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.

Trial registration: ClinicalTrials.gov NCT04058028 NCT04680637.

Keywords: Adaptive Clinical Trial Design; Autoimmune Diseases; Lupus Erythematosus, Systemic.

Figure 1

Adaptive trial schema and innovative design elements of the phase IIb studies for rozibafusp alfa and efavaleukin alfa in SLE. Innovative elements: 1. Study implements response-adaptive randomisation; 2. Multiple interim analyses that evaluate for futility and one efficacy evaluation (primary); 3. Primary endpoint (SRI-4 response at week 52) and futility analyses are evaluated using a Bayesian hierarchical model comparing the three dose levels to placebo. SOC, standard of care; SRI, Systemic Lupus Erythematosus Responder Index.

Figure 2

Response-adaptive randomisation probabilities by efficacy response rates at interim analyses using simulation of example clinical trial data. Response rates derived from each analysis of interim data are used to update the subsequent randomisation ratio. In this clinical trial data simulation, the greatest response rate was consistently observed for subjects receiving the highest dose (dose 3), which resulted in a gradual shift in the randomisation ratio in favour of dose 3 for new subjects randomised after each interim analysis.

Figure 3

(A) Average randomisation allocation to each treatment arm according to study design/result scenario; (B) Probability of success (power) of the proposed CID design and fixed study design according to simulated efficacy scenario. The adaptive design and the standard fixed design were evaluated assuming the same planned sample size (n=320). The ‘Good’ scenario was defined as linear dose-response with one dose (highest) meeting target efficacy and the others with moderate or low efficacy; the ‘nugget’ scenario was defined as only one dose meeting target efficacy and the remaining doses not being different from placebo. The line at 80% designates the power goal for this phase IIb clinical trial. CID, complex innovative design.