Office of Research Oversight 1 VHA Handbook Research Compliance Reporting Requirements Revised May 21, 2010 (Presentation prepared for HRPP 101, 01/26/2011)

Adverse Events and Unanticipated Problems Based on a presentation by: Karen Jeans, PhD, CCRN, CIP

Office of Research Oversight 3 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 Understand reporting requirements

Office of Research Oversight 4 What is the Difference Between Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others? Adverse Events UPRs AE/UPR

Office of Research Oversight 5 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 Many Unanticipated Problems Involving Risks to Subjects or Others and Many Adverse Events are not Serious

Office of Research Oversight 6 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

Office of Research Oversight 7 Regulatory Background: Unanticipated Problems Involving Risks to Subjects or Others Under the Common Rule must be reported to the IRB per 38 CFR (a) Under FDA regulations must be reported to the IRB per 21 CFR (b)

Office of Research Oversight 8 Regulatory Background: Adverse Events – Common Rule The Common Rule (36 CFR 16) does not address “adverse events” and does not require “adverse event reporting” (except when the “adverse event” constitutes an “unanticipated problem involving risks to subjects or others”) VHA Handbook §7 requires that Local, Unanticipated, Serious Adverse Events (SAEs) be reported to the IRB within 5 business days

Office of Research Oversight 9 Regulatory Background: Adverse Events – FDA Regulations Investigators must report to the Sponsor any adverse effect that may reasonably be regarded as caused by, or probably caused by, the drug (must report immediately if alarming) per 21 CFR (a)&(c) Investigators must report to the Sponsor and the IRB any Unanticipated Adverse Device Effect per 21 CFR (a) Sponsor must report to FDA and relevant Investigators any Adverse Experience that is both serious and unexpected per 21 CFR (a)&(c) and (b)(1)

Office of Research Oversight 10 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)

Office of Research Oversight 11 Types of Adverse Events Unanticipated (unexpected) Local (internal) Non-local (external) Related Not related Serious Not Serious

Office of Research Oversight 12 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)

Office of Research Oversight 13 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

Office of Research Oversight 14 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.

Office of Research Oversight 15 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))

Office of Research Oversight 16 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)

Office of Research Oversight 17 Serious Adverse Event Definitions VHA 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. FDA 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.

Office of Research Oversight 18 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)

Office of Research Oversight 19 Definition: Unanticipated Problem Involving Risks to Subjects or Others Common Rule Undefined FDA Regulations Undefined

Office of Research Oversight 20 Unanticipated Problems Involving Risks to Subjects or Others OHRP Guidance: 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 4. Harm may be physical, psychological, economic, or social Source: OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events – January 15, 2007

Office of Research Oversight 21 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.)

Office of Research Oversight 22 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

Office of Research Oversight 23 Reporting Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others The IRB determines when events, incidents, or outcomes are Unanticipated Problems Involving Risks to Subjects or Others, or Adverse Events that are serious, unanticipated, and probably related to research, and reports to Institutional Officials accordingly

Office of Research Oversight 24 Possible IRB Actions may include: 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

Office of Research Oversight 25 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

Office of Research Oversight 26 Summary Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others are not synonymous However, reporting of Serious, Unanticipated Adverse Events probably related to research, and Unanticipated Problems Involving Risks to Subjects or others is the same. 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 determines which are unanticipated problems involving risks to subjects or others, and reports as required by VHA Handbook

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Office of Research Oversight 28 Highlights (New Requirements in Red – Previous Requirements in Blue) Requirements for Designation of Facility RCO [ §6c] Requirements to Conduct Annual and Triennial Audits as Specified by ORO [ §6c] Facility Director Reporting Requirements [ §6f] Annual Facility Director Certification of Research Oversight [ §6g] RCO Roles as Consultant to Review Committees [ §4t] Requires Reporting of All RCO Audit Findings to Relevant Review Committees and R&DC [ §§6d, 6e] Time Periods for Implementing Remedial Actions [ §5d] Requires Providing ORO Compliance Reports to ACOS/R, RCO, Relevant Review Committees and R&DC [ §6g]

