Last week, the FDA held a public hearing on "Modernizing the Regulation of Clinical Trials and Approaches to Good Clinical Practice." That's important because FDA's clinical trial regulations have not been substantially updated in over two decades. And though additional hurdles have been added to the clinical trial process over the past few years -- in order to more fully explore things like cardiovascular risk and hepatotoxicity issues, for example -- not much has changed in the way of basic clinical trial design.
Increasingly, though, new computational tools and other technological advances are enabling the use of innovative methods that could improve clinical trial quality. Better use of adaptive trial design and biomarkers, for example, should help trial sponsors collect better, more robust data from fewer patients and in a shorter amount of time. But FDA is only now beginning to test the waters with these new methods.
On the other hand, over the past two decades, FDA has increasingly been demanding more of the same -- more data from more individual tests within trials with more patients. The average number of patients supporting each NDA rose by 19 percent from 1995 to 2001. This trend, on average, appears to have leveled off in recent years, according to PAREXEL's Bio/Pharma R&D Statistical Sourcebook 2010/2011. But the number of patients in trials for many conditions continues to rise. And difficulty in recruiting a sufficient number of participants now often leads to termination of clinical trials before usable data can be generated. The escalating cost of recruiting, retaining, and testing so many participants caused the editors of the journal Nature Biotechnology to recommended that the FDA "put an upper limit on the number of people who could be included in a trial."
In addition, the length and complexity of trials continues to increase, according to the Tufts Center for the Study of Drug Development. The length of trials grew by 70 percent from 1999 to 2005, and the median number of tests conducted per patient (such as routine exams, blood tests, and x-rays) rose by 49 percent from 2000 to 2007. These new hurdles have also made it more difficult to enroll patients in trials and to keep them in the trials until completion. And the problem is most acute for drugs that treat chronic conditions such as diabetes and cardiovascular disease, where many thousands of patients must be enrolled in especially lengthy trials to satisfy FDA's innate risk aversion.
All of this has had a predictable effect on drug research and development. As Avik Roy concluded in his recent Manhattan Institute paper, "The enormous cost and risk of Phase III trials create incentives for researchers and investors to avoid work on medications for the chronic conditions and illnesses that pose the greatest threat to Americans, in terms of health spending and in terms of the number of people affected."
It appears at least that FDA has begun to take this seriously. But as one might expect, the agency is moving only very cautiously to embrace the innovative clinical trial approaches that might help to alleviate the problem. The agency has, for example, been receptive to adaptive trial design proposals, but it insists that adaptive trials be designed more carefully than conventional ones in order to prevent biases from being introduced into the statistical analysis. If the rules for adaptive trials are too rigid, it could prevent firms from reaping the full benefits of the innovative methodologies. Many firms have therefore been reluctant to experiment with these innovations until more is known about how the agency will evaluate them after the fact.
The agency has to do more and faster because, as science journalist Malorye Allison explained in a January Nature Biotechnology article, "The expanding timelines, size, failure rate and cost of trials have finally reached a point where, like the towering US debt, nobody can pretend it is viable." As I wrote a few months ago, "there is no doubt that [a] radical reinvention of the standard, 20th Century clinical trial design will be necessary if the research-intensive pharmaceutical industry is going to remain sustainable in the 21st Century."
At last week's hearing, representatives from the Association of Clinical Research Organizations (ACRO) argued that FDA "should not be yoked to any political agenda, like 'saving' the current U.S. research enterprises," according to the Pharma Times. Instead, "its goal should be to facilitate a new model that can generate more medical products in less time at less cost." I couldn't agree more. But since we're talking about an extraordinarily conservative regulatory agency that abhors risk -- not just patient risk, but political risk to itself -- implementing the kind of radical re-thinking that will be necessary is easier said than done.