In pharmacovigilance/drug safety, one of the most important criteria is the presence of an adverse event in a case study. For example, if a person takes an XYZ drug and experiences any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease, then that person has experienced an adverse event.
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.
It can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.(1)
This is different from adverse drug reaction (ADR) in which all noxious and unintended responses to a medicinal product are related to any dose of the drug.(1)
Classification of AEs:
- serious or non-serious;
- expected or unexpected;
- study-related, possibly study-related, or not study-related;
Serious adverse events are the events resulting in death, requiring hospitalization or prolonged hospitalization, life-threatening, resulting in persistent or significant disability/incapacity, a congenital anomaly/birth defect or medically important condition.(2) The rest adverse events would fall under the category of non-serious events.
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death.(3)
- hemorrhaging and internal bleeding with rapid drop in blood pressure;
- Loss of consciousness from increase in pressure on the brain
Hospitalization in the serious adverse event definition refers to an admission to the hospital for longer than 24 hours or prolongation of a hospital stay due to the adverse event. (4)
Disability can be defined as a substantial disruption of a person’s ability to conduct normal life functions.
- loss of speech;
- fatigue so great the patient cannot get out of bed at all;
- loss of memory;
- paralysis. (4)
Congenital anomaly can be defined as an exposure to a medical product prior to conception or during pregnancy resulting in an adverse outcome in the child. Thalidomide is the best example of a drug causing congenital anomalies with babies born with deformed arms and legs. (4)
Medical judgement should be exercised in deciding whether other situations should be considered as serious reactions. Some medical events may jeopardise the patient or may require an intervention to prevent one of the above characteristics/consequences. Such important medical events should be considered as serious.(2)
AEs must be assessed as to whether they were expected to occur or unexpected, meaning not anticipated based on current knowledge found in the protocol, investigator brochure, product insert, or label. (6)
- Unexpected adverse reaction is an adverse reaction, the nature or severity of which is not consistent with domestic labelling or market authorization, or expected from characteristics of the drug.(5)
Expected adverse reaction is an adverse reaction which is known to be associated with the drug under study.
Relatedness to a Study
In a clinical trial/study, the potential event relationship to the study drug and/or participation is assessed by the study investigator. A comprehensive scale in common use to categorize an event is:
- Definitely Related: The adverse event is clearly related to the investigational drug/procedure – i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is confirmed by improvement on stopping and reappearance of the event on repeated exposure and that could not be reasonably explained by the known characteristics of the subject’s clinical state.
- Possibly Related: An adverse event that follows a reasonable temporal sequence from administration of the study intervention follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors.
- Not Related: The adverse event is clearly not related to the investigational agent/procedure. – i.e. another cause of the event is most plausible; and/or a clinically plausible temporal sequence is inconsistent with the onset of the event and the study intervention and/or a causal relationship is considered biologically implausible.(6)
Based on the severity, the AEs can be classified as:
Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type causing no loss of time from normal activities. Symptoms do not require therapy or a medical evaluation; signs and symptoms are transient.
Moderate: Events introduce a low level of inconvenience or concern to the patient and may interfere with daily activities, but are usually improved by simple therapeutic measures; moderate experiences may cause some interference with functioning.
Severe: Events interrupt patient’s normal daily activities and generally require systemic drug therapy or other treatment; they are usually incapacitating.
Severity is not synonymous with seriousness. A severe rash is not likely to be an SAE. Likewise, a severe headache is not necessarily an SAE. However, mild chest pain may result in a day’s hospitalization and thus is an SAE.(6)
Adverse events have significant impact not only on the public at large, but also for the entire health care system. Pharmaceutical companies have felt the pinch of mismanagement of high-profile adverse event reports that have affected the industry. In such scenarios, patient care may suffer or they may lose confidence in a drug (especially in the case of a recall). Reporting of any undesirable effects provides clinicians and health care companies valuable insight into the toxicity profile of a drug. Thus, better research and greater understanding of disease processes will lead to more effective, and hopefully, safer drug products.
ICH Harmonised Tripartite Guideline Clinical Safety Data Management: Definitions and Standards for Expedited Reporting E2A. Available at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E2A_Guideline.pdf
Guideline on good pharmacovigilance practices (GVP) Module VI – Management and reporting of adverse reactions to medicinal products. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129135.pdf
CFR – Code of Federal Regulations Title 21. Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32
A presentation on Adverse Events in Clinical Trials: Definitions and Documentation. Available at https://hub.ucsf.edu/sites/hub.ucsf.edu/files/6.%20Adverse%20Eventsd%20Definitions.pdf
Glossary of terms used in Pharmacovigilance. Available at http://who-umc.org/Graphics/24729.pdf
A document on NIA Adverse Event and Serious Adverse Event Guidelines. Available at: https://www.nia.nih.gov/sites/default/files/niaaeandsaeguidelinesfinal12_28_07.doc