CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212690Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`MEETING MINUTES
`
`IND 049641
`
`Jazz Pharmaceuticals
`Attention: Paula Hines, PhD.
`Senior Director, Global Regulatory Lead
`CNS/Sleep Global Regulatory Affairs
`3180 Porter Drive
`Palo Alto, CA 94304
`
`Dear Dr. Hines:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for JZP258.
`
`We also refer to the pre-NDA meeting between representatives of your firm and the FDA on
`October 2, 2019.
`
`A copy of the official minutes of the meeting/telecon is enclosed for your information. Please
`notify us of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, contact Vandna Kishore, Senior Regulatory Project Manager at
`vandna.kishore@fda.hhs.gov.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Eric Bastings, MD
`Acting Director
`Division of Neurology Products
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Enclosure:
` Meeting Minutes
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`MEMORANDUM OF MEETING MINUTES
`
`Meeting Type:
`Meeting Category:
`
`B
`Pre-NDA
`
`Meeting Date and Time:
`Meeting Location:
`
`October 2, 2019 10 AM
`FDA White Oak Campus, Building 22, Room 1313
`
`Application Number:
`Product Name:
`Indication:
`
`Sponsor Name:
`
`Meeting Chair:
`
`049641
`JZP-258
`Treatment of cataplexy and excessive daytime sleepiness in
`patients 7 years of age and older with narcolepsy
`Jazz Pharmaceuticals
`
`Eric Bastings, MD
`
`FDA ATTENDEES
`Billy Dunn, MD, Acting Deputy Office Director
`Eric Bastings, MD, Acting Division Director
`Ranjit Mani, MD, Clinical Reviewer
`Alice Hughes, MD, Director for Safety
`Sally Yasuda, PharmD, Team Leader for Safety
`Dawei Li, PhD, Clinical Pharmacology Reviewer
`Sharon Yan, PhD, Biometrics Reviewer
`Martha Heimann, PhD, OPQ CMC Lead
`Nandini Bhattacharya, PhD, Microbiology
`Xia Xu, PhD, Microbiology Reviewer
`Danielle Harris, PharmD, DMEPA Deputy Director
`Chad Morris, DMEPA Reviewer
`Donella Fitzgerald, DRISK Team Lead
`Jamie Wilkins Parker, DRISK
`Ingrid Chapman, PharmD, Risk Management Analyst
`John Palmer, MD, NIH Fellow
`Vandna Kishore, RPh, Regulatory Project Manager
`
`SPONSOR ATTENDEES
`
`
`Jed Black, MD
`
`Cuiping Chen, PhD
`Peng Chen, PhD
`
`Clinical Pharmacology Consultant
`Senior Fellow, Sleep/Neuroscience, Clinical
`Development
`Senior Director, Clinical Pharmacology
`Director, Biostatistics
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`(b) (4)
`
`

`

`IND 049641
`Page 2
`
`Nicole Damour
`
`Sanja Gauthier, MD
`Paula Hines, PhD
`
`Robert Iannone, MD, MSCE
`
`Philip Jochelson, MD
`
`Gunjan Junnarkar, PhD
`Sherice Mills
`Patricia Moore
`
`Judith Profant, PhD, DBSM
`
`Jeffrey Silverman, PhD
`Franck Skobieranda, MD
`
`Roman Skowronski, MD, PhD
`
`1.0
`
`BACKGROUND
`
`Associate Director, Global Regulatory
`Affairs, Chemistry, Manufacturing, and
`Controls
`Executive Director, Medical Safety
`Senior Director, Global Regulatory Lead,
`Regulatory Strategy
`Executive Vice President, Head of Research
`and Development
`Vice President, Therapeutic Area Head
`Clinical Development, Sleep and CNS
`Senior Director, Process Development
`Senior Director, Benefit Risk Management
`Vice President, Research and Development
`Quality and Global Regulatory Affairs
`Director, Medical Affairs
`Regulatory Consultant
`Vice President, Early Development
`Vice President, Clinical Development, Sleep
`
`Executive Director, Clinical Development, CNS
`Sleep and CNS
`Executive Director, Clinical Development, Sleep
`and CNS
`
`This meeting is for a Pre-New Drug Application (Pre-NDA) discussion for JZP-258, also
`referred to as “oxybate” and previously referred to as an “oxybate mixed-salt oral solution
`(OMSOS).” The proposed NDA for JZP-258 is to be submitted under the Section 505(b)(1)
`pathway.
`
`JZP-258 is an aqueous oral solution containing 0.413 g/mL of oxybate, stated to be equivalent to
`a 0.5 g/mL mixture of calcium, potassium, magnesium, and sodium oxybate. JZP-258 has been
`developed as a lower-sodium alternative to Xyrem® (sodium oxybate oral solution [500
`mg/mL]), which is notable for its high sodium content.
`
`Xyrem is currently approved for the treatment of cataplexy and excessive daytime sleepiness in
`narcolepsy in patients 7 years of age and older.
`
`The proposed indications for JZP-258 are the same as those for which Xyrem® is currently
`approved. The proposed dosing regimen for JZP-258 is
` that currently recommended in
`the Prescribing Information for Xyrem.
`
`The proposed NDA for JZP-258 is to contain reports for the following clinical studies, summary
`data for which are provided in this meeting package.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`(b) (4)
`
`Appears this way on original
`
`(b) (4)
`
`

