Regulatory Decision Summary for Wixela Inhub

This ANDS followed the principles of the "weight of evidence" approach described in the United States Food and Drug Administration (FDA) guidance "Fluticasone Propionate; Salmeterol Xinafoate, September 2013" and contains bridging comparative pharmacokinetic (PK) and in vitro data between the Advair Diskus (Canada) and Advair Diskus (United States [USA]).

The clinical efficacy was examined in a single pivotal study (Study MGR001-3001) to determine bioequivalence (BE) based on clinical endpoints. The clinical endpoints study in over 1,100 adult asthma patients was conducted to demonstrate the local bioequivalence of both fluticasone propionate and salmeterol between Wixela Inhub 100/50 mcg (Test) and Advair Diskus 100/50 mcg (Reference). Wixela Inhub and Advair Diskus both produced statistically significant improvements in the area under the curve between 0 and 12 hours after drug administration (AUC_0-12) for forced expiratory volume in 1 second (FEV₁) on Day 1, and trough FEV₁ on Day 29, in comparison to placebo treatments. The ratio of the Test/Reference least squares means for FEV₁ AUC_0-12 on Day 1 calculated from analysis of covariance demonstrated a 90% confidence interval contained within 80% - 125%, the pre-specified range required to demonstrate local BE. Similarly, the ratio of the Test/Reference least squares means for trough FEV₁ on Day 29 also demonstrated a 90% confidence interval contained within 80% - 125%. The observed changes in FEV₁ on both days were also comparable to previously published values for fluticasone propionate/salmeterol in asthma patients. These combined results support the therapeutic equivalence between Wixela Inhub and Advair Diskus.

In accordance with the aforementioned United States FDA guidance, the sponsor conducted and submitted results of PK studies comparing bioavailability of fluticasone and salmeterol from Wixela Inhub (100/50 mcg, 250/50 mcg and 500/50 mcg) versus Advair Diskus (USA; 100/50 mcg, 250/50 mcg and 500/50 mcg). In addition, a PK bridging study comparing Advair Diskus (Canada; 500/50 mcg) versus Advair Diskus (USA; 500/50 mcg) was submitted. Based on the recommendations of the Scientific Advisory Committee on Respiratory and Allergy Therapies (SAC-RAT) Record of Proceedings (November 2, 2018), the comparative pulmonary PK studies and device sameness were also assessed in support of Wixela Inhub.

The results of Study MGR000-1006 demonstrated PK bioequivalence between Advair Diskus (Canada) versus Advair Diskus (USA). The standards were met on log transformed parameters calculated from the measured data for fluticasone (AUC_t and C_max) and salmeterol (AUC_{0-30 min}, AUC_t and C_max).

Of note, Advair Diskus (USA) was administered in the clinical efficacy study MGR001-3001, as well as the comparative PK studies comparing bioavailability of Wixela Inhub (100/50 mcg, 250/50 mcg, and 500/50 mcg) versus Advair Diskus (USA; 100/50 mcg, 250/50 mcg, and 500/50 mcg). In addition, the results of the comparative PK studies between respective strengths of Wixela Inhub and Advair Diskus (USA) demonstrate PK bioequivalence between of Wixela Inhub (100/50 mcg, 250/50 mcg and 500/50 mcg) and Advair Diskus (USA; 100/50 mcg, 250/50 mcg and 500/50 mcg). The standards were met on log transformed parameters calculated from the measured data for fluticasone (AUC_t and C_max) and salmeterol (AUC_{0-30 min}, AUC_t and C_max).

Finally, from a Quality perspective, the product was shown to have the same formulation and equivalent physical and chemical properties, delivery device and in vitro performance as Advair Diskus.

This ANDS for Wixela Inhub (Fluticasone Propionate/Salmeterol; 100/50 mcg, 250/50 mcg, and 500/50 mcg) by Mylan Pharmaceuticals ULC is considered to meet the requirements of the Food and Drug Regulations. It was recommended, on the basis of the data submitted, that this product be granted clearance.