Accommodating ''History Effects'' in Long Duration, Multisite Clinical Trials to Ensure Relevant and Compelling Evidence

Over the course of a clinical trial, changes in the practice environment have the potential to reduce internal and external validity and impact change in patient outcomes. Such ''history effects''1 can take the form of changes in standard of care, clinical guidelines and recommendations, new drug/device availability in the marketplace, testing and screening procedures, and, as recently experienced, a global pandemic. Clinical trials conducted over many years are particularly susceptible to history effects. Such effects can impact foundational ability to continue a trial, including clinician equipoise and ability to implement trial interventions, necessitating awareness and action planning. For example, Curtis et al.2 acknowledged challenges with clinical guideline history effects and issued recommendations for addressing them such as consideration of participant wellbeing, stakeholder engagement, safety monitoring, review of guideline and policy changes, and development of rules for protocol changes. This session will explore how four multisite clinical trials conducted with VA Cooperative Studies Program sponsorship and coordination have weathered history effects during prolonged periods of enrollment. Topics to be covered include the implementation of pragmatic designs, monitoring of clinical guidelines, assessing control group treatment conditions, modifying protocols, adjusting quality assurance procedures, refining recruitment pathways, and training site investigators. The speakers, Study Chairs, will describe best practices and provide recommendations for navigating history effects in prolonged multisite clinical trials that can ensure outcomes remain relevant and compelling to inform public health at trial commencement. The CSP 2008/PTXRx study is a pragmatic, randomized, double-blind, placebo-controlled, multicenter clinical trial of Veteran patients with diabetic kidney disease (DKD) examining whether pentoxifylline (PTX), when added to usual care, can delay time to end-stage renal disease or death. Enrollment for the study began in 2019, and it is anticipated that 9 years of follow-up will be required to observe the required number of primary events. Given the long duration of the study, changes in clinical guidelines were anticipated and have occurred, including the approval of new DKD therapies and introduction of a new formula for estimated glomerular filtration rate (eGFR) calculation. In anticipation of these changes, the study design allows for whatever standard of care is extant at any time during the course of the study. PTXR's pragmatic trial design and protocol leverage the VA's research infrastructure and remote platforms allowing the study to be responsive to external changes and to safely continue during a global pandemic. The CSP 596/OPTION study is a randomized, double- blind, multicenter trial of Veteran patients with a first or second recurrent Clostridium difficile infection (CDI) comparing (1) fidaxomicin and (2) vancomycin, followed by a taper and pulse to (3) a standard vancomycin regimen. Since enrollment began in 2016, significant changes in CDI epidemiology and clinical management have impacted the study. The COVID-19 pandemic also resulted in an administrative hold on all trial activity followed by staggered reopening of sites due to variable COVID-19 activity and clinical priorities. Many clinical laboratories switched to algorithms that included free toxin assays in addition to polymerase chain reaction (PCR) tests out of concern for overdiagnosis based on PCR testing alone, reducing the number of potentially enrollable cases. There has been increased empirical vancomycin treatment for recurrent CDI without confirmation by stool testing, a requirement for enrollment, and a recruitment strategy for identifying potential cases. Finally, conflicting clinical guidelines for recurrent CDI has created potential equipoise when considering enrollment. Ongoing educational efforts have been made to clarify the protocol and emphasize the validity of the research question as well as protoco changes to allow safe enrollment and follow-up of participants in the face of the ongoing COVID-19 pandemic. The CSP 2005/VALOR is a phase III randomized, open label, multicenter clinical trial of Veteran patients with operable stage I non-small cell lung cancer that compares stereotactic radiotherapy and anatomic pulmonary resection with a primary outcome measure of overall survival. The study was activated in 2017 and recruitment to the trial has been affected by ongoing changes in public and clinician perceptions about stereotactic radiotherapy and surgery that have interfered with equipoise and willingness of participants to enroll. The study team perpetually addresses this challenge through group conversations with local site investigators, study coordinators, and other research personnel to preserve group equipoise across the study. Since the study's activation, new safety information about stereotactic radiotherapy has emerged necessitating protocol modifications while aiming to preserve internal and external validity. The includes modifying standard operating procedures for the study's centralized quality assurance program that has had to adapt its process to remain contemporary. STARPORT, funded by VA CSRD with CSP collaboration, is a randomized, open label, multicenter clinical trial of Veteran patients with oligorecurrent prostate cancer comparing the effects of standard systemic therapy (SST) alone or with PET-directed local therapy using surgery or radiation. Although enrollment was initiated in 2021, changes are already evident in clinical practice guidelines regarding the use of imaging in workup in this patient population. Shortly before the start of accrual, 18F-DCFPyL PSMA PET/CT received FDA-approval. Consequently, it is being rapidly adopted at the STARPORT VA medical centers and the use of conventional imaging using CT or bone scan prior to PET/CT imaging-part of the original eligibility criteria-quickly is falling out of favor. Furthermore, shortly after the start of enrollment, NCCN guidelines adopted the stance that conventional imaging was no longer required in the setting of PSMA PET/CT imaging, solidifying the transition away from conventional imaging. Thus, the protocol is being amended to remove the requirement for conventional imaging as part of workup for oligorecurrence. In addition, to be generalizable, the study is designed to integrate future PSMA radiotracers that are incorporated into practice as well as changes in SST regimens over the time of the study.

