Dealing with over-reporting: Understanding the FDA’s new regulations

By Glenn Veit, JD, CIP, Copernicus Group IRB Chairperson

The Food and Drug Administration this year published revised regulations pertaining to safety reporting for drug and biologic products under an Investigational New Drug (IND) application. The FDA also made bioavailability (BA) and bioequivalence (BE) studies conducted to support the approval of a generic drug subject to IND safety reporting requirements.

Let’s look at how these changes in 21 CFR 312 will impact IND safety reporting.

Why revise?

The FDA appears intent on reducing the number of IND safety reports that are uninterpretable or do not contribute to a better understanding of the developing safety profile of the drug or biologic. In the guidance that accompanies the new regulations, the FDA seems to acknowledge there are too many reports for adverse events in which there is little evidence of a causal relationship between the drug and the adverse event. In fact, the default position for both sponsors and investigators has been “over-reporting” safety events.

The FDA also appears intent on clearing up confusion over the term “adverse drug experience.” Under prior IND regulations (21 CFR § 312.32), there was little guidance about which “adverse drug experiences” during clinical trials required reporting, resulting in sponsors often reporting all serious adverse events, even when there was little reason to believe they were associated with the investigational drug.

As a result, the new regulations eliminate the term “adverse drug experience” and replace it with two terms: “adverse event” and “adverse reaction.” An “adverse event” is, simply, any adverse event observed during a clinical trial. An “adverse reaction” is an adverse event in which there is reason to conclude the drug caused the event.

What gets reported?

The FDA now requires sponsors to file IND safety reports for suspected adverse reactions that are both serious and unexpected. There must now be a “reasonable possibility” the drug caused the adverse event – that is, there must be evidence to suggest a causal relationship.

The FDA provides three examples of when such a “reasonable possibility” of causality may be drawn, requiring an IND safety report:

  • When the event is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome)
  • When the event is not commonly associated with drug exposure, but is uncommon in the population exposed to the investigational drug (e.g., tendon rupture)
  • When an aggregate analysis of specific events indicates the events occur more frequently in the drug treatment group than in controls

In addition, the guidance document makes it clear the FDA expects such information be based on unblinded analysis of the events, as information on what treatment the patient received could “provide critical safety information about the drug that could have implications for the ongoing conduct of the trial.”

What else must sponsors report?

In addition to serious and unexpected suspected adverse reactions, the new regulations require the sponsor to submit IND safety reports to the FDA and all investigators about:

  • Findings from other studies
  • Findings from animal or in-vitro testing
  • An increased rate of occurrence of serious suspected adverse reactions

Findings from other studies

IND safety reports must be submitted when findings “suggest a significant risk in humans exposed to the drug” in other studies. These may include epidemiological studies, analyses of multiple studies and clinical studies other than those conducted under the present IND. They can also include studies not conducted under an IND or by the sponsor of the present IND.

Information that requires reporting would typically be that which would lead to safety-related changes in the protocol, informed consent document, investigator brochure or other aspects of the clinical investigation.

Findings from animal and in-vitro testing

The new FDA rule requires sponsors to submit an IND safety report if animal or in-vitro testing suggests a significant risk to humans exposed to the drug. This would include reports of mutagenicity, teratogenicity, carcinogenicity or organ toxicity.

Findings requiring reporting would typically be those which lead to safety-related changes in the protocol, informed consent, investigator brochure or other aspects of the clinical investigation.

Increased rates of occurrence of serious suspected adverse reactions

Sponsors are also required to file an IND safety report when they discover “any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.” This requirement was added for consistency with ICH guidance and the FDA’s expectation that the sponsor track and identify changes in rates of adverse events during the conduct of a clinical trial.

In addition, there is a requirement to report serious suspected adverse reactions that are anticipated within the drug class but not specifically mentioned as occurring with the particular drug under investigation. Under this rule, a serious adverse reaction known to occur in the class of drugs, but not yet observed in the drug under study, would be considered “unexpected” – and therefore reportable the first time it occurs in the study drug.

The final rule also adds the requirement that sponsors report serious and unexpected suspected adverse reactions even if the event may be considered a component of a study endpoint. For example, death from anaphylaxis must be reported, even if a study endpoint is all-cause mortality, when death from anaphylaxis is unexpected and if there is a reasonable possibility that the drug caused the anaphylaxis. Serious and expected suspected adverse reactions that are study endpoints need not be reported as IND safety reports, and should only be reported as described in the study protocol.

What must investigators report?

Under the FDA’s revised reporting requirements in 21 CFR § 312.64 (b), investigators must immediately report to the sponsor any serious adverse event, whether it is considered related to the drug or not – including events listed as “known to occur” in the protocol or the investigator’s brochure.

The investigator must include an assessment as to whether there is a “reasonable possibility” that the drug caused the event. Study endpoints that are also serious adverse events should be reported in accordance with the study protocol unless there is evidence suggesting the event was caused by the study drug. These requirements are in addition to other protocol-specific requirements for safety reporting.

The takeaway

The new regulations are a good start on addressing the problem of over-reporting of IND safety reports under the previous regulatory scheme. But whether the new regulations will result in decreasing the number of individual IND safety reports remains to be seen.

In addition, sponsors and investigators will be dealing with new expectations pertaining to analysis of adverse events and will need to develop new processes to determine the significance of adverse events in clinical trials. We may see the role of Data Monitoring Committees (DMC) expanded for the purpose of analyzing and evaluating un-blinded data to determine whether the events must be reported.

As with any overhaul of regulations, the true effect of the changes is yet to be shown.