Office of Research Oversight 29 Highlights (New Requirements in Red – Codification of Previous Guidance in Blue) Distinguishes Rapid Reporting Requirements for Serious Adverse Events and Unanticipated Problems Involving Risks to Subjects or Others from Reporting Requirements Under Local SOPs Clarifies Definitions of Serious or Continuing Noncompliance [ §§4e, 4x] Limits Special Rapid Reporting Requirements for Serious or Continuing Noncompliance to Human Research [ §§4e, 4x] Distinguishes Apparent Serious or Continuing Noncompliance from IRB-Determined Serious/Continuing Noncompliance and Provides Specific Examples[ §7i] Defines “Reportable Events” for Non-Human of Research [ §§8-11]

Office of Research Oversight 30 Role of the RCO RCO’s primary responsibility = auditing and reviewing research projects relative to VA research requirements RCO may also serve as a nonvoting consultant, as needed, to the facility’s R&D Committee, IRB, IACUC, Subcommittee on Research Safety (SRS), and other research review committees The RCO may not serve as a voting or nonvoting member of these committees -- may attend meetings of these committees when requested by the committee or as specified in local committee SOPs [ §4t]

Office of Research Oversight 31 Non-Voting Consultant vs Non-Voting Member Real or Apparent Conflict of Interest RCO audits entail review of IRB actions – the RCO’s perceived independence is compromised if the RCO is a member of the committee under review Flexibility of RCO time and resource commitments Multiple mandatory committee memberships decrease optimal use of RCO time and resources Flexibility in developing working relationship that meet facility research protection and oversight needs [ §4t]

Office of Research Oversight 32 The IRB is responsible for determining: Whether or not apparent noncompliance is serious or continuing Remedial action(s) in response to identified noncompliance Verifying that the remediation is implemented as required. [ §7i]

Office of Research Oversight 33 Remedial Actions Remedial actions related to specific research projects should typically be completed within days of the research review committee’s determination of noncompliance. Except where remediation requires substantial renovation, fiscal expenditure, hiring, legal negotiations, or other extenuating circumstances, remedial actions related to programmatic noncompliance should typically be completed within days of the noncompliance determination. Where completion of remedial actions extends beyond the periods described in the preceding subparagraphs, the facility must provide ORO with a written justification for the delay and an acceptable timeline for completion. [ §5d]

Office of Research Oversight 34 Serious or Continuing Noncompliance vs Apparent Serious or Continuing Noncompliance Serious Noncompliance: Involves substantive harm (or genuine risk of substantive harm) to the safety, rights, welfare of human subjects, research staff or others in human research Substantively compromises the effectiveness of the facility’s human research protection/oversight programs Continuing Noncompliance: Reflects a persistent failure to adhere to the laws, regulations, or policies governing VA human research [ §§4e,4x,7e, 7f, 7g]

Office of Research Oversight 35 Serious or Continuing Noncompliance vs Apparent Serious or Continuing Noncompliance Apparent Serious or Continuing Noncompliance = a situation that, in the judgment of the individual observing it: Satisfies the Handbook’s definition of Serious Noncompliance Satisfies the Handbook’s definition of Continuing Noncompliance Reflects one or more of the examples provided in the Handbook [ §§4e,4x,7e, 7f, 7g]

Office of Research Oversight 36 Apparent Serious or Continuing Noncompliance Observed by an RCO in an Informed Consent, Regulatory, or Other Systematic Audit of Human Subjects Research Must be reported to the Facility Director, IRB, ACOS/R, R&D Committee, etc. within 5 business days Facility Director must report to ORO Regional Office within 5 business days of being notified (even if disposition complete) Facility Director must provide follow-up reports as specified by ORO Regional Office Convened IRB determines whether: Serious or Continuing Noncompliance occurred Remedial Actions are warranted [ §7h]

Office of Research Oversight 37 Apparent Serious or Continuing Noncompliance in Human Subject Research Observed by anyone in the Research Community (including RCO in context other than audit) Must be reported to the IRB within 5 business days Convened IRB determines whether: Serious or Continuing Noncompliance occurred Remedial Actions are warranted If Serious or Continuing Noncompliance, IRB must report to Facility Director, ACOS/R, R&D Committee, etc, within 5 business days Facility Director must report to ORO Regional Office within 5 business days of being notified [ §7i]

