Guidance for AUB PIs for Reporting Unanticipated Problems involving Risks to Subjects or Others, Adverse Events, and Other Problems

Transcription

1 Guidance for AUB PIs for Reporting Unanticipated Problems involving Risks to Subjects or Others, Adverse Events, and Other Problems Draft Version Number: 1 Dated: Prepared and Edited by: Mary Ellen Sheridan (Consultant) Reviewed by: IRB Chair, Biomedical Vice Chairs, and Administrator Finalized and Approved by: Ghada El Hajj Fuleihan Pending Final Institutional Approval Accessibility Level Choose One: 1. Full access to all browsers 2. Access limited to persons with AUB IDs 3. Access restricted to users designated by the champion American University of Beirut Guidance for AUB PIs for Reporting Unanticipated Problems involving Risks to Subjects or Others, Adverse Events, and Other Problems Issuing Officer: Director Office for the Human Research Protection Program Responsible Dept: Office for the Human Research Protection Program (HRPP) Initial version/date: 1.1/ Revised versions: I. Overview II. Definitions III. Events requiring prompt reporting IV. FDA guidance V. Reporting deviations/noncompliance VI. Time frame for prompt reporting VII. Events not requiring prompt reporting VIII. IRB review process IX. Additional reporting requirements X. Flowchart for Reporting Events to the IRB XI. References Page 1 of 11

2 I. OVERVIEW This document applies to non-exempt research studies involving human subjects. Federal regulations require AUB to have written procedures for insuring that unanticipated problems involving risks to subjects or others are promptly reported to the IRBs, appropriate institutional officials, and Federal agencies where appropriate. To fulfill its obligations during the conduct of a research study, an IRB must have, among other things, information concerning unanticipated problems involving risk to human subjects in the study, including adverse events (AEs) that are considered unanticipated problems. Unanticipated problems can occur in any type of research (medical or non-medical) and may include occurrences such as adverse events, research participant complaints, protocol deviations, and other untoward events involving risk. Events requiring prompt reporting may involve physical, psychological, social, legal, or economic harm. Only a small subset of adverse events are unanticipated problems that must be reported under 45 CFR 46. [Unanticipated problems may be adverse events or other types of problems, i.e. adverse events are a subset of unanticipated problems.] Clinical investigators conducting research involving human subjects governed by Food and Drug Administration regulations are required to report to the IRB all unanticipated problems involving risks to human subjects or others under 21 CFR 56 (IRB), 312 (Investigational New Drug Applications), and 812 (Investigational Device Exemptions.) Sponsors and investigators should differentiate between those unanticipated problems that must be reported to the IRB and those that do not. This is not always a straightforward decision. This Guidance is intended to assist investigators and IRBs in assessing what is required to be reported, what is recommended to be reported to the IRB (and when), help them differentiate between those adverse events that are unanticipated problems that must be reported to the IRB and those that are not, and how the IRB uses unanticipated problem reports in its oversight of research. Unanticipated problems may also arise in nonclinical research. Some unanticipated problems may be more likely to increase harm to subjects through social, legal, economic and/psychological injuries. In considering which unanticipated problems in these areas should be reported to the IRB, the investigator should promptly report to the IRB those that meet all the criteria for unanticipated problems below. Other unanticipated problems that do not rise to the level of these criteria should be summarized and included in the continuing review application. II. DEFINITIONS Unanticipated problems* involving risks to subjects or others: a problem, event or information that is not expected, given the nature of the research procedures and the subject population being studied; and which suggests that the research places subjects or Page 2 of 11

