Futility and toxicity monitoring without halting for interim analyses.

e13579 Background: Many trial designs with futility or toxicity monitoring require that accrual halt to wait for currently enrolled patients to complete their assessment window. However, logistics often prevent this. In these cases, the performance of those designs might be compromised. This study examines the performance of 2 popular designs when enrollment is not halted at interim. Methods: Simulations were run to examine the effect of continuous enrollment on the operating characteristics (OCs) of a Simon’s 2-stage design for futility monitoring and a design using Bayesian posterior probabilities for toxicity monitoring. Both sets of 10,000 simulations examined the OCs when accrual rate was 0.5, 1.5, 3 and 5 patients/month with an assessment window of 30, 60 and 180 days. Results: The first scenario examined the OCs of a Simon design with 12 patients in the first stage and 21 at the end of the second stage. Regardless of accrual rate, the expected number of patients (EN0) increased and probability of early termination (PET0) decreased under the null hypothesis. Rate of change increased as assessment window increased. EN0 was 16 and PET0 was 54% when halting enrollment between stages. With continuous enrollment, EN0 ranged from 16-19, 17-21, and 18-21 patients for the 30-, 90- and 180-day assessment windows. PET0 ranged from 54%-50% with a 30-day assessment window. It halved to 24% with 3 patients/month enrolled and a 90-day window. PET0 was essentially 0 with a 180-day window and an enrollment of 3 patients/month. OCs for toxicity monitoring were examined for the early stopping rule Pr(toxicity rate > 0.3 | data) > 0.85 with toxicity rate ̃ beta(1, 1) with a maximum sample size of 20 and cohort size of 5. Expected number of patients (EN) increased and probability of early termination (PET) decreased as accrual rate increased, with rate of change increasing as assessment window increased. When the true probability of toxicity was 50% and enrollment halted between cohorts, EN was 10 patients and PET was 78%. EN was 17 and PET 54% with an assessment window of 30 days and 5 patients were enrolled per month. With a 90-day assessment window and 3 patients/month enrolled, EN was 16 and PET 59%. EN was 20 and PET was 12% with a 180-day assessment window and 3 patients were enrolled per month. Similar results were noted for cohorts of size 10 and a maximum number of 40 patients. Conclusions: The performance of designs that require halting enrollment while waiting for results of an interim analysis can be compromised by continuous accrual when assessment windows are lengthy and the accrual is fast. In these circumstances, consideration should be given to designs, such as Bayesian multiple imputation for delayed outcomes (Cai et al Stat Med 2014) and TOP2 (Lin et al JNCI 2019), that do not require accrual halt to make real-time interim analysis in the presence of pending patients, which protects patients from excessive toxicity or a futile intervention.

Manipulating Levels of Socially Evaluative Threat and the Impact on Anticipatory Stress Reactivity

Previous work suggests that relative increases in socially evaluative threat modulate the psychobiological stress response. However, few studies have compared stressors which manipulate the level of socially evaluative threat to which the participant is exposed. Here we present two studies. In the first, we assessed the integrity of an ecologically valid, laboratory stressor (direct socially evaluated multitasking) and its effects on acute psychobiological reactivity and ability to evoke an anticipatory response prior to participation. Specifically, we assessed whether the expectation and experience of direct social evaluation (multitasking while standing and facing an evaluator) evokes greater reactivity than indirect evaluation (over-the-shoulder evaluation). In the second study, we sought to replicate the findings regarding acute stress reactivity whilst extending the assessment window to assess the extent to which the stressor evokes anticipatory responses. As hypothesized, greater reactivity was observed following direct social evaluation compared with indirect observation. Increases in anxiety, heart rate and blood pressure were demonstrated across both studies and the paradigm therefore provides an ecologically valid technique for the activation of psychological and cardiovascular stress responding. Additionally, anticipation of experiencing socially evaluated multitasking led to increases in anxiety, tension, and worry prior to the event itself, supporting previous suggestions that threat anticipation may prolong the activation of stress mechanisms. In the present studies we assessed whether the expectation and experience of direct social evaluation evokes greater reactivity than indirect evaluation. The findings have demonstrated that direct social evaluation of multitasking is a more potent stressor than multitasking with indirect evaluation. Furthermore, our findings indicate that the period of anticipation of stressful events may be critical to understanding the process of stress regulation, and as such we recommend extending the sampling window to allow for the investigation of these processes.

An Evaluation of the Utility of Big Data to Supplement Cancer Treatment Information: Linkage Between IQVIA Pharmacy Database and the Surveillance, Epidemiology, and End Results Program

Oral anticancer medications (OAMs) are increasingly utilized. We evaluated the representativeness and completeness of IQVIA, a large aggregator of pharmacy data, for breast cancer, colon cancer, chronic myeloid leukemia, and myeloma cases diagnosed in six Surveillance, Epidemiology, and End Results Program (SEER) registries between 2007 and 2011. Patient’s SEER and SEER-Medicare data were linked and compared with IQVIA pharmacy data from 2006 to 2012 for specific OAMs. Overall, 67.6% of SEER cases had a pharmacy claim in IQVIA during the treatment assessment window. This varied by location, race and ethnicity, and insurance status. IQVIA consistently identified fewer cases who received an OAM of interest than SEER-Medicare. The difference was least pronounced for breast cancer agents and most pronounced for myeloma agents. The IQVIA pharmacy database included a large portion of persons in the SEER areas. Future studies should assess receipt of OAMs for other cancer sites and in different SEER registries.

Efficiency Measure Under Inter-Temporal Dependence

In this paper, a linear programming (LP) model is proposed to estimate the efficiency of a decision-making unit (DMU) in the framework of dynamic Data Envelopment Analysis (DEA). Necessary and sufficient conditions required for characterizing dynamically efficient paths are established. An LP model is proposed to estimate the dynamic cost efficiency (DCE) measure. It is proved that the aggregate CE in an assessment window is a convex combination of CEs of available periods in the assessment window. In addition, it is shown that a DMU in an assessment window is dynamically efficient when the DMU is dynamically cost/revenue efficient. Mathematical relationships between relative, cost, revenue, and profit efficiencies are studied in the framework of dynamic DEA.