New Adverse Event Reporting Policy

New Adverse Event Reporting Policy Effective September 1, 2007

Local adverse event reporting • Local adverse eventsare those experienced by subjects enrolled by the investigator(s) at this institution or in the local community area • Local investigator typically becomes aware of the event directly from the subject, another collaborating investigator at the same site, the subject’s healthcare provider, or an affiliated hospital (MMC, SJH, etc.)

Serious adverse event – is any adverse event that: • results in death; • is life-threatening (places the subject at immediate risk of death from the event as it occurred); • results in inpatient hospitalization or prolongation of existing hospitalization; results in a persistent or significant disability/incapacity; • results in a congenital anomaly/birth defect; or • based upon appropriate medical judgment, may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Unexpected adverse event - any adverse experience, the nature, severity, or frequency of which is not consistent with the current investigator's brochure, risk information described in the investigational plan, or consent form. Expected Adverse Event- any adverse experience, the nature, severity or frequency of which is consistent with the current investigator's brochure, risk information described in the general investigational plan, or consent form.

Keep in mind, the SCRIHS reporting schedule does not relieve investigators of sponsor requirements to report earlier.

NIH funded cooperative group studies • Often include lifetime or long-term follow-up for enrolled subjects. • A subject who has completed on-study therapy can be: a subject that completed the protocol required therapy, a subject that was removed from active treatment, a subject that chose to stop treatment • New SCRIHS reporting guidelines for long-term adverse event reporting as it relates to subjects that are no longer receiving active study therapy but continue to have long-term follow-up completed as per NIH protocol guidelines and requirements

guidelines • Subject must be >30 days from the last dose of any protocol therapy. • Adverse event reporting should be consistent with the protocol guidelines. Individual protocol guidelines will mandate the required expedited reporting requirements. • Expedited Report: Special reporting of an adverse event or events directly to CTEP/NCI/NIH within a shorter/specified time frame, usually ranging from 24 hours up to 10 calendar days based on the severity of the event(s). This does NOT include routine follow-up or reporting to the cooperative group, although the cooperative group will receive copies of the expedited reports.

continued • If expedited reporting is required for any subject in long-term follow-up- a report to SCRIHS must be submitted within 5 working days of the completion of the expedited report along with a copy of the submitted expedited report. • Deaths of subjects in long-term follow-up: if unrelated to prior protocol therapy – no report to SCRIHS required. • All deaths deemed at least possibly related to prior protocol therapy require reporting under “Serious, Unexpected” guidelines regardless of length of time from last protocol therapy

Minimal Risk studies • For studies involving no risk or minimal risk, report adverse event only if the event is directly related to the study. • Minimal risk studies= exempt and expedited studies that do not involve an invasive procedures, drug or device.

Non-local Adverse Event Reporting Policy • Those adverse events experienced by subjects enrolled by investigators at other institutions engaged in a multi-center clinical trial. • Investigators at all participating institutions learn of such events via reports that are distributed by the sponsor or coordinating center of the multi-center clinical trials. • Reports of non-local adverse events represent the majority of adverse event reports currently being submitted by investigators to SCRIHS.

Individual non-local adverse events should only be reported to SCRIHS when a determination has been made that the adverse event meets the criteria for an unanticipated problem.

Ideally, these AEs should be submitted for review and analysis to a monitoring entity such as a Data Safety Monitoring Board or Committee (DSMB/DMC), a coordinating statistical center or the research sponsor in accordance with a monitoring plan described in the SCRIHS-approved protocol.In cases when there is no monitoring entity charged with this responsibility, it will be the responsibility of the local PI to review all of the non-local adverse events and determine which ones meet the criteria of an unanticipated problem (UP) and subsequently report that UP to SCRIHS.

Okay, so what is an Unanticipated Problem (UP)? Any incident, experience, or outcome that meets all of the following criteria: • unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol, IB and ICF; and (b) the characteristics of the subject population being studied • related or possibly related to participation in the research (possibly related = there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research) • 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

A UP will likely warrant consideration of substantive changes in the research protocol and/or informed consent process/document or other corrective actions in order to protect the safety, welfare and rights of subjects or others changes to the protocol initiated by the investigator prior to obtaining SCRIHS approval to eliminate apparent immediate hazards to subjects modification of inclusion or exclusion criteria to mitigate the newly identified risks implementation of additional procedures for monitoring subjects suspension of enrollment of new subjects suspension of research procedures in currently enrolled subjects modification of ICF to include a description of newly recognized risks re-consenting

Some UPs involve social or economic harm instead of the physical or psychological harm associated with adverse eventsSome UPs place subjects or others at increased risk of harm, but no harm occurs

Unexpected adverse event = the nature, severity, or frequency of which is not consistent with either: • the known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) protocol, applicable IB, and the current ICF, and (b) other relevant sources of information, such as product labeling and package inserts; or • the expected natural progression of any underlying disease, disorder, or condition of the subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile for the adverse event.

Majority of AEs are expected and thus:--do not meet criteria of unexpected--are not UPs--are not reportable

Does the event suggest that the research places subjects or others at a greater risk of harm than was previously known or recognized ? Is it serious? If event is unexpected, related or possibly related to participation in research, and serious … always suggests that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized

Timeframe? UPs should be reported to SCRIHS within 5 working days of the investigator becoming aware of the event.

