Unanticipated Problems Adverse Events Deviations

1. Unanticipated ProblemsAdverse EventsDeviations Lifespan February 2009

2. Outline • Regulations- OHRP and FDA • Reporting Criteria • Examples of Reportable Events • Timelines for Reporting • IRB Review of Reportable Events Lifespan February 2009

3. OHRP Regulations and Guidance HHS regulations 45 CFR part 46. OHRP considers unanticipated problems, in general, to include any incident, experience, or outcome that meets all of the following criteria: • unexpected (in terms of nature, severity, or frequency in relation to the research procedures that are described in the IRB-approved research protocol and informed consent document and the characteristics of the subject population being studied; • related or possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and • suggests that 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) Lifespan February 2009

4. FDA Regulations and Guidance FDA’s recent guidance for Reporting AEs to IRBs in clinical trials of drugs and biological products: • “…AE’s observed during the conduct of a study should be considered an unanticipated problem involving risk to human subjects, and reported to the IRB, only if it were unexpected, serious, and would have implications for the conduct of the study (e.g., requiring a significant and usually safety-related, change in the protocol such as revising inclusion/exclusion criteria or including a new monitoring requirement, informed consent, or investigator’s brochure). An individual AE occurrence ordinarily does not meet these criteria because, as an isolated event, its implications for the study cannot be understood.” Lifespan February 2009

5. FDA Regulations and Guidance FDA’s recent guidance for Reporting AEs to IRBs in clinical trials of devices “The investigational device exemption (IDE) regulations define an unanticipated adverse device effect (UADE) as “any serious adverse effect on health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application…, or any other unanticipated serious problem associated with a device that relates to the rights safety, or welfare of subjects” UADEs must be reported by the clinical investigator to the sponsor and the reviewing IRB.” Lifespan February 2009

6. FDA Regulations and Guidance • For device studies investigators are required to submit a report of a UADE to the sponsor and the reviewing IRB as soon as possible, but in no event later than 10 working days after the investigator first learns of the event. • Sponsors must immediately conduct an evaluation of a UADE and must report the results of the evaluation to FDA and all reviewing IRBs and participating investigators within 10 working days after the sponsor first receives notice of the effect Lifespan February 2009

7. FDA and OHRP Both the FDA and OHRP agree that adverse event reports for an isolated incident are meaningless to the IRB unless accompanied by an evaluation as to whether there has been an increase in risk which requires changes in protocol documents, the monitoring process or a corrective action. Lifespan February 2009

8. What must I report to the IRB? • Unanticipated problems which are serious, related to the study and involve increased risk to subjects or others must be reported to the IRB. • Most Adverse Events are not reportable as unanticipated problems Lifespan February 2009

9. What must I report to the IRB? Unanticipated problems which suggest that 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. • No events like this have occurred that you’re aware of; • None of the research documents, ICD, protocol, IB, etc., lists this type of event as a probability or possibility • The event is going to require changes to one of the research documents or you will be putting some corrective action in place to monitor the study because of this event, e.g., a change to the consent process, a change in your DSMP, etc. Lifespan February 2009

10. What is an unanticipated AE? Any Adverse Experience, which is not described (including specificity, severity and frequency) in the current Investigator Brochure (IB), the risk information in the general investigational plan, ICD, or any documents in the current application. • For example, under this definition, • Hepatic necrosis would be unexpected (by virtue of greater severity) if the investigator brochure only referred to elevated hepatic enzymes or hepatitis. • cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure only listed cerebral vascular accidents. Lifespan February 2009

11. What does RELATED to the research study mean? An event is “possibly related,” if there is a reasonable possibility that the event is more likely than not to have been caused by the research article or procedure. In general, adverse events that are determined to be at least partially caused by the research article or procedure would be considered related to participation in the research. This can sometimes be difficult to assess. Use the examples in the P&P Manual to assist you. If you have questions or concerns call the IRB office. Lifespan February 2009

12. What Does Serious Mean? The FDA defines serious as: • Death, reportable if the patient was on active treatment and the patient's death is suspected as being a direct outcome of the adverse event. • Life-Threatening, the patient was at risk of dying at the time of the adverse event or the use or continued use of the product would result in the patient's death. • Examples: Pacemaker failure; gastrointestinal hemorrhage; bone marrow suppression; infusion pump failure which permits uncontrolled free flow resulting in excessive drug dosing. • Hospitalization (initial or prolonged) • Examples: Anaphylaxis; pseudo membranous colitis; or bleeding causing or prolonging hospitalization. Lifespan February 2009