`

`IND 049641
`Page 3
`
`• Study JZP258-101, an open-label, randomized crossover study investigating the relative
`bioequivalence and bioavailability of JZP-258 and Xyrem under fasted conditions in
`healthy subjects.
`
`• Study 13-010, an open-label, randomized crossover study investigating the relative
`bioequivalence and bioavailability of JZP-258 and Xyrem under fasted and fed
`conditions in healthy subjects.
`
`• Study 15-003, a randomized, double-blind, placebo-controlled crossover study comparing
`the taste of JZP-258 with placebo in healthy subjects.
`
`• Study 15-006, a double-blind, placebo-controlled, randomized withdrawal study of the
`efficacy and safety of JZP-258 in the treatment of cataplexy and excessive daytime
`sleepiness in narcolepsy.
`
`All clinical studies of JZP-258 have been conducted in adult subjects only.
`
`The clinical, chemistry , nonclinical, and clinical phaim acology data to be included in the
`proposed NDA for JZP-258 ai·e summai·ized in this meeting package, as is the fonnat in which
`those data are to be submitted in that application.
`
`FDA sent Preliminaiy Comments to Jazz on September 27, 2019.
`
`2. DISCUSSION
`Please note the following regarding the text below: the Agency's initial responses to the
`sponsor's questions are in blue font, the sponsor's pre-meeting responses (dated September
`30, 2019) are in purple font, the meeting discussion is summarized in green font, and a
`single Agency post-meeting comment is in brown font.
`
`2.1. Chemistry, Manufacturing, and Controls
`Question 1: Does the Agency agree that the proposed CMC package and control strategy
`outlined in the meeting package are adequate to support the registration of JZP-258?
`FDA Response to Question 1:
`In general, your proposed Chemistry, Manufacturing, and Controls (CMC) package and control
`strategy appeai· appropriate, pending review of the data provided in the proposed NDA.
`However, you should address the concerns outlined below in the original NDA submission.
`
`U.S. Food and Drug Administration
`Silver Spring, M D 20993
`www.fda.gov
`
`Reference ID: 4641499
`
`For the NDA
`
`

