Sunday, November 27, 2011

Reporting/recording the Serious Adverse Events (SAE) vs. Adverse Event (AE) Outcomes

In clinical trials, the serious adverse event reporting is critical to the safety assessment and to fulfill the regulatory requirements. The criteria for defining an SAE have been documented in many regulatory guidelines. However, in clinical trial implementation, the confusion could arise whether or not an event should be reported as an SAE or outcome of an SAE. Misinterpretation of the regulatory guidelines could cause in the inappropriate reporting of SAEs.


                  A serious adverse event (experience) or reaction is any untoward medical occurrence that at any dose:                          * results in death,
                         * is life-threatening,
                             NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the patient was at 

                             risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death
                             if it were more severe.
                         * requires inpatient hospitalisation or prolongation of existing hospitalisation,
                         * results in persistent or significant disability/incapacity, or
                         * is a congenital anomaly/birth defect.
FDA website has provided a little bit more detail descriptions on SAE
"What is a Serious Adverse Event?

An adverse event is any undesirable experience associated with the use of a medical product in a patient. The event is serious and should be reported to FDA when the patient outcome is:

Report if you suspect that the death was an outcome of the adverse event, and include the date if known.

Report if suspected that the patient was at substantial risk of dying at the time of the adverse event, or use or continued use of the device or other medical product might have resulted in the death of the patient.
Hospitalization (initial or prolonged)

Report if admission to the hospital or prolongation of hospitalization was a result of the adverse event.

Emergency room visits that do not result in admission to the hospital should be evaluated for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; other serious medically important event).
Disability or Permanent Damage

Report if the adverse event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., the adverse event resulted in a significant, persistent or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities and/or quality of life.
Congenital Anomaly/Birth Defect

Report if you suspect that exposure to a medical product prior to conception or during pregnancy may have resulted in an adverse outcome in the child.
Required Intervention to Prevent Permanent Impairment or Damage (Devices)

Report if you believe that medical or surgical intervention was necessary to preclude permanent impairment of a body function, or prevent permanent damage to a body structure, either situation suspected to be due to the use of a medical product.
Other Serious (Important Medical Events)

Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. Examples include allergic brochospasm (a serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias (blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug dependence or drug abuse would also be examples of important medical events."

The standard coding dictionary for adverse events is MedDRA (Medical Dictionary for Regulatory Activities). The guidance document MedDRA® TERM SELECTION: POINTS TO CONSIDER gives clear explanation how death and other patient outcomes should be handled.

3.2 – Death and Other Patient Outcomes

Death, disability, and hospitalization are considered outcomes in the context of safety reporting and not usually considered ARs/AEs. Outcomes are typically recorded in a separate manner (data field) from AR/AE information. A term for the outcome should be selected if it is the only information reported or provides significant clinical information.

(For reports of suicide and self-harm, see Section 3.3).

3.2.1 Death with ARs/AEs

Death is an outcome and not usually considered an AR/AE. If ARs/AEs are reported along with death, select terms for the ARs/AEs. Record the fatal outcome in an appropriate data field.

3.2.4 Other patient outcomes (non-fatal)

Hospitalization, disability and other patient outcomes are not generally considered ARs/AEs.

There are many other examples in terms of recording the outcome instead of AE/SAE. Adverse events represent the untoward medical event, not the intervention to treat that event. For example, if a subject has appendectomy, the AE is appendicitis not the surgical procedure; if a subject has an limb amputation, the AE is the cause for amputation (perhaps, the worsening of the ischemia in the peripheral artery) and limb amputation should be reported as the outcome of the AE/SAE; If a patient is hospitalized due to congestive heart failure, congestive heart failure should be reported SAE and hospitalization should be reported as an outcome for congestive heart failure.  
We should also be aware that not every hospitalization will have an associated SAE to be reported. Any AE leading to hospitalization or prolongation of hospitalization meets ONE of the followings should not be reported as SAE.
  • A hospitalization admission is pre-planned (ie, elective or scheduled surgery arranged prior to the start of the study). European Commission’s guidelines on medical devices “CLINICAL INVESTIGATIONS: SERIOUS ADVERSE EVENT REPORTING “ indicated that a planned hospitalization for pre-existing condition, or a procedure required by the Clinical Investigation Plan, without a serious deterioration in health, is not considered to be a serious adverse event.
  • A hospitalization admission is clearly not associated with an AE (eg, social hospitalization for purposes of respite care). If a patient wants to be stay in the hospital during the drug treatment because of the fear that something bad could happen, this should not be reported as SAE just because of the hospital stay if nothing else happens
According to these definitions, the events with outcome of death, hospitalization, disability or permanent damage, congenital anomaly/birth defect, … should be reported as SAE while death, hospitalization, disability or permanent damage, congenital anomaly/birth defect…should be reported as the outcome of the corresponding SAE. To be crystal clear, the Death, Hospitalization should not be reported as SAE and the causes leading to the death and hospitalization should be reported as SAE.

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