Reporting of Adverse Events and Unanticipated Problems

Reporting of Adverse Events and Unanticipated Problems Policy date: 12/2011 Purpose The purpose of this policy is to ensure that the review, reporting and analysis of adverse events and unanticipated problems associated with Cancer protocols occur in a timely, meaningful way so that human subjects can be protected from avoidable harms. Policy This policy will outline the procedure to ensure prompt reporting to the Board, appropriate institutional officials, sponsor, coordinating center and the appropriate regulatory agency heads of adverse events and unanticipated problems involving risks to participants or others. This policy also includes procedures for the Principal Investigator (PI) and IRB with regard to reporting and review of adverse events and unanticipated problems. Due to the number and frequency of events that occur in cancer research, it is the intention of the IRB to focus its review on the reporting of serious adverse events and/or unanticipated problems to enhance the protections of research participants. This will ensure that the IRB, along with reports, monitoring, and oversight by a Data Safety Monitoring Board/Data Monitoring Committee, will provide a meaningful review to ongoing cancer research. Definitions Adverse event: any unfavorable or unintended event, physical or psychological, associated with a research study, which causes harm or injury to a research participant as a result of the participant s involvement in a research study. The event can include abnormal laboratory findings, symptoms, or disease associated with the research study. The event does not necessarily have to have a causal relationship with the research, any risk associated with the research, the research intervention, or the research assessments. Adverse events may be the result of the interventions and interactions used in the research; the collection of identifiable private information in the research; an underlying disease, disorder, or condition of the subject; and/or other circumstances unrelated to the research or any underlying disease, disorder, or condition of the subject. In general, adverse events that are at least partially the result of (a) or (b) would be considered related to the research, whereas adverse events solely related to (c) or (d) would be considered unrelated to the research. Page 1 of 11

Expected adverse event: an event previously known or anticipated to result from participation in the research study or any underlying disease, disorder, or condition of the subject. The event is usually listed in the Investigator Brochure, consent form or research protocol. Unexpected adverse event: an adverse event not previously known or anticipated to result from the research study or any underlying disease, disorder, or condition of the subject. External adverse events: adverse events experienced by subjects enrolled in multicenter clinical trials at sites other than the site(s) over which the Board has jurisdiction. Internal adverse events: adverse events experienced by subjects enrolled at the site(s) under the IRB s jurisdiction for either multicenter or single-center research projects. In the case of an internal adverse event the PI typically becomes aware of the adverse event directly from the subject, another collaborating local investigator, or the subject s healthcare provider. Studies approved by the IRB but conducted outside the United States are considered internal for the purposes of adverse event reporting. Please also refer to definitions of types of research. Unanticipated problems: those events that (1) are not expected given the nature of the research procedures and the subject population being studied; (2) related or possibly related to the participation in the research project; and (3) suggest that the research places subjects or others at a greater risk of harm or discomfort related to the research than was previously known or recognized. Unanticipated problems may or may not be related to adverse events or protocol deviations. Note: In written guidance by the United States Department of Health and Human Services (HHS) Office for Human Research Protections (OHRP), OHRP clarifies that only a small subset of adverse events that occur in human subjects participating in research meet the criteria for an unanticipated problem involving risks to subjects or others. Significance of an adverse event: is used to describe the patient/event outcome or action criteria associated with events that pose a threat to a patient s life or functioning (i.e., moderate, severe or life threatening). Based on the National Cancer Institute Guidelines for the Cancer Therapy Evaluation Program, severity can be defined by the following grades of events: Grade 1 are mild adverse events. (e.g., minor event requiring no specific medical intervention; asymptomatic laboratory findings only; marginal clinical relevance) Grade 2 are moderate adverse events (e.g., minimal intervention; local intervention; non-invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation). Page 2 of 11

