Info & Opinion
April 25, 2019
With news about big data, Aetna, Covance, GNS, Scrip, Quintiles, PPD, Icon, BioClinica, Merge, Medidata and GSK.
With news about FDA, CTMS, PMG Research, Inclinix, EMA, Hemofarm, Parexel and the Korea Drug Development Fund
David Underwood of Quanticate says some firms are giving short shrift to the basics of clinical trials
With news about Roche, Quintiles, Allscripts, Janssen, SGS, Oracle, TriReme, OpenClinica and FDA
The pace is glacial. But everything the pharmaceutical industry does is becoming more centralized, more standardized—and more electronic. Electrocardiograms (ECGs) are one example. Another is the computer-aided review of endpoints in clinical trials.
Icon has been facilitating endpoint adjudication for as long as any firm in the industry, and we recently had a chance to check in with Rafael Escandon, consulting VP of clinical outcome services. Escandon works in the contract research organization's imaging group.
The electronic, objective, independent assessment of images, he says, is an area of particular pride at Icon. But the firm's technology and services push has taken him and his clinical endpoint committee (CEC) colleagues far afield from imaging, and into a wide swath of other projects. Says Escandon: "This is a different core service. It's one we've built a dedicated team around."
That makes sense. After all, a CEC's blinded work precedes and aids that of the better-known drug safety monitoring boards (DSMB). On a country-by-country or patient-by-patient basis, the CEC tries to normalize the safety information that individual investigators report. Once those data have been aggregated, the DSMB can decide to continue or stop an arm of the trial or the whole study.
By Escandon's estimate, perhaps 15-30 percent of Phase II and Phase III projects have a CEC component. He expects that number to grow even in the absence of formal regulation, despite the 2010 release of a few terms with FDA-blessed definitions.
"There is a role for clinical event or efficacy adjudication in very broad areas of clinical development," Escandon says. "It's the way the regulators are going to require that trials are going to be conducted in the future. There is a potential application for these in all therapeutic areas."
As areas of particularly strong interest, he cites diabetes and cardiovascular disease. With regulators under political pressure to not allow another Vioxx, there's additional scrutiny of every patient experience, every claimed success, every potential drug safety issue.
No 'Check His Calendar'
"The old way that this used to be done was literally getting experts around the conference table with binders and binders of paper," he says. "For those companies who are paying attention in the electronic adjudication environment, Icon has a reputation and its system has a reputation for being very efficient."
Icon's system, for the record, is called Medical Image Review and Analysis (MIRA). It facilitates the two-physician assessment of events. It's unclear how many competing CROs have similarly robust technology offerings to support the work of a CEC.
There are several adjudication processes. By way of example, if two doctors agree on a case, the matter might be deemed to be decided; if they disagree, they may look at the evidence together. If they continue to disagree, a third doctor (the chair of the committee) could be consulted.
The efficiencies from Icon's electronic CEC, he says, depend on several factors. The system resolves the nontrivial issue of scheduling several top experts to be in the same room at the same time. Having all the necessary information in one place makes it easy to generate reports and data extracts.
There is also a simplification of the overall CEC process when using an electronic system, Escandon says. That is paradoxically comforting in a high-stakes era.
With regulatory agencies newly vigilant, an electronic system gives sponsors confidence that as soon as a critical number of ominous cases are adjudicated, they will be able to take action. For big trials with large numbers of high-risk patients, that can provide an extra level of comfort in otherwise disquieting circumstances. Waiting for the availability of experts is part of the old, paper-dependent way of working.
"You want to be able to collect the information and get the events adjudicated as quickly as you possibly can," Escandon says. "The best way to do that is not require these round table meetings of your true experts. You want the ability to push these cases to them as soon as they can be adjudicated. The process isn't encumbered by people's travel schedules."
While the industry does have a decades-long love affair with paper, Escandon says Icon is trying to nudge sponsors toward modernity. "We really believe that paper adjudication is rapidly moving toward obsolescence," he says. "We're encouraging any client that approaches us with an opportunity for endpoint adjudication to do so electronically. In the future, the company-wide philosophy is to move everything to an electronic environment—all projects, large and small."
Icon is seeing subtle shifts in the expectations of regulatory agencies. In one recent client engagement, Escandon says, his firm was helping to compile the CEC element of a regulatory submission. The FDA did not just ask for the distilled conclusions of the CEC. It requested the criteria and verbatim raw, or "source," data that the CEC considered. "They want that," Escandon says. "That is something new."
At that point, the ability to examine an audit trail from the CEC can reassure regulators that the review of efficacy and safety was handled appropriately. Says Escandon: "What really helps you the most is having an organized workflow and knowing who did what, what they did, and when they did it."
Given the natural variation in how experts interpret the same clinical data, Escandon notes that the Icon system can help identify outlier adjudicators who may not be aligned with peers. As a rule of thumb, experts on any trial might disagree 20 percent of the time. Icon's system helps its clients resolve whether a discordant opinion is resolutely held—or a result of misunderstood diagnostic terminology or some other factor that can be addressed with additional training.
Needless to say, a sponsor of a trial may also need to look at broadening or narrowing the definition of a particular clinical endpoint. As Escandon notes in recounting a variety of high-profile drug safety controversies, such definitions can lead to FDA or even Congressional scrutiny.