3 others at greater risk of harm or discomfort related to the research than was previously known. The IRB considers unanticipated problems, in general, to include any incident, experience, or outcome that meets ALL of the following criteria: 1. Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol, investigator s brochure, drug or device product information, informed consent document, or the research materials; and (b) the characteristics of the subject population being studied, including underlying diseases, behaviors, or traits; 2. Definitively, possible, or probably related to participation in the research (possible related means that that there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and 3. Suggestions that the research places subjects or others at risk of unknown harm or additional/increased frequency of harms (including physical, psychological, economic, legal, or social harm) than was previously known or recognized. Unanticipated problems may be adverse events, protocol deviations, noncompliance or other types of problems, but MUST meet all of the criteria listed above. (* OHRP definition from Guidance on Unanticipated Problems and Adverse Events, December 14, 2006) Adverse event (AE): Any undesirable and unintended (although not necessarily unexpected) effect occurring as a result of interventions, interactions, or collection of identifiable private information in research. In biomedical research, any untoward physical or psychological occurrence in research, including abnormal laboratory finding, symptom, or disease temporally associated with the use (although not necessarily related to) a medical treatment or procedure. Adverse events involving drugs are also referred to as adverse drug experiences. Serious adverse event (SAE): An adverse event that is fatal or life threatening, permanently disabling, requires or prolongs hospitalization, or results in significant disability, congenital anomaly, or birth defect. [See OHRP Guidance definition of SAE which is modified from FDA 21 CFR (a) definition of serious adverse drug experience.] Unexpected adverse event: An adverse event that has not been previously observed or is not consistent in nature, severity, or frequency with existing risk information in the consent form, such as in the investigator brochure, detailed research protocol, consent form, the reasonably expected natural history and progression of the underlying disease or condition, or other available information (e.g. IND application for an investigational drug.) [modified from 21 CFR (a)] Page 3 of 11

4 Unanticipated adverse device effect: Any serious adverse effect on health or safety, or 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 investigational plan or application; any other unanticipated, serious problem associated with a device that relates to the rights, safety or welfare of subjects. [21 CFR 812.3(s)] Related: An adverse event which is associated or having a timely relationship with; a reasonable possibility exists that an outcome may have been caused or influenced by the event in question (e.g. use of a study drug, device, or intervention), although an alternative cause/influence may also be present. Related events may be definitely, probably, or possibly related. Unrelated: Unassociated or without a timely relationship; evidence exists that an outcome is definitely related to a cause other than the event in question. Internal event: An event occurring in research at AUB or a site(s) under AUB s IRB jurisdiction. External event: An event occurring in research at a site(s) other than AUB, over which another (non AUB) IRB has jurisdiction. III. EVENTS REQUIRING PROMPT REPORTING Investigators and research staff are responsible for reporting to the IRB unanticipated problems involving risks to subjects or others. In general an Adverse Event observed during the conduct of a study should be considered an unanticipated problem involving risks to human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implications for the conduct of the study (e.g. requiring modifications to the existing approved protocol, the consent form, investigator brochure, etc.). The convened IRBs are responsible for making the final determination that a reported event (e.g. adverse event) is an unanticipated problem involving risks to subjects or others. The following events may represent unanticipated problems involving risks to subjects or others and should be promptly reported: Adverse events or injuries that are serious, unexpected, and probably, possibly, or definitively related; Anticipated adverse events occurring at a greater frequency and/or greater severity than expected Adverse device effects that are unanticipated; Protocol deviations or violations (or other accidental or unintentional changes to the protocol or procedures) involving risks or with potential to recur; Events requiring prompt reporting according to the protocol or sponsor; Complaints made by research participants indicating an unanticipated risk(s); or complaints that cannot be resolved by the research staff; Page 4 of 11

