New HRPO Requirements for Reportable Events March 19, 2019 - - PowerPoint PPT Presentation

Human Research Protection Office

New HRPO Requirements for Reportable Events

March 19, 2019 Richard Guido, MD, IRB Chair Joseph Madia, MD, Regulatory Affairs Specialist

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Outline

• Regulatory basis for reporting policies
• Importance of consistency between IRBs
• Evaluation of Pitt IRB policies and IRBs

across the country

• Impact of PittPRO
• Discussion

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HHS Regulatory Requirements

Institutions engaged in human subjects research conducted or supported by HHS must have written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and any supporting department or agency head of any unanticipated problem involving risks to subjects or others (45 CFR 46.103(b)(5)).

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HHS Regulatory Requirements

For research covered by an assurance approved for federal-wide use by OHRP, HHS regulations at 45 CFR 46.103(a) require that institutions promptly report any unanticipated problems to OHRP.

Unanticipated Problems Involving Risk To Subjects or Others

[OHRP Guidance (2007)]

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

Unexpected (in terms of nature, severity, or frequency) Related or possibly related to participation 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

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What is an Adverse Event (AE)?

Any unfavorable medical occurrence in human subjects, including abnormal signs

(e.g., abnormal physical exam or laboratory findings), symptoms, or disease temporally associated with, but not necessarily considered related to, the subject’s participation in the research.

OHRP’s Venn Diagram

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FDA Regulatory Requirements: Investigator to IRB

Investigators are required to report promptly to the IRB…

all unanticipated problems involving risks to human subjects or others,” including adverse events that should be considered unanticipated problems

(§§ 56.108(b)(1), 312.53(c)(1)(vii), and 312.66)

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FDA Guidance (January 2009)

AE should be considered an unanticipated problem involving risk to human subjects and reported to the HRPO, only if:

– unexpected and, – serious and, – would have implications for the conduct of the study (significant, and usually safety-related change in the protocol like revising inclusion/exclusion criteria, new monitoring requirements, ICF or IB)

http://www.fda.gov/cder/guidance/OC2008150fnl.pdf

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FDA Guidance January 2009

• An individual AE occurrence ordinarily does not

meet these criteria because, as an isolated event, its implications for the study cannot be understood.

• FDA provided specific examples of AE’s that

would meet the definition of an unanticipated problem involving risk to subjects.

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FDA Guidance January 2009

• Most AE’s generally require an evaluation of

their relevance and significance to the study

• Aggregate analysis of other occurrences of the

same (or similar) event

• DSMB, DSMB, DSMB!!!

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What about protocol Non- Compliance (deviations)?

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Non-Compliance

Failure on the part of the investigator or any member of the study team to follow the terms of University of Pittsburgh IRB approved protocol or to abide by applicable laws or regulations, or University of Pittsburgh IRB policies. This includes protocol deviations. Incidents of noncompliance on the part of research participants which do not involve risk do not need to be reported to the IRB.

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HHS and FDA Regulations

Prospective approval is required for changes to the research protocol except for deviations performed to eliminate apparent immediate hazards to the subject in compliance with 45 CFR 46.103 (b) (4) and 21 CFR 56.108(a)(4)

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FDA Compliance Program Manual – Chapter 48

Protocol deviations: generally an unplanned excursion from the protocol that is not implemented or intended as a systematic change…

– protocol amendments, – deviations initiated by the clinical investigator must be reviewed and approved by the IRB and the sponsor prior to implementation, unless the change is necessary to eliminate apparent immediate hazards to the human subjects (21 CFR 312.66), or to protect the life or physical well-being of the subject (21 CFR 812.35 (a)(2)), and generally communicated to FDA.

Noncompliance/Deviations

No real guidance from FDA or OHRP about what

• r how deviations should be reported to IRBs after

they occur.

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Reportable Events

Deviation or Non- Compliance

Adverse Events that are Unanticipated Problems Involving Risk to Subjects

• r Others

“Other” Unanticipated Problems Involving Risk to Subject or Others

Types of Reportable Events

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University of Pittsburgh Statistics

2017

Reports of Non-Compliance: 684 Unique protocols: 309

• Full Board:

195

• Expedited:

114 PIs with protocols at UPIRB: 1,627 Active protocols at UPIRB: 4,333 Reports from 229 PIs Two or more events submitted by 104 PIs

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Consistency Needed Between IRBs

• Same regulatory basis for policies and

procedures

• Single IRB review

– Need to follow reporting policies of the IRB of record for your study

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Consistency Needed Between IRBs

• Move to more standardized IRB electronic

submission systems

– PittPRO requires a specific format for the reports.

• Reportable New Information

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National Review of IRB Policies

• Generally consistent regarding

unanticipated problems involving risk to subject or others

• Wide variation in reporting of

deviations

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How does Pitt IRB’s reporting policy compare?

• UAPs

–Fairly similar overall –Separate reporting pathways for AEs and UAPs not always required –Deviations that are UAPs need to be reported as UAPs

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How does Pitt IRB compare?

• Non-Compliance(Deviations)

–Pitt was more conservative overall –Other IRBs require 2 levels of reporting

• Reportable event – deviations that affect

the rights and welfare of human subjects or compromise the quality of the data

• Maintain a log of “minor” deviations which
• ccurred during the review period.

