209311Orig1s000 · 2019-01-18 · Applicant: Ironshore Pharmaceuticals & Development Inc. Reference ID: 4301455. 1 INTRODUCTION On June 08, 2018, Ironshore Pharmaceuticals & Development

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

209311Orig1s000

OTHER REVIEW(S)

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

Date:

August 02, 2018

To:

Mitchell Mathis, MD Director Division of Psychiatry Products (DPP)

Through:

LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP)

From:

Shawna Hutchins, MPH, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Domenic D’Alessandro, PharmD, MBA, CDE Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name (established name):

JORNAY PM (methylphenidate hydrochloride)

Dosage Form and Route: extended-release capsules, CII

Application Type/Number:

NDA 209311

Applicant: Ironshore Pharmaceuticals & Development Inc.

Reference ID: 4301455

1 INTRODUCTION On June 08, 2018, Ironshore Pharmaceuticals & Development Inc. re-submitted for the Agency’s review an original New Drug Application (NDA) for JORNAY PM (methylphenidate hydrochloride) extended-release capsules, CII, a central nervous system (CNS) stimulant, for the proposed indication for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older. This NDA was originally submitted on September 30, 2016, but received a Complete Response (CR) letter issued by the Agency on July 28, 2017.

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 Psychiatry Products (DPP) on June 21, 2018 for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for JORNAY PM (methylphenidate hydrochloride) extended-release capsules, CII.

2 MATERIAL REVIEWED

• Draft JORNAY PM (methylphenidate hydrochloride) MG received on June 08, 2018, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on August 01, 2018.

• Draft JORNAY PM (methylphenidate hydrochloride) Prescribing Information (PI) received on June 08, 2018, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on August 01, 2018.

3 REVIEW METHODS

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 MG document using the Arial font, size 10.

In our collaborative review of the MG we:

• simplified wording and clarified concepts where possible

• ensured that the MG is consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language

• ensured that the MG meets the Regulations as specified in 21 CFR 208.20

• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS


The MG is 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 MG is 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 MG.

Please let us know if you have any questions.


10 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

--------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically. Following this are manifestations of any and allelectronic signatures for this electronic record.--------------------------------------------------------------------------------------------/s/------------------------------------------------------------

SHAWNA L HUTCHINS08/02/2018

DOMENIC G DALESSANDRO08/02/2018

Signature Page 1 of 1


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****Pre-decisional Agency Information**** Memorandum Date: August 2, 2018 To: Nancy Dickinson, M.D., Clinical Reviewer

Division of Psychiatry Products, DPP Hiren Patel, PharmD, Regulatory Project Manager, (DPP)

Kimberly Updegraff, PharmD, Associate Director for Labeling, (DPP) From: Domenic D’Alessandro, PharmD, MBA, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Aline Moukhtara, RN, MPH, Acting Team Leader, OPDP Subject: OPDP Labeling Comments for JORNAY™ PM (methylphenidate

hydrochloride) extended release capsules, for oral use, CII NDA: 209311

In response to DPP consult request dated June 21, 2018, OPDP has reviewed the proposed product labeling (PI), Medication Guide, and carton and container labeling for JORNAY™ PM (methylphenidate hydrochloride) extended release capsules, for oral use, CII. PI: OPDP’s comments on the proposed labeling are based on the draft PI received by electronic mail from DPP on July 31, 2018, and are provided below. Medication Guide: A combined OPDP and Division of Medical Policy Programs (DMPP) review was completed, and comments on the proposed Medication Guide were sent under separate cover on August 2, 2018.

Carton and Container Labeling: OPDP has reviewed the attached proposed carton and container labeling submitted by the Sponsor to the electronic document room on July 23, 2018, and our comments are provided below. Thank you for your consult. If you have any questions, please contact Domenic D’Alessandro at (301) 796-3316 or [email protected]

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion




DOMENIC G DALESSANDRO08/02/2018



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MEMORANDUM REVIEW OF REVISED LABELS

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: July 25, 2018

Requesting Office or Division: Division of Psychiatry Products (DPP)

Application Type and Number: NDA 209311

Product Name and Strength: Jornay PM (methylphenidate hydrochloride) extended-release capsules20 mg, 40 mg, 60 mg, 80 mg, and 100 mg

Applicant/Sponsor Name: Ironshore Pharmaceuticals & Development, Inc.

FDA Received Date: June 23, 2018

OSE RCM #: 2018-1350-1

DMEPA Safety Evaluator: Loretta Holmes, BSN, PharmD

DMEPA Team Leader: Lolita White, PharmD

1 PURPOSE OF MEMORANDUMThe Division of Psychiatry Products (DPP) requested that we review the revised container labels for Jornay PM (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 labels review.a

2 CONCLUSIONThe revised container labels for Jornay PM are acceptable from a medication error perspective. We have no further recommendations at this time.

a Holmes L. Labels Review Memo for Jornay PM (NDA 209311). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2018 Jul 16. RCM No.: 2018-1350.




LORETTA HOLMES07/25/2018

LOLITA G WHITE07/25/2018



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Product Name and Strength: Jornay PM (methylphenidate hydrochloride) extended-release capsules20 mg, 40 mg, 60 mg, 80 mg, and 100 mg


FDA Received Date: June 8, 2018

OSE RCM #: 2018-1350

DMEPA Safety Evaluator: Loretta Holmes, BSN, PharmD


1 PURPOSE OF MEMORANDUMThe Division of Psychiatry Products (DPP) requested that we review the revised container labels for Jornay PM (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 2 CONCLUSIONThe revised Jornay PM container labels are unacceptable from a medication error perspective. We identified areas where the presentation of certain information is not optimal and additional revisions are needed to help minimize the potential for medication errors to occur with the use of the product.

a Holmes L. Label and Labeling Review for Methylphenidate Hydrochloride (NDA 209311). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 May 19. RCM No.: 2016-2587.


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3 RECOMMENDATIONS FOR IRONSHORE PHARMACEUTICALS & DEVELOPMENT, INC.We recommend the following be implemented prior to approval of this NDA:

A. Container Labels (all strengths)

1. The established name does not appear to be at least ½ the size of the proprietary name. Revise the font size of the established name to be at least ½ the size of the proprietary name to be in accordance with 21 CFR 201.10(g)(2).

2. The statement “ In The Evening” is located below the statement of strength. Our postmarketing experience has shown that the risk of wrong dose error increases when the intended product frequency of administration is placed in close proximity to the product strength (e.g., the patient may misinterpret the information on the label as the dosing instructions). Therefore, relocate the statement “ In The Evening” away from the product strength. We suggest positioning it above the proprietary name. Additionally, decrease its size slightly so that it does not compete in prominence with the proprietary name.

3. The equivalency statement on the principal display panel creates clutter and decreases the readability of important product identifying information. We recommend that you move the equivalency statement to the side panel.



(b) (4)

(b) (4)






Clinical Outcome Assessment Review Wen-Hung Chen NDA 209311 Methylphenidate hydrochloride/Jornay PM PREMB-R and BSFQ/ADHD Functional Impairments

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double-barreled questions (asking multiple concepts in a single question) that parents commented were difficult to answer.

We have concerns regarding the content validity of BSFQ including missing important concept, assessing concepts not important to morning routine, and redundant items. The results of the factor analysis and inconsistency in findings of convergent and divergent validity also indicated the issues with the content validity.

B. SUGGESTED COMMENTS TO APPLICANT Please find our suggested comments to the applicant’s question below Clinical Question 2: The Complete Response Letter indicated that a favorable benefit-risk profile had not been established for HLD200. A complete clinical picture of HLD200 includes an assessment of effectiveness during temporal periods during the early morning routine and evening. Improved patient functioning in the morning is a unique treatment benefit of HLD200 and contributes to the benefit-risk profile for HLD200. A) Does the Agency agree that the BSFQ and PREMB-R AM measure the same underlying constructs (i.e. functional impairments in pediatric patients with ADHD) and therefore provide evidence of effectiveness during the morning period in pivotal trials HLD200-107 and HLD200-108? B) Similarly, does the Agency agree that the PREMB-R PM provides evidence of effectiveness during the evening period in pivotal trials HLD200-107 and HLD200-108?

FDA Response to Question 2A: No, we do not agree. Our review of your Clinical Outcome Dossier concludes that PREMB-R AM and BSFQ are not fit-for-purpose as measures for assessing ADHD-associated time-specific behavior impairment owing to concerns with their content validity. The results of the qualitative studies showed that PREMB-R AM did not include items that assessed some of the important morning functional impairment. On the other hand, the BSFQ included items that were not consistent with morning routine and some items assessed whole day functional impairment, instead of focusing only on the morning time period. The results of the factor analysis and the inconsistency in the findings of convergent and divergent validity also indicated issues with content validity. Altogether, the content validity and construct validity of the PREMB-R AM and BSFQ were not established based on the results presented in the dossier. Content validity:



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Results of the literature review identified that the commonly reported symptoms were hyperactivity, impulsivity, distractibility, disruptiveness, and inattention. Clinical expert interviews identified 10 ADHD morning functioning impairments, including difficulty completing morning routine to get ready for school, difficulty getting up, inattentiveness, dawdling/being late, inability to follow directions, not listening to caregiver’s instructions or demands, misplacing/losing items, distractibility, being argumentative, and hyperactivity. During caregiver interviews, the most commonly reported morning functional impairments were distracted/inattentive, misplacing and losing things, impulsivity, hyperactivity, procrastination, depending on others for basic tasks, and having problems getting to school.

• The PREMB-R AM covers only three of the important functional impairment with

three questions: difficult getting out of bed, distracted/inattentive, and argumentative. The PREMB-R AM does not cover other identified important early morning functional impairment: misplacing and losing things, impulsivity, hyperactivity, and depending on others for basic tasks.

• During caregiver interviews, some parents commented that:

o Some PREMB-R items asked about more than one concept (double-barreled question) and were difficult to answer. Specifically, parents identified items 2 and 3 in the PREMB-R AM, and items 6 and 8 items in the PREMB-R PM as difficult to answer.

o The BSFQ did not assess the important morning functional impairment of

“difficulty getting out of bed,” and included items that were not consistent with morning routine such as “silliness,” “talkativeness,” and “interruption/blurting out.”

o The BSFQ included redundant items such as “forgetfulness” and

“misplacing/losing items,” and “talkativeness” and “interruption/blurting out.”

o When completing the BSFQ they were thinking about their child’s functioning impairment throughout the entire day instead of focusing on the morning time period.

Measurement properties:

• Results of factor analysis consistently indicated that that BSFQ contained multiple domains (Table 12.23 and Figure 10 of the Clinical Outcome Dossier, and Tables 1.18 and 1.17 in Appendix W Psychometric Results of the Clinical Outcome Dossier). This finding was consistent with the qualitative data where the parents reported that some items were not consistent with morning routine, and some items were



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redundant. These results show that the BSFQ is not unidimensional, and the use of a single BSFQ total score is not appropriate.

• The test-retest reliability represented in the dossier using the parent-reported

PREMB-R was not appropriate as the parent-reported data was not used as the study endpoint. The test-retest reliability should be calculated for the PREMB-R AM and separately for PREMB-R PM using the clinician’s ratings.

• The results of the convergent and divergent validity analyses are unclear for both the

BSFQ and PREMB-R AM. High correlations were found between the BSFQ and ADHD-AM-RS (0.796 – 0.918), which the applicant designated as evidence of convergent validity. However, high correlations were also found between the BSFQ and ADHA-RS-IV (0.626-0.794), which the applicant designated as evidence of divergent validity. These results suggest that the BSFQ assessed more than morning functional impairment and was not unidimensional. The correlations between the PREMB-R AM and the BSFQ and the ADHD-AM-RS were designated as analysis of convergent validity as they all are intended to assess morning functional impairment and should be higher than the correlations between the PREMB-R PM and BSFQ and ADHD-AM-RS. Instead, the results showed that the correlations between the PREMB-R PM and BSFQ (0.561) and ADHD-AM-RS (0.524) were higher than the correlations between the PREMB-R AM and BSFQ (0.401) and ADHD-AM-RS (0.339) at baseline. Although, the magnitude of the correlation reversed at the end of the studies, where the correlation between the PREMB-R AM and BSFQ (0.804) and ADHD-AM-RS (0.732) were higher than those between the PREMB-R PM and BSFQ (0.712) and ADHD-AM-RS (0.675), these findings suggest that the PREMB-R AM might not cover most of the important morning functional impairment, as well as that the BSFQ and ADHD-AM-RS might be assessing more than morning functional impairment.

• The IRT analysis did not examine whether the basic assumptions of the IRT analysis

were met or not. For example, the unidimensional assumption appears to have been violated based on the results from the factor analysis. The IRT analysis also did not examine whether it was appropriate to pool data from all study visits. Furthermore, the category characteristic curves showed some items with reverse-ordered thresholds (e.g., BSFQ Items 11, 12, and 20) indicating that these items did not fit the underlying latent trait. The IRT analysis results presented in the dossier did not support the conclusion that the BSFQ and PREMB-R measure the same underlying latent trait.

• Meaningful change and score interpretation information were also included in the

dossier. However, owing to issues with the content validity as well as inconsistent



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psychometric findings, the results of the meaningful change analysis could only be considered as preliminary and could not be directly applied for score interpretation at this time.

Additional Comments:

• The BSFQ has one item stem and one response scale applied to a combination of positive behavior and negative behavior questions. This design is very confusing and may lead to inconsistent ratings from the parents or clinicians. As illustrated below, items 1 to 6 are positive behavior questions, and items 7 to 10 are negative behavior questions. Item 1 reads as: “Did your child have difficulty with listening?” This is a clearly worded question and the parents and clinicians are to select a response from none, mild, moderate, or severe. However, item 7 reads as “Did your child have difficulty with distraction?” This is not a clear question as it has two negatives. A clearer way to ask the same question should be “Did your child have difficulty paying attention (staying focused)?”