Grade 3 are severe and undesirable adverse events (e.g., significant symptoms requiring hospitalization or invasive intervention; transfusion; elective interventional radiological procedure; therapeutic endoscopy or operation). Grade 4 are life threatening or disabling adverse events (e.g., complicated by acute, life-threatening metabolic or cardiovascular complications such as circulatory failure, hemorrhage, sepsis; life threatening physiologic consequences; need for intensive care or emergent invasive procedure; emergent interventional radiological procedure, therapeutic endoscopy or operation). Grade 5 is a fatal adverse event resulting in death. Serious adverse event: any adverse experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood disease or disorders, or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. (Defined by United States Department of Department of Health and Human Service Food and Drug Administration, or FDA, regulations at 21 CFR 310.305(b), 312.32(a), and 314.80(a).) Interventional studies: these studies include research designed to evaluate the safety, effectiveness, or usefulness of therapies (e.g., drugs, vaccines, supplements, diet, exercise, surgical interventions, or medical devices), diagnostic procedures (e.g., scans, biopsies, or endoscopies) or preventive measures (e.g., vaccines or diet). Interventional studies include procedures, both invasive and non-invasive. The procedures include those that are done solely for research purposes and represent no apparent benefit to the participant (e.g., bone marrow aspiration or bronchoscopy in normal, healthy volunteers). Non-interventional and observational studies: these studies include research that does not involve any intervention, alteration in standard clinical care or use in participants of any invasive or non-invasive procedures. Studies limited to the recording of data on individuals receiving standard medical care, the use of existing specimens or data, or the retrospective review of health information and outcomes are, for the purposes of this policy, considered observational studies. Specific types of research that may be classified as observational include database registries, chart reviews, longitudinal outcomes data collection, certain types of survey and questionnaire research, certain types of epidemiological and behavioral studies, and analysis of patient samples. Page 3 of 11

Procedure Reporting requirements The primary responsibility for the evaluation of reportability to the IRB lies with the PI of the research project. This includes the documentation, investigation, and follow-up of these events. The mechanism and required time-frame of reporting to the IRB varies depending on the type of research study, significance, attribution, and expectedness of the event, whether it occurred internally or externally, and if it is an adverse event that is also an unanticipated problem. Additional details of the reporting requirements are included in the tables, below. At the time of continued review for an IRB-approved protocol, the PI will submit a summary of all reportable serious adverse events, including those determined to be unanticipated problems, to the IRB. The summary should include a simple and brief statement as to whether there have been any unanticipated problems and whether adverse events have occurred at the expected frequency and level of severity as documented in the research protocol, the informed consent document, and/or any investigator brochure. If new risks to the participants are identified because of an adverse event(s) that results in substantive changes to the research project, the requests for modifications to the research must be submitted to the IRB with an amendment to research request. Examples of substantive changes that might need to be considered in response to adverse events include: modification of inclusion or exclusion criteria to mitigate the newly identified risks; implementation of additional monitoring procedures for the safety of subjects; termination of enrollment of new subjects; modification of informed consent documents to include a description of newly recognized risks; and incorporation of changes to the study to address serious adverse events that are expected in some subjects, but are determined to be occurring at a significantly higher frequency or severity than expected. NOTE: The IRB does not require the PI to report adverse events that occur to subjects enrolled in observational or non-interventional studies unless the event is related to study participation, causes a change in study design, increases risk to participants or others and/or represents an unanticipated problem. Please note that reporting an event to the IRB does not relieve the PI of the requirement or obligation to report the event to other agencies such as the FDA, Data Safety Monitoring Board/Data Monitoring Committee, or the study sponsors. For multicenter research, the PI should consult with the study sponsor or coordinating center regarding any changes to the protocol and/or informed consent documents. The PI also must ensure that the adverse event is reported to the central or independent monitoring entity in accordance with the monitoring plan described in the IRB approved protocol. Page 4 of 11

Unanticipated problems: All events determined to be an unanticipated problem must be promptly reported to the IRB for review. The Board may take action appropriate for the circumstances to protect the safety, welfare and rights of research subjects. The IRB will report internal adverse events determined to be unanticipated problems to the supporting HHS agency head (or designee) and OHRP. These reports will include the same type of information provided to the IRB by the PI, along with a summary of the actions taken by the IRB and institutional officials in response to the unanticipated problem(s). If the PI determines that the adverse event is an anticipated problem, the PI needs to ensure that the internal adverse event is reported to a central or independent monitoring entity in accordance with the monitoring plan described in the IRB approved protocol. If the monitoring entity subsequently determines, in contrast to the PI s determination, that the serious adverse event does represent an unanticipated problem, the monitoring entity should communicate this determination to the PI, who then should report the unanticipated problem to the IRB. When a central monitoring entity determines that a particular adverse event or series of adverse events represents an unanticipated problem, a report of the adverse event(s) must be submitted to the PI and the IRB. If possible, reports of external adverse events submitted to the IRB should present the adverse event in the context of the entire multicenter study. In addition, the local PI should consult with the study sponsor or coordinating center regarding any changes to the protocol and/or informed consent documents independently proposed by the local PI. These central monitoring reports of external adverse events that are determined to be unanticipated problems should include: 1) A clear explanation of why the adverse event or series of adverse events has been determined to be an unanticipated problem; and 2) A description of proposed actions to be taken by the investigators and/or IRB in response to the unanticipated problem (e.g., suspension of new subject enrollment, modification of the research protocol, and/or modification of the informed consent process). Reports with no modifications to the study: As determined by the review of the IRB chairperson (or designee), reportable events may be handled as follows: 1) Filed in the IRB records without further review by the IRB and included as part of a report of actions taken on behalf of the board or, Page 5 of 11

2) Clarified through the following process: If the central monitoring entity or the PI did not propose any modifications to the protocol or informed consent process/document, but the IRB Chair (or designee) believes that modifications or additional information are needed in response to the reportable adverse event(s), the IRB chairperson (or designee) requests in writing that the PI discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by the IRB or, 3) Referred, at the discretion of the IRB Chair (or designee) to the rest of the IRB members for review and further action, as appropriate, at a convened meeting. Under HHS regulations at 45 CFR 46.109(a), the IRB has authority to require submission of more detailed contextual information by the PI, the sponsor, the study coordinating center, or Data Safety Monitoring Board/Data Monitoring Committee about any adverse event occurring in a research protocol as a condition of the continuation of the IRB s approval of the research. Reports with modifications to the study: As determined by the review of the IRB chairperson (or designee), reportable events may be handled as follows: 1) The IRB Chair (or designee) requests in writing that the PI discuss the proposed additional modifications with the study sponsor or coordinating center and submit a response or the necessary additional modifications for review by the IRB. 2) If all proposed modifications represent minor changes, the IRB Chair (or designee) may review and, if appropriate, approve the modifications under an expedited review procedure (45 CFR 46.110(b)). All IRB members are informed of the expedited approval (45 CFR 46.110(c)), and the report of the external adverse event will be filed in the IRB records. 3) If any of the proposed modifications represent more than a minor change, or if the IRB Chair (or designee) determines for any reason that he or she should not approve the proposed modifications under an expedited review procedure, the proposed modifications will be forwarded to the other IRB members for review at a convened meeting. Adverse events on a different protocol: If a PI is notified or made aware of adverse event(s), including fatal adverse events, that occurred in a study related (e.g. same study agent, device, subject population and/or procedure) to, but not the same as UH Cancer IRB-approved protocol, the adverse event(s) should only be reported to the UH Cancer IRB if the adverse event results in a change in the UH Cancer protocol, consent form, or the perceived risk/benefit ratio. If changes are required, the PI should follow the procedures outlined in the above-labeled Page 6 of 11

section, Reports with modifications to the study. If changes are not required, the reports should be kept on file by the PI. Investigator time requirement for reporting adverse events and/or unanticipated problems to the IRB: NOTE: Time requirements to report events to other agencies such as the FDA, Data Safety Monitoring Board/Data Monitoring Committee, or the study sponsors, may be different than those required by the IRB. The PI is responsible for being aware of and reporting events in accordance with all applicable timelines. PIs shall submit to the IRB site-specific reports of reportable adverse events and/or unanticipated problems involving risks to subjects or others according to the time frames listed below (days are determined by date of discovery or notice to the PI). External Adverse Events Significance of Study Related Not Study Related Adverse Event (Possible/Probable/Definite) (Unrelated/Unlikely) Expected Unexpected Expected Unexpected Fatal Events (Grade 5) 5 working days* Life-Threatening or disabling (Grade 4) Page 7 of 11

