Research participants, their family members or anyone else may have complaints, concerns or questions about a Brown research study. A participant may feel that they were unfairly screened out or withdrawn from a research study, that they did not receive their expected compensation or that they were not given enough time to read the consent document before study activities began.

Other complaints may include a member of the community being upset by the content of recruitment material posted near their home, or a research assistant believing that a study’s principal investigator (PI) is not following the study protocol approved by either the HRPP or Brown’s Institutional Review Board (IRB). Such complaints should be reported to the HRPP. All complaints or concerns reported to the HRPP are reviewed and, if necessary, further investigated.

To help with this important responsibility, this guidance document provides examples of events that must be reported and a glossary of key terms and their definitions.

The following scenarios are examples of events that may occur during conduct of a human subjects research study that must be reported to the HRPP. Some of these examples involve events that do not cause any noticeable harm to, or adverse effects on, participants or others. However, they must be reported because these events either require substantive changes to the protocol or informed consent document/process or require corrective action in order to protect the safety, welfare or rights of participants.

Stolen Identifiable, Sensitive Information

Whenever individually identifiable information is lost or stolen or was accidentally shared with someone outside the study team, it must be reported to the HRPP.

Example: A PI conducting behavioral research with college students collects individually identifiable sensitive information about drug use and other illegal behaviors. The survey data are stored on a laptop computer without encryption, and the laptop computer is stolen from the PI’s car. 

Error in Handling Identifiable, Sensitive Information

If there is an error in handling individually identifiable information, it must be reported to the HRPP.

Example: A research team member is preparing to email participants a copy of their signed consent document and completed surveys detailing their demographic information, family background and medical history. The team member accidentally sends a batch email of all signed consent documents and all completed surveys to all enrolled participants.

Negative Psychological Reaction to Study Interaction

If a participant has a negative psychological reaction through their interaction with the study, it must be reported to the HRPP.

Example: A PI conducts behavioral research with college students involving completing a detailed survey asking questions about early childhood experiences. The HRPP team and IRB determined that the research involved no more than minimal risk and it was approved under an Expedited review category. During the completion of the survey, one student participant has a temporary psychological reaction with intense sadness and depressed mood that resolves without intervention after a few hours. The protocol and informed consent document for the research does not describe any risk of negative psychological reactions. Upon evaluation, the PI determines that the participant’s negative psychological reaction resulted from survey questions that triggered memories of physical abuse as a child. The PI had not expected that such reactions would be triggered by the survey questions.

Negative Physical Reaction to Study Intervention

If a participant has a negative physical reaction through their interaction with the study, it must be reported to the HRPP.

Example: Participants with essential hypertension are enrolled in a Phase 2, nonrandomized clinical trial testing a new investigational antihypertensive drug. At the time the clinical trial is initiated, there is no documented evidence of gastroesophageal reflux disease (GERD) associated with the investigational drug, and the IRB-approved protocol and informed consent document do not describe GERD as a risk of the research. Three of the first 10 participants are noted by the PI to have severe GERD symptoms that began within one week of starting the investigational drug and resolved a few days after the drug was discontinued. The PI determines that the GERD symptoms were most likely caused by the investigational drug and the informed consent document requires modification to include a description of GERD as a risk of the research.

Dosing Error of an Investigational Drug

If a dosing error involving an investigational drug occurs, it must be reported to the HRPP.

Example: As a result of a processing error by a pharmacy technician, a participant enrolled in a multicenter clinical trial receives a dose of an investigational drug that is 10 times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the investigational drug, the participant experienced no detectable harm or adverse effect after an appropriate period of careful observation.

Negative Physical Reaction to an Investigational Device

If a participant has a negative physical reaction to an investigational device used in the study, it must be reported to the HRPP.

Example: A participant enrolled in a clinical trial receives a wearable investigational device. The participant is expected to wear the device for two weeks — even while sleeping and bathing. While wearing the device, the participant experiences an allergic reaction where the device comes in contact with their skin. The participant visited their primary care physician who recommended the individual apply a topical anti-itch ointment and inform the study team. After learning of the situation, the PI advised the participant to stop wearing the device. The participant experienced no detectable harm or adverse effect after an appropriate period of careful observation.

Failure to Conduct Appropriate Screening and Testing of Donors

If the PI fails to appropriately screen and test donors for a study, it must be reported to the HRPP.

Example: Participants with cancer are enrolled in a Phase 2 clinical trial evaluating an investigational biologic product derived from human sera. After several participants enroll and receive the investigational product, a study audit reveals that the investigational product administered was obtained from donors who were not appropriately screened and tested for several potential viral contaminants, including HIV and hepatitis B.

Increased Frequency of Emergency Surgery Due to the Study Intervention

If a participant requires emergency surgery at an increased frequency during their involvement with the study, it must be reported to the HRPP.

Example: Participants with coronary artery disease presenting with unstable angina are enrolled in a multicenter clinical trial evaluating the safety and efficacy of an investigational vascular stent. Based on prior studies in animals and humans, the research team anticipates that up to 5% of participants receiving the investigational stent will require emergency coronary artery bypass graft (CABG) surgery because of acute blockage of the stent that is unresponsive to nonsurgical interventions. The risk of needing emergency CABG surgery is described in the IRB-approved protocol and informed consent document. 

After the first 20 participants enrolled in the study, a data safety monitoring board (DSMB) conducts an interim analysis, as required by the IRB-approved protocol, and notes that 10 participants needed to undergo emergency CABG surgery soon after placement of the investigational stent. The DSMB concludes that the rate at which participants needed to undergo CABG greatly exceeds the expected rate and communicates this information to investigators.

