1. UNANTICIPATED PROBLEMS INVOLVING RISKS TO SUBJECTS OR OTHERS & INCIDENTS OF NON-COMPLIANCE ( AKA PROTOCOL DEVIATIONS ) TRACY RIGHTMER, JD, CIP COMPLIANCE MANAGER YALE UNIVERSITY HUMAN RESEARCH PROTECTION PROGRAM That Wasn’t Supposed to Happen

2. Today’s Discussion Definitions of UPIRSOs, minor non-compliance, serious non-compliance, continuing non-compliance and protocol deviations How to identify those that need to be reported How to report to the IRBs What to do if you’re not sure

3. Non Compliance The IRB recognizes that non-compliance with approved protocols may occur. It is the responsibility of the Principal Investigator to notify the IRB if: 1) the incident may expose subjects to increased risk OR 2) fewer benefits OR 3) the incident compromises the integrity of the study

4. Definitions: Minor Non-compliance Minor Noncompliance: Any behavior, action or omission in the conduct or oversight of research involving human subjects that deviates from the approved research plan, federal regulations or institutional policies but, because of its nature, research project or subject population, does not: place, or have the potential to place, participants and others at greater risk than previously anticipated; have a substantive effect on the value of the data collected; and result from willful or knowing misconduct on the part of the investigator(s) or study staff. Examples of minor noncompliance may include, when such noncompliance does not create additional risks to subjects: Changing study personnel without notifying the IRB; Shortening the duration between planned study visits; Implementing minor wording changes in study questionnaires without first obtaining IRB approval; Routine lab missed at scheduled visit and re-drawn

5. Definitions: Serious Non-compliance Serious Noncompliance: Any behavior, action or omission in the conduct or oversight of human research that has been determined to: affect the rights and welfare of participants and others; increase risks to participants and others, decreases potential benefits or otherwise unfavorably alter the risk/benefit ratio; compromise the integrity or validity of the research; or result from the willful or knowing misconduct on the part of the investigator(s) or study staff. Examples include, but are not limited to: Conducting non-exempt research that requires direct interaction or interventions with human subjects without first obtaining IRB approval; Enrolling subjects who fail to meet the inclusion or exclusion criteria in a protocol that involves greater than minimal risk and that places the participant(s) at greater risk; or Failure to report adverse events, unanticipated problems, or substantative changes to the proposed protocol to the Committee in accordance with IRB Policy 710 and Form 100 FR.4: Request for Approval of Amendment.

6. Definitions: Continuing Non-compliance Continuing Noncompliance: A pattern of noncompliance that indicates a lack of understanding or disregard for the regulations or institutional requirements that protect the rights and welfare of participants and others, compromises the scientific integrity of a study such that important conclusions can no longer be reached, suggests a likelihood that noncompliance will continue without intervention, or involves frequent instances of minor noncompliance. Continuing noncompliance may also include failure to respond to a request from the IRB to resolve an episode of noncompliance or a pattern of minor noncompliance.

7. Definitions: Unanticipated Problems Involving Risks to Subjects or Others (UPIRSO) UPIRSO is any incident, experience, or outcome that meets all of the following criteria: 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 and informed consent document; and (b) the characteristics of the subject population being studied; related or possibly related to participation in the research. Possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research; and suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.

8. UPIRSO Examples Unanticipated problems can include incidents such as: A stolen laptop containing subject data and identifiers (investigators must also file the http://www.yale.edu/its/forms/LostStolenForm.doc with Information Security and provide a copy to the IRB.) A processing error resulting in a subject receiving a dose of study medication 10 times higher than the dose dictated by the IRB approved protocol but that produces no detectable adverse effect Subjects receiving an investigational product which was obtained from donors who were not appropriately screened and tested for viral contaminants Subjects receiving the wrong medication, whether or not they experience adverse events (AEs) that are not reportable under the AE reporting policy http:/yale.edu/hrpp/policy/AdverseEventPolicy Any publication in the literature, safety monitoring reports, interim results or other findings that indiciates an unexpected change to the risks or potential benefits of the research

9. Definitions: Serious Adverse Events Serious Adverse Events Investigators must report to the IRB within 48 hours of discovery any adverse events that are: Serious AND unanticipated AND possibly, probably or definitely related events; and/or Anticipated adverse events occurring with a greater frequency than expected Serious Any event that results in any of the following outcomes: death, a life-threatening experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other adverse event that, based upon appropriate medical judgment, may jeopardize the participant’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition. Other adverse events must be summarized in the re-approval request. The summary may be a simple brief statement that adverse events have occurred at the expected frequency and level of severity as previously documented.