`

`IND 049641
`Page 4
`
`submission for such a drug product, antimicrobial activity of the drug product should be
`demonstrated by performing a microbial challenge test such as USP <51> Antimicrobial
`Effectiveness Test.
`
`In addition to the proposed microbial limits and absence of specified microorganism E. coli, the
`drug product specification for non-sterile aqueous drug products should also include a test for the
`absence of Burkholderia cepacia complex (BCC). Non-sterile aqueous drug products may
`potentially be contaminated with organisms in the BCC. BCC strains have a well-documented
`ability to ferment a wide variety of substrates and are known to proliferate in the presence of
`many traditional preservative systems. Thus, despite the presence of otherwise adequate
`preservative systems, BCC strains can survive and even proliferate in product during storage. For
`a recent review of the Agency’s perspective on BCC, please see PDA J Pharm Sci Tech 2011;
`65(5): 535-43.
`
`In order to control for the presence of BCC in your product, you should consider the
`Following
`
`1. Identifying potential sources for introduction of BCC during the manufacturing process and
`describing the steps to minimize the risk of BCC organisms in the final drug product. We
`recommend that potential sources are examined and sampled as process controls. These may
`include raw materials and the manufacturing environment. A risk assessment for this species in
`the product and raw materials is recommended to develop sampling procedures and acceptance
`criteria.
`
`2. Providing test methods and acceptance criteria to demonstrate that the drug product is free of
`BCC. Your test method should be validated and a discussion of those methods should be
`provided. Test method validation should address multiple strains of the species and cells should
`be acclimated to the conditions in the manufacturing environment (e.g., temperature) before
`testing. USP <60> Microbiological Examination of Nonsterile Products – Tests for Burkholderia
`cepacia Complex, although not yet official, is recommended as a source for reference. If BCC
`testing is not performed per USP <60>, we have provided suggestions for a potential validation
`approach and some points to consider when designing your validation studies. However, any
`validated method capable of detecting BCC organisms would be adequate. It is currently
`sufficient to precondition representative strain(s) of BCC in water and/or your drug product
`without preservatives to demonstrate that your proposed method is capable of detecting small
`numbers of BCC. Your NDA should describe the preconditioning step [time, temperature, and
`solution(s) used], the total number of inoculated organisms, and the detailed test method to
`include growth medium and incubation conditions. It is essential that sufficient preconditioning
`of the organisms occurs during these method validation studies to ensure that the proposed
`recovery methods are adequate to recover organisms potentially present in the environment.
`
`For more information, we refer you to Envir Microbiol 2011; 13(1):1-12 and J Appl
`Microbiol 1997; 83(3):322-6.
`
`Product Stability and Shelf Life:
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`IND 049641
`Page 5
`
`,
`It appears that you intend to rely on stability data for drug product manufactured by
`, to support an extended shelf life (60 months). As the commercial manufacturing
`site will be Jazz Pharmaceuticals Ireland Limited (JPIL), you should provide a detailed, side-by-
`side comparison of the manufacturing equipment and processes, in-process controls, equipment,
`container closure components and sources, and other related items, for the
`-manufactured
`stability batches versus the batches manufactured at JPIL to support reliance on the
`
`stability batch data. Additionally, you should provide executed batches records for the stability
`batches manufactured at each site. The expiration dating period will be determined based on
`review of the information provided in the NDA.
`
`Sponsor Pre-Meeting Response:
`The responses to the Microbiology and Product Stability and Shelf Life comments are
`provided below.
`
`Microbiology:
`In the planned JZP-258 NDA, Jazz intends to submit information regarding USP <51>
`Antimicrobial Effectiveness Test to demonstrate inherent anti-microbial activity of the drug
`product.
`
`Jazz will conduct additional testing specifically for Burkholderia cepacia complex (BCC) based
`on USP <51>. This additional information will also be provided in the NDA. Also, Jazz will
`conduct validation studies based on USP <60> to demonstrate adequacy of the test method to
`detect BCC.
`
`Jazz intends to conduct a risk assessment regarding the necessity for implementing a test for
`BCC and, based on the outcome, will determine if a specification for BCC is warranted.
`
`Stability and Shelf Life:
`Jazz agrees to submit detailed, side-by-side comparison of the manufacturing processes for the
`-manufactured stability batches versus the batches manufactured at Jazz Pharmaceuticals
`Ireland Limited (JPIL) to support reliance on the 60-month shelf life established by
`
`stability batch data. Jazz also will submit copies of executed master batch records for stability
`batches manufactured at both sites. Jazz intends to rely on stability data for drug product
`manufactured by
`to support an extended shelf life for drug product manufactured at
`JPIL.
`
`Meeting Discussion:
`Clarification was requested by the Agency regarding whether the absence of BCC in the finished
`drug product would be investigated per USP <51> or per USP <60>. The sponsor stated that
`those tests would be performed both per USP <51> and per USP <60>; the sponsor also stated
`that the tests per USP <51> would be performed to demonstrate that the drug product had
`inherent anti-microbial activity against BCC strain(s). The Agency conveyed that the drug
`product specification should include the absence of BCC. The sponsor stated that a risk
`assessment would also be conducted and agreed that BCC contamination would be evaluated in
`raw materials, manufacturing process/environment, and water system.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 049641
`Page 6
`
`The sponsor’s proposal to rely on the
`a matter of review.
`
` stability batch data to establish shelf-life would be
`
`2.2 Nonclinical
`Question 2: Does the Agency agree that the proposed nonclinical package outlined in the
`meeting package is adequate to support the registration of JZP-258?
`FDA Response to Question 2:
`As we have previously stated (please see the minutes of the Type C meeting held on December
`2, 2013, and our Type C written response letter [pertaining to
`] dated February 6, 2017),
`no additional nonclinical studies will be needed unless safety issues (e.g., impurities) that require
`nonclinical assessment arise.
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`2.3 Clinical Pharmacology
`Question 3: Does the Agency agree that the clinical pharmacology package is adequate to
`support the registration of JZP-258?
`FDA Response to Question 3:
`The clinical pharmacology package that you have proposed is acceptable, in form, to support the
`registration of JZP-258.
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`Question 4: Does the Agency confirm that the information from phase 1 Study 13-010 and
`the population pharmacokinetic (PPK) analysis are adequate to describe the dose
`proportionality of JZP-258 in adult and pediatric subjects?
`FDA Response to Question 4:
`Your proposed approach to describing the dose-proportionality of JZP-258 in adult and pediatric
`subjects is acceptable, in form.
`
`Sponsor Pre-Meeting Response:
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`(b) (4)
`
`(b) (4)
`
`