FDA Response to Question 2B: The results in the Clinical Outcome Dossier show that the PREMB-R PM has some content validity but leaves out one of the important function impairments that is not assessed, namely, procrastination. This does not render the PREMB-R PM totally inadequate for assessing functional impairment in the evening. However, some problematic items lead the PREMB-R PM to be considered somewhat inadequate as they make the interpretation of the results difficult and challenging. The issues with the items are as follows:

• The most commonly reported late afternoon/evening functional impairments or

symptoms via parent interviews were difficulty completing homework (n=14, 93%), procrastination (n=14, 93%), inattentiveness/forgetful (n=14, 93%), and impulsivity/hyperactivity (n=13, 87%). Via clinician interviews, 11 afternoon/evening functional impairments were reported, with difficulty with homework, trouble winding down, and restlessness being most common.

• However, during parent cognitive interviews, a few participants noted that some

items contained more than one concept, making them more difficult to answer (e.g., Item 6: How much difficulty playing quietly or running about and climbing excessively did your child have in the late afternoon and evening?; and Item 8: How much was your child arguing or struggling excessively in the late afternoon and evening?). Parents also reported variability in their interpretation of struggling excessively.



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o Item 6 (see copy below) includes opposing behaviors in the same question making the question very confusing and the answer uninterpretable. For example, if a clinician selected the answer “None,” it is unclear whether the clinician meant that the child had no difficulty playing quietly, or had no difficulty running about and climbing excessively.

o Item 8 (see copy below) includes two distinct concepts that parents considered

difficult to answer given that arguing and struggling were two distinct behaviors. In addition, “struggling” may be interpreted as “having difficulty” or as “physically resisting.”

• It is unclear what Item 9 (see copy below) is asking exactly. Specifically, children with ADHD typically have difficulty in attentiveness and concentration. Constantly moving from an activity to a different one is the primary complaint. Therefore, it is unclear what is meant clinically when the child is having difficulty moving from one activity to another one. It may be more appropriate to ask whether the child is moving or transitioning from one activity to another in an excessive manner, in order to assess the amount of inattentiveness and impulsivity/hyperactivity.

• There are also some concerns regarding the psychometric properties of the PREMB-R

PM that are mentioned in our responses to Part A of this question.



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“We acknowledge the cited supportive literature in the meeting package; however, our assessment is that the evidence of content validity and other measurement properties included in this publication for PREMB-R AM is limited. At this time, we do not have sufficient evidence to determine that the PREMB-R AM is a well-defined and reliable instrument

We ask you to submit copies of both the PREMB-R AM and BSFQ, as well as their user manuals for review. If user manuals are not available, then provide details on the instructions and administration of the PREMB-R AM and BSFQ, as well as scoring algorithm and interpretation and missing data plan. In addition, clarify when the instruments were completed and who completed the instruments (parent or clinician). The determination on the acceptability of the PREMB-R AM will depend on the adequacy of submitted data and will be a matter for review.” At the preNDA meeting, the Agency “reiterated that the publication had limited data on the measurement properties of PREMB-R and confirmed additional evidence is needed to support the adequacy of the instrument (e.g., content validity, reliability, construct validity, ability to detect change, etc.). The Sponsor verbally provided some additional information in regards to the development and validity of the PREMB-R; however, the Agency noted that the Sponsor described face validity rather than content validity, and that the Agency places a greater emphasis on content validity. Content validity refers to the extent that the instrument measures all facets of the measured concept (outcome) that are relevant and important to patients and caregivers (if applicable) and that the items of the instrument are understood and interpreted appropriately. Content validity is established by qualitative research (e.g., literature review, patient/caregiver interviews, expert opinion, etc.). The Agency noted that documentation of content validity is needed…” (PreNDA Meeting Minutes, DARRTS Reference ID 3938316) As part of the current NDA submission, sponsor “has submitted full evidence dossier in support of the Parent Rating of Evening and Morning Behavior – Revised (PREMB-R) and the Before-School Functioning Questionnaire (BSFQ) instruments with the NDA submission (including all evidence to date) for review; this Clinical Outcomes Dossier is provided in Module 5.3.5.4 of NDA 209, 311 submitted on 09/30/2016. This is a review of the clinical outcome dossier to evaluate whether PREMB-R AM and BSFQ are fit-for-purpose for use as key secondary endpoint Materials reviewed:

• EOP2 Meeting Minutes, DARRTS Reference ID 3732256 • PreNDA Meeting Minutes, DARRTS Reference ID 3938316 • COA Dossier: Evidence Supporting the PREMB-R and BSFQ for the Assessment of Early

Morning and Afternoon/Evening Functional Impairment in Children with ADHA, Version 2.0, September 20, 2016; Prepared for Ironshore Pharmaceuticals; Prepared by


(b) (4)

(b) (4)

(b) (4)


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D. CLINICAL OUTCOME ASSESSMENT REVIEW

1 CONTEXT OF USE

1.1 Clinical Trial Population Eligible subjects for the phase 3 efficacy studies (HLD200-106, HLD200-107, and HLD200-108) were male and female children 6 through 12 years of age, inclusive, with a previous diagnosis of ADHD and confirmation of diagnosis using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID); had an ADHD-RS-IV score at screening or baseline at or above 90th percentile normalized for gender and age; had a CGI-S score of 4 or greater and a CGI-P score >10 at the baseline visit; and demonstrated at least a partial clinical response to methylphenidate hydrochloride. The studies also required parental confirmation of before-school functional impairment and/or difficulties performing a morning routine

1.2 Clinical Trial Design Studies HLD200-107 and HLD200-108 were phase 3, randomized, double-blind, placebo-controlled, parallel-group studies of evening-dosed HLD200 that evaluated the efficacy and safety of HLD200 in subjects aged 6 through 12 years with ADHD. Approximately 160 subjects enrolled in each of the studies (163 subjects in HLD200-108 and 155 subjects in HLD200-107, respectively) and were randomized to receive either HLD200 or placebo in a 1:1 ratio. The primary objective of Study HLD200-108 was to demonstrate that treatment with HLD200 improves control of ADHD symptoms, compared with placebo, throughout the day, as assessed by the ADHD-RS-IV at Visit 5. The ADHD-RS-IV is a scale developed to measure the behaviors (symptoms) of ADHD in children. The primary objective of Study HLD200-107 was to assess whether prior evening treatment (8:00 pm±1.5 hours) with HLD200 improves control of ADHD symptoms, compared with placebo, throughout the day (8:00 am±15 minutes to 8:00 pm±15 minutes) in pediatric subjects with ADHD, as assessed by the SKAMP CS on the laboratory classroom day. The SKAMP is a 13-item, independent observer rating (7-point scale) of ADHD symptoms and associated impairments as evidenced by analog classroom observed behaviors (symptoms) during the laboratory school assessments.



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2 CONCEPT(S) OF INTEREST AND CONCEPTUAL FRAMEWORK The concepts of interest are the daily function impairments in the morning after waking up and for the rest of the day. Figures 1 and 2 below show the conceptual framework of PREMB-R and BSFQ, respectively.

Figure 1. Conceptual framework of PREMB-R


(b) (4)


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Figure 2. Conceptual framework of BSFQ

3 CLINICAL OUTCOME ASSESSMENTS The PREMB-R consists of 11 items, split into two sections. The first section includes three questions regarding the child’s functioning in the morning (PREMB-R AM); the remaining eight questions are about the child’s behavior during the late afternoon/evening (PREMB-R PM). The PREMB-R AM asks about any difficulties the child had getting-up, getting ready and much they argued or struggled with their caregiver. The PREMB-R PM ask about any difficulties in doing homework, sitting through dinner, playing quietly, transitioning from one activity to another, getting ready for bed, falling asleep, how inattentive they were and how much the child struggled or argued. Each item has 4 options rating severity from, 0 = none, 1= a little, 2= a moderate amount and 3= a lot. A copy of the PREMB-R is found in Appendix 1. The original DPREMB (Daily Parent Rating of Evening and Morning Behavior Scale) was developed by Michelson et al. (2002) for use in a clinical trial of atomoxetine for ADHD



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treatment in children aged 6 to 16. The original instrument included 13 items designed to assess functional impairments in the morning and late afternoon/evening not specifically addressed by existing scales. Functioning was rated using a 5-point Likert scale (0 = Not present to 4 = Extremely problematic). This instrument consisted of 4 items to assess difficulties in the morning due to ADHD and 9 items to assess difficulties in late afternoon/evening activities due to ADHD. It was administered in a daily diary format that was completed by the child’s caregiver. The items in the DPREMB were selected by surveying clinicians familiar with ADHD treatment for common problems reported by families regarding morning and evening functioning. No input from caregivers or patients was used in developing the instrument, nor was it evaluated for psychometric properties. The DPREMB was then modified by Sutton et al. (2003) who removed two questions. One asked about irritability in the morning, the other asked about irritability in the evening. The response options were also revised to a 4-point verbal rating scale, where 0 = None, 1 = A Little, 2 = A Moderate Amount and 3 = A Lot. This revised 11 item instrument, the DPREMB – R (Daily Parent Rating of Evening and Morning Behavior Scale – Revised) was used in a randomized clinical trial of atomoxetine treatment for ADHD in children aged 6 to 12 years (Kelsey et al., 2004). This version is also the one used in the Applicant’s clinical trials HLD200-107 and HLD200-108. However, because it was completed based only on the two days of the week immediately prior to the next study visit rather than daily, it is referred to as the PREMB-R. The BSFQ comprises 20 items that cover commonly reported areas of dysfunction in early morning activities associated with ADHD (i.e. breakfast, hygiene, time awareness, getting to school, etc.). Each item is rated on a severity scale of 0-3 (0=none, 1=mild, 2=moderate, 3=severe). There are also two additional items that ask the rater for the time (in minutes) it took the child to wake up and get out of bed and the time (in minutes) it took for the child to complete his/her morning routine. A copy of the BSFQ is found in Appendix 2. The BSFQ, originally named the Wil-Hammer Morning Functioning Scale, was developed by Timothy Wilens, MD and Paul Hammerness, MD from Massachusetts General Hospital’s Department of Pediatric Psychopharmacology at the time of development (Wilens et al., 2010). It evaluates the child’s early morning functioning: from the time the child awakens until the time they depart the home for school or other activities. The BSFQ has been used as both a clinician-rated and parent-rated instrument. The clinician-rated weekly scoring of the BSFQ can be completed by the clinician using a structured interview format, which will include query of the parent/guardian regarding their daily/weekly ratings, observations, and impressions of BSFQ items across the preceding week.

4 CONTENT VALIDITY To date, the following information has been submitted (check all that apply):

☒Literature review and/or publications



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☒Documentation of expert input ☒Qualitative study protocols and interview guides for focus group or patient interviews ☐Chronology of events for item generation, modification, and finalization (item tracking matrix) ☒Qualitative study summary with evidence to support item relevance, item stems and response options, and recall period ☐Qualitative support for meaningful change ☐Quantitative study summary with evidence to support item retention and scoring ☐Transcripts (if available)

Literature Review: Commonly reported ADHD symptoms included hyperactivity, impulsivity, distractibility, disruptiveness, and inattention. ADHD was shown to have profound effects on both patients and/or their families (Buitelaar & Medori, 2010: Cannon, et al., 2009; Kordon, et al., 2011; Sallee, et al., 2015; Sung, et al., 2008), particularly with respect to school/work, social interactions and family relationships. Five articles reported on early morning functioning specifically, supporting the substantial unmet need for children with ADHD in terms of early morning symptom control (Coghill, et al., 2008; Hareendran, et al., 2015; Sallee et al. 2015, Wehmeier, et al., 2009; Wilens, et al., 2010). Despite the importance of improving early morning functional impairments, few measures were identified that specifically capture this time period. Only the BSFQ (Wilens, et al., 2010), Weekly Rating of Evening and Morning Behavior-Revised (WREMB-R) (Wehmeier, et al., 2009) and the Daily Parent Rating of Evening and Morning Behavior (DPREMB) (Sung et al., 2008) were identified. The WREMB-R is a modified version of the DPREMB for making weekly rather than daily assessments. Results of literature review identified commonly reported symptoms are hyperactivity, impulsivity, distractibility, disruptiveness, and inattention. Clinician Expert Input: Five clinical experts in the United States, with experience in treating children for ADHD, participated in concept elicitation interviews. Four of the five experts were medical doctors, 3 of whom were psychiatrists. The fourth was a developmental behavioral pediatrician, and the fifth clinician was a psychologist. Clinicians reported 10 ADHD morning functioning impairments, including: difficulty completing morning routine to get ready for school, difficulty getting up, inattentiveness, dawdling/being late, inability to follow directions, not listening to caregiver’s instructions or demands, misplacing/losing items, distractibility, being argumentative, and hyperactivity. Overall, 11 afternoon/evening functional impairments were reported, with difficulty with homework, trouble winding down and restlessness being most common. The clinicians reported that caregivers are also affected, as they experience tardiness or poor performance at work, a decreased ability to tend to the needs of other family members, increased stress, decreased social/family interactions, and feelings of guilt and/or frustration.



