1. Understanding Unanticipated Problems (UPs) Elizabeth Ness, RN, MS Director, Staff Development Office of the Clinical Director Center for Cancer Research, NCI

2. Objectives Define what an unanticipated problem is. Describe 2 examples of an unanticipated problem that is also an adverse event. Describe 2 examples of an unanticipated problem that is also a protocol violation. Describe 2 examples of an unanticipated problem that is not an AE or a protocol violation. Discuss potential correction plans for unanticipated problems. Describe who should be notified of an unanticipated problem.

3. Unanticipated Problem: Definition An incident, experience, or outcome that meets ALL of the following criteria: 1.Nature, severity, or frequency is unexpected for the subject population or research activities as described in the current IRB approved protocol, supporting documents, and the IC document(s) 2.Related or possibly related to participation in the research 3.Suggests the research may place the subject or others at a greater risk of harm (e.g., physical, psychological, economic, or social harm than previously recognized)

4. Applicable Regulations 45 CFR 46.103(b)(5) – written procedures for ensuring prompt reporting to IRB, appropriate institution officials… (i) any unanticipated problems involving risks to subjects or others… 21 CFR 56.108(b) – Follow written procedure for ensuring prompt reporting to the IRB, appropriate institutional officials, and FDA of (1) any unanticipated problems involving risks to human subjects or others;…. 21 CFR 312.66 – ….The investigator shall also assure that he or she will promptly report to the IRB…and all unanticipated problems involving risk to human subjects or others, ….

5. Application Guidance Documents OHRP – Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Events, January 15, 2007 – http://www.hhs.gov/ohrp/policy/advevntguid.pdf http://www.hhs.gov/ohrp/policy/advevntguid.pdf FDA – Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting to IRBs — Improving Human Subject Protection, January 2009 – http://www.fda.gov/downloads/RegulatoryInformatio n/Guidances/UCM126572.pdf http://www.fda.gov/downloads/RegulatoryInformatio n/Guidances/UCM126572.pdf

6. Unanticipated Problems Algorithm An incident, experience, or outcome Is incident, experience, or outcome unexpected in nature, severity, or frequency? Is incident, experience, or outcome related or possibly related to participation in the research? Does the incident, experience, or outcome suggest that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized? The incident, experience, or outcome is an unanticipated problem The incident, experience, or outcome is not an unanticipated problem YES NO

7. Unanticipated Problem that is also an Adverse Event… Chronic reflux disease study is evaluating a new investigational agent that blocks acid release in the stomach. Two weeks after being randomized and started on the study intervention, subject develops acute kidney failure (increase in creatinine from BL of 1.0 mg/dl to 5.0 mg/dl). Further work-up reveals no other obvious cause for acute renal failure. The investigator concludes that the episode of acute renal failure probably was due to the investigational agent. Known risk profile of the investigational agent does not include renal toxicity, and the IRB-approved protocol and informed consent document for the study does not identify kidney damage as a risk of the research.

8. …Unanticipated Problem that is also an Adverse Event… Subjects with coronary artery disease presenting with unstable angina are enrolled in a multicenter clinical trial evaluating the safety and efficacy of an investigational vascular stent. Based on prior studies in animals and humans, the investigators anticipate that up to 5% of subjects receiving the investigational stent will require emergency coronary artery bypass graft (CABG) surgery because of acute blockage of the stent that is unresponsive to non-surgical interventions. The risk of needing emergency CABG surgery is described in the IRB-approved protocol and informed consent document. After the first 20 subjects are enrolled in the study, an interim analysis notes that 10 subjects (50%) have needed an emergency CABG soon after placement of the investigational stent. The rate at which subjects have needed to undergo CABG greatly exceeds the expected rate.

9. …Unanticipated Problem that is also an Adverse Event Behavioral study involves completion of a detailed survey asking questions about early childhood experiences. During the completion of the survey, one subject experiences sadness and depressed mood that resolved without intervention after a few hours. Protocol and informed consent document did not describe any risk of such negative psychological reactions. The investigator determines that the subject’s negative psychological reaction resulted from certain survey questions that triggered repressed memories of physical abuse as a child.

10. Unanticipated Problem that is also a Protocol Violation Malfunctioning infusion pump results in study drug being given over 15 minutes versus 1 hour as specified in protocol Ineligible patient who receives protocol intervention and experiences no adverse events Subject received more drug (10-times) than per protocol but suffers no adverse events

11. Unanticipated Problem that is not an AE or Protocol Violation Individually identifiable sensitive information stored on laptop computer without encryption, and the laptop computer is stolen Product contamination with no adverse events experienced by subjects Staff member becomes ill due to odor from IV bag of investigational product but patient with no adverse events

12. Once an UP is Identified, What Happens Next – Step 1 Develop corrective action plan which can include any of the following: Revise protocol: – Modify inclusion or exclusion criteria to mitigate the newly identified risks – Implement additional procedures for monitoring subjects Suspend enrollment of new subjects Terminate the research Informed consent – Revise the IC document Provide additional information about newly recognized risks to previously enrolled subjects – Inform enrolled subjects Increase monitoring activities Encrypt laptops, no identifiable information on laptop Provide training/re-training Work with appropriate institutional officials to correct problem

13. Once an UP is Identified, What Happens Next – Step 2a Unanticipated problems must be reported to the IRB. The report must include the following: Appropriate identifying information for the research protocol, such as the title, investigator’s name, and the IRB project number Detailed description of the adverse event, incident, experience, or outcome Explanation of the basis for determining that the adverse event, incident, experience, or outcome represents an unanticipated problem Description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the unanticipated problem

14. Once an UP is Identified, What Happens Next – Step 2b Reporting to the IRB must be done “promptly” Type of Unanticipated Problem Reporting Timeline to IRB Unanticipated problems that are serious adverse events (SAE) Within 1 week of the investigator becoming aware of the event Any unanticipated problem that is not a SAE Within 2 weeks of the investigator becoming aware of the problem Based on OHRP Guidance

15. Once an UP is Identified, What Happens Next – Step 3 Also consider reporting UP to: – CC via Occurrence Reporting System (ORS) – IND/IDE Sponsor Meets criteria for IND/IDE Safety reporting by sponsor to FDA OHRP recommends that ALL UPs should be reported to appropriate institutional officials, supporting agency, and OHRP within 1 month of the IRB’s receipt of the report of the problem from the investigator.

16. Unanticipated Problem Reporting OHSRP NIH IRB OHRP Investigator CC ORSSponsor FDA

17. Additional Resources OHRP Video (25 minutes) – http://www.youtube.com/watch?v=hsUS0k3Ie_g http://www.youtube.com/watch?v=hsUS0k3Ie_g MAS Policy: Occurrence Reports – http://internal.cc.nih.gov/policies/PDF/M88-3.pdf http://internal.cc.nih.gov/policies/PDF/M88-3.pdf MAS Policy: Identification and Management of Sentinel Events – http://internal.cc.nih.gov/policies/PDF/M00-2.pdf http://internal.cc.nih.gov/policies/PDF/M00-2.pdf

18. NCI IRB Unanticipated Problem Reporting via iRIS New: Unanticipated Problem Submission Form Updated: – Expedited Adverse Event and Follow-ups Added UP questions – Deviation Violation Submission Form Added UP questions – CR Form CTCAE TermGrade# of Events since last CR Total # of Events Attribution to Research Serious?Unexpected?