1. Reportable Events in Research Nancy C. LeGros Vinson & Elkins LLP Houston, TX Nancy C. LeGros Vinson & Elkins LLP Houston, TX 2885446

2. Background

3. 3 Office for Human Research Protections OHRP is an administrative unit within DHHS Public Health Service Act mandates that DHHS develop and implement a program to:  Obtain advance assurances from institutions that they will establish an IRB to protect human subjects;  Provide compliance oversight and guidance on ethical issues in biomedical or behavioral research. Program applies to all human subjects research supported by any federal agency

4. 4 OHRP Human Subject Assurance Federalwide Assurance is a legally binding document that commits an institution to complying with federal standards for the protection of human subjects in clinical trials  Must provide for IRB review, approval and ongoing review of all human subjects research  Assurance includes the policies and procedures of the institution’s IRB

5. 5 OHRP Human Subject Assurance Assurance must provide for prompt reporting to IRB of :  Unanticipated problems involving risks to research subjects or others  Serious continuing noncompliance with:  Federal policies for protection of human subjects  Requirements or determinations of IRB  Suspension or termination of IRB approval must be reported to institutional officials and to applicable federal agencies

6. 6 OHRP Compliance Oversight OHRP conducts complaint investigations and not-for cause investigations  Not for cause investigations can be triggered by a relatively low number of reports of unanticipated problems or noncompliance Findings of investigation published on OHRP website Based on noncompliance with assurance, OHRP can:  Suspend all research conducted under assurance  Require notice of an institution’s or investigator’s past noncompliance to DHHS scientific peer review groups prior to review of new projects  Debar an institution or investigator from all government programs

7. 7 FDA Office of Human Research Trials FDA Bioresearch Monitoring Program (BIMO)  Program of on-site inspections/data audits of clinical investigators, research sponsors, and IRBs involved in INDs to monitor compliance  FDA requirements for protection of human subjects similar to DHHS requirements  No assurance process or registration of IRBs  IRB responsible for review of study designated in IND application

8. 8 OHRT Inspections Based on noncompliance with FDA requirements, agency can :  Withhold approval of new studies conducted at the institution or reviewed by the IRB  Direct that no new subjects be added to ongoing studies  Terminate ongoing studies  Notify regulatory agencies/other parties of the deficiencies in the operation of an IRB  Disqualify institution or IRB  FDA will not approve an application for a research permit  May refuse to consider data from disqualified institution in agency’s consideration of a marketing permit application

9. 9 Other Considerations Litigation

10. The Methodist Hospital Research Institute Official Procedure Reportable Events in Research Official Procedure Reportable Events in Research

11. 11 Official Reporting Procedure Applies to all investigators conducting or participating in research at a Methodist facility or using The Methodist Hospital Research Institute (TMHRI) IRB or Institutional Biosafety Committee (IBC)

12. 12 Reportable Events Serious adverse events Unexpected adverse events Unanticipated problems that involve risks to subjects or others Unanticipated adverse device effects Protocol deviations

13. 13 Definition – Adverse Events Adverse Event: any undesirable experience concerning the health of a participant during human subject research, whether or not it is considered related to the study intervention Examples of common adverse events include:  Neutropenia  Opportunistic infections  Gastric disturbances  Skin rashes  Headaches

14. 14 Definition – Serious Adverse Events Serious Adverse Event (SAE): any adverse event that results in death, life threatening adverse experiences, hospitalization or prolongation of hospitalization, disability or incapacitation, overdose, congenital anomalies, and any other serious events that may jeopardize the subject or require medical or surgical intervention to prevent one of the above outcomes.

15. 15 Definition – Unexpected Adverse Event Unexpected Adverse Event: any adverse event that occurs with more frequency or greater severity than expected or described in the investigator brochure, package inserts, protocol, and/or informed consent form.  Unexpected = Unanticipated

16. 16 Definition – Unanticipated Adverse Devise Effect Unanticipated Adverse Device Effect: 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 (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of subjects.

