FDA Pivotal Trial Costs Vary By More than $300 Million

Joseph S. Ross, MD, MHS

In the first systematic evaluation of the estimated costs of clinical trials, a total of 138 pivotal clinical trials established the basis for approval of 59 new therapeutic agents by the US Food and Drug Administration (FDA) from 2015-2016—at a median estimated cost of $19 million.

The new study identified more than 100-fold differences in the costs of pivotal trials that the FDA required to provide substantial evidence of benefit, with a central cluster of trials with estimated costs of $12.2 million to $33.1 million.

The results support numerous conclusions regarding factoring that account for the costs of significant clinical trials. In the lowest cost clinical trials, the FDA approved therapeutic agents based on uncontrolled trials without any major protections against bias, including a comparison group, randomization or blinding. The research sample included 26 pivotal trials without controls, with a mean estimated cost of $13.5 million, and 3 pivotal trials for rare diseases with fewer than 15 patients enrolled at an estimated mean cost of less than $5 million per study, according to the study.

Conversely, trials were expensive when the benefits of the new agent were similar to those of agents already available with well-established clinical benefits. The most expensive trial in the study, for the sacubitril-valsartan combination drug for chronic heart failure, came with a mean-estimated cost of $346.8 million.

This particular trial was designed to demonstrate non-inferiority in cardiovascular mortality and other clinical benefits when compared to enalapril, according to the study.

In an essay accompanying the study, Joseph S. Ross, MD, MHS, of the Yale University School of Medicine, noted that it is universally agreed that a clinical trial provides invaluable insights and knowledge “through the use of randomization, blinded allocation, by including a control arm, and by focusing on a clinical outcome as opposed to a surrogate marker of disease.”

“Clinical trials form the basis of many of the most important determinations in medicine and health care broadly, including the FDA’s determination of medical product safety and efficacy, the determination made by the Centers for Medicare & Medicaid Services and other commercial payers to provide coverage for a medical product, and clinical recommendations made by professional societies and government agencies to guide practice,” Ross wrote.

The current costs of pivotal clinical trials comprised a modest potion of published estimates for overall costs of drug development. Recent estimates ranged from a median of $648 million for new cancer drugs, to $2.8 billion for broader pharmaceutical company developmental costs for a wider variety of agents.

“A common objection to performing a clinical trial is that trials are expensive, requiring extensive time and resources,” Ross wrote. “Although such costs pale in comparison to the costs of the health care interventions spent after approval, with or without coverage.”

In an MD Magazine ® report last week, it was found that FDA-approved novel therapies are backed by clinical trials that similarly range in patient population size—from just 4 to more than 21,000.

Overall, the study provided a novel perspective addressing this very concern: that elaborate and expensive clinical trials are the primary reason for the high cost of developing a new drug. The data suggests expensive trails occur, primarily when drug effects are small or a known drug already provides a clinical benefit. Pivotal trials for new drugs with substantial clinical benefits, however, can be conducted at a lower cost.

The study, “Estimated Costs of Pivotal Trials for Novel Therapeutic Agents Approved by the US Food and Drug Administration, 2015-2016,” was published online in JAMA.