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Active-comparator design and new-user design in observational studies

Abstract

Over the past decade, an increasing number of observational studies have examined the effectiveness or safety of treatments for rheumatoid arthritis. Unlike randomized controlled trials (RCTs), however, observational studies of drug effects have methodological limitations such as confounding by indication. Active-comparator designs and new-user designs can help mitigate such biases in observational studies and improve the validity of their findings by making them more closely approximate RCTs. In an active-comparator study, the drug of interest is compared with another agent commonly used for the same indication, rather than with no treatment (a 'non-user' group). This principle helps to ensure that treatment groups have similar treatment indications, attenuating both measured and unmeasured differences in patient characteristics. The new-user study includes a cohort of patients from the time of treatment initiation, enabling assessment of patients' pretreatment characteristics and capture of all events occurring during follow-up. These two principles should be considered when designing or reviewing observational studies of drug effects.

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Figure 1: Schematic illustration of how confounding by indication can cause a spurious statistical association.
Figure 2: Differences in patient characteristics are greater between users of the study drug and non-users, than between users of the study drug and users of an active comparator.
Figure 3: Comparison of how observations are utilized in new-user design and prevalent user design.
Figure 4: Schematic illustration of the difference between confounders and mediators.

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Acknowledgements

S.C.K.'s work is supported by a grant from the NIH (K23AR059677).

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K.Y. researched data for the article. All authors provided substantial contributions to discussion of the content, writing and reviewing or editing of the manuscript before submission.

Corresponding author

Correspondence to Kazuki Yoshida.

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Competing interests

K.Y. has received tuition support jointly from Japan Student Services Organization (JASSO) and Harvard T. H. Chan School of Public Health (supported in part by training grants from Bayer, PhRMA, Pfizer and Takeda). D.H.S. has received research/funding support from Amgen, Lilly and CORRONA, received royalties from UpToDate and served in unpaid roles in studies funded by Lilly, Novartis and Pfizer. S.C.K. has received research support from Lilly and Pfizer.

Supplementary information

Supplementary Table 1

Cohort studies of infections associated with biologic DMARD use in patients with rheumatoid arthritis. (DOCX 1071 kb)

Supplementary Table 2

Cohort studies of cancers associated with biologic DMARD use in patients with rheumatoid arthritis. (DOCX 949 kb)

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Yoshida, K., Solomon, D. & Kim, S. Active-comparator design and new-user design in observational studies. Nat Rev Rheumatol 11, 437–441 (2015). https://doi.org/10.1038/nrrheum.2015.30

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