1. Protocol Deviations : Identification, Responses and Solutions The Office of Human Subjects Research’s Compliance Monitoring Program Educational Seminars: 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)

2. Presentation Agenda JHM IRB Policies and Guidelines JHM IRB Policies and Guidelines Applicable IRB resources and forms Applicable IRB resources and forms Interactive Workshop with example scenarios Interactive Workshop with example scenarios Interactive Q&A session to discuss tools to improve compliance Interactive Q&A session to discuss tools to improve compliance

3. Our Goals To understand how to identify, document, report, and resolve Protocol Deviations. To understand how to identify, document, report, and resolve Protocol Deviations. To appreciate research site responsibilities and requirements regarding 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. To be prepared to apply skills to develop plans to augment compliance for current and future studies.

4. Why are we here? 2008 revisions to IRB policies, guidelines, and forms. 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. 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. The Compliance Team fields call from investigators and study-team members for clarifications and instructions.

5. Protocol Deviations Definition Definition The term “protocol deviation” is not defined by either HHS human subjects regulations (45 CFR 46) or FDA human subjects regulations (21 CFR 50). 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 Organization Policy 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. 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. Please note that inclusion/exclusion exceptions DO NOT fall under this definition, as they are safety criteria.

6. Types of Deviations & Reporting Requirements Deviations constituting unanticipated problems 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. 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. 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.

7. Types of Deviations & Reporting Requirements (cont.) Major, non-emergent deviations without prior approval Major, non-emergent deviations without prior approval 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. 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, non- emergent deviation occurs without prior IRB approval the event is considered non-compliance. Non- compliance must be reported to the IRB promptly, using the Unanticipated Problems Form. The IRB must approve the request before the proposed change is implemented. If a major, non- emergent deviation occurs without prior IRB approval the event is considered non-compliance. Non- compliance must be reported to the IRB promptly, using the Unanticipated Problems Form.

8. Types of Deviations & Reporting Requirements (cont.) Deviations that are minor or administrative 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.” 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. 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.

9. Types of Deviations & Reporting Requirements (cont.) Deviations involving Investigational Device Exemptions (IDEs) Deviations involving Investigational Device Exemptions (IDEs) 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. 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.

10. Types of Deviations & Reporting Requirements (cont.) Exceptions to Eligibility Criteria for Clinical Trials: 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 (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. 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.

11. Types of Deviations & Reporting Requirements (cont.) For “non-clinical trials,” such as studies not involving drugs, devices, interventions, or are observational, all IRB approved study procedures must be followed, including: For “non-clinical trials,” such as studies not involving drugs, devices, interventions, or are observational, all IRB approved study procedures must be followed, including: Subject enrollment criteria Subject enrollment criteria Consent (if applicable) Consent (if applicable) Procedural compliance Procedural compliance Event/deviation/annual reporting Event/deviation/annual reporting

12. IRB’s Deviation Handling Flow-Chart

13. 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.

14. 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.

15. eIRB FSA “Change in Research”: Mechanism for Reporting Deviations

16. eIRB Continuing Review “Deviation” Summary

17. Protocol Deviation Case-Example #1 Missing a Study Visit: Missing a Study Visit: 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. 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. 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. 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. No other documentation is made. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

18. Case Example #1: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in Research or a minor change requiring 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 on a protocol deviation log. Documentation of the change in schedule should be made on a protocol deviation log. Correct guidance response: Correct guidance response: The change in schedule should be reported at the time of continuing review. The change in schedule should be reported at the time of continuing review. Compliance Tool(s) consideration? Compliance Tool(s) consideration? Use the protocol deviation log to continuously monitor protocol deviations for submission at the time of Continuing Review to the IRB. Use the protocol deviation log to continuously monitor protocol deviations for submission at the time of Continuing Review to the IRB.

