Background/Purpose: Randomized clinical trials (RCTs) are accepted as the ‘gold standard’ to evaluate the efficacy/effectiveness of treatment. However, generalizing results from RCTs to daily practice poses a challenge with treatment effectiveness often being different. Pragmatic clinical trials have been posed as a solution. The objective was to identify whether pragmatic clinical trials are indeed generalizable to clinical practice and investigate how efficacy estimates from RCTs can be translated into effectiveness estimates for daily practice populations.

Methods: Data from pragmatic clinical trials of the Utrecht Rheumatoid Arthritis Study Cohort and the observational Nijmegen inception cohort study with comparable inclusion criteria (RA < 1 year disease duration and no prior DMARD use) were used.  Patient characteristics were compared between the studies. The treatment effectiveness of MTX and Hydroxychloroquine both compared to the so-called Pyramid approach were compared between the pragmatic trials and observational data using a modified comprehensive cohort design analysis. Change from baseline in DAS28 and HAQ and EULAR good- and moderate response both at 6 months were the outcomes studied in the regression analyses. To study extrapolation of the treatment effect from Phase II/III clinical trials to clinical practice, published results from recent clinical trials evaluating biological treatment compared to control therapy were used. A metaregression analysis was performed to study the influence of population and treatment characteristics on ACR50% response at 6 months. Relative risk (RR) and risk difference (RD) were studied as outcome.

Results: Age, higher disease activity and response to treatment were higher in patients included in the pragmatic trial as compared to daily practice and rheumatoid factor positive patients were lower. DAS28 and HAQ generally improved more in trial patients as compared to daily practice. Using EULAR response as outcome, the relative effect of treatment (relative risk) was not found to be different. For extrapolating RCT results, glucocorticoid use, disease duration and co treatment with DMARD increased the RR in the study. Higher values of baseline DAS28 and HAQ decreased RD and the use of corticosteroids increased RD.

Conclusion: Pragmatic clinical trials might be directly generalizable only regarding relative treatment effects. In extrapolating RCT results to daily practice, population characteristics associated with disease activity, disease duration and treatment history or co-treatment need to be taken into account, regardless whether the treatment effect is expressed absolute or relative. Extrapolations of RCT results could also considerably impact costs-effectiveness results.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/generalization-and-extrapolation-of-treatment-effects-from-clinical-studies-in-rheumatoid-arthritis/