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Human Research Protection Program 101

Human Research Protection Program 101. March 19-20, 2007 Cincinnati, OH. Adverse Events and Unanticipated Problems. Presented by: David A. Rickaby, PhD Research Compliance Officer Milwaukee VAMC. IRB Mission. To assure maximal protection for human research participants, the IRB must

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Human Research Protection Program 101

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  1. Human Research Protection Program 101 March 19-20, 2007 Cincinnati, OH

  2. Adverse Events and Unanticipated Problems Presented by: David A. Rickaby, PhD Research Compliance Officer Milwaukee VAMC

  3. IRB Mission To assure maximal protection for human research participants, the IRB must • ensure local management of unanticipated problems in research • do so in compliance with all laws, regulations, and standards.

  4. Local Management • PI initiated change • Revision of inclusion/exclusion criteria • Closer monitoring • Suspension of enrollment • Suspension of certain procedures • Modification of the Consent Form • Contacting previously enrolled subjects

  5. Regulations for Reporting “… prompt reporting… any unanticipated problems involving risks to subjects or others…” (Common Rule) • 38 CFR 16.103(b)(5)…….…VA • 21 CFR 56.108(b)(1)…….…FDA [IRB] • 21 CFR 312.53(c)(1)(vii)…FDA [Drugs] • 45 CFR 46.103(b)(5)…….…DHHS

  6. Regulatory Guidance • VHA ORD Handbook 1200.5 Requirements for the Protection of Human Subjects in Research • OHRPGuidance(January 15, 2007) Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events • Local IRB SOP Manual

  7. Reporting Criteria The unanticipated problem is • unexpected in terms of nature, severity or frequency and • related to or possibly related to participation in research and • places subjects or others at a greater risk of harm OHRP Guidance Topic I

  8. Adverse Event • Is any untoward physical or psychological occurrence in a human subject participating in research • Expanded by VA to include social and economic • Can be any unfavorable event including abnormal laboratory finding, symptom or disease • Does not necessarily have to have a casual relationship with the research VHA 1200.5§3(a)

  9. Problems vs. Adverse Events Unanticipated Problems AdverseEvents UAEs • Unanticipated problems include things not • considered AEs • Most adverse events are not unanticipated (UAEs) OHRP Guidance Topic III

  10. Most AEs not UAEs • Procedures consistent with sound design • Procedures based on standard practice • Research progresses in stages • Experience with animal, in vitro models • Thorough investigation • Expected natural progression • Pre-disposing risk factors • Known toxicities

  11. Is AE an Unanticipated Problem? OHRP Algorithm: OHRP Guidance Topic III

  12. Adverse Events IRB Involves risk No risk Involves risk No risk Involves risk No risk Involves risk No risk Related* Unrelated  Related*  Unrelated  Unexpected Expected  *or possibly related

  13. Adverse Events Sponsor Involves risk No risk Involves risk No risk Involves risk No risk Involves risk No risk Unexpected Expected Unexpected  Expected  Related* Unrelated  *or possibly related

  14. Unexpected Adverse Event Any AE and/or reaction, the specificity or severity of which is not consistent with: • Informed consent • Investigator brochure or product label • Risks identified in investigational plan or protocol OHRP Guidance Topic III A &VHA 1200.5§3(a)(2)

  15. Related Adverse Event • Caused or possibly caused by research procedures… Related • Solely caused by underlying disease, condition, treatment… Unrelated • Solely caused by circumstances other than research, disease… Unrelated OHRP Guidance Topic III B

  16. Greater Risk of Harm If… • Research places subjects or others at greater risk of physical or psychological harm than was previously known or recognized • Serious adverse events always pose greater risk of harm OHRP Guidance Topic III C

  17. Death Life threatening experience Hospitalization or prolongation of hospitalization Persistent or significant disability or incapacity Congenital anomaly and/or birth defects Event that jeopardizes the subject and may require medical or surgical treatment to prevent one of the preceding outcomes Serious Adverse Event (SAE) VHA 1200.5§3(a)(1)

  18. Death Life threatening adverse drug experience Hospitalization or prolongation of hospitalization Persistent or significant disability/ incapacity Congenital anomaly/ birth defect Important medical events that… may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed... Serious Adverse Drug Experience 21 CFR 312.32(a)

  19. “Important medical event…” • allergic bronchospasm requiring intensive treatment in an emergency room or at home • blood dyscrasias or convulsions that do not result in inpatient hospitalization • development of drug dependency or drug abuse 21 CFR 312.32(a)

  20. Navigating the Roadway… Inadequate Control Poor local management of adverse events 

  21. Navigating the Roadway… Over-regulation  Volume of information provided to IRB can hamper detection of important “signals” from background “noise”

  22. Reporting Adverse Events to the IRB

  23. Federal Regulations “… prompt reporting… to the IRB… any unanticipated problems involving risks to subjects or others…” Common Rule

  24. Investigator Responsibilities Serious Adverse Events and/or Unanticipated Adverse Events must be reported to the IRB and other required entities… VHA 1200.5§10(f)

