CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`022063Orig1s000
`
`CLINICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 022063
`Priority or Standard Standard
`
`Submit Date(s) 12/20/16
`Received Date(s) 12/20/16
`PDUFA Goal Date 6/20/17
`Division / Office Division of Psychiatry
`Products/ODE 1
`
`Reviewer Name(s) Nancy Dickinson, PharmD.
`Review Completion Date 5/19/17
`
`Established Name Mixed salts of a single-entity
`amphetamine
`(Proposed) Trade Name Mydayis
`Therapeutic Class stimulant
`Applicant Shire
`
`Formulation(s) Extended release capsule
`Dosing Regimen Once daily in morning
`Indication(s) Attention deficit hyperactivity
`disorder (ADHD)
`Intended Population(s) Adults, pediatrics
`
`
` years
`
`Template Version: March 6, 2009
`
`Reference ID: 4113852
`
`(b) (4)
`
`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`2
`
`Table of Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment. ................................................................................... 6
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 7
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 8
`2.1 Product Information ............................................................................................ 8
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 8
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 9
`2.4
`Important Safety Issues With Consideration to Related Drugs ........................... 9
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 9
`2.6 Other Relevant Background Information .......................................................... 13
`3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 18
`3.1 Submission Quality and Integrity ...................................................................... 18
`3.2 Compliance with Good Clinical Practices ......................................................... 18
`3.3 Financial Disclosures ........................................................................................ 19
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 19
`4.1 Chemistry Manufacturing and Controls ............................................................ 19
`4.2 Clinical Microbiology ......................................................................................... 20
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 20
`4.4 Clinical Pharmacology ...................................................................................... 20
`4.4.1 Mechanism of Action .................................................................................. 20
`4.4.2 Pharmacodynamics.................................................................................... 20
`4.4.3 Pharmacokinetics ....................................................................................... 21
`5 SOURCES OF CLINICAL DATA............................................................................ 21
`5.1 Tables of Studies/Clinical Trials ....................................................................... 21
`5.2 Review Strategy ............................................................................................... 23
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 23
`6 REVIEW OF EFFICACY ......................................................................................... 23
`6.1
`Indication .......................................................................................................... 24
`6.1.1 Methods ..................................................................................................... 24
`6.1.2 Demographics ............................................................................................ 27
`6.1.3 Subject Disposition .................................................................................... 31
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 32
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 33
`6.1.6 Other Endpoints ......................................................................................... 34
`
`Reference ID: 4113852
`
`2
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`6.1.7 Subpopulations .......................................................................................... 34
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 34
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ................. 34
`6.1.10 Additional Efficacy Issues/Analyses ........................................................... 34
`7 REVIEW OF SAFETY ............................................................................................. 35
`Safety Summary ........................................................................................................ 35
`7.1 Methods ............................................................................................................ 35
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 35
`7.1.2 Categorization of Adverse Events .............................................................. 35
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence .................................................................................................... 36
`7.2 Adequacy of Safety Assessments .................................................................... 36
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations ..................................................................................... 36
`7.2.2 Explorations for Dose Response ................................................................ 37
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 37
`7.2.4 Routine Clinical Testing ............................................................................. 37
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 37
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 37
`7.3 Major Safety Results ........................................................................................ 37
`7.3.1 Deaths ........................................................................................................ 37
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 37
`7.3.3 Dropouts and/or Discontinuations .............................................................. 38
`7.3.4 Significant Adverse Events ........................................................................ 39
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 43
`7.4 Supportive Safety Results ................................................................................ 43
`7.4.1 Common Adverse Events .......................................................................... 43
`7.4.2 Laboratory Findings ................................................................................... 44
