Summary of Cancellation for Atropine Sulfate (Optipine Preservative Free)

This purpose of this New Drug Submission (NDS) was to obtain market authorization for Optipine Preservative Free (atropine sulfate monohydrate) 0.01% ophthalmic drops to slow the progression of myopia in children and adolescents.

The Sponsor submitted a pivotal meta-analysis of 17 studies selected through a systematic review using the PRISMA method for preferred reporting items. Additionally, the Sponsor provided 10 supporting meta-analyses published between 2014 and 2022, which followed the Cochrane Systematic Review model using the PRISMA method. Furthermore, 10 randomized controlled studies—excluded from both the pivotal and supporting meta-analyses—were submitted, along with 29 review articles detailing clinical experiences in treating pediatric myopia to reduce its progression.

At the time of cancellation, Health Canada had issued a Notice of Deficiency (NOD) to the Sponsor on December 21, 2023. An extension for the response to the NOD until June 18, 2024 was granted by Health Canada upon a request from the Sponsor. This was an interim decision, and the sponsor had an opportunity to provide additional evidence to support their proposed indication for Optipine Preservative Free (atropine sulfate). However, on May 31, 2024, the sponsor opted to withdraw the submission from review. Voluntary withdrawal of a submission does not disqualify a sponsor from refiling the application at a later date based on new evidence.

This submission was relying on the Guidance Document: Drug Submissions Relying on Third-Party Data, with respect to safety and efficacy evidence. During the review, major deficiencies were identified, details of which are provided below.

The Sponsor did not provide evidence that the product used in the pivotal literature studies to support the safety and efficacy of their product is representative of the proposed commercial product to satisfy Criteria 2.3 of the Guidance Document which states that “In accordance with requirement C.08.002(2)(m) of the Regulations, evidence, based on comparative pharmaceutical and/or comparative bioavailability data, to establish that the product used in studies reported in the literature (i.e. reference product) is representative of the proposed commercial product.” A reference product was not identified and it is unknown if the products used in the literature are the same as the proposed commercial product under review.

No evidence of extensive current foreign market experience could be found in the submission for the medicinal ingredient under the same conditions of use (i.e., strength, dose, use for proposed indication, pediatric population, etc.), including foreign post-market reports to satisfy Criteria 2.4 of the Guidance Document which states that “Evidence of extensive current foreign market experience with the same medicinal ingredient (for a minimum of 10 years under the same conditions of use), or evidence that the same medicinal ingredient is currently or has previously been marketed in Canada (under the same conditions of use).”

The meta-analysis identified by the Sponsor as pivotal to support safety and efficacy of the product did not qualify as an acceptable source of information for regulatory assessment and decision-making. In particular, in the Chen and Yao (2021) meta-analysis, the studies used (i) a patient population that varied between 4 and 12 years of age, (ii) products with different strengths and doses of atropine (1%, 0.5%, 0.25%, 0.1%, 0.025%, and 0.01%), (iii) different treatment durations (ranging from 6 to 60 months), (iv) different comparator arms (i.e., placebo, tropicamide, various lenses), and (iv) different measured outcomes, such that the primary efficacy endpoint used to demonstrate the product’s efficacy could not be determined. Also, patients used in the studies had different baseline characteristics that are linked to treatment success, notably the baseline refraction differed across the populations studied. This does not satisfy Criteria 2.5 of the Guidance document which states that “For the published literature-based evidence, sponsors are expected to provide a systematic review using the methodology outlined in the Cochrane Handbook for Systematic Reviews of Interventions and presented in the form as outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.”

Overall, major objections included (1) a lack of data to establish that the reference product was representative of the proposed commercial product; (2) a lack of evidence demonstrating extensive foreign or domestic market experience under the same conditions of use; and (3) concerns regarding the adequacy of the systematic review and meta-analysis to support the proposed indication. The benefit-risk-uncertainty profile for Optipine Preservative Free for the proposed indication cannot be determined at this time.

There is no expected impact for patients using SAP or in clinical trials.