CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`
`
`
`APPLICATION NUMBER:
`
`
`210875Orig1s000
`
`
`
`OTHER REVIEW(S)
`
`
`
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`Division of Medication Error Prevention and Analysis (DMEPA)
`
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`Office of Surveillance and Epidemiology (OSE)
`
`Center for Drug Evaluation and Research (CDER)
`
`
`
`
` Date of This Memorandum:
`
`May 19, 2020
`Requesting Office or Division:
` Division of Neurology 1 (DN 1)
`Application Type and Number: NDA 210875
`Product Name and Strength:
`Kynmobi (apomorphine hydrochloride) film, 10 mg, 15 mg,
`20 mg, 25 mg and 30 mg
`Sunovion Pharmaceuticals Inc
`2019-2408-1
`Ebony Whaley, PharmD, BCPPS
`Lolita White, PharmD
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`PURPOSE OF MEMORANDUM
`1
`
`The Applicant submitted revised carton labeling, Instructions for Use (IFU), and Integrated IFU
`
`
`received on May 18, 2020 for Kynmobi. The Division of Neurology 1 (DN 1) requested that we
`
`review the revised carton labeling, IFU, and Integrated IFU for Kynmobi (Appendix A) to
`determine if they are acceptable from a medication error perspective. The revisions are in
`
`response to recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`
`The Applicant implemented our recommendations and we have no additional
`recommendations at this time.
`
` a Whaley E. Human Factors Study Results and Label and Labeling Review for Kynmobi (NDA 210875). Silver Spring
`
`(MD): FDA, CDER, OSE, DMEPA (US); 2020 APR 20. RCM No.: 2019-2407 and 2019-2408.
`1
`
`
`
`Reference ID: 4610918Reference ID: 4613103
`
`10 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`EBONY A WHALEY
`05/19/2020 12:01:41 PM
`
`LOLITA G WHITE
`05/19/2020 12:28:48 PM
`
`
`
`Reference ID: 4610918Reference ID: 4613103
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
` PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
` CENTER FOR DRUG EVALUATION AND RESEARCH
`DIVISION OF CARDIOVASCULAR AND RENAL PRODUCTS
`
`Date:
`
`May 13, 2020
`
`
`
`From:
`
`Through:
`
`Interdisciplinary Review Team for Cardiac Safety Studies
`
`Christine Garnett, PharmD
`Clinical Analyst
`DCN
`
`To:
`
`Jack Dan, RPM
`DN1
`
`Subject:
`
`QT Consult to NDA 210875 (SDN 044)
`
`Note: Any text in the review with a light background should be inferred as copied from the
`sponsor’s document.
`
`This memo responds to your consult to us dated 5/11/2020 regarding the sponsor’s QT related
`language in the proposed product label. We reviewed the following materials:
` Previous IRT reviews for NDA 210875 dated 09/25/2018 in DARRTS;
` Previous IRT reviews for NDA 21264 dated 07/09/2019 in DARRTS; and
` Proposed label (Submission 0044).
`
`1 Responses for the Division
`
`During our review of the TQT study (CTH-201), we found the results to be inconclusive and
`cannot be used to exclude a 10-ms mean increase in the QTc interval at the maximum
`recommended dose of 35 mg (QT-IRT review dated 09/25/2018 in DARRTS). The maximum
`therapeutic exposure in the current submission is comparable to that in the previous submission.
`Therefore, we disagree with the sponsor’s proposed QT-related language in Section 12.2:
`12 CLINICAL PHARMACOLOGY
`12.2 Pharmacodynamics
`
`Cardiac Electrophysiology
`
`
`
`Reference ID: 4607705Reference ID: 4613103
`
`(b) (4)
`
`