`7.4.3 Vital Signs .................................................................................................. 44
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 44
`7.4.5 Special Safety Studies/Clinical Trials ......................................................... 44
`7.4.6
`Immunogenicity .......................................................................................... 44
`7.5 Other Safety Explorations ................................................................................. 45
`7.5.1 Dose Dependency for Adverse Events ...................................................... 45
`7.5.2 Time Dependency for Adverse Events ....................................................... 45
`7.5.3 Drug-Demographic Interactions ................................................................. 45
`7.5.4 Drug-Disease Interactions .......................................................................... 45
`7.5.5 Drug-Drug Interactions ............................................................................... 45
`7.6 Additional Safety Evaluations ........................................................................... 45
`7.6.1 Human Carcinogenicity .............................................................................. 45
`7.6.2 Human Reproduction and Pregnancy Data ................................................ 45
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 46
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 46
`
`Reference ID: 4113852
`
`3
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`7.7 Additional Submissions / Safety Issues ............................................................ 46
`8 POSTMARKET EXPERIENCE ............................................................................... 47
`9 APPENDICES ........................................................................................................... 47
`9.1 Literature Review/References .......................................................................... 47
`9.2 Labeling Recommendations ............................................................................. 47
`9.3 Advisory Committee Meeting ............................................................................ 47
`9.4 Clinical Investigator Financial Disclosure ......................................................... 48
`9.5 Safety Assessment Table Study SHP465-306 and 305 ................................... 50
`
`
`
`Reference ID: 4113852
`
`4
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`Table of Tables
`Table 1: Drugs approved for attention deficit hyperactivity disorder ................................ 8
`Table 2: Studies Reviewed in Original NDA July 2006 .................................................. 13
`Table 3: Inspection of Four Clinical Sites ...................................................................... 18
`Table 4: Trial Summary for Studies in NDA 22063 Resubmission ................................ 22
`Table 5: Subject demographics in adults (SHP465-306) #1 ......................................... 28
`Table 6: Subject demographics in adults (SHP465-306) #2 ......................................... 29
`Table 7: Subject demographics in pediatric patients by age group (SHP465-305) #1 . 29
`Table 8: Subject demographics in pediatric patients by age group (SHP465-305) #2 . 30
`Table 9: Subject Disposition SHP465-306 ................................................................... 31
`Table 10: Summary of Primary Endpoint Statistics ...................................................... 32
`Table 11: Summary of Primary Endpoint Statistics ...................................................... 33
`Table 13: Adverse Event Occurrence >2% in Adults, Study SHP465-306 ................... 40
`Table 12: Pooled Adult Safety Data, >2% Adverse Events .......................................... 41
`Table 14: Adverse Events in 6 to 12 year olds- Study SHP465-305 ............................. 42
`Table 15: Adverse Events in 13 to 17 year olds- Study SHP465-305 ........................... 43
`Table 16: Pulse Rate Increase, Study SHP465-306 ..................................................... 44
`Table 17: Safety Assessments Study SHP465-306 and 305 ....................................... 50
`
`
`
`Table of Figures
`Figure 1: Mean plasma concentrations of 37.5mg in adults of d- and l- amphetamine
`16-hour capsule compared to 8-hour capsule + 4-hour tablet........................ 21
`Figure 2: Study Design Flow Chart (SHP465-306 and 305) ......................................... 26
`Figure 3: Age Distribution ............................................................................................. 28
`Figure 4: Pediatric Discontinuations by Age Group ...................................................... 38
`
`
`Reference ID: 4113852
`
`5
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`The efficacy and safety of SHP465 (mixed salts of a single-entity
`amphetamine extended release capsule) are adequate to recommend
`approval for the treatment of attention deficit hyperactivity disorder (ADHD).
`SHP465 was studied in pediatric patients 6 to 17 years and adults. I
`recommend limiting the approved indication to pediatric patients 13 years and
`above because patients 12 years and younger experienced higher plasma
`exposure than patients 13 years and older at the same dose and experienced
`higher rates of adverse reactions, mainly insomnia and decreased appetite.
`
`
`
`1.2 Risk Benefit Assessment.
`
`ADHD is primarily a childhood disorder that may extend into adulthood. The prevalence
`of ADHD in pediatrics is about 9%, staying relatively stable over the past three decades
`using adequate diagnoses (Polanczyk, 2014). The prevalence in adults is 2.5% (Simon,
`2009).
`
`Fortunately, there are many highly effective pharmacological options to treat ADHD,
`most of these are stimulants. Stimulant preparations can be quick-acting (within 30
`minutes) and short lasting (four to six hours) or longer lasting (eight to 12 hours). The
`Agency’s drug use data demonstrates that adults and children are currently using 8- or
`12-hour extended-release stimulants followed by a 4-hour immediate-release dosage
`form. Because patients are already using stimulants for 16 hours a day, it appears that
`taking one capsule in the morning may be beneficial for some patients with ADHD; the
`proposed product was designed to provide 16-hour symptom relief.
`
`Benefit: SHP465 has the same active moiety as the highly efficacious Adderall XR
`(mixed salts of a single-entity amphetamine extended release capsule); there is no
`surprise that SHP465 demonstrates robust efficacy in adults and pediatrics.
