Does an Adverse Event Have to Be Caused by the Research to Be Reportable?

If the research did not cause the event, do you still have to report it?

A participant becomes ill during a study, but the investigator thinks the illness is probably unrelated to participation. Should the event still be documented? Does it need to be sent to the sponsor? What about the IRB or REC? If it is clearly unrelated, can the research team simply ignore it?

The difficulty is that researchers often use the word report for several different actions. Recording an event in study records, notifying a sponsor or monitoring entity, promptly reporting an unanticipated problem to an IRB or REC, and submitting a regulatory safety report are not necessarily governed by the same criteria.

Causality therefore matters, but not at the same point in every reporting pathway.

No single causality rule applies to every type of adverse-event reporting

Why causality and reportability must be assessed separately

An adverse event does not inherently mean a research-caused event

The starting point is the definition of an adverse event in research. OHRP uses the term broadly for an unfavorable medical occurrence temporally associated with participation, whether or not it is considered related to the research. FDA similarly defines an adverse event in the IND context as an untoward medical occurrence associated with drug use in humans, whether or not considered drug related.

So the label adverse event does not answer the causality question. An AE can be related, possibly related, unlikely to be related, or unrelated, depending on the framework and the evidence available.

“Reportable” does not describe one destination

This is where much of the confusion begins. Researchers may be required to capture or communicate safety information through several channels.

Consequently, saying “this AE is not reportable” without identifying the reporting pathway can be misleading. An event may not qualify for one expedited report but may still need to be documented, communicated elsewhere, followed clinically, or included in other safety information.

OHRP does not require every adverse event to be promptly reported to the IRB

For HHS-regulated research under OHRP's framework, the key issue is whether an adverse event constitutes an unanticipated problem involving risks to subjects or others.

OHRP describes an unanticipated problem as an incident, experience, or outcome that is unexpected, related or possibly related to participation in the research, and suggests that the research places participants or others at greater risk of harm than was previously known or recognized. All three criteria are required under that framework.

For relatedness, OHRP uses a “reasonable possibility” threshold for possibly related events. It recognizes that causality can be difficult to determine and that judgments commonly fall along a continuum rather than into an immediately obvious yes-or-no answer.

OHRP explicitly states that many individual AEs are unrelated to research participation and therefore fail the relatedness criterion for an unanticipated problem. Those events do not require prompt reporting under that particular HHS unanticipated-problem requirement merely because they are AEs.

But an unrelated event may still need to go to a monitoring entity

Not qualifying as an unanticipated problem does not necessarily end the matter. OHRP states that, regardless of whether an internal AE is determined to be an unanticipated problem, investigators must ensure that it is reported to a monitoring entity such as the sponsor, coordinating or statistical center, independent medical monitor, or DSMB/DMC when required by the monitoring provisions of the IRB-approved protocol or institutional policy.

This illustrates why “unrelated” should not be translated automatically into “do nothing.” The protocol may require broader safety collection than the threshold used for prompt IRB reporting.

FDA distinguishes an adverse event from a suspected adverse reaction

FDA's IND framework provides another useful example of why causality changes the reporting category rather than the basic existence of an AE.

FDA defines an adverse event without requiring drug relatedness. A suspected adverse reaction, however, is an AE for which there is a reasonable possibility that the drug caused the event. For IND safety reporting, FDA explains that reasonable possibility means there is evidence suggesting a causal relationship.

For the expedited IND safety-reporting pathway for a serious and unexpected suspected adverse reaction, seriousness and unexpectedness alone are therefore insufficient. The sponsor also needs evidence suggesting causality.

Causality is not always obvious from one participant

Some events have alternative explanations. A participant may have an underlying disease that itself causes the outcome. The event may be common in the study population regardless of treatment. A concomitant medication may be responsible. An unrelated accident may occur during follow-up.

FDA's current IND guidance recognizes that causal evidence can sometimes emerge from patterns rather than from one isolated case. Its examples include aggregate analyses showing that events occurring naturally in the study population appear more frequently in the treatment group than in a concurrent or historical control group.

This is one reason researchers should avoid making causal judgments solely from chronology. “It happened afterward” and “the research caused it” are not equivalent statements.

Uncertainty should not be silently converted into “unrelated”

OHRP acknowledges that determining relatedness or possible relatedness can be difficult. Its threshold of reasonable possibility is deliberately different from requiring proof that the research caused an event.

The study should specify who performs this assessment and how categories are assigned. The question of who decides whether an adverse event is related to the research is therefore more than administrative detail. It affects the consistency and defensibility of safety decisions.

An SAE can be unrelated and still matter to the study

The important distinction is that serious, related, and reportable through a particular pathway are separate determinations.

Common mistakes about causality and adverse-event reporting

Ask “reportable to whom?” before deciding that an event is not reportable

When an AE occurs, avoid making one global reportability decision. Work through the obligations separately.

The detailed timing and destinations for these reports vary considerably. Once you know what kind of event you have, determine when the adverse event needs to be reported under the requirements governing your study.

Before deciding that an adverse event is not reportable

Frequently asked questions about causality and AE reporting

An event can matter even before you know what caused it

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