Tools to Reduce Low-Value Care: Lessons From COVID-19 Pandemic Comment on "Key Factors that Promote Low-Value Care: Views of Experts From the United States, Canada, and the Netherlands".

Based on a summary of interviews with 18 experts, Verkerk et al defined the seven key factors that promoted low-value care, which included system, social, and knowledge factors. During the ongoing coronavirus disease 2019 (COVID-19) pandemic, these key factors have been influential due to the uncertainty of the disease at the beginning of the pandemic. Globally, several measures have been implemented to reduce low-value care practices and promote high-value care for COVID-19 patients. From huge multicenter, non-industry sponsored or multiplatform trials, to the use of social networks sites is an indispensable and effective way to disseminate medical information. Thanks to these measures, we have transformed a scenario of ignorance into an evidence-based medical scenario in less than a year. Verkerk and colleagues' proposed key factors are an excellent framework for characterizing and highlighting the lessons that can be learnt from how we have fought against the pandemic and low-value practices.

POTENTIAL OVERUSE OF DIAGNOSTIC TESTS FOR EVALUATION OF PULMONARY EMBOLISM

SESSION TITLE: All About the CLOT: VTE SESSION TYPE: Original Investigations PRESENTED ON: 10/16/2022 10:30 am - 11:30 am PURPOSE: Pulmonary embolism (PE) is a disorder of coagulation that results in significant morbidity, mortality and emergency department visits. The usage of advanced imaging for the diagnosis of PE has increased greatly, almost 400% from 1998 to 2008. The Well’s Criteria for PE uses historical features, clinician gestalt, and heart rate to risk stratify patients for PE. The score ranges from 0-12.5 and is broken down into low risk 0-2, intermediate risk 3-6, and high risk 7+. The current American College of Emergency Physician guidelines advise that a patient suspected to be at risk for PE with a low or intermediate risk can undergo age adjusted D-Dimer testing. A further addition was the PERC rule. This rule applies 8 questions to the low risk PE patient and 8 negative responses mean the clinician can forgo D-Dimer testing. How well are we adhering to this guidance, and are deviations leading to unnecessary testing which could expose our patients to harm? METHODS: 280 sequential patients receiving diagnostic testing for PE were evaluated and 156 were excluded due to known, suspected, or history of COVID-19 infection. The work-up for the included patients was reviewed and Well’s criteria and the PERC rule were applied by retrospective review. Descriptive statistics were used to describe the proportion of patients evaluated with tests not suggested for their risk strata. RESULTS: Of the 124 patients evaluated, 31/124 (25%) had potentially unnecessary testing. 18 low risk patients underwent advanced imaging—17 CTAs and 1 VQ scan– without being tested by D-Dimer. 