Adverse event reporting for research site staff

What counts as an adverse event

ICH E6(R3) defines an adverse event (AE) as any unfavorable medical occurrence in a trial participant who was given the investigational product, and says the event does not need to have a causal relationship with the treatment (ICH E6(R3), Glossary). For drug studies in the United States, 21 CFR uses its own words for the same idea: any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug related (21 CFR 312.32(a)).

So you do not decide whether the drug caused an event before you write it down. And the protocol may ask for more than events after dosing: events during screening, before any investigational product is given, are considered and reported to the sponsor if the protocol requires it (ICH E6(R3) 2.7.2(a)). Possible adverse events reach a site in several ways:

• A participant mentions a symptom at a visit, on the phone or in a diary, often in passing.
• An abnormal laboratory value or test result that the protocol says must be reported for safety evaluation (ICH E6(R3) 2.7.2(a)).
• A record from another hospital or clinic: an emergency visit, an admission or a new diagnosis.
• Data from outside the site, such as central laboratory results. The investigator is responsible for reviewing such data in time when they can affect a participant's safety (ICH E6(R3) 2.12.3).

When an adverse event is serious

Seriousness is defined by outcome. An adverse event is serious if it results in death, is life-threatening, requires inpatient hospitalization or prolongs an existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect (ICH E6(R3), Glossary). For drug studies under an IND, 21 CFR uses a matching list and adds a substantial disruption of the ability to conduct normal life functions (21 CFR 312.32(a)).

An important medical event can be serious without any of those outcomes, when it may put the participant at risk and may need intervention to prevent one of them. ICH E6(R3) says such an event should generally be considered serious (ICH E6(R3), Glossary), and 21 CFR says it may be considered serious based on medical judgment (21 CFR 312.32(a)).

Serious is not the same as severe. Neither definition asks how intense the event was: they ask what it led to. A mild event that ends in a hospital admission is serious, and a severe headache that settles at home is not, unless it meets one of the criteria above. Mixing them up can delay the report of a serious event, and the lessons linked at the end of this guide practice telling them apart.

What site staff must do, step by step

The order matters. Care comes first, then the investigator, then the report.

• Recognize it. Ask open questions at every contact, and treat anything new or worse as a possible adverse event until the investigator has assessed it.
• Make sure the participant gets care. The investigator or institution should ensure adequate medical care for adverse events related to the trial, and trial-related medical decisions belong to a qualified physician, dentist or other qualified healthcare professional who is an investigator or sub-investigator, as local rules allow (ICH E6(R3) 2.7.1(a) and 2.7.1(c)).
• Tell the investigator now. Judging seriousness and causality is the investigator's medical call. Coordinators and nurses often do much of the reporting work, but the investigator may delegate safety reporting only to qualified site staff and keeps overall responsibility for it (ICH E6(R3) 2.7.2(d)).
• Report a serious adverse event to the sponsor immediately after the investigator reasonably becomes aware of it, with an assessment of causality (ICH E6(R3) 2.7.2(b)). For drug studies under an IND, the investigator must immediately report any serious adverse event to the sponsor, whether or not it is considered drug related (21 CFR 312.64(b)).
• Record every other adverse event and report it to the sponsor on the timetable the protocol sets (ICH E6(R3) 2.7.2(a); 21 CFR 312.64(b)).
• Follow up. Send new information as a follow-up report as it arrives (ICH E6(R3) 2.7.2(b)). After a death, give the sponsor, the IRB or ethics committee and, where applicable, the regulator any further information they request, such as autopsy and terminal medical reports (ICH E6(R3) 2.7.2(c)).

A protocol may name serious events that do not need immediate reporting, such as deaths or other events that are study endpoints (ICH E6(R3) 2.7.2(b)). That exception exists only where the protocol states it, and for drug studies under an IND an endpoint event is still reported immediately if there is evidence suggesting the drug caused it (21 CFR 312.64(b)).

Reporting timelines

The clock that matters at a site starts when the investigator reasonably becomes aware of the event, not when the event began (ICH E6(R3) 2.7.2(b)). A hospital admission on a Friday that the site hears about on a Monday is reported on that Monday, immediately.

• Serious adverse event, drug or biologic study: to the sponsor immediately (ICH E6(R3) 2.7.2(b); 21 CFR 312.64(b)). If the protocol sets a specific time limit, follow it.
• Adverse event that is not serious: recorded, and reported to the sponsor within the time the protocol specifies (ICH E6(R3) 2.7.2(a); 21 CFR 312.64(b)).
• Unanticipated adverse device effect, device study: to the sponsor and the reviewing IRB as soon as possible, and no later than 10 working days after the investigator first learns of it (21 CFR 812.150(a)(1)).
• Unanticipated problems involving risk to participants or others: to the IRB promptly (21 CFR 312.66). Suspected unexpected serious adverse reactions (SUSARs) are reported promptly to the IRB or ethics committee as the applicable regulations require (ICH E6(R3) 1.4.8(c)).

Speed at the site matters because the sponsor has deadlines of its own. For a drug under an IND, the sponsor must send FDA and all participating investigators an IND safety report no later than 15 calendar days after it determines the information qualifies (21 CFR 312.32(c)(1)), and must tell FDA about an unexpected fatal or life-threatening suspected adverse reaction no later than 7 calendar days after it first receives the information (21 CFR 312.32(c)(2)). A report that waits at the site uses up that time.

