Risk, Harm and What Counts as an Adverse Event

Part of Human Subjects Protection for Clinical Research Staff: Risks, Adverse Events and Unanticipated Problems.

About 5 minutes. Free, in your language, no account needed.

Why this matters

Every study carries some risk, and your job on the ground is to notice when something goes wrong and make sure the right people hear about it. Three terms matter here: minimal risk, harm and adverse event. They are easy to mix up, and the mix-up shows up later as late reports or missing notes.

ICH E6(R3) is the international baseline in this course. The US federal regulations (HHS 45 CFR 46, FDA 21 CFR 50 and 56) are taught as the detailed worked example, and passages that name them are US law. Outside the United States, follow your national law and ethics committee requirements. State or local rules may add requirements, and your protocol and IRB set the reporting details for your study.

Minimal risk and balancing risk

Minimal risk means the probability and magnitude of harm or discomfort anticipated are not greater in and of themselves than those ordinarily encountered in daily life or during routine physical or psychological examinations or tests (45 CFR 46.102(j)).

For research that carries more risk, the IRB has to find that risks are minimized and reasonable in relation to anticipated benefits, and, when appropriate, that there are adequate provisions for monitoring data to ensure subject safety (45 CFR 46.111(a)(1), (2), (6); 21 CFR 56.111(a)(1), (2), (6)).

ICH E6(R3) frames the same idea. A trial is initiated and continued only if anticipated benefits justify known and anticipated risks (Principle 1.3). The safety of participants should be reviewed in a timely manner as new safety information becomes available (Principle 1.2).

What counts as an adverse event

OHRP defines an adverse event as any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom or disease, temporally associated with participation in the research, whether or not considered related to the participation.

"Temporally associated" means it happened while the person was in the study. "Whether or not considered related" means you do not need to decide the cause first. A participant who breaks an ankle falling off a curb has had an adverse event under this definition, even if the study had nothing to do with it.

OHRP also says that only a small subset of adverse events are unanticipated problems that must be reported under 45 CFR part 46. Lesson 2 covers that subset. Nothing in this course gives a rule that every adverse event goes to the IRB. What goes where depends on the protocol, the sponsor's requirements and your IRB's written procedures.

Reporting to the sponsor

ICH E6(R3) section 2.7.2 describes investigator safety reporting. Adverse events and abnormal test results that are required for safety evaluation are reported to the sponsor according to the protocol and its time periods. All serious adverse events are reported immediately to the sponsor, after the investigator reasonably becomes aware of them, with an assessment of causality, unless the protocol identifies certain serious events that do not need immediate reporting (an example is events that are study endpoints). For reported deaths, the investigator supplies any requested information. The investigator may delegate safety reporting activities but keeps overall responsibility.

At your site, record every adverse event, follow the protocol's time periods, and treat serious events as urgent.

Care for participants

The investigator or institution ensures adequate medical care for any trial-related adverse events, including clinically significant lab values, during and after participation. The participant is told when medical care is needed for an intercurrent illness (section 2.7.1(c)).

When a participant withdraws or is discontinued, the investigator follows the protocol, which may include steps to avoid loss of data already collected. The participant need not give a reason, but the investigator makes a reasonable effort to learn it while fully respecting the participant's rights and without interfering with the decision to withdraw (sections 2.9.1, 2.9.2).

In practice

A research nurse is on the phone with a participant who says she has had a severe headache for two days and saw an emergency doctor yesterday. The nurse does not wait to work out whether the study drug caused it. She makes sure the participant gets care, writes down the date, symptoms and who she spoke with, and tells the investigator the same day. The investigator decides on seriousness, causality and the protocol's reporting steps.

What this looks like when it goes wrong

A coordinator hears that a participant had a minor fall last week. She decides it is unrelated and does not put it in the record. Two months later a monitor reviews the visit notes and finds a hospital discharge summary that mentions the same fall and a fractured wrist. Under the definition, the fall was an adverse event whether or not it was related. The record is incomplete, and the investigator never had the chance to assess it.

Key takeaways