Augmenting control arms with real-world data for cancer trials: Hybrid control arm methods and considerations.

Background: Hybrid controlled trials with real-world data (RWD), where the control arm is composed of both trial and real-world patients, could facilitate research when the feasibility of randomized controlled trials (RCTs) is challenging and single-arm trials would provide insufficient information. Methods: We propose a frequentist two-step borrowing method to construct hybrid control arms. We use parameters informed by a completed randomized trial in metastatic triple-negative breast cancer to simulate the operating characteristics of dynamic and static borrowing methods, highlighting key trade-offs and analytic decisions in the design of hybrid studies. Results: Simulated data were generated under varying residual-bias assumptions (no bias: HRRWD = 1) and experimental treatment effects (target trial scenario: HRExp = 0.78). Under the target scenario with no residual bias, all borrowing methods achieved the desired 88% power, an improvement over the reference model (74% power) that does not borrow information externally. The effective number of external events tended to decrease with higher bias between RWD and RCT (i.e. HRRWD away from 1), and with weaker experimental treatment effects (i.e. HRExp closer to 1). All dynamic borrowing methods illustrated (but not the static power prior) cap the maximum Type 1 error over the residual-bias range considered. Our two-step model achieved comparable results for power, type 1 error, and effective number of external events borrowed compared to other borrowing methodologies. Conclusion: By pairing high-quality external data with rigorous simulations, researchers have the potential to design hybrid controlled trials that better meet the needs of patients and drug development.

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.

Characterizing the Feasibility and Performance of Real-World Tumor Progression End Points and Their Association With Overall Survival in a Large Advanced Non-Small-Cell Lung Cancer Data Set.

PURPOSE: Large, generalizable real-world data can enhance traditional clinical trial results. The current study evaluates reliability, clinical relevance, and large-scale feasibility for a previously documented method with which to characterize cancer progression outcomes in advanced non-small-cell lung cancer from electronic health record (EHR) data. METHODS: Patients who were diagnosed with advanced non-small-cell lung cancer between January 1, 2011, and February 28, 2018, with two or more EHR-documented visits and one or more systemic therapy line initiated were identified in Flatiron Health's longitudinal EHR-derived database. After institutional review board approval, we retrospectively characterized real-world progression (rwP) dates, with a random duplicate sample to ascertain interabstractor agreement. We calculated real-world progression-free survival, real-world time to progression, real-world time to next treatment, and overall survival (OS) using the Kaplan-Meier method (index date was the date of first-line therapy initiation), and correlations between OS and other end points were assessed at the patient level (Spearman's ρ). RESULTS: Of 30,276 eligible patients,16,606 (55%) had one or more rwP event. Of these patients, 11,366 (68%) had subsequent death, treatment discontinuation, or new treatment initiation. Correlation of real-world progression-free survival with OS was moderate to high (Spearman's ρ, 0.76; 95% CI, 0.75 to 0.77; evaluable patients, n = 20,020), and for real-world time to progression correlation with OS was lower (Spearman's ρ, 0.69; 95% CI, 0.68 to 0.70; evaluable patients, n = 11,902). Interabstractor agreement on rwP occurrence was 0.94 (duplicate sample, n = 1,065) and on rwP date 0.85 (95% CI, 0.81 to 0.89; evaluable patients n = 358 [patients with two independent event captures within 30 days]). Median rwP abstraction time from individual EHRs was 18.0 minutes (interquartile range, 9.7 to 34.4 minutes). CONCLUSION: We demonstrated that rwP-based end points correlate with OS, and that rwP curation from a large, contemporary EHR data set can be reliable, clinically relevant, and feasible on a large scale.

An evaluation of the impact of missing deaths on overall survival analyses of advanced non-small cell lung cancer patients conducted in an electronic health records database.

PURPOSE: The aim of this study was to assess the impact of missing death data on survival analyses conducted in an oncology EHR-derived database. METHODS: The study was conducted using the Flatiron Health oncology database and the National Death Index (NDI) as a gold standard. Three analytic frameworks were evaluated in advanced non-small cell lung cancer (aNSCLC) patients: median overall survival [mOS]), relative risk estimates conducted within the EHR-derived database, and "external control arm" analyses comparing an experimental group augmented with mortality data from the gold standard to a control group from the EHR-derived database only. The hazard ratios (HRs) obtained within the EHR-derived database (91% sensitivity) and the external control arm analyses, were compared with results when both groups were augmented with mortality data from the gold standard. The above analyses were repeated using simulated lower mortality sensitivities to understand the impact of more extreme levels of missing deaths. RESULTS: Bias in mOS ranged from modest (0.6-0.9 mos.) in the EHR-derived cohort with (91% sensitivity) to substantial when lower sensitivities were generated through simulation (3.3-9.7 mos.). Overall, small differences were observed in the HRs for the EHR-derived cohort across comparative analyses when compared with HRs obtained using the gold standard data source. When only one treatment arm was subject to estimation bias, the bias was slightly more pronounced, but increased substantially when lower sensitivities were simulated. CONCLUSIONS: The impact on survival analysis is minimal with high mortality sensitivity with only modest impact associated within external control arm applications.

