Clinical trialist perspectives on the ethics of adaptive clinical trials: a mixed-methods analysis

Abstract Background In an adaptive clinical trial (ACT), key trial characteristics may be altered during the course of the trial according to predefined rules in response to information that accumulates within the trial itself. In addition to having distinguishing scientific features, adaptive trials also may involve ethical considerations that differ from more traditional randomized trials. Better understanding of clinical trial experts’ views about the ethical aspects of adaptive designs could assist those planning ACTs. Our aim was to elucidate the opinions of clinical trial experts regarding their beliefs about ethical aspects of ACTs. Methods We used a convergent, mixed-methods design employing a 22-item ACTs beliefs survey with visual analog scales and open-ended questions and mini-focus groups. We developed a coding scheme to conduct thematic searches of textual data, depicted responses to visual analog scales on box-plot diagrams, and integrated findings thematically. Fifty-three clinical trial experts from four constituent groups participated: academic biostatisticians (n = 5); consultant biostatisticians (n = 6); academic clinicians (n = 22); and other stakeholders including patient advocacy, National Institutes of Health, and U.S. Food and Drug Administration representatives (n = 20). Results The respondents recognized potential ethical benefits of ACTs, including a higher probability of receiving an effective intervention for participants, optimizing resource utilization, and accelerating treatment discovery. Ethical challenges voiced include developing procedures so trial participants can make informed decisions about taking part in ACTs and plausible, though unlikely risks of research personnel altering enrollment patterns. Conclusions Clinical trial experts recognize ethical advantages but also pose potential ethical challenges of ACTs. The four constituencies differ in their weighing of ACT ethical considerations based on their professional vantage points. These data suggest further discussion about the ethics of ACTs is needed to facilitate ACT planning, design and conduct, and ultimately better allow planners to weigh ethical implications of competing trial designs.http://deepblue.lib.umich.edu/bitstream/2027.42/111302/1/12910_2015_Article_22.pd

The S troke H yperglycemia I nsulin N etwork E ffort ( SHINE ) trial protocol: a randomized, blinded, efficacy trial of standard vs. intensive hyperglycemia management in acute stroke

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102726/1/ijs12045.pd

Bayesian hierarchical EMAX model for doseâ response in early phase efficacy clinical trials

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149669/1/sim8167_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149669/2/sim8167.pd

Platelet‐Oriented Inhibition in New TIA and Minor Ischemic Stroke ( POINT ) Trial: Rationale and design

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99014/1/ijs12129.pd

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

BACKGROUND—Combination antiplatelet therapy with clopidogrel and aspirin may reduce the rate of recurrent stroke during the first 3 months after a minor ischemic stroke or transient ischemic attack (TIA). A trial of combination antiplatelet therapy in a Chinese population has shown a reduction in the risk of recurrent stroke. We tested this combination in an international population. METHODS—In a randomized trial, we assigned patients with minor ischemic stroke or high-risk TIA to receive either clopidogrel at a loading dose of 600 mg on day 1, followed by 75 mg per day, plus aspirin (at a dose of 50 to 325 mg per day) or the same range of doses of aspirin alone. The dose of aspirin in each group was selected by the site investigator. The primary efficacy outcome in a time-to-event analysis was the risk of a composite of major ischemic events, which was defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days. RESULTS—A total of 4881 patients were enrolled at 269 international sites. The trial was halted after 84% of the anticipated number of patients had been enrolled because the data and safety monitoring board had determined that the combination of clopidogrel and aspirin was associated with both a lower risk of major ischemic events and a higher risk of major hemorrhage than aspirin alone at 90 days. Major ischemic events occurred in 121 of 2432 patients (5.0%) receiving clopidogrel plus aspirin and in 160 of 2449 patients (6.5%) receiving aspirin plus placebo (hazard ratio, 0.75; 95% confidence interval [CI], 0.59 to 0.95; P = 0.02), with most events occurring during the first week after the initial event. Major hemorrhage occurred in 23 patients (0.9%) receiving clopidogrel plus aspirin and in 10 patients (0.4%) receiving aspirin plus placebo (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). CONCLUSIONS—In patients with minor ischemic stroke or high-risk TIA, those who received a combination of clopidogrel and aspirin had a lower risk of major ischemic events but a higher risk of major hemorrhage at 90 days than those who received aspirin alone. (Funded by the National Institute of Neurological Disorders and Stroke; POINT ClinicalTrials.gov number, NCT00991029.