`
`Risk: SHP465 has the expected adverse events of a stimulant. See Section 7. During
`the drug’s development, Shire lowered the proposed dose strengths, leading to
`increased tolerability in adult and adolescent (13 to 17 years) patients.
`
`In general, the risk-benefit ratio is considered favorable in patients over 13 years old.
`For children under 13 years (i.e., 6 to 12 years), there is a small portion of children with
`severe ADHD (e.g., sequelae of fetal alcohol syndrome) for whom a 16-hour stimulant
`may be necessary, especially if those patients are already taking an extended-release
`
`Reference ID: 4113852
`
`6
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`stimulant followed by an immediate-release one. The risk-benefit ratio of once daily
`SHP465 is considered favorable in the younger children with severe attention deficit
`hyperactivity disorder who are already taking stimulants multiple times a day.
`
`However, for most children less than 12 years old with ADHD, the risk-benefit ratio of
`SHP465 is less certain. As noted in this review, there was a concerning incidence of
`insomnia and decreased appetite reported in the 6 to 12 year old age group during
`clinical development. Given that there are only 24 hours in a day, there are only eight
`hours for sleep left in the day if patients take a 16-hour stimulant; this is clearly
`insufficient for children in this age group to rest, grow, and not be irritable. The
`American Academy of Pediatrics and the American Academy of Sleep Medicine
`currently recommend for children in this age group to sleep nine to 12 hours per 24
`hours on a regular basis to promote optimal health. Additionally, SHP465 causes
`decreased appetite that may contribute to long-term growth suppression and weight
`loss from a chronically taken stimulant.
`
`
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`No REMS is recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`A postmarketing requirement (PMR) addressing the Pediatric Research Equity Act
`(PREA) requirement to ensure a pediatric-appropriate formulation is recommended to
`ensure a lower dose (6.25mg) of SHP465 is available for pediatric patients within two
`years post approval.
`
`Shire submitted a Pediatric Study Plan in their NDA resubmission, December 20, 2016,
`to study SHP465 in 4 to 5 year old preschool attention deficit hyperactivity disorder
`patients and to manufacture a lower dose formulation, 6.25mg. The lowest dose of
`SHP465 to be approved in this application is 12.5mg.
`
`Prior to the NDA resubmission, on November 3, 2016, Shire submitted a Proposed
`Pediatric Study Request (PPSR). On, February 27, 2017, the Agency issued an
`inadequate letter denoting the need for the pediatric study plan to address decreased
`appetite and insomnia in the preschool population, based on preliminary review of the
`clinical study report for 6 to 12 years in the NDA (SHP465-305). On March, 17, 2017,
`Shire submitted a revised PPSR including an updated pediatric study plan. That PPSR
`is currently under review. The Applicant may decide not to pursue the PPSR if the
`timing for when the approval of NDA 22063 and the pediatric exclusivity do not align.
`
`
`Reference ID: 4113852
`
`7
`
`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`Therefore, a PMR to formulate a 6.25mg dose and to evaluate its safety and efficacy in
`the 4 to 5 year old preschool population is important. Additionally, we will require a
`PMR to evaluate the 6.25mg dose of SHP465 for the 6 to 12 year old ADHD population.
`In Section 7.2.1, I will discuss my concerns about the plasma concentration levels of the
`pediatric patients compared to adults receiving SHP465 12.5mg.
`
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`SHP465 (proposed trade name: Mydayis) is an extended-release capsule of mixed salts
`of a single-entity amphetamine. It was previously known as SPD465. It is an oral
`product comprised of four amphetamine salts: dextro- and levoamphetamine sulfate,
`dextroamphetamine saccharate, and amphetamine aspartate monohydrate. The ratio
`of d- to l- isomers is three to one (3:1). The extended-release capsule contains three
`types of drug-releasing beads, which provide immediate-release, pulsatile delayed-
`release, and delayed, extended-release of the mixed amphetamine salts. The mixed
`salts of a single-entity amphetamine are the same active ingredient in Adderall XR.
`SHP465 is intended to last for sixteen hours.
`
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`All of the drug products listed below are approved for ADHD in children over 6 years
`old, adolescents, and adults.