`

`IND 049641
`Page 7
`
`No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`Question 5: Does the Agency agree that the proposed extrapolation approach is
`appropriate to support inclusion of pediatric patients (7 years of age and older) in the
`indication for JZP-258?
`FDA Response to Question 5:
`We do not think that an extrapolation analysis is necessary to support the inclusion of children 7
`years and older in the indication for JZP-258. If the efficacy findings in adults are similar
`between JZP-258 and Xyrem, the dosage and administration instructions for JZP-258 in children
`aged 7 to 17 years will likely be similar to those in the Prescribing information for Xyrem.
`
`Sponsor Pre-Meeting Response
`As the available data support similar efficacy between Xyrem and JZP-258, Jazz does not intend
`to submit the pediatric extrapolation analysis in the NDA. No further discussion is required at the
`meeting.
`
`Meeting Discussion:
`None.
`
`2.4 Clinical
`Question 6: Does the Agency agree that the results of the primary and the secondary
`efficacy endpoints and the safety data from the JZP-258 phase 3 Study 15-006 presented in
`the meeting package will support the proposed indications?
`FDA Response to Question 6:
`The efficacy and safety data for Study 15-006 that you have briefly summarized in this package
`suggest that those data may, in form, be sufficient to support the approval of JZP-258 for the
`entire range of indications that you are currently proposing for that product, subject to the
`Agency’s full review of those data after your planned NDA is submitted.
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`IND 049641
`Page 8
`
`Question 7: Does the Agency agree that the statistical methods as described in the final
`statistical analysis plan (submitted in IND 49,641, Seq. No. 0332) are appropriate for the
`analyses of the primary and key secondary endpoints in Study 15-006 and adequate to
`support approval?
`FDA Response to Question 7:
`The primary analysis methods for the primary and key secondary endpoints, as described in the
`final statistical analysis plan for Study 15-006, are acceptable if missing values are limited. The
`appropriateness of the proposed methods of imputation for missing data and proposed sensitivity
`analysis for addressing possible missing data will be a matter of review.
`
`Sponsor Pre-Meeting Response:
`Jazz acknowledges FDA’s comments on missing data and sensitivity analyses. No further
`discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`Question 8: With regards to the supporting Xyrem safety information to be submitted in
`the JZP-258 NDA, does the Agency agree that cross-reference to the most recently
`submitted Xyrem Periodic Benefit Risk Evaluation Report (PBRER), and the approved
`United States Prescribing Information (USPI) is appropriate to demonstrate the most
`current and representative safety information for Xyrem?
`
`FDA Response to Question 8:
`It is acceptable for you to include the USPI and the most recent PBRER for Xyrem as supporting
`safety information in the proposed NDA for JZP-258. However, please do not cross-reference
`the current USPI and most recent PBRER for Xyrem; instead, please include those documents in
`your planned NDA.
`
`Sponsor Pre-Meeting Response:
`Jazz acknowledges FDA’s response and will include the Xyrem PBRER and USPI in the JZP-
`258 NDA. No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`Question 9: Based on the single pivotal trial registration plan, Jazz intends to summarize
`the clinical safety and efficacy data from Study 15-006 in Module 2 of the NDA, and does
`not plan to provide separate integrated summary of safety (ISS) and integrated summary
`of efficacy (ISE) documents. Does the Agency agree?
`FDA Response to Question 9:
`Your stated plan for summarizing the efficacy data for Study 15-006 in Module 2 of your
`planned NDA is acceptable.
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`IND 049641
`Page 9
`
`Regarding your plan for summarizing the safety data for Study 15-006, it is acceptable to include
`the summary of safety in Module 2, with links between (i.e., to and from) the datasets, narratives,
