1. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Unanticipated Problems 15 th FERCAP International Conference 24 Nov 15 Nagasaki, Japan Bussara Sukpanichnant, CIP USAMD-AFRIMS 1

2. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Why I need to know about Unanticipated Problems? Unanticipated Problem Involving Risks to Subjects or Others (UPIRTSO) reporting requirements apply to all nonexempt human subjects research that is conducted, supported, or funded- by the U.S. Department of Health and Human Services (HHS) (e.g. NIH, CDC, FDA) by other institutes adopting the Common Rule and covered by a Federal-wide Assurances (FWA) (e.g. All U.S. Department of Defense Components) orFederal-wide Assurances covered by an FWA, regardless of funding source (e.g. Most universities that accept U.S. Federal funding, even just in part). Guidance on Reporting Incidents to OHRP 2

3. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Problem Involving Risks to Subjects or Others (UPIRTSO) Any incident, experience, or outcome that meets all of these: UNEXPECTED in terms of nature, severity, or frequency RELATED or possibly related to participation in 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 OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Event 3

4. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Example of an UPIRTSO A subject who was a control in a malaria challenge trial (so, we knew he was going to get malaria) became incarcerated at day 7. We had to walk thru the 3 steps of whether this was an UP. – Unexpected- YES – Related to participation in the research-YES – Places subjects at a greater risk of harm-YES We had to work with the prison health clinic to get him treated. 4

5. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS UP vs. UPIRTSO An Unanticipated Problem (UP) is an unexpected problem/adverse event/minor deviation- that does not mean that it caused or could have caused harm. (These are reported in the Continuing Review Report.) An Unanticipated Problem Involving Risks to Subjects or Others (UPIRTSO) is what we are about speaking. It is hereinafter referred to as an unanticipated problem or UP. 5

6. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Adverse Events (AE) An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. ICH GCP E6 6

7. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Adverse Events (AE) The HHS regulations at 45 CFR part 46 do not use the term adverse event but it is described in the ICH GCP E6 and recommended when generating clinical trial data that are intended to be submitted to regulatory authorities (e.g. US FDA). 7

8. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS UPs vs AEs Adverse Events that are NOT Unanticipated Problems Unanticipated Problems that are NOT Adverse Events that are Unanticipated Problems Adverse Events Unanticipated Problems C = A = B = 8

9. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Example an AE that is NOT an UP (Area A) A subject had a broken right arm involving a car accident on the way to work which he was not a driver. – Unexpected- YES – Related to participation in the research-NO – Places subjects at a greater risk of harm-YES 9

10. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Example an AE that is an UP (Area B) In a study in Kenya- sickle cell drug in children a child died from an aneurism (she bled to death) and it was thought that the study drug contributed. The IRB had to walk thru the 3 steps of whether this drug "caused" the death... and was thus a UP. – Unexpected- YES – Related to participation in the research-YES – Places subjects at a greater risk of harm-YES 10

11. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Examples of UPs that are not AEs (Area C) Collected individually identifiable sensitive information of subjects are stored on a laptop computer without encryption, and the laptop computer is stolen from the PI. A subject receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB- approved protocol. However, the subject experienced no detectable harm or AE. After several subjects are enrolled and receive an investigational biologic product derived from human sera. It was found that the product was obtained from donors who were not appropriately screened and tested for several potential viral contaminants e.g. hepatitis B virus. 11

12. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS UPs Reporting to IRB Investigators must promptly report the IRB when there is an AE or series of AEs which are determined to meet the criteria for an UP (Area B) OR an UP not related to adverse events (Area C). (45 CFR 46.103(b)(5)) 12

13. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Information in UP report to IRB Title and number of the research project Name of the PI Description of the event Explanation of the basis for determining that the adverse event 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 UP OHRP Guidance on Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects or Others and Adverse Event 13

14. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS IRB Review and Action When reviewing a report of an unanticipated problem, the IRB should consider whether risks to subjects are still minimized and reasonable in relation to the anticipated benefits, any action and/or a protocol amendment is required? The IRB or appropriate institutional official, is responsible for reporting UPs to the supporting HHS agency head (e.g. NIH) and OHRP. In addition it may need to report to higher level office as required by the institute policy. Guidance on Reporting Incidents to OHRP, 45 CRF 46.103(b) 14

15. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Conflict with ICH GCP? All SAEs should be reported immediately to the SPONSOR. UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS (ADR = related AEs) should be reported to the regulatory authority(ies) and the IRB/IEC. ICH GCP 4.11.1 15

16. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Take Home Messages UP Reports are required for human subjects research that is conducted or supported by most of US government institutions and other institutes covered by FWAs. All UPs must be reported promptly per 45 CRF 46. Not all AEs are UPs. (see definitions) In addition to UPs, AE and SAE must be reported per ICH GCP E6 and local requirements where applicable. 16

17. Bussara Sukpanichnant, Human Subject Protection Office, USAMD-AFRIMS Disclaimer The opinions expressed in this presentation are those of the author and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government. 17