Adverse Events and Unanticipated Problems Presented by: Karen Jeans, PhD, CCRN, CIP COACH Program Analyst

Objectives Define “adverse event” Describe “unanticipated problems involving risks to subjects to others” Identify examples of adverse events and unanticipated problems involving risks to subjects to others

Why Report Adverse Events and Unanticipated Problems? Because it helps ensure the safety of participants in human subject research, by providing information to the IRB and cognizant oversight agencies, and Because it is required

Regulatory Background Common Rule “Adverse Events” do not exist Unanticipated problems involving risks to subjects or others (38 CFR (a))

Regulatory Background FDA Regulations Adverse Event (21 CFR ) Adverse Experience (21 CFR ) Adverse Effect (21 CFR ) Unanticipated Adverse Device Effect (21 CFR ) Unanticipated Problems involving risks to subjects or others (21 CFR (b))

The Common Rule Requires: “… 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 … ; and (ii) any suspension or termination of IRB approval. ” Source: 38 CFR (b)(5)

Criteria for IRB Approval (.111) A. Required determinations: 1. Risks to subjects are minimized (i) By using procedures consistent with sound research design… (ii) When appropriate, using procedures already being performed… 2. Risks are reasonable in relation to benefits 3. Selection of subjects is equitable 4. Informed consent will be sought prospectively 5. Informed consent is appropriately documented 6. Research plan makes adequate provisions for safety monitoring 7. There are adequate provisions to protect privacy and confidentiality B. When appropriate, additional protections for Vulnerable Subjects

What Is An Adverse Event (AE)? An AE is any untoward occurrence (physical, psychological, economic, social, or legal) which affects a study subject Includes any abnormal sign, symptom, or disease temporally associated with the subject’s participation in the research An AE does not require (or imply) a causal relationship with the research. Source: Modified from definition of Adverse Events in the 1996 International Conference on Harmonization E-6 Guidelines for Good Clinical Practice in OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events – January 15, 2007

What Is An Adverse Event (AE) according to VHA requirements? An AE is any untoward physical or psychological occurrence in a human subject participating in research. Can be unfavorable and unintended event Includes any abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article. Does not necessarily have to have a causal relationship with the research. Source: VHA Handbook , Paragraph 4(b)

Adverse Event Definitions VHA OHRP Guidance An AE is any untoward physical or psychological occurrence in a human subject participating in research. Can be unfavorable and unintended event Includes any abnormal laboratory finding, symptom, or disease associated with the research or the use of a medical investigational test article. Does not necessarily have to have a causal relationship with the research. An AE is any untoward occurrence (physical, psychological, economic, social, or legal) which affects a study subject Includes any abnormal sign, symptom, or disease temporally associated with the subject’s participation in the research An AE does not require (or imply) a causal relationship with the research.

Types of Adverse Events Unanticipated (unexpected) Local (internal) Non-local (external) Related Not related Serious Not Serious

Types of Adverse Events: Unanticipated Unanticipated (unexpected) Event or problem that is new or greater than previously known in terms of nature, severity, or frequency, given the population described in protocol-related documents and the characteristics of the study population. Source: VHA Handbook , Paragraph 4(bb)

Types of Adverse Events: Local and Non-Local Local (internal) Adverse event occurring at the reporting individual’s own facility Source: VHA Handbook , Paragraph 7(c) Non-local (external) Adverse events occurring by subjects enrolled by investigators at other institutions

Types of Adverse Events: Related Related There is a reasonable possibility based upon the available information that the event or outcome may have been caused by or resulted from participation in the research by the subject.

Types of Adverse Events: Serious FDA Regulations An Adverse Event that Results in death, a life-threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or Requires, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above. Source: Section 761(a)(2) of the Food Drug &Cosmetic Act (21 U.S.C. 379aa-1(a)(2))

Types of Adverse Events: Serious VHA Requirements An Adverse Event in Human Research that Results in death, a life-threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect. Also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome. Source: VHA Handbook , Paragraph 4(w)

Serious Adverse Event Definitions VA FDA Results in death, a life- threatening experience, inpatient hospitalization, prolongation of hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect. Also considered serious when medical, surgical, behavioral, social, or other intervention is needed to prevent such an outcome. Results in death, a life- threatening experience, inpatient hospitalization, a persistent or significant disability or incapacity, or a congenital anomaly or birth defect; or Requires, based on a reasonable medical judgment, a medical or surgical intervention to prevent an outcome described above.

What is the Difference Between Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others? Adverse Events UPs AE/UPR

Definition: Unanticipated Problem Involving Risks to Subjects or Others Common Rule Undefined FDA Regulations Undefined

Unanticipated Problems Involving Risks to Subjects or Others Any incident, experience, or outcomes that meets all three criteria: 1. Unexpected 2. Related or possibly related to participation in research 3. Suggests that the research places subjects or others at a greater risk of harm than was previously known or recognized May be physical, psychological, economic, or social harm Source: OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events – January 15, 2007

Unanticipated Problems Involving Risks to Subjects or Others vs. Adverse Events Most Adverse Events are not Unanticipated Problems Involving Risks to Subjects or Others All Unanticipated Problems Involving Risks to Subjects or Others are not Adverse Events All Unanticipated Problems Involving Risks to Subjects or Others Adverse are not Serious

Research-related Events or Problems Which Could Be (Or Could Reveal) Unanticipated Problems Involving Risks to Subjects or Others PI-initiated changes in protocol Study amendments, for example: revision of the Consent Form; revision of inclusion/exclusion criteria; addition/deletion of study procedures; etc. Suspension of enrollment New Information (e.g., DSMB reports, publications, sponsor alerts, etc.)

Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others Study sponsors (if multisite study) make reports to PIs, who, in turn, report them to the IRB. Members of the VA research community are responsible for reporting to the IRB per local IRB Standard Operating Policies and Procedures Local IRB Standard Operating Policies and Procedures can exceed but not be less stringent than federal requirements

Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others The IRB determine when events, incidents, or outcomes are Unanticipated Problems Involving Risks to Subjects or Others and report to Institutional Officials

IRB Actions Require study modification Providing additional information to subjects Modify informed consent process/document Educational plan Assignment of Mentor Require additional monitoring Suspension or termination of IRB approval Other actions as determined by the IRB

Reporting By The IRB And Institutional Officials When the IRB determines that a study-related event is an Unanticipated Problem involving Risk to subjects or others, it must be reported to Institutional Official Institutional Official reports to Oversight Agencies and entities as applicable Office of Research Oversight Office for Human Research Protections U.S. Food and Drug Administration Sponsors Other entities

Summary Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others are not synonymous Policies and procedures must describe when and how adverse events and possible unanticipated problems involving risks to subjects or others are reported to the IRB. The IRB reviews reports and determines which are unanticipated problems involving risks to subjects or others