On September 29, 2010, the Food and Drug Administration (FDA) announced a final rule amending 21 CFR Part 312 regulations regarding safety reporting requirements for human drug and biological products subject to an IND. This was coupled with the establishment of new safety reporting requirements for those bioavailability/bioequivalence studies otherwise exempt from IND requirements under 21 CFR 320.31. The new rule is slated to become effective March 28, 2011. The Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) also released a draft guidance document to accompany the rule changes titled, “Guidance for Industryand Investigators: Safety Reporting Requirements for INDsand BA/BE Studies.” It is available at http://www.fda.gov/

downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM227351.pdf. The guidance explains that the changes are designed to “improve the overall quality of safety reporting, strengthen FDA’s ability to review critical safety information, improve safety monitoring of human drug and biological products, and harmonize safety reporting internationally.”

Rationale for the New Rule

The major goal of the new rule is to improve the signal-to-noise ratio for emerging safety signals by reducing the proportion of uninformative safety reports received by the agency, investigators, and institutional review boards. FDA blames ambiguous and insufficiently explained requirements language for the flood of uninformative safety reports that has deluged those bodies responsible for safety monitoring and diverted their resources. FDA pinpointed ambiguous language in the requirement for safety reports for serious and unexpected adverse experiences “associated with the use of the drug.” “Association,” in turn, meant that there was a “reasonable possibility” that the drug caused the experience. The agency said that sponsors interpreted the term “reasonable possibility” too liberally, and frequently reported events where there was little reason to believe in a causal connection.

FDA said that these reports, generally uninformative when reported for single events, are exemplified by events such as manifestations of the underlying disease commonly occurring in the study population independent of drug exposure, and events where the study was designed to evaluate whether the drug reduced the very type of event being reported, i.e. study endpoints. The new rule and companion guidance, therefore, address key definitions to clarify what events should and, especially, should not be reported.

Key Definitions

The most important provisions of the new rule articulate definitions necessary to clarify what must be reported. These involve the probability that a drug caused the event, and the determination of whether an event is expected or unexpected.

Causality

The terms “adverse event,” “adverse reaction,” and “suspected adverse reaction” have been defined in the new rule. An adverse event is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related, whereas an adverse reaction is any adverse event caused by a drug. The standard for calling an adverse event an adverse reaction is that there is a reason to conclude that the drug caused the event. Between these two terms, on the dimension of causality, lies the “suspected adverse reaction.” The suspected adverse reaction is an adverse event where there is a reasonable possibility that it was caused by the drug. This requires only that there is evidence suggestive of a causal relationship. The word “association” is no longer synonymous with any level of suspicion of causality. The new rule uses the word “association” only to indicate that the event bears a temporal association to the use of the drug. While the term “reasonable possibility” is still used, it is now supported with an explanation that this requires suggestive evidence and provides examples of such suggestive evidence.

Suspicion of causation is raised for a single occurrence of an uncommon event if the event is one known to be strongly related to drug exposures, such as angioedema, hepatic injury, or Stevens-Johnson Syndrome. A single occurrence of an event not commonly associated with drug exposure, but that is uncommon in the study population, may also elevate suspicion of causation. Additionally, an aggregate analysis of a specific event from a clinical trial, even when the specific event is a known consequence of the underlying disease investigated or when the specific event is common in the study population independent of drug exposure, also may raise suspicion of causality if the event is discovered to occur more frequently in the drug-treated group. The three types of events described above involve evidence suggestive of a causal relationship.

Expectation

The new rule specifies what constitutes an unexpected adverse event or an unexpected suspected adverse reaction. There has been no change in the general definitional criteria of “unexpected.” As before, an event is considered unexpected if it is not listed in the investigator brochure (IB) or not listed with the specificity or severity that has been observed (or in other specified materials if no IB is available). The new rule clarifies that an event is also unexpected even if the adverse event is listed in the IB as occurring with the same class of drugs, or as anticipated from the pharmacological properties of the drug, because it has not yet been observed with the particular drug under investigation. The first occurrence of the event is, therefore, still unexpected for reporting purposes.

Severity

The term “life-threatening” continues to have the same meaning as under the prior rule, with the exception that, in the new rule, either the sponsor or the investigator may decide that an event meets this definition. Previously only the investigator could make this decision. The term “serious” has been modified. The prior rule stated that, among other things, a persistent or significant disability qualified as an outcome that suffices to make an event serious. The new rule removes the word “disability” but adds in its place, “a substantial disruption of the ability to conduct normal life functions.” FDA gave no further guidance on what it regards as “substantial” disruption. An additional change is that either the investigator or the sponsor may decide that an event is serious.

Study Conduct Impact

While the new rule does not mention unblinding, FDA has inserted its opinion regarding this aspect of clinical trials conduct into the guidance document. The agency opines that the blind should be broken for serious and unexpected adverse events that would meet the reporting criteria, either as single or multiple occurrences, because knowledge of treatment assignment may be essential for medical management of the subject, and may provide safety information having implications for the conduct of the trial. If the subject is receiving placebo, then a safety report would not be made because there is no possibility that the drug could have caused the event.

What Must Be Reported

Under the prior rule, sponsors were required to notify FDA and all participating investigators within 15 calendar days of serious and unexpected adverse experiences associated with the use of the drug and any findings from tests in laboratory animals suggesting a significant risk for humans subjects (including mutagenicity, teratogenicity or carcinogenicity). The new rule gives a fuller picture of the agency’s expectation.

Under the new rule sponsors must, within 15 calendar days, notify FDA and all investigators to whom the sponsor is providing drug under its INDs or under any investigator’s IND of potential serious risks from clinical trials or any other source, by reporting serious and unexpected suspected adverse reactions. The rule reminds the reporter that these must be reported only if there is evidence suggesting a causal relationship. A new description states that the sponsor must report findings from other studies, such as epidemiological studies, pooled analysis of multiple studies, or clinical studies, whether or not conducted under an IND and whether or not conducted by the sponsor, if the information suggests a significant risk in humans exposed to the drug. Significant risk is described as a level of risk that should result in safety-related changes to the protocol, informed consent, IB, and perhaps other aspects of the conduct of the clinical investigation. The sponsor must also report any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk to humans exposed to the drug. These include, as before, mutagenicity, teratogenicity or carcinogenicity, but now also include significant organ toxicity at or near the expected human exposure. Once again, these reportable events should be of a significance that would be expected to drive protocol and other investigational safety changes.

If there is a clinically important increase in the rate of a serious suspected adverse reaction, over that listed in the protocol or IB, this too is reportable. The guidance says that clinical importance is a judgment call, which includes consideration of the nature of the study population, the nature and seriousness of the reaction, and the magnitude of the observed rate increase. Unexpected fatal and life-threatening suspected adverse reactions must be reported no later than seven calendar days after sponsor’s initial receipt of the information, consistent with the prior rule’s timing requirements for fatal and life-threatening events.

The new IND safety reporting rule has clarified many terms, and its accompanying guidance document provides concrete examples designed to assist sponsors in determining when an adverse event is reportable.

Colleen Heisey is a partner in the Washington, D.C. office of Hunton & Williams LLP (hunton.com) in the firm’s Food and Drug Practice. She can be reached at [email protected] Gilpin is an associate in the firm’s Food and Drug Practice.