Reportable Events

1. Reportable Events Donna Singleton, RN, CCRC Director, HRPP Operations

2. What Are Reportable Events? How am I suppose to know what to report? How long do I have to report? What form do I use? This is a lot of work!

3. How can I know what needs to be reported?“Some Things to Consider” • The IRB reviews and approves each research protocol or plan according to criteria based on applicable laws, regulations, codes, and guidance. • The IRB must have and follow written policies and procedures for identifying and analyzing risks and identifying measures to minimize such risks. • The analysis of risk includes a determination that the risks to participants are reasonable in relation to the potential benefits to participants and to society.

4. How Does the IRB identify and analyze the risks to subjects? When one of the following is affected in the research process it usually requires reporting to the IRB. Risks to participants Selection of participants Safety monitoring Privacy of participants Confidentiality of data Vulnerable populations Consent from participants Conflict of Interest

5. What is the Risk-Benefit Ratio? • The anticipated benefit, either to new knowledge or improved health of subjects should justify the subject taking the risk to participate in the research study. The IRB considers all of the following:

6. What are the different types of risks that Subjects may be exposed to?

7. Classifications of Risk

8. What About Legal Risks? Mandatory reporting of child abuse discovered during the research may cause legal problems for the subject.

9. Anything that tips the risk-benefit ratio usually results in reporting

10. Two Types of Reporting Internal Investigators must promptly report to the IRB. External Organization must promptly report to the federal agencies.

11. Internal Reporting Investigators Report to the IRB • Unanticipated Problems • Change to the protocol to eliminate apparent immediate hazard to the subject • New safety information that indicates a change in risk • Premature suspension or termination of research by the sponsor or the investigator • Failure to follow the protocol: protocol deviation, violation or exception • Monitoring reports • Non-compliance • Audit, inspection, or inquiry by a Federal Agency • Participant Incarceration • Breech of Confidentiality • Unanticipated adverse device effect

12. External ReportingOrganization Must Report to the Federal Agencies • Unanticipated Problems Involving Risks to Participants or Others • Terminations or Suspensions of IRB approval of research • Serious or Continuing Non-Compliance

13. Researchers are expected to adhere to all of the following:

14. YourInvestigator Commitment • At the time of your submission to the IRB, the Principal Investigator (PI) signs the PI Statement of Assurance committing to seek and obtain prior approval from the IRB for any change in the protocol submitted andto report promptly to the IRB any unexpected or otherwise significant adverse effects encountered in the course of the study. • Prior to the beginning of the study, the PI must sign the Clinical Study Agreement and/or the Investigators signature page documenting his/her agreement to conduct the study in accordance with the IRB approved protocol.

15. Once you have IRB approval of the research protocol now what? Planned changes to the protocol with IRB approval • Modification/Amendment • Protocol Exception/Eligibility Waiver • Change made to eliminate apparent immediate harm to a subject Unplanned changes to the protocol without IBR approval • Protocol deviations • Protocol violations

16. Planned Changes to A Research Protocol • Modification to the previously approved protocol through the submission of an Amendment to the Protocol to the IRB for review and approval. (Not considered a protocol deviation) • Protocol Exception or Eligibility Waiver which requires prior sponsor and IRB approval prior to the implementation. (Although IRB approval is obtained, the FDA still considers the exception to be a violation) • A change made to eliminate apparent immediate harm to a subject and may be considered an Unanticipated Problem. This type of change can be initiated without IRB approval provided it is immediately reported to the IRB and any subsequent change is not implemented before IRB approval is obtained. (Considered a subset of protocol deviations)

17. Unplanned Changes to the Protocol • Unplanned changes made to the IRB approved protocol without IRB approval are either protocol deviations or protocol violations. • These unplanned changes may include unapproved changes or non-adherence to the IRB-approved research protocol, to GCP guidelines, to regulatory standards or to any of the LSUHSC-S HRPP/IRB SOPs. • Repetitive deviations/violations are non-compliance and may be ruled by the IRB to constitute serious or continuing non-compliance resulting in suspension or termination of IRB approval. • Repeated failure of an investigator to not report protocol deviations will be viewed as serious non-compliance.

18. The term “Protocol Deviation” or “Protocol Violation is not defined by either the Health and Human Services human subjects regulations, (45 CFR 46) Common Rule or the Food and Drug Administration (FDA) human subjects regulations (21 CFR 50). For the sake of research under the auspices of LSUHSC-S the following definitions and policies apply.

