Abstract
Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To characterise the relative safety profile of tofacitinib to biologic disease-modifying antirheumatic drugs (bDMARDs), the accrued patient-years (pt-yrs) of exposure needed in an RA clinical trial programme to detect a potential increase in risk of specific adverse events (AEs) was determined. This case study/framework was constructed on the pt-yrs’ accrual within pooled phase (P)1, P2 and P3, as well as long-term extension, studies of tofacitinib in RA (March 2015 data-cut) and published AE incidence rates for bDMARDs. Sample size calculations were based on a Poisson distribution to estimate pt-yrs’ exposure required for 90 % probability that the lower bound of the 95 % confidence interval for tofacitinib/bDMARD would be >1, assuming that tofacitinib rates were 1.2×/1.5×/2.0× greater than comparator rates. AE rates for bDMARDs were derived from sources intended to optimise similarity with the tofacitinib database in terms of baseline characteristics, study duration and follow-up. Based on the tofacitinib exposure accrued (19,406 pt-yrs), data were sufficient (90 % probability) to detect potential differences over external bDMARD comparator rates in serious infections (≥1.2×), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, major adverse cardiovascular events (MACE) and lymphoma (each ≥1.5×), as well as opportunistic infections and gastrointestinal perforations (≥2×), should they exist. This risk characterisation approach can support the comparative safety of new RA medications. To date, tofacitinib safety appears similar to approved published data from bDMARDs with respect to serious infections, malignancies (excluding NMSC), NMSC, MACE, lymphoma, opportunistic infections and gastrointestinal perforations.
Highlights
Safety data collected during the development of new rheumatoid arthritis (RA) therapies are generally derived from randomised controlled trials (RCTs) and long-term extension (LTE) studies
Sample size calculations were based on a Poisson distribution to estimate the minimum pt-yrs’ exposure needed to have 90 % power to detect that the lower bound of the confidence interval (CI) of tofacitinib/bDMARD would be >1, assuming that the true tofacitinib incidence rates (IRs) were 1.2×, 1.5× or 2.0× greater than bDMARD IRs; multiplier thresholds were based on clinical relevance and 1.5× was used by Curtis et al, as agreed upon with the FDA for characterising tocilizumab safety [1]
Given the rarity of opportunistic infections (OIs) and GI perforations reported in RA populations, the accrued pt-yrs’ exposure allows for the detection of a potential two-fold increase with tofacitinib relative to bDMARD IRs
Summary
Safety data collected during the development of new rheumatoid arthritis (RA) therapies are generally derived from randomised controlled trials (RCTs) and long-term extension (LTE) studies. Individual RCTs typically include small patient numbers and limited treatment periods [1, 2]. LTE studies are conducted over longer treatment periods, many of these typically do not include a comparator arm, are open-label and may lack generalisability due to possible selection biases [2]; such factors complicate comparisons with controls. The number of pt-yrs’ exposure within the pooled dataset was compared with the calculated minimum tofacitinib exposure to detect a 1.2×, 1.5× or 2.0× increase in risk over external bDMARD comparator populations for each AE
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