protocol deviations : identification, responses and solutions the office of human subjects...

Protocol Deviations :Protocol Deviations :Identification, Responses and Identification, Responses and

SolutionsSolutions

The Office of Human Subjects Research’sThe Office of Human Subjects Research’sCompliance Monitoring Program Compliance Monitoring Program

Educational Seminars:Educational Seminars:

Jenna L. Tress, BA, CCRPRamesh Ghodgaonkar, BPHARM, MSITS, MSB,

MBAFrederick W. Luthardt, MA, MA, CCRP

Barbara L. Starklauf, MAS, CIPSeptember 22, 2008 (Bayview – Carroll Auditorium)September 23, 2008 (East Baltimore – BRB G01-03)

Presentation AgendaPresentation Agenda

JHM IRB Policies and GuidelinesJHM IRB Policies and Guidelines Applicable IRB resources and formsApplicable IRB resources and forms Interactive Workshop with example Interactive Workshop with example

scenariosscenarios Interactive Q&A session to discuss Interactive Q&A session to discuss

tools to improve compliancetools to improve compliance

Our GoalsOur Goals

To understand how to identify, To understand how to identify, document, report, and resolve document, report, and resolve Protocol Deviations.Protocol Deviations.

To appreciate research site To appreciate research site responsibilities and requirements responsibilities and requirements regarding deviations.regarding deviations.

To be prepared to apply skills to To be prepared to apply skills to develop plans to augment compliance develop plans to augment compliance for current and future studies.for current and future studies.

Why are we here?Why are we here?

2008 revisions to IRB policies, 2008 revisions to IRB policies, guidelines, and forms.guidelines, and forms.

Monitoring and auditing findings, as Monitoring and auditing findings, as well as reports to the IRBs, indicate well as reports to the IRBs, indicate some confusion persists in the some confusion persists in the handling of deviations.handling of deviations.

The Compliance Team fields call from The Compliance Team fields call from investigators and study-team members investigators and study-team members for clarifications and instructions.for clarifications and instructions.

Protocol DeviationsProtocol Deviations DefinitionDefinition

The term “protocol deviation” is not defined by The term “protocol deviation” is not defined by either HHS human subjects regulations (45 CFR either HHS human subjects regulations (45 CFR 46) or FDA human subjects regulations (21 CFR 46) or FDA human subjects regulations (21 CFR 50).50).

Organization PolicyOrganization Policy For JHM purposes, a protocol deviation is defined For JHM purposes, a protocol deviation is defined

as a minor or administrative departure from the as a minor or administrative departure from the protocol procedures approved by the IRB that was protocol procedures approved by the IRB that was made by the PI without prior IRB approval.made by the PI without prior IRB approval.

Please note that inclusion/exclusion exceptions DO Please note that inclusion/exclusion exceptions DO NOT fall under this definition, as they are safety NOT fall under this definition, as they are safety criteria.criteria.

Types of Deviations & Reporting Types of Deviations & Reporting RequirementsRequirements

Deviations constituting Deviations constituting unanticipated problemsunanticipated problems

Emergency deviation: When a deviation Emergency deviation: When a deviation occurs in an occurs in an emergency situationemergency situation,, such as such as when a departure from the protocol is when a departure from the protocol is required to protect the life or physical well-required to protect the life or physical well-being of a participant.being of a participant.

Reporting guidelines require that the sponsor Reporting guidelines require that the sponsor and the IRB must be notified and the IRB must be notified as soon as as soon as possiblepossible, but in no event later than 5 days , but in no event later than 5 days after the after the emergencyemergency occurs. occurs.

Types of Deviations & Reporting Types of Deviations & Reporting Requirements (cont.)Requirements (cont.)

Major, non-emergent deviations Major, non-emergent deviations without prior approvalwithout prior approval

A planned deviation that is non-emergent and A planned deviation that is non-emergent and represents a major change in the protocol as represents a major change in the protocol as approved by the IRB must be submitted as a approved by the IRB must be submitted as a Change in ResearchChange in Research. .

The IRB must approve the request The IRB must approve the request beforebefore the the proposed change is implemented. If a major, proposed change is implemented. If a major, non-emergent deviation occurs without prior non-emergent deviation occurs without prior IRB approval the event is considered non-IRB approval the event is considered non-compliance. Non-compliance must be reported compliance. Non-compliance must be reported to the IRB promptly, using the to the IRB promptly, using the Unanticipated Unanticipated Problems FormProblems Form..


