Assessing the Comparative Effectiveness of Newly Marketed Medications: Methodological Challenges and Implications for Drug Development

Abstract

Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.

Interpreting the quality of health care database studies on the comparative effectiveness of oral anticoagulants in routine care

“…Consistent with the bias expected from such an approach, the results showed a substantial increase in the risk of embolic events among those previously treated with warfarin as compared with those who were naïve to anticoagulants. The authors acknowledged that multiple unrecorded and therefore unadjusted patient risk factors may have triggered switching from warfarin to dabigatran, 1 and more importantly, the absence of complications promotes continued warfarin use. The authors conducted a subgroup analysis in which they limited the study population to new users of either dabigatran or warfarin.…”

“…1 In a premarketing randomized controlled trial, the direct thrombin inhibitor dabigatran, the first new oral anticoagulant to reach the market, was more efficacious than warfarin in reducing the risk of stroke when given at a dose of 150 mg twice daily to patients with nonvalvular atrial fibrillation (hazard ratio 0.66; 95% confidence interval 0.53-0.82). 2 There was no substantial difference in major bleeding rates comparing dabigatran 150 mg submit your manuscript | www.dovepress.com…”

“…Ideally, an effort would be made to continuously grow balanced cohorts of new users as data refresh and become more plentiful. 1,43,44 …”

“This Drug May Work, But Is It Worth the Cost?” Can Comparative Effectiveness Research Help Tame Rising Health Care Costs?

“…The advantages and disadvantages of clinical trial data versus real-world data have been contrasted by a few recent publications on a general basis or, specifically, for diabetes. 20 As noted by Schneeweiss et al (2011), the role of efficacy data from clinical trials and comparative effectiveness data from observational studies changes over a drug's life cycle, with RCT and placebo trials more important in the early phases, and CER becoming more important late in phase 3 and particularly in phase 4 studies. 21 As Schneeweiss et al point out, there are a number of methodological challenges in using post-marketing observational data for CER.…”

Do Patients Who Take Part in Stroke Research Differ from Non-Participants? Implications for Generalizability of Results

“…One of the factors that can potentially account for the differences between research participants and the general patient populations is that research studies, particularly randomised controlled trials (RCTs), often have narrow inclusion and exclusion criteria [6,7]. As a result, trial-eligible stroke patients tend to have fewer risk factors and are in better overall health than trial-ineligible patients.…”