11 low risk, PERC rule negative patients still received D-Dimers–all negative, and 1 underwent CTA. One negative age-adjusted D-Dimer still lead to a CTA. One patient with a negative D-Dimer received CTA. These 18 CTAs and 1 VQ scan were all interpreted negative for PE. CONCLUSIONS: Patients undergoing evaluation in emergency departments in the United States may be undergoing unnecessary diagnostic testing based on current guidelines and the summation of the highest quality evidence available for directing the choice of how best to evaluate this patient population. CLINICAL IMPLICATIONS: The utilization of CTA for the diagnosis of PE is not without risk. Some estimate 20 additional breast cancers per 100,000 women undergoing the test. CTA studies for PE also pose the risk of unnecessary anticoagulation. A meta-analysis of imaging for PE showed an over diagnosis rate as high as 60% for subsegmental PE when these studies were re-reviewed by a panel of expert chest radiologists. This is quite high, but even more modest meta-analyses have shown a 10% false positive rate. Patients placed on anticoagulation have an annual bleeding risk attributed to anticoagulation of 7% and mortality attributed to anticoagulation of 0.4%. Creative strategies aimed at reducing unnecessary testing can help mitigate some of this risk and protect our patients. DISCLOSURES: No relevant relationships by Parth Gandhi research support relationship with Bristol Myers Squibb Please note: 2021-2022 Added 03/31/2022 by Jason Nomura, value=Grant/Research Consultant relationship with Philips Please note: 2020-2022 Added 03/31/2022 by Jason Nomura, value=Consulting fee No relevant relationships by Dustin Slagle

Hidden pandemic: Handling behavioral addiction during COVID-19 chaos in Low Middle-Income Countries

Symposium summary: Over the last few decades, the medical concept of addiction disorders has undergone tremendous development. Addictive disorders are currently considered a multifactorial chronic disease and have become a significant cause of global health problems and other psychiatric disorders. Not only drug addiction but also the number of behavioral addiction patients continues to increase. The outbreak of Coronavirus Disease 2019 (COVID-19) spread across the entire world has curtailed most individuals' daily activities and movements. In response, the COVID-19 pandemic lets individuals engage more with technology use, providing escapism to several activities (e.g., shopping, eating, gambling, gaming, doing physical exercise, watching pornography). These activities allow them to find some acute emotional relief, albeit pathologically. These behaviors happened by accessibility, availability, and the absence of prevention and management programs for excess use. The COVID-19 pandemic and the lockdown policies in several countries have created a new paradigm regarding the prevention of specific strategies for behavioral addiction, primarily due to the increase in internet use that leads to addiction. A standard is needed to manage behavioral addiction, both pharmacological and non-pharmacological, in a holistic and comprehensive manner. Besides, an instrument is needed to distinguish healthy gamers, problematic gamers, and gaming disorders in order to prevent overdiagnosis. Notably, the symposium will highlight the emerging issue of behavioral addiction such as gambling, gaming, and pornography in Low Middle-Income Countries during the pandemic, exploring global solutions to international problems in the field of addiction medicine. In this symposium, there will be one chair and four speakers.

