Examination of Clinical Trial Costs and Barriers for Drug Development. 4.5.2 Safety Reporting Requirements for Investigational New Drugs (INDs) and Biologics (21 CFR 312)


In the course of clinical investigations conducted under investigational new drug (IND) applications, information regarding adverse events must be communicated among investigators, sponsors, IRBs, and FDA in safety reports. There are a number of terms that are used to categorize adverse events and thereby determine which must be reported. The most up-to-date definitions of these terms from 21 CFR 312.32(a) are provided below:

  • Adverse event: “[A]ny untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.”
  • Life-threatening adverse event or life-threatening suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘life-threatening’ if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.”
  • Serious adverse event or serious suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘serious’ if, in the view of either the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.”
  • Suspected adverse reaction: “[A]ny adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug.”
  • Unexpected adverse event or unexpected suspected adverse reaction: “An adverse event or suspected adverse reaction is considered ‘unexpected’ if it is not listed in the investigator brochure or is not listed at the specificity or severity that has been observed; or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the current application, as amended.”

In the past, the FDA, IRBs, and clinical investigators in multicenter trials have been flooded with expedited reports of serious adverse events (SAEs), making it difficult to determine which were true signals of significant safety events and which were simply “noise.” This high-volume reporting occurred largely as a result of the FDA’s previous safety reporting requirements, which were insufficiently specific with regard to the threshold for determining whether an adverse event was reportable (Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011), combined with cautious over-reporting on the part of sponsors (see Section 4.6). These reports did not provide enough context—such as aggregate data by treatment group—to allow for interpretation of the events and evaluation of their causal relationship with drug therapy. For example, it is impossible to determine whether a single reported case of myocardial infarction is causally related to drug exposure in a study population comprised of elderly patients (Kramer, Smith, & Califf, 2012; Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011).

A new FDA safety reporting regulation (effective March 2011) seeks to remedy these problems by clarifying the roles and responsibilities of sponsors and clinical investigators in the safety reporting process (Kramer, Smith, & Califf, 2012; Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011). The new regulation requires that clinical investigators continue to report all serious adverse events to the sponsor, regardless of whether they are considered to be drug-related. The sponsor, in turn, is required under 21 CFR 312.32(c) to submit an expedited IND safety report to the FDA and all participating investigators within 15 days when any of the following criteria are met: (1) there has been a suspected adverse reaction that is both serious and unexpected (as defined above); (2) there are findings from other studies or animal or in vitro studies that suggest that exposure to the drug results in a significant risk to humans; or (3) there has been a “clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.” The crux of the new rule is that sponsors should send expedited reports only for those events that the sponsor believes are causally linked to exposure to the investigational agent, rather than sending expedited reports for all events that either the sponsor or the investigator believes are even possibly linked to exposure to the investigation agent. 

In contrast to the previous regulations, which permitted either the sponsor or the investigator to make causality determinations, assessment of which events are likely caused by the drug is now solely the responsibility of the sponsor, who has more complete information than the individual investigators. Additionally, more guidance is provided to help sponsors evaluate causality for adverse events and what types of reactions need to be reported. The new requirements are thus intended to reduce the excessive volumes of events being reported to FDA, investigators, and IRBs and more clearly identify which events actually have important patient safety implications (Sherman, Woodcock, Norden, Grandinetti, & Temple, 2011).

Still, it is too early to tell how sponsors will adapt to the change and to what extent the changes will succeed in their intended purpose (Kramer, Smith, & Califf, 2012). Despite the revisions that were made in the spring of 2011 (to 21 CFR parts 312 and 320), some remaining issues were raised by industry and IRB representatives at the public FDA hearing held in April, 2012. For one thing, there may be inconsistent reporting requirements. Investigators are required (under 21 CFR parts 56.108(b)(1), 312.53(d)(1)(vii), and 312.66) to report promptly “to the IRB…all unanticipated problems involving risks to human subjects or others”; however, investigators might interpret an event to be “anticipated” (and therefore not required to be submitted) on one occasion, and then might interpret the same event to be “unanticipated” at another time (Public Hearing, 2012). Another speaker expressed concern that 21 CFR part 56 is still interpreted by sponsors and investigators as requiring every investigator to send every IND safety report to the IRB, and IRBs have trouble interpreting safety data received in a “piecemeal” fashion. The speaker asked that FDA clarify sponsors’ reporting obligations. Individual investigators are also burdened by the need to act as middle men between sponsors and the IRB, which, the speaker argued, is inefficient and unnecessary (U.S. Food and Drug Administration, 2012).

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