology Products
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`
`ENCLOSURE(S):
`
`REMS
`
`
`
`Reference ID: 3709011
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILLIAM H Dunn
`02/27/2015
`
`Reference ID: 3709011
`
`