19. What are Protocol Deviations? • Any change or alteration from the procedures stated in the study protocol, consent document, recruitment process, or study materials (e.g. questionnaires) originally approved by the IRB (but the change or alteration itself is not IRB approved). • Protocol deviation is a general term and includes 1) protocol exceptions, 2) changes made to avoid an immediate hazard to a subject, and 3) protocol violations. • Protocol deviations can be examples of non-compliance, serious non-compliance or continuing non-compliance.

20. Protocol Deviations…. • Deviations that increase the risk, have the potential to recur, or are undertaken to eliminate an immediate hazard, would be considered an Unanticipated Problem and should be handled in accordance with the policy for Unanticipated Problems.

21. Protocol Deviation Tips…… • Everyone at some time or another may accidently deviate from the protocol. The IRB is aware that to err is human; however, the IRB becomes concerned when there is a failure to adhere to protocol that occurs more than once or without consideration as to how to prevent the deviation from reoccurring. • When a sponsor requests that the IRB be notified of a deviation that has not already been reported to the IRB, the deviation is to be submitted to the IRB according to the HRPP/IRB SOPs, with all of the supporting documentation to include a corrective action plan as to how this event will not occur again.

22. Repetitive Deviations…….. • Repetitive deviations will be determined by the IRB to constitute non-compliance that can result in suspension or termination of the IRB approval. • The IRB will review all reports of protocol deviations for frequency and will audit any protocol reporting frequent deviations.

23. What are Protocol Violations? • A protocol violation is a subset of protocol deviations. • A protocol violation includes: • Any planned or unplanned change or deviation from the IRB approved study protocol, consent document, recruitment process, or study materials that were not approved by the IRB prior to implementationthat may affect the subject’s rights, safety, or welfare and/or the completeness, accuracy and reliability of the study data. • Any significant divergence from the protocol, i.e., non-adherence on the part of the patient, investigator, or the sponsor to protocol-specific inclusion/exclusion criteria, primary objective variable criteria, and/or GCP guidelines without prior Sponsor and IRB approval. • A divergence from the protocol that has the ability to increase the risk and/or decrease the benefits; affect the rights, safety, or welfare and/or the completeness, accuracy, integrity or reliability of the research data.

24. Protocol Violations…….. • The investigator should not intentionally deviate from the protocol-specific procedures except in cases of medical emergencies without submitting and receiving IRB approval for an amendment to the study. • The investigator may deviate from the IRB approved protocol without IRB approval only when the change is necessary to eliminate an apparent hazard to the subject. • Protocol violations create serious situations that require immediate investigation by the IRB Chair/Human Research Protections Program and reporting to the Institutional Official (Chancellor) and appropriate external agencies, including Office of Human Research Protections (OHRP) and other applicable agencies when warranted. • All departures from the IRB approved protocol are considered to be protocol deviations and they are viewed by the Federal Agencies as such.

25. What is the difference between major and minor protocol violations?

26. What are Minor Protocol Violations? • A minor protocol violation is one that does not usually have the potential to impact subject safety, compromise the integrity of the study data, or affect the subject’s willingness to participate in the study. • The minor protocol violation is to be reported to the IRB by the investigator whether identified by the PI, study staff, or during a monitoring visit within 5 days of becoming aware of the violation. • If the study coordinator or monitor identifies the violation, the PI is to be notified immediately.

27. Examples of Minor Protocol Deviations • Research visits that occur outside the study window, however do not impact subject safety or study data. • A rescheduled study visit. • Failure to collect an ancillary self-report questionnaire (the first time). • Use of an unapproved recruitment procedures or materials (e.g. when slightly altered) (the first time). • Study visits outside the protocol specific visit window (the subject is on vacation or visit is late due to an illness). • Failure of the subject to return unused study medications unless there is drug left that will affect drug accountability. • Subject’s refusal to complete scheduled research activities not adversely affecting the subject or data

28. Oh by the way……….. • the IRB understands about minor protocol violations the first time….. • Thereafter repetitive occurrences constitutes continuing non-compliance.

29. What are Major Protocol Violations? • A major protocol violation is a deviation that has an impact on or the potential to have an impact on subject safety, may substantially alter risks to subjects, may have an effect on the integrity of the study data, or may affect the subject’s willingness to participate in the study. • Major protocol violations can vary in the degree of seriousness according to how the changes impact subject safety, the degree of non-compliance with Federal regulations, State laws, the HRPP, HRPP/IRB policies or procedures, and the degree of foreknowledge of the event.

30. Major Protocol Violations Tips • All major protocol violations must be reported to the IRB no later than 5 days of learning of the violation. • If it is necessary to make a permanent change to the study procedures in order to avoid harm to other subjects, then a protocol amendment should be submitted as soon as possible by the PI. • If appropriate to maintain the safety of the subjects, new subject enrollment should be temporarily stopped by the PI until the amendment is approved. • Regardless of who discovers a major protocol deviation, the PI is responsible for reporting the event to the IRB as soon as possible but no later than 5 days.