Severe and undesirable (Grade 3) Moderate and Mild (Grades 1 & 2) Unanticipated Problem that is a Reportable Event 5 working days *All study related, unexpected deaths should be carefully assessed against the definition of an unanticipated problem. Internal Adverse Events Significance of Study Related Not Study Related Adverse Event (Possible/Probable/Definite) (Unrelated/Unlikely) Expected Unexpected Expected Unexpected Fatal Events (Grade 5) 5 working days 5 working days* 10 working days Life-Threatening or disabling (Grade 4) 10 working days Page 8 of 11

Severe and undesirable (Grade 3) 10 working days Moderate and Mild (Grades 1 & 2) Unanticipated Problem that is a Reportable Event 5 working days and reportable to HHS agency head and OHRP *All study related, unexpected deaths should be carefully assessed against the definition of unanticipated problem. IRB Review and Reporting Procedures: The IRB s review of an adverse event and/or unanticipated problem will include analysis of the following information: 1) The description of known or foreseeable adverse events and risks in the IRBapproved research protocol, any applicable investigator brochure, the current IRBapproved informed consent document, and other relevant sources of information, such as scientific literature, product labeling, and package inserts; 2) Any underlying diseases or conditions of the subject(s) experiencing the adverse event; 3) A careful assessment of whether the adverse event is related or possibly related to subject s participation in the research study; and Page 9 of 11

4) An analysis of whether the risk versus potential benefit of the research is altered as a result of the adverse event and a determination of whether the adverse event warrants consideration of substantive changes in the research protocol or informed consent process/document. At the time of continued review for an IRB-approved protocol, the IRB will request a summary of all reportable adverse events, including those determined to be unanticipated problems, to be included in s submitted to the IRB by investigators. The summary should include a simple and brief statement as to whether there have been any unanticipated problems and whether adverse events have occurred at the expected frequency and level of severity as documented in the research protocol, the informed consent document, and/or any investigator brochure. Notification of IRB Actions The IRB shall notify the PI in writing of its actions in approving, accepting, disapproving or requiring changes to (in order to approve or accept) the reportable adverse event(s) report(s) for an IRB approved protocol. A disapproval notice shall include the basis for the disapproval and provide an opportunity for the investigator to address the Board in person or in writing regarding its action. All such written correspondence from the UH Cancer IRB will be signed by the UH Cancer IRB Chairperson or his designee who will be named by written correspondence. Reporting to the Institution and Government Agencies The administrative office of the UH Cancer IRB shall notify and cooperate with the General Counsel and the appropriate federal agencies in accordance with the Reporting to Regulatory Agencies, Department Heads and Institutional Officials policy. Regulatory Citations: 21 CFR 50 21 CFR 56 21 CFR 312 21 CFR 812 45 CFR 46 Page 10 of 11

Related Policies and Procedures: Non-compliance with Human Subject Regulations [Version 4-2010] Reporting to Federal Agencies, Department Heads and Institutional Officials [Version 3-2007] Guidance: NIH Guidelines on Reporting Adverse Events to Institutional Review Boards, June 11, 1999 OHRP Guidance January 15, 2007 - Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events FDA Guidance January 2009 - Adverse Event Reporting s Improving Human Subject Protection FDA Good Clinical Practice Program National Cancer Institute, Cancer Therapy Evaluation Program - CTEP, NCI Guidelines: Adverse Event Reporting Requirements, Effective January 1, 2005 Page 11 of 11