`

` One of the major issues with the TQT study was that the selected doses did not cover the
`
`exposures associated with clinical dosing regimen. The final dose levels were achieved through
`individual titrations based on tolerability rather than by randomized treatment assignment. The
`
`higher dose groups did not result in higher exposures compared to lower dose groups as would
`have been expected with linear PK. The mean Cmax across dose levels is ~4 ng/mL, which is
`inadequate to cover Cmax of the maximum recommended therapeutic dose of 30 mg (~9 ng/ml)
`[based on Clinical Pharmacology review in DARRTS dated 05/02/2020] that is being considered
`in the current resubmission. Furthermore, higher exposures are expected in patients with renal
`
`impairment (50% higher Cmax with renal impairment). Note that there were too few patients
`receiving 15 mg and doses above 20 mg (2 for 25 mg, 3 for 35 mg and 1 for 50 mg) to be able to
`adequately characterize the change in QTc interval at those dose levels.
`
`We note that the RLD, APOKYN, was shown to prolong the QTc interval in a TQT study (see
`QT-IRT review under NDA 21264 dated 07/09/2019 in DARRTS) and has Warning and
`Precautions for QT Prolongation in the label. Even though a positive exposure-response was
`observed in the TQT study submitted under NDA 21264, QTc at a given concentration may
`not be well predicted. Therefore, we cannot use TQT study submitted under APOKYN to
`exclude a small effect for KYNMOBI.
`
`
`Thank you for requesting our input into the development of this product. We welcome more
`discussion with you now and in the future. Please feel free to contact us via email at
`cderdcrpqt@fda.hhs.gov
`
`
`
`Reference ID: 4607705Reference ID: 4613103
`
`2
`
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NAN ZHENG
`05/13/2020 08:35:30 AM
`Gopichand Gottipati is the primary clinical pharmacology reviewer.
`
`GOPICHAND GOTTIPATI
`05/13/2020 08:59:45 AM
`
`CHRISTINE E GARNETT
`05/13/2020 09:01:21 AM
`
`
`
`Reference ID: 4607705Reference ID: 4613103
`
`

`

`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
` Memorandum
`
`
` Date:
`
` May 6, 2020
`
`
`
`
`
`
`To:
`
`
`
`From:
`
`
`
`
`
`CC:
`
`
`Subject:
`
`
`
`
`Dave Podskalny, M.D.
`
`
`
`
`
`Division of Neurology I (DN I)
`
`
`
`Jack Dan, Regulatory Project Manager
`
`
`
`
`Tracy Peters, Associate Director for Labeling, DN I
`
`
`
`Dhara Shah, Regulatory Review Officer
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`Aline Moukhtara, Team Leader, OPDP
`
`
`OPDP Labeling Comments for TRADENAME™ (apomorphine
`
`
`hydrochloride) sublingual film
`
`
`NDA:
`
`
`
`
`
`
`210875
`
`
`
`
`
`
`
`In response to the DN I consult request dated January 22, 2020, OPDP has reviewed the
`
`
`
`
`
`
`proposed product labeling (PI), Patient Prescribing Information (PPI), Instructions for Use
`
`
`
`
`
`
`
`
`(IFU), and carton and container labeling for the original NDA submission for TRADENAME™
`
`
`(apomorphine hydrochloride) sublingual film.
`
`PI, PPI, IFU: OPDP’s comments on the proposed labeling are based on the draft PI received
`
`
`
`
`
`
`
`
`by electronic mail from DN I (Jack Dan) on April 24, 2020, and are provided below.
`
`
`
`
`
`A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed,
`
`
`
`
`
`
`and comments on the proposed PPI and IFU was sent under separate cover on May 5, 2020.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`
`
`
`
`
`
`
`
`container labeling submitted by the Sponsor to the electronic document room on November 21,
`
`
`2019, and our comments are provided below.
`
`
`
`
`Thank you for your consult. If you have any questions, please contact Dhara Shah at (240)
`
`
`402-2859 or Dhara.Shah@fda.hhs.gov.
`
`
`
`
`
`Reference ID: 4604345Reference ID: 4613103
`
`
`
` 1
`
`61 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`DHARA SHAH
`05/06/2020 03:05:30 PM
`
`
`
`Reference ID: 4604345Reference ID: 4613103
`
`

