WASHINGTON -- The FDA has finalized new procedures aimed at speeding up reporting and analysis of potential safety problems encountered in clinical trials while cutting down on adverse-event filings the agency considers useless.
Under a final rule that will go into effect in March, 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, although serious unexpected events should be reported immediately.
The rule applies only to adverse events in trials conducted under Investigational New Drug (IND) protocols, including bioavailability and bioequivalence studies of generic drugs covered by INDs. The FDA is still developing separate rules for postmarketing safety reporting.
It is not necessary for sponsors or investigators to decide that a study drug actually caused the event, the FDA emphasized in a guidance document explaining the new rule. On the other hand, the agency doesn't want to receive reports on events that are probably or definitely unrelated to study drugs.
The standard the agency wants sponsors and investigators to apply is whether there is "a reasonable possibility" that a study drug caused the event.
Events that would be expected to occur at some level in the study population anyway -- such as strokes or heart attacks in elderly individuals -- or those counted as endpoints in a trial should generally not be reported in individual filings, the guidance document indicated.
"These 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," according to the guidance document.
Instead, investigators or sponsors should aggregate such events and compare the totals with a control group, the agency indicated.
The FDA clarified that, in placebo-controlled trials, treatment assignments for patients suffering unexpected adverse events will typically have to be unblinded.
"In general, if the blind is broken and the subject was receiving placebo, the event should not be reported in an IND safety report because there is not a reasonable possibility that the drug caused the adverse event," the guidance document said.
The document also urged that individual investigators not try to assess whether a study drug caused a given event.
"FDA believes that the sponsor is better positioned ... to assess the overall safety of the investigational drug because the sponsor has access to serious adverse event reports from multiple study sites and is able to aggregate and analyze these reports," according to the document.
Therefore, the agency indicated, investigators should promptly report all serious events to trial sponsors, which will then make a judgment about whether to relay the reports immediately to the FDA or roll them into summary statistics.
Other issues highlighted in the guidance document included:
- 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
- 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
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.
Originally, the agency intended for the same set of procedures to cover postmarketing event reports as well as those from investigational drug trials.
However, the FDA decided that the situations were different enough to warrant separate procedures.