Noncompliance
JERI R. BARNEY, JD
HRPP COMPLIANCE MANAGER
YALE UNIVERSITY
HUMAN RESEARCH PROTECTION PROGRAM
WWW.YALE.EDU/HRPP
DECEMBER 13, 2012
Today’s Discussion
 HRPP Compliance Unit
 What is Noncompliance?
Minor Noncompliance
 Serious Noncompliance
 Continuing Noncompliance
 Protocol deviations
 Reporting:
 How to report to the IRBs and when
 Corrective and preventive action (CAPA) plans
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 IRB Actions
 Lapses in IRB Approval
HRPP Compliance Unit
Mission:
To facilitate compliance with the federal regulations (and
University policies) and protection of research participants
 IRB
What do they say they will do?
 Compliance
 Are they doing what they said they would do?

Regulatory Oversight
 Office for Human Research
Protections (OHRP)

45 CFR Part 46
 U.S. Food & Drug
Administration (FDA)

21 CFR Parts 50, 50, 56, 312 and
812
 Office for Civil Rights (OCR)
 45 CFR Parts 160, 162 and 164
Noncompliance
 OHRP Guidance
 FDA Guidance
 http://www.fda.gov/downloads/Drugs/Guidance
ComplianceRegulatoryInformation/Guidances/U
CM187772.pdf
 Association for the Accreditation of Human
Research Protection Programs (AAHRPP)
Standards
Definition of Noncompliance
 HRPP Policy 700 (HRRP website;
http://www.yale.edu/hrpp/policies/index.html)
 Defined as “any action or activity associated with the
conduct or oversight of research involving human
participants that fails to comply with either the research
plan as approved by a designated IRB, or federal
regulations or institutional policies governing human
subject research.”
What is Noncompliance?
 Noncompliance may range from minor to serious, be unintentional
or willful, and may occur once or several times.
 Noncompliance includes failure to have protocols reviewed by the
IRB as required, protocol deviations from IRB-approved protocols,
including deviations made in the interest of a single participant such
as changing a participant’s scheduled study visits.
 Noncompliance may result from the action of the investigator,
research personnel, or a participant, and may or may not impact the
rights and welfare of research participants or others or the integrity
of the study.
 Complaints or reports of noncompliance from someone other than
the Principal Investigator or study team personnel are handled as
allegations of noncompliance until such time that the report is
validated or found to be invalidated or dismissed.
Minor Noncompliance
 Defined as any behavior, action or omission in the conduct or oversight
of research involving human participants that deviates from the
approved research plan, federal regulations or institutional policies but,
because of its nature, the research project, or subject population, does
or did not:
 harm or pose an increased risk of substantive harm to a research
participant;
 result in a detrimental change to a participant’s clinical or emotional
condition or status;
 have a substantive effect on the value of the data collected; and
 result from willful or knowing misconduct on the part of the
investigator(s) or study staff.
Examples of Minor Noncompliance
Examples of minor noncompliance may include, but are not
limited to, the following:
 Changing study personnel (excluding PI) without notifying
the IRB;
 Shortening the duration between planned study visits;
 Implementing minor wording changes in study
questionnaires without first obtaining IRB approval;
 Routine lab missed at scheduled visit and re-drawn.
Serious Noncompliance
 Defined as any behavior, action or omission in the conduct or
oversight of human research that, in the judgment of a convened
IRB, has been determined to:
 adversely affect the rights and welfare of participants;
 result in a detrimental change to a participant’s clinical or
emotional condition or status;
 compromise the integrity or validity of the research;
 result from willful or knowing misconduct on the part of the
investigator(s) or study staff; or
 harm or pose an increased risk of substantive harm to a
research participant.
Examples of Serious Noncompliance
 Conducting research that requires direct interaction or
interventions with human participants without first obtaining
IRB approval;
 Enrolling participants who fail to meet the inclusion or exclusion
criteria in a protocol that in the opinion of the IRB Chair,
designee, or convened IRB, places the participant(s) at greater
risk;
 Failing to submit a continuing review application to the IRB
before study expiration for an ongoing study (resulting in a lapse
of IRB approval) and continuing with engaged activities;
 Failing to obtain and/or document a participant’s informed
consent provided the IRB has not granted a waiver of consent;
More Examples
 Failing to retain copies of informed consent forms (signed or
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unsigned);
Performing a study procedure not approved by the IRB; or failing
to perform a required study visit or procedure that, in either
case, may affect subject safety or data integrity;
Failing to follow the safety monitoring plan;
Enrolling study subjects after the IRB-approval of a study has
expired; or
Failing to report serious adverse events and/or unanticipated
problems to the IRB in accordance with IRB Policy 710,
Reporting Adverse Events and Unanticipated Problems.
Continuing Noncompliance
 Defined as a pattern of noncompliance that
indicates a lack of understanding or disregard for the
regulations or institutional requirements that protect the
rights and welfare of participants and others,
 suggests a likelihood that noncompliance will continue
without intervention, or
 involves frequent instances of minor noncompliance.

