The Office of Human Subjects Research’s
Compliance Monitoring Program
Educational Seminars:
Protocol Deviations :
Identification, Responses and Solutions
Jenna L. Tress, BA, CCRP
Ramesh Ghodgaonkar, BPHARM, MSITS, MSB, MBA
Frederick W. Luthardt, MA, MA, CCRP
Barbara L. Starklauf, MAS, CIP
September 22, 2008 (Bayview – Carroll Auditorium)
September 23, 2008 (East Baltimore – BRB G01-03)
Presentation Agenda
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JHM IRB Policies and Guidelines
Applicable IRB resources and forms
Interactive Workshop with example
scenarios
Interactive Q&A session to discuss tools to
improve compliance
Our Goals
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To understand how to identify, document,
report, and resolve Protocol Deviations.
To appreciate research site responsibilities
and requirements regarding deviations.
To be prepared to apply skills to develop
plans to augment compliance for current
and future studies.
Why are we here?
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2008 revisions to IRB policies, guidelines,
and forms.
Monitoring and auditing findings, as well
as reports to the IRBs, indicate some
confusion persists in the handling of
deviations.
The Compliance Team fields call from
investigators and study-team members for
clarifications and instructions.
Protocol Deviations
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Definition
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The term “protocol deviation” is not defined by either
HHS human subjects regulations (45 CFR 46) or FDA
human subjects regulations (21 CFR 50).
Organization Policy
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For JHM purposes, a protocol deviation is defined as a
minor or administrative departure from the protocol
procedures approved by the IRB that was made by
the PI without prior IRB approval.
Please note that inclusion/exclusion exceptions DO
NOT fall under this definition, as they are safety
criteria.
Types of Deviations & Reporting
Requirements
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Deviations constituting unanticipated
problems
Emergency deviation: When a deviation occurs in an
emergency situation, such as when a departure
from the protocol is required to protect the life or
physical well-being of a participant.
 Reporting guidelines require that the sponsor and
the IRB must be notified as soon as possible, but in
no event later than 5 days after the emergency
occurs.
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Types of Deviations & Reporting
Requirements (cont.)
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Major, non-emergent deviations without
prior approval
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A planned deviation that is non-emergent and
represents a major change in the protocol as
approved by the IRB must be submitted as a Change
in Research.
The IRB must approve the request before the
proposed change is implemented. If a major, nonemergent deviation occurs without prior IRB approval
the event is considered non-compliance. Noncompliance must be reported to the IRB promptly,
using the Unanticipated Problems Form.
Types of Deviations & Reporting
Requirements (cont.)
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Deviations that are minor or administrative
At JHM, minor or administrative protocol deviations
are defined as those which do not “affect the scientific
soundness of the research plan or the rights, safety,
or welfare of human subjects.”
 If a protocol deviation occurs which meets this
definition, the deviation should be reported to the JHM
IRB at the time the continuing review application is
submitted.
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Types of Deviations & Reporting
Requirements (cont.)
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Deviations involving Investigational Device
Exemptions (IDEs)
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FDA device regulations at 21 CFR 812.150(a)(4) require prior
approval from the sponsor of all planned deviations,
including administrative and minor deviations. Planned
deviations requested of a sponsor must be submitted for IRB
review as a “Change in Research” and approved by the JHM
IRB prior to instituting any IDE research planned
deviations. For device research, the PI must keep on file a
copy of the written approval document from the sponsor and
IRB when a deviation is granted.
Types of Deviations & Reporting
Requirements (cont.)
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Exceptions to Eligibility Criteria for Clinical Trials:
Eligibility exceptions (or eligibility waivers granted by
a sponsor) for enrollment of a specific individual who
does not meet the inclusion/exclusion criteria in the
IRB approved protocol are not deviations.
 Eligibility exceptions are considered changes in
research that require IRB review and approval before
a subject who does not meet the approved protocol
inclusion/exclusion criteria may be enrolled.
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Types of Deviations & Reporting
Requirements (cont.)