`

`
`
`
`
`
`
`
`
`
`
`
` Date:
`
` To:
`
`
`
`
` Through:
`
`
`
`
` From:
`
`
`
`
`
` Subject:
`
` Department of Health and Human Services
`
`
` Public Health Service
`
` Food and Drug Administration
`
`
` Center for Drug Evaluation and Research
`
`
`
` Office of Medical Policy
`
`
`
`PATIENT LABELING REVIEW
`
`
` May 4, 2020
`
` Jack Dan, Regulatory Project Manager
`
` Division of Neurology I (DN1)
`
`
` LaShawn Griffiths, MSHS-PH, BSN, RN
`
`
` Associate Director for Patient Labeling
` Division of Medical Policy Programs (DMPP)
`
`
`Marcia Williams, PhD
`
`Team Leader, Patient Labeling
`
`
` Division of Medical Policy Programs (DMPP)
`
`
`
` Maria Nguyen, MSHS, BSN, RN
`
`
` Patient Labeling Reviewer
` Division of Medical Policy Programs (DMPP)
`
` Dhara Shah, PharmD, RAC
`Regulatory Review OFficer
`
` Office of Prescription Drug Promotion (OPDP)
`
`
` Review of Patient Labeling: Patient Package Insert (PPI)
` and Instructions for Use (IFU)
`
`
`
`
` TRADENAME (apomorphine hydrochloride)
`
` sublingual film
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Drug Name (established
`
` name):
`
` Dosage Form and
`
` Route:
`Application
`Type/Number:
`
` Applicant:
`
`
`
`
`
` NDA 210875
`
`
`
` Sunovion Pharmaceuticals, Inc.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4603077Reference ID: 4613103
`
`

`

`
`
`1
`
`
`
` INTRODUCTION
`
`
` On November 21, 2019, Sunovion Pharmaceuticals, Inc., submitted for the Agency’s
` review a Class 2 resubmission for New Drug Application (NDA) 210875 for
`
`TRADENAME (apomorphine hydrochloride) sublingual film. The proposed
`indication for TRADENAME (apomorphine hydrochloride) sublingual film is for the
`
`
`acute, intermittent treatment of “OFF” episodes associated with Parkinson’s disease.
`
`The purpose of this submission is to review recommendations made by, and
`
`
`
`agreements reached with the Division of Neurology 1 (DN1) during milestone
`
`
`
`meetings, including the Type A meeting.
`
`
`This collaborative review is written by the Division of Medical Policy Programs
`
`
`(DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a
`
`request by the Division of Neurology 1 (DN1) on January 23, 2020, for DMPP and
`
`on January 22, 2020 for OPDP to review the Applicant’s proposed Patient Package
`
`Insert (PPI) and Instructions for Use (IFU) for TRADENAME (apomorphine
`
`hydrochloride) sublingual film.
`
`
`
`
`2 MATERIAL REVIEWED
`
`• Draft TRADENAME (apomorphine hydrochloride) PPI and IFU received on
`
`
`
`
`
`November 21, 2019, revised by the Review Division throughout the review cycle,
`and received by DMPP and OPDP on April 24, 2020.
`
`
`
`• Draft TRADENAME (apomorphine hydrochloride) Prescribing Information (PI)
`
`
`
`received on November 21, 2019, revised by the Review Division throughout the
`
`
`review cycle, and received by DMPP and OPDP on April 24, 2020.
`
`
`
`• Approved APOKYN (apomorphine hydrochloride) comparator labeling dated
`
`
`
`December 3, 2019.
`
`
`
`
`3 REVIEW METHODS
`
`
`To enhance patient comprehension, materials should be written at a 6th to 8th grade
`
`
`
`
`
`reading level, and have a reading ease score of at least 60%.
`Additionally, in 2008 the American Society of Consultant Pharmacists Foundation
`
`(ASCP) in collaboration with the American Foundation for the Blind (AFB)
`published Guidelines for Prescription Labeling and Consumer Medication
`
`
`Information for People with Vision Loss. The ASCP and AFB recommended using
`
`
`
`
`fonts such as Verdana, Arial or APHont to make medical information more
`
`accessible for patients with vision loss. We reformatted the PPI and IFU document
`
`using the Arial font, size 10.
`
`
`
`
`In our collaborative review of the PPI and IFU we:
`
`simplified wording and clarified concepts where possible
`
`•
`
`
`
`
`
`ensured that the PPI and IFU are consistent with the Prescribing Information
`
`•
`
`(PI)
`
`
`
`
`
`
`
`
`
`Reference ID: 4603077Reference ID: 4613103
`
`

