Drug Safety Reports Still Uninformative, FDA Officials Say

Regulatory NewsRegulatory News | 04 May 2016 |  By 

Most expedited safety reports for investigational new drugs (INDs) are uninformative, despite recent efforts to improve the quality of such reports, FDA officials wrote in a recent research article.

Sponsors are required to compile all adverse events for drugs they are studying in annual safety reports. If an adverse event is serious, unexpected or suspected to be caused by the drug being studied, sponsors are required to submit an expedited report to FDA within 15 days of the event, or within 7 days if the event is fatal.

Final Rule and Guidance

The study comes as each year, FDA receives tens of thousands of expedited safety reports from sponsors. FDA's Office of Hematology and Oncology Products alone received an average of 17,686 of these reports each year from 2006 to 2014.

In 2010, FDA issued a final rule clarifying how sponsors should assess adverse event causality in an effort to cut down the number of "uninformative safety reports with no reasonable possibility that the drug caused the adverse event."

The final rule also instructs sponsors to analyze adverse events in aggregate in order to limit the number of reports where causality is impossible to determine. It also requires clinical investigators to submit adverse event reports directly to sponsors to make a determination of causality.

Shortly after the final rule went into effect, a team of top FDA officials wrote that they "believe that the [rule] will improve the quality of safety reporting and strengthen the FDA's ability to monitor the safety of drug and biologic products. It will minimize reports that do not contribute to the understanding of a drug's developing safety profile and decrease the number of uninterpretable reports."

Since then, FDA has issued two guidances intended to further clarify safety reporting requirements for sponsors, Safety Reporting Requirements for INDs and BA/BE Studies, and a follow-on draft guidance Safety Assessment for IND Safety Reporting.

Uninformative Reports

However, the vast majority of these reports are still uninformative, according to a recent review headed by Jonathan Jarow, Senior Medical Advisor to FDA's Center for Drug Evaluation and Research (CDER) and Sean Khozin, Senior Medical Officer at FDA's Office of Hematology and Oncology Products.

The research looked at a random sampling of 160 expedited safety reports submitted to FDA in 2015 and found that 86% of the reports were uninformative or did not meet FDA's criteria for submission.

"More than half (54%) were expedited reports of expected adverse events, listed in the product labeling of the investigator's brochure … of the 38 expedited safety reports that met all three criteria, 16 (42%) were anticipated," the authors said.

However, according to the study authors, FDA's efforts not only failed to improve the quality of the reports but also failed to reduce the sheer number of expedited reports submitted each year.

"The results of our study suggest that not only was there no reduction in the number of expedited safety reports submitted to the FDA's Office of Hematology and Oncology Products by commercial sponsors following the final rule, but also a slight increase was detected," they said.

The authors say the main barriers to improving the quality of expedited reports are a "lack of international harmonization for reporting rules, liability risks, and lack of clarity of threshold rules for aggregate reporting."

While the authors say FDA is looking into ways to "modernize" expedited safety reporting, they call on sponsors to work to "identify and address" the underlying issues that result in over reporting.

In a response to the study, Apostolia Tsimberidou, an associate professor at the MD Anderson Cancer Center in Houston, Texas, calls on FDA to work together with industry, institutional review boards and clinical investigators "to develop dynamic standardized electronic forms with preferred, predetermined terms to harmonize their practices and to help optimize the quality of clinical research and maximize patient safety."

The Majority of Expedited Investigational New Drug Safety Reports are Uninformative


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