New Adverse Event New Adverse Event Reporting PolicyReporting Policy

Effective September 1, 2007Effective September 1, 2007

Local adverse event Local adverse event reportingreporting• Local adverse eventsLocal adverse events are those experienced are those experienced

by subjects enrolled by the investigator(s) at by subjects enrolled by the investigator(s) at this institution or in the local community area this institution or in the local community area

• Local investigator typically becomes aware of Local investigator typically becomes aware of the event directly from the subject, another the event directly from the subject, another collaborating investigator at the same site, collaborating investigator at the same site, the subject’s healthcare provider, or an the subject’s healthcare provider, or an affiliated hospital (MMC, SJH, etc.) affiliated hospital (MMC, SJH, etc.)

Serious adverse eventSerious adverse event – is any adverse event – is any adverse event that: that:

• results in death; results in death; • is life-threatening (places the subject at is life-threatening (places the subject at

immediate risk of death from the event as it immediate risk of death from the event as it occurred); occurred);

• results in results in inpatientinpatient hospitalization or hospitalization or prolongation of existing hospitalization; prolongation of existing hospitalization; results in a persistent or significant results in a persistent or significant disability/incapacity; disability/incapacity;

• results in a congenital anomaly/birth defect; orresults in a congenital anomaly/birth defect; or• based upon appropriate medical judgment, based upon appropriate medical judgment,

may jeopardize the subject’s health and may may jeopardize the subject’s health and may require medical or surgical intervention to require medical or surgical intervention to prevent one of the other outcomes listed in prevent one of the other outcomes listed in this definition.this definition.

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

Expected Adverse EventExpected Adverse Event- any adverse - any adverse experience, the nature, severity or experience, the nature, severity or frequency of which is consistent with the frequency of which is consistent with the current investigator's brochure, risk current investigator's brochure, risk information described in the general information described in the general investigational plan, or consent form. investigational plan, or consent form.

Keep in mind, the SCRIHS reporting schedule does not relieve Keep in mind, the SCRIHS reporting schedule does not relieve

investigators of sponsor requirements to report earlier.investigators of sponsor requirements to report earlier. Expected seriousExpected serious ReportableReportable 5 5

working working daysdays

Unexpected seriousUnexpected serious ReportableReportable 48 hours48 hours

Expected non-Expected non-seriousserious

Not Not reportablereportable

Unexpected non-Unexpected non-seriousserious

Reportable Reportable IF IF definitely definitely or possibly or possibly relatedrelated

5 5 working working daysdays

NIH funded cooperative group studiesNIH funded cooperative group studies

• Often include lifetime or long-term follow-up Often include lifetime or long-term follow-up for enrolled subjects. for enrolled subjects.

• A subject who has completed on-study A subject who has completed on-study

therapy can be:therapy can be: a subject that completed a subject that completed the protocol required therapy, a subject the protocol required therapy, a subject that was removed from active treatment, a that was removed from active treatment, a subject that chose to stop treatmentsubject that chose to stop treatment

• New SCRIHS reporting guidelines for long-New SCRIHS reporting guidelines for long-term adverse event reporting as it relates to term adverse event reporting as it relates to subjects that are no longer receiving active subjects that are no longer receiving active study therapy but continue to have long-study therapy but continue to have long-term follow-up completed as per NIH term follow-up completed as per NIH protocol guidelines and requirements protocol guidelines and requirements

guidelinesguidelines• Subject must be >30 days from the last dose of any Subject must be >30 days from the last dose of any

protocol therapy.protocol therapy.