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Clinicians were asked about the severity of the ADHD functional impairments during the day. The majority confirmed that the morning and late afternoon/evening time periods tended to be the most difficult due to ADHD functional impairment severity in children, 6 to 12 years of age, in part due to the effects of medication wearing off during these times. As a result, when asked about desired treatment benefits, clinicians mentioned improvement in morning routines such as the ability to get out of bed on time, follow basic self-care routines, and better manage time. In terms of late/afternoon treatment benefits, clinicians mentioned reduced difficulty with homework and improved ability to wind down at the end of the day. Concept Elicitation: Concept elicitation interviews were conducted with 15 caregivers in the United States. The vast majority of caregivers were mothers (n = 14); one father also participated. The children in question ranged in age from 7 – 12 years. All the children with ADHD were taking stimulants at the time of the interview. Caregivers reported a wide range of ADHD-related functional impairments, including 28 early morning functional impairments, 13 of which were spontaneously reported by at least one caregiver. Overall, the most commonly reported functional impairments in the early mornings reported either spontaneously or after probing were distracted/inattentive (n=15, 100%), misplacing and losing things (n=15, 100%), impulsivity (n=15, 100%), hyperactivity (n=15, 100%), procrastination (n=15, 100%), depending on others for basic tasks (n=15, 100%), and having problems getting to school (n=15, 100%). In terms of late afternoon/evening functional impairments, 27 functional impairments were reported by caregivers, 14 of which were spontaneously reported by at least one caregiver. In general, the most commonly reported late afternoon/evening functional impairments or symptoms either spontaneously or after probing, were difficulty completing homework (n=14, 93%), procrastination (n=14, 93%), inattentiveness/forgetful (n=14, 93%), and impulsivity/hyperactivity (n=13, 87%). Concepts identified from the literature and concept elicitation interviews were mapped against the items in the PREMB-R and BSFQ. The findings are presented in Tables 4 and 5. <Reviewer note: Mapping concepts identified against the items in the PREMB-R and BSFQ was inadequate. Instead, the mapping should be conducted with items against the concepts identified. The Applicant’s mapping was able to name BSFQ items not consistent with morning functional impairment, but wat not able to examine whether important concepts were missing in the PREMB-R.>



17

Table 4. Concept mapping of PREMB-R



18

Table 5. Concept mapping of BSFQ



19

Cognitive Interview:



20

Six clinicians and 10 caregivers participated in cognitive interviewing. The semi-structured interview guides included questions asking 1) the meaning of each item in the PREMB-R and BSFQ; 2) the ease or difficulty of understanding or answering; 3) the time period the caregiver was thinking of when answering each item; 5) if the response options allowed them to choose an accurate response to each item; and 6) the relevance of each item to this specific patient population. A few participants noted that some PREMB-R items contained more than one concept, making them more difficult to answer (Item 6: How much difficulty playing quietly or running about and climbing excessively did your child have in the late afternoon and evening?; Item 3: How much was your child arguing or struggling excessively with you this morning; and the evening equivalent, Item 8: How much was your child arguing or struggling excessively in the late afternoon and evening?) and Item 2: How much difficulty did your child have getting ready this morning (e.g., getting washed, dressed, eating breakfast and getting to school) because of being distracted and inattentive (not because of arguing or refusing to do things)?). There also was some variability in the interpretation of struggling excessively. For the two items of particular concern to FDA in terms of relevance, getting out of bed and arguing/struggling excessive, the data suggest that these are relevant morning-related ADHD functional impairments. Getting out of bed was spontaneously reported by 4 caregivers, and during cognitive interviewing, all caregivers and all but one HCP indicated the item was relevant. Arguing was reported by more than half the caregiver sample after probing, and all but one caregiver and all but one HCP considered the item to be relevant. When the caregivers and clinicians were asked about the relevance of each specific item in the BSFQ, the majority found each item to be relevant and appropriate for evaluating early morning functional impairments in the study population, with the exception of silliness, which most clinicians (3/5) thought was not relevant. While the majority found the instrument to be clear and appropriate, there were some issues noted. Some caregivers reported that they were thinking about their child’s functioning throughout the entire day instead of focusing on the morning period, or they discussed functional impairments that were inconsistent with the morning routine. This was particularly the case for the items on ‘Distraction,’ Forgetfulness,’ ‘Talkativeness,’ and ‘Interrupt/Blurt Out’. In addition, some issues were reported with the wording of several items of the BSFQ. In addition, some issues were reported with the wording of several items of the BSFQ. Caregiver DID-003 thought Item 5 on ‘Attention” signified the need for attention, rather than “focusing on morning routines or activities” as the item described. DID-006 Caregiver thought Item 9 on ‘Forgetfulness’ tied together with Item 10 on ‘Misplacing/Losing Items’, making it a little more difficult to answer. Confusion was noted by two caregivers (DID-005 and DID-006) on the meaning of Item 18 on ‘Independence’. DID-001 found the last item on ‘Getting to School’ to be difficult to answer because the school year had not started at the time of the interview. However, because the instrument is administered by an interviewer, such issues related to timeframe and clarity can be easily clarified.



21

There was some reported redundancy with items, for example, one caregiver reported that Talkativeness was the same concept as Interruption/Blurting Out, and one caregiver thought Item 9 on ‘Forgetfulness’ tied together with Item 10 on ‘Misplacing/Losing Items’. Although most participants considered Silliness to be relevant, this was not a problem in the mornings for one caregiver and only 2 clinicians reported this to be a concept specifically relevant to ADHD. Prior to the qualitative study assessing content validity of the PREMB-R, the Applicant independently administered an online survey to 10 ADHD clinical experts on the content of the PREMB-R morning and late afternoon/evening subscales. The purpose of the survey was to gather information about which functional impairments were most relevant or most likely to be exhibited by children with ADHD. Physicians were asked to rate each of the PREMB-R items using a 5-point scale (Strongly disagree- 1, Disagree- 2, Neither agree nor disagree- 3, Agree- 4, Strongly agree- 5). Across PREMB-R items, mean agreement scores were greater than 4 for all items, providing further support for the relevance of the PREMB-R for assessing morning and afternoon/evening functional impairments among children with ADHD. Overall, the qualitative study findings do not support that the PREMB-R and BSFQ contain the full content validity in terms of concepts assessed. In addition, issues have been identified that may affect the clarity and comprehension of the items and may attenuate the instruments’ ability to detect changes. The issues identified were: double barrel questions, function impairments assessed inconsistent with morning routine and redundant items.

5 OTHER MEASUREMENT PROPERTIES (RELIABILITY, CONSTRUCT VALIDITY, ABILITY TO DETECT CHANGE)

There was no report of the psychometric properties of PREMB-R and BSFQ based on data from phase 2 studies. Instead, the psychometric properties were evaluated using the same data from phase 3 studies, HLD200-107 and HLD200-108. <Reviewer note: Generally, the Agency’s preference is that content validity and the psychometric properties should be established and agreed with the Agency prior to phase 3 studies. In addition, psychometric properties are generally considered as only preliminary when the content validity has not been established. This is the case for PREMB-R and BSFQ.> Test-retest Reliability: The PREMB-R AM marginally met the minimum ICC threshold set in these analyses for study 107, in showing marginal/low test-retest reliability with an ICC value of 0.59. It demonstrated, however, very good test-retest in study 108 with an ICC value of 0.81. The BSFQ showed very good test-retest reliability, with ICC values of 0.84 (study 107) and 0.95 (study 108).



22

<Reviewer note: The test-retest reliability represented in the dossier using the parent reported PREMB-R was not appropriate as the parent reported data was not used as the study endpoint. The test-retest reliability should be calculate for the PREMB-R AM and separately for PREMB-R PM using the clinician’s ratings.> Construct Validity: There were strong positive correlations between the BSFQ and the ADHD-AM-RS (r = 0.796 at baseline and r > 0.888 at final treatment optimization visits), demonstrating convergent validity for the BSFQ. However, when correlated with ADHD-RS-IV that was not designed to measure morning function, there were high positive correlations (r = 0.696 and 0.626 at baseline, and 0.608 ≤ r ≤ 0.794 at final treatment optimization visits) indicating strong association. There were no significant correlations between the BSFQ and the PERMP and SKAMP scores (r = 0.008), which provides evidence of divergent validity of the BSFQ with measures of classroom behavior and mathematical skill. There was a moderate positive correlation between the PREMB-R AM scores and the ADHD-AM-RS scores at treatment optimization (r = 0.732) and a weaker correlation at baseline (r = 0.339). There were moderate positive correlations with the BSFQ at baseline (r = 0.498 and 0.401) and at treatment optimization in study 107 (r = 0.486) with a stronger correlation evident at treatment optimization in study 108 (r = 0.804). There were weak positive correlations between the PREMB-R AM and the ADHD-RS-IV at baseline (r = 0.278 and 0.199) but slightly more moderate correlations at final treatment optimization (r = 0.302 and 0.621). Domain Structure: The factor analyses conducted on the Normative Survey data suggest that the BSFQ is made up with one primarily factor (on which organization items loaded) which explained 92% of the variance in the data, and two other factors (on which hyperactivity and talkativeness items loaded (Table 6). Results of factor analysis showed the PREMB-R contained 2 factors as hypothesized, with the first 3 items making up the ‘Morning’ domain and the remaining 8 items making up the ‘Afternoon/evening’ domain (Table 7). <Reviewer note: The eigenvalues and % of variance explained in Tables 6 and 7 were incorrect. The maximum possible eigenvalues are 20 and 11 for BSFQ and PREMB-R, respectively, and the total % of variance explained cannot exceed 100.>



23

Table 6. Factor Structure: Rotated factor loadings for the BSFQ Normative Survey data. Maximum likelihood extraction and Oblimin rotation.



24

Table 7. Factor Structure: Rotated factor loadings for the PREMB-R Normative Survey data. Maximum likelihood extraction and Oblimin rotation.

Item Response Theory Analysis: Multiple visits data were used to conduct the item response theory analysis to evaluate the performance of the items of BSFQ and PREMB-R. This analysis was adjusted for repeated measures by clustering on subjects. The objective was to confirm that BSFQ and PREMB-R AM items assess the same underlying construct. <Reviewer note: The IRT analysis cannot fully address the issue of whether BSFQ and PREMB-R AM items assess the same underlying construct. First, the IRT analysis was not appropriate as BSFQ and PREMB-R AM items were not unidimensional as was suggested by the results of qualitative studies and factor analysis. Second, repeated measures IRT requires very strict assumptions about correlation across visits that were not tested. Finally, IRT model fit statistics were not presented in the dossier, therefore it cannot be concluded that the items fit the IRT model.> Ability to detect change: Smaller reductions in scores on the ADHD-RS-IV, ADHD-AM-RS and CGI-P scores (defined as tertiles of direction and magnitude of the change in the score, or standard response criteria) were associated with smaller reductions in the BSFQ, PREMB-R AM and PREMB-R PM scores from baseline to the final treatment optimization/test visit (p<0.0001). Similarly, improvement in ADHD functioning according to the CGI-I scores at final treatment optimization/test visit were associated with greater reductions in the BSFQ, PREMB-R AM and PREMB-R PM scores



25

(p<0.0001). These results show that the BSFQ, PREMB-R AM and PREMB-R PM are sensitive to change.

6 INTERPRETATION OF SCORES <Reviewer note: Owing to issues with the content validity as well as inconsistent psychometric findings, the results of the meaningful change analysis could only be considered as preliminary and could not be directly applied for score interpretation at this time.> Large changes in BSFQ score, decreases of between 30 and 40 points, were observed in patients reaching each anchor outcome, with the effect size of the change being correspondingly large at around 3.0 standard deviations. With a maximum score of 60, the decrease in BSFQ score in those reaching the standard response criteria is above 50% of the possible maximum. Likewise, the change in PREMB-R AM and PREMB-R PM scores are equivalent to an effect size of around 2.0 SDs, and in terms of the maximum score of 9 for the PREMB-R AM and 24 for the PREMB-R PM, the score decreases of approximately 5 and 12 points, respectively, are similarly equivalent to decreases of around 50% of the possible maximum scores.

7 LANGUAGE TRANSLATION AND CULTURAL ADAPTATION This submission does include language translation or cultural adaption information for review.

8 REFORMATTING FOR NEW METHOD OR MODE OF ADMINISTRATION

Not applicable.

9 REVIEW USER MANUAL

This submission does not include user manual for review.

10 KEY REFERENCES FOR COA



26

E. APPENDICES (INCLUDE COPY OF INSTRUMENT(S)) Appendix 1. Parent Rating of Evening and Morning Behavior – Revised (PREMB-R)


Participant ID: ________ Date: __________

Copyright © Eli Lilly and Company 2009. All rights reserved. Version: DPREMB-R-L01

Daily Parent Rating of Evening and Morning Behavior-Revised Morning: 1. How much difficulty did your child have getting up and out of bed this

morning? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

2. How much difficulty did your child have getting ready this morning (e.g., getting washed, dressed, eating breakfast and getting to school) because of being distracted and inattentive (not because of arguing or refusing to do things)? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

3. How much was your child arguing or struggling excessively with you this morning? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

Late Afternoon and Evening: 4. How much difficulty did your child have doing or completing homework or

other tasks? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

5. How much difficulty did your child have sitting through dinner (evening meal)? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

6. How much difficulty playing quietly or running about and climbing excessively did your child have in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

1app-a-premb-r Pg. 1Reference ID: 4206434

(b) (4)



7. How inattentive and distractible was your child in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= Moderately ----- 3= A lot

8. How much was your child arguing or struggling excessively in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= Moderately ----- 3= A lot

9. How much difficulty did your child have moving or transitioning from one activity to a different one this afternoon and evening? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

10. How much difficulty did your child have settling down and getting ready for

bed tonight? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

11. How much difficulty did your child have falling asleep? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot


(b) (4)


27

Appendix 2. Before School Functioning Questionnaire (BSFQ)


Subject ID:__________________ Date:________________ Rater Initials:__________

Version 1 0 Page 1 of 3

Before School Functioning Questionnaire – 6 AM to 9 AM (approx.) (Scale should be based on the past week) Total Score: Time to wake up and get out of bed: minutes Time to complete routines (from out of bed to exit home): minutes

Rating: Mild - somewhat different than peers/siblings; some days Moderate - different than peers/siblings; most days