Safety assessment of high-dose narcotic analgesia for emergency department procedures

Study objective:To evaluate the safety of high-dose IV narcotics in patients requiring analgesia for painful emergency department procedures.Design:Prospective multicenter clinical trial.Setting:Five adult urban EDs.Methods and measurements:All patients received IV meperidine (1.5 to 3.0 mg/kg) titrated to analgesia followed by a painful procedure. Vital signs and alertness scale were recorded at regular intervals, and patients were observed for four hours. Adverse events were monitored and documented. Comparisons between baseline and postanalgesia intervals were made with a repeated measures ANOVA (Dunnett's test).Results:Although statistically significant changes in vital signs and alertness scale occurred, they were not clinically significant. Opiate reversal with naloxone was not needed in any patient, and no significant respiratory or circulatory compromise occurred.Conclusion:This study of 72 patients demonstrates that high-dose narcotic analgesia is appropriate, well tolerated, and safe when used in selected patients before painful procedures in the ED. Narcotic antagonists and resuscitation equipment nonetheless should be available to maximize safety.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30581/1/0000218.pd

The Empirical Foundations of Telemedicine Interventions for Chronic Disease Management

The telemedicine intervention in chronic disease management promises to involve patients in their own care, provides continuous monitoring by their healthcare providers, identifies early symptoms, and responds promptly to exacerbations in their illnesses. This review set out to establish the evidence from the available literature on the impact of telemedicine for the management of three chronic diseases: congestive heart failure, stroke, and chronic obstructive pulmonary disease. By design, the review focuses on a limited set of representative chronic diseases because of their current and increasing importance relative to their prevalence, associated morbidity, mortality, and cost. Furthermore, these three diseases are amenable to timely interventions and secondary prevention through telemonitoring. The preponderance of evidence from studies using rigorous research methods points to beneficial results from telemonitoring in its various manifestations, albeit with a few exceptions. Generally, the benefits include reductions in use of service: hospital admissions/re-admissions, length of hospital stay, and emergency department visits typically declined. It is important that there often were reductions in mortality. Few studies reported neutral or mixed findings.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140284/1/tmj.2014.9981.pd

Reflections on the adaptive designs accelerating promising trials into treatments (ADAPT-IT) process—Findings from a qualitative study

ContextThe context for this study was the Adaptive Designs Advancing Promising Treatments Into Trials (ADAPT-IT) project, which aimed to incorporate flexible adaptive designs into pivotal clinical trials and to conduct an assessment of the trial development process. Little research provides guidance to academic institutions in planning adaptive trials.ObjectivesThe purpose of this qualitative study was to explore the perspectives and experiences of stakeholders as they reflected back about the interactive ADAPT-IT adaptive design development process, and to understand their perspectives regarding lessons learned about the design of the trials and trial development.Materials and methodsWe conducted semi-structured interviews with ten key stakeholders and observations of the process. We employed qualitative thematic text data analysis to reduce the data into themes about the ADAPT-IT project and adaptive clinical trials.ResultsThe qualitative analysis revealed four themes: education of the project participants, how the process evolved with participant feedback, procedures that could enhance the development of other trials, and education of the broader research community.Discussion and conclusionsWhile participants became more likely to consider flexible adaptive designs, additional education is needed to both understand the adaptive methodology and articulate it when planning trials