Vicky Thomas

Quality standards for real-world research. Focus on observational database studies of comparative effectiveness

Real-world research can use observational or clinical trial designs, in both cases putting emphasis on high external validity, to complement the classical efficacy randomized controlled trials (RCTs) with high internal validity. Real-world research is made necessary by the variety of factors that can play an important a role in modulating effectiveness in real life but are often tightly controlled in RCTs, such as comorbidities and concomitant treatments, adherence, inhalation technique, access to care, strength of doctor-caregiver communication, and socio-economic and other organizational factors. Real-world studies belong to two main categories: pragmatic trials and observational studies, which can be prospective or retrospective. Focusing on comparative database observational studies, the process aimed at ensuring high-quality research can be divided into three parts: preparation of research, analyses and reporting, and discussion of results. Key points include a priori planning of data collection and analyses, identification of appropriate database(s), proper outcomes definition, study registration with commitment to publish, bias minimization through matching and adjustment processes accounting for potential confounders, and sensitivity analyses testing the robustness of results. When these conditions are met, observational database studies can reach a sufficient level of evidence to help create guidelines (i.e., clinical and regulatory decision-making).

switching patients from other inhaled corticosteroid devices to the easyhaler ® : historical, matched-cohort study of real-life asthma patients

Purpose To investigate the clinical and cost effectiveness of switching real-life asthma patients from other types of inhalers to the Easyhaler® (EH) for the administration of inhaled corticosteroids (ICS). Patients and methods Historical, matched-cohort study of 1,958 asthma patients (children and adults) treated in UK primary-care practices, using data obtained from the Optimum Patient Care Research Database and Clinical Practice Research Datalink. Other inhalers (OH) included pressurized metered-dose inhalers, breath-actuated inhalers, and dry-powder inhalers, delivering beclomethasone, budesonide, fluticasone, or ciclesonide. Patients remaining on OH unchanged (same drug, dosage, and device; n=979) were matched 1:1 with those switched to the EH (beclomethasone or budesonide) at the same or lower ICS dosage (n=979), based on age, sex, year of index patient review/switch, most recent ICS drug, dosage, and device, and the number of severe exacerbations and average daily short-acting β2 agonist (SABA) dosage in the preceding year. Clinical outcomes and health care costs were compared between groups for 12 months before and after the switch. Co-primary clinical outcomes were: 1) risk domain asthma control (RDAC) – no asthma-related hospitalization, acute oral steroid use, or lower respiratory tract infection (LRTI); 2) exacerbation rate (American Thoracic Society [ATS] definition) – where exacerbation is asthma-related hospitalization or acute oral steroid use; 3) exacerbation rate (clinical definition) – where exacerbation is ATS exacerbation or LRTI; and 4) overall asthma control (OAC) – RDAC plus average salbutamol-equivalent SABA dosage ≤200 μg/day. Non-inferiority (at least equivalence) of EH was tested against OH for the four co-primary outcomes in order (hierarchical approach) by comparing the difference in proportions of patients [EH-OH] achieving asthma control or having no exacerbations in the outcome year, using a limit of 10% difference. Results Non-inferiority was shown for the EH for all four co-primary outcomes. There were no significant differences between groups for RDAC or exacerbation rates, but EH patients were significantly more likely to achieve OAC (adjusted odds ratio [95% confidence interval]: 1.26 [1.05, 1.52]), as significantly more EH than OH patients had an average SABA dosage of ≤200 μg/day (52% versus 47%, respectively; P<0.001). Mean asthma-related health care costs increased from baseline to outcome years in both groups, but SABA costs increased significantly more in OH than EH patients (mean difference £5.5/patient/year) and consultation costs decreased significantly more in EH than OH patients (mean difference £13.5/patient/year). Conclusion Typical asthma patients may be switched from other ICS devices to the Easyhaler® with no reduction in clinical effectiveness or increase in cost.