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For “non-clinical trials,” such as studies
not involving drugs, devices, interventions,
or are observational, all IRB approved
study procedures must be followed,
including:
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Subject enrollment criteria
Consent (if applicable)
Procedural compliance
Event/deviation/annual reporting
IRB’s Deviation Handling Flow-Chart
Forms
To report a deviation constituting an unexpected problem, complete Form R.F.1
for paper protocols, or an FSA for a problem/event report for an eIRB protocol.
Forms (cont.)
To report minor or administrative protocol deviations, use either R.F.4 or
another (e.g., sponsor’s) protocol event summary form, and submit
annually with the continuing review application for the protocol.
eIRB FSA “Change in Research”:
Mechanism for Reporting Deviations
eIRB Continuing Review “Deviation” Summary
Protocol Deviation Case-Example #1
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Missing a Study Visit:
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Discussion:
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After consent and enrollment, a study subject is given a calendar and is
scheduled for the next visit (“Visit 2”) to begin the collection of
important time-sensitive baseline information.
But on the scheduled visit date, the subject contacts the study
coordinator and states he can’t come to the clinic.
The PI decides because there’s no risk to the subject, the next visit (in
30 days) will become the “new Visit 2,” with the calendar “corrected”
and reprinted with the adjusted schedule.
No other documentation is made.
Is this an administrative change requiring a Change in Research or a
minor change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #1: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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Documentation of the change in schedule should be made on a
protocol deviation log.
Correct guidance response:
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Yes, this constitutes an administrative deviation.
The change in schedule should be reported at the time of
continuing review.
Compliance Tool(s) consideration?
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Use the protocol deviation log to continuously monitor protocol
deviations for submission at the time of Continuing Review to
the IRB.
Protocol Deviation Case-Example #2
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Subject non-compliance:
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Discussion:
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A study with a strict drug accountability schema requires the subject to
return all unused tablets at each subsequent visit.
The consent describes that anything less than 100% drug return
compliance from the subject is grounds for study dismissal.
On the subsequent visit the subject’s drug diary indicates tablets leftover, which she neglects to return.
The subject is dismissed from the study per the consent.
A subject log verifies the subject’s early termination from the protocol.
Is this an administrative change requiring a Change in Research or a
minor change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #2: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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Yes.
Correct guidance response:
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No, this would not constitute a deviation; the site followed the
protocol as written.
The response, according to guidance, was correct.
Compliance Tool(s) consideration?
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N/A
Protocol Deviation Case-Example #3
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Should a subject continue with the study?
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Discussion:
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A subject enrolled in a sponsored clinical trial develops a complaint that
represents a minor change in her clinical status from baseline.
The complaint is qualified as an Adverse Event using the sponsor’s
definition. The PI further describes the event as major, but not related
to the investigational agent.
The protocol directs the PI to withdraw the subject if an AE is greater
than mild, regardless of the attribution.
The PI appeals to the sponsor that the subject, despite the protocol
instruction, should be allowed to continue and endorse a protocol
exception, maintaining that it would be in the subject’s “best interest.”
The sponsor approves the PI’s request.
The PI retains all the correspondence documenting the sponsor’s
approval.
Is this an administrative change requiring a Change in Research or a
minor change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #3: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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Keeping all correspondence from the Sponsor is a correct
response, but the IRB must be involved in the process as well.
Correct guidance response:
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Yes, this does constitute a deviation from protocol.
Documentation of the exception must be submitted to the IRB
as a Change in Research, requesting an exception for one
subject. This case involves subject safety, which is why the site
would request the exception.
Compliance Tool(s) consideration?
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The site should consider further training on IRB policies in order
to be able to accurately address this issue in the future.
Protocol Deviation Case-Example #4
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Eligibility consideration:
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Discussion:
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An inclusion criterion in a study stipulates that a potential subject’s
TSH be <3.0uIU/mL.
The PI decides to enroll a subject with a TSH of 3.3uIU/mL because
the upper range is varied by many factors and the difference is not
considered clinically significant.
The PI also reasons that flexibility with the TSH criterion will improve
enrollment.
Subsequent measurements demonstrate a stabilization of the subject’s
TSH.
The PI indicates in a note-to-file that an exception was granted to
allow this subject inclusion into the protocol. No further action is
taken.
