OBJECTIVES: In December 2023, two Phase III trials (evolutionRMS1 and evolutionRMS2) comparing evobrutinib and teriflunomide in people with relapsing multiple sclerosis (RMS) were terminated as it was indicated that teriflunomide annualised relapse rates (ARR) were lower than those reported in recent Phase III randomised controlled trials (RCTs). We conducted a predictive meta-analysis of studies assessing teriflunomide 14mg in patients with RMS, to ascertain whether teriflunomide performed better than the expectations.

METHODS: Embase and MEDLINE databases were searched to identify RCTs and real-world studies (RWS) assessing the efficacy/effectiveness of teriflunomide 14mg in adult patients with RMS and reporting ARR and associated variance. Predictive meta-analyses were conducted using Statav18.0 to generate pooled ARR along with 95% prediction intervals (PIs). Impact of baseline variables and temporal effect on ARR results were assessed using meta-regression and cumulative meta-analysis, respectively.

RESULTS: Thirty studies (phase 3 RCTs: 9; RWS: 21) contributed to the meta-analysis. At 2-years, pooled ARR from RWS was comparable to RCTs (0.18 vs 0.20) with 95% PIs ranging from 0 to 0.56 in RWS and 0.11 to 0.39 in RCTs. The observed ARR for teriflunomide within evolutionRMS trials was well within the PIs of both RWS and RCT evidence base. Based on a cumulative meta-analysis by publication year, a decreasing trend in ARR (better efficacy) was observed with teriflunomide in RWS. Age, relapses in prior year, prior treatment status, and publication year were significant predictors of ARR.

CONCLUSIONS: PIs could support better decision-making about clinical trial planning and execution. With wide PIs, as in the case of teriflunomide, there is a higher risk that the new trial may not show statistically significant difference. Future phase III studies planning should consider both RCT and RWS evidence and clinical and HEOR stakeholders should work in collaboration to enhance the strategic planning and execution for a successful trial.