What is it? Why is it important?

Safety assessments (SA) of Investigational Medicinal Products (IMP) are standardised procedures used to evaluate adverse events, (AEs) and other reportable events, during study conduct.

In IMP studies, SA of AEs is based on 4 main criteria:

  • Severity: grades the intensity of an AE, such as:
    • CTCAE, criteria mainly used in oncology
    • Other grading systems. Such as to distinguish between mild, moderate, and severe AEs (ICHE2A)
  • Seriousness: grades the effective harm of an AE to study participants. The grading is based on clear regulatory definitions (e.g. serious / non-serious)
  • Causality: assesses the suspected relationship between IMP exposure and AE occurrence
  • Expectedness: assesses AE occurrence based on previously observed and documented events in the RSI (e.g. in the “product information” for marketed MPs, the IB for non-marketed MPs (IMP))

More

Severity

Suggested ratings:

  • *Mild: minor discomfort which does not interfere with normal daily activity
  • Moderate: discomfort which reduces or affects normal activity
  • Severe: incapacitating with the inability to work or perform normal daily activity, life-threatening or fatal

Seriousness

For IMP, serious is defined as any untoward medical occurrence that at any dose (ICH E6(R2)):

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

Causality

There is no current standard, which provides precise and reliable quantitative estimation of causality. Still, for IMP the following grading system is suggested (ICH E2A):

  • Certainly
  • Definitively
  • Probably
  • Possibly
  • Likely not related
  • Not related

Expectedness

Based on AEs mentioned in the RSI, it refers to the previous occurrence of serious AEs similar in nature and severity.

What do I need to do?

As a Site-INV, assess each AE and:

  • Determine its severity (e.g. intensity) as defined in the study protocol
  • Determine whether the AE qualifies as serious. A serious AE is named a Serious Adverse Event (SAE)
  • Determine if there is a relationship between IMP exposure and AE occurrence. A related AE is named an Adverse Drug Reaction (ADR)
  • Determine if the ADR is serious. If so, it is named a Serious Adverse Drug Reaction (SADR)

As a SP-INV:

  • Re-assess each AE reported by the Site-INV(s) on severity, seriousness, and relationship
  • Determine expectedness (in nature, intensity or frequency) based on current AE documentation in the RSI
  • Events that are serious, related and not expected are named Suspected Unexpected Serious Adverse Reaction (SUSAR).
  • If applicable, re-evaluate the risk-benefit of the study
  • Inform the Site-INV
  • Report safety events as required by applicable laws (e.g. to EC/RA such as Swissmedic)

More

For all AEs, Site-INV and SP-INV both assess intensity, seriousness, and causality. The SP-INV assesses expectedness based on previous occurrence of the same AE (in nature, intensity or frequency).

In the event that the SP-INV and Site-INV disagree on the assessment, they should try to find a consensus. If not possible, the opinion of both the Site-INV and the SP-INV should be included in the safety report.

Where can I get help?

Your local CTU can support you with experienced staff regarding this topic

References

ICH E2A – see in particular guideline

  • Chapter II Definition

ICH GCP E6(R2) – see in particular guidelines

  • 1.50 SAE / SADR definition
  • 6.8 Assessment of safety

Swiss Law

FEDLEX – law is available online under number

  • 810.305 ClinO

ClinO – see in particular articles

  • Art. 39 AE definition
  • Art. 40 SAE definition
  • Art. 41 SUSAR definition
Abbreviations
  • ADR - Adverse Drug Reaction
  • AE – Adverse Event
  • ClinO – Clinical Trials Ordinance
  • CTCAE – Common Terminology Criteria for Adverse Events
  • CTU – Clinical Trials Unit
  • EC/RA – Ethics Committee / Regulatory Authorities
  • FEDLEX – Publication Platform for Federal Laws
  • IB – Investigator’s Brochure
  • ICH GCP – International Council for Harmonisation - Good Clinical Practice
  • ICH – International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
  • IMP – Investigational Medicinal Product
  • RSI – Reference Safety Information
  • SA – Safety Assessment
  • SADR – Serious Adverse Drug Reaction
  • SAE – Serious Adverse Event
  • Site-INV – Site Investigator
  • SP-INV – Sponsor Investigator
  • SUSAR – Suspected Unexpected Serious Adverse Reaction
Conduct ↦ Safety ↦ Safety Assessment ↦ Medicinal Product
Study
Basic

Provides some background knowledge and basic definitions

Basic Protocol
Basic Statistics
Basic Monitoring
Basic Drug or Device
Basic Biobanking
Concept

Starts with a study idea

Ends after having assessed and evaluated study feasibility

Concept Protocol
Concept Statistics
Concept Drug or Device
Concept Biobanking
Development

Starts with confidence that the study is feasible

Ends after having received ethics and regulatory approval

Development Protocol
Development Statistics
Development Drug or Device
Development Biobanking
Set-Up

Starts with ethics and regulatory approval

Ends after successful study initiation

Set-Up Protocol
Set-Up Ethics and Laws
Set-Up Statistics
Set-Up Drug or Device
Set-Up Biobanking
Conduct

Starts with participant recruitment

Ends after the last participant has completed the last study visit

Conduct Protocol
Conduct Statistics
Conduct Drug or Device
Conduct Biobanking
Completion

Starts with last study visit completed

Ends after study publication and archiving

Completion Protocol
Completion Statistics
Completion Drug or Device
Completion Biobanking
Current Path (click to copy): Conduct ↦ Safety ↦ Safety Assessment ↦ Medicinal Product

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