– May be submitted at time of annual review

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Reporting Requirement

University of Pittsburgh IRB requires the reporting of:

• Adverse events and other unanticipated

events which meet the definition of an “unanticipated problem involving risks to human subjects or others”

• r
• Non-compliance

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Protocol Deviation or Non-Compliance

Previous Reporting Requirement

• Investigators must submit

all incidents of non- compliance/protocol deviations within 10 working days of the investigator becoming aware of the event

New Reporting Policy: Effective March 1, 2019

Non-compliance that:

• significantly adversely affects

the rights or welfare of participants, or

• significantly compromises

the quality of the research data, or

• may represent serious and/or

continuing non-compliance

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What’s Changed?

• Investigator and research team will make

initial determination as to if an event needs to be reported

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Timing of Events

(e.g. occurred in 2018 but identified by the research team or the ECO after March 1, 2019)

Deviations meeting the new policy

• ccurring prior to March 1, 2019 will

follow the new policy and be documented on the log

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Management of Non-Compliance that is not reported

• Documentation in study chart
• Documentation in a log for the study
• Reviewed as part of the Data Safety

Monitoring Plan

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Non-Compliance Log

• Mandatory:

– Greater than minimal risk studies – Studies that meet the federal definition of a “clinical trial” – If required by funding agency

• Strongly Recommended for all other studies
• Not required to be submitted at annual review
• Must be available upon request

Example of log

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UAPs and NC/Deviations that must be reported to Pitt IRB within 10 days include but are not limited to:

• Any accidental or intentional deviation from the IRB-approved

protocol that involves risks (e.g., missed safety labs, incorrect dosing or labeling)

• Any deviation from the protocol taken without prior IRB review to

eliminate apparent immediate hazard to a given research subject

• Any publication in the literature, safety monitoring report, interim

result, or other finding that indicates an unexpected increase in the risk to benefit ratio of the research

• Any complaint of a subject that indicates an unanticipated risk or

which cannot be resolved by the research staff

• Any other untoward event that affects the welfare or the privacy,

confidentiality or other rights of research subjects or members of their family (e.g. lost or stolen research data)

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UAPs and NC/Deviations that must be reported to Pitt IRB within 10 days include but are not limited to:

• Performing non-exempt human subject research without
• btaining prospective IRB approval
• Initiating research activities prior to obtaining consent
• Implementing protocol modifications without obtaining

prospective IRB approval

• Altering the informed consent process from that

described in the IRB approved protocol

• Obtaining consent using an outdated consent form,

when the new consent form contained new information that may have caused the subject to change their mind about participating

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UAPs and NC/Deviations that must be reported to Pitt IRB within 10 days include but are not limited to:

• Having research activities performed by individuals who

are not sufficiently trained or credentialed to perform the task

• Having non-licensed physician investigators or research

staff obtain consent for studies that involve a drug, a device or surgical procedure

• Conducting research during a lapse in IRB approval;
• Not adhering to inclusion/exclusion criteria
• Enrolling more subjects than were approved in the

protocol of a greater than minimal risk study

• Performing research at an unapproved site

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Noncompliance/ Deviations that are not reportable but should be documented in a log include:

• Obtaining consent using an outdated consent form when

there were no substantive differences between the consent form that was used and the consent form that should have been used (i.e., dates in the footer)

• Protocol deviations that do NOT adversely affect the rights

and welfare of human subjects or significantly compromise the quality of the research data

• Subject noncompliance that does not involve risk or alter the

data

• Performing non-safety related research procedures outside

the protocol specified window, i.e., involuntarily administering a questionnaire outside of the protocol specified window.

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• Live as of January 1, 2019
• Reportable events = Reportable New

Information

• Reporting process looks very different

PittPRO RNI Reporting

PittPRO RNI Reporting

• PittPRO RNI# = OSIRIS UAP#
• Must select “STUDY#” to associate with RNI

submission (later slide)

PittPRO RNI Reporting

• Select all categories that apply (continued on next

slide)

PittPRO RNI Reporting

PittPRO RNI Reporting

PittPRO RNI Reporting

• #7 associates the PittPRO study with this RNI
• Select study number from pop-up box
• In OSIRIS, reportable events had to be associated with only one study
• PittPRO allows PI to associate one reportable event with multiple studies
• Examples
• New risk for medication being used in multiple different

protocols

• Non-compliance that affects multiple protocols (human error)
• Protocols in OSIRIS should still have UAPs reported in OSIRIS (until

transition). Important! Medwatch reports, DSMB reports, patient medical documentation, publications, etc.

PittPRO RNI Reporting

PittPRO RNI Reporting

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PittPRO RNI Reporting

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After Submission of RNI

• AE Coordinator receives info

– Reviews and files administratively OR – RNI is discussed at IRB Committee Meeting

• IRB Committee discusses RNI

– Makes determination of:

• Serious or continuing non-compliance
• Unanticipated problem involving risk to human subjects or
• thers
• No further action required

– May request corrective actions and/or protocol modifications even if no determination of UAP or S/C/NC

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Further Information

• IRB Policies and Procedures Chapter 17
• IRB Policies and Procedures, Reporting

Responsibilities of the investigator

• Reportable New Information FAQs
• Federal regulations related to OHRP
• Related FDA regulations
• Download links to Adverse

Events/Unanticipated Problems Log

• Download links to Noncompliance/Deviation

Log

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QUESTIONS?