Noncompliance:
Deviations, Solutions and
Corrective Actions
JERI BARNEY, JD, MS, CIP, SENIOR COMPLIANCE MANAGER
JESS RANDALL, MA, CIP, COMPLIANCE MANAGER
HUMAN RESEARCH PROTECTION PROGRAM (HRPP)
RESEARCH QUALITY ASSURANCE & COMPLIANCE (RQA&C)
YALE UNIVERSITY
Agenda

Who is the HRPP RQA&C group

Deviations

Best Practices to prevent deviations

Reporting SNC ,CNC or minor deviations to the Yale IRBs

Designing an Effective CAPA Plan

Interactive Case Scenarios

Questions
Human Research Protection Program (HRPP)
Research Quality Assurance & Compliance
(RQA&C)
[aka “the HRPP Compliance Team”]
Located within the Human Research Protection Program
(HRPP) office (Yale IRBs (i.e., HIC, HSC))
 3 Compliance Team members
 5 IRBs (one oncology board, 3 biomedical and 1
social/behavioral)
 RQA&C Main Responsibilities:
 Conduct Not-for-Cause (NFC) reviews
 Conduct For-Cause (FC) reviews
 Respond to human subjects research complaints (subject,
non-subject, all)
 Develop & ensure effective implementation of Corrective
and Preventative Action (CAPA) plans

COMMON DEVIATIONS
#10 Not sending information to the IRBs
timely (e.g., amendments/modifications to
protocol)
Best Practice:
 Promptly submit to the Yale IRBs any information that
may affect the risk/benefit assessment or substantively
changes the protocol
 Adhere to any Departmental SOPs, or sponsor/protocol
requirements regarding the submission of amendments
to the IRB
COMMON DEVIATIONS
#9
Not following Departmental or
Internal Standard Operating
Procedures (SOPs)
Best Practice:
 Be
familiar with your department SOPs/internal
policies (as applicable)
COMMON DEVIATIONS
#8
Late Reporting of Deviations
Best Practice:
HRPP Policy 700 Noncompliance, Suspension
and Termination
“700.1 Reporting Noncompliance
Principal Investigators are responsible for reporting
instances of serious or continuing noncompliance that
occur at Yale’s research site(s) to the IRB within five (5)
working days of discovery…”
HRPP Policy 700 Noncompliance,
Suspension and Termination
 Protocol
Deviation
“Any alteration/modification to an IRB-approved protocol made without prior
IRB approval.”
 Serious
Noncompliance
“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:
1.
adversely affect the rights and welfare of participants;
2.
harm or pose an increased risk of substantive harm to a research participant;
3.
result in a detrimental change to a participant’s clinical or emotional condition or
status;
4.
compromise the integrity or validity of the research; or
5.
result from willful or knowing misconduct on the part of the investigator(s) or study
staff.”
HRPP Policy 700 Noncompliance,
Suspension and Termination
 Continuing
Noncompliance
“A pattern of noncompliance that, in the judgement of a convened IRB:
1. Indicates a lack of understanding or disregard for the regulations or
institutional requirements that protect the rights and welfare of subjects or
participants; or
2. Compromises the scientific integrity of a study such that important
conclusions can no longer be reached; or
3. Suggests a likelihood that noncompliance will continue without
intervention; or
4. Involves frequent instances of minor noncompliance, for example,
repetitive protocol deviations.”
#8 Late Reporting of Deviations
(continued)

Use the Form: “Notification of Deviation from
Protocol/Noncompliance Report Form (Form 700FR1)” to
report potentially serious and/or continuing
noncompliance.

HRPP Policy 700: “Noncompliance includes…protocol
deviations…”

700.1 Reporting Noncompliance
“…All instances of minor noncompliance should be
summarized for the IRB at the time of continuing review.”

When in doubt call the IRB!
www. Yale.edu/hrpp/policies
COMMON DEVIATIONS
#7
CONSENT, CONSENT, CONSENT
Use of:
 Incorrect version of consent or consent addendum
 Expired consent form or NO IRB approval stamp or final IRB
approval
Best Practice:


Always review the consent/addendum prior to the subject’s
arrival to ensure that the subject will be signing the correct IRBapproved version
Consenting is a PROCESS (IRB consent and HIPAA authorization),
not just a signature.
COMMON DEVIATIONS
#6

MORE CONSENT, CONSENT, CONSENT
Incomplete content (i.e. missing checkbox elections, signatures,
initials) OR Improper changes made to the consent (e.g., writing
on the consent form, crossing out, no corresponding note to file).
Best Practice:

Always review the signed consent/addendum just before the
subject leaves to ensure it is complete and signed

Consenting is a PROCESS (IRB consent and HIPAA authorization),
not just a signature.
COMMON DEVIATIONS
#5 “The approved protocol SAYS that??”

