Study highlights lack of transparency in FDA’s regulatory safety actions

Regulatory NewsRegulatory News | 12 October 2022 |  By 

Only about one-third of the US Food and Drug Administration’s (FDA) regulatory safety actions were supported by published studies and none were corroborated by public assessments from the Sentinel Initiative, according to a study of the agency’s adverse event reporting system.
“These findings suggest that either the FDA is taking regulatory actions based on evidence not made publicly available or that more comprehensive safety evaluations might be needed when potential safety signals are identified,” Meera M. Dhodapkar, of Yale School of Medicine, and colleagues wrote in the BMJ.
The cross-sectional study examined potential safety signals identified by the FDA Adverse Event Reporting System (FAERS) from 2008 to 2019 (RELATED: Making Sense of FAERS: Researchers Suggest Fixes to FDA’s Adverse Event Database, Regulatory Focus 29 August 2017). Of the 608 potential safety signals identified during that time, nearly 70% were resolved, of which 78% resulted in regulatory actions, such as drug labeling changes or drug safety communications.
To examine the evidence supporting those regulatory actions, the researchers conducted a subset analysis of potential safety signals reported in 2014-2015 and reviewed relevant literature published before and after the signals were reported, as well as assessments from the Sentinel Initiative. For the 82 potential safety signals reported in 2014-2015, 76 signals (93%) were resolved, and 60 signals (73%) resulted in regulatory action. Among the resolved signals, published literature was identified for 57 signals (75%) – mostly from case reports or case series -- and Sentinel Initiative assessments were identified for four signals (5.3%).
However, the agency’s regulatory actions were corroborated by at least one published research study in just 17 of the 57 resolved signals (30%). None of the Sentinel Initiative assessments corroborated the agency’s regulatory actions.
The researchers considered a regulatory action to be corroborated when at least one study type confirmed a significant relationship between the safety signal and the drug in the same direction, such as increased risk of harm. They determined that case series, case reports, and other descriptive studies could not provide inferential evidence of associations, so those studies were not considered adequate to corroborate a regulatory action. Of the 1,712 publications considered relevant to potential safety signals from 2014-2015, 70% were case reports or case series.
The researchers acknowledged that published research and public assessments are not feasible or necessary in every case. For instance, there is unlikely to be a study offering inferential evidence for a rare adverse event. Additionally, FDA staff members have access to other information sources not routinely made public, including the full details on all adverse event reports, clinical trial data submitted to the agency, and decisions made by regulators from other countries. However, the researchers called for greater transparency.
“We found that few regulatory safety actions documented evidence beyond case reports when making changes to a product label. While we cannot rule out that the agency was taking other evidence into account, no other evidence was documented,” Joseph Ross, MD, professor of medicine and public health at Yale School of Medicine, and the senior author of the study, told Regulatory Focus. “It would help all parties, but especially patients and clinicians, who may be forced to change the medications they are taking or prescribing after the product label change, to better understand what evidence was used to inform the regulatory safety action. So, this information should be made routinely available when a potential safety signal evaluation is resolved, regardless of whether the decision is to take a safety action.”
In a related editorial, Barbara Mintzes, PhD, of the University of Sydney, and Colleen Fuller, of Independent Voices for Safe and Effective Drugs, called for “radical transparency” around available evidence and the basis of regulatory decisions. They pointed to the differences in safety warnings for medicines in the US, United Kingdom, Canada, and Australia, which contain different boxed warnings and adverse events in the product information, as one example of a lack of regulatory transparency related to postmarket safety.
“Publication of safety signals is important, but this step is only the first towards transparency, with full public access needed to the evidence supporting all decision making, including decisions not to act,” Mintzes and Fuller wrote.
BMJ research article, Editorial


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