31. Examples of Major Protocol Violations • Failure to obtain valid consent. • Verbal consent rather than face to face IRB-required signed informed consent process and document. • Enrolling a subject who does not meet inclusion/exclusion criteria. • By the way, many clinical trial agreements disclose that payment is not made for subjects enrolled that did not meet inclusion/exclusion criteria. • Continuing research activities after IRB approval. has expired (lapse in approval). • Obtaining research-related procedures prior to obtaining informed consent. • Hospitalization or death caused by or contributed to by a Humanitarian Use Device • Delegation of research to someone not qualified to perform the research related task. • Failure to perform required lab tests or protocol procedures that has the potential to impact safety of the subject (screening lab, tests, physical exams) • An investigator deliberately decides to follow a different procedure than that set forth in the protocol for one or more subjects (other than to eliminate an immediate hazard to the subject or others

32. Examples of Major Protocol Deviations • The investigator not reviewing, signing and dating safety assessments in a timely manner or prior to randomization. • Dosage calculations based upon the wrong weight. • Safety assessments not performed according to protocol (Vital Signs). • Sponsor imposed suspension or early termination of a study for cause. • Failure to document the consent process. • Failure to report to the IRB in accordance with IRB policy (5 days). • Failure to report Unanticipated Problems. • Failure to submit monitoring reports. • Study coordinator performing physician required research procedures. • Failure to obtain mandatory training (CITI) prior to being engaged in research. • Failure to provide adequate oversight of the research protocol.

33. What is a Protocol Exception? • A protocol exception is a temporary protocol deviation or eligibility waiver that is granted by the Sponsor or funding agency and the IRB prior to implementation • The exception is usually for a single subject. • The exception is evaluated by both the sponsor and the IRB in order to determine that the exception does not increase the risk to the subject or jeopardize the integrity of the research data

34. Protocol Exception Tips • Documentation of the sponsor approval should be forwarded to the IRB with the request for consideration. • Documentation of sponsor and IRB approval of the exception should be maintained in the investigator’s research file. • Prior approval may be required from the FDA in investigational device studies. • It is the investigator’s responsibility to obtain the approval from the sponsor and the IRB prior to any implementation. • Exceptions that involve a greater than minimum risk to the subject will need to be reviewed and approved by the convened IRB.

35. What happens if someone is enrolled who does not qualify? If the investigator becomes aware of a subject that is enrolled in a study who did not meet protocol eligibility criteria (a protocol violation), the investigator must immediately inform the sponsor and the IRB. Such subjects will be discontinued from the study, except in the rare instance following review and written approval by the Sponsor and the IRB that it is in the best interest of the Subject to remain in the study.

36. What do the regulations require of an IRB to ensure compliance? • In accordance with 45 CFR 46.103 each institution engaged in research which is covered by this policy and which is conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in this policy. • 46.103(5)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 non-compliance with this policy or the requirements or determinations of the IRB; and (ii) any suspension or termination of IRB approval. • All human subject research engaged in at LSUHSC-S is covered by the HRPP. The HRPP covers all research regardless of the funding source. Therefore the same protections are provided to all subjects regardless of the funding source or type of research.

37. All individuals engaged in research are required to conduct research projects in accordance with the IRB approved protocol, federal regulations, state law, and Institutional policy. The failure to do so is non-compliance.

38. What is Non-compliance? Non-compliance is any action or omission associated with the conduct or oversight of research involving human subjects that fails to comply with the research plan as approved by the IRB or federal regulations or institutional policies governing such research. Non-compliance may range from minor to serious, be non-intentional or willful, and may occur once or several times.

39. What constitutes the degree of non-compliance? Minor non-compliance: Any action or omission in conduct or oversight of research involving human subjects that deviates from the approved research plan, federal regulations or institutional policies but because of the nature of the deviation, research project or subject population does not place, or have the potential to place, participants at greater risk than previously anticipated. Examples of minor non-compliance include but are not limited to the following: • Changing study personnel without notifying the IRB. • Shortening the duration between planned study visits. • Implementing minor word changes in study questionnaires without first obtaining IRB approval. • Routine lab missed at scheduled visit and re-drawn.

40. What is serious non-compliance? • Any behavior, action or omission in the conduct or oversight of human subject research that has been determined: • to affect the rights and welfare of participants • increases risks to participants and others, • decreases potential benefits or otherwise unfavorably alter the risk/benefit ratio; • compromises the integrity or validity of the research, or • results from the willful or knowing misconduct on the part of the investigator(s) or study staff.