Deviations that are minor or Deviations that are minor or administrativeadministrative

At JHM, minor or administrative protocol At JHM, minor or administrative protocol deviations are defined as those which do not deviations are defined as those which do not “affect the scientific soundness of the research “affect the scientific soundness of the research plan or the rights, safety, or welfare of human plan or the rights, safety, or welfare of human subjects.” subjects.”

If a protocol deviation occurs which meets this If a protocol deviation occurs which meets this definition, the deviation should be reported to definition, the deviation should be reported to the JHM IRB at the time the continuing review the JHM IRB at the time the continuing review application is submitted.application is submitted.


Deviations involving Investigational Deviations involving Investigational Device Exemptions (IDEs)Device Exemptions (IDEs)

FDA device regulations at 21 CFR 812.150(a)(4) FDA device regulations at 21 CFR 812.150(a)(4) require prior approval from the sponsor of all planned require prior approval from the sponsor of all planned deviations, including administrative and minor deviations, including administrative and minor deviations. Planned deviations requested of a deviations. Planned deviations requested of a sponsor must be submitted for IRB review as a sponsor must be submitted for IRB review as a “Change in Research” and “Change in Research” and approvedapproved by the JHM IRB by the JHM IRB prior to instituting any IDE research planned prior to instituting any IDE research planned deviations. For device research, the PI must keep on deviations. For device research, the PI must keep on file a copy of the written approval document from the file a copy of the written approval document from the sponsor and IRB when a deviation is granted.sponsor and IRB when a deviation is granted.


Exceptions to Eligibility Criteria for Clinical Exceptions to Eligibility Criteria for Clinical Trials:Trials:

Eligibility exceptions (or eligibility waivers Eligibility exceptions (or eligibility waivers granted by a sponsor) for enrollment of a granted by a sponsor) for enrollment of a specific individual who does not meet the specific individual who does not meet the inclusion/exclusion criteria in the IRB approved inclusion/exclusion criteria in the IRB approved protocol protocol are not deviationsare not deviations. .

Eligibility exceptions are considered changes in Eligibility exceptions are considered changes in research that require IRB review and approval research that require IRB review and approval beforebefore a subject who does not meet the a subject who does not meet the approved protocol inclusion/exclusion criteria approved protocol inclusion/exclusion criteria may be enrolled.may be enrolled.


For “non-clinical trials,” such as For “non-clinical trials,” such as studies not involving drugs, devices, studies not involving drugs, devices, interventions, or are observational, interventions, or are observational, all IRB approved study procedures all IRB approved study procedures must be followedmust be followed, including:, including: Subject enrollment criteriaSubject enrollment criteria Consent (if applicable)Consent (if applicable) Procedural complianceProcedural compliance Event/deviation/annual reportingEvent/deviation/annual reporting

IRB’s Deviation Handling Flow-IRB’s Deviation Handling Flow-ChartChart

FormsFormsTo 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.)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”:eIRB FSA “Change in Research”:Mechanism for Reporting DeviationsMechanism for Reporting Deviations

eIRB Continuing Review “Deviation” eIRB Continuing Review “Deviation” SummarySummary

Protocol Deviation Case-Protocol Deviation Case-Example #1Example #1

Missing a Study Visit:Missing a Study Visit: After consent and enrollment, a study subject is given a After consent and enrollment, a study subject is given a

calendar and is scheduled for the next visit (“Visit 2”) to begin calendar and is scheduled for the next visit (“Visit 2”) to begin the collection of important time-sensitive baseline information.the collection of important time-sensitive baseline information.

But on the scheduled visit date, the subject contacts the study But on the scheduled visit date, the subject contacts the study coordinator and states he can’t come to the clinic.coordinator and states he can’t come to the clinic.

The PI decides because there’s no risk to the subject, the next 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 visit (in 30 days) will become the “new Visit 2,” with the calendar “corrected” and reprinted with the adjusted schedule.calendar “corrected” and reprinted with the adjusted schedule.

No other documentation is made. No other documentation is made. Discussion: Discussion:

Is this an administrative change requiring a Change in Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting?Research or a minor change requiring annual reporting?

Is the response correct?Is the response correct? What would you do?What would you do?

Correct guideline responseCorrect guideline response Compliance Tool(s) consideration?Compliance Tool(s) consideration?

Case Example #1: DiscussionCase Example #1: Discussion Is this an administrative change requiring a Is this an administrative change requiring a

Change in Research or a minor change requiring Change in Research or a minor change requiring annual reporting?annual reporting?