17. 17 Example - Adverse Event Anticipated: A subject in a trial evaluating the safety and efficacy of a new investigational anti-inflammatory agent for osteoarthritis develops severe abdominal pain and nausea one month after randomization. Subsequent medical evaluation reveals gastric ulcers. The investigator learns that the subject received the active investigational agent. The protocol and informed consent document indicated a 10% chance of mild to moderate gastritis and a 2% chance of gastric ulcers for subjects assigned the active investigational agent. The investigator withdraws the subject from the study. A review of subject data shows the incidence of gastritis and gastric ulcers were within expected frequency.

18. 18 Example- Adverse Event Unanticipated : A behavioral researcher conducts a study in which college students complete a survey about early childhood experiences. The research was judged to involve no more than minimal risk and was approved under expedited review. While completing the survey, one student had a psychological reaction that involved sadness and depressed mood. The informed consent document did not describe this risk. Further evaluation revealed that the subject’s reaction resulted from certain questions that reminded him of physical abuse as a child. The investigator had not anticipated such a reaction.

19. 19 Example - Unanticipated Adverse Event Unanticipated : Subjects with coronary artery disease presenting with unstable angina are enrolled in a trial evaluating the safety and efficacy of an investigational vascular stent. Based on prior studies, it is anticipated that up to 5% of subjects receiving the investigational stent will require emergency coronary artery bypass graft surgery because of acute blockage of the stent that is unresponsive to non-surgical interventions. The risk of needing emergency CABG surgery is included in the informed consent. After the first 20 subjects are enrolled, the investigators note that 10 subjects have needed to undergo the emergency CABG surgery soon after placement of the stent.

20. 20 Example – Unexpected Adverse Event Unexpected: Subjects with essential hypertension are enrolled in a trial testing a new investigational antihypertensive drug. When the trial is initiated, there is no evidence of gastro esophageal reflux disease (GERD) associated with the investigational drug. Three of the first ten subjects develop severe GERD symptoms within one week of starting the investigational drug, which are resolved a few days after drug was discontinued. PI determines that the GERD symptoms were most likely caused by the investigational drug, may alter the IRB’s risk:benefit assessment, and warrant modification of the informed consent document.

21. 21 Example – Serious Adverse Event Anticipated: A subject participating in a trial comparing the safety and efficacy of a new chemo agent combined with the current standard chemo regimen versus a placebo combined with the current standard chemo regimen for the management of multiple myeloma develops neutropenia and sepsis, subsequently develops multi-organ failure, and dies. This is a known complication of the chemo regimens being tested. Investigators conclude the death was directly related to the study interventions. A review of subject data reveals that the incidence of neutropenia, infection, and death are within expected frequency.

22. 22 Example – Serious Adverse Event Unanticipated: A subject with seizures enrolls in a trial comparing a new investigational anti-seizure agent to a standard, FDA-approved anti-seizure medication. The subject is randomly assigned to receive the investigational agent. One month after enrollment, the subject is hospitalized with severe fatigue and is noted to have severe anemia. Evaluation suggests an immune- mediated hemolytic anemia. The known risk profile of the investigational agent does not include anemia and the informed consent document does not identify anemia as a risk. Investigators determine that the hemolytic anemia is possibly due to the investigational agent.

23. 23 Examples of Unanticipated Adverse Device Effects Pacemaker malfunction occurs after less than the expected service life resulting in the replacement of the device in subjects An external defibrillator fails to deliver the programmed level of energy due to malfunction Patient undergoing endometrial ablation of the uterus suffers burns to adjacent organs due to thin uterine walls

24. 24 Unanticipated Problems That Involve Risks to Subjects or Others Whenever an investigator determines that there may be an unanticipated change to the risk/benefit ratio of the research Improper disclosure of confidential information/lost or stolen confidential information Complaint from participant or family member that indicates an unanticipated risk Laboratory or medication errors Changes in FDA labeling or withdrawal from marketing (due to adverse consequences) of drug, device or biologic used in protocol

