Towards the end of last year, FDA added two new final guidances related to the safety reporting requirements for investigational new drug exemptions (“INDs”) and bioavailability and bioequivalence (“BA/BE”) studies entitled: Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies and Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies-Small Entity Compliance Guide. These guidances are intended to explain final rules published on September 29, 2010 that amended the IND safety reporting requirements under 21 C.F.R. Part 312 and added safety reporting requirements for individuals conducting BA/BE studies under 21 C.F.R. Part 320. We blogged on that development then.
A key focus of the new regulations was to add clarifying definitions to certain terms, “adverse event”, “suspected adverse reaction”, “unexpected” adverse event or reaction, “serious” adverse event or reaction, and “life-threatening”, as well as further define reporting requirements. According to the main Guidance (not the one for small entities), sponsors frequently took a broad reading of the phrase “associated with the use of the drug” in the context of the former 21 C.F.R. § 312.32(a), which stated, “there is a reasonable possibility that the experience may have been caused by the drug.” With this broad reading, the Guidance continues, “sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event.” The Guidance includes three examples of overzealous reporting, including reporting adverse experiences that were manifestations of the underlying disease, common occurrences in the study population independent of drug exposure, or study endpoints. FDA described these types of reporting as a drain on agency resources and “uninformative when reported as single events (i.e., without a comparison of the incidence of the event in treated and untreated subjects), they do not contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection.”
Interestingly, this appears to be somewhat of a departure from how FDA had enforced its reporting regulations on clinical investigators. Shortly after I first joined FDA in the 1990s, I was involved in a clinical investigator disqualification proceeding that resulted in a clinical investor being disqualified from further clinical studies because, among other things, he had not timely or accurately reported certain adverse events. While the Presiding Officer took into account that many of the patients had underlying conditions prior to the experimental therapy, the Center for Drug Evaluation and Research (“CDER’s”) approach appeared to focus on the need for the investigator to report all adverse event associated with the therapy. In this case, the therapy had to do with infusing a drug with a catheter to help dissolve gall bladder and common bile duct stones, which the CDER described as a drug/device. The investigator admitted that he had not immediately reported certain events that occurred as a result of the catheter insertion (most likely not due to the drug) or the patient’s underlying conditions, because in his opinion, they were not associated with the drug therapy. At that time, CDER took the approach that the investigator’s opinion was irrelevant, because the adverse events were at least temporally associated with the drug/device and therefore had to be timely reported.