 Continuing noncompliance may also include failure to
respond to a request from the IRB to resolve an
episode of noncompliance or a pattern of minor
noncompliance.
Examples of Continuing Noncompliance
 Multiple lapses in IRB approval
 Continuing to conduct research after IRB orders a
stop due to an issue of noncompliance
 10% of consents missing on 5 protocols
 “PI doesn’t get it”
Protocol Deviations
 Defined as “any alteration/modification to an IRB-approved protocol
made without prior IRB approval.”
 A protocol deviation constitutes noncompliance.
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Whether a protocol deviation qualifies as minor or serious noncompliance
depends heavily on the specific facts of the situation.
The key to whether a protocol deviation will qualify as “minor” or “serious”
depends upon whether, under the specific circumstances, it may
 adversely affect the rights and welfare of participants,
 harm or pose an increased risk of substantive harm to a research
participant,
 have a substantive effect on the value of the data collected, or
 result from willful or knowing misconduct on the part of the
investigator(s) or study staff.
 A pattern of protocol deviations may constitute continuing
noncompliance, which may have serious ramifications for the Principal
Investigator.
Reporting Requirement
Principal Investigators, co/sub-investigators, research
personnel, or other individuals who believe that an
instance of serious or continuing noncompliance has
occurred must report it to the IRB within five (5)
working days of becoming aware of the
noncompliance.
All instances of minor noncompliance should be
summarized for the IRB at the time of continuing
review.
Additional Reporting Requirements
 Principal Investigators are also required to report results of
audits or inspections conducted by sponsors, other external
entities such as the FDA or internal oversight committees.
 Investigators are not required to report instances of
noncompliance that occur at other sites unless a Yale
investigator serves as the lead PI or managing investigator
acting as the lead coordinating center for a multi-center
study.
Reporting Form for Noncompliance
Form can be found at http://www.yale.edu/hrpp/forms-templates/biomedical.html
What corrective actions are necessary?
 Issue may warrant
consideration of substantive
changes in the research protocol or informed
consent process/document or other corrective
actions in order to protect the safety, welfare or
rights of the subjects or others.
 The PI must include a proposed corrective and
preventive action (CAPA) plan with the report of
noncompliance.
Corrective and Preventive Action Plan
 In crafting an effective plan, the investigator needs to
really think about why the event occurred. Is it a
system problem? Problem with procedure or
something in the protocol? A training issue?
 Once the “why” is determined, the plan must address
ways to prevent it from happening again
 Additional education/training is virtually always
appropriate
 The IRB will make the final determination regarding
the sufficiency of the CAPA
Reporting at Continuing Review
 All instances of minor noncompliance should be summarized for the
IRB at the time of continuing review on the Form 5R.
 When applicable, the summary may be a simple brief statement that
there have been no protocol deviations or other instances of
noncompliance.
HRPP Review & Inquiry
 The HRPP Compliance Manager, HRPP Director, an IRB Chair or
Manager, or other qualified designee will initially assess a
report/allegation of noncompliance and make a preliminary
determination as to the seriousness or continuing nature of the
noncompliance.
 Next, a fact-finding inquiry will be conducted which may
include:
 examination of study records; and
 discussions with the research team, other personnel,
research participants, witnesses, the complainant (if
applicable and not anonymous), and others, as appropriate.
 If the inquiry suggests that the incident may constitute serious
or continuing noncompliance, then the matter will be referred
to a fully-convened IRB.
Actions By IRB
 The IRB has the authority to take whatever action it
deems appropriate, up to and including suspending or
terminating approval of research.
 Such actions may include, but are not limited to:
 Remediation or educational measures required of PI
and research team.
 Monitoring of research activities by appropriate
person(s).
 Notification of past or current research participants.
 Re-consenting of participants.
Additional Actions By IRB
 Additional actions may include, but are not limited to:
More frequent continuing review (renewal of
approval) schedule.
 Periodic audits by the HRPP Compliance Manager.
 Restrictions to the PI’s research practice (e.g., limiting
the privilege to minimal risk or supervised projects).
 PI may put the study on a voluntary partial or full
hold.
 Suspension or termination of approval for one or
more of the PI’s studies.

