In 2021, a new drug to treat bone marrow cancer showed enough promise in early trials that the Food and Drug Administration quickly approved it through an accelerated process. But that promise didn’t hold up once it was on the market. The FDA pulled it earlier this year after confirmatory trials showed it didn’t work. In this case, it only took three years to get the ineffective drug off the market, but that’s not always the case. Nearly 40 percent of drugs that got accelerated approval between 1992 and 2021 still hadn’t finished their required clinical trials in 2022, according to the Office of the Inspector General (OIG).
These include Beleodaq, used to treat a rare form of non-Hodgkin lymphoma, and Exondys 51, used to treat duch*enne muscular dystrophy. These drugs were granted accelerated approval in 2014 and 2016, respectively, and trials remain incomplete.
The FDA approves some new medical treatments quickly, before confirmatory trials are carried out, to get them to patients with serious conditions. This is a valuable alternative to the lengthy traditional approval process, but it comes with the risk that the treatments may not be as effective as expected.
Accelerated approval was instituted in 1992 as a way to expedite treatments for serious, life-threatening, and often rare diseases, such as cancer, HIV/AIDS, and Alzheimer’s, for which patients have few other options. Accelerated approval is conditional, meaning that companies agree to conduct rigorous confirmatory clinical trials after the treatment is already on the market to determine how well the drug works. Traditional approval is the standard pathway for new treatments to enter the market. The FDA aims to approve a drug (or not) within 10 months of application. Before a company even applies, it has already completed years of clinical trials to establish that the treatment works. For example, the development of Brenzavvy, a new drug to treat Type II diabetes, started in 2016, and the FDA approved it through its standard process in 2023.
The problem with accelerated approval is that confirmatory clinical trials can take years to complete — the average is seven to nine — and many aren’t ever finished.
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There are three main reasons why confirmatory clinical trials may be delayed or remain incomplete.
First, there is no real incentive for companies to finish them. When drugs receive accelerated approval, they go to market and companies immediately start profiting. The OIG found that Medicare and Medicaid spent over $18 billion in three years on drugs with accelerated approval but incomplete confirmatory clinical trials.
The OIG also found that changes in drug ownership can delay trials — effectively bringing them to a halt while a new company onboards staff and familiarizes them with the FDA’s regulatory standards. One drug approved to treat lymphoma in 2009 was acquired by a new pharmaceutical company in 2012. It’s been 15 years since its approval, and the drug’s confirmatory clinical trials remain incomplete, far exceeding the average time it takes to finish them.
Finally, recruiting patients for clinical trials for a drug that’s already on the market is challenging. Patients may be unwilling to enroll and risk getting a placebo when they can already get the drug from their doctor.
This is a clear challenge for the FDA, but there are possible solutions.
One solution is already in play. In 2023, Congress granted the FDA the power to require that drug companies at least begin confirmatory clinical trials before receiving accelerated approval. This helps ensure that the companies honor their evidence-gathering commitment. It also eases recruitment challenges, as the clinical trial is a patient’s only option to get the drug. However, companies can begin trials before receiving approval and still drag them out over the long term.
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To fix that problem, we could borrow an approach from the European Medicines Agency, which is essentially the European Union’s FDA. The European Medicines Agency requires reassessment and renewal of accelerated approval every few years rather than providing a one-time indefinite approval. Companies have to provide evidence at each renewal that their trials are underway or complete.
The Centers for Medicare & Medicaid Services is also evaluating a model that would reduce the price that Medicare pays for drugs with accelerated approval until confirmatory trials are complete. Offering a financial incentive could encourage companies to complete their confirmatory clinical trials.
The accelerated approval process is important for patients with life-threatening conditions and few treatment options. But it only works if the drugs it approves work, too.
Katherine O’Malley is a policy analyst at the Partnered Evidence-Based Policy Resource Center with Boston University School of Public Health.