Office of Research Oversight 38 Note Change in Reporting Requirements Involving  UNANTICIPATED Adverse Events  UNANTICIPATED Problems Involving Risks to Subjects/Others The 5-day requirement for reporting Adverse Events (AEs) and Problems Involving Risks to Subjects or Others TO THE IRB Now applies only to AEs and Problems that are UNANTICIPATED and SERIOUS

Office of Research Oversight 39 “UNANTICIPATED” refers to an event/problem that is new or greater than previously known in terms of nature, severity, or frequency, given the procedures described in protocol-related documents and the characteristics of the study population. “SERIOUS” refers to: Events that qualify as Serious Adverse Events (SAEs) as defined by FDA; or Problems/events that involve: Substantive harm, or a genuine risk of substantive harm to the safety, rights, or welfare of research subjects, staff, or others; or Substantively compromise the effectiveness of the facility’s human research protection or human research oversight programs

Office of Research Oversight 40 This change is meant to improve oversight by: Decreasing the overload experienced by IRBs from rapidly reviewing large numbers of clinical events that are unlikely to reflect substantive, unconsidered risks Allowing timely expert peer review focused on events that are more likely to reflect substantive concerns All SAEs and Problems Involving Risks to Subjects or Others still require review by the IRB as described in local Standard Operating Procedures consistent with: VHA Handbook , The Common Rule at 28 CFR 16, and Applicable FDA regulations

Office of Research Oversight 41 Serious Adverse Event (SAE) Reporting Investigator (or other person) must report any local AE that is SERIOUS and UNANTICIPATED to the IRB within 5 business days: Serious = untoward physical or psychological occurrence in a human subject resulting in death, life-threatening experience, impatient hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, or that requires medical, surgical, behavioral, social, or other intervention to prevent such an outcome Unanticipated = reflects a risk that is new or greater than previously known Special review by IRB (or qualified IRB member) within 5 business day after the report to categorize the event [ §§ 4b,4p,4x,4y,4bb,7c, 7d]

Office of Research Oversight 42 Serious Adverse Event (SAE) Reporting IRB must report any Unanticipated, Related, Local SAE to the Facility Director within 5 business days of categorization Related = event may reasonably be regarded as caused by, or as probably caused by, the research Facility Director must report to ORO Regional Office within 5 business days of being notified IRB (or qualified IRB member) must also document whether or not action is needed to prevent immediate hazard to subjects If consent or protocol modifications are required, convened IRB must determine whether previously enrolled subjects must be notified, and if so when, how, and how documented [ §§ 4b,4p,4x,4y,4bb,7c,7d]

Office of Research Oversight 43 Unanticipated Problem Reporting Investigator (or other person) must report any Unanticipated Problem Involving Risks to Subjects or Others in human research to the IRB within 5 business days if it: May reasonably be regarded to involve substantive harm, or a genuine risk of substantive, to safety, rights, or welfare, or Substantively compromises the effectiveness of the facility’s human research protection or human research oversight programs Special review by IRB (or qualified IRB member) required within 5 business days after the report to categorize the event Investigator (or other person) must report any other unanticipated problems involving risks to subjects or others in human research to the IRB promptly per local SOPs [ §§ 4y,4bb,7a,7b,7d]

Office of Research Oversight 44 Unanticipated Problem Reporting IRB must report Related, Serious, Unanticipated Problem Involving Risk to Subjects or Others to Facility Director within 5 business days of categorization Related = event may reasonably regarded as caused by, or as probably caused by, the research Facility Director must report to ORO Regional Office within 5 business days of being notified IRB (or qualified IRB member) must also document whether or not action is needed to prevent immediate hazard to subjects If consent or protocol modifications are required, convened IRB must determine whether previously enrolled subjects must be notified, and if so when, how, and how documented [ §§ 4b,4p,4x,4y,4bb,7c,7d]

Office of Research Oversight 45 Animal Research, Research Safety, Research Lab Security, Research Information Protection, Research Misconduct Reporting not based on “Serious or Continuing Noncompliance” as defined in human research Reportable Events defined for each type of research No special requirements for Rapid Review / Rapid Reporting to ORO 5-day standard for reporting: Reportable Event to Research Review Committee Review Committee Determination to Facility Director To ORO by Facility Director [ §§ 8, 9, 10, 11, 12]

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