`Table 1: Drugs approved for attention deficit hyperactivity disorder
`Stimulants
`Non-stimulant
`Drug name
`Drug name
`amphetamine
`atomoxetine
`mixed salts of a
`single-entity
`clonidine
`amphetamine
`dextroamphetamine guanfacine
`dexmethylphenidate
`lisdexamfetamine
`methylphenidate
`[Source: Reviewer created]
`
`
`
`
`
`Reference ID: 4113852
`
`8
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`

`

`Clinical Review
`
`Nancy Dickinson, PharmD.
`NDA 022063
`
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Currently, the active ingredients in SHP465, mixed salts of a single-entity amphetamine,
`are available under the trade name Adderall and Adderall XR. Both formulations are
`
`approved for the treatment of ADHD in children, adolescents, and adults.
`
`2.4 Important Safeg Issues With Consideration to Related Drugs
`
`The stimulants for the treatment of ADHD have class warnings that are applicable to
`SHP465. The boxed warning about abuse and dependence of stimulants warns about
`choosing patients who are less likely to abuse stimulants. The class warnings about
`serious cardiovascular reactions, including sudden death, are applicable, especially to
`adult patients. The warnings about heart rate increases are relevant to both pediatric
`patients and adults for SHP465. The class warning for seizure was not present in newly
`approved extended-release amphetamines; however, based on clinical trial data for
`SHP465, the seizure warning will be present in this label. Finally, the class warning
`about growth suppression is applicable to pediatric patients, as weight loss and
`decreased appetite was prominent in the Phase 3 SHP465 pediatric trial.
`
`
`
`2.5 Summa of Presubmission Re ulato Activi Related to Submission
`
`Regulatory History of IND 066329
`
`0 December 4, 2002: SPD465 was submitted as an lnvestigational New Drug
`(IND) 066329. No clinical holds were placed during the IND Phases of clinical
`development program.
`0 November 18, 2003: Shire met with the Agency on to discuss Phase 2 and
`Phase 3 development of SHP465 (formerly named SPD465). Three points were
`agreed to at that meeting.
`0 Shire may seek approval for four dosing strengths (12.5, 25, 37.5, and
`50mg)
`0)“)
`
`o Shire informed the Agency that one of the two planned duration of effect
`studies was to be conducted in adolescents in order to support an
`adolescent duration of effect claim.
`
`0 Further, the Agency informed Shire that a Pediatric Written Request for
`adolescents aged 13 to 17 would not be issued, following advice from the
`Office of Counter Terrorism and Pediatric Drug Development that SHP465
`would not provide a significant public health benefit over existing
`therapies.
`0 November 11, 2004: The Agency issued a letter in response to a Special
`Protocol Assessment on study SHP465-301. The proposed flexible-dose design
`was not adequate to establish dose response safety and efficacy so a fixed-dose
`study was recommended instead to establish cardiovascular safety in adults.
`
`Reference ID: 41 13852
`
`

`

`Clinical Review
`
`Nancy Dickinson, PharmD.
`NDA 022063
`
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`0 November 18, 2005: Shire met with the Agency regarding the clinical
`implications of changes to the formulation of SHP465
`
`M"
`
`Hence, Shire
`reported that an additional Phase 2 study, Study SHP465-203, would establish
`the duration of effect in adults with the intended market formulation at the 25mg
`strength. The Agency agreed that duration of effect at the 25mg dose would
`translate to higher dose strengths.
`
`0 March 8, 2006: At a pre-NDA meeting, the Agency stated we would allow for
`consideration of a m“) to 16-hour duration of effect labeling claim for the adult
`dose ranges of 12.5mg to 75mg if the claim was supported by the data submitted
`to the NDA.
`
`Regulatory History of the Original NDA (0220631
`
`0
`
`July 21, 2006: The original NDA 022063 was submitted to FDA and filed
`September 5, 2006.
`0 August 29, 2006, September 7, 18, 29, 2006, October 9, 2006, November 9, 14,
`17, 29, 2006, January 22, 31, 2007, March 7, 2007 and April 10 and 27, 2007:
`Dates of amendments submitted to NDA 022063.
`
`0 April 2007: Shire sought a PREA partial waiver from pediatric studies for children
`less than age 12 as “clinicians are not likely to prescribe SHP465 in children 12
`years of age and below due to the long duration of effect, potentially leaving
`younger children to stay awake past their bedtime.” (Source: FDA Clinical
`Review April 15, 2007)
`0 May 18, 2007: The Agency issued an Approvable letter for original NDA 022063.
