Klinik çalışmalarda güvenlik bildirimi gereksinimleri (İng)


Safety Reporting Requirements for INDs and BA/BE Studies

Under the former 21 CFR 312.32(c)(1)(i)(A) and (B), sponsors investigating a drug under an IND were required to notify FDA and all participating investigators, in a written IND safety report, of any adverse experience associated with the use of the drug that was both serious and unexpected, and any finding from tests in laboratory animals that suggested a significant risk for human subjects.  The phrase associated with the use of the drug was defined as “there is a reasonable possibility that the experience may have been caused by the drug” (former 21 CFR 312.32(a)).  Notwithstanding this definition, sponsors frequently reported, as individual cases, serious adverse experiences for which there was little reason to believe that the drug caused the event.  For example, sponsors often reported:

  • Serious adverse experiences (e.g., mortality or major morbidity) that were likely to have been manifestations of the underlying disease.
  • Serious adverse experiences that commonly occurred in the study population independent of drug exposure (e.g., strokes or acute myocardial infarctions in an elderly population) 
  • Serious adverse experiences that were study endpoints (i.e., the study was evaluating whether the drug reduced the rate of these events)

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 they do not  contribute meaningfully to the developing safety profile of an investigational drug or to human subject protection.  Attempting to review and evaluate these reports without the necessary context was also a drain on resources for FDA, investigators, and institutional review boards (IRBs),  diverting them from other activities.  

The tendency for sponsors to report such uninformative individual cases seems to have been primarily related to interpretation of the reasonable possibility standard in the definition of associated with the use of the drug.  For an individual case of the types of adverse events described above, there would generally not be enough evidence to suggest that there was a reasonable possibility that the drug caused the adverse event.  Such events would therefore not meet the definition of “associated with the use of the drug” and should not have been reported as IND safety reports.  

Under 21 CFR 312.32, the amended requirements revise the definitions used for safety reporting and make clear when to submit expedited safety reports.  The requirements distinguish circumstances in which it is appropriate to submit individual cases and circumstances in which cases should be aggregated and compared to cases in a control group and submitted only if the event occurs more frequently in the drug treatment group.  Compliance with these requirements will increase the likelihood that submitted information will be interpretable and will meaningfully contribute to the developing safety profile of the investigational drug and improve the overall quality of safety reporting.  In addition, reducing the number of uninformative individual reports will enhance the ability of sponsors, FDA, investigators, and IRBs to focus on safety issues that affect public health. Because the regulations require reporting certain adverse events in the aggregate rather than as individual cases, it is important for sponsors to collect and evaluate safety data systematically during product development, including accumulating safety data (see section V.A.3).  


Safety Reporting Requirements for BA and BE Studies (21 CFR 320.31(d)(3)) Under former 21 CFR 320.31(d), certain in vivo BA and BE studies in humans were exempted from the IND requirements under part 312 if specific conditions were satisfied (i.e., samples of any test article and reference standard were reserved by the persons conducting the study and released to FDA upon request, studies were conducted in compliance with the requirements for institutional review set forth in 21 CFR part 56 and informed consent set forth in 21 CFR part 50).  Although these studies were not subject to the IND safety reporting requirements under 21 CFR 312.32, FDA received safety information from these studies that provided important information about drugs under investigation.  For this reason, the final rule contains safety reporting requirements under 21 CFR 320.31(d)(3) for persons conducting BA or BE studies that are exempt from the IND requirements.  These requirements will help FDA monitor the safety of these drugs and better protect human subjects enrolled in BA or BE studies.

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