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Randi Hernandez was science editor at BioPharm International from September 2014 to May 2017.
A new study published in JAMA Internal Medicine found that manufacturers do not report a portion of adverse events to FDA within the federally mandated time frame of 15 days.
Drug manufacturers have a little more than two weeks to communicate to FDA any expedited adverse events (AE) complaints that they receive. A new study published in JAMA Internal Medicine found, however, that approximately 10% of AEs are not reported within the 15 days required by current mandates. Additionally, the report authors concluded that many of the events that were not reported were the most serious in nature; AEs resulting in patient death were more likely to be delayed. According to current requirements, any AE that is both serious and unexpected qualifies for expedited reporting timelines to the FDA.
The authors analyzed 1.6 million adverse-event reports sent to FDA between 2004 and 2014 dealing with medications. Of that group, 160,383 were filed beyond the mandatory 15-day reporting window, including 40,464 reports that involved a patient death. The authors attributed the lag in reporting to manufacturers taking extra time to verify patient deaths, but also commented that, “this discretion is outside the scope of the current regulatory regime.”
A 1995 guidance document from FDA, Guidance for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, explicitly states that “Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting.” “Unexpected” reactions are described in regulatory documents as reactions that are not listed in the federally approved warning labels or brochures.
However, FDA’s Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies explicates that the reporting time frame for submitting an IND safety report to FDA and all participating investigators is "no later than 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting." However, the same document also says that, "the determination of whether an adverse event is life-threatening can be based on the opinion of either investigator or sponsor.” Thus, a manufacturer could argue that it was not on the hook to report within 15 days if it did not believe the adverse event caused the patient death or did not deem the death to be unexpected. For unexpected fatal or life-threatening AE reports for investigational new drugs (IND), a seven-day investigational IND safety report is typically required.
A death, according to that guidance, ordinarily would not be reported as an individual case in an expedited report from a trial designed to compare all-cause mortality in subjects receiving either drug treatment or a placebo. The death would be reported as an individual event if there is evidence of a causal relationship between the drug and the death, however, which is likely what takes manufacturers a bit of time to determine.
Regardless of the reason, delays in reporting can have a negative impact on patients, said the authors of the JAMA report, “particularly if manufacturers selectively delay reporting based on relevant patient outcomes.”
In a separate editorial accompanying the featured article, author Rita F. Redberg, MSc, editor of JAMA Internal Medicine, suggested that rather than being routed through drug manufacturers, AE reports should go directly to FDA.
Source: JAMA Internal Medicine