Severe - all days; all settings

Did your child have difficulty with: None

Mild

Moderate

Severe

1. Listening (to parents, other caregivers, siblings) 0 1 2 3 2. Following Directions (coming to breakfast, getting

dressed, picking up necessary things) 0 1 2 3

3. Overall Organization (morning routines, getting things together, time awareness)

0 1 2 3

4. Dressing (putting on shirts, blouse, pants, shoes, coats) 0 1 2 3 5. Attention (focusing on morning routines or activities) 0 1 2 3 6. Being Quiet (loud, cannot occupy self unless with TV/

electronics 0 1 2 3

7. Distraction (easily off task, distracted by objects, noise, others)

0 1 2 3

8. Procrastination (waiting until last moment to complete morning tasks)

0 1 2 3

9. Forgetfulness (memory of specific items; gym clothes, instrument, equipment)

0 1 2 3

10. Misplacing/Losing Items (book bag, lunch tickets, school work/projects)

0 1 2 3

11. Hyperactivity (excessive motor activity, running around in morning)

0 1 2 3

12. Talkativeness (talking excessively) 0 1 2 3 13. Interrupt/Blurt Out (interrupting/intruding, blurting out

before question is completed) 0 1 2 3

14. Silliness (goofiness, silliness, joking around) 0 1 2 3 15. Awaiting Turn (at breakfast, in line for bus or ride, 0 1 2 3

app-b-bsfq Pg. 1Reference ID: 4206434



bathroom time) Before School Functioning Questionnaire – 6 AM to 9 AM (continued)

Rating: Mild - somewhat different than peers/siblings; some days

Moderate - different than peers/siblings; most days Severe - all days; all settings


Mild

Moderate

Severe

16. Breakfast (not sitting down to eat, distracted while eating)

0 1 2 3

17. Hygiene (washing, combing hair, brushing teeth) 0 1 2 3 18. Independence (ability to perform tasks by him/herself) 0 1 2 3 19. Time Awareness (not using time correctly, taking too

long) 0 1 2 3

20. Getting to School (missing bus, disruptive car/bus ride, walking to school, tardy)

0 1 2 3





---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

WEN-HUNG CHEN01/11/2018

ELEKTRA J PAPADOPOULOS01/22/2018


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

Date:

July 21, 2017

To:

Mitchell Mathis, MD Director Division of Psychiatry Products (DPP)

Through:

LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Barbara Fuller, RN, MSN, CWOCN Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) Mathilda Fienkeng, PharmD, RAC Team Leader Office of Prescription Drug Promotion (OPDP)

From:

Shawna Hutchins, MPH, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Christine Bradshaw, PharmD & Aline Moukhtara, RN, MPH Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name (established name):

JORNAY PM (methylphenidate hydrochloride)

Dosage Form and Route: extended-release capsules, CII

Application Type/Number:

NDA 209311

Applicant: Ironshore Pharmaceuticals & Development Inc.


1 INTRODUCTION On September 30, 2016, Ironshore Pharmaceuticals & Development Inc. submitted for the Agency’s review an original New Drug Application (NDA) for JORNAY PM (methylphenidate hydrochloride) extended-release capsules, CII, a central nervous system (CNS) stimulant, for the proposed indication for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in patients 6 years and older.

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 Psychiatry Products (DPP) on November 14, 2016, and November 09, 2016, respectively, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) for JORNAY PM (methylphenidate hydrochloride) extended-release capsules, CII.

2 MATERIAL REVIEWED

• Draft JORNAY PM (methylphenidate hydrochloride) MG received on November 22, 2016, and received by DMPP and OPDP on November 23, 2016.

• Draft JORNAY PM (methylphenidate hydrochloride) Prescribing Information (PI) received on September 30, 2016, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on July 10, 2017.

3 REVIEW METHODS

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 MG document using the Arial font, size 10.

In our collaborative review of the MG we:

• simplified wording and clarified concepts where possible

• ensured that the MG is consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the MG is free of promotional language or suggested revisions to ensure that it is free of promotional language

• ensured that the MG meets the Regulations as specified in 21 CFR 208.20

• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS

The MG is 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 MG is 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 MG.

Please let us know if you have any questions.




SHAWNA L HUTCHINS07/21/2017

ALINE M MOUKHTARA07/21/2017

BARBARA A FULLER07/21/2017

LASHAWN M GRIFFITHS07/21/2017


1

****Pre-decisional Agency Information****

Memorandum Date: July 21, 2017

To: Martin Yoon, Regulatory Project Manager Division of Psychiatry Products (DPP)

Glenn Mannheim, Clinical Reviewer, DPP

Jasmine Gatti, Clinical Team Leader, DPP From: Christine Bradshaw, Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Through: Mathilda Fienkeng, Team Leader, OPDP Subject: NDA 209311/O-1

OPDP labeling comments for JORNAY PM™ (Methylphenidate Hydrochloride) Extended-Release Capsules, for oral use, CII (Jornay PM)

In response to DPP’s consult request dated November 9, 2016, OPDP has reviewed the draft product labeling (PI) and carton/container labeling for Jornay PM. OPDP’s comments on the draft PI for Jornay PM are provided below, and are based on the substantially complete version of the PI provided via email by Martin Yoon on July 10, 2017. Combined OPDP and Division of Medical Policy Programs (DMPP) comments on the proposed Medication Guide will be provided to DPP under separate cover. Carton and Container Labeling OPDP has reviewed the draft carton/container labeling submitted by the Sponsor on July 14, 2017, and downloaded from Global Submit on July 20, 2017.

1. OPDP notes that the formulation located on the label is listed as “ ” and “

”, while the draft substantially complete version of the PI provided by DPP states, “Extended-Release Capsules.” OPDP

FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion


(b) (4) (b) (4)

2

recommends that the established name on the carton/container labeling be revised to be consistent with the PI. We defer to DPP.

2. We note that on June 7, 2017, DMEPA conveyed to the Sponsor that, “the modifier “PM” would help to convey the evening administration time of the proposed product and help to differentiate this product from other marketed extended-release methylphenidate products that are administered in the morning.” OPDP notes that the proposed modifier “PM” is presented in smaller type size than the rest of the proprietary name on the carton/container labeling. We defer to DPP and DMEPA.

If you have any questions, please feel free to contact me by phone at 301-796-6796 or by email at [email protected]. OPDP appreciates the opportunity to provide comments on these materials. Thank you!




CHRISTINE J BRADSHAW07/21/2017


1







Product Name and Strength: Jornay PM (methylphenidate hydrochloride) extended release capsules20 mg, 40 mg, 60 mg, 80 mg, and 100 mg


Submission Date: July 14, 2017

OSE RCM #: 2016-2587-1

DMEPA Primary Reviewer: Loretta Holmes, BSN, PharmD


1 PURPOSE OF MEMOThe Division of Psychiatry Products requested that we review the revised container labels for Jornay PM (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 Additionally, we sought input from the Office of Pharmaceutical Quality (OPQ) reviewer. The reviewer provided comments that are included in Section 3 of this review.2 CONCLUSIONThe revised container labels are unacceptable from a medication error perspective for the following reasons:

The modifier in the proprietary name is difficult to read because it is in superscript font. The product strengths are not differentiated and may lead to wrong strength selection

errors.

a Holmes, L. Labels and Labeling Review for methylphenidate extended release capsules (NDA 209311). Silver Spring (MD): FDA, CDER, OSE, DMEPA (US); 2017 May 19. RCM No.: 2016-2587.


2

We note that the dosage form stated on the container labels (“ ”) is inconsistent with the dosage form stated in the Prescribing

Information (i.e. “Extended Release Capsules”). The Office of Pharmaceutical Quality (OPQ) has comments regarding the established

name, storage statement and equivalency statement.

3 RECOMMENDATIONS FOR IRONSHORE PHARMACEUTICALS & DEVELOPMENT, INC.We recommend the following be implemented prior to approval of this NDA: Container Labels

1. The proprietary name’s modifier, “PM”, is presented in superscript font and does not appear to be a part of the proprietary name. This presentation is difficult to read and may lead to confusion. For improved readability consider revising the modifier “PM” so that it is presented in the same font size as the root name “Jornay”.

2. The font and background used for the statement of strength lacks sufficient color contrast. Additionally, there is inadequate differentiation between the strengths. To minimize the potential risk of wrong strength selection errors, we recommend each statement of strength have its own unique color and the color should not overlap with the color used for the proprietary name or any other colors utilized in the trade dress.

3. The dosage form statement on the container labels (“ ”) differs from the dosage form statement in the Prescribing Information

(“Extended Release Capsules”). Revise the dosage form statement to read “Extended Release Capsules”.

Comments from OPQ1. Remove references to ”, as it is unnecessary.

2. Ensure that the storage statement matches that of the package insert (i.e. includes the temperature storage range, etc.).

3. Change the statement “ to “Each capsule contains xx mg

methylphenidate hydrochloride (equivalent to xx.x mg of methylphenidate free base)”.



(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)





Page 2 Addendum - Clinical Inspection Summary

NDA 209311, methylphenidate (

#10, #12, #15, and #16) when it should have sent double-blind shipment IP supplies

to these sites according to the instructions provided by the Clinical Team Lead in

preparation for the Visit 8, randomization visit. This caused inadequate IP inventory

at multiple sites for completion of Visit 8 randomization, necessitating the need for

multiple site to site transfers of IP and resulting in the Site 15 randomization issues

identified in #1 above.

maintained adequate oversight of the clinical trials and provided adequate monitoring

of investigator sites. Although regulatory violations were noted above, the data integrity is

unlikely to be impacted. The sponsor reported both the IP shipment error and the

subsequent randomization issue in the Site 15 in CSR. The ITT population included these

subjects which were assigned to treatment associated with the randomization number

ultimately used; the efficacy analyses were performed on this population. The sensitivity

analysis population excluded the 17 subjects in Cohort 2 at Site 15 and was used for

sensitivity analysis of the primary and secondary endpoints. Data from these 17 subjects

were included in the safety analysis.

Observations noted above are based on the Form FDA 483 and communications with the

field investigator; another inspection summary addendum will be generated if conclusions

change upon receipt and review of the EIR.

{See appended electronic signature page}

Jenn W. Sellers, M.D., PhD

Good Clinical Practice Assessment Branch

Division of Clinical Compliance Evaluation

Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Susan Thompson on behalf of

Kassa Ayalew, M.D., M.P.H.

Branch Chief

Good Clinical Practice Assessment Branch

Division of Clinical Compliance Evaluation

Office of Scientific Investigations


(b) (4)

(b) (4)

Page 3 Addendum - Clinical Inspection Summary

NDA 209311, methylphenidate (

cc:

Central Doc. Rm. NDA #209311

DPP/Division Director/Mitchell Mathis

DPP/Project Manager/Martin Yoon

DPP/Medical Officer/Glenn Mannheim

OSI /Office Director/David Burrow

OSI/DCCE/Division Director/Ni Khin

OSI/DCCE/Branch Chief/Kassa Ayalew

OSI/DCCE/Team Leader/Susan Thompson

OSI/DCCE/GCP Reviewer/Jenn Sellers

OSI/ GCP Program Analysts/Joseph Peacock/Yolanda Patague

OSI/Database PM/Dana Walters


(b) (4)


JENN W SELLERS07/06/2017

SUSAN D THOMPSON07/06/2017


HLD200 NDA 209311

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1.1 Substance Information...............................................................................................................3 2. Nonclinical Pharmacology.................................................................................................................4 3. Clinical Pharmacology......................................................................................................................5 3.1 Drug/Product Interactions ..............................................................................................................5 4. Clinical Studies .................................................................................................................................5 4.1 Adverse Event Profile Through all Phases of Development .....................................................5

4.2 Safety Profile .............................................................................................................................74.3 Evidence of Abuse, Misuse and Diversion in Clinical Trials ...................................................74.4 Tolerance and Physical Dependence Studies in Humans..........................................................9

5. Regulatory Issues and Assessment ...................................................................................................9III. REFERENCES .............................................................................................................................10

I. SUMMARY

1. BackgroundThis memorandum responds to a consult request by the Division of Psychiatry Products (DPP) to evaluate abuse related preclinical and clinical data submitted by Ironshore Pharmaceuticals & Development Inc. in NDA 209311 (IND 118074) for Trade Name, [Methylphenidate (MPH) Hydrochloride (HCl) Modified Release (MR) Capsules (HLD200)]. The drug product is indicated for Attention Deficit Hyperactivity Disorder (ADHD) and the recommended dose is 20mg-100mg once daily in the evening..

MPH HCl is a central nervous system (CNS) stimulant. The mechanism of action of MPH in ADHD is not entirely understood, although it is believed to block the reuptake and enhance release of dopamine and norepinephrine in the mammalian brain. Methylphenidate has been used as a treatment for ADHD in children for several years. The Sponsor is submitting a New Drug Application (NDA) via the 505(b)(2) pathway, with Ritalin® as the reference listed drug (RLD). MPH HCl is a Schedule II controlled substance under the Controlled Substances Act (CSA).

The Sponsor states that within the MPH HCl MR Capsules (HLD200; Trade Name) methylphenidate is incorporated into a delayed release (DR) and extended release (ER) coated core that allows for release of MPH in plasma at a controlled rate following an initial delay of approximately 8 to 10 hours. This DR/ER profile is designed to allow for once-daily dosing during the evening with HLD200, leading to control of symptoms and improved functioning in ADHD patients during the early morning, afternoon, and evening.

2. Conclusions Methylphenidate hydrochloride is a Schedule II controlled substance under the CSA.


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The Sponsor is submitting an NDA via the 505(b)(2) pathway, with Ritalin® as the listed drug.

Methylphenidate HCl MR Capsule (HLD200) is not significantly different from Ritalin® in terms of bioavailability. Consistent with the formulation differences, HLD200 exhibits a longer Tmax relative to Ritalin®.

Adverse events were classified using standard terminology (i.e., system organ class and preferred term) from the verbatim description (investigator term) according to MedDRA, Version 18.0.

The abuse related adverse event profile of HLD200 is similar to other approved MPH products

The product label includes a black box warning regarding abuse and discusses abuse and dependence in section 9.The Sponsor does not propose any schedule change to the CII classification of MPH in HLD200.

3. Recommendations1. Based on the profile of effects in animal and human studies following MPH products, including HLD200, administration and withdrawal, CSS agrees with the Sponsor’s request to maintain HLD200 in Schedule II of the CSA.

2. Standard Periodic Adverse Event Reports (PADERS) are adequate for reviewing and reporting abuse related adverse events

3. Label:

The following sentence should be added under Dependence section (9.3) to be consistent with other MPH products and include the full spectrum of MPH withdrawal symptomatology: ‘Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include fatigue, depression , dysphoric mood,vivid unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.’

