Protecting the confidentiality of interim data: addressing current challenges

Abstract

There is compelling evidence supporting the importance of maintaining confidentiality of interim data in clinical trials designed to reliably address the benefit-to-risk profile of interventions. While this is widely recognized, creative approaches are needed to achieve this in challenging settings where interim data are released for regulatory review and action, even though the trial would be continued to address its primary hypothesis. An illustration is the recently emerging setting of cardiovascular safety trials in type 2 diabetes mellitus. At the first stage of such trials, if large relative increases in cardiovascular major morbidity/mortality can be ruled out, data can be released solely for the purpose of allowing regulatory decision making about marketing approval. The trial is then continued in the post-marketing setting to address the primary hypothesis regarding whether smaller relative increases can be ruled out. Active rather than passive approaches are needed to protect the integrity of cardiovascular safety trials. Given the importance to trial integrity of maintaining confidentiality of interim data such as the estimated relative effect on cardiovascular risk, a Data Access Plan should be in place in these trials to ensure such data are not revealed to study participants and their caregivers, investigators involved in trial conduct, the sponsor's management team, and the public, until trial completion. A Performance Standards Document also should be developed to pre-specify targeted and minimally acceptable levels for recruitment rate, best real-world achievable adherence, avoidance of cross-ins, and retention rate. This document should specify creative approaches for achieving these targets, oversight procedures during trial conduct to monitor performance levels, and actions to be taken if emerging data indicate minimally acceptable levels are not being reached. In settings where meaningful breaches in confidentiality have occurred, such oversight allows adverse effects on trial integrity to be detected earlier and more effectively addressed.

Keywords: Data Access Plan; Data Monitoring Committee; Performance Standards Document; cardiovascular safety trials.

Figure #1

The Commuity Programs for Clinical Research on AIDS compared zalcitabine (ddC) against the control, didanosine (ddI). The number of events on ddC and ddI, respectively are provided in parentheses under the calendar date of each of the 4 analyses. At each analysis, the estimated ddC to ddI hazard ratio for the rate of progression to symptomatic AIDS or death is represented by asterisks, the square brackets represent nominal 95% confidence intervals, and the orange parentheses represent the O'Brien-Fleming repeated confidence intervals properly adjusting for the group sequential analyses.

Figure #2

The Normal Hematocrit Trial was designed to evaluate the rates of death/MI events on a high dose relative to a standard dose regimen of an erythropoietin stimulating agent. The figure presents a monitoring boundary for superiority (in blue), ruling out the null hypothesis of a 1.00 hazard ratio, and a monitoring boundary to rule out a 0.75 hazard ratio (in black), when analyses are conducted after equal increments in the occurrence of the trial's planned 742 death/MI events. L denotes the number of events available at each analysis. The orange asterisks illustrate estimates for the hazard ratio that could be obtained at the mid-point of the trial.

Figure #3

In the type 2 diabetes mellitus setting, a 610-event cardiovascular safety trial may be conducted to determine whether one can rule out an experimental to control hazard ratio of 1.3 for the composite endpoint, ‘CV death, stroke, myocardial infarction’. At that final analysis, if the estimated experimental to control hazard ratio is less than 1.10, then the ‘1.3 margin’ is ruled out, if it is less than 0.85, then superiority is established, and if it is greater than 1.18, then harm is established. Early termination for superiority occurs if the blue boundary is crossed and for harm occurs if the black boundary is crossed. L denotes the number of events available at each interim analysis. Data from the 122-event analysis might be used to support early regulatory decisions about marketing approval if an experimental to control hazard ratio of 1.8 for the composite endpoint can be ruled out, requiring an estimate less than 1.26. Orange asterisks illustrate hazard ratio estimates that could be obtained at that analysis. Boundaries that do not trigger decisions for trial termination are denoted by dashed lines.

Figure #4

Some of the important performance standards measures in CV safety trials are provided. Illustrations are given for potential adverse consequences when there is direct or indirect public disclosure of the estimate from interim data for the experimental to control hazard ratio for the CV safety endpoint, such as when interim data yield a favorable 0.8 or an unfavorable 1.2 estimate.