JAMA study: the US FDA is loosening its new drug review standards

Republished with permission: Pharmascan

Over the past several decades, the FDA's standards for reviewing new drugs appear to have gradually loosened.

According to a study published in JAMA Netw Open, a leading internal medicine journal, 65% of approvals in 2022 rested on a single study as their evidence base—up from just 20% in 2016, before the 21st Century Cures Act was enacted.

The study also revealed that in 2016, roughly 55% of newly approved drugs were supported by at least three studies, but by 2022 that share had plunged to just 11%.

The FDA's key review question: do benefits outweigh risks?

Before a prescription drug can be marketed, the FDA must review all human studies and preclinical data to confirm that the drug is truly effective and safe. In general, FDA approvals are grounded in so-called "pivotal" trials. These trials typically require rigorous design: selecting an appropriate population, determining the right drug dose, setting endpoints suited to the characteristics of the disease (such as clinical improvement or survival), and using suitable control groups to compare the drug's effects. The agency then decides whether the drug can reach the market based on whether these pivotal trials demonstrate that benefits outweigh risks.

Take Wegovy (semaglutide), the recently popular weight-loss drug, as an example: when it received its weight-management indication in 2021, the FDA reviewed at least five trials, all of them randomized and double-blind.

The FDA generally prefers evidence from at least two pivotal trials, which helps guard against unexpected systematic bias and gives greater confidence that the drug's effect is truly as the trials suggest.

Yet in the study published by Dr. Kaplan and colleagues, only four drugs (abrocitinib, oteseconazole, xenon Xe 129 hyperpolarized, tirzepatide) were approved on the basis of at least three studies. The study's scope covered only drugs approved in 2022 that had never previously been approved for any indication.

From rigorous trials to flexible review: why is the evidence shrinking?

In fact, the decline in evidence supporting drug approvals did not begin in 2016. One study found that between 1995 and 1997, 81% of approvals relied on two pivotal trials, falling to 53% between 2015 and 2017. Meanwhile, approvals based solely on single-arm, non-randomized trials rose from 4% to 17%.

The roots of this shift may lie in regulatory changes and a growing awareness of ethical concerns. The 21st Century Cures Act, for example, gave the US FDA greater flexibility in reviewing drugs, which has helped advance treatments for rare diseases and regenerative medicine.

Rare diseases are a case in point: running clinical trials through Phase 3 is enormously expensive, and the small patient populations mean follow-up must stretch longer before benefits can be observed—while the unusual nature of these diseases also makes control groups harder to find. Rare diseases also raise issues of medical ethics and inequity. Using early biomarkers and historical controls can accelerate approval and get drugs to patients sooner, meeting otherwise unmet needs.

JAMA study: concerns behind the approvals

Dr. Kaplan, the study's author, is nonetheless deeply concerned: most of these drugs were industry-sponsored, and only 25% of the study results were publicly published.

In this JAMA study, 55% of the trials were randomized and 21% used a single-group design; nearly 80% (79%) were industry-sponsored, while less than 1% were funded by the US National Institutes of Health. Fewer than half (40%) of the drug trials were completed before approval was granted (by an average of 8.4 months).

Dr. Kaplan and colleagues argue that patients have the right to unrestricted access to all the evidence about the drugs they are taking, not merely a selected slice of data released to the public.

The JAMA study lays bare a trend in the pharmaceutical industry in recent years: although review depends on the totality of the evidence, new drug approvals in 2022 show that, compared with the era before the 21st Century Cures Act, the FDA is relying on fewer trials—most of them industry-sponsored.

The content of this article has been licensed by Pharmascan to PatientForce™ (Media-WIND Communications Co., Ltd. / Unified Business No.: 27903403), and the intellectual property rights are jointly owned by PatientForce™ and Pharmascan in accordance with the law. If you believe this article may infringe any rights, please contact the relevant department of our company by email and we will respond as soon as possible.