It takes on average five years before the confirmatory trial is even started.
In 1992, the U.S. Food and Drug Administration (FDA) developed its Accelerated Approval Program. It was designed to move certain new drugs to the market faster.
The Accelerated Approval leans on a surrogate endpoint, which is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that can be used to predict clinical benefit, but isn’t by itself a measure of clinical benefit. However, use of the surrogate endpoint can shorten the time required for FDA approval.
The FDA states, “Drug companies are still required to conduct studies to confirm the anticipated clinical benefit. These studies are known as Phase IV confirmatory trials. If the confirmatory trial shows that the drug actually provides a clinical benefit, then the FDA grants traditional approval for the drug. If the confirmatory trial does not show that the drug provides clinical benefit, FDA has regulatory procedures in place that could lead to removing the drug from the market.”
The problem, as a new study notes, is that about a third of these drugs approved via this pathway never complete the process and, in fact, it takes on average five years before the confirmatory trial is even begun. Although perhaps a coincidence, the FDA grants drug developers market exclusivity for five years after a new drug is approved, and orphan drugs are given even longer periods of exclusivity.
There are actually four different FDA approaches to speeding drugs to the market. They are:
• Fast Track, designed to facilitate development and expedite review of drugs for serious conditions and fill an unmet medical need. This can make drugs eligible for Accelerated Approval and Priority Review, as well as Rolling Review, where sections of the Biologic License Application (BLA) or New Drug Application (NDA) are submitted as the data comes in instead of waiting for all data to be completed and submitted at one time.
• Breakthrough Therapy designation is designed to speed approval for drugs that show early clinical evidence that they can substantially improve over available therapies on a clinically significant endpoint or endpoints. It also utilizes surrogate endpoints, as well as other criteria.
• Accelerated Approval, which as described above, depends on use of a surrogate endpoint and requires follow-up studies.
• Priority Review, which is part of its two-tiered system, with the other tier being Standard Review. Priority Review means the FDA plans to take action on the BLA or NDA within six months compared to the 10 months typical of standard review. Although FDA decides on the review designation, companies can request it.
A new research study published in the INFORMS journal Manufacturing & Service Operations Management found that more than a third of drugs in this program failed to complete the approval process—meaning that there are lot of drugs on the market that haven’t been fully approved.
Typically, the Accelerated Approval Program requires that the drug companies must complete post-market studies proving the effectiveness of every drug that was pre-approved. Only at that point can they receive full, regular approval.
The study found that from 1992 to 2008, 36% of post-market studies hadn’t been completed. It also found that 50% of the uncompleted studies took an average of five years to even start.
“Manufacturers apparently have little incentive to do the post-market studies because they are not easily enforced and they are expensive,” stated Liang (Leon) Xu, the lead researcher and a professor of supply chain and analytics at the University of Nebraska-Lincoln College of Business. “Withdrawing a drug from the market takes time and without proof of ineffectiveness cannot be enforced immediately.”
Xu also worked with colleagues Hui Zhao and Nicholas Petruzzi, both at the Smeal College of Business at The Pennsylvania State University.
Part of the problem on the part of the FDA is the difficulties in determining and enforcing deadlines because of “unbalanced information and moral hazard.” The agency has to balance providing public access to life-saving drugs and ensuring that those drugs are safe and effective.
Xu and his colleagues suggest a solution.
“Currently, the FDA requires drug manufacturers to pay a fixed fee to fund its new drug application review,” Xu stated. “By replacing this fixed fee with a new one tied to a post-market study deadline, we can leverage an existing tool to make sure these studies get done.”
That fee would be based on the probability of a drug’s success and the enforceability of being able to pull the drug from the market. They also developed another option, where if the current fee can’t be changed into a deadline-dependent fee, the analysis can be edited to calculate a single deadline.