5 Unapproved changes made to the research to eliminate an apparent immediate hazard to a research participant; Data and Safety Monitoring Board (DSMB) reports, interim analyses, or other oversight committee/monitoring reports altering the risk/benefit profile; New information indicating an unexpected change in risks or potential benefits (e.g., literature/scientific reports or other published findings); Investigator s Brochure (IB or IDB) updates or revisions to safety information; and Other problem or finding (e.g., breach of confidentiality, loss of study data or forms, etc.) that an Investigator or research staff member believes could influence the safe conduct of the research. IV. FDA GUIDANCE FDA regulations use different terms when referring to an adverse event (e.g. adverse effect is used in 21 CFR ; adverse experience is used in ; and unanticipated problems is used in 21 CFR For device studies, part 812 uses the term unanticipated adverse device effect, defined above. There are some differences between the requirements for investigational new drug (IND) and investigational device exemption studies, as they concern obligations to report to a reviewing IRB. (These are noted in the Timeframes for Reporting below.) In general, an AE observed during the conduct of a study should be considered an unanticipated problem involving risk to human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implication for the conduct of the study (e.g., requiring a significant and usually safety-related, change in the protocol such as revising inclusions/exclusions criteria or including a new monitoring requirement, revised informed consent, or investigator s brochure). FDA recommends that there be careful consideration of whether an AE is an unanticipated problem that must be reported to IRBs. For example, because they have been previously observed with a drug, the AEs listed in the investigator s brochure would, by definition, not be considered unexpected and thus would not be unanticipated problems. (Possible exceptions would include situations in which the specificity or severity of the event is not consistent with the description in the investigator s brochure, or it can be determined that the rate of occurrence for a serious, expected AE in the clinical trial represents a clinically important increase in the expected rate of occurrence. In summary, FDA believes that only the following AEs should be considered unanticipated problems that must be reported to the IRB. A single occurrence of a serious, unexpected event that is uncommon and strongly associated with drug-exposure (such as angiodema, agranulocytosis, hepatic injury or Stevens-Johnson syndrome) A single occurrence, or more often a small number of occurrences, of a serious, unexpected event that is not commonly associated with drug exposure, but uncommon in the study population (e.g. tendon rupture, progressive multifocal leukoencephalopathy) Multiple occurrences of an AE that, based on an aggregated analysis, is determined to be an unanticipated problem. There should be a determination that Page 5 of 11

6 the repetitiveness and/or seriousness of the AEs represents a signal that the AEs were not just isolated occurrences and involve risk to human subjects (e.g., a comparison of rates across treatment groups reveals higher rate in the drug treatment arm versus a control). Summary and analyses documentation should support the determination accompanying the AE report. A serious AE that is described or addressed in the investigator s brochure, protocol, or informed consent documents, but for which the rate of occurrence in the study represents a clinically significant increase in the expected rate of occurrence (ordinarily, reporting would only be triggered if there were a credible baseline for comparison.) A discussion of the divergence from the expected rate should accompany the AE report. Any other AE or safety finding (e.g., based on animal or epidemiological data) that would cause the sponsor to modify the investigator s brochure, study protocol, or informed consent document, or would prompt other action by the IRB to ensure the protection of human subjects. An explanation of the conclusion should accompany the AE report, and, if necessary, an amendment of the IRBapproved protocol to implement such change(s) into the study. Major deviations from an IRB-approved protocol should be reported within 10 working days of the investigator s knowledge of the deviation. Reports should be made using the Unanticipated Problem report form. In a multicenter study, individual investigators must rely on the sponsor to provide them information about AEs occurring at other study sites. Although the FDA regulations state than an investigator must report all unanticipated problems, FDA guidance recognizes that for multicenter studies, the sponsor is in a better position to analyze adverse event information for the entire study and to assess whether an adverse event occurrence is both unanticipated and a problem for the study. Therefore an investigator participating in a multicenter study may rely on the sponsor s assessment and provide to the IRB a report of the unanticipated problem prepared by the sponsor for adverse events external to AUB. Internal Adverse Events, and in particular, Serious Adverse Events must be reported to the AUB IRB as detailed in the time frame reporting below. V. REPORTING DEVIATIONS/NONCOMPLIANCE An IRB is asked to ensure prompt reporting of serious or continuing noncompliance with regulations or noncompliance with IRB s own requirements/determinations [45 CFR (b)(5)]. Deviations from the approved protocol, i.e. any change, modification, divergence, or departure from the study design or procedures of an already approved IRB research protocol that is under the Principal Investigator s control, and that has not been approved by the IRB. Deviations range in seriousness according to how the changes may impact subject safety, the subject s willingness to participate in the research, the integrity of the research data, the degree of noncompliance with Federal and national regulations, and the degree of foreknowledge of the event. Page 6 of 11

