Adverse Event – Regulations Requirement of the IRB

1. Adverse Event – RegulationsRequirement of the IRB • 45 CFR 46 Sec 103 (b)(5) Institutions must have “Written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Department or Agency head of (i) any unanticipated problems involving risks to subjects or others or any serious or continuing noncompliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval.” • 21 CFR 56 Sec 108 (b) Institutions must have “written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drugs Administration of: (1) Any unanticipated problems involving risks to human subjects or others……” Words “prompt” and “others” are not clarified. Word “any” implies all unanticipated problems involving risk to subjects and others must be reported (those that are not on the consent form are unaticipated).

2. Definition of Adverse Event An Adverse Event (AE) is an unanticipated problem involving “risk” to subjects that ultimately results in harm to the subject (impacts on subjects morbidity and mortality) or others. AE reports must be filed with the sponsor and the Institutional Review Board (IRB) when any of the following happens to a subject on a study: • Death • Unanticipated “risk” requiring treatment, hospitalization or prolongation of existing hospital stay • Any suspicious findings that may have relationship to the study • Adverse pregnancy outcome before, during and at the time of delivery • Birth defects or congenital anomaly • Loss of research records that contain identifiable information • Overdose of drug

3. Definition Continued • Unusual frequency or intensity of expected effects described in the informed consent document or trends in one type of AE event toward within a protocol (serious or not) • Breach of confidentiality • Unanticipated problems involving risks to “others” (Example: A nurse in a research study is inadvertently stuck by a needle containing a chemotherapeutic agent that is teratogenic, mutogenic, etc ) • Abnormal test results that is critical to evaluate the “risk” or “safety” of subjects • Unexpected – any adverse experience that is not identified in nature, severity or frequency in the consent form and is not due to a disease process

4. Definition for Devices (21 CFR 812) • Unanticipated Adverse Device Effect (ADE) means any serious adverse effect on health and safety of 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 • Degree of incidence in the: • In the investigational plan or application • Supplementary plan or application • Any other unanticipated serious problem associated with the device that relates to the: • Rights • Safety • Welfare of subjects

5. Sponsor-Investigator-IRB Interrelationship • The interrelationship and interaction between the research sponsor (e.g., drug, biologic and device manufacturers), the investigator and the Institutional Review Board (IRB) is very complex. • The sponsor customarily interacts with the IRB through the investigator who conducts the clinical study. • The clinical investigator generally provides the communication link between the IRB and the sponsor. However, the regulations do not prohibit direct sponsor-IRB contacts. • This linkage is agreed to by the sponsors and investigators when they sign forms FDA-1571 and FDA-1572, respectively, for drug and biologic studies or an investigator agreement for device studies. • There are occasions when direct communication between the IRB and the sponsor may facilitate resolution of concerns about study procedures or specific wording in an informed consent document. The clinical investigator should be kept apprised of the discussion.

6. Responsibilities of Data safety Monitoring Board (DSMB) • The responsibilities for safety monitoring for multicenter clinical trails rests with DSMB • Data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose- finding studies (phase I); efficacy studies (phase II); efficacy, effectiveness and comparative trials (phase III); etc. • DSMB will have all the data which helps them make an informed decision and advise IRBs • DSMBs should provide the investigator/IRB with safety information at appropriate intervals to allow IRBs to perform reliable assessment of the significance of the AE data to protect research subjects • Drexel University College of Medicine’s (DUCOM) IRBs are not data safety monitoring committees • Both DSMB and DUCOM IRB have the right to halt a study. However, the DUCOM IRB that approved the study has the ultimate authority to the rights and welfare of research subjects and to halt the study at DUCOM.

7. AE ReportingInvestigator Responsibility • Investigator is responsible for knowing the policies of the DUCOM IRB, adhering to these policies, and maintaining a copy of the policies in the study file. • Investigator is also responsible for the accurate documentation, investigation and follow-up of all possible study-related adverse events. • For NIH-supported multicenter clinical trials, investigators do not report these events to off- site IRBs as long as the DUCOM IRB has been notified (Example: ECOG and COG Trials fall into this category). However, it must be reported to the ECOG, etc. • In a multicenter trial, submit a summary report to DUCOM IRB whenever a data safety monitoring board (DSMB) review has taken place. • These summary reports do not replace other reporting requirements to the DUCOM IRB, e.g., annual reports or periodic reports • Any protocol submitted for DUCOM IRB approval should both identify the DSMB (not members’ names), if any, that will be reviewing interim results. • The report should include a brief description of the monitoring plan as well as procedures for transmitting the DSMB’s summary reports to the IRB. • For multicenter clinical trials, individual adverse event reports from off-sites should be presented using the Adverse Event Report Form. It is not uncommon to receive duplicate reports; therefore check for duplicity before submitting a report. • Reports are received, sometimes, months apart, but make sure to submit off-site AE reports as they arrive

8. Safety Reporting Investigator’s Responsibility • All unanticipated and serious adverse events (SAE) should be reported immediately to sponsor • The immediate report should be followed promptly by detailed, written reports • Reports should not include subjects identifiable information rather it should identify subjects by unique code numbers assigned to a trial • Investigator should also comply with applicable regulatory requirements (some may require reporting to the FDA or DHHS) and the IRB • Adverse events or laboratory abnormalities (that are critical for safety evaluations) should be reported to the sponsor and the IRB • For reported deaths, the investigator should supply autopsy and terminal medical reports.

9. AE Reporting Investigator’s Responsibility in Determining and Notifying the Problem • Investigator’s conclusion on the relation of the problem to the study drug or device • Related to the study • Unrelated • Possibly related • Not related • Unknown • Investigator’s estimation of the severity of the Problem to the study drug or device • Mild • Severe • Life Threatening • Investigator’s recommendation to change the protocol, informed consent or assent form • Notification of the problem to the sponsor, the IRB and if necessary, to regulatory agencies

10. AE Report Submission • To report an Adverse Event, the Researcher or his/her designated research coordinator should complete and submit the Adverse Event Report Form, which can be downloaded from www.research.drexel.edu, typed and submitted to the Office of Research. • Submit a separate adverse event report for each subject and each protocol by completing all questions on the form. • Submit a copy of the current approved and stamped consent form with each adverse event reporting. • AE reports should be mailed to the Office of Research at MS 444, Suite 2105, New College Building, 245 N 15th Street, Philadelphia, PA 19102. • The report should be submitted promptly as they occur followed by any appropriate follow-up report (s) on a timely basis. • In order to maintain subject confidentiality, please remember to remove subject names and/or other personally identifiable information from your AE report.

11. AE Report Submission • If multiple AEs are reported by the sponsor in one letter, then only one DUCOM AE report is necessary. • However, if over a period of time (days, weeks, etc.) you receive more than one letter with multiple events, you will need to submit a single DUCOM AE report for each letter.