In clinical trials and medical studies, an adverse event refers to any undesirable experience that occurs in a patient during treatment with a drug or medical device. Adverse events span a wide range of symptoms, from mild side effects to serious reactions that can be life-threatening. The term “severe adverse event” refers specifically to adverse events that are highly serious, dangerous or fatal.
Definition of a Severe Adverse Event
The United States Food and Drug Administration (FDA) defines a severe adverse event as any adverse experience that:
- Results in death
- Is life-threatening (places the patient at immediate risk of death)
- Requires inpatient hospitalization or prolongs existing hospitalization
- Results in persistent or significant disability or incapacity
- Leads to a congenital anomaly or birth defect
- Requires intervention to prevent permanent impairment or damage
Essentially, a severe adverse event is any adverse reaction with serious consequences that pose a significant threat to the patient’s health and well-being. While all adverse events should be carefully monitored in clinical trials, severe adverse events require urgent medical attention and prompt action by investigators overseeing the study.
Examples of Severe Adverse Events
Some examples of adverse reactions that would be classified as severe include:
- Anaphylaxis – A life-threatening allergic reaction that can lead to breathing difficulty, a precipitous drop in blood pressure and death.
- Stevens-Johnson syndrome – A rare, serious skin disorder characterized by painful blistering and erosions of mucous membranes.
- Toxic epidermal necrolysis – A severe skin reaction causing reddening, blistering and peeling of large areas of skin.
- Agranulocytosis – A condition involving severe lowering of white blood cells, which leaves the body vulnerable to life-threatening infections.
- Hepatotoxicity – Drug-induced liver injury causing liver failure.
- Anaphylactoid purpura – A disorder causing inflammation and bleeding in small blood vessels, which can lead to kidney failure.
- Acute renal failure – A sudden loss of kidney function leading to a dangerous buildup of waste products in the blood.
- Seizure – Uncontrolled electrical disturbances in the brain that can result in violent shaking, loss of awareness and loss of bowel/bladder control.
- Coma – A state of profound unresponsiveness, absence of voluntary movement and lack of awareness.
- Hemolytic anemia – Breakdown of red blood cells, which can be fatal if severe.
- Agranulocytosis – Dangerously low white blood cell count leaving the body open to infections.
- Respiratory depression – Slowed or stopped breathing, which can lead to brain damage or death if prolonged.
As these examples illustrate, severe adverse events require emergency medical treatment. They can be severely debilitating or fatal if not addressed immediately.
Identifying Severe Adverse Events in Clinical Trials
In clinical trials, investigators are responsible for detecting, documenting and reporting any adverse events that occur in study participants. This allows the risks associated with an experimental drug or device to be carefully evaluated.
To identify severe adverse events, investigators must grade each adverse event according to severity. The following general criteria are used:
- Mild: Symptoms are transient and generally do not interfere with normal activities
- Moderate: Symptoms interfere with normal activities but respond to symptomatic therapies
- Severe: Symptoms are incapacitating or life-threatening
Any adverse event graded as severe must be promptly reported to ethics committees and regulatory agencies overseeing the clinical trial. Reporting requirements help ensure severe events get proper follow-up and that risks associated with the treatment under investigation are understood.
Monitoring Period for Adverse Events
Investigators must actively monitor for adverse events throughout the entire study period. The monitoring period depends on the treatment being evaluated:
- For one-time treatments like vaccines or surgeries, adverse events are monitored for a defined period post-treatment (e.g. 6 weeks).
- For drugs or devices requiring prolonged or repeated use, adverse events are monitored during the entire treatment period and often for a defined time after discontinuing use (e.g. 4 weeks post-treatment).
Extending the monitoring period beyond the actual treatment duration increases the chance of detecting adverse events with delayed onsets or prolonged courses.
Causality Assessment
Besides grading severity, investigators must also assess causality for each adverse event. Causality assessment evaluates the likelihood that the study treatment actually caused or contributed to the adverse event:
- Definite: The adverse event is clearly related to the study treatment.
- Probable: Evidence strongly suggests the study treatment caused the event.
- Possible: The study treatment may have contributed to the event.
- Unlikely: The study treatment is probably not related to the event.
- Unrelated: The study treatment clearly did not cause the event.
Only adverse events with causality classified as definite, probable or possible are considered treatment-related. However, all adverse events meeting the definition of “severe” must be reported regardless of the causality assessment.
Regulatory Reporting of Severe Adverse Events
Severe adverse events require expedited reporting to regulators and ethics committees overseeing the trial:
- Investigators must report severe events to the regulatory body (e.g. FDA) and lead ethics committee within 7-15 days of learning about the event.
- Detailed descriptions of the event, treatment provided and outcome must be provided.
- Any additional follow-up information must be promptly reported as it becomes available.
Stringent reporting rules aim to ensure regulators have current information on rare but dangerous reactions occurring in trials. This allows regulatory agencies to take swift action when needed to better protect participants.
Impact on the Clinical Trial
When a severe adverse event occurs, investigators must pause and carefully consider if it is ethically appropriate for the clinical trial to continue unchanged. Options include:
- Continuing the trial unchanged
- Modifying the trial to improve safety monitoring
- Changing the study design or treatment regimen
- Temporarily suspending recruitment of new participants
- Permanently stopping the trial
Any decision to significantly alter or stop an ongoing trial due to safety concerns will be made jointly by investigators, ethics committees and regulatory bodies. Key considerations include whether the risks still appear acceptable compared to the expected benefits, and whether participants can be adequately informed of any new safety issues identified.
Preventing Severe Adverse Events
While there is always some risk when testing new medical treatments, steps can be taken to minimize the likelihood of severe adverse events in clinical trials:
- Thorough preclinical testing in animals helps predict safety in humans.
- Excluding participants at high risk of adverse effects (e.g. due to pre-existing conditions).
- Starting with small doses and safety cohorts to look for early warning signs.
- Closely monitoring participants and having defined stopping rules for certain reactions.
- Educating participants on recognizing and reporting concerning symptoms promptly.
- Allowing careful dose escalations and long enough washout periods between dose cohorts.
- Using an independent data safety monitoring board to oversee safety data during the trial.
Despite best efforts, severe adverse events can still occur unexpectedly. Clear protocols for detecting, reporting and responding to severe events are essential safeguards for clinical trial participants.
Conclusion
Severe adverse events are highly serious medical occurrences that result in death, are life-threatening, require or prolong hospitalization, result in disability or congenital defects, or require interventions to prevent permanent impairments. Such events must be promptly identified, thoroughly documented and reported to ethics committees and regulatory bodies overseeing clinical trials. Strict adherence to established safety reporting requirements helps ensure the wellbeing of participants is protected when new interventions are being studied in research. Careful risk-benefit analyses must be performed when severe adverse events emerge to determine if a trial should continue as originally designed.