Not adhering to the IRB approved study protocol (e.g., missing tests or
assessments, dosing not in accordance with the approved study
protocol, non IRB-approved staff performing research related activities)
Best Practice:

Re-Review the protocol on a regular basis at team meetings to refresh the
team’s memory/provide clarity to areas of question.

Perform Quality Assurance/Quality Improvement checks to ensure
adherence/identify issues and re-train study staff.
COMMON DEVIATIONS
#4
Not reconsenting subjects in a timely
fashion/or in accordance with the
protocol
Best Practice:

OnCore (if applicable) has a reconsent function; “RR” flag is
indicated for subjects that need to be reconsented

Maintain a tracking spreadsheet for those subjects in need of
reconsent

Flag the folders (paper or electronic) of subjects in need of
reconsent
COMMON DEVIATIONS
#3
Not adhering to the Yale IRB approved
advertisement content or using an
unapproved advertisement or recruitment
method
Best Practice:

Always confirm the approved recruitment method and ads/language
in the IRB application (Recruitment/Consent and Assent Procedures
section) prior to the use of the material
COMMON DEVIATIONS
#2
Poor/nonexistent Corrective and
Preventative Action (CAPA) plan or no
preventative measures
 Question
#10 in the Notification of Deviation from
Protocol/Noncompliance Report Form (700FR1) asks:
“Please provide a CAPA to prevent such protocol
deviations/noncompliance from occurring in the future.”
Best Practice:

Provide a detailed CAPA that will address the deviations
being reported and ensure they won’t happen again in the
future
COMMON DEVIATIONS
#1 Enrolling Ineligible Subjects
Best Practice:

Carefully re-review inclusion and exclusion criteria prior to enrolling
each subject to ensure they meet the appropriate criteria for the
study.

Create and use an itemized check sheet (that lists all inclusion and
exclusion criteria) for each subject enrolled.

Have 2 sets of eyes confirm each subject meets the appropriate
criteria prior to enrollment.
Take Away Best Practice…
ALCOA 1999 FDA Guidance
Documentation should be:
1. Attributable – Who wrote it and when? That is, you can easily
understand who it is from and what their role is.
2. Legible – you can read it clearly, and it is identifiable.
3. Contemporaneous – as close to real time as possible and in
chronological order. Dated when written. Writing notes well after
the actual encounter will be problematic. The current note-to-file
strategy would “not” be considered the standard practice but for
the purposes of retrospective remediation (which is what this
represents for this study) it is what is recommended.
4. Original - the first time it is written down, recorded or dictated is
the source document, and
5. Accurate – consistent and doesn’t conflict with other
documentation.
Additional Take Away Best
Practices…

Maintaining frequent and open communication between the
PI and students/staff is essential.

Set standard study team and PI meeting dates/times
(monthly, weekly or perhaps daily considering how fast
subjects are enrolled and/or challenges arise). In-person
meetings, Skype or teleconference are preferred, not just
email correspondence.

Discuss challenges, items in need of clarifications, deviations.

Follow-up all meetings with a quick email to all (those in
attendance and those not in attendance) to make sure
everyone left the meeting understanding the same take
away points and action items.
Creating an Effective Corrective and
Preventative Action (CAPA) Plan
A good CAPA plan takes a two-pronged approach, and
adequately addresses the following:
1. The current issue at hand (e.g., include a specific
remedy for the affected subject(s))
AND
2. The larger issue as a whole (what steps or actions
have been put in place to ensure that, going
forward, the issue won’t reoccur in the
future/transpire again)
Creating an Effective Corrective and
Preventative Action (CAPA) plan
(continued)

Make sure the CAPA addresses the particular issue

Include a timeframe for completion of CAPA items

Provide detail

Don’t overpromise

Demonstrate ownership of the issue

“It won’t happen again” is not a CAPA.
Case Scenarios
Case Scenario #1

Deviation report: An amendment was approved
by the IRB three (3) months ago that added new
procedures to the research protocol and an
updated consent form. Seven (7) newly enrolled
subjects were inadvertently provided with the
previous/incorrect version of the IRB-approved
consent form.

The CAPA provided by the PI stated that no
corrective or preventive actions were needed.
Case Scenario#1:
What would be an acceptable CAPA for this deviation?
1.
Promptly: report the deviation to the sponsor (if
applicable), reconsent the 7 affected subjects,
communicate to all study staff that a new consent
version (with changes) has been approved for use, and
develop a mechanism to track consent versions going
forward.
2.
Promptly: report the deviation to the sponsor (if
applicable), communicate to all study staff that a new
consent version (with changes) has been approved for
use, and develop a mechanism to track consent
versions going forward.
3.
As provided by the PI, a CAPA is not necessary for this
deviation.
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Case Scenario #2

Deviation report: During a self-review, the study team
noticed that for one subject the study team member
obtaining consent used the previous version of the study
consent form, and, in writing, edited the form to include the
revised information (i.e., increase in target number, addition
of urine collection).

The CAPA from the PI advised that the subject has since
been provided with and signed a new, clean, current
consent form. The study team member obtaining consent
has been reeducated regarding this issue.
Case Scenario# 2:
What action is missing from the provided CAPA?
1.
2.
3.
A Note to File (NTF) should be written by the
study team and added to the study file to
explain the consent deviation and efforts to
remedy it (ALCOA).
The PI should work with departmental
leadership to develop a policy regarding
consenting subjects.
No additional CAPA items are necessary for
this deviation.
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Case Scenario #3

Deviation report: 4 subjects provided verbal consent to
participate in a study. 10 subjects in total have been
enrolled into this study at Yale. The protocol states that
written informed consent will be obtained.

The PI advises that the 4 subjects were not able to provide
written consent for various reasons (legally blind, Parkinson’s
disease, etc. Mental capacity was not a concern).
Case Scenario#3:
How could this deviation have been prevented?
1.
2.
3.
If the protocol requires written consent, subjects that could
not provide written consent should not be enrolled into this
study under any circumstance. Period.
As soon as members of the study team noticed written
informed consent would not be feasible for the subject
population being enrolled, the Yale IRB should have been
contacted and a protocol amendment submitted to
request approval to obtain only verbal consent for a
certain subset of subjects into this study.
Verbal consent is acceptable in these specific situations
(i.e., legally blind individual, individual with Parkinson’s
disease, etc.) because it’s still consent.
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Case Scenario #4

Deviation report: Two sponsor amendments were submitted
to the Yale IRB (together) for review/approval 5 and 7
months after they were initially available to the PI.

When the amendments were initially available to the Yale
PI, the study was still open to enrollment. By the time the
amendments were submitted to the Yale IRB, the study was
closed to enrollment.

The amendments included some language clarifications
and an additional follow-up visit at week 10.
Case scenario#4:
How could this deviation have been prevented?
1.
5 and 7 months is still an acceptable time frame
to submit protocol amendments to the IRB.
2.
The study team should have a system in place to
ensure the prompt processing/review of
communications from the sponsor, including
amendments (incoming submissions, etc.), to the
IRB in a timely manner.
3.
Once the study was closed to enrollment, the
study was no longer obligated to promptly submit
amendments to the IRB.
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Case Scenario #5

Deviation report: Subject #321 transferred from University X to
Yale mid-participation in the study (visit 3 of 6 were completed at
University X). Upon arrival at Yale, the subject was provided with
the same consent form that would have been provided to a
subject initially enrolling at Yale.

At the time Subject #321 was transferred to Yale, the study was
closed to enrollment at Yale.
Case Scenario # 5
How could this deviation have been prevented?
1.
Given that the protocol closed at Yale, ensure that the last consent
form approved by the IRB is not expired. If it is expired, contact the IRB.
If it isn’t expired, use this consent form to consent the subject. This
subject is a transfer so there is no need to consider reopening the study
at Yale again.
2.
Upon learning of the plans to transfer the subject to Yale, submit an
amendment to the IRB to allow for the “enrollment” of the transfer
subject, and include for approval a new, one time consent form that
will address the visits that the subject will be partaking in at Yale (visits 46). Having an open dialogue with a member of the Yale IRB office is a
good idea to ensure IRB review occurs prior to the subject’s first visit at
Yale.
3.
Contact the appropriate IRB Regulatory Analyst the day before the
subject is due to arrive at Yale to alert them of the subject’s first visit.
Follow their guidance at that time.
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Questions?