What if sponsor says they require reporting? • What if AE does not meet the criteria for a UP and is non-reportable, per SCRIHS, but the sponsor requirements are inconsistent with our reporting policy? It would be acceptable for the PI/Study Coordinator to refer the company to the SIU policy located on the SCRIHS website. It would also be acceptable for the PI/Study Coordinator to indicate in the Case Report Form and AE log "...that the AE was not reported to the IRB per institutional policy."

Consequences of reporting out of timeframe or incomplete reporting • PI and research staff will receive an email from SCRIHS staff reminding them of the reporting time-frame requirements (mainly for local AEs of less serious nature) • PI receive a letter from the SCRIHS Chairman • Review by the full SCRIHS committee who will decide on the course of action which can include but is not limited to: requesting written response from the PI, requesting presence of PI at next SCRIHS meeting to address the issue with the committee, scheduling an audit of the PI’s research, suspension of enrollment into one or more of the PI’s ongoing studies, and report of non-compliance to OHRP and/or the FDA

What needs to be on a UP report? • protocol title, PI name, and the SCRIHS protocol number • a detailed description of the adverse event, incident, or experience, and the outcome • an explanation of the basis for determining that the adverse event, incident, or experience represents an UP; and • a description of any changes to the protocol, ICF or other corrective actions that have been taken or are proposed in response to the UP (these changes must be submitted on an Amendment Summary Form with all of the necessary documents)

What happens if a local PI independently proposes changes to the protocol or informed consent document in response to an unanticipated problem? SCRIHS requires that the local PI provide documentation of the communication with the sponsor and the outcome of such communication to SCRIHS.

SCRIHS review process • Chairman will review all UP reports • Is this indeed a UP? • Further review by SCRIHS subcommittee or full SCRIHS committee at convened meeting • Does research still meet requirements for IRB approval? • Are risks to subjects still minimized and reasonable in relation to the anticipated benefits? • As a condition of continued approval of the research study, does SCRIHS need more detailed information from the investigator(s), the sponsor, the study coordinating center, or DSMB/DMC? • Are we satisfied with the corrective action taken?

Changes to protocol and/or consent as a result of a UP • Most likely will require full-board approval • If SCRIHS requires additional changes in a multi-center trial, SCRIHS will request in writing that the local PI discuss the proposed modifications with the study sponsor or coordinating center and submit a response or necessary modifications for review by SCRIHS

For multi-center studies, only the institution at which the subject(s) experienced an adverse event determined to be an UP (or the institution at which any other type of UP occurred) must report the event to OHRP and/or the FDA.

Requirements for initial SCRIHS approval Sufficient information regarding the risk profile of the proposed study, including the type, probability, and expected level of severity of the adverse events that may be caused by the procedures involved in the research, and how the risks of the research will be minimized The IRB is responsible for determining if a study needs formal ongoing monitoring of data to ensure that research subjects will be protected. If the study presents greater than minimal risks to subjects or risks that are unforeseeable, SCRIHS will likely require adequate provisions for monitoring the adverse event data collected to ensure the safety of subjects

Adequate monitoring provisions for research involving greater than minimal risk must include: • The type of data or events that are to be captured under the monitoring provisions. • The entity responsible for monitoring the data collected, including data related to unanticipated problems and adverse events, and their respective roles (e.g., the investigators, the research sponsor, a coordinating or statistical center, an independent medical monitor, a DSMB/DMC, and/or some other entity). • The required time frames in which investigators must report adverse events and unanticipated problems to the monitoring entity.

continued • The frequency of assessments (e.g., how often the sponsor, DSMB/DMC, etc. will meet to review the information) of data or events captured by the monitoring provisions. • Definition of specific triggers or stopping rules that will dictate when some action is required by the monitoring entity to ensure patient safety. • As appropriate, procedures for communicating to the IRB(s), the study sponsor, the investigator(s), and other appropriate officials the outcome of the reviews by the monitoring entity. • Added to the Application

Requirements for continuing review approval • Confirm that any provisions under the previously approved protocol for monitoring study data to ensure safety of subjects have been implemented and are working as intended • A report from the monitoring entity described in the approved protocol including: 1) A statement indicating what information (e.g., study- wide AEs, interim findings, and any recent literature that may be relevant to the the research) was reviewed by the monitoring entity 2) The date of the review(s) 3) The monitoring entity’s assessment of the information reviewed

What if there is no monitoring entity? The local PI is responsible for reviewing and assessing all adverse events (local and non-local) and he/she is required to document all adverse events, whether reportable to SCRIHS or not.

What does the local PI need to submit with the continuing review? Two spreadsheets (one for local AEs and one for non-local AEs) with the following information about each event: • Description of the AE • Date the event occurred • Outcome of the event • Determination of serious vs non-serious • Determination of causality (relatedness to the research procedures)

Since, prior to this policy, SCRIHS did not review data monitoring plans for any of the currently approved SCRIHS studies, a review of such plans will be done at the time of CR for all studies. Therefore, it will be the responsibility of the PI to obtain the data monitoring plan (including all of the required elements) from the monitoring entity, along with the most current report, and include these items in the continuing review submission

New Adverse Event Reporting Policy