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LEARNING OBJECTIVES:
► Definition and classification of adverse events.
► Definition of protocol deviations/violations.
► Process and guidelines for the reporting of all adverse events, protocol deviations/violations related to approved IRB research studies.
► An adverse event is “any untoward event that occurs during a drug or medical treatment whether or not a causal relationship with the treatment is suspected or proven.”
► The untoward event may be a sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants’ involvement in the research.
► The Medical Dictionary for Regulatory Activities (MedDRA) is uniform internationally accepted terminology for describing AEs.
► AE events may be missed in the clinical trial due to small sample or short follow up and are discovered after licensing the drug.
► Any untoward medical occurrence, whether it is considered related to the study or not, that is any of 7 situations below.
► Results in death.
► Is life threatening, or places the participant at immediate risk of death from the event as it occurred?
► Requires or prolongs hospitalization.
► Causes persistent or significant disability or incapacity.
► Results in congenital anomalies or birth defects.
► Is another condition which investigators judge to represent significant hazards?
► Suspected AE: There is a reasonable possibility that the event is related to the research.
► Related AE: An AE that more than likely was caused by study product or study procedures (e.g., “probably related” or “definitely related”). The relationship may be to the research procedure or the research intervention (drug or device).
► Unexpected AE: An AE that is not identified in nature, severity, or frequency in the relevant safety documents(s) for the study product or is not identified as a possible risk in the study protocol or the informed consent form for the study. The protocol or investigator brochure pre-specifies expected events.
► Unanticipated AE: An AE that is not expected in the study.
► AE is either elicited (patient asked or researcher given a check-list)m or is reported voluntarily.
► Not Reportable Events: Typically, a number of events occur during the course of a study that doesn’t meet reporting requirements.
o Example 1: Non-serious adverse events that, in the PI’s judgment, are not related to the study.
o Example 2: Non-serious adverse events that are anticipated or expected as part of the study.
o Example 3: External serious adverse event reports (e.g., IND Safety Reports) that, in the PI’s judgment, do not adversely affect the conduct of the PI’s study at his/her research facility.
o Example 4: Minor protocol deviations (such as study visits performed slightly out of window).
o Example 5: Minor research participant complaints that are adequately resolved by the research staff.
► Adversely affects the risk/benefit ratio of the study.
► Adversely affects the rights of participants.
► Adversely affects safety of participants.
► Adversely affects welfare of participants or others.
► Adversely affects the integrity of the study.
► A divergence from the approved protocol that, in the PI’s judgment, DOES NOT adversely affects the risk/benefit ratio of the study, the rights, safety, or welfare of the participants or others, or the integrity of the study. Examples of possible minor protocol deviations may include but are not limited to:
o Example 1: Study visit(s) or study procedure(s) conducted out of timeframe.
o Example 2: Participant failure to initial every page of the consent form.
o Example 3: Participant failure to return diary.
o Example 4: Other protocol deviations/violations that only affect logistical or administrative aspects of the study.
► PI must promptly report all unanticipated events that may involve risk to research participants or others or that may provide new or updated safety information related to their research study.
► PI must promptly report all protocol deviations and/or violations to the IRB Chair.
► Report any unanticipated event to be on the safe side and leave the classification to IRB.
► Report all severe adverse events to the IRB within 24 hours whether they are study-related or not.
► Reporting is done utilizing the Adverse Events, Protocol Deviations, and/or Protocol Violations Reporting Form (Appendix A) which is delivered to the IRB office or sent directly to the IRB Chair through the electronic system.
► PI/Research Specialists are encouraged to contact IRB if they have a question about whether or not an event requires a report. The general advice is that when in doubt, report.
► Investigate the event.
► Decide one of three: (a) suspend/terminate the study (b) continue the study (c) modify the protocol (e.g., change dose, drop participants) then continue the study with re-consenting participants.
► Consider Early AEs vs. long-term AEs.
► Notify the PI and if necessary, the sponsor and SFDA. PI must notify the participant. Compensation and damages' awards to the participants usually covered by indemnity insurance.
► Include the event in the 6-month report to the CEO and the Monitoring Office of NCBE.
► Pre-specified vs. Post hoc.
► Meta-analysis by combining several studies may reveal AEs not shown by individual trials.
► Published paper shows few details.
- If the study collected data on harms and benefits, the title or abstract should so state.
- If the trial addresses both harms and benefits, the introduction should so state.
- List adverse events with definitions for each (with attention, when relevant, to grading, expected vs. unexpected reactions, reference to standardized and validated definitions, and description of new definitions).
- Clarify how harms-related information was collected (mode of data collection, timing, attribution methods, the intensity of ascertainment, and harms-related monitoring and stopping rules, if pertinent).
- Describe plans for presenting and analyzing information on harms (including coding, handling of recurrent reactions, specification of timing issues, handling of continuous measures, and any statistical analyses).
- Describe for each arm the participant withdrawals that are due to harm and the experience with the allocated treatment.
- Provide the denominators for analyses on harms.
- Present the absolute risk of each adverse event (specifying type, grade, and seriousness per arm), and present appropriate metrics for recurrent reactions, continuous variables, and scale variables, whenever pertinent.
- Describe any subgroup analyses and exploratory analyses for harm.
- Provide a balanced discussion of benefits and harms with emphasis on study limitations, generalizability, and other sources of information on harms.
- Ioannidis JPA, Evans SJ, Gøtzsche PC, et al. for the CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004;141:781-788.