Consequences for Serious and/or Continuing
Noncompliance
 Could result in
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Reporting to federal agencies (OHRP and FDA), including
funding agencies (e.g., NIH)
Mandatory re-education/independent certification of the PI
and study team
Removal of PI from study or all studies
Tarnished reputation
Loss of funding or sponsorship
Debarment from research
Regulatory Requirement for Continuing Review
DHHS regulations
45 CFR 46.109(e)
Regulatory Requirement for Continuing Review
FDA regulations
21 CFR 56.109(f)
Lapse in IRB Approval: Preventive Measures
 Lapse in IRB approval constitutes noncompliance with the
federal regulations
 Approval & reapproval letters include reminders regarding
regulatory obligations
 Reminder letters are sent out of Coeus at 60, 45 and 30
days (HIC) and 60 & 30 days (HSC) prior to expiration of
the approval period
Reminder Notices
Current template language:
This letter serves as a reminder that the above-cited protocol is due for reapproval by the HIC. It is the
primary responsibility of the Principal Investigator to ensure continued reapproval status for
protocols. All protocols must be reviewed and approved annually by the HIC unless shorter intervals
have been specified.
It is a violation of Yale policy and federal regulations to continue human research activities after the
(IRB) approval period has expired. If the HIC does not receive renewal materials within reasonable
time to review and reapprove this research by its current expiration date, all enrollment, research
activities and intervention on previously enrolled subjects must stop.
If the approval of this protocol lapses, and if the research activities (including the
analysis of identifiable private information) are supported by a sponsored award(s), no
further expenses related to the research activities may be incurred and charged to the
sponsored award(s) until the protocol has been reapproved. Should the research
activities no longer involve human participants and you are only conducting data
analysis of de-identified data, IRB approval is no longer required but the IRB does
require notification of this change in order to close the study. Note also that some
research sponsors may require documentation that IRB approval is no longer required.
Need Assistance or Have Questions
Call HRPP Compliance Manager at 785-6471
or send email to jeri.barney@yale.edu
Call HRPP office directly at 785-4688
References
 http://www.yale.edu/hrpp/
 http://www.yale.edu/hrpp/policies/index.html
 http://www.yale.edu/hrpp/responsibility/complianc
e.html
 http://www.fda.gov/downloads/Drugs/GuidanceCo
mplianceRegulatoryInformation/Guidances/UCM18
7772.pdf
 http://answers.hhs.gov/ohrp/search/results?q=non
compliance
Questions