OHRP recognizes that it may be difficult to determine whether a particular incident, experience, or outcome is unexpected and whether it is related or possibly related to participation in the research. OHRP notes that an incident, experience, or outcome that meets the three criteria above generally will warrant consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions in order to protect the safety, welfare, or rights of subjects or others.

Adverse Events

Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research (modified from the definition of adverse events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice).

Adverse events encompass both physical and psychological harms. They occur most commonly in the context of biomedical research, although on occasion, they can occur in the context of social and behavioral research.

The key question regarding a particular adverse event is whether it meets the three criteria described outlined above and therefore represents an unanticipated problem. To determine whether an adverse event is an unanticipated problem, the following questions should be asked: Is the adverse event unexpected? Is the adverse event related or possibly related to participation in the research? Does the adverse event suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized? If the answer to all three questions is yes, then the adverse event is an unanticipated problem and must be reported to appropriate entities.

For further clarifications as to whether or not a particular adverse event is an unanticipated problem that requires reporting, researchers should consult the OHRP guidance.

12.2 Types of Unanticipated Problems

The following are situations that may meet OHRP's definition of unanticipated problems involving risks to subjects or others and should be reported:

• Any serious accidental or unintentional change to the IRB-approved protocol that involves risk or has the potential to recur.
• Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate hazard to a research subject.