Our Clinical Research 101 series takes an in-depth look at key steps and tips for navigating the clinical research process. The eighteenth installment in our Clinical Research 101 series is by Allison Coleman, Project Manager at CHÉOS. The following is a brief discussion of adverse events in clinical research, how to collect and report them, and why they’re important.
Ms. Coleman is a certified clinical research professional with over 15 years of experience in a number of research environments — both industry and investigator sponsored. Her primary role is to provide project management services to CHÉOS- and CIHR Canadian HIV Trials Network–supported investigators. Ms. Coleman has recently joined the group of project managers at CHÉOS. The Centre’s project managers are experts in the regulatory, policy, budgeting, and implementation requirements for clinical research studies.
What are Adverse Events?
When studying any type of intervention — a drug, medical device, or new procedure or questionnaire — it is essential to determine if the intervention may cause any kind of harm. It is not enough to examine how well something works (efficacy), it also needs to be determined if the intervention is safe to use.
An adverse event (AE) is any unwanted medical occurrence experienced by a patient or study participant given a pharmaceutical product or treatment/intervention. An AE does not necessarily indicate a causal relationship with the treatment. The International Council for Harmonization Good Clinical Practice Guidelines (ICH GCP) states that “an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease having been absent at baseline, or, if present at baseline, appears to worsen and is temporally associated with medical treatment or procedure, regardless of the attribution (i.e., relationship of event to medical treatment or procedure).”
An adverse reaction, a type of AE, is an event that is directly related to the intervention in question. Health Canada defines adverse reactions as any “undesirable effects to health products.” These health products can be drugs, medical devices, and natural health products, including prescription and non-prescription pharmaceuticals or biologically derived products like vaccines and blood products.
Adverse events and reactions can occur during a clinical research study or the normal use of a product or treatment. They can arise within minutes or years after exposure to the product or treatment and may range from mild reactions like nausea or headache to serious and life-threatening events such as a stroke, heart attack, or cancer. If participants experience AEs during a clinical research study, it is vital to determine if their AEs are related to the intervention (i.e., adverse reactions).
Why is AE collection and assessment important?
This aspect of conducting clinical research aligns with the third principle of ICH-GCP:
The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.
Beyond aligning with GCP, there are several reasons for AE collection and assessment in clinical research. The most important of these is to identify events that pose an immediate risk to the health and safety of a research participant. An additional reason is to provide ongoing information to regulators, investigators, and others stakeholders about new and important AEs that occur in clinical research studies. Finally, the compilation of AEs deemed related to a study intervention can then be used to develop a drug or regimen toxicity/risk profile for inclusion in an updated Investigator’s Brochure or Product Monograph.
What are the important elements of AE collection?
The documentation of AEs is typically done on a case report form (CRF), which is a type of participant-specific log or list and may be quite general or very detailed. Since we often don’t know in advance if a particular AE could be related to an intervention, it is important to clearly outline the scope of AE collection that will be undertaken in the study protocol. In some studies, all AEs experienced by participants will be collected. For others, depending on the study population, phase of study (1–4), and product or treatment being evaluated (small molecule, therapeutic biologic, device, vaccine, etc.), only specified AEs will be captured.
The most common elements of AE recording are:
- Date the AE began
- Term or description for the AE
- Severity/grade of the AE (e.g., mild, moderate, severe)
- Relatedness of AE to intervention (e.g., not related, unlikely, possibly, likely, definitely related)
- Serious AE status (yes, no)
- Action taken/treatment provided due to AE
- Outcome of event (e.g., resolved, resolved with sequalae, not resolved, fatal, unknown)
- Date the AE resolved
- Initials of assessor and date of review and assessment
The assessment of the severity and relatedness of AEs must be done by the Principal Investigator or Qualified Investigator in a regulated study, or their designee (typically a certified medical professional). This assessment, combined with the ‘expectedness’ of an event (as per the Investigator’s Brochure or Product Monograph), helps in determining the timelines for reporting of serious AEs to the Research Ethics Board (REB), sponsor, or other regulatory or oversight groups.
What about serious adverse events?
Serious adverse events (SAEs) are a subset of adverse events which, at any dose or treatment level, put a research participant’s health at significant risk and:
- result in death
- require either inpatient hospitalization
- cause the prolongation of hospitalization
- are life-threatening
- result in a persistent or significant disability/incapacity
- result in a congenital anomaly/birth defect
There are specific guidelines and regulations that apply to the collection, documentation, and reporting of SAEs as an additional layer of protection for research participants. Sponsors and investigators are expected to include a section in study protocols that clearly describing how SAEs will be identified, documented, and reported in accordance ICH-GCP and local and federal regulations. Additional information can be found here.
When do you need to collect AEs?
Collection of AE information may begin as soon as the informed consent form is signed, or at the initiation of study intervention (as per the protocol). AE information may also be collected from the start of an observational period intended to establish a baseline status for the participant. The Schedule of Events section of study protocols commonly outlines particular visits or timepoints where AE inquiry with a participant must occur. However, in practice, it is best to ask participants about possible AEs at every opportunity after consent in order to capture any emerging risks in a timely fashion. Ongoing AEs should be followed to resolution or stabilization. Adverse events that cause interruption or discontinuation of an intervention, or that are still present at the end of the study, should also be followed until an outcome is known.
The collection and recording of AEs in clinical research is critical to patient safety and data integrity. It is essential to address this thoroughly in study protocols, and to ensure those conducting clinical research regularly refer to the protocol for guidance for specifics on AE collection and data abstraction.
If you would like further information on our services, and how CHÉOS can assist you with addressing AE collection and documentation in your clinical research projects, please submit your inquiry here.
Adverse Reaction Information (Government of Canada)
ICH harmonised guideline integrated addendum to ICH E6(R1): Guideline for Good Clinical Practice ICH E6(R2) ICH Consensus Guideline
Glossary of Terms (UBC Ethics)
Adverse Events (ClinicalTrials.gov)
Clinical Investigator Course (US FDA)