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Open research questions in Statistical Methods in Clinical Trials

272 gap statements mined from Statistical Methods in Clinical Trials papers in our 7.9M-paper local library, which holds 3,241 papers on the topic — drawn mostly from each paper's own stated research gap, future-work, challenge and limitation notes, and its abstract. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one.

What the literature leaves open

  • Future research should focus on improving the robustness of clinically important endpoints through better-powered trials, stronger retention, and more transparent handling of missing data. Finally, the conceptual validity of CFI remains debated because it modifies participant allocation rather than outcome status and therefore differs from the original FI framework.

    Statistical fragility of significant outcomes in spine surgery randomized controlled trials: a systematic review of binary and continuous outcomes · 2026 · DOI

  • The choice of statistical estimator can affect the interpretation of results, and different estimators target different estimands. Missing data, such as study withdrawal, need to be addressed in the statistical analysis.

    Applying the estimand framework to safety: aligning estimators with treatment effects in the presence of intercurrent events · 2026 · DOI

  • The application of the estimand framework to safety outcomes remains limited. There is a lack of clarity on the estimand of interest and the statistical estimator used in safety analyses. Practical guidance on how common safety estimators align with different estimand strategies is scarce.

    Applying the estimand framework to safety: aligning estimators with treatment effects in the presence of intercurrent events · 2026 · DOI

  • It remains unclear whether trials investigating QoL outcomes in stable angina routinely incorporate blinded designs.

    Blinding and quality of life endpoints in randomised trials of stable angina: a meta-epidemiological study · 2026 · DOI

  • These are primarily reflected in the imprecision of parameters, the incompleteness of validation, and the lack of standardization.

    The Evolution and Future Directions of PBPK Modeling in FDA Regulatory Review · 2025 · DOI

  • Although these trials guide clinical decision-making through hypothesis testing, relying solely on a significant P-value is insufficient; it is essential to convey in addition the magnitude of the treatment effect.

    Rethinking survival analysis: advancing beyond the hazard ratio? · 2024 · DOI

  • The development of new methods for sample size determination is needed. The evaluation of the effectiveness of the methods used for sample size determination is needed.

    A systematic review of sample size determination in Bayesian randomized clinical trials: full Bayesian methods are rarely used · 2026 · DOI

  • Future research should investigate the factors contributing to the increase in issues raised over time. Further studies should examine the impact of regulatory pathways on the development of new oncology medicines.

    Trends in EU regulatory assessment of oncology medicines · 2026 · DOI

  • The research gap is related to the lack of comprehensive analysis of the impact of application characteristics on procedural metrics.

    Trends in EU regulatory assessment of oncology medicines · 2026 · DOI

  • However, when the normality, linearity, or the random-intercept assumption is violated, the validity and efficiency of the mixed-model ANCOVA estimators for estimating the average treatment effect remain unclear.

    On the Mixed-Model Analysis of Covariance in Cluster-Randomized Trials · 2026 · DOI

  • Lack of clear interpretability in existing ranking methods. Failure to adequately account for uncertainty in existing ranking methods. Overinterpretation of minor differences in existing ranking methods.

    Producing treatment hierarchies in network meta-analysis using probabilistic models and treatment-choice criteria · 2026 · DOI

  • Existing ranking methods in network meta-analysis have limitations. There is a need for a more reliable and clinically meaningful treatment hierarchy.

    Producing treatment hierarchies in network meta-analysis using probabilistic models and treatment-choice criteria · 2026 · DOI

  • The review is limited to pairwise meta-analyses of oncology therapies. The review only includes meta-analyses published since 2021.

    Treatment switching in evidence synthesis in oncology: A systematic review of current meta-analytical practices · 2026 · DOI

  • Future research should investigate the impact of treatment switching on the interpretation of efficacy estimates. Future research should develop methods to address treatment switching in meta-analyses.

    Treatment switching in evidence synthesis in oncology: A systematic review of current meta-analytical practices · 2026 · DOI

  • The asymptotic properties of sandwich estimators may not hold in small sample sizes. There is a lack of guidance for researchers working with limited data.

