OIG: One-third of Accelerated Approvals have Delayed Confirmatory Trials

Medicare and Medicaid spent more than $18 billion from 2018 to 2021 for 18 drugs granted accelerated approval that have incomplete confirmatory trials past their original planned completion date, according to new analysis by the Office of Inspector General, the U.S. Department of Health and Human Services. The OIG estimated that Medicare Part B and Part D spent more than $14 billion, and Medicaid spending —for both fee-for-service and managed care— for these drugs was nearly $3.6 billion.

“For a variety of reasons, sponsors do not always complete trials promptly,” OIG officials said in a statement. “This can result in drugs staying on the market-and being administered to patients for years without the predicted clinical benefit being verified. And insurers — including Medicare and Medicaid — are paying billions for treatments that are not verified to have clinical benefit.”

OIG officials began this review after the accelerated approval of Biogen’s Aduhelm (aducanumab) to treat patients with Alzheimer’s disease. The approval in June 2021 was made after an advisory committee voted against approval. Biogen is currently recruiting patients for its confirmatory trial ENVISION, which is expected to be completed in October 2026.

OIG officials indicated this review stemmed from concern that the regulator’s oversight of accelerated approval was lax. Accelerated approvals often use surrogate endpoints that predict clinical benefit, but don’t measure clinical benefit. The pathway is meant to provide earlier access to drugs to treat serious diseases. Companies are required to conduct confirmatory trials to verify clinical benefit and to provide a timeline for completion.

Since the accelerated approval pathway began in 1992, 278 drug applications have been granted accelerated approval by the FDA’s Center for Drug Evaluation and Research (CDER). Of these applications, 104 have incomplete confirmatory trials. Of those 104, 34% (35 of 104) have at least one trial past its original planned completion date. Additionally, 13% of all accelerated approval drug applications have been withdrawn, half of which were withdrawn since January 2021.

Four drug applications have confirmatory trials that are significantly late — ranging from more than five years to nearly 12 years past their original completion dates. OIG researchers found that of these four drugs that were significantly late with confirmatory trials, Proamatine (midodrine hydrochloride) had the highest Medicare Part D estimated spending at $142 million and Makena (hydroxyprogesterone caproate) had the highest estimated Medicaid spending, nearly $700 million.

Proamatine was given accelerated approval in 1996 to treat postural hypotension, and the FDA attempted to withdraw the application in 2010. Although the original sponsor no longer markets the product, generics are available even though a complete picture of risk and benefits doesn’t exist. OIG researchers speculate that the generic competition and the fact that the brand is no longer on the market may have decreased the sponsor’s incentive to complete confirmatory trials.

Makena was granted accelerated approved in 2011 to reduce the risk of preterm birth. It was developed by Amag Pharmaceuticals, now a subsidiary of Covis Pharma. The regulatory agency in 2020 began the process of removing Makena from the market, but the process can be lengthy if a manufacturer disagrees. An FDA hearing is scheduled for Oct. 17, 2022 to Oct. 19, 2022, to discuss the withdraw accelerated approval of Makena and whether available evidence demonstrates that Makena is effective for its approved indication.