Info & Opinion
June 25, 2016
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David Underwood of Quanticate says some firms are giving short shrift to the basics of clinical trials
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Jeff Sloan is a professor of oncology and health sciences at the Mayo Clinic. His specialty is the quality of life of the cancer patient. Sloan has been involved in patient-reported outcome (PRO) research for years, in both academic and industry projects.
“The science is progressing,” Sloan told a Center for Business Intelligence (CBI) symposium dedicated to the topic in May of this year. “We really have not taken a step backward. We should knock on wood.”
Over the past 5 to 15 years, Sloan said, his colleagues in the clinical realm have changed their view of patient-reported outcomes. “The opinion of our clinical colleagues has changed substantially. The majority of clinicians think PROs are valuable, are usable,” Sloan says.
Even the National Cancer Institute is contracting a new instrument to assess adverse events from a patient perspective. Memorial Sloan Kettering has the lead on the effort, known as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE); the FDA is involved. Which is a sign, Sloan says, that the field of PRO has reached a new level of prominence. “To me,” he said, “that is an indication by a regulatory agency of potentially thinking of having every trial have a PRO outcome.”
Sloan suspects patients could have a very different experience of adverse events. “The patient perspectives on adverse events are quite different than clinicians,” Sloan says. “The clinician-rated toxicity scores are not necessarily terribly correlated with the patient scores of the same systems. This is not to say the clinician ratings are bad. They're just different.”
To be clear, patients might rate various adverse events as more or less serious, depending on the overall burden of their illnesses. A case in point, he notes, is an approved cancer drug that produces a buzzing sensation, almost as if bees are flying around the hands. The cancer patients understand that they face more life-threatening issues. But a PRO instrument can help identify and quantify the buzzing before it becomes a distraction to clinicians or regulators.
Sloan says that the issue in some trials is usually not whether PRO is appropriate in the abstract, but exactly how to proceed in a way that the FDA will accept as scientifically valid. That’s not a new problem for industry, of course. But in the case of PRO projects, it can add new terminology and hurdles along the path to finalizing a protocol.
Those obstacles are surmountable, Sloan says. For starters, does the sponsor have a defensible conceptual framework—a rigorous model of what it is going to measure? Sponsors may need to adapt timelines and budgets to include a few related steps for planning; a short survey; and a PRO-related conversation with regulators.
“This doesn't have to be burdensome,” Sloan says. “You don't have to study 500 people do this. The basic message you need out of qualitative data can be obtained relatively quickly and effectively. It is a worthwhile endeavor.”
After the conference, we sat down with Sloan for a bit of context to the PRO field. In the 1980s, he related, there was a burst of enthusiasm for measuring patients' quality of life (QOL). As the notion of QOL was incorporated into trials, however, the results were less transformative than some scientists and clinicians had anticipated. The reasons are not clear. Perhaps the burden of recording the experiential information from patients was excessive. Perhaps the trials didn’t frame the correct questions.
Today, with PRO in the 21st century, the clinical trial community has built upon the QOL research. Says Sloan: “Guidelines have come out and scientific papers have come out, to say this is the way you should go about it. We've got more precise definitions of how to go about things. I see companies incorporating PROs in the process much earlier.”
Sloan acknowledged that the ultimate goal of putting some of the PRO results into a drug's label is one appeal. It has attracted not only the industry's epidemiologists and outcomes researchers, but also marketing professionals intrigued by PRO instruments that reveal competitive differences between products. Putting PRO claims on drug labels is feasible, Sloan says, as long as the project unfolds with rigor. Said Sloan: “The key is to define what you claim as your target, in terms of which things are measurable by PROs—and justify that.”
Does having an electronic PRO tool make a difference? As an academic, Sloan is not a guy promoting paperless, computerized approaches. He will say there should be no significant differences between paper- and electronically-gathered patient experiences. And in reflecting on some of the presentations at the CBI conference, he acknowledged that in some trials, ePRO appears to reduce the labor that sponsors require of patients in trials.
Recalling an earlier project in bowel disease, he notes that its patients were asked to collect their stool samples for a considerable period of time. Such trial data may contain bias, he surmised, simply because of the onerous demands made upon patients with unusual dedication to advancing the frontier of science.
In that research, he said, the central question became clearer over time. The most clinically relevant issue was not just a tabulation of the number of daily bowel movements. (That varied between individuals.) Rather, the more practical question turned out to be, Is the number of bowel movements a problem for you? That pointed toward other disruptions in sleep patterns and job and family responsibilities in ordinary life.
At the conference in Virginia, Wyeth presented a case history for electronic devices in women's health. Sloan found that presentation worthwhile and its handheld diary a significant improvement over the methodology of the earlier bowel movement research. But he was careful to say that for some therapeutic areas, there are still not yet widely accepted, precise instruments which correlate a) what patients experience individually and b) what scientists can measure physiologically. Still, that is changing as PRO research becomes more sophisticated.
So Sloan can imagine an era in the future when almost every trial uses PRO. “I don't think that is far fetched," he muses. "Every doctor is interested in their patients’ well being, in their patients’ quality of life. There are going to be routinely collected data in the majority of clinical trials that would involve the patient.”