What to document

Write it down where it is first captured, in the source record, so that the record is attributable, legible, contemporaneous, original, accurate and complete (ICH E6(R3) 2.12.2). For an adverse event that usually means:

• What happened, in the participant's words, and the diagnosis once the investigator makes one.
• When it started, when the site became aware of it, and when and how it was reported.
• The investigator's assessment of seriousness and causality, and who made it (ICH E6(R3) 2.7.2(b); ICH E6(R3) 2.12.2).
• Treatment given, the outcome, and any change to investigational product dosing.
• Any premature unblinding, including unblinding because of a serious adverse event, which the investigator should promptly document and explain to the sponsor (ICH E6(R3) 2.11).

What goes on the case report form or the SAE report should match the source records, or the difference should be explained, and a correction should never hide the original entry (ICH E6(R3) 2.12.5 and 2.12.6). For drug studies, each participant's case history must record all observations pertinent to the investigation (21 CFR 312.62(b)).

Who to tell

Each report has an owner and a route. Check the protocol and your IRB's procedures for the local detail.

• The investigator: first, every time. The investigator makes the medical judgment and is responsible for the reporting, even when site staff do the work (ICH E6(R3) 2.7.2(d)).
• The sponsor: serious adverse events immediately, and other adverse events as the protocol says (ICH E6(R3) 2.7.2(a) and 2.7.2(b); 21 CFR 312.64(b)).
• The IRB or ethics committee: unanticipated problems involving risk promptly (21 CFR 312.66), unanticipated adverse device effects within the device timeline (21 CFR 812.150(a)(1)), and SUSARs as the applicable regulations require (ICH E6(R3) 1.4.8(c)). Your IRB must have written procedures for prompt reporting of unanticipated problems (21 CFR 56.108(b)), so read them.
• The regulator: the sponsor makes the expedited safety reports to regulators (ICH E6(R3) 3.13.2(b); 21 CFR 312.32(c)(1)) and sends SUSARs on to investigators and IRBs in a way that reflects how urgent they are (ICH E6(R3) 3.13.2(d)). Where an investigator is also the sponsor of a drug study, both sets of duties are theirs (21 CFR 312.3(b)). Otherwise, the site's job is to get complete information to the sponsor quickly.

Practice these decisions in CRLN

Knowing the rules is the start. Applying them is harder on a weekend phone call than on a page. CRLN's Practice Lab has scenarios and lessons where you make these decisions, and each decision in a scenario is scored against ICH E6(R3):

Scores describe performance in simulation. They are not a license or a certification.

Scenario: The Weekend SAE, a call from a participant who has been admitted to the hospital: https://crln-practice-lab.crln-learn.com/scenarios/crc-d4

Lesson: Adverse Events: Recognizing and Recording Them: https://crln-practice-lab.crln-learn.com/learn/crc-coordinator-training/09-participant-safety/adverse-events-recognizing-and-recording

Lesson: Serious Adverse Events and Reporting: https://crln-practice-lab.crln-learn.com/learn/crc-coordinator-training/09-participant-safety/serious-adverse-events-and-reporting

Lesson: Severity, Seriousness and Why They Differ: https://crln-practice-lab.crln-learn.com/learn/pi-investigator-training/07-adverse-event-assessment/severity-seriousness-and-why-they-differ

Lesson: Causality: Making a Defensible Judgment: https://crln-practice-lab.crln-learn.com/learn/pi-investigator-training/07-adverse-event-assessment/causality-a-defensible-judgment

The Clinical Research Coordinator track: https://crln-practice-lab.crln-learn.com/roles/crc

Frequently asked questions

What is an adverse event in a clinical trial?

Any unfavorable medical occurrence in a trial participant who was given the investigational product, whether or not it was caused by the treatment (ICH E6(R3), Glossary). For drug studies in the United States, 21 CFR 312.32(a) defines it as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related.

What makes an adverse event serious?

Its outcome: death, a life-threatening event, inpatient hospitalization or a longer hospital stay, persistent or significant disability or incapacity, or a congenital anomaly or birth defect. An important medical event that may put the participant at risk can also be serious (ICH E6(R3), Glossary; 21 CFR 312.32(a)).

How quickly must a serious adverse event be reported?

To the sponsor immediately after the investigator reasonably becomes aware of it (ICH E6(R3) 2.7.2(b); 21 CFR 312.64(b)), unless the protocol names it as an event that does not need immediate reporting. Follow any specific time limit the protocol sets.

Do I report an adverse event I think is unrelated to the study drug?

Yes. An adverse event is recorded whether or not anyone thinks the treatment caused it (ICH E6(R3), Glossary), and a serious adverse event is reported to the sponsor whether or not it is considered drug related (21 CFR 312.64(b)). The investigator's causality assessment goes with the report.

Is a severe adverse event always serious?

No. Seriousness depends on outcome, such as hospitalization or a life-threatening event, not on how intense the event was (ICH E6(R3), Glossary). A severe event that resolves without any of the serious outcomes is not serious, and a mild one that leads to a hospital admission is.

Who is responsible for reporting adverse events at a site?

The investigator. Safety reporting work can be delegated to qualified site staff, such as a Clinical Research Coordinator or a Research Nurse, but the investigator keeps overall responsibility for participant safety and for meeting the reporting requirements (ICH E6(R3) 2.7.2(d)).