During my years as a Food and Drug Administration official, I learned that the available data on a new drug are seldom as complete and unequivocal as you might like. But getting drugs to patients can be a matter of life or death, so you need to make hard decisions. Fortunately, the regulations offer some flexibility so that the criteria for demonstrating efficacy are more lenient in certain critical situations. One of those pathways is called "accelerated approval."
In 1992, the FDA instituted accelerated approval regulations, which allow drugs for serious conditions that fill an unmet medical need to be approved based on "surrogate endpoints." A surrogate endpoint is an indirect indicator of improvement in the illness or disease, such as a laboratory measurement, radiographic image, physical sign, or other measure that is thought to predict clinical benefit but is not itself definitive. Using such an endpoint can considerably shorten the time to FDA approval.
The drug's sponsor (usually a drug company) is then required to conduct studies to confirm the anticipated clinical benefit. If the confirmatory trial shows that the drug provides an actual clinical benefit, then the FDA grants full or traditional approval for the drug. If the confirmatory trial fails to show that the drug provides clinical benefit, in theory the FDA has regulatory procedures in place that could lead to removing the drug from the market.
That is the idealized scenario, however, and there are several possible complications.
First, the confirmatory studies to demonstrate a clinical benefit can take years — a decade or more — while the accelerated approval is in effect.
Second, it might be hard to do confirmatory studies while the drug is available to patients under accelerated approval. Many patients would prefer to take the drug than be enrolled in a clinical trial.
Third, if the confirmatory studies fail, the companies sometimes resist having the accelerated approval withdrawn even if the "confirmatory" studies show that the drug doesn't work.
Consider the example of a drug called Makena to prevent preterm births, which affect one in 10 babies in the U.S. The drug was granted accelerated approval in 2011 based on a reduction in the rate of preterm births, but the follow-up studies did not verify the actual clinical benefit of the drug: namely, the health of the babies. In fact, they showed the opposite, that the drug's adverse effects include an increased risk of cancer. The FDA finally withdrew the accelerated approval on April 6 of this year.
Congress tried to improve the accelerated approval process in the omnibus spending bill that was passed and signed into law last December. It gave the FDA the power to request that confirmatory trials be initiated before a company receives accelerated approval, and once a company does receive it, the company is required to provide status reports on the confirmatory trials to the FDA every six months. The bill also created an accelerated approval oversight council with members from various FDA components.
But those tweaks represent meager progress. In a recent article in the Journal of the American Medical Association, two law professors argued persuasively that following accelerated approvals, the FDA needs "adequate independent authority to rapidly remove ineffective products" and that "the agency's regulatory flexibility to withdraw should match its flexibility to approve."
They suggested that a combination of voluntary postmarketing commitments, specified conditions for withdrawal of the approval, and explicit waiver of the right to a post-withdrawal hearing would bring us closer to an effective model of accelerated approval.
I am inclined to agree.
Henry I. Miller, a physician and molecular biologist, is the Glenn Swogger distinguished fellow at the American Council on Science and Health. He was the founding director of the FDA's Office of Biotechnology.