Adverse Event and Serious Adverse Event Definitions

Part of Good Clinical Practice (GCP) — ICH E6(R3): Safety Reporting and Pharmacovigilance.

About 8 minutes. Free, in your language, no account needed.

Why this matters

Classification decides everything that follows. Call an event serious and an immediate report goes to the sponsor. Call it non-serious and it waits for the next data entry. Get the classification wrong and a safety signal is delayed. The most common error is confusing how bad an event feels with whether it meets the regulatory definition of serious.

Adverse event

The International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guideline E6(R3) defines an Adverse Event (AE) in its Glossary as:

"Any unfavorable medical occurrence in a trial participant administered the investigational product. The adverse event does not necessarily have a causal relationship with the treatment."

Read the second sentence again. An AE does not have to be caused by the product. A broken ankle from a fall in the street is an AE. A worsening of a pre-existing condition is an AE. A clinically significant laboratory abnormality is an AE.

Do not filter events because you think they are unrelated. Record them, then assess causality separately.

Adverse drug reaction

An Adverse Drug Reaction (ADR) is narrower. For a new investigational product before approval, the E6(R3) Glossary describes ADRs as:

"unfavorable and unintended responses, such as a sign (e.g., laboratory results), symptom or disease related to any dose of a medicinal product where a causal relationship between a medicinal product and an adverse event is a reasonable possibility."

The Glossary notes that the level of certainty will vary. Where an ADR is suspected to be product-related with a high level of certainty, it should be included in the reference safety information (RSI) or the Investigator's Brochure (IB).

So the difference between an AE and an ADR is causality. An AE is an occurrence. An ADR is an occurrence where a causal relationship is a reasonable possibility.

Serious adverse event

The E6(R3) Glossary defines a Serious Adverse Event (SAE) as any unfavorable medical occurrence that is considered serious at any dose if it:

• Results in death,
• Is life-threatening,
• Requires inpatient hospitalization or prolongation of existing hospitalization,
• Results in persistent or significant disability or incapacity, or
• Is a congenital anomaly or birth defect.

Note "at any dose". A low dose does not make an event non-serious.

The important medical event clause

The list above is not the whole definition. The Glossary continues:

"An important medical event that may not be immediately life-threatening or result in death or hospitalization, that may jeopardise the participant or that may require intervention to prevent serious outcomes … should generally be considered as serious."

This clause exists because the five criteria miss real emergencies. A severe allergic reaction treated successfully in the clinic with adrenaline did not lead to hospitalization, because the intervention prevented it. It is still serious. So is a seizure that did not require admission, or a suspected drug-induced liver injury caught on a routine test. When you find yourself saying "we stopped it in time", think about this clause. The Glossary cross-refers to ICH E2A and ICH E19.

Severity is not seriousness

This is the classic examination trap, and it is also a real source of site error.

A severe headache that resolves with paracetamol is severe but not serious. A short hospital admission for a mild fever is mild but serious, because it required inpatient hospitalization.

Only seriousness triggers the expedited reporting route. Severity is a description you record on the form. Never write "severe" in the seriousness field.

From SAE to SUSAR

Expedited regulatory reporting depends on three questions stacking up. The E6(R3) Glossary defines a Suspected Unexpected Serious Adverse Reaction (SUSAR) as "an adverse reaction that meets three criteria: suspected, unexpected and serious".

1. Suspected — "There is a reasonable possibility that the drug caused the adverse drug reaction."
2. Unexpected — "An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator's Brochure or alternative documents …; see RSI)."
3. Serious — it meets the SAE definition above.

Expectedness is judged against the reference safety information, not against your own experience. If the reaction is listed in the RSI at that nature and severity, it is expected. If it is not, or if it is more severe than described, it is unexpected.

The ladder is: adverse event, then adverse drug reaction if causality is a reasonable possibility, then serious adverse reaction if it meets the seriousness criteria, then SUSAR if it is also unexpected.

Causality

E6(R3) §2.7.2(b) requires the investigator to include an assessment of causality when reporting an SAE. Many protocols use a scale such as unrelated, possibly related, probably related or definitely related. Others use two points: related or not related. Use the scale your protocol defines, and record your reasoning in the source.

Causality is a clinical judgment. Under Principle 1.5 and E6(R3) §2.7.1(a), a qualified physician, or where appropriate a qualified dentist or other qualified healthcare professional per local requirements, is responsible for trial-related medical decisions.

The medical care duties alongside the reporting duties

Section 2.7.1 is titled Medical Care of Trial Participants, and the qualified-physician rule above is only its first paragraph. Three more sit with it:

• §2.7.1(b) — other appropriately qualified healthcare professionals may be involved in participants' medical care, in line with their normal activities and with local regulatory requirements.
• §2.7.1(c) — during and following participation, the investigator or institution should ensure adequate medical care is provided for any adverse events related to the trial, including clinically significant laboratory values, and should tell a participant when medical care is needed for an intercurrent illness the investigator becomes aware of.
• §2.7.1(d) — the investigator should inform the participant's primary physician of their involvement in the trial, if the participant has one and agrees to their being informed.

Note what (c) and (d) each contain. "Following participation" means the care duty does not end at the last visit, and (d) is a permission to be asked for, never assumed.

In practice

Dr. Sarah is the investigator at a site running an oncology trial. Three events occur in one week.

Participant 004 reports severe nausea for two days. It resolves with an antiemetic at home. This is an AE. Its severity is severe. It is not serious, because no seriousness criterion is met.

Participant 011 is admitted overnight for observation after a mild fever. The fever itself is trivial. This is an SAE, because it required inpatient hospitalization.

Participant 017 develops acute pancreatitis, treated in the emergency department and discharged the same day. No admission. No death. No disability. Dr. Sarah checks the important medical event clause. Acute pancreatitis may jeopardize the participant and required intervention to prevent a serious outcome, so she classifies it as serious. She then checks the RSI in the Investigator's Brochure. Pancreatitis is not listed. She assesses causality as possibly related.

That makes participant 017's event suspected, unexpected and serious. The sponsor will handle it as a SUSAR.

Seriousness is a definition, not an opinion.

Key takeaways

• An adverse event is any unfavorable medical occurrence in a participant who has been administered the investigational product, and it does not need a causal relationship with the treatment.
• An adverse drug reaction is an event where a causal relationship with the medicinal product is a reasonable possibility.
• The E6(R3) Glossary lists five seriousness criteria: death, life-threatening, inpatient hospitalization or its prolongation, persistent or significant disability or incapacity, and congenital anomaly or birth defect.
• An important medical event that may jeopardize the participant or require intervention to prevent a serious outcome should generally be considered serious, even when none of the five criteria is met.
• Severity describes intensity and seriousness describes regulatory outcome; only seriousness drives expedited reporting, so a severe event can be non-serious and a mild event can be serious.
• A SUSAR is an adverse reaction that is suspected, unexpected and serious, and expectedness is judged against the reference safety information in the Investigator's Brochure.
• Section 2.7.1 also requires adequate medical care for trial-related adverse events during and after participation, and requires the participant's primary physician to be informed of their involvement where the participant has one and agrees.