Regulatory Decision Summary for Quillivant ER chewable tablets and Quillivant ER oral suspension

This New Drug Submission (NDS) was filed to obtain market authorization for Quillivant XR Oral suspension / Quillichew ER Chewable tablet (renamed Quillivant ER Oral suspension and Quillivant ER Chewable tablet) for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children (aged 6-12), adolescents (aged 13-18) and adults (greater than 18 years of age). Upon review, an indication for both Quillivant ER products for children aged 6 to 12 years old only was granted.

Methylphenidate is a well-known drug product used in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). This New Drug Submission is to seek approval of a new extended-release formulation of methylphenidate, Quillivant ER, available as a chewable tablet and an oral suspension.

A single pivotal clinical trial (laboratory classroom study) was submitted for each formulation that was administered to children aged 6 to 12 years old (NWP06-ADD-100 and B7491005, respectively for the oral suspension and the chewable tablet), with a single evaluation of efficacy conducted at the definitive dose level (after open-label titration). Both trials used slight variations of the SKAMP combined scale (Swanson, Kotkin, Agler, M-Flynn and Pelham) as their primary endpoint (one with an average of all assessed timepoints [Study B7491005; chewable tablet], the other with a comparison at the 4-hour timepoint only [Study NWP06-ADD-100; oral suspension]).

Based on the results from the studies with children, the sponsor proposed to extend efficacy to adolescents and adults using pharmacokinetics (Studies S09-0238 and B7491004) compared to Methylin (reference United States-approved immediate release formulation, not approved in Canada), and literature-based evidence from other approved methylphenidate formulations. A Notice of Deficiency (NOD) was issued on September 22, 2021, since it was not possible at that point in time to establish a benefit-harm-uncertainty profile for methylphenidate hydrochloride for extended release (Quillivant ER) in the treatment of ADHD (for children, adolescents and adults). The deficiencies were focused around the following three key aspects: Good Manufacturing Practice (GMP) issues identified by a foreign regulator, which affected data integrity; Based on the results from two studies conducted in healthy subjects (Studies S09-0238 and B7491004), the comparative pharmacokinetic evidence between Quillivant ER products and Methylin was not considered sufficient to support the efficacy, and; Limited evidence was provided to support the pharmacokinetic comparison and dose proportionality of the Quillivant ER products between children, adolescents and adults with ADHD.

The sponsor responded to the NOD (R-NOD) on December 21, 2021, highlighting that comparative bioavailability and dose proportionality, along with the application of exposure-response models for safety and efficacy, were adequate to sufficiently establish efficacy for both Quillivant ER products in children, adolescents and adults with ADHD. Upon review and internal consultation with the Division of Biopharmaceutic Evaluation, it was decided that due to significantly different pharmacokinetic profiles between the proposed extended-release products administered once a day and immediate-release products administered twice a day, the results from Studies 09-0238 and B7491004 could not be used to support the efficacy of Quillivant ER Oral Suspension and Quillivant ER Chewable Tablets. By extension, literature reviews in support of efficacy for the Quillivant ER products through indirect pharmacokinetic bridging to the United States-approved Methylin and subsequently to the Canadian-approved Ritalin was not considered acceptable, given the aforementioned issues surrounding differing pharmacokinetic profiles. Therefore, efficacy for the Quillivant ER products relied on the single pivotal trial provided for each of the formulations (NWP06-ADD-100 and B7491005, respectively for the oral suspension and the chewable tablet, conducted with children aged 6 to 12). The sponsor had provided adequate responses to concerns regarding age subgroup analyses and trial design.

The safety profile across the clinical development programs for both Quillivant ER products was consistent with the well-established safety profiles of approved Canadian methylphenidate products. Based on the efficacy evidence limited to only children, a restricted indication for both Quillivant ER products to children aged 6 to 12 years old was granted, and the Product Monograph was updated accordingly and approved.

The chemistry and manufacturing reviews initially concluded that the nitrosamine impurity risk assessments were not satisfactory as a risk was identified for the formation of N-nitroso-methylphenidate and confirmatory testing was required. As a result, a Notice of Non-compliance was issued on December 16, 2022. Additional requested information provided in the Response to the Notice of Non-compliance filed on March 9, 2023, lead to the conclusion that the risk of nitrosamine formation for both of the drug products was low.

Overall, the benefit-harm-uncertainty profile is favourable for Quillivant ER chewable tablets and Quillivant ER oral suspension for the recommended indication. A Notice of Compliance (NOC) was issued.

For further details about Quillivant ER chewable tablets or Quillivant ER oral suspension, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.