Regulatory Decision Summary for QTERN
Review decision
The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.
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What was the purpose of this submission?
This New Drug Submission (NDS) was filed to obtain marketing authorization for the immediate release fixed-dose combination (FDC) tablets of Qtern (dapagliflozin and saxagliptin) to achieve glycemic control in adults with type 2 diabetes mellitus who are inadequately controlled on metformin and either component alone or already treated with metformin, saxagliptin and dapagliflozin. This was restricted to use in combination with metformin in patients who are inadequately controlled on metformin and saxagliptin (not on metformin and dapagliflozin), or already controlled with metformin, saxagliptin and dapagliflozin.
Why was the decision issued?
The proposed Qtern FDC tablets were not used in Phase III clinical studies. The approval of Qtern is based in part on a pivotal comparative bioavailability study bridging the proposed product to its individual components, saxagliptin and dapagliflozin.
The Quality review determined that the biowaiver request for the Qtern 5 mg/ 5 mg (5 mg saxagliptin/5 mg dapagliflozin) was acceptable based on its proportionality to the 5 mg/10 mg (5 mg saxagliptin/10 mg dapagliflozin) strength used in the bioequivalence study.
Two pivotal, randomized, double blind, placebo-controlled, phase 3 trials (CV181168 and MB1021029) with an open label period followed by a 24 week double-blind phase and a 28 week subject-blind long term phase were filed in support of the proposed indications. Study CV181168 assessed the safety and efficacy of the addition of saxagliptin to a background of dapagliflozin and metformin, and study MB1021029 assessed the safety and efficacy of the addition of dapagliflozin to a background of saxagliptin and metformin.
Study MB1021029 showed a statistically significant and clinically meaningful benefit over placebo in reduction from baseline HbA1c, which was adequately sustained following 52 weeks of treatment. Common treatment-related adverse events (AE) were urinary tract infections and vulvovaginal mycotic infections, while adverse reactions resulting in discontinuation were urinary tract infections and decreased renal function. Overall, no important new or synergistic adverse reaction was observed.
However, the use of Qtern in combination with metformin in patients inadequately controlled on metformin and dapagliflozin was not supported by study CV181168. Although a statistically significant difference of saxagliptin added on to metformin and dapagliflozin relative to placebo was demonstrated, the treatment effect was small, secondary endpoints and long-term efficacy were not clearly supportive, and evidence from an important supportive study were not convincing of a meaningful benefit. The benefit did not outweigh the potential risk of adding saxagliptin, which includes rare but potentially serious events of hypersensitivity, pancreatitis, heart failure and severe arthralgia.
Risk mitigation was achieved with adequate labelling of all safety issues, restriction of the indication, and assessment of the Risk Management Plan by Marketed Health Products Directorate.
The benefit risk assessment of Qtern as indicated is positive.
Decision issued
Approved; issued Notice of Compliance in accordance with the Food and Drug Regulations