41. Examples of Serious non-compliance 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/exclusion criteria in a protocol that involves greater than minimal risk and places the participant(s) at greater risk. • Failure to report adverse events, unanticipated problems or substantive changes to the proposed protocol to the IRB in accordance with the IRB policy. • Failure to follow recommendations made by the IRB to ensure the safety of subjects.

42. Serious Non-compliance continued • Failure to adequately provide informed consent as described in the IRB approved protocol such as obtaining phone consent rather than face to face documentation of the consent. • Serious protocol deviation/violations that place, or have the potential to place, participants at increased risk from the research

43. What is Continuing Non-compliance? A pattern of non-compliance that, in the judgment of the IRB Chair, designee, or convened IRB committee, indicates a lack of understanding or disregard for the regulations or institutional requirements that protect the rights and welfare of participants, compromises the scientific integrity of a study such that important conclusions can no longer be reached, suggests a likelihood that non-compliance will continue without intervention, or frequent instances of minor non-compliance. Continuing non-compliance may also include failure to respond to a request from the IRB to resolve an episode of non-compliance or a pattern of minor non-compliance.

44. 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 subject’s 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 the risks. • The regulations also require the IRB to follow written procedures for reporting certain types of non-compliance to Institutional Officials and Federal Authorities (if applicable).

45. OOPS! I think I may be out of compliance, what should I do? Investigators, research personnel, or other individuals who believe that an incident of non-compliance has occurred must report the incident to the IRB within 5 days as required by institutional requirements that protect the rights and welfare of participants. Please call 318-813-1364 to report such incidents for Committee 1 and 318-813-1361 for Committee 2. If you are unsure whether or not the incident meets any of the definitions above, please contact us as soon as possible and we will work with you to determine the best course of action. When in doubt…..call your IRB!

46. How do I report all of the reportable events? • Reportable New Information Form (cover sheet for all reportable supplements) • Supplement R-1 Deviations, Violations, and Exceptions • Supplement R-2 Monitoring Reports and Sponsor Correspondence (NOT SAFETY INFORMATION) • Supplement R-3 Unanticipated Problems and Other Events Requiring Prompt Reporting • Supplement R-4 All other Explanations • Notification of Emergency Use of a Test Article

47. I’ve received notification that my study is going to be audited. What does this mean? The QA/QI coordinator or the HRPP will conduct Periodic, or Random reviews to ensure compliance with ethical standards and human subjects protection. The selection of your study will be either randomly selected or based upon other criteria such as the number enrolled and does not necessarily mean you are out of compliance. The QA/QI coordinator will send you a letter to provide instructions as to the date of the audit. You will be given approximately one week notice. The letter will provide you with the information that will be reviewed and what you will need to have available for the coordinator. During the review the coordinator may talk with the research staff, tour your facility, review study records, and IRB records. This process should be collaborative and helpful with the end goal of facilitating your research and the protection of your participants. Please feel free to ask questions.

48. Directed For Cause Audits The Directed audit is conducted by the HRPP QA/QI coordinator(s) and are initiated upon request by the IRB, the Institutional Official (IO) or the HRPP Director, due to unusual circumstances, any situation that compromises the integrity of the HRPP, significant risks to subjects, routine failure of an investigator to comply with federal and/or institutional requirements, allegations or concerns about the conduct of the study brought to the attention of the IRB or the HRPP, or any case requiring further scrutiny as deemed appropriate by the IRB.

49. I have received a notice of a Directed “for cause” audit. What Now? • Directed audits are usually conducted within 24 hours of notice . • The institution recognizes that research personnel will be need to be re-directed to comply with the short notice required in a “directed” or “for cause” audit. • To allow for subject safety, the HRPP will notify the Department Chair of an impending directed audit; the purpose of the advance notice is to allow any necessary reassignment or management of study personnel. • The timeframe for notification will be determined by the organizational official ordering the audit. The notification period will be the minimum necessary time period. • To protect the safety and well-being of subjects, the research may be suspended by the IRB until the audit is complete and the findings reviewed. • The scope of the evaluation may initially be limited to the investigation of the matter, but the scope may be expanded based on the initial results of the audit.

50. What Issues can trigger For-Cause Audits? • Directed by the IRB, HRPP, or the IO • Unexpected research participant death • Research subject, family, or research staff complaint • Numerous and/or significant unanticipated problems and/or protocol violations • Reports or allegations of non-compliance by investigators, research personnel, subjects or others • Results of audits or monitoring by other entities (internal or external to LSUHSC-S. • Concerns expressed by the Department Chair or other committees