`

`
`•
`
`•
`
`
`•
`
`
`•
`
`
`
` removed unnecessary or redundant information
`
` ensured that the PPI and IFU are free of promotional language or suggested
`
`
`
` revisions to ensure that it is free of promotional language
`
` ensured that the PPI and IFU meet the criteria as specified in FDA’s Guidance
`
` for Useful Written Consumer Medication Information (published July 2006)
`
`
`
`
`
`
`
` ensured that the PPI and IFU are consistent with the approved comparator
` labeling where applicable.
`
`
`
`
`
`
`4 CONCLUSIONS
`
`
`
`The PPI and IFU are acceptable with our recommended changes.
`
`
`
`
`5 RECOMMENDATIONS
`
`
`
`
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`
`
`correspondence.
`
`• Our collaborative review of the PPI and IFU are appended to this memorandum.
`
`
`
`
`Consult DMPP and OPDP regarding any additional revisions made to the PI to
`
`
`determine if corresponding revisions need to be made to the PPI and IFU.
`
` Please let us know if you have any questions.
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4603077Reference ID: 4613103
`
`14 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARIA T NGUYEN
`05/04/2020 07:06:18 PM
`DMPP-OPDP review of TRADENAME (apomorphine HCL) NDA 210875 PPI and IFU
`
`DHARA SHAH
`05/05/2020 09:46:49 AM
`
`MARCIA B WILLIAMS
`05/05/2020 09:51:26 AM
`
`LASHAWN M GRIFFITHS
`05/05/2020 10:14:36 AM
`
`
`
`Reference ID: 4603077Reference ID: 4613103
`
`

`

`
`
` HUMAN FACTORS STUDY REPORT AND LABELS AND LABELING REVIEW
`
`
`
`
`
` Division of Medication Error Prevention and Analysis (DMEPA)
`
` Office of Medication Error Prevention and Risk Management (OMEPRM)
`
`
`
` Office of Surveillance and Epidemiology (OSE)
`
` Center for Drug Evaluation and Research (CDER)
`
`
`
` *** This document contains proprietary information that cannot be released to the public***
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Date of This Review:
`
`
` April 20, 2020
`
` Requesting Office or Division:
`
` Division of Neurology 1 (DN1)
`
`
` Application Type and Number: NDA 210875
`
`
`
`
` Product Type:
`
` Single-ingredient
`
`Drug Constituent Name and
`
`
` Apomorphine hydrochloride sublingual film,
`
`
`
` Strength
`
`
`
`
`10 mg, 15 mg, 20 mg, 25 mg and 30 mg
`
` Rx or OTC:
`
`
`
` Rx
`
` Applicant/Sponsor Name:
` Sunovion Pharmaceuticals Inc
`
`
`
` Submission Date:
` November 21, 2019; February 3, 2020; March 10, 2020
`
`
` OSE RCM #:
`
` 2019-2407; 2019-2408
`
` DMEPA Safety Evaluator:
`
` Ebony Whaley, PharmD, BCPPS
`
`
`
`
` DMEPA Team Leader:
`
` Lolita White, PharmD
`
`
`
` DMEPA Associate Director for
` QuynhNhu Nguyen, MS
`
`
` Human Factors:
`
`
` DMEPA Associate/Deputy
` Danielle Harris, PharmD
`
` Director:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4595119Reference ID: 4613103
`
`1
`
`
`
`