10. Adverse Events vs. Unanticipated Problems The following Venn diagram summarizes the general relationship between adverse events and unanticipated problems:

11. Federal Regulations The rationale for reporting non-compliance to the IRB is to enable the IRB to fulfill its role of oversight for protection of human subjects. Federal regulations (21 CFR 56.108(b)(1) (FDA) and 45 CFR 46.103.b.5 (HHS)), require the IRB to review reports of non-compliance that may impact subjects’ welfare. In doing so, the IRB can ask investigators to think about and implement additional subject protections. Consideration should involve assessing whether there has been a change to the risk/benefit ratio and assessing whether changes to the protocol or procedures are necessary in order to minimize risks. The regulations also require the IRB to follow written procedures for reporting certain types of non-compliance to the Institutional Officials and Federal Authorities (if applicable).

12. IRB Policy Investigators are required to report serious or continuing non- compliance that occur only at Yale’s research site(s) to the IRB within 5 working days of their occurrence or within 5 days of the investigator becoming aware of their occurrence. UPIRSOs must be reported within 48 hours. Investigators are also required to report results of audits or inspections conducted by sponsors or other external entities such as the Food and Drug Administration (FDA), which involve any of the above. Minor noncompliance should be summarized for the IRB at the time of continuing review http://www.yale.edu/hrpp/policies/index.html#PostApproval

13. What Do I Do? Determine if the incident of non-compliance is minor or if it qualifies as serious or continuing or is an unanticipated problem  Serious non-compliance: does it affect the rights and welfare of subjects, increase risks or decrease benefits, compromise the integrity or validity of the research, is it knowing or willful? If yes- then report.  Continuing non-compliance: is there a pattern of non-compliance that indicates a lack of understanding or respect of the regulations, a pattern of non-compliance that compromises the integrity of the research? If yes- then report.  UPIRSO: is it unexpected, related or possibly related and place the subject at greater risk than previously known? If yes- then report. Report serious or continuing non-compliance to the IRB within 5 days using the UPIRSO report form on the HRPP website Report UPIRSOs to the IRB within 48 hours using the UPIRSO report form Report incidents of non-compliance and UPIRSOs from the School of Medicine and School of Nursing to the Compliance Manager located at the Human Investigation Committee (203-785-4688, YSMhic@yale.edu). Report incidents of non-compliance and UPIRSOs from other areas of the University to the Human Subjects Committee (203-436-3650, human.subjects@yale.edu). When in doubt…call your IRB!

15. http://www.yale.edu/hrpp/

16. UPIRSO Report Form The form asks for several things:  Description of the event  Why the event occurred  Outcome  Were subjects adversely affected  Description of changes to the protocol/consent  A Corrective Action Plan

18. Corrective Action Plan In crafting an effective plan, the investigator needs to really think about why the event occurred. Is it a system problem? Problem with procedure? A training issue? Once the “why” is determined, the plan must address ways to prevent it from happening again Education is almost always appropriate

19. Examples Study participant cancels a study visit and reschedules for 3 days outside the visit window. A research assistant forgets to perform one of the assessments for a study participant. Inclusion/exclusion criteria for a study prohibit enrollment of participants with a cardiac history. A participant with a history of myocardial infarction is enrolled and begins study medication. A study participant receives the wrong study medication but experiences no adverse events. A research participant doesn’t receive an infusion of study medication according to the schedule as set out in the protocol. A participant currently enrolled in a medication study dies from causes not related to participation. Study PHI is accidentally emailed to the wrong recipient. Flashdrive with PHI on it is lost. PI enrolls/conducts research during study lapse.

20. Other Examples? Questions? Call 785-6471 tracy.rightmer@yale.edu

21. References http://www.yale.edu/hrpp/ http://www.yale.edu/hrpp/policies/index.html http://www.yale.edu/hrpp/responsibility/complianc e.html http://www.yale.edu/hrpp/responsibility/complianc e.html http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm http://www.hhs.gov/ohrp/humansubjects/guidance /45cfr46.htm http://www.hhs.gov/ohrp/humansubjects/guidance /45cfr46.htm http://www.fda.gov/AboutFDA/CentersOffices/ORA /default.htm http://www.fda.gov/AboutFDA/CentersOffices/ORA /default.htm