Regulatory Decision Summary for Olumiant
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.
Type of submission:
What was the purpose of this submission?
This New Drug Submission (NDS) was filed to obtain market authorization for the new active substance Olumiant (baricitinib) for the treatment of moderate to severe rheumatoid arthritis (RA) in patients who are naïve to, have responded inadequately to, or who are intolerant to disease-modifying anti-rheumatic drugs (DMARDs), including conventional and biologic DMARDs. Upon review, Olumiant was approved in combination with methotrexate (MTX) for reducing the signs and symptoms of moderate to severe RA in adult patients who have responded inadequately to one or more DMARDs. Olumiant may be used as monotherapy in cases of intolerance to MTX.
Why was the decision issued?
A NDS was filed to support approval of the 4 mg (proposed as the recommended dose) and the 2 mg (proposed as a dose reduction for certain patients) once daily (QD) doses of Olumiant (baricitinib) for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA).
The efficacy and safety of Olumiant were originally assessed in four Phase 3 trials in patients with active RA. These studies showed a statistically significant increase in the proportion of patients exhibiting a positive ACR20 response (>20 percent improvement in selected signs and symptoms of RA) for the Olumiant 2 mg QD dose when compared to placebo, as well as a statistically significant improvement across several other efficacy measures. While the efficacy of both the 2 mg and 4 mg QD doses were established in the baricitinib program, the data did not support an added benefit of the 4 mg QD dose.
There were also dose-related safety concerns, including a dose-related imbalance in adverse events and several laboratory parameters. Additionally, there was an imbalance of cases of thromboembolism which appeared to be unique to baricitinib as this risk had not been previously identified for the other drugs approved in Canada in this class. The imbalance in safety data showed an inferior benefit/harm profile for the baricitinib 4 mg QD dose compared to the baricitinib 2 mg QD dose. Furthermore, there were insufficient data provided to support clinical efficacy, safety and exposure for the baricitinib 2 mg QD dose as a reduced dose in patients with moderate renal impairment, or as an alternative dose in some patients, as originally proposed in the Product Monograph (PM).
A Notice of Non-Compliance (NON) was issued due to the uncertainty regarding the relative efficacy of the 2 mg QD dose compared to the 4 mg QD dose of Olumiant, and to the dose-related safety issues, including thromboembolic events which were more pronounced with the 4 mg QD dose. The response to the NON provided a safety update, including longer patient exposure data, as well as data from two new smaller studies. The data submitted in the response to the NON did not provide sufficient evidence to dismiss the increased safety concerns associated with the higher 4 mg QD dose relative to the lower 2 mg QD dose.
While efficacy was supported for both the 2 mg and 4 mg QD doses for patients who had an inadequate response to one or more DMARDs, there was insufficient evidence provided in the response to the NON to support a gain in efficacy with the 4 mg QD dose, compared to the 2 mg QD dose. Therefore, the benefit-harm-uncertainty assessment was considered to be favourable for the 2 mg QD dose but not for the 4 mg QD dose. The indication recommended for approval reflects the pivotal data supporting the 2 mg QD dose. Olumiant is not recommended for use in patient populations requiring dose reduction due to increased exposure.
Approving 2 mg QD as the recommended dose of Olumiant, and limiting the indication to second line use provides a safe and effective treatment option for patients with moderate to severe RA. Safety risks with the 2 mg QD dose are considered manageable through risk mitigation strategies which sufficiently convey the risks and provide information and guidance for prescribers and patients. The PM was revised to include new restrictions and provide information about safety concerns, including the risk of thrombosis.
Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations.