Better Clinical Trials for Myogenesis and Angiogenesis
Previous efforts have been hampered by overenthusiasm with weak endpoint measures and post hoc subgroup analysis, expert says.
As a researcher at the National Institutes of Health for 30 years, Stephen Epstein, MD, now at the Cardiovascular Research Institute at the Washington Hospital Center, witnessed the beginning of research into myogenesis and angiogenesis.
“We first thought we could improve what nature does in terms of developing collaterals. Although there were some intriguing results with animals, the human trials proved negative,” Epstein said during an interview with TCT-TV.
Epstein said investigators have spent an enormous amount of time doing animal studies and are eager to bring some benefit to patients.
The eagerness to get to clinical therapy sometimes results in questionable clinical trial protocols.
“There is a tendency to find whatever little positive nugget there might be in a study that was negative. When we do that, we’re accused of data dredging, which is not too far off,” Epstein said.
Understanding the mechanisms
Epstein said that the difference in outcomes in animal vs. human trials has persisted as the field has moved from gene therapy to cell therapy. “We know there are a lot of molecules that stimulate growth of endothelial cells and can inhibit apoptosis,” Epstein said. “We have seen this work in humans, but it has not been as robust in human clinical trials. It is a controversy, because if we wait until we know all the mechanisms, it might be another generation or two, so when do we just go ahead?”
Trial difficulties
One of the major problems in designing a clinical trial in angiogenesis is that there are currently no strong clinical endpoints.
“We use endpoints like treadmill time, when what we really need to do is measure blood flow, which we can’t do as well in humans as we can in animals,” Epstein said.
Even in a clinical trial of 100 patients, some will benefit and some will be refractory. Post hoc subgroup analysis is not going to solve the problem, Epstein said.
“Whenever a study is presented on angiogenesis with borderline significance, the idea of thrombolytic therapy is brought up. We didn’t know thrombolytic therapy would work until we did the 20,000-patient trial. Unfortunately, it’s going to be difficult to get a trial like that together for angiogenesis,” Epstein said.
Molecular motivations
Epstein said cardiology has been slow to come to the table with molecular therapies because the specialty has had such great success with coronary artery bypass graft and valvular surgery.
“By contrast, in cancer there was nothing happening so they had to move to molecular methods to move the field forward. Cardiology had to play a bit of catch-up,” Epstein said.
Since then, however, the field has exploded with new knowledge. “Research evolves so rapidly you don’t have time to be bored. You constantly have to keep learning,” Epstein said.
He said future treatment strategies would focus on targeted therapies for subgroups.
“One of our biggest problems is that if you give a drug or any intervention systemically, you run the risk of toxic effects in tissue and organ systems that are not the target of your therapy,” Epstein said. “With the evolution of new nanotechnologies, we will be able to target therapies much more effectively.”
Epstein was mentored early in his career by Eugene Braunwald, MD, who he said was “inspirational in creating an atmosphere. I was hooked. I continued with clinical cardiology, but my first orientation was research.”