Yes, this constitutes an administrative deviation.Yes, this constitutes an administrative deviation. Is the response correct?Is the response correct? Documentation of the change in schedule should be made Documentation of the change in schedule should be made

on a protocol deviation log.on a protocol deviation log. Correct guidance response:Correct guidance response: The change in schedule should be reported at the time of The change in schedule should be reported at the time of

continuing review.continuing review. Compliance Tool(s) consideration?Compliance Tool(s) consideration? Use the protocol deviation log to continuously monitor Use the protocol deviation log to continuously monitor

protocol deviations for submission at the time of Continuing protocol deviations for submission at the time of Continuing Review to the IRB.Review to the IRB.


Subject non-complianceSubject non-compliance: A study with a strict drug accountability schema requires the A study with a strict drug accountability schema requires the

subject to return all unused tablets at each subsequent visit.subject to return all unused tablets at each subsequent visit. The consent describes that anything less than 100% drug return The consent describes that anything less than 100% drug return

compliance from the subject is grounds for study dismissal.compliance from the subject is grounds for study dismissal. On the subsequent visit the subject’s drug diary indicates tablets On the subsequent visit the subject’s drug diary indicates tablets

left-over, which she neglects to return.left-over, which she neglects to return. The subject is dismissed from the study per the consent.The subject is dismissed from the study per the consent. A subject log verifies the subject’s early termination from the A subject log verifies the subject’s early termination from the

protocol.protocol. Discussion:Discussion:

Is this an administrative change requiring a Change in Research or Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting?a minor change requiring annual reporting?



Case Example #2: DiscussionCase Example #2: Discussion Is this an administrative change requiring a Is this an administrative change requiring a

Change in Research or a minor change requiring Change in Research or a minor change requiring annual reporting?annual reporting?

No, this would not constitute a deviation; the site followed No, this would not constitute a deviation; the site followed the protocol as written.the protocol as written.

Is the response correct?Is the response correct? Yes.Yes. Correct guidance response:Correct guidance response: The response, according to guidance, was correct.The response, according to guidance, was correct. Compliance Tool(s) consideration?Compliance Tool(s) consideration? N/AN/A


Should a subject continue with the study?Should a subject continue with the study? A subject enrolled in a sponsored clinical trial develops a A subject enrolled in a sponsored clinical trial develops a

complaint that represents a minor change in her clinical status complaint that represents a minor change in her clinical status from baseline.from baseline.

The complaint is qualified as an Adverse Event using the sponsor’s The complaint is qualified as an Adverse Event using the sponsor’s definition. The PI further describes the event as major, but not definition. The PI further describes the event as major, but not related to the investigational agent.related to the investigational agent.

The protocol directs the PI to withdraw the subject if an AE is The protocol directs the PI to withdraw the subject if an AE is greater than mild, regardless of the attribution.greater than mild, regardless of the attribution.

The PI appeals to the sponsor that the subject, despite the The PI appeals to the sponsor that the subject, despite the protocol instruction, should be allowed to continue and endorse a protocol instruction, should be allowed to continue and endorse a protocol exception, maintaining that it would be in the subject’s protocol exception, maintaining that it would be in the subject’s “best interest.”“best interest.”

The sponsor approves the PI’s request.The sponsor approves the PI’s request. The PI retains all the correspondence documenting the sponsor’s The PI retains all the correspondence documenting the sponsor’s

approval.approval. Discussion:Discussion:

Is this an administrative change requiring a Change in Research or Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting?a minor change requiring annual reporting?



Case Example #3: DiscussionCase Example #3: Discussion Is this an administrative change requiring a Change in Is this an administrative change requiring a Change in

Research or a minor change requiring annual reporting?Research or a minor change requiring annual reporting? Yes, this does constitute a deviation from protocol.Yes, this does constitute a deviation from protocol. Is the response correct?Is the response correct? Keeping all correspondence from the Sponsor is a correct response, Keeping all correspondence from the Sponsor is a correct response,

but the IRB must be involved in the process as well.but the IRB must be involved in the process as well. Correct guidance response:Correct guidance response: Documentation of the exception must be submitted to the IRB as a Documentation of the exception must be submitted to the IRB as a

Change in ResearchChange in Research, requesting an exception for one subject. This , requesting an exception for one subject. This case involves subject safety, which is why the site would request case involves subject safety, which is why the site would request the exception.the exception.