`

`
`
`REASON FOR REVIEW
`1.
`
`
`
`
`This review evaluates the human factors (HF) validation study results and labels and labeling
`
`
`
`
`
`
`submitted as part of the 505(b)(2) submission under NDA 210875 for apomorphine
`
`
`
`
`
`
`hydrochloride sublingual film for areas of vulnerability that may lead to medication errors.
`
`
`
`
`PRODUCT DESCRIPTION
`1.1.
`
`
`
`Apomorphine hydrochloride sublingual film is a single-ingredient product intended for
`
`
`
`
`acute, intermittent treatment of “OFF” episodes associated with Parkinson’s disease
`
`
`(PD) including end-of-dose wearing “OFF” (including early morning “OFF”),
`
`
`
`
`
`partial/delayed/No-ON and unpredictable “OFF”. Apomorphine hydrochloride sublingual
`
`
`
`
`
`film is intended for administration by patients, caregivers and healthcare providers
`
`
` (HCPs) in the home or healthcare setting. Apomorphine s hydrochloride sublingual film
`
`
`
`
` has been submitted under the 505(b)(2) pathway, and the reference product is Apokyn
`
`
`
`
` (NDA 21264).
`
` The Applicant proposes the product be supplied in 30-count cartons and also as a
`
`
`
`
`
` titration kit for patient and caregiver use which will contain a total of 15 individually
`
`
`
`
`
`
` packaged films of: (3) 10 mg films, (3) 15 mg films, (3) 20 mg films, (3) 25 mg films, and
`
`
`
`
`
` (3) 30 mg films. Both packaging configurations will include child-resistant cartons (e.g.
`
`
`packaging). (See Appendices A and F).
`
`
`
`
`
`
`REGULATORY HISTORY RELATED TO THE PROPOSED PRODUCT’S HUMAN
`1.2.
`
`
`
`
`FACTORS DEVELOPMENT PROGRAM
`
`On March 29, 2018, the Applicant submitted an HF validation study results report as
`
`
`
`part of their initial 505(b)(2) submission for NDA 210875. We reviewed the HF validation
`
`
`study results and noted several use errors and close calls that occurred on critical tasks.
`
`
`
`
`We also noted that the Applicant implemented revisions to the labeling in response to
`
`
`
`
`
`
`the use errors and close calls but did not validate the revisions. Additionally, our review
`
`
`
`
`identified areas of vulnerability in the labels and labeling that may lead to medication
`
`
`
`
`errors, and we recommended additional labeling revisions. Our review of the HF
`
`
`
`validation study results also noted a study methodology concern: the user interface
`
`
`used in the HF validation study did not include the intend-to-market carton packaging
`
`(i.e.
`packaging). Overall, we determined the HF validation study
`
`
`methodology was deficient and the results did not demonstrate that the intended users
`
`
`can use the proposed product safely and effectively for the intended uses. As such, we
`
`
`recommended that the Applicant complete an additional HF validation study to support
`
`
`
`
`that the intended users can safely and effectively use the intend-to-market product.
`
`
`
`
`
`
`
`Reference ID: 4595119Reference ID: 4613103
`
`2
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
` Subsequently, NDA 210875 received a Complete Response (CR) on January 29, 2019 due
`
`
`
`
`
`
` to the aforementioned HF deficiencies and also due to clinical pharmacology,
` biopharmaceutics, and safety deficiencies.
`
`
`
`
`
`
`
`On February 27, 2019, the Applicant submitted their HF validation study protocol for an
`
`
`
`
`additional HF validation study to address our previously identified concerns, and we
`
`
`
`
`
`provided recommendations to the Applicant.a On November 21, 2019, the Applicant
`
`
`
`submitted the results of the HF validation study testing as part of a Class 2 resubmission
`
`
`
`
`for NDA 210875 which is the focus of this review.
`
`
`
`MATERIALS REVIEWED
`2.
`
`
`We considered the materials listed in Table 1 for this review. The Appendices provide our
`
`findings and evaluation of each material reviewed.
`
`
`
` Table 1. Materials Considered for this Review
`
`
` Material Reviewed
`
`
`
`
`
` Product Information/Prescribing Information
`
` Background Information
`Previous HF Reviews (DMEPA and CDRH)
`
`
` Background Information on Human Factors
`
`
` Engineering (HFE) Process
`
`
` Human Factors Validation Study Report
` Information Requests Issued During the Review
`
`
` Labels and Labeling
`
`
`
`
`
`
`
`
` Appendix Section (for
`
` Methods and Results)
`
` A
`
` B
`
`
`
` C
`
`
` D
`
` E
`
` F
`
`
`
`
`
`
`
`
` a Whaley E. Human Factors Protocol Review for apomorphine hydrochloride IND 110955. Silver Spring (MD): FDA,
` CDER, OSE, DMEPA (US); 2019 MAY 15. RCM No.: 2019-671.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4595119Reference ID: 4613103
`
`
`
` 3
`
`