Acute Effects from a Study Drug Not Described in the Drug’s Risk Profile

If a participant experiences acute effects from a study drug that are not described in the drug’s risk profile, it must be reported to the HRPP.

Example: A participant develops severe hepatic failure complicated by encephalopathy one month after enrolling in a Phase 2, open-label, uncontrolled clinical study and starting the new, oral biologic under evaluation for treatment of severe psoriasis unresponsive to treatments approved by the U.S. Food and Drug Administration (FDA). The known risk profile of the new oral biologic prior to this event included mild elevation of serum liver enzymes in 10% of participants receiving the biologic during previous clinical studies, and there was no other history of participants developing clinically significant liver disease. The IRB-approved protocol and informed consent document for the study identifies mild liver injury as a risk of the research. The investigators identify no other etiology for the liver failure in this participant and attribute it to the study biologic.

An adverse event is any untoward or unfavorable occurrence (physical or psychological) in a human participant, including any abnormal sign, symptom or disease, temporally associated with the participant’s time in a research study, whether or not considered related to their participation. These events can occur in the context of biomedical or social/behavioral research. This term is construed broadly.

Continuing Noncompliance

Continuing noncompliance is any demonstrated pattern of noncompliance that may indicate:

• an insufficient understanding or misapplication of federal, state or local regulations that govern human subjects research, or institutional policies and procedures that apply to human subjects research; 
• a compromise of the study quality or scientific integrity such that important conclusions can no longer be reached; or 
• frequent instances of noncompliance suggesting a likelihood that noncompliance will continue without intervention.

Minimal Risk

Nonincarcerated Populations

Minimal risk to nonincarcerated populations means that the probability (likelihood) and magnitude (consequences) of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

Incarcerated Populations

Minimal risk to incarcerated populations means the probability (likelihood) and magnitude (consequences) of physical or psychological harm anticipated in the research is what is normally encountered in the daily lives, or in the routine medical, dental or psychological examination of healthy persons.

Noncompliance

Noncompliance includes, but is not limited to, any incident involving: 

• a failure to comply with federal, state or local regulation that governs human subjects research;
• a violation of institutional policies or procedures applicable to human subjects research; 
• any unapproved deviation from stipulations imposed by the institution as a condition of HRPP/IRB approval; and 
• any unapproved deviation from an HRPP/IRB-approved protocol, unless such deviation is necessary to preserve the life or health of a participant and the HRPP team and IRB, as appropriate, are notified as soon as possible after the deviation occurs.

Related or Possibly Related to Participation

An adverse event may be related or possibly related if there is a reasonable possibility that the incident, experience or outcome may have been caused by the research activities.

Serious Adverse Event (SAE)

An SAE is any adverse event that:

• results in death;
• is life-threatening (places the subject at immediate risk of death from the event as it occurred);
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in persistent or significant disability/incapacity; 
• results in congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Serious Noncompliance

Serious noncompliance is any incident of noncompliance that involves a willful disregard or knowing violation of the federal, state or local regulations that governs human subjects research, or the institutional policies and procedures that apply to human subjects research, which may have included or led to a significant harm, or a risk of significant harm, to the rights, welfare or safety of participants; or significant compromise of the quality or scientific integrity of a human subjects research study.

Suggests Research Places Participants or Others at a Greater Risk of Harm than Previously Known

An adverse event may suggest the research places participants or others at a greater risk of harm than previously known or recognized based on the information available at the time of IRB approval or new information revealed while the study is underway. The risk of harm includes but is not limited to physical, psychological, economic or social harm.

Suspension

Suspension is an action taken by the convened IRB, the IRB chair, a federal agency, a sponsor or a sponsor-investigator to temporarily stop some or all approved research activities in order to protect participants pending completion of an investigation. Suspended studies remain open until the convened IRB or applicable federal agency determines to lift the suspension or terminate the study or some activities of the study.

Termination

Termination is an action taken by the convened IRB, the IRB chair, a federal agency, a sponsor or a sponsor-investigator to permanently stop all research activities in an approved research study.

Unanticipated Adverse Device Effects

Unanticipated adverse device effects are any serious adverse effects on health or safety, any life-threatening problem or death caused by, or associated with a device, if that effect, problem or death was not previously identified in nature, severity or degree of incidence in the FDA Investigational Device Exemption application; or any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of subjects.

Unanticipated Problem Involving Risks to Participants or Others

An unanticipated problem is any incident, experience or outcome in the course of human subjects research that:

• is unexpected (in terms of nature, severity or frequency); 
• is related or possibly related to participation in research; and 
• suggests that the research places participants or others at greater risk of harm (including physical, psychological, economic or social harm) than was previously known or recognized.

Unexpected

An adverse event may be unexpected (in terms of nature, severity or frequency) given the research procedures described in the IRB-approved study documents and the characteristics of the enrolled participant population.

Unexpected Adverse Event (AE)

Any AE occurring in one or more participants in a research study, the nature, severity or frequency of which:

• is not considered consistent with either the known or foreseeable risk of AEs associated with the procedures involved in the research that are described in the protocol-related documents, investigator brochure, informed consent document, or other relevant sources of information regarding the research, such as product or device labeling and package inserts; or 
• is not considered consistent with the expected natural progression of any underlying disease, disorder, or condition of the participant(s) experiencing the AE and the participant’s predisposing risk factor profile for the AE.