1. Paula Peyrani, MD Division of Infectious Diseases University of Louisville p0peyr01@louisville.edu Performing the Study

2. OUTLINE AE, SAE, UPIRSO Follow-up visits Data collection and Data quality

3. AE, SAE, UPIRSO AND MORE Adverse event Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research.

4. AE, SAE, UPIRSO AND MORE Adverse event External Internal AE experienced by subjects enrolled by investigators in other study sites AE experienced by subjects enrolled at the investigator’s sites

5. AE, SAE, UPIRSO AND MORE Serious Adverse Event  Results in death  Life-threatening  Requires inpatient hospitalization or prolongation of existing hospitalization  Results in a persistent or significant disability/incapacity  Results in a congenital anomaly/birth defect

6. AE, SAE, UPIRSO AND MORE Serious Adverse Event  Any other adverse event that may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition (e.g. allergic bronchospasm requiring intensive treatment in the emergency room or at home)

7. AE, SAE, UPIRSO AND MORE Unanticipated Problem Involving Risks to Subjects or Others Any incident, experience, or outcome that meets all of the following criteria:  Unexpected (not in the consent form, sponsor brochure, or labeling; not expected as part of subject’s disease or condition  Related or possibly related to study participation  Research places subjects or others at a greater risk of harm

8. AE, SAE, UPIRSO AND MORE Unexpected event Any adverse event occurring in study subjects where the specificity and severity of the event are NOT consistent with the information provided in the IRB-approved research protocol, any applicable investigator brochure, the current IRB-approved informed consent document, and any other relevant sources of information, such as product labeling and package inserts

9. WHAT NEEDS TO BE REPORTED TO THE IRB? Only when a particular local adverse event or series of adverse events is determined to meet the criteria for an UPIRTSO should a report of the adverse event(s) be submitted to the UofL IRBs under the HHS regulations.

10. AE that are NOT unanticipated problems AE that are NOT unanticipated problems Unanticipated problems that are not AE Unanticipated problems that are not AE AE that are unanticipated problems Unanticipated problems A A B B C C WHAT NEEDS TO BE REPORTED TO THE IRB?

11. A AE that are NOT unanticipated problems A AE that are NOT unanticipated problems Unanticipated problems that are not AE Unanticipated problems that are not AE AE that are unanticipated problems Unanticipated problems Do not report REPORT B B C C WHAT NEEDS TO BE REPORTED TO THE IRB?

12. AE, incident, experience or outcome Is the event unexpected in nature, severity of frequency? NO Is the event related or possibly related to participation in the study? NO Does the event suggest that the research places subject or others at a greater risk of harm? NO STOP Not a UPIRSO STOP Not a UPIRSO YES SAE This is a UPIRTSO WHAT NEEDS TO BE REPORTED TO THE IRB? REPORT

13. Do adverse event that are not unexpected need to be reported to the IRB? WHAT NEEDS TO BE REPORTED TO THE IRB? Do adverse event that are not unexpected need to be collected?

14. Most of the adverse events seen during clinical trials will not be a SAE or UPIRTSO Although not reported to the IRB, still need to be collected in CRFs and they will be reviewed by study monitor WHAT NEEDS TO BE REPORTED TO THE IRB?

15. Promptly report UPIRSO Incorrect labeling of study medication/test article Incorrect dosing of study medication/test article Incarceration of a subject while participating in research Suicide attempt related to participation in a research study WHAT NEEDS TO BE REPORTED TO THE IRB?

16. Key items Definitions:  What is an AE, SAE?  Related?  Expected/Unexpected? Event collection period:  Pre-treatment, during treatment, during follow-up? Unresolved AEs at end of study:  Follow until resolution?  Follow for 30 days? WHAT DO I NEED TO KNOW FROM THE STUDY PROTOCOL?

17. Key items Timing:  SAE: as soon as possible (within 24 hrs of becoming aware) Even if details are not available (follow-ups can be done)  Expected/Unexpected? Non-serious AE:  Collected in CRF  No real timing specified. WHAT DO I NEED TO KNOW FROM THE STUDY PROTOCOL?

18. Scheduling subjects for visits  If missed, may be a problem for data analysis  If missed, sponsor may not pay for the visit  Try to schedule visits at the beginning of the window period  Develop a reminder system: email, calendar, excel, phone  Complete CRF including med log and adverse events  Develop a reminder system: email, calendar, excel, phone Maximize retention: reminder calls, goodies, thank you notes, bonus gift certificates, birthday cards… FOLLOW-UP VISITS

19. Keep in mind… if you want to avoid future queries Data entered should be accurate, complete and legible Check that answers are within range, dates are correct Make sure that information makes sense If source documents will be reviewed and collected, they need to agree with the CRF Remember that if CRF is modified, this may have an impact on other data Take errors as learning tools and make sure that you understand why the modification is requested DATA COLLECTION AND DATA QUALITY

20. Internal quality assurance May have a person solely dedicated to review CRF internally Should be someone different from the person who collected the information Prepare for the monitor visit: check CRF and source document (all or part of them) Request to have a monitor visit soon after the first case/s DATA COLLECTION AND DATA QUALITY

21. Unanticipated Problems that Do Not Involve Adverse Events and Need to be Reported As a result of a processing error by a pharmacy technician, a subject enrolled in a multicenter clinical trial receives a dose of an experimental agent that is 10-times higher than the dose dictated by the IRB-approved protocol. While the dosing error increased the risk of toxic manifestations of the experimental agent, the subject experienced no detectable harm or adverse effect after an appropriate period of careful observation.

22. Adverse Events that Do Not Represent Unanticipated Problems and Do Not Need to be Reported Phase 3, randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of a new investigational anti-inflammatory agent for management of osteoarthritis Subject develops severe abdominal pain and nausea one month after randomization (gastric ulcers) The IRB-approved protocol and IC indicated that the there was a 10% chance of developing mild to moderate gastritis and a 2% chance of developing gastric ulcers for subjects assigned to the active investigational agent Subject is withdrawn from the study

23. Adverse Events that Represent Unanticipated Problems and Need to be Reported Subject with chronic gastroesophageal reflux disease enrolls in a randomized, placebo- controlled, double-blind, phase 3 clinical trial evaluating a new investigational agent that blocks acid release in the stomach Two weeks after being randomized and started on the study intervention the subject develops acute kidney failure Known risk profile of the investigational agent does not include renal toxicity, and the IRB-approved protocol and IC for the study does not identify kidney damage as a risk of the research.

24. References 1. Woodin K. The CRC’s Guide to Coordinating Clinical Research. Thompson Centerwatch. 2004 2. University of Louisville. Investigator’s Guide for Human Research. Version November 29, 2010.