13. What does Serious Mean? • Disability, the AE resulted in a significant, persistent, or permanent change, impairment, damage or disruption in the patient's body function/structure, physical activities or quality of life. • Examples: Cerebrovascular accident due to drug-induced hypercoagulability; toxicity; peripheral neuropathy. • Congenital Anomaly, there are suspicions that exposure to the research product prior to conception or during pregnancy resulted in an adverse outcome in the child. • Examples: Vaginal cancer in female offspring from diethylstilbestrol during pregnancy; malformation in the offspring caused by thalidomide. • Requires Intervention to Prevent Permanent Impairment or Damage, • Examples: Acetaminophen overdose-induced hepatotoxicity requiring treatment to prevent permanent damage; burns from radiation equipment requiring drug therapy; breakage of a screw requiring intervention to prevent malunion. Lifespan February 2009

14. What is an Unanticipated Problem that is not an AE? Unanticipated Problems related to the study and involving risk to subjects or others must be reported to the IRB Events that were unexpected in nature, related to participation in the research, and resulted in new circumstances that increased the risk of harm to subjects or others must be reported to the IRB. (e.g., lost or stolen laptop/thumbdrive/documents with PHI; email or letter containing PHI forwarded to wrong recipient) These events may not have actually caused harm but increased the risk for breach of confidentiality. Another type of example could be wrong dose of drug given to subject that may not have caused actual harm but was unexpected and increased the risk of harm to the participants. Lifespan February 2009

15. REPORTING AEs TO THE IRB OS/External AEs- only reportable to the IRB if the sponsor indicates that significant and safety related changes to the study documents or monitoring process are required. Local AEs- PIs must report local AEs to the Lifespan IRB which meet the reporting requirements since those have not yet undergone an evaluation in their relevance and significance to the study. (please refer back to slide 2 and Section 8 in the P&P Manual for reporting requirements) Lifespan February 2009

16. A subject with seizures enrolls in a randomized, phase 3 clinical trial comparing a new investigational anti-seizure agent to a standard, FDA-approved anti-seizure medication. The subject is randomized to the group receiving the investigational agent. One month after enrollment, the subject is hospitalized with severe fatigue and on further evaluation is noted to have severe anemia (hematocrit decreased from 45% pre-randomization to 20%). Further hematologic evaluation suggests an immune-mediated hemolytic anemia. The known risk profile of the investigational agent does not include anemia, and the IRB-approved protocol and informed consent document for the study do not identify anemia as a risk of the research. The investigators determine that the hemolytic anemia is possibly due to the investigational agent. This is an example of an unanticipated problem that must be reported because the hematologic toxicity was (a) unexpected in nature; (b) possibly related to participation in the research; and (c) serious REPORTABLE AE-REPORT TO IRB Lifespan February 2009

17. A behavioral researcher conducts a study in college students that involves completion of a detailed survey asking questions about early childhood experiences. The research was judged to involve no more than minimal risk and was approved by the IRB chairperson under an expedited review procedure. During the completion of the survey, one student subject has a transient psychological reaction manifested by intense sadness and depressed mood that resolved without intervention after a few hours. The protocol and informed consent document for the research did not describe any risk of such negative psychological reactions. Upon further evaluation, 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. The investigator had not expected that such reactions would be triggered by the survey questions. This is an example of an unanticipated problem that must be reported in the context of social and behavioral research because, although not serious, the adverse event was (a) unexpected; (b) related to participation in the research; and (c) suggested that the research places subjects at a greater risk of psychological harm than was previously known or recognized REPORTABLE AE – REPORT TO IRB Lifespan February 2009

18. How to Decide Whether or not You Should Report an Event to the IRB If an event meets the reporting criteria and warrants consideration of substantive changes in the research protocol or informed consent process/document or other corrective actions such as a change in the consent process or DSMP, in order to protect the safety, welfare, or rights of subjects, then the event must be reported to the IRB. Additional information is included in slide 2 and Section 8 of the P&P Manual Lifespan February 2009