Compliance Tool(s) consideration?Compliance Tool(s) consideration? The site should consider further training on IRB policies in order to The site should consider further training on IRB policies in order to

be able to accurately address this issue in the future.be able to accurately address this issue in the future.


Eligibility consideration: Eligibility consideration: An inclusion criterion in a study stipulates that a potential An inclusion criterion in a study stipulates that a potential

subject’s TSH be <3.0uIU/mL.subject’s TSH be <3.0uIU/mL. The PI decides to enroll a subject with a TSH of 3.3uIU/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 because the upper range is varied by many factors and the difference is not considered clinically significant. difference is not considered clinically significant.

The PI also reasons that flexibility with the TSH criterion will The PI also reasons that flexibility with the TSH criterion will improve enrollment.improve enrollment.

Subsequent measurements demonstrate a stabilization of the Subsequent measurements demonstrate a stabilization of the subject’s TSH.subject’s TSH.

The PI indicates in a note-to-file that an exception was The PI indicates in a note-to-file that an exception was granted to allow this subject inclusion into the protocol. No granted to allow this subject inclusion into the protocol. No further action is taken.further action is taken.

Discussion:Discussion: Is this an administrative change requiring a Change in Is this an administrative change requiring a Change in

Research or a minor change requiring annual reporting?Research or a minor change requiring annual reporting? Is the response correct?Is the response correct?

What would you do?What would you do? Correct guideline responseCorrect guideline response Compliance Tool(s) consideration?Compliance Tool(s) consideration?

Case Example #4: DiscussionCase Example #4: Discussion Is this an administrative change requiring a Change Is this an administrative change requiring a Change

in Research or a minor change requiring annual in Research or a minor change requiring annual reporting?reporting?

This does not constitute a deviation, this would constitute a This does not constitute a deviation, this would constitute a Change in ResearchChange in Research..

Is the response correct?Is the response correct? The site should have submitted a The site should have submitted a Change in ResearchChange in Research request, request,

and obtained IRB approval, prior to enrolling the subject in the and obtained IRB approval, prior to enrolling the subject in the protocol.protocol.

Correct guidance response:Correct guidance response: According to IRB guidance, all inclusion/exclusion exceptions According to IRB guidance, all inclusion/exclusion exceptions

must be approved by the IRB prior to the subject being enrolled must be approved by the IRB prior to the subject being enrolled into the protocol.into the protocol.

Compliance Tool(s) consideration?Compliance Tool(s) consideration? The site should consider further training of study personnel, as The site should consider further training of study personnel, as

well as the development of SOPs for eligibility determination.well as the development of SOPs for eligibility determination.


Retrospective Chart Review:Retrospective Chart Review: A study is IRB approved to enroll adults previously seen in clinic to A study is IRB approved to enroll adults previously seen in clinic to

develop a database of potential subjects for future clinical trials.develop a database of potential subjects for future clinical trials. The database contains PHI, including contact information and The database contains PHI, including contact information and

diagnostic data. diagnostic data. The IRB approves the protocol’s consent process, which states only 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 patients who physically present to the clinic at a return visit are to be approached to discuss enrollment and the consent form reviewed.approached to discuss enrollment and the consent form reviewed.

The PI decides to mail the consent form to every patient seen in the The PI decides to mail the consent form to every patient seen in the past to increase participation, and use the signed, returned consent past to increase participation, and use the signed, returned consent form to build the database.form to build the database.

The PI interprets this departure as insignificant and does not notify The PI interprets this departure as insignificant and does not notify the IRB.the IRB.

Discussion:Discussion: Is this an administrative change requiring a Change in Research or a Is this an administrative change requiring a Change in Research or a

minor change requiring annual reporting?minor change requiring annual reporting? Is the response correct?Is the response correct?


Case Example #5: DiscussionCase Example #5: Discussion Is this an administrative change requiring a Change Is this an administrative change requiring a Change

in Research or a minor change requiring annual in Research or a minor change requiring annual reporting?reporting?

This instance does constitute a deviation from protocol.This instance does constitute a deviation from protocol. Is the response correct?Is the response correct? The response is not adequate to address this deviation.The response is not adequate to address this deviation. Correct guidance response:Correct guidance response: According to IRB guidance, prior to mailing out consent forms According to IRB guidance, prior to mailing out consent forms

to all patients, the site should submit a to all patients, the site should submit a Change in ResearchChange in Research request, and obtain IRB approval, for a change in recruitment request, and obtain IRB approval, for a change in recruitment methods.methods.

