FDA enforcement of clinical research regulations has often been "light-handed, slow-moving, and secretive," a new look at the agency's enforcement track record concludes.

Published today in the journal Science, the analysis said the shortcomings may be harming both patients and trial integrity.

"Clear corrections of inspector-reported dangerous or unlawful clinical trial practices were the exception, even amid signs that trial participants were harmed and that data underpinning evidence-based medicine were corrupted," investigative journalist Charles Piller, author of the story, concludes.

When the FDA did formally warn researchers over law-breaking, follow-up was often neglected, he wrote, and frequently cases were closed "on the basis of unverified claims of those accused.”

The article, "Official Inaction," draws on about 1,600 agency inspection and enforcement documents for trials the FDA said violated rules and law. Among them, Piller found that 99 warning letters were sent by the regulator regarding issues characterized as "serious clinical trial transgressions" during President Barack Obama's first three years in office. In Obama's last three years, though, that number dropped to 36 such letters.

Even as the number of FDA inspections per year significantly increased during the first three years of President Donald Trump's administration, the number of warning letters has dropped further, to just 12 over the entire span of the time period reviewed.

Since 2009, Piller found that the FDA issued "official action indicated" designations to direct 291 inspected researchers or institutions, or about 4%, to correct "serious, illegal, and potentially dangerous clinical trial problems." But sometimes those designations were downgraded to another less onerous designation, "voluntary action."

Both trends were troubling, Piller's sources said, suggesting dangers to both trial participants' welfare and the quality of medical products. "When errors, fraud, or simply sloppiness occurs in clinical experiments, it can affect data stream; it can affect data that FDA uses to approve treatments for any kind of disease," he told BioWorld.

An alternate view?

Sarah Hardison, head of product, regulatory and pharmacovigilance at BioWorld's parent, Clarivate plc, saw the possibility for a different story in the data. "You could have looked at this data and told a story that 96% of clinical trials in the United States are running very well," she said.

No one Piller interviewed for his investigation supported that alternative view. Furthermore, shortcomings in enforcement could very well mean that the extent of trial issues and patient harms hasn’t been fully disclosed, he said.

However, both the FDA's defense of its risk-based approach and Clarivate data could support the more charitable interpretation. During the period Piller reviewed, more than 86,000 clinical trials were initiated across the U.S., according to Cortellis Clinical Trials Intelligence. "So, if you're looking at the 291 official actions that were required, that's 0.3% of all the clinical trials in the U.S. over that period of time," Hardison said.

Furthermore, the FDA's willingness to work with clinical trial investigators and company sponsors, giving them scientific advice, guidance, and pointers on which data are needed to prove efficacy and how to stay in compliance with the rules governing their work is ultimately a good thing. "The FDA could be more stringent with egregious offenses, but a close working relationship with clinical researchers and industry sponsors only benefits all involved," she said.

COVID-19 concerns

Piller's investigation is bound to be viewed as political in some quarters, given the implications for the current COVID-19 pandemic. The White House is pressing for results on COVID-19 vaccines and remedies, he said, and public concern about initial products to fight the infection seems to be running high. But a broader point and one likely to be well-received by Science readers globally is clear: "Clinical trials can't be rushed faster than the science and patient safety permits," he said.

Though not addressed directly in the article, high turnover in leadership at the FDA could be viewed as an important factor associated with the issues it explores. Since Margaret Hamburg left the FDA in mid-2015, after a tenure of six years, there have been seven acting or permanent FDA commissioners appointed.

“In these ever-changing times where advanced medicinal therapies and digital health are disrupting the clinical landscape, and the race for a COVID-19 vaccine is on, we need consistent leadership in the FDA that can adjust their sails," Hardison said.

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