Is this an administrative change requiring a Change in Research or a
minor change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #4: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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The site should have submitted a Change in Research request,
and obtained IRB approval, prior to enrolling the subject in the
protocol.
Correct guidance response:
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This does not constitute a deviation, this would constitute a
Change in Research.
According to IRB guidance, all inclusion/exclusion exceptions
must be approved by the IRB prior to the subject being enrolled
into the protocol.
Compliance Tool(s) consideration?
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The site should consider further training of study personnel, as
well as the development of SOPs for eligibility determination.
Protocol Deviation Case-Example #5
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Retrospective Chart Review:
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Discussion:
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A study is IRB approved to enroll adults previously seen in clinic to develop
a database of potential subjects for future clinical trials.
The database contains PHI, including contact information and diagnostic
data.
The IRB approves the protocol’s consent process, which states only patients
who physically present to the clinic at a return visit are to be approached to
discuss enrollment and the consent form reviewed.
The PI decides to mail the consent form to every patient seen in the past to
increase participation, and use the signed, returned consent form to build
the database.
The PI interprets this departure as insignificant and does not notify the IRB.
Is this an administrative change requiring a Change in Research or a minor
change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #5: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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The response is not adequate to address this deviation.
Correct guidance response:
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This instance does constitute a deviation from protocol.
According to IRB guidance, prior to mailing out consent forms to
all patients, the site should submit a Change in Research
request, and obtain IRB approval, for a change in recruitment
methods.
Compliance Tool(s) consideration?
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The site should consider developing a recruitment SOP, and
implementing further site training and IRB site review.
Protocol Deviation Case-Example #6
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Developing a blood-repository for future research:
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Discussion:
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A research protocol is IRB approved for enrollment of clinic patients for
the collection of blood samples to be available for future research to
isolate unknown genetic markers and develop novel gene therapies.
The IRB approved consent and protocol specify that only adults may be
enrolled.
In the PI’s clinic, many patients under 18 also present for treatments
and blood is routinely draw from them for clinical purposes.
The PI decides to expand the cohort to include minors (ages 15-17), as
there is minimal risk and the future studies could yield therapies for
younger members of the proband who could potentially benefit from
decreased morbidity and mortality.
The PI does not notify the IRB but makes sure both the parents and
minor-aged subjects sign the informed consent form.
Is this an administrative change requiring a Change in Research or a
minor change requiring annual reporting?
Is the response correct?
What would you do?
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Correct guideline response
Compliance Tool(s) consideration?
Case Example #6: Discussion
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Is this an administrative change requiring a Change in
Research or a minor change requiring annual reporting?
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Is the response correct?
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The response is not correct.
Correct guidance response:
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There are two deviations requiring reporting.
According to IRB guidance, the site must submit a Change in
Research request prior to changing the study population.
In addition, the enrollment of minor children without IRB
approval must be submitted as an Unanticipated Problem, as it is
an instance of non-compliance.
Compliance Tool(s) consideration?
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The site should consider developing training for all site personnel,
as well as the development of a consent SOP and checklists.
Compliance Suggestions
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Checklists and Logs
SOPs for assuring protocol compliance and
deviation reporting
Notes-to-File to account for events,
responses, and corrective action plans
For further information and examples of the
above and other useful compliance tools,
please go to the Compliance Website at:
http://irb.jhmi.edu/Monitoring/index.html
Take Home Points…
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Follow the IRB approved protocol
Develop and implement mechanisms such as
checklists, SOPs, and Notes-to-File to maximize
compliance and minimize deviations
Be mindful of possible changes to the protocol
Make sure to check the IRB’s website regularly
for updates and changes to policies and
guidances
Maintain Transparency
Contact Information
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The monitors may be contacted at the
OHSR office at 410-955-3008 for
questions and assistance.
Reed Hall, Suite B-130
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The monitors may also be contacted directly by email:
[email protected]
[email protected]
[email protected]
Regulatory questions concerning recordkeeping
requirements may be directed to: Regulatory Affairs
Specialists or the Assistant Dean for Human Subjects
Research.