`subject data listings, patient case report forms, and other relevant documents for Study 15-006
`and the text and tables included in the safety summary in Module 2. We refer you to Appendix 1
`for our general safety request document that includes details on additional specific aspects of the
`safety submission.
`
`Please provide summaries and datasets separately for the open-label extension to Study 15-006.
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed on FDA’s comments in the first two paragraphs regarding
`Module 2.
`
`Regarding FDA’s request to provide summaries and datasets separately for the open-label
`extension (OLE), Jazz seeks agreement with the following strategy for the presentation of the
`OLE information within the NDA:
`
`Study 15-006, main and OLE, is treated as a single study from the point of view of the protocol,
`Electronic Data Capture (EDC), associated submission ready (CDISC) datasets and clinical study
`report (CSR).
`
`Information from the OLE part of Study15-006 will be readily identifiable within the submission
`ready CDISC datasets (SDTM and ADaM) in the NDA. SDTM datasets will identify OLE
`information via EPOCH variable. ADaM datasets will identify OLE information using
`APERIOD or other relevant flags. For example, within AE dataset (ADAE), main study and
`OLE study treatment emergent AEs will be identified via respective flags, MTRTEMFL and
`OTRTEMFL.
`
`While a single CSR is planned for Study 15-006 with safety presented and discussed across all
`study periods, presentation of safety data from each period (e.g., main study, open-label
`extension) will be included.
`
`Therefore, Jazz does not intend to provide summaries and datasets separately for the OLE part of
`Study 15-006.
`
`Does the Agency agree?
`
`Meeting Discussion:
`The Agency agreed with the sponsor’s proposal.
`
`Question 10: Does the Agency agree that the proposal for clinical site datasets for
`Study 15-006 only will satisfy Office of Scientific Investigations requirements?
`FDA Response to Question 10:
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`IND 049641
`Page 10
`
`Your proposal to include clinical site datasets for Study 15-006 only is acceptable to the Office
`of Scientific Investigations.
`
`Please refer to the updated draft Guidance for Industry entitled "Standardized Fonnat for
`Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring
`(BIMO) Inspections for CDER Submissions" (Febrnary 2018) and the associated "Bioresearch
`Monitoring Technical Confonnance Guide" (Febrnary 2018) containing technical specifications,
`which are available at the following links, respectively:
`
`https://www.fda.gov/ downloads/Drngs/DevelopmentApprovalProcess/F onnsSubmission
`Requirements/lJ CM3 3 2466. pdf
`
`https://www.fda.gov/ downloads/Drngs/DevelopmentApprovalProcess/F onnsSubmission
`Reguirements/lJ CM3 3 2468. pdf
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`2.5 Regulatory
`Question 11: Does the Agency agree that consistent with the USP Salt Polic. the
`non ro rietar name for JZP-258 will be
`
`(bJ<4I
`
`?
`
`FDA Res onse to Question 11:
`
`~---------------------~(ll)(~l
`
`....... ~~~~ ........ ..-~ ................... ~--~--~ ............ --....... ~.....-~~~ ....... -
`
`a final detennination of
`that matter will be made during the review of the NDA. The proposed dosing regimen for JZP
`258 should be weight-based and include an initial dosage, maximum weekly dosage increase,
`and a maximum recommended dosage that account for exposure to the inactive ingredient of salt.
`
`Sponsor Pre-Meeting Response:
`Jazz acknowled es FDA's res onse and would like to confnm that FDA a ·ees that dosin of
`4
`JZP-258 will be
`Ml
`'
`
`Can FDA confirm this?
`
`Meeting Discussion:
`The A ency indicated that labelin
`is not acceptable
`at t e reqmrement or consistency etween
`er note
`Th e Agency
`established name and labeled potency (USP Chapter <7>) is separate from the "USP Salt Policy"
`
`~-~~~--~
`
`(bf(4J
`
`(bJ<4I
`
`~~~~~'?""!'f~""!'l""~~--~~-,..-~~~~~·~~~~~~-
`
`U.S. Food and Drug Administration
`Silver Spring, M D 20993
`www.fda.gov
`
`Reference ID: 4641499
`
`