7 Repeated deviations of the same type may be an indication that an amendment is needed to permanently change study criteria. A major deviation is one that may affect the subject s welfare, safety, and health of human subjects or the integrity of the research data. Specifically, the protocol deviation might result in either actual harm to the research subjects, potential harm or risk to the research subjects, a compromise to the integrity of the research data, a breach of human subjects protection regulations, policies, or procedure, and/or a serious or continuing noncompliance with federal, local, and institutional regulations, policies, and procedures governing human subject protection. A Major Deviation should be made using the Unanticipated Problem report form. A minor deviation is one that does not impact subject safety, compromise the integrity of the study data, or affect subjects willingness to participate in the study. Minor deviations should be summarized at the time of continuing review on the continuing review form. VI. TIME FRAME FOR PROMPT REPORTING It is the responsibility of the investigator to ensure that written notification of unanticipated problems is submitted in a timely manner to the IRB. The investigator must complete an Unanticipated Problem Report Form with his/her original signature and attach any additional information necessary in evaluating the report. While 45 CFR 46 requires prompt reporting of unanticipated problems, the regulations do not define prompt. The appropriate time frame will vary depending on the specific nature of the unanticipated problem, the nature of research associated with the problem, and the entity to which reports are to be submitted. OHRP recommends certain guidelines to satisfy the prompt reporting. FDA regulations spell out certain reporting requirements for various clinical studies. The time frames described below take OHRP recommendation and FDA requirements into account. All other events or adverse events that do not meet reporting criteria can be submitted as a summary at the time of continuing review. All Internal Serious Adverse Events (Fatal/Life-threatening unanticipated problems under the jurisdiction of the AUB IRB; see list under definition of SAE above) should be reported immediately (within 48 hours) to the IRB Chair. Events, both Internal and External, resulting in temporary or permanent interruption of study activities by the PI or sponsor to avoid potential harm to participants should be reported to the IRB immediately (within 48 hours). Anticipated adverse events occurring at a greater frequency and/or greater severity than expected should be reported to the IRB immediately (within 48 hours) Other events described under Events Requiring Prompt Reporting, both Internal and External, should be reported to the IRB using the Unanticipated Problem Report Form within 10 business days of the Investigator s or research staff member s learning of the event. Page 7 of 11

8 Device Studies any unexpected adverse event that occurs on a device trial, excluding serious adverse events must be reported to the IRB within 10 business days of the investigator s knowledge of the adverse event. Any changes that are made to eliminate apparent immediate hazards to a subject should be reported to the IRB within 10 business days of the occurrence, using the Unanticipated Problem Report Form and an amendment should be submitted for the next IRB deadline to change the protocol to eliminate future hazards of this type, as appropriate. [In such cases where a change to eliminate immediate hazards to a subject was made, enrollment of new subjects should be halted until the IRB has had an opportunity to consider such changes.] Major deviations from approved IRB protocol should be reported within 10 business days of the investigator s knowledge of the deviation. Reports should be made using the Unanticipated Problems Report Form and may involve submission of an amendment should change(s) need to be made permanently to the research study methodology and/or study criteria. New information regarding studies that have been closed, expired or terminated, and that may have an impact on former participants; the principal investigator is required to notify the IRB within 10 business days of any unanticipated problems involving risks to subjects or others when it may be in the best interest of the participants to be informed of the findings. The investigator must also include a description of any corrective actions that have been initiated in the conduct of the research to prevent a reoccurrence of the problem or to protect research participants from potential or further harm. VII. EVENTS NOT REQUIRING PROMPT REPORTING Potential risks and adverse events that may be reasonably anticipated (i.e. expected ) should be described in the informed consent process/form and do not require prompt reporting to the IRB by investigators and research staff. The following are examples (but not an inclusive list) of events that do not require prompt reporting: Adverse events that are non-serious, expected, or unrelated; Adverse device effects that are non-serious, anticipated, or unrelated; Deaths not attributed to the research, e.g. from natural causes, accidents, or underlying disease and the Investigator has ruled out any connection between the study procedures and the participant s death; Protocol deviations or violations not involving risks to participants or unlikely to recur; Complaints made by research participants not involving risks or complaints that were resolved; DSMB reports, interim analyses, or other reports, findings, or new information not altering the risk/benefit profile Investigator Brochure updates not involving safety information; and Page 8 of 11