Compliance Tool(s) consideration?Compliance Tool(s) consideration? The site should consider developing a recruitment SOP, and The site should consider developing a recruitment SOP, and

implementing further site training and IRB site review.implementing further site training and IRB site review.

Protocol Deviation Case-Protocol Deviation Case-Example #6Example #6 Developing a blood-repository for future research:Developing a blood-repository for future research:

A research protocol is IRB approved for enrollment of clinic A research protocol is IRB approved for enrollment of clinic patients for the collection of blood samples to be available for patients for the collection of blood samples to be available for future research to isolate unknown genetic markers and develop future research to isolate unknown genetic markers and develop novel gene therapies.novel gene therapies.

The IRB approved consent and protocol specify that only adults The IRB approved consent and protocol specify that only adults may be enrolled.may be enrolled.

In the PI’s clinic, many patients under 18 also present for In the PI’s clinic, many patients under 18 also present for treatments and blood is routinely draw from them for clinical treatments and blood is routinely draw from them for clinical purposes. purposes.

The PI decides to expand the cohort to include minors (ages 15-The PI decides to expand the cohort to include minors (ages 15-17), as there is minimal risk and the future studies could yield 17), as there is minimal risk and the future studies could yield therapies for younger members of the proband who could therapies for younger members of the proband who could potentially benefit from decreased morbidity and mortality.potentially benefit from decreased morbidity and mortality.

The PI does not notify the IRB but makes sure both the parents The PI does not notify the IRB but makes sure both the parents and minor-aged subjects sign the informed consent form. and minor-aged subjects sign the informed consent form.

Discussion: Discussion: Is this an administrative change requiring a Change in Research Is this an administrative change requiring a Change in Research

or a minor change requiring annual reporting?or a minor change requiring annual reporting? Is the response correct?Is the response correct?


Case Example #6: DiscussionCase Example #6: Discussion Is this an administrative change requiring a Change in Is this an administrative change requiring a Change in

Research or a minor change requiring annual Research or a minor change requiring annual reporting?reporting?

There are two deviations requiring reporting.There are two deviations requiring reporting. Is the response correct?Is the response correct? The response is not correct.The response is not correct. Correct guidance response:Correct guidance response: According to IRB guidance, the site must submit a According to IRB guidance, the site must submit a Change in Change in

ResearchResearch request prior to changing the study population. request prior to changing the study population. In addition, the enrollment of minor children without IRB In addition, the enrollment of minor children without IRB

approval must be submitted as an approval must be submitted as an Unanticipated ProblemUnanticipated Problem, as it , as it is an instance of non-compliance.is an instance of non-compliance.

Compliance Tool(s) consideration?Compliance Tool(s) consideration? The site should consider developing training for all site The site should consider developing training for all site

personnel, as well as the development of a consent SOP and personnel, as well as the development of a consent SOP and checklists.checklists.

Compliance SuggestionsCompliance Suggestions Checklists and LogsChecklists and Logs SOPs for assuring protocol compliance SOPs for assuring protocol compliance

and deviation reportingand deviation reporting Notes-to-File to account for events, Notes-to-File to account for events,

responses, and corrective action plansresponses, and corrective action plans For further information and examples of For further information and examples of

the above and other useful compliance the above and other useful compliance tools, please go to the Compliance tools, please go to the Compliance Website at: Website at: http://irb.jhmi.edu/Monitoring/index.htmlhttp://irb.jhmi.edu/Monitoring/index.html

Take Home Points…Take Home Points… Follow the IRB approved protocolFollow the IRB approved protocol Develop and implement mechanisms such Develop and implement mechanisms such

as checklists, SOPs, and Notes-to-File to as checklists, SOPs, and Notes-to-File to maximize compliance and minimize maximize compliance and minimize deviationsdeviations

Be mindful of possible changes to the Be mindful of possible changes to the protocolprotocol

Make sure to check the IRB’s website Make sure to check the IRB’s website regularly for updates and changes to regularly for updates and changes to policies and guidancespolicies and guidances

Maintain TransparencyMaintain Transparency

Contact InformationContact Information The monitors may be contacted at

the OHSR office at 410-955-3008 for questions and assistance.

Reed Hall, Suite B-130 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.

mailto:[email protected]



protocol deviations : identification, responses and solutions the office of human subjects...

Documents

handling of deviations

protocol procedures

compliance slide

term protocol deviation

guidelines jhm irb policies

prior irb approval

forms applicable irb

compliance team fields