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Design of paediatric trials with benefit-risk endpoints using a composite score of adverse events of interest (AEI)
Yodit Seifu1, Shahrul Mt-Isa2, Kyle Duke3
1GBDS, Bristol-Myers Squibb, Berkeley Heights, New Jersey, USA.
Insights
This study introduces a novel composite endpoint for clinical trials, integrating efficacy and adverse event data to assess therapy benefit-risk. This approach may significantly reduce sample sizes, particularly for pediatric studies.
Area of Science:
- Clinical trial design
- Regulatory science
- Biostatistics
Background:
- Assessing the benefit-risk balance of therapies is crucial for regulatory evaluation.
- Current trial designs often face challenges in efficiently capturing both efficacy and safety.
- Pediatric studies are particularly susceptible to enrollment and patient availability issues.
Purpose of the Study:
- To propose a novel trial design centered on a composite endpoint that integrates benefit (efficacy) and risk (adverse events).
- To develop a comprehensive measure for adverse events of interest (AEI) incorporating incidence, severity, and duration.
- To demonstrate the potential for sample size reduction in pediatric trials using this composite endpoint approach.
Main Methods:
- The proposed method utilizes a composite score for adverse events of interest (AEI composite score).
- Priorities between efficacy measures and the AEI composite score are specified.
- Win-statistics (win ratio, win odds, net benefit) are employed to compare treatments.
- Simulations are conducted to evaluate power and sample size requirements.
- The approach is illustrated using Dupixent adult study data for a hypothetical pediatric trial design.
Main Results:
- The proposed composite endpoint design allows for a unified assessment of benefit and risk.
- Simulations indicate potential for substantial sample size reduction compared to traditional co-primary efficacy endpoints.
- The AEI composite score effectively captures multifaceted aspects of adverse events.
- The methodology is adaptable for designing pediatric trials with improved efficiency.
Conclusions:
- A novel composite endpoint integrating efficacy and a comprehensive adverse event score offers a robust framework for benefit-risk assessment.
- This trial design strategy shows promise in mitigating challenges in pediatric study enrollment and patient recruitment.
- The proposed method could enhance the efficiency and feasibility of clinical trials, particularly in pediatric populations.
Abstract:
A fundamental problem in the regulatory evaluation of a therapy is assessing whether the benefit outweighs the associated risks. This work proposes designing a trial that assesses a composite endpoint consisting of benefit and risk, hence, making the core of the design of the study, to assess benefit and risk. The proposed benefit risk measure consists of efficacy measure(s) and a risk measure that is based on a composite score obtained from pre-defined adverse events of interest (AEI). This composite score incorporates full aspects of adverse events of interest (i.e. the incidence, severity, and duration of the events). We call this newly proposed score the AEI composite score. After specifying the priorities between the components of the composite endpoint, a win-statistic (i.e. win ratio, win odds, or net benefit) is used to assess the difference between treatments in this composite endpoint. The power and sample size requirements of such a trial design are explored via simulation. Finally, using Dupixent published adult study results, we show how we can design a paediatric trial where the primary outcome is a composite of prioritized outcomes consisting of efficacy endpoints and the AEI composite score endpoint. The resulting trial design can potentially substantially reduce sample size compared to a trial designed to assess the co-primary efficacy endpoints, therefore it may address the challenge of slow enrollment and patient availability for paediatric studies.
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