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))
- *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
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
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):
- Likely not related
- Not related
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)
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
Basel, Clinical Trials Unit, CTU, dkf.unibas.ch
Bellinzona, Clinical Trials Unit, CTU-EOC, www.ctueoc.ch
Bern, Clinical Trials Unit, CTU, www.ctu.unibe.ch
Geneva, Clinical Research Center, CRC, crc.hug.ch
Lausanne, Clinical Research Center, CRC, www.chuv.ch
St. Gallen, Clinical Trials Unit, CTU, www.kssg.ch
Zürich, Clinical Trials Center, CTC, www.ctc.usz.ch
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
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