`

`IND 049641
`Page 11
`
`and has been in effect for several years. Additionall
`the individual salts present in solution,
`acknowled ed the s onsor's concerns w.....,...it,....h-r-es- e-ct_t_o __ __,_....,....-,,.,......_
`
`~---~~--~-~
`
`The inclusion of information in labeling to clarify that the concentration of the active moiety in
`JZP-258 and Xyrem is the same would be acceptable to the Agency.
`
`The sponsor may request an exception to the USP Salt Policy, if adequately supported by clinical
`considerations. However, based on recent discussions within the Agency, the use of an
`41
`established name such as '
`" would not be acceptable.
`CbH
`
`Agency Post-Meeting Note:
`Please see the minutes of the Type C teleconference held on May 8, 2017, under NDA 21196,
`and specifically the text under Question 6 regarding the
`<b><
`
`for a previous discussion regarding the established name and label potency. Please also refer to
`USP Chapter <7> Labeling, specifically the section titled "LABELS AND LABELING FOR
`DRUG PRODUCTS AND COMPOUNDED PREPARATIONS EXPRESSED AS ACTIVE
`MOIETY IN NAME AND STRENGTH" for cmTent USP labeling requirements.
`
`4f
`
`Question 12: Does the Agency agree with the proposed content and cross reference plan of
`the NDA as outlined in Section 4.7 and Appendix 3?
`FDA Response to Question 12:
`We note that Section 4.7 of this meeting package omits reference to the Quality Overall
`Summaiy in Module 2 and states, with respect to Module 3, that "A summaiy of the drng
`substance and diug product infonnation, including the control strategy, will be provided in the
`JZP-258 NDA." We assume that this is an eITor, and that a full CMC package will be submitted
`as outlined in Appendix 3 of the meeting package. The proposed content related to product
`quality microbiology appeai·s acceptable, although a final detennination will be made dming
`NDA review based on the infonnation that is provided in that application.
`
`Sponsor Pre-Meeting Response
`Jazz confinns that the NDA will include a Module 2.3 Quality Overall Summa1y as well as
`complete Module 3 CMC package, as described in Appendix 3 of the meeting package.
`Jazz considers that there will be adequate infonnation to support the anti-microbial effectiveness
`of the foimulation over its in-use period in the final Module 3 for submission (as discussed in the
`response to FDA Question 1. No futiher discussion is needed at the meeting.
`
`Meeting Discussion:
`None.
`
`ADDITIONAL COMMENTS
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4641499
`
`