• Adverse event reporting should be consistent with Adverse event reporting should be consistent with the protocol guidelines. Individual protocol the protocol guidelines. Individual protocol guidelines will mandate the required expedited guidelines will mandate the required expedited reporting requirements. reporting requirements. – Expedited Report: Special reporting of an Expedited Report: Special reporting of an

adverse event or events directly to CTEP/NCI/NIH adverse event or events directly to CTEP/NCI/NIH within a shorter/specified time frame, usually within a shorter/specified time frame, usually ranging from 24 hours up to 10 calendar days ranging from 24 hours up to 10 calendar days based on the severity of the event(s). This does based on the severity of the event(s). This does NOT include routine follow-up or reporting to the NOT include routine follow-up or reporting to the cooperative group, although the cooperative cooperative group, although the cooperative group will receive copies of the expedited reports.group will receive copies of the expedited reports.

continuedcontinued

• If expedited reporting is required for any If expedited reporting is required for any subject in long-term follow-up- a report to subject in long-term follow-up- a report to SCRIHS must be submitted within 5 working SCRIHS must be submitted within 5 working days of the completion of the expedited days of the completion of the expedited report along with a copy of the submitted report along with a copy of the submitted expedited report.expedited report.

• Deaths of subjects in long-term follow-up: if Deaths of subjects in long-term follow-up: if unrelated to prior protocol therapy – no unrelated to prior protocol therapy – no report to SCRIHS required. report to SCRIHS required.

• All deaths deemed at least possibly related All deaths deemed at least possibly related to prior protocol therapy require reporting to prior protocol therapy require reporting under “Serious, Unexpected” guidelines under “Serious, Unexpected” guidelines regardless of length of time from last regardless of length of time from last protocol therapyprotocol therapy

Minimal Risk studiesMinimal Risk studies

• For studies involving no risk or For studies involving no risk or minimal risk, report adverse event minimal risk, report adverse event only if the event is directly related to only if the event is directly related to the study.the study.

• Minimal risk studies= exempt and Minimal risk studies= exempt and expedited studies that do not involve expedited studies that do not involve an invasive procedures, drug or an invasive procedures, drug or device.device.

Non-local Adverse Event Non-local Adverse Event Reporting PolicyReporting Policy

• Those adverse events experienced by subjects Those adverse events experienced by subjects enrolled by investigators at other institutions enrolled by investigators at other institutions engaged in a multi-center clinical trial.engaged in a multi-center clinical trial.

    • Investigators at all participating institutions learn Investigators at all participating institutions learn

of such events via reports that are distributed by of such events via reports that are distributed by the sponsor or coordinating center of the multi-the sponsor or coordinating center of the multi-center clinical trials. center clinical trials. 

• Reports of non-local adverse events represent the Reports of non-local adverse events represent the

majority of adverse event reports currently being majority of adverse event reports currently being submitted by investigators to SCRIHS. submitted by investigators to SCRIHS.

Individual non-local adverse Individual non-local adverse events should only be reported events should only be reported

to SCRIHS when a to SCRIHS when a determination has been made determination has been made that the adverse event meets that the adverse event meets

the criteria for an the criteria for an unanticipated problem.unanticipated problem.

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

subsequently report that UP to SCRIHS.subsequently report that UP to SCRIHS.

Okay, so what is an Okay, so what is an Unanticipated Problem (UP)?Unanticipated Problem (UP)?

Any incident, experience, or outcome that meets Any incident, experience, or outcome that meets allall of of the following criteria: the following criteria:

• unexpectedunexpected (in terms of nature, severity, or frequency) (in terms of nature, severity, or frequency) given (a) the research procedures that are described given (a) the research procedures that are described in the protocol-related documents, such as the IRB-in the protocol-related documents, such as the IRB-approved research protocol, IB and ICF; and (b) the approved research protocol, IB and ICF; and (b) the characteristics of the subject population being studiedcharacteristics of the subject population being studied

• related or possibly relatedrelated or possibly related to participation in the to participation in the research (research (possibly related possibly related = there is a reasonable = there is a reasonable possibility that the incident, experience, or outcome possibility that the incident, experience, or outcome may have been caused by the procedures involved in may have been caused by the procedures involved in the research)the research)

