Regulatory Decision Summary for Symbicort 100 Turbuhaler, Symbicort 200 Turbuhaler, Symbicort Forte Turbuhaler

The efficacy and safety of Symbicort Turbuhaler 200/6 mcg as-needed anti-inflammatory reliever treatment for patients with mild persistent asthma who require treatment with inhaled corticosteroids (ICS) was evaluated in two similar 52-week, randomized, double-blind, parallel-group, active-controlled, multicentre studies (Symbicort Given as-needed in Mild Asthma, SYGMA 1 and SYGMA 2). SYGMA 1 had three treatment arms, Symbicort Turbuhaler as-needed to relieve asthma symptoms, terbutaline (short-acting beta2-agonist; SABA) as-needed and low-dose budesonide (200 mcg) twice daily (b.i.d.) plus SABA as-needed. SYGMA 2 had two treatment arms, Symbicort Turbuhaler as-needed to relieve asthma symptoms and low-dose budesonide (200 mcg) bid plus SABA as-needed.

Symbicort Turbuhaler as-needed provided greater symptom control (primary composite endpoint of well-controlled asthma weeks, WCAW) and a reduction in the annual severe exacerbation rate (secondary endpoint), compared to SABA-as needed in SYGMA 1. In both SYGMA studies, Symbicort Turbuhaler as-needed was comparable to budesonide b.i.d. for the annual rate of severe asthma exacerbations (primary endpoint in SYGMA 2). However, Symbicort Turbuhaler as-needed was inferior to budesonide b.i.d. for symptom control (WCAW) in SYGMA 1. Symbicort Turbuhaler had numerically lower improvements in lung function, and patient-reported outcomes compared to budesonide b.i.d., in both studies. However, these differences were not clinically relevant. The median total daily dose of ICS was 70 - 80% lower for the Symbicort as-needed treatment arm, compared to budesonide b.i.d. in both studies, however with a similar outcome for severe exacerbation rate.

The safety profile of Symbicort Turbuhaler (200/6 mcg) as-needed was similar in all treatment groups in the two studies, however more patients discontinued in the SABA as-needed group (SYGMA 1) which may be a result of undertreatment. The incidence of the most common adverse events of (viral) upper respiratory infection and asthma was similar between treatment groups. There are appropriate Warnings and Precautions already included in the Product Monograph (PM) for Symbicort Turbuhaler maintenance and reliever therapy. No new safety concerns were identified.

There was some uncertainty regarding whether the patient population were mild asthmatics or whether they had more severe asthma, based on the inclusion/exclusion criteria and baseline symptom control according to current treatment recommendations. Asthma severity can vary over time due to various reasons; therefore, patients may need step-up or step-down treatment under different conditions. However, the majority of patients in the clinical trials were considered to have mild persistent asthma.

The comparison of two different treatment regimens (Symbicort as-needed versus daily budesonide b.i.d.) for WCAW is interpreted with caution since as-needed use is a component of the composite endpoint. Overall, there is some uncertainty regarding asthma symptom control with Symbicort Turbuhaler as-needed which was not as good as with daily low-dose budesonide bid, the standard of care for patients with mild persistent asthma. However, the annual rate of severe asthma exacerbations were comparable which is important for long-term treatment of asthma. It is also noted that the daily treatment compliance in the clinical trials were higher than the estimated real-world compliance to daily ICS. Low treatment compliance with daily ICS can result in over-reliance on SABA reliever treatment resulting in uncontrolled asthma and a higher risk for exacerbations.

The indication was modified to reflect the patient population evaluated in the clinical trials (mild persistent asthma) as well as to remove reference to the prevention of asthma symptoms since this was not demonstrated in the clinical trials compared to the standard of care. In addition, the prevention of allergen- and exercise-induced bronchoconstriction was removed due to uncertainties regarding the design of the supportive clinical trials.

In summary the benefit-risk-uncertainty assessment of Symbicort Turbuhaler (200/6 mcg) was favourable for the recommended indication. Overall, the benefit-risk-uncertainty assessment for Symbicort Turbuhaler remains favourable.