Under Section 17 (Patient counseling information), we recommend the following be added: ‘Alcohol effect: Advise patients to avoid alcohol while taking Trade Name. Consumption of alcohol while taking Trade Name may result in a more rapid release of the dose of methylphenidate.’ This is consistent with other methylphenidate products.

II. DISCUSSION

1. Chemistry

1.1 Substance InformationChemical Name:2-Piperidineacetic acid, α-phenyl-, methyl ester, hydrochloride(R*,R*)-(±)-.Methyl α-phenyl-2-piperidineacetate hydrochlorideAPI ChemicalGeneric Name: Methylphenidate Hydrochloride

Structural Formula: Methylphenidate Hydrochloride


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Non-Clinical Abuse Liability Assessment

Methylphenidate was tested orally at 2.5, 5, and10 mg/kg for its physical dependence potential in a repeated-dose, nonprecipitated withdrawal test, for its drug profiling in a drug discriminationlearning procedure (single escalating doses), and for its reinforcing properties in a conditionedplace preference test (alternate dosing days) and an IV self-administration procedure (0.05 to 1 mg/kg/IV infusion during 5 daily 1-hour test sessions). Young (6 to 9 weeks), specificpathogen-free, male Sprague-Dawley (Crl:CD®) rats were tested (Teuns et al., 2014) (1). Cessation of subchronic dosing up to 10 mg/kg methylphenidate led to sustained, or even exacerbated, effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10 mg/kg doses of methylphenidate. Distinct reinforcing properties were present in the conditioned place preference test at 10 mg/kg and in the IV self-administration study from 0.05 mg/kg IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10 ng/mL, a plasma level that is considered representative of the human efficacious methylphenidate dose. The human/rat ratio of maximum plasma concentration (Cmax) calculated from the IV self-administration data ranged from 14.9 to 576.5.

3. Clinical Pharmacology In study HLD200-110 the estimate of MPH bioavailability from a single dose of HLD200, 100 mg, relative to a single dose of immediate release Ritalin®, 20 mg, based on dose normalized AUC was 73.9%. Consistent with the formulation differences, HLD200 exhibited a longer Tmax relative to Ritalin®. Exposure-by-time profiles for HLD200 and Ritalin® are similar with the exception of an initial delay in exposure for HLD200 lasting for approximately 8 to 10 hours after administration. Overall, the results from PK studies with HLD200 demonstrate the delayed and extended-release properties of the MPH formulation.

3.1 Drug/Product Interactions An in vitro dose-dumping study with HLD200 was conducted. Data from this study demonstrated no release of MPH at ethanol concentrations up to and including 20% alcohol levels (Report . Some release of MPH was observed at the 40% alcohol level after 30 minutes (0.3%) and up to approximately 96% release of MPH after 120 minutes on average. As continuous exposure to 40% alcohol for more than 30 minutes in the stomach is extremely unlikely to occur, and there was no measurable MPH release at lower alcohol concentrations, clinically significant dose dumping in the presence of alcohol in vivo is not expected.

4. Clinical Studies

4.1 Adverse Event Profile Through all Phases of Development


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IPD-MPH-001 (Phase 1) There were 2 co-primary objectives in the study: to determine pharmacokinetic properties of 54 mg MPH00400 and 54 mg MPH00500, modified-release formulations of MPH and to assess their bioavailability compared with immediate-release Ritalin® (20 mg MPH) when administered as single treatments in healthy adult volunteers.Secondary Objective: The secondary objective of this study was to assess the safety and tolerability of MPH00400 and MPH5000 when administered as single treatments in healthy adult volunteers. A total of 12 subjects were randomized to 3 treatment-sequence cohorts of 4 subjects each, and received all 3 treatments in crossover fashion, There were no reports of euphoric mood, feeling abnormal, or hallucinations. These formulations were not developed as the to-be- marketed formulations.

HLD200-110 (Phase 1) The primary objective was to compare the bioavailability of HLD200 (100 mg) to immediate release Ritalin® (20 mg).The secondary objectives were to determine safety and tolerability in healthy adult volunteers. This was a single-dose, open-label, randomized, crossover, comparative bioavailability study of HLD200 and Ritalin® in healthy adult volunteers. A total of 12 subjects were randomly assigned to 2 treatment sequence cohorts of 6 subjects each in crossover fashion. One episode of hyperalertness was noted in the Ritalin arm

HLD200-106: A Phase 3 clinical endpoint evaluation study examining the safety and efficacy of HLD200 in pediatric subjects with attention-deficit hyperactivity disorder.The study consisted of three phases:1. Screening/Washout Phase (up to 4 weeks);2. Open-label, Treatment-optimization Phase (Open-label Phase) (6 weeks); and3. Double-blind, Placebo-controlled Test Phase (Double-blind Phase) (1 week).Forty three subjects were administered HLD 200 orally at a dose range of 20 to 100 mg/day at 9:00 pm (± 2 hours). Six weeks of open-label treatment was followed by 1 week of double-blind treatment. Weight-matched placebo capsules using the same excipients as HLD200 with microcrystalline cellulose in place of MPH were administered during the double blind phase.In the open label phase affect lability occurred in 4 (9.3%) and emotional disorder in 1(2.3%) of patients. In the double blind phase no adverse events (AEs) related to abuse were reported in the HLD200 group and emotional disorder was reported in 1 (4.8%) patient in the placebo group.

HLD200-107 was a Phase 3, Study conducted across 3 distinct study phases:• Screening/ADHD Medication Withdrawal (up to 4 weeks with a minimum 5-day washout)• Open-label Treatment-optimization Phase (6 weeks)• Double-blind Placebo-controlled Test Phase (1 week)Subjects: Male or female children aged 6 to 12 years with diagnosis of ADHD were randomized; n= 155 (83 HLD200 and 72 placebo) to doses ranging from 20 mg to a maximum of 100 mg once daily between 6:30 pm and 9:30 pm. A total of 3 subjects discontinued study drug because of AEs, all of which occurred during the Open-label Dose-optimization Phase. The events included affect lability, agitation and aggression, and anxiety and 2 events of panic attack. During the open label phase affect lability was reported in 17.4% of patients

HLD200-108 was a Phase 3 Multicenter, Double-blind, Randomized, Placebo-controlled study.


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Study procedures were conducted across 2 study phases: Screening/Washout Phase (up to 2 weeks with a minimum 72-hour washout) and Randomized Placebo-controlled Test Phase (3 weeks). At the start of the Randomized Placebo-controlled Test Phase (Visit 2), subjects (n=163) were randomized to receive either HLD200 (n=82) or placebo (n=81). Subjects were instructed to begin dosing at 40 mg each evening for 1 week, with scheduled titration, as medically indicated and tolerated, over the subsequent 2 weeks to 60 mg (Visit 3) and 80 mg (Visit 4). Five subjects, 1 in the HLD200 group and 4 in the placebo group, reported 10 AEs that led to early discontinuation of study drug. The events consisted of irritability in 2 placebo subjects; mood swings in 1 HLD200 subject; dizziness, sleep disorder, somnolence, and tremor in 1 placebo subject; and flatulence, regurgitation, and enuresis in 1 placebo subject. Four subjects, 3 (3.7%) in the HLD200 group and 1 (1.3%) in the placebo group, reported 4 severe AEs. The severe events in the HLD200 subjects were mood swings, affect lability, and fatigue, and the severe event in the placebo group was irritability.

No HLD200-specific nonclinical or clinical abuse-related studies have been conducted as part of the HLD200 development program.

4.2 Safety Profile In Studies HLD200-107, HLD200-106, and HLD200-108, AEs were collected by observation ofsubjects, questioning of subjects/parents in an unbiased and nonleading manner, and/or receivingunsolicited complaints from subjects/parents.The safety profile of HLD200 is similar to that of other approved methylphenidate products with regards to abuse related adverse events. Affect lability has been observed with other methylphenidate products as well. The studies conducted by the Sponsor in children and adults did not reveal other abuse related adverse events such as euphoria, hallucinations, feeling abnormal etc. There was no evidence of drug diversion or drug accountability issues.

4.3 Evidence of Abuse, Misuse and Diversion in Clinical Trials The following tables from the Sponsor address subject disposition and reasons for premature discontinuation in the Phase 3 trials.


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Label: The following sentence should be added under Dependence section (9.3) to be consistent with other MPH products and include the full spectrum of MPH withdrawal symptomatology: ‘Withdrawal symptoms after abrupt cessation following prolonged high-dosage administration of CNS stimulants include fatigue, depression, dysphoric mood, vivid unpleasant dreams, insomnia or hypersomnia, increased appetite, and psychomotor retardation or agitation.’

Under Section 17 (Patient counseling information) we recommend the following be added: ‘Alcohol effect: Advise patients to avoid alcohol, while takingTrade Name. Consumption of alcohol while taking Trade Name may result in a more rapid release of the dose of methylphenidate.’ This is consistent with other methylphenidate products.

III. REFERENCES

1. Teuns GB, Geys HM, Geuens SM, Stinissen P, Meert TF. Abuse liability assessment inpreclinical drug development: predictivity of a translational approach for abuse liability testingusing methylphenidate in four standardized preclinical study models. J Pharmacol ToxicolMethods. 2014 Nov-Dec;70(3):295-309.


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SHALINI M BANSIL06/21/2017

MARTIN S RUSINOWITZ06/23/2017

SILVIA N CALDERON06/27/2017


Clinical Outcome Assessment Review Wen-Hung Chen NDA 209311 Methylphenidate hydrochloride/HLD200 ( PREMB-R and BSFQ/ADHD Behavior Impairments

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• The PREMB-R AM covers only three of the important functional impairment with three

questions: difficult getting out of bed, distracted/inattentive, and argumentative. The PREMB-R AM does not cover other identified important early morning functional impairment: misplacing and losing things, impulsivity, hyperactivity, and depending on others for basic tasks.

• During caregiver interviews, some parents commented that some PREMB-R items asked

more than one concept (double-barreled question) and were difficult to answer. Specifically, parents identified items 2 and 3 in the PREMB-R AM, and items 6 and 8 items in the PREMB-R PM as difficult to answer.

• During caregiver interviews, some parents commented that BSFQ did not assess an

important morning functional impairment, ‘difficulty getting out of bed”, and included items that were not consistent with morning routine such as “silliness”, “talkativeness”, and “interruption/blurting out”.

• During caregiver interviews, some parents commented that BSFQ included redundant items such as “forgetfulness” and “misplacing/losing items”, and “talkativeness” and “interruption/blurting out”.

• During caregiver interviews, some parents commented that when completing BSFQ they

were thinking about their child’s functioning impairment throughout the entire day instead of focusing on the morning period.

Measurement properties:

• Results of factor analysis suggested that BSFQ contained multiple domains. This finding was consistent with the qualitative data where the parents reported that some items were not consistent with morning routine, and some items were redundant. Because BSFQ is not unidimensional, it is necessary to provide rationale to support the use of a single BSFQ total score as the study endpoint.

• The test-retest reliability represented in the dossier using the parent reported PREMB-R

was not appropriate as the parent reported data was not used as the study endpoint. The test-retest reliability should be calculate for the PREMB-R AM and separately for PREMB-R PM using the clinician’s ratings.


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• The results of convergent and divergent validity are unclear for both BSFQ and PREMB-R AM. The results found high correlation between BSFQ and ADHD-AM-RS (0.796 – 0.918) that the Application designated as convergent validity. However, high correlation also was found between BSFQ and ADHA-RS-IV (0.626-0.794) that the Applicant designated as divergent validity. These results suggested that BSFQ assessed more than morning functional impairment and was not unidimensional. The correlations of PREMB-R AM with BSFQ and ADHD-AM-RS were designated as convergent validity as they all assessed morning functional impairment and should be higher than the correlations between PREMB-R PM with BSFQ and ADHD-AM-RS. Instead, the results showed that the correlations of PREMB-R PM with BSFQ (0.561) and ADHD-AM-RS (0.524) were higher than the correlation of PREMB-R AM with BSFQ (0.401) and ADHD-AM-RS (0.339) at baseline. Although, the magnitude of the correlation reversed at the end of the studies, where the correlation of PREMB-R AM with BSFQ (0.804) and ADHD-AM-RS (0.732) were higher than those of PREMB-R PM with BSFQ (0.712) and ADHD-AM-RS (0.675). These findings suggested that PREMB-R AM might not cover most of the important morning functional impairment, as well as that BSFQ and ADHD-AM-RS might be assessing more than morning functional impairment.

• Meaningful change and score interpretation information were also included in the dossier. However, owing to issues with the content validity as well as inconsistent psychometric findings, the results of the meaningful change analysis could only be considered as preliminary and could not be directly applied for score interpretation at this time.

Additional Comments:

• BSFQ has one item stem and one response scale applied to mixed positive behavior and negative behavior questions. This design is very confusing and may lead to inconsistent ratings from the parents or clinicians. As illustrated below, items 1 to 6 are positive behavior questions, and items 7 to 10 are negative ones. Item 1 reads as: “Did your child have difficulty with listening?” This is a clearly worded question and the parents and clinicians are to select a response from none, mild, moderate, or serve. However, item 7 reads as “Did your child have difficulty with distraction?” This is not a clear question as it has two negatives. A clearer way to ask the same question should be “Did your child have difficulty with paying attention (staying focus)?”

Conclusion: The results of the qualitative and quantitative studies showed that PREMB-R AM did not include items that assessed some of the important morning functional impairment. On the other hand, the BSFQ included items that were not consistent with morning routine and some items assessed whole day functional impairment, instead of morning ones. Results of the quantitative analysis


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(PM). The BSFQ and PREMB-R AM are clinician-rated measures to assess ADHD treatment response during the early morning period, while the PREMB-R PM is similarly utilized for assessment of the late afternoon/evening period. These measures were included in HLD200-107 study during a 6-week open-label treatment optimization phase. In addition, the PREMB-R AM and PM subscales were utilized as key secondary and secondary endpoints, respectively, following a 1-week double-blind, randomized treatment period. All three measures were also included in the HLD200-108 study during a 3-week double-blind, randomized treatment period as key secondary endpoints. The Applicant had an end-of-phase 2 (EOP2) meeting with DPP and the COA Team on May 5, 2016 regarding its program to develop Methylphenidate Modified-Release Capsules (HLD200) for pediatric ADHD. At the meeting, the Agency “informed the sponsor that a positive finding on the PREMBR morning subscale in trial HLD200-107 may be used to replicate a finding of efficacy based on the BSFQ in trial HLD200-108 provided that 1) Ironshore submits data to support the validity and reliability of the PREMBR morning subscale to measure early morning functioning and 2) this measure is designated as a key secondary endpoint in the protocol for HLD200-107.” (EOP2 Meeting Minutes, DARRTS Reference ID 3732256) Subsequently, the Applicant submit a publication regarding the reliability and validity of the Daily PREMB-R (Faraone, Childress, et al 2015) as part of the briefing package for the preNDA meeting. After reviewing the publication, the Agency prepared the following comments prior to the preNDA meeting: “We acknowledge the cited supportive literature in the meeting package; however, our assessment is that the evidence of content validity and other measurement properties included in this publication for PREMB-R AM is limited. At this time, we do not have sufficient evidence to determine that the PREMB-R AM is a well-defined and reliable instrument

. We ask you to submit copies of both the PREMB-R AM and BSFQ, as well as their user manuals for review. If user manuals are not available, then provide details on the instructions and administration of the PREMB-R AM and BSFQ, as well as scoring algorithm and interpretation and missing data plan. In addition, clarify when the instruments were completed and who completed the instruments (parent or clinician). The determination on the acceptability of the PREMB-R AM will depend on the adequacy of submitted data and will be a matter for review.” At the preNDA meeting, the Agency “reiterated that the publication had limited data on the measurement properties of PREMB-R and confirmed additional evidence is needed to support the adequacy of the instrument (e.g., content validity, reliability, construct validity, ability to detect change, etc.). The Sponsor verbally provided some additional information in regards to the development and validity of the PREMB-R; however, the Agency noted that the Sponsor described face validity rather than content validity, and that the Agency places a greater emphasis on content validity. Content validity refers to the extent that the instrument measures


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all facets of the measured concept (outcome) that are relevant and important to patients and caregivers (if applicable) and that the items of the instrument are understood and interpreted appropriately. Content validity is established by qualitative research (e.g., literature review, patient/caregiver interviews, expert opinion, etc.). The Agency noted that documentation of content validity is needed…” (PreNDA Meeting Minutes, DARRTS Reference ID 3938316) As part of the current NDA submission, sponsor “has submitted full evidence dossier in support of the Parent Rating of Evening and Morning Behavior – Revised (PREMB-R) and the Before-School Functioning Questionnaire (BSFQ) instruments with the NDA submission (including all evidence to date) for review; this Clinical Outcomes Dossier is provided in Module 5.3.5.4 of NDA 209, 311 submitted on 09/30/2016. This is a review of the clinical outcome dossier to evaluate whether PREMB-R AM and BSFQ are fit-for-purpose for use as key secondary endpoint . Materials reviewed:

• EOP2 Meeting Minutes, DARRTS Reference ID 3732256 • PreNDA Meeting Minutes, DARRTS Reference ID 3938316 • COA Dossier: Evidence Supporting the PREMB-R and BSFQ for the Assessment of Early

Morning and Afternoon/Evening Functional Impairment in Children with ADHA, Version 2.0, September 20, 2016; Prepared for Ironshore Pharmaceuticals; Prepared by

D. CLINICAL OUTCOME ASSESSMENT REVIEW

1 CONTEXT OF USE

1.1 Clinical Trial Population Eligible subjects for the phase 3 efficacy studies (HLD200-106, HLD200-107, and HLD200-108) were male and female children 6 through 12 years of age, inclusive, with a previous diagnosis of ADHD and confirmation of diagnosis using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID); had an ADHD-RS-IV score at screening or baseline at or above 90th percentile normalized for gender and age; had a CGI-S score of 4 or greater and a CGI-P score >10 at the baseline visit; and demonstrated at least a partial clinical response to methylphenidate hydrochloride. The studies also required parental confirmation of before-school functional impairment and/or difficulties performing a morning routine


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1.2 Clinical Trial Design Studies HLD200-107 and HLD200-108 were phase 3, randomized, double-blind, placebo-controlled, parallel-group studies of evening-dosed HLD200 that evaluated the efficacy and safety of HLD200 in subjects aged 6 through 12 years with ADHD. Approximately 160 subjects enrolled in each of the studies (163 subjects in HLD200-108 and 155 subjects in HLD200-107, respectively) and were randomized to receive either HLD200 or placebo in a 1:1 ratio. The primary objective of Study HLD200-108 was to demonstrate that treatment with HLD200 improves control of ADHD symptoms, compared with placebo, throughout the day, as assessed by the ADHD-RS-IV at Visit 5. The ADHD-RS-IV is a scale developed to measure the behaviors (symptoms) of ADHD in children. The primary objective of Study HLD200-107 was to assess whether prior evening treatment (8:00 pm±1.5 hours) with HLD200 improves control of ADHD symptoms, compared with placebo, throughout the day (8:00 am±15 minutes to 8:00 pm±15 minutes) in pediatric subjects with ADHD, as assessed by the SKAMP CS on the laboratory classroom day. The SKAMP is a 13-item, independent observer rating (7-point scale) of ADHD symptoms and associated impairments as evidenced by analog classroom observed behaviors (symptoms) during the laboratory school assessments.

1.3 Endpoint Hierarchy and Definition Tables 2 and 3 below show the endpoint hierarchy for Study HLD200-107 and HLD200-108, respectively. Table 2. Study HLD200-107 Endpoint Hierarchy


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Figure 2. Conceptual framework of BSFQ

3 CLINICAL OUTCOME ASSESSMENTS The PREMB-R consists of 11 items, split into two sections. The first section includes three questions regarding the child’s functioning in the morning (PREMB-R AM); the remaining eight questions are about the child’s behavior during the late afternoon/evening (PREMB-R PM). The PREMB-R AM asks about any difficulties the child had getting-up, getting ready and much they argued or struggled with their caregiver. The PREMB-R PM ask about any difficulties in doing homework, sitting through dinner, playing quietly, transitioning from one activity to another, getting ready for bed, falling asleep, how inattentive they were and how much the child struggled or argued. Each item has 4 options rating severity from, 0 = none, 1= a little, 2= a moderate amount and 3= a lot. A copy of the PREMB-R is found in Appendix 1. The original DPREMB (Daily Parent Rating of Evening and Morning Behavior Scale) was developed by Michelson et al. (2002) for use in a clinical trial of atomoxetine for ADHD


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treatment in children aged 6 to 16. The original instrument included 13 items designed to assess in the morning and late afternoon/evening not specifically addressed by

existing scales. Functioning was rated using a 5-point Likert scale (0 = Not present to 4 = Extremely problematic). This instrument consisted of 4 items to assess difficulties in the morning due to ADHD and 9 items to assess difficulties in late afternoon/evening activities due to ADHD. It was administered in a daily diary format that was completed by the child’s caregiver. The items in the DPREMB were selected by surveying clinicians familiar with ADHD treatment for common problems reported by families regarding morning and evening functioning. No input from caregivers or patients was used in developing the instrument, nor was it evaluated for psychometric properties. The DPREMB was then modified by Sutton et al. (2003) who removed two questions. One asked about irritability in the morning, the other asked about irritability in the evening. The response options were also revised to a 4-point verbal rating scale, where 0 = None, 1 = A Little, 2 = A Moderate Amount and 3 = A Lot. This revised 11 item instrument, the DPREMB – R (Daily Parent Rating of Evening and Morning Behavior Scale – Revised) was used in a randomized clinical trial of atomoxetine treatment for ADHD in children aged 6 to 12 years (Kelsey et al., 2004). This version is also the one used in the Applicant’s clinical trials HLD200-107 and HLD200-108. However, because it was completed based only on the two days of the week immediately prior to the next study visit rather than daily, it is referred to as the PREMB-R. The BSFQ comprises 20 items that cover commonly reported areas of dysfunction in early morning activities associated with ADHD (i.e. breakfast, hygiene, time awareness, getting to school, etc.). Each item is rated on a severity scale of 0-3 (0=none, 1=mild, 2=moderate, 3=severe). There are also two additional items that ask the rater for the time (in minutes) it took the child to wake up and get out of bed and the time (in minutes) it took for the child to complete his/her morning routine. A copy of the BSFQ is found in Appendix 2. The BSFQ, originally named the Wil-Hammer Morning Functioning Scale, was developed by Timothy Wilens, MD and Paul Hammerness, MD from Massachusetts General Hospital’s Department of Pediatric Psychopharmacology at the time of development (Wilens et al., 2010). It evaluates the child’s early morning functioning: from the time the child awakens until the time they depart the home for school or other activities. The BSFQ has been used as both a clinician-rated and parent-rated instrument. The clinician-rated weekly scoring of the BSFQ can be completed by the clinician using a structured interview format, which will include query of the parent/guardian regarding their daily/weekly ratings, observations, and impressions of BSFQ items across the preceding week.

4 CONTENT VALIDITY To date, the following information has been submitted (check all that apply):

☒Literature review and/or publications


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☒Documentation of expert input ☒Qualitative study protocols and interview guides for focus group or patient interviews ☐Chronology of events for item generation, modification, and finalization (item tracking matrix) ☒Qualitative study summary with evidence to support item relevance, item stems and response options, and recall period ☐Qualitative support for meaningful change ☐Quantitative study summary with evidence to support item retention and scoring ☐Transcripts (if available)

Literature Review: Commonly reported ADHD symptoms included hyperactivity, impulsivity, distractibility, disruptiveness, and inattention. ADHD was shown to have profound effects on both patients and/or their families (Buitelaar & Medori, 2010: Cannon, et al., 2009; Kordon, et al., 2011; Sallee, et al., 2015; Sung, et al., 2008), particularly with respect to school/work, social interactions and family relationships. Five articles reported on early morning functioning specifically, supporting the substantial unmet need for children with ADHD in terms of early morning symptom control (Coghill, et al., 2008; Hareendran, et al., 2015; Sallee et al. 2015, Wehmeier, et al., 2009; Wilens, et al., 2010). Despite the importance of improving early morning functional impairments, few measures were identified that specifically capture this time period. Only the BSFQ (Wilens, et al., 2010), Weekly Rating of Evening and Morning Behavior-Revised (WREMB-R) (Wehmeier, et al., 2009) and the Daily Parent Rating of Evening and Morning Behavior (DPREMB) (Sung et al., 2008) were identified. The WREMB-R is a modified version of the DPREMB for making weekly rather than daily assessments. Results of literature review identified commonly reported symptoms are hyperactivity, impulsivity, distractibility, disruptiveness, and inattention. Clinician Expert Input: Five clinical experts in the United States, with experience in treating children for ADHD, participated in concept elicitation interviews. Four of the five experts were medical doctors, 3 of whom were psychiatrists. The fourth was a developmental behavioral pediatrician, and the fifth clinician was a psychologist. Clinicians reported 10 ADHD morning functioning impairments, including: difficulty completing morning routine to get ready for school, difficulty getting up, inattentiveness, dawdling/being late, inability to follow directions, not listening to caregiver’s instructions or demands, misplacing/losing items, distractibility, being argumentative, and hyperactivity. Overall, 11 afternoon/evening functional impairments were reported, with difficulty with homework, trouble winding down and restlessness being most common. The clinicians reported that caregivers are also affected, as they experience tardiness or poor performance at work, a decreased ability to tend to the needs of other family members, increased stress, decreased social/family interactions, and feelings of guilt and/or frustration.