• suggests suggests that the that the research places subjectsresearch places subjects or others or others at at a greater risk of harma greater risk of harm (including physical, (including physical, psychological, economic, or social harm) psychological, economic, or social harm) than was than was previously known or recognizedpreviously known or recognized

A UP will likely warrant consideration of substantive changes A UP will likely warrant consideration of substantive changes in the research protocol and/or informed consent in the research protocol and/or informed consent

process/document or other corrective actions in order to process/document or other corrective actions in order to

protect the safety, welfare and rights of subjects or othersprotect the safety, welfare and rights of subjects or others • changes to the protocol initiated by the investigator prior changes to the protocol initiated by the investigator prior to obtaining SCRIHS approval to eliminate apparent to obtaining SCRIHS approval to eliminate apparent immediate hazards to subjectsimmediate hazards to subjects

• modification of inclusion or exclusion criteria to mitigate modification of inclusion or exclusion criteria to mitigate the newly identified risksthe newly identified risks

• implementation of additional procedures for monitoring implementation of additional procedures for monitoring subjectssubjects

• suspension of enrollment of new subjectssuspension of enrollment of new subjects

• suspension of research procedures in currently enrolled suspension of research procedures in currently enrolled subjectssubjects

• modification of ICF to include a description of newly modification of ICF to include a description of newly recognized risks recognized risks

• re-consentingre-consenting

Some UPs involve social or Some UPs involve social or economic harm instead of the economic harm instead of the physical or psychological harm physical or psychological harm

associated with adverse eventsassociated with adverse events

Some UPs place subjects or others Some UPs place subjects or others at increased at increased riskrisk of harm, but no of harm, but no

harm occursharm occurs

Unexpected adverse event Unexpected adverse event ==

the nature, severity, or frequency of which is the nature, severity, or frequency of which is notnot consistent with either:  consistent with either:  

• the known or foreseeable risk of adverse the known or foreseeable risk of adverse events associated with the procedures events associated with the procedures involved in the research that are described in involved in the research that are described in (a) protocol, applicable IB, and the current ICF, (a) protocol, applicable IB, and the current ICF, and (b) other relevant sources of information, and (b) other relevant sources of information, such as product labeling and package inserts; such as product labeling and package inserts; or or 

• the expected natural progression of any the expected natural progression of any underlying disease, disorder, or condition of underlying disease, disorder, or condition of the subject(s) experiencing the adverse event the subject(s) experiencing the adverse event and the subject’s predisposing risk factor and the subject’s predisposing risk factor profile for the adverse event.profile for the adverse event.

Majority of AEs are expected and Majority of AEs are expected and thus:thus:

--do not meet criteria of --do not meet criteria of unexpectedunexpected

--are not UPs--are not UPs

--are not reportable--are not reportable

Does the event suggest that the research Does the event suggest that the research places subjects or others at a greater risk places subjects or others at a greater risk of harm than was previously known or of harm than was previously known or

recognizedrecognized ? ?

Is it serious?Is it serious?

If event is unexpected, related or possibly If event is unexpected, related or possibly related to participation in research, and related to participation in research, and seriousserious … …

alwaysalways suggests that the research places suggests that the research places subjects or others at a greater risk of physical subjects or others at a greater risk of physical or psychological harm than was previously or psychological harm than was previously known or recognizedknown or recognized

Timeframe?Timeframe?

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

What if sponsor says they What if sponsor says they require reporting?require reporting?