19. The principal investigator must promptly report unanticipated problems to the IRBthat meet the reporting criteria. Examples: • An unanticipated event related to the research that exposes individual research participants or others to GREATER risk of physical or psychological harm than was previously known. (Others can include investigators, research assistants, students, the public, etc.). • Interim DSMB or Monitoring reports indicating non-compliance or other issues that could increase risk to subjects or others • Publications or new information that indicate an increase or change in the risk/benefit ratio • Warnings from the FDA or changes in FDA labeling or withdrawal of a marketed drug/device/biologic used in the study Lifespan February 2009

20. The principal investigator must promptly report unanticipated problems to the IRBthat meet the reporting criteria. • Suspension of the study or investigator by the sponsor or regulatory agency • Certain protocol deviations (see below) • Complaints from subjects that indicate a previously unrecognized risk related to the study • Incarceration of a participant in a protocol not approved to enroll prisoners who remains actively involved in the research protocol. • Breach of Confidentiality (e.g. loss of a laptop containing identifiable research data; transmittal of unencrypted study data) • Any other problems/events that impact the risk/benefit ratio of the study Lifespan February 2009

21. Deviations may be Unanticipated Problems Investigators must promptly report protocol deviations to the Lifespan IRB if the deviation was a major deviation from the protocol that adversely affected the rights and welfare of the subjects, the safety of the subjects, the integrity of the study data and/or the subject’s willingness or ability to continue study participation. • Major protocol deviations are: • Intentional deviations to eliminate an immediate hazard • Enrollment deviations • Consent deviations (signing an outdated informed consent that has had revisions since that version was approved; not signing an informed consent). • Procedural deviations that may have resulted in an increase risk to the subjects or others (dosing error; missed evaluation being used to assess subject safety or eligibility). • Protocol deviation (accidental or unintentional change to the IRB approved protocol without prior IRB approval) that harmed participants or others or that indicates participants or others may be at increased risk of harm. Lifespan February 2009

22. Local (Internal) Unanticipated problems Unanticipated problems which meet the reporting criteria must be reported to the IRB. Regardless of whether or not the internal adverse event is reportable to the IRB: • the investigator must ensure that the adverse event is reported to the sponsor as per the agreement with the sponsor; And, • the FDA if applicable (e.g., if you are the holder of the IND or IDE), promptly, within 10 working days of the date the investigator became aware of the event. If the investigator determines that an adverse event is not an unanticipated problem, BUT the monitoring entity subsequently determines that the adverse event does in fact represent an unanticipated problem (e.g., due to an unexpectedly higher frequency of the event, the monitoring entity should report this determination to the investigator and the investigator should promptly report this to the IRB. Lifespan February 2009

23. What about External AEs? Other Site (OS or External) AEs whichmeet the reportable criteria and require a significant change to the protocol, (such as revising the Inclusion/Exclusion criteria, monitoring procedures, change in the informed consent or investigator brochure) must be reported to the IRB and must be accompanied by: (1) a clear description of why the AE or series of AE was determined to be an unanticipated problem; and (2) a description of any proposed protocol changes or other corrective actions to be taken by the investigators in response to the unanticipated problem. If all of these criteria are met the report should be forwarded to the IRB within 10 working days of the date the investigator became aware of the event. Lifespan February 2009

24. How Soon Do I Have To Report the Problem/AE? Only Reportable Unanticipated Problems or Adverse Events have a timeline. • Reportable events must be reported to the IRB within 10 working days from the time you became aware of the event. Lifespan February 2009

25. REPORTING LOCAL FATALITIES ALL Local fatalities, occurring with subjects on Active Treatment whether related or unrelated, must be reported to the IRB within 24 hours of the investigator becoming aware of the event. This 24 hour notification may be via phone, fax, email or report form and should be followed by a written report as soon as possible. Any (related) local fatality must be reported to the sponsor and the FDA, if applicable. Lifespan February 2009

26. Sponsored Required but Otherwise not Reportable • If an adverse event does not meet the reportable criteria but the sponsor requires they be reported to the IRB, these reports may be submitted on the “Sponsor Required but Otherwise Not Reportable Event Form (AE3)” • Sponsored Required (AE3) reports will be acknowledged as being received by the IRB office. (The report form will be stamp dated received). An acknowledged copy of the report form only (not attachments) will be sent back to the investigator. These reports may be submitted in report form accompanied by a Sponsor Required Form page completed as indicated on the form. Lifespan February 2009

