Improving resource utilisation in SLE drug development through innovative trial design

Abstract

SLE is a complex autoimmune disease with considerable unmet need. Numerous clinical trials designed to investigate novel therapies are actively enrolling patients straining limited resources and creating inefficiencies that increase enrolment challenges. This has motivated investigators developing novel drugs and treatment strategies to consider innovative trial designs that aim to improve the efficiency of generating evidence; these strategies propose conducting fewer trials, involving smaller numbers of patients, while maintaining scientific rigour in safety and efficacy data collection and analysis. In this review we present the design of two innovative phase IIb studies investigating efavaleukin alfa and rozibafusp alfa for the treatment of SLE which use an adaptive study design. This design was selected as a case study, investigating efavaleukin alfa, in the Food and Drug Administration’s Complex Innovative Trial Design Pilot Program. The adaptive design approach includes prospectively planned modifications at predefined interim timepoints. Interim assessments of futility allow for a trial to end early when the investigational therapy is unlikely to provide meaningful treatment benefits to patients, which can release eligible patients to participate in other—potentially more promising—trials, or seek alternative treatments. Response-adaptive randomisation allows randomisation ratios to change based on accumulating data, in favour of the more efficacious dose arm(s), while the study is ongoing. Throughout the trial the placebo arm allocation ratio is maintained constant. These design elements can improve the statistical power in the estimation of treatment effect and increase the amount of safety and efficacy data collected for the optimal dose(s). Furthermore, these trials can provide the required evidence to potentially serve as one of two confirmatory trials needed for regulatory approval. This can reduce the need for multiple phase III trials, the total patient requirements, person-exposure risk, and ultimately the time and cost of investigational drug development programmes.

Lupus clinical trials and the promise of future therapies

“…[ 18 ] Inclusion criteria usually specifies a disease activity in the moderate to severe range; however, exclusion criteria restrict the range of disease activity by limiting use of steroids or other immunosuppressive treatments. [ 19 , 20 ] More medications have been approved for SLE and the standard of care treatment is evolving but inclusion/exclusion mostly remains the same, and as such more patients are excluded from studies.…”

“…Despite recent advances in phase 2 clinical trial design including adaptive designs and withdrawal of standard of care therapies, SLE clinical trial design has remained vastly unchanged. [ 20 ] While phase 2/dose finding study design randomizes patients 1:1:1:1 (drug:drug:drug:placebo), phase 3 studies have most often randomized patient 1: 1 drug to placebo. Possibly, investigators and patients with higher disease activity are more comfortable enrolling in phase 2 trials given the higher chance of receiving study drug, as such phase 3 trials may discourage enrollment of sicker patients.…”

“…At an investigator and site level, there are an insufficient number of investigators with experience in SLE management and clinical trials; as disease activity measures are complex and require expertise in SLE. [ 20 ] Rheumatology training programs for clinicians focus on clinical training, and there are no formal programs for training SLE investigators. Additionally, site staff problems such as high turnover in coordinators and clinical research managers may further hinder clinical trial operations.…”