Negative Confirmatory Trial Did Little to Drive Down Use of Questionable Preterm Drug

By Megan Brooks

December 07, 2021

NEW YORK (Reuters Health) - Use of hydroxyprogesterone caproate injection (Makena) for recurrent preterm birth remained high in the U.S. after a "confirmatory" clinical trial failed to show a benefit of the drug, a new analysis indicates.

"Despite the negative trial results and FDA (Food and Drug Administration) efforts to remove the drug from the market, use and spending continue, demonstrating a level of support for the drug among physicians, likely owing to conflicting evidence supporting the drug's use," researchers report in JAMA Internal Medicine.

"The FDA has faced difficulties removing accelerated approval drugs from the market even when they fail to show a clinical benefit in their required confirmatory trials," first author Rachel E. Sachs, a professor of law at Washington University School of Law in St. Louis, told Reuters Health by email.

"We wanted to look at whether the publication of negative trial results and statements by the agency or its advisory committees would be sufficient to drive down a drug's use and therefore its spending," she said.

"We found that while use and spending did decline after these events, use has remained high, meaning that states may be spending their limited financial resources on products with weak or no clinical benefits," Sachs said.

"In other words, issuing statements about the drug's clinical efficacy does not on its own significantly drive down use and spending - the agency does need to take steps to remove the drug from the market in order to have that effect," she added.

Makena received accelerated approval in February 2011 based on a clinical trial demonstrating that it reduced the risk of preterm birth in women with previous spontaneous preterm birth.

In March 2019, however, results of the FDA-required confirmatory trial failed to replicate the initial trial's reduction in recurrence preterm births.

In October 2019, an FDA advisory committee narrowly voted to withdraw approval and a year later the FDA Center for Drug Evaluation and Research (CDER) proposed taking the drug off the market.

But Makena's manufacturer requested a hearing, which FDA granted in August 2021. The proceedings remain ongoing.

Sachs and colleagues used national Medicaid drug utilization and spending data to examine changes in hydroxyprogesterone caproate fills from 2010 to 2020.

They found that use of the drug increased from less than 11,000 fills per quarter between 2010 and 2014 to more than 30,000 fills per quarter in the first quarter of 2019. In the second quarter 2019, after the failed the post-approval trial, there was no decline in use.

Between the third and fourth quarters of 2019, use of the drug declined more than 8,000 fills per quarter, coinciding with formal publication of the negative trial and the FDA advisory committee recommendation to withdraw it from the market.

A subsequent decline in use was noted in quarter three of 2020, but use remained high at 19,554 fills per quarter (54.9% of the maximum volume reached in the second quarter of 2017).

Since the second quarter of 2019, brand name Makena has maintained more than half of market share, despite availability of generic versions of the drug since 2018.

Sachs and colleagues say low uptake of the generics may be driven by the newer branded autoinjector formulation of Makena that the FDA approved in February 2018.

"The autoinjector has resulted in continued high spending on hydroxyprogesterone caproate, despite generic availability," they note. In the third quarter of 2020 alone, "state Medicaid programs reimbursed (before rebates) $41,872,080 for all forms of hydroxyprogesterone caproate, 73.2% of which was for the Makena autoinjector," they report in their article.

Sachs told Reuters Health, "The results provide support for states' concern about the accelerated approval program and its impact on state Medicaid budgets. As long as Medicaid is required to cover drugs approved through the accelerated approval pathway, even when they fail to demonstrate a clinical benefit, state resources are being devoted to pay for these drugs with limited or unproven clinical benefits. That's a challenge for states operating under limited budgets."

"We are continuing to study the impact of the accelerated approval pathway on state Medicaid programs, and we encourage policymakers to take a look at these questions as well," Sachs said.

Funding support for the study was provided by Arnold Ventures. Sachs has received personal fees from Institute for Clinical and Economic Review, National Academy of State Health Policy, and West Health.

SOURCE: https://bit.ly/3IoN415 JAMA Internal Medicine, online December 6, 2021.

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