On September 29, 2010, FDA issued a final rule1 and draft guidance document2 revising and explaining the new safety reporting requirements for investigational new drug (IND) products in 21 C.F.R. Part 312 and for bioavailability and bioequivalence studies in humans in 21 C.F.R. Part 320. The rule is intended to improve the quality of safety reporting, strengthen FDA’s ability to detect safety signals and improve FDA’s monitoring, and harmonize the regulations with the existing standards of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), the World Health Organization’s Council for International Organizations of Medical Sciences (CIOMS) and the European Union (EU).

Although the proposed rule3 included revisions to the premarketing and postmarketing reporting requirements, FDA’s final rule addresses only the premarketing reporting obligations; FDA is still developing its final rule for postmarketing reporting. Clinical trial sponsors must ensure their policies, procedures and protocols reflect these new requirements, which become effective March 28, 2011. The key features of the new rule are described below.

Minimize and Simplify Reports

The final rule attempts to minimize and simplify IND safety reports by refining definitions to narrow the scope of the reporting requirements. Under the former rule, sponsors frequently reported events that were likely to have been manifestations of underlying disease, that commonly occurred in the study population independent of drug exposure, or that were study endpoints. These reports were generally uninformative when reported as single events, and created a drain on FDA resources.

In an attempt to minimize reporting that does not meaningfully contribute to the developing safety profile of an investigational drug, the final rule clarifies that reporting is triggered where the event is serious, unexpected, and there is a "reasonable possibility" that the drug caused the adverse event, which requires evidence of a causal relationship between the drug and the adverse event. To assist sponsors in determining whether there is evidence of a causal relationship, the rule provides the following examples of a threshold for causality:

  • A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
  • One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture)
  • An aggregate analysis of specific events observed in a clinical trial (such as known consequences of the underlying disease or condition under investigation or other events that commonly occur in the study population independent of drug therapy) that indicates those events occur more frequently in the drug treatment group that in a concurrent or historical control group

The rule also clarifies the timing and format of an IND safety report to FDA and participating investigators. Specifically, FDA declined to require a minimum data set to be established before reporting and will not require a chronological history of efforts to acquire that information to be included in an IND safety report. Instead, the final rule requires the sponsor to submit an IND safety report no later than 15 days after it determines that the information qualifies for reporting under the regulations. Certain unexpected reactions must still be reported within seven days of the sponsor’s receipt of the information.

FDA has also modified its regulations to permit electronic report submission, and allows for alternative reporting arrangements to minimize over-reporting of uninformative events. One such method of alternative reporting would be to include in study protocols or other documentation a list of known consequences of the disease that would not be submitted to FDA in an expedited manner as individual case safety reports (e.g., events that are study endpoints). Although FDA’s final rule clarifies that study endpoints such as morbidity or mortality would be reported to FDA as described in the protocol and ordinarily would not be reportable as an IND safety report, in some cases events may be reportable in an IND safety report if a serious and unexpected adverse event occurs for which there is evidence suggesting a causal relationship between the drug and the event, regardless of whether it is a component of the study endpoint. Where an expedited report is required, FDA generally expects the sponsor to unblind.

Improved Monitoring

The final rule is anticipated to permit FDA to better monitor and evaluate the drug’s safety by adding a requirement for expedited reporting of (1) findings from clinical studies, epidemiological studies, or pooled analyses of multiple studies that suggest a significant risk in humans exposed to the drug; (2) serious suspected adverse reactions that occur at an increased rate than listed in the protocol or investigator brochure, and (3) findings from animal or in vitro studies that suggest a significant risk in humans.

Additionally, all serious adverse events from bioavailability and bioequivalence studies are now reportable under the regulations. FDA’s preamble to the final rule reasoned that FDA has received safety information from these studies that has provided important information about the drugs under investigation. Thus, expanding the reporting obligations to non-IND bioavailability and bioequivalence studies may improve FDA’s ability to monitor safety of the product.


FDA’s final rule revises the definitions and reporting standards to harmonize with international definitions and standards. Specifically, the definitions section for the IND safety reporting regulations will now include the following terms: (1) adverse event, (2) suspected adverse reactions, (3) life-threatening adverse event or life-threatening suspected adverse reaction, (4) serious adverse event or serious suspected adverse reaction and (5) unexpected adverse event or unexpected suspected adverse reaction. An adverse event is defined as "any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related." A suspected adverse reaction means any adverse event for which there is evidence to suggest a causal relationship between the drug and the adverse event.

The final rule requires that the investigator or sponsor make the determination for reporting purposes about whether an adverse event or suspected adverse reaction is "life-threatening" or "serious." The rule also clarifies that an adverse event or suspected adverse reaction that has not been previously observed with the drug under investigation can be "unexpected" when mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, but not specifically mentioned as occurring with the particular drug under investigation.