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Clinicians were asked about the severity of the ADHD functional impairments during the day. The majority confirmed that the morning and late afternoon/evening time periods tended to be the most difficult due to ADHD functional impairment severity in children, 6 to 12 years of age, in part due to the effects of medication wearing off during these times. As a result, when asked about desired treatment benefits, clinicians mentioned improvement in morning routines such as the ability to get out of bed on time, follow basic self-care routines, and better manage time. In terms of late/afternoon treatment benefits, clinicians mentioned reduced difficulty with homework and improved ability to wind down at the end of the day. Concept Elicitation: Concept elicitation interviews were conducted with 15 caregivers in the United States. The vast majority of caregivers were mothers (n = 14); one father also participated. The children in question ranged in age from 7 – 12 years. All the children with ADHD were taking stimulants at the time of the interview. Caregivers reported a wide range of ADHD-related functional impairments, including 28 early morning functional impairments, 13 of which were spontaneously reported by at least one caregiver. Overall, the most commonly reported functional impairments in the early mornings reported either spontaneously or after probing were distracted/inattentive (n=15, 100%), misplacing and losing things (n=15, 100%), impulsivity (n=15, 100%), hyperactivity (n=15, 100%), procrastination (n=15, 100%), depending on others for basic tasks (n=15, 100%), and having problems getting to school (n=15, 100%). In terms of late afternoon/evening functional impairments, 27 functional impairments were reported by caregivers, 14 of which were spontaneously reported by at least one caregiver. In general, the most commonly reported late afternoon/evening functional impairments or symptoms either spontaneously or after probing, were difficulty completing homework (n=14, 93%), procrastination (n=14, 93%), inattentiveness/forgetful (n=14, 93%), and impulsivity/hyperactivity (n=13, 87%). Concepts identified from the literature and concept elicitation interviews were mapped against the items in the PREMB-R and BSFQ. The findings are presented in Tables 4 and 5. <Reviewer note: Mapping concepts identified against the items in the PREMB-R and BSFQ was inadequate. Instead, the mapping should be conducted with items against the concepts identified. The Applicant’s mapping was able to name BSFQ items not consistent with morning functional impairment, but wat not able to examine whether important concepts were missing in the PREMB-R.>


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Table 4. Concept mapping of PREMB-R


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Table 5. Concept mapping of BSFQ


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Cognitive Interview:


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Six clinicians and 10 caregivers participated in cognitive interviewing. The semi-structured interview guides included questions asking 1) the meaning of each item in the PREMB-R and BSFQ; 2) the ease or difficulty of understanding or answering; 3) the time period the caregiver was thinking of when answering each item; 5) if the response options allowed them to choose an accurate response to each item; and 6) the relevance of each item to this specific patient population. A few participants noted that some PREMB-R items contained more than one concept, making them more difficult to answer (Item 6: How much difficulty playing quietly or running about and climbing excessively did your child have in the late afternoon and evening?; Item 3: How much was your child arguing or struggling excessively with you this morning; and the evening equivalent, Item 8: How much was your child arguing or struggling excessively in the late afternoon and evening?) and Item 2: How much difficulty did your child have getting ready this morning (e.g., getting washed, dressed, eating breakfast and getting to school) because of being distracted and inattentive (not because of arguing or refusing to do things)?). There also was some variability in the interpretation of struggling excessively. For the two items of particular concern to FDA in terms of relevance, getting out of bed and arguing/struggling excessive, the data suggest that these are relevant morning-related ADHD functional impairments. Getting out of bed was spontaneously reported by 4 caregivers, and during cognitive interviewing, all caregivers and all but one HCP indicated the item was relevant. Arguing was reported by more than half the caregiver sample after probing, and all but one caregiver and all but one HCP considered the item to be relevant. When the caregivers and clinicians were asked about the relevance of each specific item in the BSFQ, the majority found each item to be relevant and appropriate for evaluating early morning functional impairments in the study population, with the exception of silliness, which most clinicians (3/5) thought was not relevant. While the majority found the instrument to be clear and appropriate, there were some issues noted. Some caregivers reported that they were thinking about their child’s functioning throughout the entire day instead of focusing on the morning period, or they discussed functional impairments that were inconsistent with the morning routine. This was particularly the case for the items on ‘Distraction,’ Forgetfulness,’ ‘Talkativeness,’ and ‘Interrupt/Blurt Out’. In addition, some issues were reported with the wording of several items of the BSFQ. In addition, some issues were reported with the wording of several items of the BSFQ. Caregiver DID-003 thought Item 5 on ‘Attention” signified the need for attention, rather than “focusing on morning routines or activities” as the item described. DID-006 Caregiver thought Item 9 on ‘Forgetfulness’ tied together with Item 10 on ‘Misplacing/Losing Items’, making it a little more difficult to answer. Confusion was noted by two caregivers (DID-005 and DID-006) on the meaning of Item 18 on ‘Independence’. DID-001 found the last item on ‘Getting to School’ to be difficult to answer because the school year had not started at the time of the interview. However, because the instrument is administered by an interviewer, such issues related to timeframe and clarity can be easily clarified.


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There was some reported redundancy with items, for example, one caregiver reported that Talkativeness was the same concept as Interruption/Blurting Out, and one caregiver thought Item 9 on ‘Forgetfulness’ tied together with Item 10 on ‘Misplacing/Losing Items’. Although most participants considered Silliness to be relevant, this was not a problem in the mornings for one caregiver and only 2 clinicians reported this to be a concept specifically relevant to ADHD. Prior to the qualitative study assessing content validity of the PREMB-R, the Applicant independently administered an online survey to 10 ADHD clinical experts on the content of the PREMB-R morning and late afternoon/evening subscales. The purpose of the survey was to gather information about which functional impairments were most relevant or most likely to be exhibited by children with ADHD. Physicians were asked to rate each of the PREMB-R items using a 5-point scale (Strongly disagree- 1, Disagree- 2, Neither agree nor disagree- 3, Agree- 4, Strongly agree- 5). Across PREMB-R items, mean agreement scores were greater than 4 for all items, providing further support for the relevance of the PREMB-R for assessing morning and afternoon/evening functional impairments among children with ADHD. Overall, the qualitative study findings do not support that the PREMB-R and BSFQ contain the full content validity in terms of concepts assessed. In addition, issues have been identified that may affect the clarity and comprehension of the items and may attenuate the instruments’ ability to detect changes. The issues identified were: double barrel questions, function impairments assessed inconsistent with morning routine and redundant items.

5 OTHER MEASUREMENT PROPERTIES (RELIABILITY, CONSTRUCT VALIDITY, ABILITY TO DETECT CHANGE)

There was no report of the psychometric properties of PREMB-R and BSFQ based on data from phase 2 studies. Instead, the psychometric properties were evaluated using the same data from phase 3 studies, HLD200-107 and HLD200-108. <Reviewer note: Generally, the Agency’s preference is that content validity and the psychometric properties should be established and agreed with the Agency prior to phase 3 studies. In addition, psychometric properties are generally considered as only preliminary when the content validity has not been established. This is the case for PREMB-R and BSFQ.> Test-retest Reliability: The PREMB-R AM marginally met the minimum ICC threshold set in these analyses for study 107, in showing marginal/low test-retest reliability with an ICC value of 0.59. It demonstrated, however, very good test-retest in study 108 with an ICC value of 0.81. The BSFQ showed very good test-retest reliability, with ICC values of 0.84 (study 107) and 0.95 (study 108).


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<Reviewer note: The test-retest reliability represented in the dossier using the parent reported PREMB-R was not appropriate as the parent reported data was not used as the study endpoint. The test-retest reliability should be calculate for the PREMB-R AM and separately for PREMB-R PM using the clinician’s ratings.> Construct Validity: There were strong positive correlations between the BSFQ and the ADHD-AM-RS (r = 0.796 at baseline and r > 0.888 at final treatment optimization visits), demonstrating convergent validity for the BSFQ. However, when correlated with ADHD-RS-IV that was not designed to measure morning function, there were high positive correlations (r = 0.696 and 0.626 at baseline, and 0.608 ≤ r ≤ 0.794 at final treatment optimization visits) indicating strong association. There were no significant correlations between the BSFQ and the PERMP and SKAMP scores (r = 0.008), which provides evidence of divergent validity of the BSFQ with measures of classroom behavior and mathematical skill. There was a moderate positive correlation between the PREMB-R AM scores and the ADHD-AM-RS scores at treatment optimization (r = 0.732) and a weaker correlation at baseline (r = 0.339). There were moderate positive correlations with the BSFQ at baseline (r = 0.498 and 0.401) and at treatment optimization in study 107 (r = 0.486) with a stronger correlation evident at treatment optimization in study 108 (r = 0.804). There were weak positive correlations between the PREMB-R AM and the ADHD-RS-IV at baseline (r = 0.278 and 0.199) but slightly more moderate correlations at final treatment optimization (r = 0.302 and 0.621). Domain Structure: The factor analyses conducted on the Normative Survey data suggest that the BSFQ is made up with one primarily factor (on which organization items loaded) which explained 92% of the variance in the data, and two other factors (on which hyperactivity and talkativeness items loaded (Table 6). Results of factor analysis showed the PREMB-R contained 2 factors as hypothesized, with the first 3 items making up the ‘Morning’ domain and the remaining 8 items making up the ‘Afternoon/evening’ domain (Table 7). <Reviewer note: The eigenvalues and % of variance explained in Tables 6 and 7 were incorrect. The maximum possible eigenvalues are 20 and 11 for BSFQ and PREMB-R, respectively, and the total % of variance explained cannot exceed 100.>


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Table 6. Factor Structure: Rotated factor loadings for the BSFQ Normative Survey data. Maximum likelihood extraction and Oblimin rotation.


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Table 7. Factor Structure: Rotated factor loadings for the PREMB-R Normative Survey data. Maximum likelihood extraction and Oblimin rotation.

Item Response Theory Analysis: Multiple visits data were used to conduct the item response theory analysis to evaluate the performance of the items of BSFQ and PREMB-R. This analysis was adjusted for repeated measures by clustering on subjects. The objective was to confirm that BSFQ and PREMB-R AM items assess the same underlying construct. <Reviewer note: The IRT analysis cannot fully address the issue of whether BSFQ and PREMB-R AM items assess the same underlying construct. First, the IRT analysis was not appropriate as BSFQ and PREMB-R AM items were not unidimensional as was suggested by the results of qualitative studies and factor analysis. Second, repeated measures IRT requires very strict assumptions about correlation across visits that were not tested. Finally, IRT model fit statistics were not presented in the dossier, therefore it cannot be concluded that the items fit the IRT model.> Ability to detect change: Smaller reductions in scores on the ADHD-RS-IV, ADHD-AM-RS and CGI-P scores (defined as tertiles of direction and magnitude of the change in the score, or standard response criteria) were associated with smaller reductions in the BSFQ, PREMB-R AM and PREMB-R PM scores from baseline to the final treatment optimization/test visit (p<0.0001). Similarly, improvement in ADHD functioning according to the CGI-I scores at final treatment optimization/test visit were associated with greater reductions in the BSFQ, PREMB-R AM and PREMB-R PM scores


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(p<0.0001). These results show that the BSFQ, PREMB-R AM and PREMB-R PM are sensitive to change.

6 INTERPRETATION OF SCORES <Reviewer note: Owing to issues with the content validity as well as inconsistent psychometric findings, the results of the meaningful change analysis could only be considered as preliminary and could not be directly applied for score interpretation at this time.> Large changes in BSFQ score, decreases of between 30 and 40 points, were observed in patients reaching each anchor outcome, with the effect size of the change being correspondingly large at around 3.0 standard deviations. With a maximum score of 60, the decrease in BSFQ score in those reaching the standard response criteria is above 50% of the possible maximum. Likewise, the change in PREMB-R AM and PREMB-R PM scores are equivalent to an effect size of around 2.0 SDs, and in terms of the maximum score of 9 for the PREMB-R AM and 24 for the PREMB-R PM, the score decreases of approximately 5 and 12 points, respectively, are similarly equivalent to decreases of around 50% of the possible maximum scores.

7 LANGUAGE TRANSLATION AND CULTURAL ADAPTATION This submission does include language translation or cultural adaption information for review.

8 REFORMATTING FOR NEW METHOD OR MODE OF ADMINISTRATION

Not applicable.

9 REVIEW USER MANUAL

This submission does not include user manual for review.

10 KEY REFERENCES FOR COA


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E. APPENDICES (INCLUDE COPY OF INSTRUMENT(S)) Appendix 1. Parent Rating of Evening and Morning Behavior – Revised (PREMB-R)


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Daily Parent Rating of Evening and Morning Behavior-Revised Morning: 1. How much difficulty did your child have getting up and out of bed this

morning? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

2. How much difficulty did your child have getting ready this morning (e.g., getting washed, dressed, eating breakfast and getting to school) because of being distracted and inattentive (not because of arguing or refusing to do things)? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

3. How much was your child arguing or struggling excessively with you this morning? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

Late Afternoon and Evening: 4. How much difficulty did your child have doing or completing homework or

other tasks? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

5. How much difficulty did your child have sitting through dinner (evening meal)? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

6. How much difficulty playing quietly or running about and climbing excessively did your child have in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot


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7. How inattentive and distractible was your child in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= Moderately ----- 3= A lot

8. How much was your child arguing or struggling excessively in the late afternoon and evening? ----- 0= None ----- 1= A little ----- 2= Moderately ----- 3= A lot

9. How much difficulty did your child have moving or transitioning from one activity to a different one this afternoon and evening? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

10. How much difficulty did your child have settling down and getting ready for

bed tonight? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot

11. How much difficulty did your child have falling asleep? ----- 0= None ----- 1= A little ----- 2= A moderate amount ----- 3= A lot


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Appendix 2. Before School Functioning Questionnaire (BSFQ)


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Before School Functioning Questionnaire – 6 AM to 9 AM (approx.) (Scale should be based on the past week) Total Score: Time to wake up and get out of bed: minutes Time to complete routines (from out of bed to exit home): minutes

Rating: Mild - somewhat different than peers/siblings; some days Moderate - different than peers/siblings; most days

Severe - all days; all settings


Mild

Moderate

Severe

1. Listening (to parents, other caregivers, siblings) 0 1 2 3 2. Following Directions (coming to breakfast, getting

dressed, picking up necessary things) 0 1 2 3

3. Overall Organization (morning routines, getting things together, time awareness)

0 1 2 3

4. Dressing (putting on shirts, blouse, pants, shoes, coats) 0 1 2 3 5. Attention (focusing on morning routines or activities) 0 1 2 3 6. Being Quiet (loud, cannot occupy self unless with TV/

electronics 0 1 2 3

7. Distraction (easily off task, distracted by objects, noise, others)

0 1 2 3

8. Procrastination (waiting until last moment to complete morning tasks)

0 1 2 3

9. Forgetfulness (memory of specific items; gym clothes, instrument, equipment)

0 1 2 3

10. Misplacing/Losing Items (book bag, lunch tickets, school work/projects)

0 1 2 3

11. Hyperactivity (excessive motor activity, running around in morning)

0 1 2 3

12. Talkativeness (talking excessively) 0 1 2 3 13. Interrupt/Blurt Out (interrupting/intruding, blurting out

before question is completed) 0 1 2 3

14. Silliness (goofiness, silliness, joking around) 0 1 2 3 15. Awaiting Turn (at breakfast, in line for bus or ride, 0 1 2 3




bathroom time) Before School Functioning Questionnaire – 6 AM to 9 AM (continued)

Rating: Mild - somewhat different than peers/siblings; some days

Moderate - different than peers/siblings; most days Severe - all days; all settings


Mild

Moderate

Severe

16. Breakfast (not sitting down to eat, distracted while eating)

0 1 2 3

17. Hygiene (washing, combing hair, brushing teeth) 0 1 2 3 18. Independence (ability to perform tasks by him/herself) 0 1 2 3 19. Time Awareness (not using time correctly, taking too

long) 0 1 2 3

20. Getting to School (missing bus, disruptive car/bus ride, walking to school, tardy)

0 1 2 3






WEN-HUNG CHEN05/27/2017

ELEKTRA J PAPADOPOULOS05/28/2017


Page 4 Clinical Inspection Summary NDA 209311, methylphenidate ( Dr. Brams has 40 INDs and 3 prior CDER inspections.

