Considerations for Master Protocols Using External Controls

There has been an increasing use of master protocols in oncology clinical trials because of its efficiency and flexibility to accelerate cancer drug development. Depending on the study objective and design, a master protocol trial can be a basket trial, an umbrella trial, a platform trial, or any other form of trials in which multiple drugs and/or multiple subpopulations are studied in parallel under a single protocol. External data and evidence (EDE) can be used in the design and analysis of master protocols such as external controls for treatment effect estimation, which can further improve efficiency of the master protocol trial. This paper provides an overview of different types of external controls and their unique features when used in master protocols. Some key considerations in master protocols with external controls are discussed including construction of estimands and assessment of fit-for-use real-world data. A targeted learning-based causal roadmap is presented which constitutes three key steps: (1) define a target statistical estimand that aligns with the causal estimand for the study objective, (2) use an efficient estimator to estimate the target statistical estimand and its uncertainty, and (3) evaluate the impact of causal assumptions on the study conclusion by performing a sensitivity analysis. Two illustrative examples are provided for master protocols using external controls

Efficiency of a randomized confirmatory basket trial design constrained to control the family wise error rate by indication

Basket trials pool histologic indications sharing molecular pathophysiology, improving development efficiency. Currently basket trials have been confirmatory only for exceptional therapies. Our previous randomized basket design may be generally suitable in the resource-intensive confirmatory phase, maintains high power even with modest effect sizes, and provides nearly k-fold increased efficiency for k indications, but controls false positives for the pooled result only. Since family-wise error rate by indications (FWER) may sometimes be required, we now simulate a variant of this basket design controlling FWER at 0.025k, the total FWER of k separate randomized trials. We simulated this modified design under numerous scenarios varying design parameters. Only designs controlling FWER and minimizing estimation bias were allowable. Optimal performance results when k=3,4. We report efficiency (expected # true positives/expected sample size) relative to k parallel studies, at 90% power (“uncorrected”) or at the power achieved in the basket trial (“corrected”, because conventional designs could also increase efficiency by sacrificing power). Efficiency and power (percentage active indications identified) improve with higher percentage of initial indications active. Up to 92% uncorrected and 38% corrected efficiency improvement is possible. Even under FWER control, randomized confirmatory basket trials substantially improve development efficiency. Initial indication selection is critical

A comparison of hepatitis B viral markers of patients in different clinical stages of chronic infection

Hepatitis B viral markers may be useful for predicting outcomes such as liver-related deaths or development of hepatocellular carcinoma. We determined the frequency of these markers in different clinical stages of chronic hepatitis B infection. We compared baseline hepatitis B viral markers in 317 patients who were enrolled in a prospective study and identified the frequency of these tests in immune-tolerant (IT) patients, in inactive carriers , and in patients with either hepatitis B e antigen ( HBeAg)- positive or HBeAg-negative chronic hepatitis or cirrhosis. IT patients were youngest (median age 27 years) and HBeAg- negative patients with cirrhosis were oldest (median age 58 years) (p = 0.03 to < 0.0001). The male to female ratio was similar both in IT patients and in inactive carriers, but there was a male preponderance both in patients with chronic hepatitis and in patients with cirrhosis (p < 0.0001). The A1896 precore mutants were most prevalent in inactive carriers (36.4%) and HBeAg- negative patients with chronic hepatitis (38.8%; p < 0.0001), and the T 1762/A1764 basal core promoter mutants were most often detected in HBeAg- negative patients with cirrhosis (65.1%; p = 0.02). Genotype A was detected only in 5.3% of IT patients, and genotype B was least often detected in both HBeAg-Positive patients with chronic hepatitis and cirrhosis (p = 0.03). The hepatitis B viral DNA levels were lowest in inactive carriers (2.69 log(10) IU/mL) and highest in IT patients (6. 80 log(10) IU/mL; p = 0.02 to < 0.0001). At follow-up, HBeAg-positive and HBeAg-negative patients with cirrhosis accounted for 57 of 64 (89.1%) liver-related deaths (p < 0. 0001). Differences in baseline hepatitis B viral markers were detected in patients in various clinical stages of hepatitis B virus infection. HBeAg-positive and HBeAg- negative patients with cirrhosis accounted for the majority of the liver-related fatalities

A Statistical Approach to Characterizing the Reliability of Systems Utilizing HBT Devices

This paper presents a statistical approach to characterizing the reliability of systems with HBT devices. The proposed approach utilizes the statistical reliability information of the HBT individual devices, along with the analysis on the critical paths of the system, to provide more accurate and more comprehensive reliability information about the HBT systems compared to the conventional worst-case method

CMOS Active Pixel Sensor Technology and Reliability Characterization Methodology

This paper describes the technology, design features and reliability characterization methodology of a CMOS Active Pixel Sensor. Both overall chip reliability and pixel reliability are projected for the imagers

A Methodology for FPGA to Structured-ASIC Synthesis and Verification

Structured-ASIC design provides a mid-way point between FPGA and cell-based ASIC design for performance, area and power, but suffers from the same increasing verification burden associated with cell-based design. In this paper we address the verification issue with a methodology and fabric to directly tie FPGA prototype and functional in-system verification with a clean migration path to structured ASIC. The most important aspects of this methodology are the use of physically identical blocks for difficult-to-verify PLLs, I/O and RAM and a structured re-synthesis of FPGA logic blocks to target cells that guarantees anchor points for easy formal verification. 1