25. 25 Reporting Adverse Events to IRB Unanticipated Adverse Device Effects should be reported to the IRB and the study sponsor within 72 hours Drugs and biologics:  For Methodist patients and external patients in a study for which Methodist is the Coordinating Center:  All Serious and/or Unexpected Adverse Events, regardless of relationship, must be reported within 72 hours of being known  All fatal or life-threatening events must be reported immediately

26. 26 Reporting Adverse Events to IRB For non-Methodist patients when Methodist is not the Coordinating Center, but is part of a multi-site protocol:  An Adverse Event that is both Serious AND Unexpected and which, in the opinion of the PI, more likely than not is related to the research procedures, must be reported within 10 days Unanticipated problems that involve risks to subjects or others:  As soon as an Investigator becomes aware of them

27. 27 Required Written Reports to IBC PIs shall submit a written report to the IBC and the NIH Office of Biotechnology Activities (OBA) on the following events:*  Any SAE that is fatal or life-threatening, unexpected, and associated with the use of the gene transfer product, not later than 7 days after initial receipt of information  Any SAE that is unexpected and associated with the use of the gene transfer product, but is not life-threatening, not later than 15 days after initial receipt of information  Any Adverse Event initially thought not to be associated with the use of the gene transfer product, but subsequently determined to be associated, within 15 days of the determination  Any follow-up information relevant to a SAE, within 15 days * In accordance with NIH Guidelines for Research Involving Recombinant DNA Molecules

28. 28 Required Written Reports to IBC PIs shall submit a written report on the following events within 15 days:  If a SAE occurs after a trial ends and is determined to be associated with the use of the gene transfer product  Any finding from tests in lab animals that suggests a significant risk for human research participants  Any research-related accidents/spills involving hazardous agents or recombinant DNA materials  No additional report to OBA required if accident/spill involves hazardous chemicals

29. 29 Submitting Reports to TMHRI PIs must complete an “Adverse Event Report Form” and an “Adverse Events Table”  If protocol is maintained in MORTI system, PIs must submit a Reportable Event within this system  Information such as a summary of the event, the Coordinating Center, or drug company reports may be attached to the forms PIs should indicate on the Adverse Event Report Form whether the event is possibly related to the test article Any other individual may report an event, issue, or situation for a research protocol that they are concerned represents an Unanticipated Problem or Adverse Event

30. 30 Definition – Protocol Deviations Protocol Deviation: an inconsistency in a research study between the protocol that has been reviewed and approved by the IRB and the actual activities being done Common examples of protocol deviations include:  Enrollment of subjects outside protocol inclusion/exclusion criteria  Failure to perform certain study-related tasks or follow-up visits  Exceeding IRB-approved enrollment numbers

31. 31 Reporting Protocol Deviations to IRB Protocol deviations in emergency situations  An investigator may deviate from the clinical protocol to protect the life or physical well-being of a subject in emergency situations  Investigator shall notify the IRB as soon as possible, but no later than 5 working days after the deviation occurred Protocol deviations in non-emergency situations  An investigator must receive approval from the study sponsor or the IRB (for Investigator-initiated studies) prior to implementing changes in the investigational plan when the changes may affect the:  Scientific soundness of the plan; or  Rights, safety, or welfare of human subjects

32. 32 Reporting Protocol Deviations to IRB Forms:  Investigators shall complete a “TMHRI IRB Protocol Deviation Form” (accessible in paper format or online)  If the protocol exists within the Methodist Online Research Technology Initiative (MORTI) system, the deviation should be submitted electronically to the IRB through this system Investigators shall keep records of all Protocol Deviations, which state the dates of and reasons for the deviations

33. 33 Corrective and Preventive Actions In addressing an Adverse Event, a protocol deviation, or a potential Unanticipated Problem, the IRB or IBC may take any action authorized by law or regulation Actions include, but are not limited to:  Initiate immediate corrective action  Delegate a subcommittee to perform further investigation  Require modification of recruitment and informed consent procedures  Alter the frequency of continuing review  Suspend or terminate protocol  Report to institutional officials and OBA  Suspend PI or investigators  Report information to sponsors and/or appropriate regulatory agencies

