CENTER FOR DRUG EVALUATION AND
RESEARCH

APPLICATION NUMBER:

208147 

SUMMARY REVIEW

 

MEMORANDUM

DEPARTMENT OF HEALTH AND HUMAN SERVICES

PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION

CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Date (electronic stamp)

From Mitchell V. Mathis, MD

Subject Division Director Summary Review

208147

Applicant Name Tris Pharma, Inc.

Date of Submission 12/19/2014

PDUFA Goal Date 10/19/2015

Proprietary Name Dyanavel XR/Arnphetamine ER Oral Suspension
Established (U SAN) Name

Dosage Forms Strength 2.5 mg/mL

Proposed Indication(s) Attention De?cit Hyperactivity Disorder (ADHD)
Action/Recommended Action for Approval

NME:

 

 

Material Reviewed/Consulted
OND Action Package, including:

Names of discipline reviewers

 

Medical Of?cer Review

Tiffany Farchione, MD

 

Statistical Review

Semhar? Ogbagaber, 
Eiji Ishida, MS

Peiling Yang, 

H.M. James Hung, 

 

Pharmacology Toxicology Review
Supervisory

Ikram Elayan, 
Linda Fossom, 

 

CMC Review/OBP Review

David laffey, 
Fang Wu, 
John Duan, 

 

Clinical Pharmacology Review,
Genomics Review, and

Ko? Kruni, 
Li Zhang, 

 

 

 

 

 

Pharmacometrics Kevin Krudys, 
Hao Zhu, 
OPDP Susannah O?Donnell, MPH, RAC
Jen Sellers, MD
of New Drugs

of Scienti?c Investigation

of Prescription Drug Promotion

DSI=Division of Scienti?c Investigations
Division of Drug Risk Evaluation

CMC=ChemislIy, Manufacturing, and Controls

Background and Summary

 

 

With this application, the applicant is seeking approval to market Amphetamine ER oral suspension
(TR1102) for the treatment of attention de?cit hyperactivity disorder (ADHD) in patients ages six to

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Reference ID: 3834803

twelve years old. The applicant submitted a phase 3 dose-optimized, randomized, double-blind,
placebo-controlled study in the laboratory classroom setting. This study was conducted in five US
sites. This 505(b)(2) application references Adderall immediate release as the reference listed drug
(RLD). This was a positive study and no safety issues identified for this formulation that were
different from the RLD.
This product is an ion-exchange resin (polystyrene sulfonate) complexed with amphetamine to
provide an extended-release profile for once daily treatment of symptoms of ADHD. This product
was formulated for patients who have difficulty swallowing pills or capsules.
Clinical Summary and Statistics
Efficacy
Drs. Farchione and Ogbagaber and Eiji Ishida reviewed the clinical and statistical data to support
this application. The single efficacy study, TRI102 used the SKAMP Combined Score to evaluate
efficacy. The pre-specified efficacy endpoints were based on change from pre-dose baseline
SKAMP score to evaluation time (four hours after dose was primary) and multiple evaluation times
were tested (1, 2, 4, 6, 8, 10, 12, and 13 hours after dose). Two secondary endpoints of interest
were measured: time of onset of clinical effect and duration of clinical effect. Using a pre-specified
multiple testing procedure that controlled study-wise Type I error, the statistical team concluded
that the study met its primary and secondary objectives. Dr. Farchione reviewed the data and
agreed with the statistical reviewers, and I agree that the study is well-designed and a positive study.
Study Design
TRI102-ADD-001 was a dose-optimized, randomized, double-blind, placebo-controlled study in
pediatric patients with ADHD. The schematic of the study is below.

Source: Dr. Farchione’s Review
Results
The primary efficacy endpoint was change from Time 0 in model-adjusted SKAMP Combined scores at four
hours post-dose measured during the laboratory school day (Visit 8). Onset of clinical effect and duration of
clinical effect were secondary measures determined by change from time 0 in SKAMP Combined scores at 1,
2, 6, 8, 10, 12, and 13 hours post-dose during Visit 8. A total of 108 patients enrolled, 100 were randomized
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Reference ID: 3834803

 and 99 patients completed the study. The primary efficacy analysis at 4 hours was clearly positive (p less
than 0.0001); secondary endpoints were similarly positive (see the clinical and statistical reviews for details).
Safety was evaluated in the usual fashion and no new meaningful safety signals were identified for this
formulation of this well-known active drug.

Office of Clinical Pharmacology (OCP)
Dr. Kumi was the primary reviewer for this application. His findings are summarized below.





An adequate link has been established between the amphetamine ER oral suspension and
amphetamine IR tablet.
The similarity of PK profiles in adults, adolescents, and children in combination with what
is known about the PK of amphetamine IR tablet and common clinical practice support the
approval and dosing recommendations made in labeling.
The pharmacokinetic profiles of amphetamine ER oral suspension in patients of different
age ranges are sufficient to support once daily dosing.
Food does not affect exposure.

OCP has recommended approval.
Chemistry Manufacturing and Controls (CMC)
The CMC team recommended approval from a product quality perspective and recommended a
post-marketing commitment to develop more discriminatory single-medium dissolution methods for
(b) (4)
both the drug product and for the extended-release
. They confirmed that oncedaily dosing was supported by data from the RLD. Dose-dumping was identified at 40 percent
alcohol and the labeling reflects this fact.
Office of Scientific Investigation—Facilities Inspections
OSI inspected two sites and no significant regulatory violations were noted and the data were
judged to be acceptable and the study was found to have been conducted adequately.
Office of Prescription Drug Promotion (OPDP)
OPDP reviewed the medication guide, the prescribing information, and the carton/container labeling
and had several recommendations which were included in the final negotiated labels/container
labeling.
Nonclinical Pharmacology/Toxicology
Drs. Elayan and Fossom conducted the nonclinical review. No new non-clinical data submitted with
the application and no outstanding chemistry issues regarding impurities or new excipients were
(b) (4)
identified. The inactive polystyrene sulfonate is present in the formulation at
which is
considered safe. They concluded that the application was approvable.
Labeling
The team constructed labeling based upon the data from this application using other drugs in the
class as models. Comments/suggestions/edits from the team were considered and sent to the
applicant multiple times for concurrence. The Office of Prescription Drug Promotion also reviewed
the label and the changes that they suggested were incorporated. The applicant has accepted the
labeling changes and a final version will be attached to the letter.
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Reference ID: 3834803

 Advisory Committee
Not applicable.
Postmarketing Requirements/Commitments
In addition to the post-marketing commitment recommended by the Quality team, there will be
post-marketing requirements to conduct PK and efficacy and safety studies in pediatric patients ages
4 to 5 years old.
Conclusions
Sufficient information has been submitted to conclude that amphetamine ER suspension is safe and
effective for the treatment of pediatric patients with ADHD. I recommend that this application be
approved.
The labeling has been negotiated to current Division standards.
Post-marketing requirements and commitments have been identified and agreed upon.
The applicant has agreed to the negotiated label.
This application will be approved by the PDUFA date.

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Reference ID: 3834803

 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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---------------------------------------------------MITCHELL V Mathis
10/19/2015

Reference ID: 3834803