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

Consequences of reporting out Consequences of reporting out of timeframe or incomplete of timeframe or incomplete reportingreporting

• PI and research staff will receive an email from PI and research staff will receive an email from SCRIHS staff reminding them of the reporting time-SCRIHS staff reminding them of the reporting time-frame requirements (mainly for local AEs of less frame requirements (mainly for local AEs of less serious nature)serious nature)

• PI receive a letter from the SCRIHS ChairmanPI receive a letter from the SCRIHS Chairman

• Review by the full SCRIHS committee who will decide Review by the full SCRIHS committee who will decide on the course of action which can include but is not on the course of action which can include but is not limited to: requesting written response from the PI, limited to: requesting written response from the PI, requesting presence of PI at next SCRIHS meeting to requesting presence of PI at next SCRIHS meeting to address the issue with the committee, scheduling an address the issue with the committee, scheduling an audit of the PI’s research, suspension of enrollment audit of the PI’s research, suspension of enrollment into one or more of the PI’s ongoing studies, and into one or more of the PI’s ongoing studies, and report of non-compliance to OHRP and/or the FDA report of non-compliance to OHRP and/or the FDA

What needs to be on a UP What needs to be on a UP report?report?• protocol title, PI name, and the SCRIHS protocol protocol title, PI name, and the SCRIHS protocol

numbernumber

• a detailed description of the adverse event, a detailed description of the adverse event, incident, or experience, and the outcomeincident, or experience, and the outcome

• an explanation of the basis for determining that an explanation of the basis for determining that

the adverse event, incident, or experience the adverse event, incident, or experience represents an UP; andrepresents an UP; and

• a description of any changes to the protocol, ICF a description of any changes to the protocol, ICF or other corrective actions that have been taken or other corrective actions that have been taken or are proposed in response to the UP (these or are proposed in response to the UP (these changes must be submitted on an Amendment changes must be submitted on an Amendment Summary Form with all of the necessary Summary Form with all of the necessary documents) documents)

What happens if a local PI What happens if a local PI independently proposes changes to independently proposes changes to the protocol or informed consent the protocol or informed consent document in response to an document in response to an unanticipated problem? unanticipated problem?

SCRIHS requires that the local PI SCRIHS requires that the local PI provide documentation of the provide documentation of the communication with the sponsor and communication with the sponsor and the outcome of such communication the outcome of such communication to SCRIHS.to SCRIHS.

SCRIHS review processSCRIHS review process• Chairman will review all UP reports Chairman will review all UP reports • Is this indeed a UP?Is this indeed a UP?• Further review by SCRIHS subcommittee or full Further review by SCRIHS subcommittee or full

SCRIHS committee at convened meetingSCRIHS committee at convened meeting• Does research still meet requirements for IRB Does research still meet requirements for IRB

approval?approval?• Are risks to subjects still minimized and Are risks to subjects still minimized and

reasonable in relation to the anticipated benefits?reasonable in relation to the anticipated benefits?• As a condition of continued approval of the As a condition of continued approval of the

research study, does SCRIHS need more detailed research study, does SCRIHS need more detailed information from the investigator(s), the sponsor, information from the investigator(s), the sponsor, the study coordinating center, or DSMB/DMC?the study coordinating center, or DSMB/DMC?

• Are we satisfied with the corrective action taken?Are we satisfied with the corrective action taken?

Changes to protocol and/or Changes to protocol and/or consent as a result of a UPconsent as a result of a UP

• Most likely will require full-board Most likely will require full-board approvalapproval

• If SCRIHS requires additional changes If SCRIHS requires additional changes in a multi-center trial, in a multi-center trial, SCRIHS will SCRIHS will request in writing that the local PI request in writing that the local PI discuss the proposed modifications discuss the proposed modifications with the study sponsor or coordinating with the study sponsor or coordinating center and submit a response or center and submit a response or necessary modifications for review by necessary modifications for review by SCRIHSSCRIHS

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

Requirements for initial SCRIHS Requirements for initial SCRIHS approvalapproval

Sufficient information regarding the risk profile Sufficient information regarding the risk profile of the proposed study, including the type, of the proposed study, including the type, probability, and expected level of severity of probability, and expected level of severity of the adverse events that may be caused by the the adverse events that may be caused by the procedures involved in the research, and how procedures involved in the research, and how the risks of the research will be minimizedthe risks of the research will be minimized