`

`
`OVERALL ASSESSMENT OF MATERIALS REVIEWED
`3.
`
`
`The sections below provide a summary of the study design, errors, use difficulties, and close
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`
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`calls observed (Table 2), and our analysis to determine if the results support the safe and
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`effective use of the proposed product.
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`3.1 SUMMARY OF STUDY DESIGN
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`The Applicant submitted the results from two HF validation studies as part of this NDA
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`submission. The studies included similar use tasks; however, there was variability in the
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`
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`user interface.
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`In the first study, the Applicant provided the regular instructions for use (IFU) in the carton
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`and an IFU specific to opening the child-resistant (CR) packaging was available on the study
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`table. The HF validation study included 90 study participants: 30 patients with PD (15
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`untrained and 15 trained), 30 lay caregivers (15 untrained and 15 trained), and 30
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`healthcare providers (HCPs) (15 untrained and 15 trained). The HF validation study included
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`
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`the following scenarios: Use Scenario 1 (Opening CR packaging), Use Scenario 2 (full use of
`
`
`
`the product including opening packaging and administration), and knowledge task
`
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`questions. Participants were not explicitly instructed to refer to or review either IFU during
`
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`simulated use testing.
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`Following the completion of the first HF validation study and based on participant
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`
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`performance and root cause analysis, the Applicant reorganized content and revised the
`
`formatting of Steps 1, 6, and 7 of the regular IFU. Additionally, the Applicant determined
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`that instead of supplying the product with a CR packaging IFU, they would supply the
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`product with an Integrated IFU which combined the contents of the product IFU and the CR
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`
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`packaging IFU into one document. The Applicant intends that the Integrated IFU will be
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`supplied as a tear sheet at the pharmacy level and that the regular product IFU will be
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`supplied within the product carton.
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`In the second study, the goal was to validate the user interface changes implemented
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`
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`following the first study. The Applicant provided the regular IFU supplied in the carton and
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`the Integrated IFU supplied on the study table. The second study (also referred to as the
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`
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`supplemental HF validation study) included 30 study participants: 10 patients with PD (5
`
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`untrained and 5 trained), 10 lay caregivers (5 untrained and 5 trained), and 10 HCPs (5
`
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`untrained and 5 trained). The supplemental HF validation study only included Use Scenario
`
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`2.
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`3.2 RESULTS AND ANALYSES
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`4
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`Reference ID: 4595119Reference ID: 4613103
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`

`

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` Table 2 describes the study results, Applicant’s analyses of the results, and DMEPA’s
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` analyses and recommendations.
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`Reference ID: 4595119
`Reference ID: 4613103
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`
`5
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`