27. IRB REVIEW OF REPORTABLE EVENTS • A report of an unanticipated problem involving risks to participants or others will be immediately forwarded by the research review committee (IRB) Office staff to the IRB Chair or designee if the IRB Office staff believes that immediate intervention may be required to protect participants or others from serious harm. • Upon receipt of a report of a possible unanticipated problem from someone other than the investigator or study staff, the IRB manager will notify the PI on the study when appropriate Lifespan February 2009

28. IRB REVIEW OF REPORTABLE EVENTS Local Reports: If the reviewer considers that either • (1) the problem was foreseen OR • (2) no participants or others were harmed AND participants or others are not at increased risk of harm (e.g. the PI did not indicate changes were to be made to the protocol, ICD, IB, etc.), the reviewer signs the report form and does not check the box requesting further information or review by the full board. The reviewer returns the signed report to the Review Committee office and a copy of the form is forwarded to the investigator. The original signed form is filed in the study file in the Review Committee office. Lifespan February 2009

29. IRB REVIEW OF REPORTABLE EVENTS • If the unanticipated problem was deemed by the chair or designee to put subjects at risk based on the information received from the investigator, the IRB Chair or designee may suspend research to ensure protection of the rights and welfare of participants. Suspension directives made by the IRB Chair or designee must be reported to a meeting of the convened IRB. • All reported unanticipated problems where subjects or others were placed at a greater risk than was previously known or recognized will be reviewed at a convened IRB meeting. Lifespan February 2009

30. IRB REVIEW OF REPORTABLE EVENTS If the IRB finds that the event is an unanticipated problem involving risks to participants or others, according to the definition in the policy, the IRB may recommend any of the following actions: • Require modifications to the protocol • Reconsider approval and/or revise the continuing review timetable • Modify the consent process and/or consent form document • Provide additional information to current and/or past participants (e.g. whenever the information may relate to the participant’s willingness to continue participation) • Requirement that current participants re-consent to participation • Require additional training of the investigator and/or study staff • Monitor the research and/or consent process • Referral to other organizational entities (e.g., legal counsel, risk management, institutional official) • Suspend or Terminate the research • Suspend Enrollment (recruitment) in the Research until changes are made to the protocol, consent form or any other documents as applicable • Other actions (corrective actions) Lifespan February 2009

31. The Importance of a Good Data Safety Monitoring (DSM) Plan Plans for Data and Subject Safety Monitoring describe how the researchers will monitor and review unanticipated problems, including AEs. The adequacy of the DSM plan is included in the IRBs assessment of risk to subjects during initial and continuing review. • DSM plans should describe the procedures for safety monitoring, reporting of adverse events and/or unanticipated problems involving risks to subjects or others, descriptions of interim safety reviews and the procedures planned for transmitting the results to the IRB. This description should include information regarding an independent Data and Safety Monitoring Board (DSMB), if one exists, or an explanation why an independent data safety monitor is not necessary. See Section 3.75 of the P&P Manual. • When the convened IRB reviews a DSM plan and requests modifications to the plan as presented the investigator must comply with the IRBs requests and present the revised plan to the NEXT convened IRB for review and approval. IN OTHER WORDS A STUDY MAY BE DEFERRED BECAUSE THE DSMP WAS NOT ACCEPTABLE TO THE IRB. Lifespan February 2009

32. ADDITIONAL INFORMATION/GUIDANCE Additional guidance is located in Section 8 of the HRPP Manual, http://www.lifespan.org/research/policies/docs/irbpoliciesandmanual/lifespanp&pmanual.pdf FDA’s guidance document http://www.fda.gov/Cder/guidance/OC2008150fnl.pdf OHRP’s guidance document http://www.hhs.gov/ohrp/policy/AdvEvntGuid.htm#Q1 Lifespan February 2009

33. Contacts for IRB Questions If you have any questions you can contact: • Peg McGill, Director ORA • pmcgill@lifespan.org • Patricia Houser, IRB Manager phouser@lifespan.org 444-2099 • Jacqui Poore, Sr. Coordinator jpoore@lifespan.org 444-2093 • Adrienne McParlin, TMH IRB Coordinator, • amcparlin@lifespan.org 444-3527 • Dawn Roux, RIH IRB 1 Coordinator, droux@lifespan.org, 444-7547 • Alisa Luciano, RIH IRB Panel 2 Coordinator, • alucino@lifespan.org, 444-2032 Lifespan February 2009