Assessing breast cancer screening results through the lens of COVID-19 pandemic

Background: In January, 2020 World Health Organization (WHO) declared the COVID-19 outbreak as the first global health emergency. Lockdowns and restrictive procedures with the full and partial cancellation of preventive measures, including breast cancer (BC) screening, took place in Kazakhstan in 2020-2021. Purpose of this study: to determine the impact of the COVID-19 pandemic on BC screening results. Methods: The main screening indicators before (2018-2019) and during the COVID-19 pandemic (2020-2021) were studied: planned coverage and number of examined patients, the proportion of BI-RADS categories (where BI-RADS categories 4-5 are accepted as suspicious for malignancy, additional imaging by ultrasound and/or mammography followed biopsy is recommended), the number of detected cancer cases, the stage of the disease according to the screening database and the Electronic Cancer Registry. Results: 1,624,667 women underwent BC screening in 2018-2019 (96.2% of the planned amount of 1,688,829 women). 1,532,591 (79.4%) women were examined in 2020- 2021, though the planned amount was 1,930,515. Before the epidemic, 23,296 patients received BI-RADS categories 4-5 (1.43% from examined women) and were referred for additional ultrasound and mammography examination, in 2020-2021 - 25,008 women (1.63%). 74.2% (1,205,094 women) had BI-RADS category 1 in 2018-2019 and 63.4% (971,754 patients) - during the pandemic. In 2018-2019 - 3,377 BC cases were detected (cancer detection rate was 2.0 per 1000 investigations). In 2020-2021 - 2,474 BC cases were identified (cancer detection rate 1.6 per 1000 investigations). Proportion of screen-detected cancers in stage 0-I was 45.1% in 2018-2019 and 47.5% in 2020- 2021. During the pandemic, the number of participants who underwent BC screening significantly decreased (by 20.6% of the planned). The level of cancer detection decreased too (by 22.8%). There was an increase in patients requiring further examination (BI-RADS categories 4-5) and decrease the number women with BI-RADS 1. With an increase in indications for additional ultrasound and radiological examination, the number of revealed cancers reduced by 1.5 times (in 2018-2019, 14.5% patients with BI-RADS categories 4-5 had BC confirmed, in 2020-2021 - only 9.9%). Conclusions: BC screening has been significantly reduced during the COVID-19 pandemic. At the same time, attention should be paid to the increase in overdiagnosis of mammographic pathology, possibly due to an increase in the density of breast tissue on the background of nonspecific inflammation accompanied by lymphadenopathy. The impact of COVID-19 on BC is still unknown. Further research will be needed to confirm the link between COVID-19 and mammography picture and BC.

Computed tomography (CT) utility for diagnosis and triage during COVID-19 pandemic

The nasopharyngeal smear with PCR analysis is the first diagnostic test proposed to confirm infection with COVID-19 SARS-CoV-2. However, its usefulness in emergency centers is limited due to its imperfect sensitivity (56-83%), limited availability and the time required to obtain results. For this reason, the chest CT-scan has been proposed as a rapid triage tool for diagnosis in these suspect Covid-19 patients. However, its specificity is limited, exposing to the risk of over-diagnosis, and further data are needed to confirm its usefulness, and to highlight the possible prognostic value of the CT, in detecting early lesions associated with poor outcome, indicating the need for admission to intensive care.

Evidence That the Diagnosis of ADHD Does Not Reflect a Chronic Bio-Medical Disease

Is attention deficit hyperactivity disorder (ADHD) the “diabetes of psychiatry”? According to the dominant bio-medical model, ADHD is a chronic neuro-genetic condition with numerous negative outcomes. Without clear biological markers, however, this model receives support from the notions that the diagnosis (a) is stable overtime and across populations and (b) requires a constant treatment with chemical substances (e.g., Ritalin). Through three consecutive studies, this research investigates the validity of these two notions in Israel. Studies 1 (N = 502) and 2 (N = 853) addressed young adults while Study 3 (N = 195) focused on mothers to children with ADHD during the COVID lockdown. The findings indicated that the ADHD diagnosis is unreliable. Its prevalence exceeded 20%, a substantially higher figure than the consensual 5% estimate, and was not consistent between different communities (i.e., the less conservative the person is, the more likely that she/he will be diagnosed). The diagnosis also did not reflect a chronic and harmful condition that requires constant pharmacological management. Indeed, rates of prescribed medications were extremely high, thus implying the dominancy of the bio-medical model. However, in practice, medications were used very selectively, mainly during school/college times (i.e., not when schools were closed), to improve school-related performances. These findings, alongside a critical review of the current status of the physiological literature on ADHD (offered in the general discussion), undermine the bio-medical perception of ADHD. The clinical label of ADHD does not seem to reflect an objective chronic brain disease, but a modern social phenomenon in which children's normative traits are being medicalized, mainly in response to external school-related demands. © Copyright 2021 Springer Publishing Company, LLC.