More than 40,000 drug-related deaths in the last decade were not reported by manufacturers within the time frame required by the US Food and Drug Administration (FDA), according to a research letter published online July 27 in JAMA.
"Our analysis provided evidence that drug manufacturers delay reporting of serious AEs [adverse events] to the FDA. Strikingly, AEs with patient death were more likely to be delayed. It is possible that manufacturers spend additional time in verifying reports concerning deaths, but this discretion is outside the scope of the current regulatory regime," write Pinar Karaca-Mandic, PhD, from the University of Minnesota School of Public Health in Minneapolis, and colleagues.
Federal regulations stipulate a 15-day "expedited" maximal reporting period for serious adverse events, including death, life-threatening hospitalization, disability, and birth defects. The mandate also applies to unexpected events, defined as AEs not included in the current labeling information.
However, when researchers analyzed data for 1,613,079 serious AEs reported from January 2004 through June 2014, they found that an estimated 160,383 (9.94%) cases were not submitted to the FDA within the 15-day threshold, including 40,464 with patient death.
More specifically, AEs resulting in death were significantly less likely to be reported within the 15-day threshold than those associated with survival (88.25% [95% confidence interval (CI), 86.49% - 90.02%] vs 90.71% [95% CI, 89.48% - 91.94%]; P < .05) after adjusting for factors such as polypharmacy, report source, electronic submission, and patient age, sex, and weight.
According to the authors, the findings likely underestimate the actual rate of overall underreporting or misreporting, given the anecdotal evidence of FDA warning letters to manufacturers alleging "downward misclassification of serious AEs."
Accurate "real world" data are of critical importance to clinicians prescribing new drugs, given the limitations of safety profiles compiled in premarket trials which enroll select patient populations, are of limited duration, and are unlikely to uncover rare events.
Improving Manufacturer Reporting of AEs
In a related editor's note, Rita F. Redberg, MD, editor of JAMA Internal Medicine, spotlights the lack of FDA disciplinary action against companies failing to submit reports in a timely manner, which in turn exposes patients to potentially avoidable morbidity and mortality.
"Clearly, the lack of consequences contributes to a lack of deterrence for these illegal and dangerous delays," Dr Redberg writes. She suggests that FDA suspension of drug sales or withdrawing drug approval may be an efficacious method of achieving manufacturer compliance with federal regulations.
However, the study authors suggest that circumventing manufacturers' reporting role may be a more viable option.
"While increased enforcement may decrease violations, a simple alternative would be to recommend direct submission of reports to the FDA rather than via the manufacturer," they write, indicating that further research is needed to develop an optimal regulatory policy toward mandatory AE disclosure.
Dr Redberg concurs, concluding that, "[Direct reporting] would address the delay problem, although additional efforts to make the data available and take appropriate actions are still necessary. Physicians and their patients must be knowledgeable of benefits, harms, and alternatives for a wide choice of treatments, especially those recently approved for which clinical experience is limited."
The study was supported by research funding from the University of Minnesota Accounting Research Center and by a grant from the National Institute of Aging. The authors and editorialist have disclosed no relevant financial relationships.
JAMA. Published online July 27, 2015. Research letter extract, Editor's note extract
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Cite this: Companies Stall on Reporting Drug Deaths - Medscape - Jul 27, 2015.
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