Development and Validation of a High-Quality Composite Real-World Mortality Endpoint.

OBJECTIVE: To create a high-quality electronic health record (EHR)-derived mortality dataset for retrospective and prospective real-world evidence generation. DATA SOURCES/STUDY SETTING: Oncology EHR data, supplemented with external commercial and US Social Security Death Index data, benchmarked to the National Death Index (NDI). STUDY DESIGN: We developed a recent, linkable, high-quality mortality variable amalgamated from multiple data sources to supplement EHR data, benchmarked against the highest completeness U.S. mortality data, the NDI. Data quality of the mortality variable version 2.0 is reported here. PRINCIPAL FINDINGS: For advanced non-small-cell lung cancer, sensitivity of mortality information improved from 66 percent in EHR structured data to 91 percent in the composite dataset, with high date agreement compared to the NDI. For advanced melanoma, metastatic colorectal cancer, and metastatic breast cancer, sensitivity of the final variable was 85 to 88 percent. Kaplan-Meier survival analyses showed that improving mortality data completeness minimized overestimation of survival relative to NDI-based estimates. CONCLUSIONS: For EHR-derived data to yield reliable real-world evidence, it needs to be of known and sufficiently high quality. Considering the impact of mortality data completeness on survival endpoints, we highlight the importance of data quality assessment and advocate benchmarking to the NDI.

A phase I clinical trial of a ribozyme-based angiogenesis inhibitor targeting vascular endothelial growth factor receptor-1 for patients with refractory solid tumors.

PURPOSE: This study intended to determine the maximum tolerated dose, safety, pharmacokinetic variables, clinical response, and pharmacodynamic markers of daily s.c. administration of Angiozyme. PATIENTS AND METHODS: Patients with refractory solid tumors were enrolled in a dose escalation and expanded cohort design. Dose escalation involved cohorts of patients at doses of 10, 30, 100, or 300 mg/m(2)/d for 29 days. A second component enrolled 15 additional patients at a daily dose of 100 mg/m(2). Patients were eligible to continue on therapy until disease progression. RESULTS: Thirty-one patients were enrolled and 28 were evaluable (range, 29-505 days; median, 89.5 days). A maximum tolerated dose was not defined by toxicity but rather by the maximal deliverable dose of 300 mg/m(2)/d. Grade 1 to 2 injection site reactions were the most common toxicities. One patient in the 300 mg/m(2) group experienced a reversible grade 3 injection site reaction. Angiozyme showed dose-dependent plasma concentrations with good bioavailability. Surrogate markers showed Angiozyme localization in tumor biopsies and a significant increase in serum von Willebrand factor antigen, a marker for endothelial cell dysfunction. Although Angiozyme-reactive antibody production was noted for some patients, no antibody-related adverse events were noted. Seven of 28 (25%) evaluable patients had stable disease for >or =6 months, with the longest treatment duration of > or =16 months. Two patients (nasopharyngeal carcinoma and melanoma) showed minor responses. CONCLUSION: Angiozyme was well tolerated with satisfactory pharmacokinetic variables for daily s.c. dosing. Results have provided the basis for subsequent clinical trials of this first-of-class biologically targeted therapeutic.

Comparing the power of the discontinuation design to that of the classic randomized design on time-to-event endpoints.

The discontinuation design has been proposed as an alternative to the classic randomized design for evaluating the effect of an experimental agent on time-to-disease progression and survival duration. With this design, all enrolled patients are treated with an experimental agent for a fixed course of therapy. Those patients with progressive disease at or before the end of this fixed period are removed from trial while those with stable disease or better are randomized to continued treatment with the experimental agent or standard of care. Simulations presented in this paper demonstrate that for realistic situations, the loss in information on patients enrolled but not randomized in the discontinuation design is of sufficient magnitude that it is underpowered as compared to the classic design of randomizing all enrolled subjects.