The IRB is responsible for determining if a study The IRB is responsible for determining if a study needs formal ongoing monitoring of data to ensure needs formal ongoing monitoring of data to ensure that research subjects will be protectedthat research subjects will be protected.. If the If the study presents greater than minimal risks to study presents greater than minimal risks to subjects or risks that are unforeseeable, subjects or risks that are unforeseeable, SCRIHS will likely require adequate provisions SCRIHS will likely require adequate provisions for monitoring the adverse event data for monitoring the adverse event data collected to ensure the safety of subjectscollected to ensure the safety of subjects

Adequate monitoring provisions for Adequate monitoring provisions for research involving greater than minimal research involving greater than minimal

risk must include:risk must include:• The type of data or events that are to be The type of data or events that are to be

captured under the monitoring provisions.captured under the monitoring provisions.

• The entity responsible for monitoring the data The entity responsible for monitoring the data collected, including data related to unanticipated collected, including data related to unanticipated problems and adverse events, and their problems and adverse events, and their respective roles (e.g., the investigators, the respective roles (e.g., the investigators, the research sponsor, a coordinating or statistical research sponsor, a coordinating or statistical center, an independent medical monitor, a center, an independent medical monitor, a DSMB/DMC, and/or some other entity).  DSMB/DMC, and/or some other entity). 

• The required time frames in which investigators The required time frames in which investigators must report adverse events and unanticipated must report adverse events and unanticipated problems to the monitoring entity.problems to the monitoring entity.

continuedcontinued

• The frequency of assessments (e.g., how often The frequency of assessments (e.g., how often the sponsor, DSMB/DMC, etc. will meet to review the sponsor, DSMB/DMC, etc. will meet to review the information) of data or events captured by the information) of data or events captured by the monitoring provisions. the monitoring provisions.

• Definition of specific triggers or stopping rules Definition of specific triggers or stopping rules that will dictate when some action is required by that will dictate when some action is required by the monitoring entity to ensure patient safety.the monitoring entity to ensure patient safety.

  • As appropriate, procedures for communicating As appropriate, procedures for communicating

to the IRB(s), the study sponsor, the to the IRB(s), the study sponsor, the investigator(s), and other appropriate officials investigator(s), and other appropriate officials the outcome of the reviews by the monitoring the outcome of the reviews by the monitoring entity.entity.

• Added to the ApplicationAdded to the Application

Requirements for continuing Requirements for continuing review approvalreview approval

• Confirm that any provisions under the previously Confirm that any provisions under the previously approved protocol for monitoring study data to approved protocol for monitoring study data to ensure safety of subjects have been implemented ensure safety of subjects have been implemented and are working as intendedand are working as intended

• A A report from the monitoring entity described report from the monitoring entity described in the approved protocol including:in the approved protocol including:  

1) A statement indicating what information (e.g., 1) A statement indicating what information (e.g., study-study- wide AEs, interim findings, and any wide AEs, interim findings, and any recent literature recent literature that may be relevant to the the that may be relevant to the the research) was research) was reviewed by the monitoring entityreviewed by the monitoring entity

2) The date of the review(s)2) The date of the review(s)

3) The monitoring entity’s assessment of the 3) The monitoring entity’s assessment of the information reviewedinformation reviewed

What if there is no monitoring What if there is no monitoring entity?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 What does the local PI need to submit with the continuing review?submit with the continuing review?

Two spreadsheets (one for local AEs and Two spreadsheets (one for local AEs and one for non-local AEs) with the following one for non-local AEs) with the following information about each event:information about each event:

• Description of the AEDescription of the AE

• Date the event occurredDate the event occurred

• Outcome of the eventOutcome of the event

• Determination of serious vs non-seriousDetermination of serious vs non-serious

• Determination of causality (relatedness to Determination of causality (relatedness to the research procedures)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