FDA Sets New Rules For Reporting Adverse Trial Events

The U. S. Food and Drug Administration is announcing a final rule that will improve the quality of safety reports and better protect people participating in clinical trials for drugs. The final rule clarifies the safety information that drug sponsors (drug manufacturers) must report to FDA for Investigational New Drug applications (INDs).

NOTE: The FDA is still developing separate rules for postmarketing safety reporting.


The newly announced procedures are aimed at speeding up reporting and analysis of potential safety problems encountered in clinical trials while cutting down on adverse-event filings that the agency considers useless. The new rules cap more than seven years of work for the FDA, which first proposed a revision of safety reporting from drug studies in early 2003.


The rule applies only to adverse events in trials for drugs and biologics that are conducted under IND protocols, including (for the first time) bioavailability and bioequivalence (BA/BE) studies of generic drugs covered by INDs.


Under a final rule that will go into effect in March, 2011, reportable events are redefined as “any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.” Such events must be reported to the FDA within 15 days of becoming aware of an occurrence (which was previously not required), although serious unexpected events should be reported immediatelyThe standard the agency wants sponsors and investigators to apply is whether there is “a reasonable possibility” that a study drug caused the event. 

Reports of adverse events are to include:


*      findings from clinical studies, epidemiological studies or pooled analyses of multiple studies that suggest a significant risk to humans exposed to the drugs in the studies;


*      serious suspected adverse reactions that occur at an increased rate than expected, as listed in the protocol or investigator brochure;


*      serious adverse events from bioavailability studies which determine what percentage and at what rated the drug is absorbed by the bloodstream and bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug.


Sources: MedPage Today, published September 29, 2010, and the FDA’s press release of September 28, 2010.




For the new rule:

Investigational New Drug Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for Bioavailability and Bioequivalence Studies in Humans (PDF - 163KB)



To obtain the draft guidance information document for industry and investigators, click here.


The proposed rule will replace the defined phrase “associated with the use of the drug” with the term “suspected adverse drug reaction (SADR).” The rule also will permit the determination that an SADR is life-threatening to be based on the opinion of either the investigator or sponsor (as opposed to only the investigator). It will now be required that a “minimum data set” be submitted for each report of an SADR.


Examples of evidence are provided by the rule document that would suggest that an investigational product may be the cause of a safety problem. Under current regulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event.  The examples also address when a single event should be reported or when there is a need to wait for more than one occurrence.


The document urged that individual investigators not try to assess whether a study drug actually caused a given event. However, the agency doesn’t want to receive reports on events that are probably or definitely unrelated to study drugs. Some events should not generally be reported in individual filings, such as those that are counted as endpoints in such a trial, and also those that would be expected to occur at some level in the study population anyway, such as strokes or heart attacks in elderly individuals. As the document explains, “[t]hese types of reports are generally uninformative when reported as single events, (i.e., without a comparison of the incidence of the event in treated and untreated subjects) and, therefore, do not meaningfully contribute to the developing safety profile of an investigational drug.” Such events should be aggregated by the investigators or sponsors and the totals compared with a control group, and be presented in a narrative format.


The FDA clarified that, in placebo-controlled trials, treatment assignments for patients suffering unexpected adverse events will typically have to be unblinded: “[i]n general, if the blind is broken and the subject was receiving placebo, the event should not be report in an IND safety report because there is not a reasonable possibility that the drug caused the adverse event.”

Furthermore, the agency explained that, since many clinical trials are conducted in countries outside the United States, the new rule revises definitions and reporting standards so that they are more consistent with two international organizations -- the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, and the World Health Organization’s Council for International Organizations of Medical Sciences. The changes are designed to help ensure harmonized reporting of globally conducted clinical trials. 


Other issues highlighted in the guidance document:

  • Each event report submitted by sponsors must also include information on previous reports of similar events and how the new event fits into the overall context;
  • Sponsor-produced brochures explaining study protocols to investigators must be updated whenever new safety information comes up;
  • As before, sponsors must report relevant safety-related findings from other sources such as animal experiments or epidemiological data;
  • Safety events occurring in offshore trials must be reported if the trial is included in a U.S. IND; and
  • All serious adverse events occurring in bioavailability or bioequivalence studies conducted under INDs, whether or not they are potentially drug related, must be reported to the FDA.


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