• 2010: VAI • 2007: NAI • 2003: NAI

The following CI sites were selected for inspections mostly due to high enrollment, and no prior inspection histories: Dr. Sharon Wigal, Dr. Andrea Marraffino, and Dr. Samantha Bostrom. Rationale for the Sponsor and CRO Inspections: Inspections of the sponsor and the CRO of the study are warranted in order to ensure that there are no data integrity and subject protection concerns with the data submitted for this application. The sponsor Ironshore was responsible for manufacturing, packaging, and labeling of Investigational Product (IP); review and approval of applicable project documents; management of the vendors for IP and the Medication Event Monitoring System; and archival of all electronic and paper documentation. The CRO, , was responsible for most of the conduct of Studies HLD200-107 and HLD200-108 such as project management, study site startup and management, clinical monitoring of study sites, randomization, IP distribution, data management, pharmacovigilance, medical monitoring, biostatistical analysis of study data, preparation of the clinical study report, Trial Master File (TMF) creation and maintenance; and return of study documents to the sponsor for archiving. The sponsor reported randomization errors in Study Protocol HLD200-107 at Site 15 due to IP shipment errors in the submission dated September 30, 2016. On December 13, 2016, FDA field investigators at the site of Andrea Marraffino, Ph.D. in Florida detected the discrepancies in ADHD Rating Scale Individual Item Scores between the CRFs and the line listing submitted by the sponsor. Upon request, the sponsor investigated and reported the line listing error of the ADHD Rating Scale Individual Item Scores was due to a programming error.

III. RESULTS (by site): Name of CI, Address, Site # Protocol # and

Subject # Inspection Date

Classification

Matthew Brams, M.D. 550 Westcott, Suite 200 Houston, TX 77007 HLD200-107 (Site #10) HLD200-108 (Site #21)

HLD200-107 36 randomized HLD200-108 3 randomized

02/13/2017 to 02/17/2017, 2/21/2017 and 2/23/2017

VAI Preliminary

Sharon Wigal, Ph.D. 1600 Dove Street, Suite 305 Newport Beach, CA 92660 HLD200-107 (Site #16) HLD200-108 (Site #42)


7 days in the period of 2/17/2017 to 3/6/2017

NAI


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Page 5 Clinical Inspection Summary NDA 209311, methylphenidate ( Name of CI, Address, Site # Protocol # and

Subject # Inspection Date

Classification

Andrea Marraffino, Ph.D. 2300 Maitland Center Parkway, Suite 230 Maitland, FL 32751 HLD200-107 (Site #14) HLD200-108 (Site #23)


12/12/2016 to 12/16/2016

VAI

Samantha Bostrom, M.D. 1477 N. 2000 W, Suite D & C Clinton, UT 84015 HLD200-108 (Site #26)

HLD200-108 22 randomized

01/30/2017 to 02/03/2017

NAI

Ironshore Pharmaceuticals & Development, Inc. 10 Market Street, Suite 715 Camana Bay, Grand Cayman Cayman Islands, KY1-9006

HLD200-107 HLD200-108

02/27/2017 to 03/02/2017

NAI Preliminary

HLD200-107 HLD200-108

3/3/2017 The inspection is scheduled to be resumed 6/26/2017 to 6/30/2017

Inspection pending

Key to Compliance Classifications NAI = No deviation from regulations. VAI = Deviations from regulations. OAI = Significant deviations from regulations. Data unreliable Pending =Preliminary classification based on information in 483 or preliminary

communication with the field; EIR has not been received from the field, and complete review of EIR is pending. Final classification occurs when the post-inspectional letter has been sent to the inspected entity.

1. Matthew Brams, M.D. The inspection of Dr. Brams’ site focused on Study HDL200-107 (Site 10). In this study, 36 subjects were screened and all were enrolled and completed the study. A complete review was conducted for 21 enrolled subjects in the study. The following regulatory deviation was detected at Dr. Brams’ site: an investigation was not conducted in accordance with the signed statement of investigator and investigational plan. Specifically:

1. Review of source documents revealed 12 duplicate pairs of vital sign records that involved eighteen (18) out of thirty six (36) subjects in the


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Page 7 Clinical Inspection Summary NDA 209311, methylphenidate (

screened and all were enrolled into the study. Three subjects discontinued and 7 subjects finished the study. A complete review of all 10 subject records was conducted for this study.

The primary endpoint data were verified. There was no evidence of under-reporting of AEs. Some minor regulatory violations were noted as following: An investigation was not conducted in accordance with the signed statement of investigator investigational plan. Specifically: 1) Per section 4.3 of Protocol HLD200-107, subjects must meet the following

criteria to be randomized to the Double-blinded Placebo-controlled Test Phase (Visit 8): "Maximal symptom control during the morning and throughout the day while remaining safe and well tolerated with a minimum improvement of at least one-third (33%) from the baseline (Visit 2) total score to the total score at randomization (Visit 8) for each of the 3 scales (ADHD RS-IV, BSFQ, and CGI-P), and a stable BSFQ total score as defined by a difference of less than 10 points between Visits 7 and 8." The source documents for Subjects and showed that between visits 7 and 8, their BSFQ scores differed by 10 points (not less than 10 points as required by the protocol). Therefore, these two subjects did not meet the inclusion criteria to be randomized to Double Blinded Placebo-controlled Test Phase.

2) Two subjects used prohibited medications during the Randomization, Placebo-control Test Phase. Subject used Calm Child, a dietary supplement, for 6 days. Subject used oral prednisone for 10 days for “bronchitis”.

Although regulatory violations were noted, the data integrity is unlikely to be significantly impacted. The written response from the investigator was adequate. The data generated by this site appear acceptable in support of the respective indication.

4. Samantha Bostrom, M.D. This site participated in Study HLD200-108. At this site, 29 subjects were screened, 5 subjects were considered a screen failure, and 24 subjects were enrolled. Among these enrolled, 3 discontinued and 21 completed the study. A complete review of the primary endpoint, AEs and vital signs was conducted for all enrolled subjects. The secondary endpoints and Concomitant Medication records were randomly check for some subjects. No significant regulatory violations were noted. The primary endpoint data were verified. There was no evidence of under-reporting of AEs. This clinical site appeared to be in compliance with Good Clinical Practices, and the data generated by this site appear acceptable in support of the respective indication.


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Page 9 Clinical Inspection Summary NDA 209311, methylphenidate (

{See appended electronic signature page} Jenn W. Sellers, M.D., PhD Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations


Susan Thompson, M.D.

Team Leader, Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations


Kassa Ayalew, M.D., M.P.H Branch Chief Good Clinical Practice Assessment Branch Division of Clinical Compliance Evaluation Office of Scientific Investigations

cc: Central Doc. Rm. NDA #209311 DPP/Division Director/Mitchell Mathis DPP /Project Manager/Martin Yoon DPP/Medical Officer/Glenn Mannheim OSI /Office Director/David Burrow OSI/DCCE/Division Director/Ni Khin OSI/DCCE/Branch Chief/Kassa Ayalew OSI/DCCE/Team Leader/Susan Thompson OSI/DCCE/GCP Reviewer/Jenn Sellers OSI/ GCP Program Analysts/Joseph Peacock/Yolanda Patague OSI/Database PM/Dana Walters


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JENN W SELLERS05/19/2017

SUSAN D THOMPSON05/19/2017

KASSA AYALEW05/19/2017


1

LABELS AND LABELING REVIEWDivision 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: May 19, 2017



Product Name and Strength: methylphenidate hydrochloride extended release capsules20 mg, 40 mg, 60 mg, 80 mg, and 100 mg

Product Type: Single Ingredient Product

Rx or OTC: Rx


Submission Date: September 30, 2016

OSE RCM #: 2016-2587

DMEPA Primary Reviewer: Loretta Holmes, BSN, PharmD



2

1 REASON FOR REVIEW

This review evaluates the proposed container labels and prescribing information for methylphenidate extended-release capsules, NDA 209311, submitted by Ironshore Pharmaceuticals & Development, Inc. on September 30, 2016. The Division of Psychiatry Products requested that we review the proposed container labels and prescribing information for areas of vulnerability that may lead to medication errors.

2 MATERIALS REVIEWED

We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed.

Table 1. Materials Considered for this Label and Labeling Review

Material Reviewed Appendix Section (for Methods and Results)

Product Information/Prescribing Information A

Previous DMEPA Reviews B N/A)

Human Factors Study C (N/A)

ISMP Newsletters D (N/A)

FDA Adverse Event Reporting System (FAERS)* E (N/A)

Other F (N/A)

Labels and Labeling G

N/A=not applicable for this review*We do not typically search FAERS for our label and labeling reviews unless we are aware of medication errors through our routine postmarket safety surveillance

3 OVERALL ASSESSMENT OF THE MATERIALS REVIEWED

We reviewed the proposed container labels and prescribing information and identified the following:

1. The NDC number on the container label is denoted by a placeholder. This important product identifier should be provided for Agency review.

2. The font color and size used for the established name differs from that used for the dosage form statement. The use of different font colors and sizes causes the statements to compete in prominence which decreases the readability of these statements.

3. As written, the language contained in the Medication Guide (MG) statement is directed towards the patient. However, the statement should instruct the pharmacist to provide a MG to the patient and state how the MG is supplied.


3

4. The “Rx Only” statement, net quantity statement, and storage statements are in bold font and are too prominent. Their prominence may draw attention away from important product identifying information on the label.

5. The expiration date format is not provided. The format of this important information should be provided for Agency review to determine whether it is potentially confusing and therefore error-prone.

6. The usual dosage statement can be improved to clearly convey the time of day the dose is intended to be administered. Adding the time of day of administration to the labels may help to prevent “wrong time” medication errors.

Our review of the PI did not identify any areas that are error-prone and could lead to medication errors

In Section 4.1, we provide recommendations regarding the areas of needed improvement to help minimize the potential for medication errors to occur with the use of this product.

4 CONCLUSION & RECOMMENDATIONS

We identified areas on the proposed container labels where important information should be revised to help ensure the safe use of the product. We provide recommendations in Section 4.1 to address our concerns. We advise these recommendations are implemented prior to the approval of this application.

4.1 RECOMMENDATIONS FOR IRONSHORE PHARMACEUTICALS & DEVELOPMENT

We recommend the following be implemented prior to approval of this NDA:

Container Labels

1. The NDC number is denoted by a placeholder. Please specify the actual NDC number so that we may review this important product identifying information.

2. The font color and size used for the established name differs from that used for the dosage form statement. The use of different font colors and sizes causes the statements to compete in prominence and pose risk of product selection error. Therefore, we recommend use of the same font size and color for the established name and dosage form. Additionally, revise the font size of the established name to be at least ½ the size of the proprietary name to be in accordance with 21 CFR 201.10(g)(2).

3. As written, the language contained in the Medication Guide (MG) statement is directed towards the patient. However, it should be directed towards the pharmacist such that the language clearly instructs the pharmacist to provide a MG to the patient and conveys how the MG is supplied. Depending upon how the MG is provided, please revise the statement to read (or use similar wording):


4

a. “Attention Pharmacist: Dispense the enclosed Medication Guide to each patient.” or

b. “Attention Pharmacist: Dispense the accompanying Medication Guide to each patient.”

4. The “Rx Only” statement, net quantity statement, and storage statement are in bold font and are too prominent. Their prominence may draw attention away from important product identifying information on the label. Decrease the prominence of these statements by unbolding the fonts.

5. The expiration date format is not provided. Please indicate the format that you intend to use (for example, MMMYYYY or MMMDDYYYY). Clearly presented formatting may help to decrease the risk of dispensing or using deteriorated drug product.

6. The Usual Dosage statement may be improved to clearly convey the time of day the dose is intended to be administered. As currently presented, the Usual Dosage statement reads “ .” Your proposed product differs from currently marketed extended-release methylphenidate products in that it is administered once daily in the evening. Therefore, please consider revising the Usual Dosage statement on the side panel to read “Once daily in the evening. See package insert for dosage information.” (or use similar wording).

To further highlight this difference in dosage administration time, place the statement “ ” within a textbox on the principal display panel (PDP). In order to make room for this statement to be placed on the PDP, relocate the equivalency statement from the PDP to the side panel.


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5

APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED

APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION

Table 2 presents relevant product information for methylphenidate extended-release capsules that Ironshore Pharmaceuticals & Development submitted on September 30, 2016.

Table 2. Relevant Product Information for methylphenidate extended-release capsules

Initial Approval Date N/A

Active Ingredient methylphenidate hydrochloride

Indication Treatment of Attention Deficit Hyperactivity Disorder (ADHD)

Route of Administration Oral

Dosage Form Extended release capsules

Strengths 20 mg, 40 mg, 60 mg, 80 mg, and 100 mg

Dose and Frequency The recommended starting dose for patients 6 years and older is 20 mg once daily in the evening. The dose may be titrated weekly in increments of 20 mg. Daily doses above 100 mg have not been studied.

How Supplied 100-count bottles

Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F)

Container Closure


(b) (4)

(b) (4)

6

APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling Reviewed

Using the principles of human factors and Failure Mode and Effects Analysis,a along with postmarket medication error data, we reviewed the following methylphenidate extended-release capsules labels and labeling submitted by Ironshore Pharmaceuticals & Development submitted on September 30, 2016.

Container labels Prescribing Information (no image)

G.2 Labels Images (not to scale)

a Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI: 2004.



(b) (4)





Documents

209311Orig1s000 · 2019-01-18 · Applicant: Ironshore Pharmaceuticals & Development Inc. Reference ID: 4301455. 1 INTRODUCTION On June 08, 2018, Ironshore Pharmaceuticals & Development