`

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` Table 2: Summary and analyses of errors/close calls/use difficulties with critical tasks during the HF validation study and supplemental study
` Participants: P – untrained patients, PT – trained patients, C – untrained caregivers, CT – trained caregivers, H – untrained HCPs, HT – trained HCPs
`
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`
`
` Number of, Description of, and Participant’s Subjective
`Applicant’s Root Cause
` Applicant’s Discussion of
`
`
`
` Critical Tasks
` DMEPA’s Analysis and
`
`
` Feedback on Use Errors, Close Calls, and Use Difficulties
`
` Mitigation Strategies
`
` Analysis
`
` Recommendations
` Use Scenario 1 – HF validation study only (patient participants only - ON state)
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`
`
` HF validation study – CR packaging IFU/Quick Guide as tear sheet on the study table and regular IFU in carton
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`
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`
`
` Depresses child Use difficulty
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`
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` • Reliance on users to possess
`
`
` n = 1
`
` resistant (CR)
`sufficient dexterity to
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` tabs on carton’s • One patient participant experienced difficulty
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`
`depress tabs.
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`
`
` side – ON state
`simultaneously depressing the CR tabs on the carton’s
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`
` sides. The participant required assistance, explaining
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`
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` that they would cut the carton open with scissors. The
` participant indicated that that the tabs’ offset position
`
`
`required them to stretch their fingers in an unnatural
`
`position, thereby compromising their grip strength.
`
`The Applicant states that
`Based on the Applicant’s use-
`despite the use difficulty and
`related risk analysis (URRA), failure
`
`
`
`
`
`
`close call, both participants
`to open the carton might result in
`
`were able to open the CR
`delay in therapy resulting in the
`
`
`
`carton and that both
`user remaining in OFF state or in
`
`
`
`
`participants did not have
`the user removing the pouching
`
`
`difficulty opening the CR
`from the carton in a manner that
`
`carton during Use Scenario 2, eliminates the child-resistant
`
`
`indicating that once users
`feature and could result in
`
`become familiar with the
`accidental exposure.
`
`
`
`product, this
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`difficulty is diminished.
`Our review of the study results did
`
`
`not identify subjective feedback
`
`
`The Applicant determined
`indicating that the labels and
`labeling should be improved. We
`that the level of residual risk
`
`
`
`note that two participants were
`associated with difficulty of
`
`
`able to open the packaging after
`opening the carton has been
`
`initial difficulty. We also note that
`minimized to the extent
`
`
`in Use scenario 1, participants had
`possible and is outweighed
`
`
`
`access to a CR packaging IFU.
`by the clinical benefit of
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`
`using the product. Therefore,
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`the Applicant states that no We note that dexterity concerns
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`
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`are a common clinical
`
`additional mitigation is
`
`warranted and is unlikely to manifestation of Parkinson’s
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`
`
`disease. We also acknowledge and
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`improve the level of residual
`
`agree with the Applicant’s assertion
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`risk.
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`that users who have difficulty
`opening the CR packaging may seek
`
`alternative means to access the
`medication, such as caregiver
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`
` assistance.
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`Close call
`
`n = 1
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`
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`• One patient participant experienced difficulty with
`
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`simultaneously depressing the CR tabs on the carton’s
`
`
`sides but was able to open the packaging within two
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`
`
`minutes. The participant indicated that that the tabs’
`
`offset position required them to stretch their fingers in
`an unnatural position, thereby compromising their grip
`
`strength.
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`Reference ID: 4595119Reference ID: 4613103
`
`
`
` 6
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`

`

`
`
`
` Table 2: Summary and analyses of errors/close calls/use difficulties with critical tasks during the HF validation study and supplemental study
` Participants: P – untrained patients, PT – trained patients, C – untrained caregivers, CT – trained caregivers, H – untrained HCPs, HT – trained HCPs
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Number of, Description of, and Participant’s Subjective
`Applicant’s Root Cause
` Applicant’s Discussion of
`
`
`
` Critical Tasks
` DMEPA’s Analysis and
`
` Feedback on Use Errors, Close Calls, and Use Difficulties
`
` Mitigation Strategies
`
`
`
` Analysis
` Recommendations
`
` Our review of the labels and
`
`labeling finds that the Integrated
`IFU includes instructions regarding
`
` how to open the CR packaging. We
` also note the Integrated IFU states
`
`
` “For assistance with the KYNMOBI
`
`child-resistant carton, please ask
`your care partner for help”.
`However, we note that the CR
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`
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`packaging IFU is intended to be
`
`
`supplied as a tear sheet at the
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`pharmacy level. As such, the user
`
`
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`would need to receive and review
`
`the CR packaging IFU in order to
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`
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`access the instructions on how to
`
`open the CR packaging. To mitigate
`the risk of users not receiving or
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`reviewing the CR packaging IFU, we
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`recommend including instructions
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`regarding how to open the CR
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`packaging directly on carton itself.
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`As such, we provide carton
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`labeling recommendation #1 in
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`Section 3.4 below. Given that this
`
`same information was provided to
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`
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`users in the CR packaging IFU in the
`
`study environment (e.g.
`
`instructions for how to open the CR
`
`packaging supplied on study table),
`
`
`in this particular instance, we find
`
`that this revision does not require
` additional HF validation data.
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`
`
`Reference ID: 4595119Reference ID: 4613103
`
`
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` 7
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`