9 Problems or findings not involving risk (unless the Investigator or research staff member believes the information could affect the participants willingness to continue in the research.) Related internal and external events involving risk, but not meeting the prompt reporting requirements, should be reported to the IRB in summary form at the time of Continuing Review. VIII. IRB REVIEW PROCESS Unanticipated Problem event reports are screened by the IRB office for completeness. Event reports are forwarded to the IRB Chair/Vice Chair for a determination about whether the event represents a possible unanticipated problem involving risks to subjects or others. These latter are discussed at the convened IRB meeting. In reviewing unanticipated problem reports, the IRB will consider whether the event, incident or information impacts the risk/benefit ratio to ensure adequate protection of the welfare of subjects. Based on the review the IRB may (1) require modifications to the protocol and/or consent form, (2) revising the continuing review timetable, or (3) reconsider approval of the study. The IRB will consider the rights and welfare of participants when suspending, terminating, or modifying research. Reports of events that do not meet the requirements for prompt reporting may be returned to the PI. IX. ADDITIONAL REPORTING REQUIREMENTS Adverse events must be reported immediately to the sponsor, except for those events that the protocol or investigator s brochure identifies as not needing immediate reporting. The sponsor protocol should indicate when and how adverse events are to be reported. Investigators should contact the study sponsor for specific reporting requirements. For clinical research governed under FDA regulations, adverse events that are both serious and unexpected must be reported to the FDA. In the case of industry-supported protocols, reporting to the FDA is usually accomplished through the normal reporting channel (i.e. investigator to sponsoring company to the FDA). In the case of investigatorinitiated research or research that does not involve funding from a sponsoring company, the PI of the protocol assumes the responsibility to report adverse events to the FDA. In such instances, investigators should follow the reporting procedure of the FDA Medical Products Reporting Program (MedWatch.) The time requirement for MedWatch reporting varies according to the reporting method used, (i.e. mailed, faxed, or on-line.) Additional information on FDA MedWatch reporting can be obtained from the FDA website Page 9 of 11

10 X. FLOW CHART FOR REPORTING EVENTS TO IRB (Adopted with permission from Ohio State University) Page 10 of 11

11 XI. RESOURCES OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 17, 2007 FDA Guidance for Clinical Investigators, Sponsors, and IRBs, Adverse Event Reporting to IRBs Improving Human Subject Protection, January 2009 Ohio State University HRPP Policies and Procedures, Event Reporting Unanticipated Problems Involving Risks to Subjects or Others, Adverse Events, and Other Problems Ohio State University Event Reporting Form version 2.2., September, 2009 University of Chicago Biomedical IRB Unanticipated Problem Reporting Policy, June 26, 2009 University of Chicago Biomedical IRB Unanticipated Problem Report Form, May 2009 University of California Irvine, HRPP Policy Reporting Adverse Events, Unanticipated Problems Involving Risks to Subjects and Others, and Protocol Violations University of Pennsylvania, Office of Regulatory Affairs, Policy Events Requiring Prompt Reporting to the IRB including Unanticipated Problem Involving Risks to Subjects or Others Page 11 of 11