  25. ORO Interpretation “Any research-related problems involving risks that are not anticipated in terms of nature, severity, or frequency of occurrence… must be reported promptly to the IRB.” [§5(a)] Reporting Unanticipated Problems and Adverse Events to the IRB VA ORO Memorandum; December 6, 2006

  26. Data Monitoring Plan • The Plan needs to include procedures for reporting AEs • Spectrum of events that might occur • Time frame for reporting • Stopping rules when action is needed • The Plan must be approved by the IRB VHA 1200.5§7(a)(6) & OHRP Guidance Topic VI

  27. Continuing Review The investigator must submit to the IRB a written progress report that includes: • Information that may impact on risk benefit ratio: summary of AEs (Adverse Events) and UPs (Unanticipated Problems) • An assurance that all AEs and UPs have been reported as required • DSMB/DMC reports if applicable VHA 1200.5§7(g)

  28. IRB Authority • IRBs must have SOPs that provide detailed instructions on how to report and manage AEs • IRBs have flexibility in establishing local adverse event reporting requirements. • Investigators must comply with the reporting requirements of the IRB.

  29. Adverse Event Report IRB establishes investigator reporting requirements that • Provide adequate protection • Minimize the volume • Are easy to follow

  30. ORO Guidance “A popular strategy employed by many facilities involves requiring a certain degree of ‘over-reporting’ by investigators and the use of triage mechanisms to determine which of the items reported by the investigator must actually be reviewed by the convened IRB.”[§7(a)] ORO 12-6-06 Memo

  31. ORO Guidance “ORO strongly recommends against allowing investigators to make all of the… determinations… as this may result in un-reviewed problems that cause harm to future subjects.”[§7(f)] ORO 12-6-06 Memo

  32. What to put in a report • Appropriate identifying information • Complete, detailed description of event • Analysis of the event with respect to criteria for reportable events • Nature, severity, frequency • Relationship to participation • Expected risk profile • Actions taken, if any

  33. External Adverse Events Individual adverse events occurring at other centers should only be reported to investigators and IRBs at all institutions if they meet the criteria for a reportable unanticipated problem. OHRP Guidance Topic IV B

  34. Reporting External AEs Investigator’s report to the local IRB should include • reason it was determined to be an unanticipated problem • description of changes/actions to be taken in response to the problem OHRP Guidance Topic IV B

  35. Institutional Officials • Institutions must have written procedures for reporting problems to appropriate institutional officials. 45 CFR 46.103(a)

  36. Reporting Adverse Events to the Federal Agencies Office of Human Research Protection

  37. Federal Regulations “… to… appropriate institutional officials and the department or agency head any unanticipated problems involving risks to subjects or others…” Common Rule

  38. IRBs are also responsible for ensuring that reports of unanticipated problems involving risks to human subjects or others are reported to the FDA. Usually, this reporting is accomplished through the normal reporting channel, i.e., the investigator to the sponsor to FDA. FDA Information Sheets: Continuing Review after Study Approval 3(b)

  39. Investigational New Drug Safety Reports: “The sponsor shall notify FDA and all participating investigators in a written IND safety report of… any adverse experience associated with the drug that is both serious and unexpected…” • Report due within 15 calendar days 21 CFR 312.32(c)

  40. FDA Form 3500A http://www.fda.gov/medwatch

  41. An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated adverse device effect occurring during an investigation as soon as possible, but in no event later than 10 working days after the investigator first learns of the effect. 21 CFR 812.150(a)(1)

  42. A sponsor who conducts an evaluation of an unanticipated adverse device effect shall report the results of such evaluation to FDA and to all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect. 21 CFR 812.150(b)(1)

  43. For FDA-regulated device studies, user facilities must report suspected medical device-related deaths to both the FDA and the manufacturer. Serious injuries must be reported to the manufacturer or the FDA if the manufacturer is unknown. 21 CFR 803.30(a)

  44. Office of Human Research Protection • Report any unanticipated problems involving risks to subjects or others. • Report should include • Project identification • Description of problem • Action plan • Report “promptly” 45 CFR 46.103(b)(5)

  45. Office of Human Research Protection START www.hhs.gov/ohrp Policy and Guidance  Incident Reporting  Reporting Incidents to OHRP Do NOT report Report to OHRP

  46. ORO VHA Handbook 1058.1 Reporting Adverse Events in Research to the Office of Research Oversight 11/19/04 VA Memorandum What to Report to ORO 9/8/05

  47. Report AE or imminent threat of AE that results in: • IRB taking substantive action, e.g. change in protocol, restriction, suspension or termination of a study (within 10 days) • An unexpected death regardless of IRB action (within 24 hours) Report using VA Form 10-0420 VHA Handbook 1058.1§6(a)

  48. In conclusion… “IRBs are not policing bodies, watchdogs, or auditing agents. They were established to weigh the risks the proposed research may pose to the research subjects against the benefits the research may offer to the patient and society. IRBs were established to work collaboratively with investigators, the vast majority of whom are altruistically motivated and intend to do the right thing.” Robert Levine, M.D. Testifying before Congress, June 11, 1998

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