`

`
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`
`
` Table 2: Summary and analyses of errors/close calls/use difficulties with critical tasks during the HF validation study and supplemental study
` Participants: P – untrained patients, PT – trained patients, C – untrained caregivers, CT – trained caregivers, H – untrained HCPs, HT – trained HCPs
`
`
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`
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`
`
`
`
`
`
`
`
` Number of, Description of, and Participant’s Subjective
`Applicant’s Root Cause
` Applicant’s Discussion of
`
`
`
` Critical Tasks
` DMEPA’s Analysis and
`
` Feedback on Use Errors, Close Calls, and Use Difficulties
`
` Mitigation Strategies
`
` Analysis
`
`
` Recommendations
`The Applicant states that
`
` Based on the Applicant’s URRA,
` Store materials Use errors
`
`
`
` • Habit – no children in home
`
`
`they have taken all
`
` n = 2
` failure to store the product away
`away from
`
`
`environment
`
`reasonable measures to help
` from children might result in
`
`
`children (ON
`
`• Two patient participants did not respond correctly to
`
`
`
`ensure users understand to
`
`state)
`accidental exposure.
`
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` the associated question. One participant reported that
`
`keep the proposed product
`
`
`
` they would store the pouches outside the carton in a
`
`out of the reach of children.
`
`Our review of the study results did
`
`
`box on the bedroom floor because opening the carton
`The Applicant notes that the
`
`not identify subjective feedback
`
`
`
`
` with their dexterity impairments was too challenging.
`IFU includes instruction to
`indicating that the labels and
`
`
` The other participant, who required the carton to be cut
`keep the product and all
`
`labeling should be improved. We
`
`
`
`
` open, reported that they would store the pouches out
`medicines out of the reach of
`note that the participants indicated
`of the carton in a kitchen drawer about three feet from
`children.
`they would manipulate the CR
`
`
` the floor. Both participants reported that they do not
`packaging in a manner that would
`
`
` have young children in their homes, so they did not
`
`pose risk to accidental exposure.
`consider the need to keep the medication away from
`
`However, we also note that the
` young children when deciding where they should store
`
`
`participants’ incorrect responses
`
` it.
`
`may have been due to them not
`
`having children in their home
`
`environment.
`
`
`Our review of the labels and
`labeling finds that Integrated IFU
`
`and regular IFU include the
`
`
`instruction “Keep TRADENAME and
`
`all medicines out of the reach of
`
`children”.
`
`
`
`Based on our overall assessment of
`
`the study results, participant
`subjective feedback, and review of
`
`the labels and labeling, we have no
`recommendations for revision to
`
` the user interface at this time.
`
`
`
` Use Scenario 2 – HF validation study and supplemental validation study
`
`
`
`
`
`
`
`
`
`Reference ID: 4595119Reference ID: 4613103
`
`
`
` 8
`
`

`

`
`
`
` Table 2: Summary and analyses of errors/close calls/use difficulties with critical tasks during the HF validation study and supplemental study
` Participants: P – untrained patients, PT – trained patients, C – untrained caregivers, CT – trained caregivers, H – untrained HCPs, HT – trained HCPs
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Number of, Description of, and Participant’s Subjective
`Applicant’s Root Cause
` Applicant’s Discussion of
`
`
`
` Critical Tasks
` DMEPA’s Analysis and
`
` Feedback on Use Errors, Close Calls, and Use Difficulties
`
`
` Mitigation Strategies
`
` Analysis
`
` Recommendations
` HF validation study – CR pack