`The following major issues were outstanding:
`a. Clinical Pharmacology dissolution studies must be completed according to
`certain specifications.
`b. The Division of Medication Error Prevention and Analysis (DMEPA) was
`concerned with Adderall XR and SHP465 having the same established
`name and asked Shire to plan an educational campaign to discern the 12-
`hour product from the 16-hour product.
`c. Update the Periodic Safety Report with cases of abuse, misuse, and
`diversion.
`
`d. Revised draft labeling did not include the proposed 37.5 mg and 50 mg
`strengths because the Agency stated there was no additional efficacy at
`these higher doses and there were additional adverse events associated
`with these higher doses. However if new information relating to the safety
`or effectiveness of SHP465 becomes available, revision of the labeling
`may be required.
`e. Postmarketing Commitment for studying exploration of dose response for
`effectiveness
`
`f. Postmarketing Commitment for studying exploration of cardiovascular risk
`
`Reference ID: 41 13852
`
`10
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`• May 24, 2007: Shire submitted a notice of intent to file an amendment to support
`approval but did not progress this activity further due to a business decision.
`
`
`
`Regulatory History of Class 2 Resubmission of NDA 022063
`• April 25, 2014: The Agency provided Written Responses Only (WRO) comments
`in which they classified Shire’s response to the SHP465 2007 Approvable Letter
`as a Class 2 resubmission of the original NDA 022063.
`Items addressed from the May 18, 2007, Approvable letter:
`a. Dissolution studies completed.
`b. Agreement on the educational plan for discerning between the three
`formulations of mixed salts of single-entity amphetamine (i.e., Adderall,
`Adderall XR, and the proposed product, Mydayis).
`c. Agreement on a voluntary risk management plan (not a REMS) to address
`abuse, misuse, and diversion.
`d. Agreement on Shire’s proposed study SHP465-306 to address safety and
`efficacy of 12.5, 25, 37.5, and 50mg doses in adults. The 75mg dose is not
`included due to increased adverse events without added efficacy.
`e. Agreement that the cardiovascular risk study was not necessary. After seven
`years since the 2007 Approvable letter, the Agency already has data on
`cardiovascular risk of amphetamines.
`• August 4, 2014: A teleconference was held to discuss SHP465 and the need for
`pediatric premarketing studies before making a Class 2 resubmission.
`• June 17, 2015: The Agency issued meeting minutes from the cancelled June 8,
`2015, Type C meeting. There was final agreement on the Phase 3 study in
`adults (Study SHP465-306) and discussion of pathways for NDA resubmission.
`• July 27, 2015: WRO comments issued to Shire regarding adequacy of the abuse
`potential evaluation.
`• February 13, 2016: WRO comments issued to Shire’s questions regarding the
`effects of alcohol on the bioavailability of the drug product, studies comparing the
`pharmacokinetics of several dosages of SHP465 and Adderall XR to clarify the
`recommended dose range and abuse potential, and additional product stability
`data for 48 months and less to address concerns about the dose range proposal
`planned for NDA resubmission.
`• July 14, 2016: A Type C meeting was held to obtain the Agency’s concurrence
`on the presentation and content of the NDA resubmission.
`• December 20, 2016: Shire resubmitted NDA 22063; a 6-month review clock
`started.
`• January 17, 2017: The Agency issued an acknowledgment letter of the Class 2
`NDA resubmission.
`
`•
`
`
`
`
`
`Reference ID: 4113852
`
`11
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`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`Proprietary Name
`. The NDA
`Shire’s original NDA submission contained a proposed trade name
`resubmission and formal Proprietary Name Request for Review dated January 17,
`2017, contains a different proposed trade name, Mydayis. The trade name Mydayis is
`acceptable to DMEPA.
`
`See Section 2.6 for a table of studies submitted and reviewed under the original NDA
`22063. The Applicant submitted seven Phase 1 studies in adults; three Phase 2
`studies, one in adolescents (SHP465-202) and two in adults; and three Phase 3 trials in
`adults.
`
`This review will concentrate on the two new Phase 3 trials in the December 20, 2016,
`resubmission.