Real-life effectiveness and safety of salbutamol Steri-Neb™ vs. Ventolin Nebules® for exacerbations in patients with COPD : Historical cohort study

Introduction Ventolin Nebules® (reference product; GlaxoSmithKline) was the first licensed nebulizer solution containing the rapid-onset, short-acting β2-agonist salbutamol. Salbutamol Steri-Neb™ (comparator; Teva Pharmaceuticals, Inc.) has the same chemical composition as the reference product. This study evaluated whether the effectiveness of the comparator is non-inferior to the reference product alongside concomitant medications during real-life clinical management of COPD exacerbations. Safety in terms of adverse events (AEs) was also examined. Methods This matched (1:1) historical cohort study evaluated data from 2 UK primary care databases on patients prescribed the salbutamol comparator or reference. The study included a 1-year baseline period, starting 1 year before the index prescription date, and 1-year outcome period. Cohorts were matched for baseline COPD respiratory medications. The primary outcome was analysis of non-inferiority for the comparator versus reference product for the rate of moderate and severe COPD exacerbations. Non-inferiority was satisfied if the 95% confidence interval (CI) upper limit for mean differences in proportions between treatments was <15%. Secondary outcomes were examined through rate ratios (RR) of severe exacerbations and AEs. Results After matching, 1191 patients were included in each cohort. Adjusted upper 95% CI for the difference in proportion of patients experiencing moderate or severe exacerbations between comparator and reference groups was 0.032 (3.2%), demonstrating non-inferiority. No significant differences were observed in rates of moderate and severe exacerbations (RR: 1.00; 95% CI: 0.91, 1.10), severe exacerbations (RR: 0.76; 95% CI: 0.49, 1.17), or AEs (RR: 0.98; 95% CI: 0.78, 1.22) after adjusting for baseline confounders. No significant differences across cohorts were observed for rates of any AE or death. Conclusion This matched cohort study of real-life management of COPD patients supports the salbutamol comparator as non-inferior to the reference product, providing an effective treatment alternative for COPD exacerbations. Comparator and reference safety profiles were similar.

Real-life effectiveness and safety of the inhalation suspension budesonide comparator vs the originator product for the treatment of patients with asthma: a historical cohort study using a US health claims database

Objective The objective of this study was to determine whether the effectiveness of budesonide comparator is non-inferior to budesonide reference in the prevention of asthma exacerbations. Asthma-related hospitalizations and safety were also examined. Methods This study used a matched, historic cohort design. Data were drawn from the Clinformatics™ Data Mart US claims database and included a 1-year baseline, starting 1 year before the index prescription date, and a 1-year outcome period. Patients received budesonide comparator or reference treatment. The primary outcome was the rate of asthma exacerbations. Non-inferiority for budesonide comparator vs budesonide reference was established if the 95% confidence interval (CI) upper limit of mean difference in proportions between treatments was <15%. Secondary outcomes examined rate of asthma-related hospitalizations and adverse events (AEs). Results The budesonide comparator and reference-matched cohorts each included 3109 patients. The adjusted upper 95% CI for the difference in proportions of patients experiencing asthma exacerbations was 0.035 (3.5%), demonstrating non-inferiority. Cohorts did not significantly differ in the rate of asthma exacerbations (adjusted rate ratio [RR]=1.04, 95% CI: 0.95–1.14) or rate of asthma-related hospitalizations (adjusted RR=1.10, 95% CI: 0.99–1.24) after adjusting for baseline confounders. No asthma exacerbations occurred during the outcome period in 72.9% of budesonide comparator patients and 71.8% of budesonide reference patients. No asthma-related hospitalizations occurred in 77.9% of patients in the budesonide comparator cohort and 79.0% of patients in the budesonide reference cohort. The most frequent AEs were throat irritation (≤0.4% of patients) and hoarseness/dysphonia (0.02% of patients). AEs did not significantly differ between treatment cohorts. Conclusion In this real-life study, non-inferiority of the budesonide comparator vs reference was met for the primary end point of asthma exacerbation rates. Asthma-related hospitalization and AE rates did not differ between the two treatment cohorts. The budesonide comparator is an effective and safe treatment alternative for asthma exacerbations.