    Improving Variance and Confidence Interval Estimation in Small‐Sample Propensity Score Analyses: Bootstrap Versus Asymptotic Methods · 2026 · DOI

  • There remains a great need to discover and develop novel agents that will improve survival for patients with lung cancer. The number of responders to immunotherapy is relatively low, approximately 20%. Established tumors can have potent immunosuppressive effects.

    UCDCC263 Clinical Trial Protocol · 2026 · DOI

  • There is a need for more accurate methods for detecting selection bias in randomized controlled trials. The current methods for detecting selection bias have limitations.

    The Accuracy of the I2 Statistic for Detecting Baseline Imbalances and Selection Bias in Randomized Controlled Trials: A Simulation Study · 2026 · DOI

  • The traditional oncology dose selection strategy has proven inadequate for targeted and immunotherapies. Doses lower than MTD may provide similar efficacy benefit with reduced toxicity.

    A Two-Stage Dose Optimization Framework for Oncology Drug Development with Multiple Efficacy and Safety Endpoints via an Integrated Benefit-Risk Assessment · 2026 · DOI

  • The sample size was limited to 100 trials. The study did not account for other types of bias.

    The Accuracy of the I2 Statistic for Detecting Baseline Imbalances and Selection Bias in Randomized Controlled Trials: A Simulation Study · 2026 · DOI

  • Claims with Insufficient Evidence in High-Impact Cell Culture Studies.

    Assessment of Cell Viability in Drug Therapy: IC50 and Other New Time-Independent Indices for Evaluating Chemotherapy Efficacy · 2025 · DOI

  • Lack of standardized international criteria for AI-based solutions - Limited clinical translation of patient-centered AI models - Insufficient standardization of data formats, model validation, and performance…

    Patient-Centered Artificial Intelligence Approaches in Pharmaceutical Formulation Development: A Review · 2026 · DOI

  • Although the mathematical results could, in principle, be extended to one-arm trials…

    On the Interplay Between Prior Weight and Variance of the Robustification Component in Robust Mixture Prior Bayesian Dynamic Borrowing Approach · 2026 · DOI

  • In our simulation study, we observed that the Clayton copula does not lead any invalid inference, whereas with the Frank and Gumbel copulas, the proposed methods might suffer from bias in estimation, poor control of the nominal level of the confidence interval and non-convergence in iteration steps for estimation probably due to difficulty to handle extra parameters in dependence with limited information…

    Literature-based meta-analysis of adverse events accounting for heterogeneous follow-up duration in oncology clinical trials · 2026 · DOI

  • 76× relative to standard biomarker analysis, supports both clearance-modifying and injury-modifying mechanism inference, and accommodates sparse data.

    Efficacy inference in early-phase non-controlled clinical trials via Bayesian biomarker deconvolution · 2026 · DOI

  • Establishing methods for comparing rerandomization with quadratic forms to other rerandomization methods and experimental design strategies, - Extending the quadratic form framework to multi-armed experiments, - Layering Quadratic Form Rerandomization on top of other randomization…

    A Unified Framework for Rerandomization using Quadratic Forms · 2026 · DOI

Most-cited papers in Statistical Methods in Clinical Trials

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Open questions raised by papers listed on this page include: (1) Future research should focus on improving the robustness of clinically important endpoints through better-powered trials, stronger retention, and more transparent handling of missing data (“Statistical fragility of significant outcomes in spine surgery randomized…”, 2026); (2) The application of the estimand framework to safety outcomes remains limited (“Applying the estimand framework to safety: aligning estimators with treatment…”, 2026); (3) It remains unclear whether trials investigating QoL outcomes in stable angina routinely incorporate blinded designs (“Blinding and quality of life endpoints in randomised trials of stable angina: a…”, 2026); (4) The development of new methods for sample size determination is needed (“A systematic review of sample size determination in Bayesian randomized…”, 2026); (5) Future research should investigate the factors contributing to the increase in issues raised over time (“Trends in EU regulatory assessment of oncology medicines”, 2026). 272 gap statements have been mined from Statistical Methods in Clinical Trials papers in our 7.9M-paper local library, which holds 3,241 papers on the topic; the gaps come from whichever of those papers state one. They are mostly the research gaps the authors state and the papers' abstracts, plus future-work, limitations and challenges passages. The ones listed below are a selection still marked open; each names the study that raised it, with a DOI link where the paper has one, so you can read the original claim in context.

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