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Addressing the challenges unique to purely industry-sponsored trials is explored.
Closer collaboration between academia and industry in the design and execution of clinical trials is vital to produce the best results, delegates were told at the European Society of Cardiology (ESC) annual meeting, held in London last month.
Industry-funded trials have many excellent features and have convincingly demonstrated the benefit of many medicines, but challenges to the external and internal validity of pure industry trials
must be addressed more effectively, according to Marc S. Sabatine, MD, Chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group and a Professor of Medicine at Harvard Medical School, Boston. Government and professional society funding can fill important gaps in this area, he said during a special ESC lecture on pressures and conflicts in industry-sponsored trials.
Problems and delays tend not to occur in Phase III trials because they are extremely well-resourced, Sabatine explained. In general, a careful central review of endpoints and safety takes place, case report forms are comprehensive, and there is a large sample size, number of events, and statistical power. Therefore, usually these trials are completed rapidly.
“Acceptance of a new drug depends on clear and compelling evidence of helping patients,” says Sabatine, adding that pharmaceutical companies are very good at reading Phase II trial data because their future survival depends on selecting the right compounds to take through to Phase III studies. “There is intense scrutiny of every piece of data, which is picked over and checked.”
When it comes to the questions being asked in a trial, a practical challenge is to retain a focus on commercial value, particularly when the end of a compound’s patent life approaches. Trials organizers must think about indications early on, later turning to government and academic society funding, Sabatine recommends. Furthermore, some Phase IV studies offer nominal assurance in a specific disease or patient subgroup, but are not well-powered, in which case the solution is to be more discerning about how to use such trial data.
In the control arm of a study, two challenges are dealing with the suboptimal comparator and the need to avoid head-to-head comparisons against roughly similarly active controls. Possible solutions are to partner with academic clinical trialists and to see government and academic society funding.
Often, there is a pressure for rapid selection of dose, leading to reliance on imperfect surrogates. Sabatine’s solution is for greater investment of time and resources in Phase II trials in order to optimize the likelihood of positive results. Also, to avoid multiple doses in Phase III studies, guidance from academic trialists and support from regulators for analyses of trials testing multiple doses can help, he says.
To achieve composite outcomes, inclusion of “softer” components is an appealing option, but the answer is to focus on harder outcomes, Sabatine contends. When amalgamating directionally opposite components into a single composite, it is advisable to present data on efficacy and safety separately and then analyze the benefits and risks.
To keep patients on a study drug and guarantee follow-up, thereby maximizing trial quality, sponsors should make sure those individuals directly interacting with and guiding sites understand and appreciate the importance of metrics for trial integrity, Sabatine pointed out.
Heart of the matter
Session moderator Kim Fox, Professor of Clinical Cardiology and Head of the National Heart and Lung Institute at Imperial College London, says the major problem for trial organizers in cardiology is that the outcome in cases of stable coronary disease is so good now that it becomes impossible to test a drug for mortality because so many patients are required and it is necessary to add softer composite endpoints like admission for stable angina and revascularization.
“In some senses, we are a victim of our own success for getting the event rates down,” Sabatine noted. “We need to accept that we will use these composites, but then we need to look at them very carefully.”
An overall goal should be to conduct trials that give a definitive answer for all-cause mortality, but provided there is no hazard for non-cardiovascular (CV) mortality; Sabatine does not insist that a particular trial shows a reduction for all-cause mortality.
“As long as it’s neutral for non-CV mortality, I then like to see a reduction in CV mortality," he says. "If there’s only a reduction in MI (myocardial infarction) and stroke and the trial doesn’t impact CV mortality, I’m still OK with that. I’m a cardiologist, and I want to decrease the number of patients having heart attacks and strokes.”