It’s one of the most seductive ideas in medicine: that “real-world evidence,” including data from electronic health record systems and even records of insurance payouts, could replace the far more expensive and time-consuming studies currently considered the gold standard.
The Food and Drug Administration is required, under the 21st Century Cures Act, to explore this idea. And late last month, New York private health care company Aetion published the findings of a study in which real-world evidence was used to try to replicate the results of a specific randomized, controlled clinical trial.
Did it work? It depends on who you ask.
Aetion’s co-founder, Dr. Sebastian Schneeweiss of Brigham and Women’s Hospital, argued that the study was “quite an achievement.” “It has elevated the conversation from ‘real-world evidence is all bad’ to ‘let’s have a differentiated conversation about this, maybe there is something really good about this,’” he said.
But several other experts who reviewed the data had a different reaction, with two saying no amount of new information would convince them that Aetion’s approach is workable. One of them called the attempt “dangerous.”
The FDA, which funded the study, came down somewhere in the middle. An agency spokeswoman said there is a “stronger scientific justification” for randomized controlled trials, but that “recent efforts to use rigorous design and statistical methods” might lead to a greater chance of obtaining valid results with real-world evidence.
The FDA has contracted with Aetion and the Brigham to try to duplicate the results of 30 completed randomized trials. The agency has also challenged Aetion to duplicate seven randomized trials that are currently underway.
The new data, however, come from a separate attempt by Aetion researchers — one in which they initiated a pilot attempt to replicate the CAROLINA study, which was being run by Boehringer Ingelheim and Eli Lilly to compare their diabetes drug, Tradjenta, to an older treatment, glimepiride. The pilot was funded by the FDA and the Brigham.
Results of the clinical trial have not been published, but they were presented at the annual scientific meeting of the American Diabetes Association on June 10. The data showed Tradjenta was “non-inferior” when it came to reducing the combination of heart attacks, strokes, and cardiovascular deaths.
Aetion came to the same conclusion based on its use of real-world data.
But there was also a difference. While both the Aetion study and CAROLINA showed that Tradjenta was also non-inferior in terms of episodes of hypoglycemia, or low blood sugar, the reduction in hypoglycemia was bigger in the clinical trial than in Aetion’s prediction.
The FDA spokesman said the agency and the researchers “will closely examine the full results of the trial when they are publicly available.”
Dr. Robert Califf, a former FDA commissioner and Duke University professor, said that Aetion “does careful work” and that the paper “looks solid.” He also said, as he has in the past, that he favors an approach to research whereby randomized controlled trials are conducted more cheaply and quickly by building the capacity to conduct them into electronic health records.
But Dr. Steven Nissen, who is the chief academic officer of the Sydell and Arnold Miller Family Heart and Vascular Institute at the Cleveland Clinic, was less complimentary.
“I didn’t know whether to laugh or cry when I read this,” Nissen said. “The fact that they got the right answer doesn’t mean it’s good research. And it’s not a good methodology and it’s not a substitute for careful, thoughtful prospective clinical trials,” he said.
“Is it useless? It’s not completely useless as a hypothesis-generating approach, but it is certainly not something that ought to be used for regulatory decisions,” he added. “And it’s certainly not the type of study that should be used to make clinical decisions. Full stop.”
A top diabetes expert with similar views, Dr. David Nathan, said real-world evidence simply cannot supplant traditional clinical trials. In his view, real-world evidence can only correct for biases that researchers already understand. By randomly assigning patients to one treatment or another, clinical trials rely on chance to cancel out any biases, whether researchers are aware of them or not.
“We have to be really careful if you want to supplant what has really generated huge amounts of important data,” said Nathan, director of the Diabetes Center and Clinical Research Center at Massachusetts General Hospital.
How many times would Aetion have to replicate a clinical trial before Nathan believed the results? “Infinite,” he said.
Nissen had a similar answer as to whether he’d ever be OK replacing randomized controlled trials with observational data. “Absolutely not,” he said. “One hundred percent not. It’s dangerous. How often have we been misled by observational research over the years?”
Still, Aetion’s study is particularly interesting because it represents an area where real-world evidence might be useful: testing the safety of diabetes drugs.
After a firestorm of controversy erupted around the diabetes drug Avandia, the FDA mandated that drug makers had to conduct large clinical trials to tell if their medicines might cause heart attacks. Some in the industry have griped that these trials are slowing the development of new medicines; they have also resulted in proof that some new medicines, such as Lilly and Boehringer’s Jardiance, prevent heart attacks.
If it were possible to use data from insurance databases to monitor a heart drug’s safety, it might represent a solution. And Aetion’s study was far faster than the CAROLINA study. It took six weeks to complete, but required four years of insurance claim data on the two drugs.
CAROLINA took eight years, so being able to use “real-world evidence” could cut the time to get data in half — at a considerably lower cost.
Dr. Harlan Krumholz, director of the Center for Outcomes Research and Evaluation at Yale New Haven Hospital, said he worried that using insurance claims, as Aetion does, faces substantial challenges. But he disagreed with the idea that observational data couldn’t ever fill the role of clinical trials in understanding diabetes drug safety.
He pointed to numerous examples, over the years, where his own observational studies have replicated the results from clinical trials. And he said that using electronic health record systems could make the process easier, and that it’s feasible to get good enough data from observational studies. “Once we have established efficacy, we simply cannot afford to do all these trials for safety,” Krumholz said.
Aetion’s chief executive, Carolyn Magill, is hoping there’s space for real-world evidence. “We’re not advocating for replacing randomization, and that’s really critical,” she said. “It’s just that there are also examples where we believe that data can credibly be used to come to the same result more quickly, and at a lower cost and less disruption to patients.”
Good luck, though, getting doctors to agree where real-world data should be used.