`
`
`
`
`Reference ID: 4113852
`
`12
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`(b) (4)
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`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`2.6 Other Relevant Background Information
`Table 2: Studies Reviewed in Original NDA July 2006
`
`
`Type of
`Study
`
`Study
`ID
`
`Objective(s) of
`the Study
`
`Study Design and
`Type of Control
`
`Test Product(s); Dosage
`Regimen;
`Route of Administration
`
`No. of
`Subjects
`Enrolled
`
`Healthy
`Subjects or
`Diagnosis
`
`Duration of Tx
`
`BA/BE
`
`101
`
`BA/BE
`
`102
`
`Phase 1, randomized,
`open- label, 4-way
`crossover,
`4 periods
`
`Phase 1, randomized,
`open- label, 4-way
`crossover,
`5 periods
`
`Assess PK
`profiles and
`bioequivalence of
`3 SHP465
`delayed- release
`(DR) bead
`prototypes vs.
`ADDERALL
`
`Assess PK
`profiles of 3
`SHP465 DR
`composite
`formulations vs.
`ADDERALL XR
`Safety,
`tolerability, effect
`of food on
`bioavailability
`
`12
`
`20
`
`•SHP465 12.5 mg
`1×12.5 mg DR bead prototype
`1,1×12.5 mg DR bead prototype
`2,1×12.5 mg DR bead prototype
`3
`•1×10 mg (tablet) ADDERALL l
`Capsule, oral
`Pilot formulation
`
`•1×20 mg ADDERALL XR and
`2×5 mg Capsule C (fed)
`•1×15 mg Capsule A and
`3×5 mg Capsule C (fed)
`•1×15 mg Capsule B and
`3×5 mg Capsule C (fed)
`•1×20 mg ADDERALL XR followed
`by 1×10 mg ADDERALL 8 h later
`Capsule, oral
`Pilot formulation
`
`Healthy
`Adults
`(fasting)
`
`Healthy
`Adults
`18-55 years,
`inclusive
`
`4 single doses
`(Periods
`1-4;
`7-day washout
`between
`periods)
`
`5 single doses
`(Periods
`1-4 fed; Period
`5 fasted;
`7-day washout
`between
`periods)
`
`Reference ID: 4113852
`
`13
`
`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`Type of
`Study
`
`Study
`ID
`
`Objective(s) of
`the Study
`
`Study Design and
`Type of Control
`
`Test Product(s); Dosage
`Regimen;
`Route of Administration
`
`No. of
`Subjects
`Enrolled
`
`Healthy
`Subjects or
`Diagnosis
`
`Duration of Tx
`
`PK
`
`103
`
`Assess PK
`profile vs.
`ADDERALL XR
`Safety
`
`Phase 1,
`randomized, open-
`label, single-dose,
`2-treatment crossover
`2 periods
`
`•SHP465 37.5 mg
`1×37.5 mg (fasted)
`•1×25 mg ADDERALL XR (fasted)
`followed by 1×12.5 mg MAS IR
`8 h later
`Capsule, oral
`Intended to market formulation
`
`BA
`
`105
`
`Assess the effect
`of a high-fat meal
`on
`bioavailability
`relative to fasted
`state
`Safety and
`tolerability
`
`Phase 1,
`randomized, open-
`label,
`3-way crossover
`3 periods
`
`•SHP465 50 mg
`1×50 mg (fasted),
`1×50 mg (fed high fat
`meal),1×50 mg (fasted, sprinkled
`1 tbsp applesauce) Capsule, oral
`Intended to market formulation
`
`PK
`
`106
`
`Assess dose
`proportionality
`Safety and
`tolerability
`
`Phase 1, open-label,
`single-ascending
`doses, 4 periods
`
`•SHP465 12.5-75 mg
`1×12.5 mg,1×37.5 mg,1×50 mg,
`1×75 mg
`Capsule, oral
`Intended to market formulation
`
`20
`
`16
`
`28
`
`Healthy
`Adults
`18-
`55 years,
`inclusive
`
`2 single
`doses
`(Periods
`1,2;
`7-day washout
`between
`periods)
`
`Healthy
`Adults
`18-55 years,
`inclusive
`
`3 single doses
`(Periods
`1-3;
`7-day washout
`between
`periods)
`
`Healthy
`Adults
`18-55 years,
`inclusive
`
`Single dose (4
`planned
`periods,
`7-day washout
`between
`periods)
`
`Reference ID: 4113852
`
`14
`
`

`

`Clinical Review
`Nancy Dickinson, PharmD.
`NDA 022063
`Mydayis (mixed salts of a single-entity amphetamine extended release capsule)
`
`
`Type of
`Study
`
`Study
`ID
`
`Objective(s) of
`the Study
`
`