Comparability of critical quality attributes for establishing biosimilarity.

To develop a biosimilar product, it is essential to demonstrate the biosimilarity between the proposed biosimilar product and the reference product first in terms of quality in a stepwise approach that can then help inform the extent of safety and efficacy data that will be required to establish biosimilarity. These comparability studies should have direct side-by-side comparisons of the test and the reference products. In this paper, we develop a statistical method for unpaired head-to-head quality attribute comparisons. The method uses a plausibility interval derived from comparing the reference against the reference itself as the goalpost for claiming comparability. The idea behind this is that any observed difference between the reference and the reference itself should be considered as the random noise and as a part of the variability. We illustrate the performance of the proposed method by using simulation and real data sets.

Effectiveness of ciclesonide nasal spray in the treatment of seasonal allergic rhinitis.

BACKGROUND: Ciclesonide is an investigational corticosteroid under development for treatment of allergic rhinitis. Ciclesonide is converted to active metabolite, desisobutyryl-ciclesonide (des-CIC), by upper and lower airway esterases. In vitro studies in human nasal epithelial cells and bronchial epithelial cells have demonstrated a long duration of anti-inflammatory activity of des-CIC. OBJECTIVE: To evaluate the dose-dependent efficacy and safety of a hypotonic intranasal formulation of ciclesonide in patients with seasonal allergic rhinitis (SAR). METHODS: This was a phase 2, randomized, parallel-group, double-blind, placebo-controlled study. Adults (n = approximately 145 per treatment group) with a minimum 2-year history of SAR received placebo or ciclesonide (25, 50, 100, or 200 microg/d) for 14 days. The primary end point was change in the sum of morning and evening reflective total nasal symptom scores (TNSSs) over 2 weeks. Safety was monitored throughout the study. RESULTS: Ciclesonide, 100 microg/d (P = .04) and 200 microg/d (P = .003), significantly improved the sum of morning and evening reflective TNSS vs placebo at more than 2 weeks of treatment. Baseline values for morning and evening reflective TNSS ranged from 17.80 to 18.82 across treatment groups. The average change from baseline in reflective TNSS was -4.2 for placebo and -4.8, -4.8, -5.3, and -5.8 for ciclesonide, 25, 50, 100, and 200 microg/d, respectively. There were no dose-related differences in the incidence of adverse events among treatment groups. CONCLUSIONS: Results from this study indicate that 100-microg and 200-microg daily doses of ciclesonide are effective in the treatment of SAR. Ciclesonide, 200 microg/d, appears to be the optimal dose studied for reducing the symptoms of SAR while maintaining an acceptable safety profile.

Efficacy and safety of ciclesonide nasal spray for the treatment of seasonal allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR), an inflammatory disease of the nasal mucosa, affects approximately 25% of adults and 40% of children in the United States. Ciclesonide nasal spray is a corticosteroid being developed as a hypotonic formulation for AR. OBJECTIVE: We sought to evaluate the efficacy, safety, and tolerability of ciclesonide nasal spray in adult and adolescent patients with seasonal AR (SAR). METHODS: In this double-blind study patients (age, >or=12 years) were randomized to receive 200 microg of intranasal ciclesonide (n = 164) or placebo (n = 163) once daily for 28 days. The primary measure was morning and evening patient-assessed reflective total nasal symptom score (TNSS). Additionally, instantaneous TNSSs, physician-assessed overall nasal signs and symptoms severity, and the results of the Rhinoconjunctivitis Quality of Life Questionnaire were evaluated. Adverse events were monitored throughout the study. RESULTS: Ciclesonide significantly improved average morning and evening reflective and instantaneous TNSSs compared with placebo over days 1 to 14 (P < .001). Improvements were also noted over days 1 to 28 (P < .001) and over days 15 to 28 (P = .011). Ciclesonide was well tolerated. CONCLUSION: Intranasal ciclesonide was superior to placebo in relieving nasal symptoms in adult and adolescent patients with SAR. These results confirm the dose range-finding study in patients with SAR and support the efficacy of ciclesonide in AR. CLINICAL IMPLICATIONS: In a clinical setting ciclesonide was shown to be safe and effective in the treatment of SAR in adolescent and adult patients.

Evaluating assumptions for least squares analysis using the general linear model: a guide for the pharmaceutical industry statistician.

A review of graphical and test based methods for evaluating assumptions underlying the use of least squares analysis with the general linear model is presented along with some discussion of robustness. Alternative analyses are described for situations where there is evidence that the assumptions are not reasonable. Evaluation of the assumptions is illustrated through the use of an example from a clinical trial used for US registration purposes. It is recommended that: (1) most assumptions required for the least squares analysis of data using the general linear model can be judged using residuals graphically without the need for formal testing, (2) it is more important to normalize data or to use nonparametric methods when there is heterogeneous variance between treatment groups, and (3) nonparametric analyses can be used to demonstrate robustness of results and that it is best to specify these analyses prior to unblinding.