Drug therapies with sales exceeding $1 billion should be subject to a mega-trial, a randomized clinical trial with at least 10,000 patients. That's what John Ioannidis, MD, DSc, chief of the Stanford Prevention Research Center, argues in a perspective published today in the Journal of the Americal Medical Association.
In the piece, Ioannidis points out that while so-called "blockbuster" drugs are used by hundreds of thousands of individuals, the supporting randomized trials typically include only a few hundred participants, "often with relatively short-term follow-up." Describing how larger trials could benefit what we know about psychiatric drugs, he writes:
...5 of the top 24 blockbusters are mental health–related drugs: aripiprazole (Abilify), quetiapine (Seroquel), duloxetine (Cymbalta), olanzapine (Zyprexa), and escitalopram (Lexapro). None of them has ever been tested in a mega-trial, and most evidence comes from short-term trials of 3- to 4-months’ duration with only hundreds of participants. Nevertheless, several million doses of each of these drugs are dispensed annually. Mega-trials would help settle and even preemptively address concerns about deaths and suicides associated with some mental health interventions.
Besides mortality outcomes, mega-trials can focus on other specific major questions of interest. For example, for mental-health interventions, these trials would provide sufficient power to address the effects of drug interventions on important outcomes such as suicide attempts, hospitalizations, and job loss instead of relying solely on subjective scales and also would help define the spectrum of disease severity at which these treatments are effective, another issue debated endlessly based on small trials and meta-analyses thereof...
Ioannidis also outlines how challenges relating to cost and recruitment for such large trials could be overcome, and he proposes a framework for carrying out the studies. He calculates that streamlining the design, monitoring, data collection and outcomes of the traditional clinical trial process could greatly reduce the cost of mega-trials. With an intervention with $2 billion in annual sales, for example, the expense of a study consisting of 80,000 participants could be covered with one month of sales - about $167 million.
Under Ioannidis' proposal, companies would be required to pay one month's worth of previous year's sales into a special fund, which would be used for funding mega-trials. In return, companies with drugs that performed well during the trials could receive incentives such as a patent extension. Ioannidis notes, "For instance, a 4-year extension of the patent would offset by 50 times the cost of the mega-trial."
Previously: NIH funding mechanism “totally broken,” says Stanford researcher, Research shows small studies may overestimate the effects of many medical interventions, Animal studies: necessary, but often flawed, says Stanford’s Ioannidis and Outing bias in scientific research
Photo by Keith Ramsey