Evaluating eligibility criteria of oncology trials using real-world data and AI.

There is a growing focus on making clinical trials more inclusive but the design of trial eligibility criteria remains challenging1-3. Here we systematically evaluate the effect of different eligibility criteria on cancer trial populations and outcomes with real-world data using the computational framework of Trial Pathfinder. We apply Trial Pathfinder to emulate completed trials of advanced non-small-cell lung cancer using data from a nationwide database of electronic health records comprising 61,094 patients with advanced non-small-cell lung cancer. Our analyses reveal that many common criteria, including exclusions based on several laboratory values, had a minimal effect on the trial hazard ratios. When we used a data-driven approach to broaden restrictive criteria, the pool of eligible patients more than doubled on average and the hazard ratio of the overall survival decreased by an average of 0.05. This suggests that many patients who were not eligible under the original trial criteria could potentially benefit from the treatments. We further support our findings through analyses of other types of cancer and patient-safety data from diverse clinical trials. Our data-driven methodology for evaluating eligibility criteria can facilitate the design of more-inclusive trials while maintaining safeguards for patient safety.

Penalized regression for left-truncated and right-censored survival data.

High-dimensional data are becoming increasingly common in the medical field as large volumes of patient information are collected and processed by high-throughput screening, electronic health records, and comprehensive genomic testing. Statistical models that attempt to study the effects of many predictors on survival typically implement feature selection or penalized methods to mitigate the undesirable consequences of overfitting. In some cases survival data are also left-truncated which can give rise to an immortal time bias, but penalized survival methods that adjust for left truncation are not commonly implemented. To address these challenges, we apply a penalized Cox proportional hazards model for left-truncated and right-censored survival data and assess implications of left truncation adjustment on bias and interpretation. We use simulation studies and a high-dimensional, real-world clinico-genomic database to highlight the pitfalls of failing to account for left truncation in survival modeling.

Systematic analysis of off-label and off-guideline cancer therapy usage in a real-world cohort of 165,912 US patients.

Patients with cancer may be given treatments that are not officially approved (off-label) or recommended by guidelines (off-guideline). Here we present a data science framework to systematically characterize off-label and off-guideline usages using real-world data from de-identified electronic health records (EHR). We analyze treatment patterns in 165,912 US patients with 14 common cancer types. We find that 18.6% and 4.4% of patients have received at least one line of off-label and off-guideline cancer drugs, respectively. Patients with worse performance status, in later lines, or treated at academic hospitals are significantly more likely to receive off-label and off-guideline drugs. To quantify how predictable off-guideline usage is, we developed machine learning models to predict which drug a patient is likely to receive based on their clinical characteristics and previous treatments. Finally, we demonstrate that our systematic analyses generate hypotheses about patients' response to treatments.

Machine Learning Prediction of Clinical Trial Operational Efficiency.

Clinical trials are the gatekeepers and bottlenecks of progress in medicine. In recent years, they have become increasingly complex and expensive, driven by a growing number of stakeholders requiring more endpoints, more diverse patient populations, and a stringent regulatory environment. Trial designers have historically relied on investigator expertise and legacy norms established within sponsor companies to improve operational efficiency while achieving study goals. As such, data-driven forecasts of operational metrics can be a useful resource for trial design and planning. We develop a machine learning model to predict clinical trial operational efficiency using a novel dataset from Roche containing over 2,000 clinical trials across 20 years and multiple disease areas. The data includes important operational metrics related to patient recruitment and trial duration, as well as a variety of trial features such as the number of procedures, eligibility criteria, and endpoints. Our results demonstrate that operational efficiency can be predicted robustly using trial features, which can provide useful insights to trial designers on the potential impact of their decisions on patient recruitment success and trial duration.

Systematic pan-cancer analysis of mutation-treatment interactions using large real-world clinicogenomics data.

Quantifying the effectiveness of different cancer therapies in patients with specific tumor mutations is critical for improving patient outcomes and advancing precision medicine. Here we perform a large-scale computational analysis of 40,903 US patients with cancer who have detailed mutation profiles, treatment sequences and outcomes derived from electronic health records. We systematically identify 458 mutations that predict the survival of patients on specific immunotherapies, chemotherapy agents or targeted therapies across eight common cancer types. We further characterize mutation-mutation interactions that impact the outcomes of targeted therapies. This work demonstrates how computational analysis of large real-world data generates insights, hypotheses and resources to enable precision oncology.

Using Electronic Health Records to Derive Control Arms for Early Phase Single-Arm Lung Cancer Trials: Proof-of-Concept in Randomized Controlled Trials.

Oncology drug development increasingly relies on single-arm clinical trials. External controls (ECs) derived from electronic health record (EHR) databases may provide additional context. Patients from a US-based oncology EHR database were aligned with patients from randomized controlled trials (RCTs) and trial-specific eligibility criteria were applied to the EHR dataset. Overall survival (OS) in the EC-derived control arm was compared with OS in the RCT experimental arm. The primary outcome was OS, defined as time from randomization or treatment initiation (EHR) to death. Cox regression models were used to obtain effect estimates using EHR data. EC-derived hazard ratio estimates aligned closely with those from the corresponding RCT with one exception. Comparing log HRs among all RCT and EC results gave a Pearson correlation coefficient of 0.86. Properly selected control arms from contemporaneous EHR data could be used to put single-arm trials of OS in advanced non-small cell lung cancer into context.