`

`IND 049641
`Page 12
`
`Controlled Substances Staff
`You should provide data on abuse-related adverse events that have occurred in Study 15-006, in
`tabular form, for all reports that occurred in the following categories: abuse; overuse; and lost,
`stolen, missing, or unaccounted-for product. Those data should include subject ID number and
`detailed narratives.
`
`Sponsor Pre-Meeting Response:
`Jazz acknowledges FDA’s requests, which will be provided in the NDA. No further discussion is
`needed at the meeting.
`
`Meeting Discussion:
`None.
`
`Human Factors
`We understand that you intend to market JZP-258 as an oral solution containing 0.413 g/mL of
`oxybate. However, we are unclear if you intend to co-package JZP-258 with an oral dosing
`device. If you intend to co-package your product with an oral dosing device, we recommend that
`you conduct a comprehensive use-related risk analysis if you have not already completed one.
`The comprehensive use-related risk analysis should include a comprehensive and systematic
`evaluation of all the steps involved in using your product (e.g., based on a task analysis) the
`errors that users might commit or the tasks they might fail to perform and the potential negative
`clinical consequences of use errors and task failures.
`
`We also recommend you consider the Agency’s Response to Question 11 above in your use-
`related risk analysis. If models of the same or similar combination products exist, your use-
`related risk analysis should incorporate applicable information on known use-related problems
`with those products. Useful information can be obtained from your own experience as well as
`from public sources such as the literature, adverse event reports, and product safety
`communications. Please see the draft Guidance for Industry entitled “Human Factors Studies
`and Related Clinical Study Considerations in Combination Product Design and Development.”1
`
`Additionally, if models of the same or similar combination products exist, it may be useful to
`conduct comparative analyses such as a labeling comparison, a comparative task analysis, and a
`physical comparison between your proposed product and the comparator for the purposes of
`identifying what differences exist between the user interfaces and where the same or similar risks
`may apply to your proposed product.
`
`Based on the aforementioned information and data, you should determine whether you need to
`submit the results of a human factors validation study conducted under simulated use conditions
`with representative users performing necessary tasks to demonstrate safe and effective use of the
`product. If you determine that human factors validation study does not need to be submitted for
`your product, you should submit your risk analysis, comparative analyses, and justification for
`not submitting the human factors validation study to the Agency for review under this IND.
`When submitting the requested information to the IND, you should place that information in
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`
`
`Reference ID: 4512493Reference ID: 4644439
`
`

`

`IND 049641
`Page 13
`
`eCTD Section 5.3.5.4. The Agency will notify you if we concur with your detennination.
`Guidance on human factors procedures to follow can be found in the following guidance
`documents.2
`1. Applying Human Factors and Usability Engineering to Medical Devices.
`2. Guidance on Safety Considerations for Product Design to Minind=e Medication Errors.
`
`Please note that we have also recently published three draft guidance documents that, while not
`yet finalized, might also be useful in understanding our current thinking and our approach to
`human factors for combination products, product design, and labeling.3
`
`1. Human Factors Studies and Related Clinical Study Considerations in Combination Product
`Design and Development.
`2. Safety Considerations for Container Labels and Carton Labe/;ng Design to Minbni=e
`Medication Errors.
`3. Contents of a Complete Submission for Threshold Analyses and Human Factors Submissions
`to Drug and Biologic Applications.
`
`Sponsor Pre-Meeting Response
`Jazz acknowledges FDA's comments.
`
`JZP-258 is an oral solution containin
`in redient.
`
`mL ox bate equivalent to 0.5 g/mL of active
`(b)(4f
`
`. The dosing syringe to be provided with JZP-258 is the
`same as t at cmTently used for Xyrem for which a human factors (HF) study was conducted to
`support the pediatric supplement submitted on 27 April 2018 for Xyrem (NDA 021196, S-030,
`approved 26 October 2018). As such, Jazz intends to include the risk analysis and the HF study
`perfo1med for Xyrem in the JZP-258 NDA to suppo1t use of the same dosing syringe.
`
`Jazz will submit a risk analysis, comparative analyses, and justification for not repeating an HF
`study in the NDA.
`
`Meeting Discussion:
`The Agency acknowledged the sponsor 's proposal to reference the Human Factors (HF) study
`performed with Xyrem (and referred to in the sponsor's pre-meeting response) in the planned
`NDA for JZP-258 to support use of the same dosing syringe. The Agency recommended that the
`sponsor design its HF development program taking into consideration the Agency 's initial
`response to Question 11 and the meeting discussion under that question. Specifically, the use(cid:173)
`related risk analysis (URRA) and comparative analyses should consider the product's established
`name, statement of strength, and labeled potency. The Agency strongly recommended that Jazz
`submit its planned analyses and HF development plan to this IND for Agency review, and will
`notify the sponsor if it concurs with those proposals.
`
`Risk Evaluation and Mitigation Strategy (REMS)
`Based on the information available at this time, a risk evaluation and mitigation strategy will be
`necessaiy to ensure that the benefits of JZP-258
`(bl\-4 ' outweigh its risks. JZP-
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4641499
`
`

`

`IND 049641
`Page 14
`
` should be incorporated into the currently approved Xyrem REMS.
`258
`This REMS should be included in the initial NDA submission.
`
`Sponsor Pre-Meeting Response:
`No further discussion is needed at the meeting.
`
`Meeti