Oops, That Wasn’t Supposed
to Happen
(Noncompliance/Protocol Deviations)
JERI R. BARNEY, JD, MS
HRPP COMPLIANCE MANAGER
YALE UNIVERSITY
HUMAN RESEARCH PROTECTION PROGRAM
WWW.YALE.EDU/HRPP
MAY 2013
Today’s Discussion
 HRPP Compliance
 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

 IRB Actions
 Lapses in IRB Approval
HRPP Compliance Unit
Mission:
To facilitate compliance with the federal
regulations & 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
 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.”
 HRPP Policy 700
(http://www.yale.edu/hrpp/policies/index.html)
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.
What is Noncompliance?
 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 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”
What is a Protocol Deviation?
 Defined as “any alteration/modification to an IRB-
approved protocol made without prior IRB
approval.”
 A protocol deviation constitutes noncompliance.
Level of Noncompliance
 Whether a protocol deviation qualifies as minor or serious
noncompliance depends heavily on the specific facts of the
situation. The key 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 PI.
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
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