34. 34 Withdrawal of Approval by IRB or IBC A PI or other investigator shall report to the study sponsor, within 5 working days, any withdrawal of approval of the research study or the investigator’s part of the study

35. Enforcement Efforts/Litigation

36. 36 University of Pennsylvania FDA investigated Penn’s research of gene therapy to treat ornithine transcarboxylase deficiency (OTCD) after the death of 18 year old Jesse Gelsinger in Sept. 1999 Investigation uncovered serious deficiencies in how the study was being conducted, including researcher’s failure to:  Submit protocol revisions to the FDA  Incorporate changes into the protocol agreed upon with the FDA  Immediately report the occurrence of adverse reactions  Update informed consent when requested to do so by the FDA  Provide potential subjects with new info. regarding risks  Ensure the eligibility of patients before enrolling them in the study  Gelsinger’s high ammonia levels should have excluded him

37. 37 University of Pennsylvania, cont. Based on findings from the FDA investigation:  OTCD trial was immediately shut down  All of Penn’s INDs were placed on a clinical hold until adequate standard operating procedures were developed and reviewed by the FDA Penn settled a civil suit with Gelsinger’s family in 2000 and settled with the federal government in 2005

38. 38 Johns Hopkins University OHRP launched investigation into human subject protection systems at Johns Hopkins after 24-yr-old Ellen Roche died after inhaling hexamethonium in a study of severe, life-threatening asthma in July 2001 Deficiencies relating specifically to asthma study included:  Failure of Johns Hopkins’ two IRBs to look closely enough into the history of hexamethonium, which is known to cause lung damage  Failure to promptly report unanticipated adverse events to officials  Two patients had suffered lung problems before Roche  Failure to seek IRB approval of protocol deviations A total of 31 research-related deficiencies were identified  24 unrelated to the asthma study

39. 39 Johns Hopkins, cont. General concerns included such findings as:  Failure by the IRB to ensure minimal risks to subjects  Failure to adequately describe research procedures and foreseeable risks in consent forms  “Laxness” in following IRB procedures, such as:  Failure to conduct initial review of research not eligible for expedited review  Failure to conduct substantive review of ongoing research  Failure to prepare and maintain documentation of IRB activities  Using expedited procedures when not appropriate  Issuing approval letters to investigators prior to receiving and confirming adequacy of IRB required revisions

40. 40 Johns Hopkins, cont. July 19, 2001, OHRP ordered Johns Hopkins to suspend all federally funded research until plans of corrective action were developed and approved July 21, 2001, Johns Hopkins submitted plan of correction  Engaged an outside consultant to develop standard guidelines for literature searches to ensure minimal risks  Launched an education effort to reinforce requirement that protocol deviations be approved by the IRB  Developed an informed consent form checklist for investigators  Instituted an education program addressing adverse event reporting Also developed an “IRB 101” educational plan with OHRP  Mandatory for all IRB members and staff

41. 41 Johns Hopkins, cont. July 22, 2001, OHRP accepted the plan of correction Effective immediately:  Federally funded research allowed to resume if eligible for expedited review, or reviewed and approved by an IRB at a convened meeting  All other research remained suspended until an IRB could review and approve the research at a convened meeting  Essentially, IRBs were required to “re-review’ most protocols  Affected Johns Hopkins institutions required to submit monthly progress reports to OHRP about implementation of correction plans

42. 42 Tufts University School of Medicine FDA put four gene therapy studies at St. Elizabeth’s Medical Center (associated with Tufts) on clinical hold after PI Dr. Isner failed to promptly report deaths of two volunteers  Studies sought to use gene therapy to reverse heart disease  At least one death may have been related to study treatment St. Elizabeth’s submitted plan of correction in Feb. 2000  Enhancement of IRB responsibilities, especially with respect to reviewing and reporting adverse events  Development of a training program relating to adverse event reporting  Updating of all adverse events associated with gene therapy research conducted by Dr. Isner  Simplification of documentation of IRB policies