19. Protocol Deviation Case-Example #2 Subject non-compliance Subject non-compliance: A study with a strict drug accountability schema requires the subject to return all unused tablets at each subsequent visit. 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. 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 left- over, which she neglects to return. On the subsequent visit the subject’s drug diary indicates tablets 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 protocol. A subject log verifies the subject’s early termination from the protocol. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

20. Case Example #2: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? No, this would not constitute a deviation; the site followed the protocol as written. No, this would not constitute a deviation; the site followed 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/A N/A

21. Protocol Deviation Case-Example #3 Should a subject continue with the study? Should a subject continue with the study? A subject enrolled in a sponsored clinical trial develops a complaint that represents a minor change in her clinical status from baseline. 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 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 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 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 sponsor approves the PI’s request. The PI retains all the correspondence documenting the sponsor’s approval. The PI retains all the correspondence documenting the sponsor’s approval. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

22. Case Example #3: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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, but the IRB must be involved in the process as well. Keeping all correspondence from the Sponsor is a correct response, 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 Change in Research, requesting an exception for one subject. This case involves subject safety, which is why the site would request the exception. 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? Compliance Tool(s) consideration? The site should consider further training on IRB policies in order to be able to accurately address this issue in the future. The site should consider further training on IRB policies in order to be able to accurately address this issue in the future.

23. Protocol Deviation Case-Example #4 Eligibility consideration: Eligibility consideration: An inclusion criterion in a study stipulates that a potential subject’s TSH be <3.0uIU/mL. 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 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. The PI also reasons that flexibility with the TSH criterion will improve enrollment. Subsequent measurements demonstrate a stabilization of the subject’s TSH. 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. 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. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

24. Case Example #4: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? This does not constitute a deviation, this would constitute a Change in Research. This does not constitute a deviation, this would constitute a Change in Research. Is the response correct? Is the response correct? The site should have submitted a Change in Research request, and obtained IRB approval, prior to enrolling the subject in the protocol. 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: Correct guidance response: According to IRB guidance, all inclusion/exclusion exceptions must be approved by the IRB prior to the subject being enrolled into the protocol. 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? Compliance Tool(s) consideration? The site should consider further training of study personnel, as well as the development of SOPs for eligibility determination. The site should consider further training of study personnel, as well as the development of SOPs for eligibility determination.

25. Protocol Deviation Case-Example #5 Retrospective Chart Review: Retrospective Chart Review: A study is IRB approved to enroll adults previously seen in clinic to develop a database of potential subjects for future clinical trials. 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 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 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 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. The PI interprets this departure as insignificant and does not notify the IRB. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

26. Case Example #5: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in Research or a minor change requiring annual 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 to all patients, the site should submit a Change in Research request, and obtain IRB approval, for a change in recruitment methods. 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? Compliance Tool(s) consideration? The site should consider developing a recruitment SOP, and implementing further site training and IRB site review. The site should consider developing a recruitment SOP, and implementing further site training and IRB site review.

27. Protocol Deviation Case-Example #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 patients for the collection of blood samples to be available for future research to isolate unknown genetic markers and develop novel gene therapies. 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. 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. 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 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. The PI does not notify the IRB but makes sure both the parents and minor-aged subjects sign the informed consent form. Discussion: Discussion: Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in 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 response Correct guideline response Compliance Tool(s) consideration? Compliance Tool(s) consideration?

28. Case Example #6: Discussion Is this an administrative change requiring a Change in Research or a minor change requiring annual reporting? Is this an administrative change requiring a Change in Research or a minor change requiring annual 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 Change in Research request prior to changing the study population. 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. 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? Compliance Tool(s) consideration? The site should consider developing training for all site personnel, as well as the development of a consent SOP and checklists. The site should consider developing training for all site personnel, as well as the development of a consent SOP and checklists.

29. Compliance Suggestions Checklists and Logs Checklists and Logs SOPs for assuring protocol compliance and deviation reporting SOPs for assuring protocol compliance and deviation reporting Notes-to-File to account for events, responses, and corrective action plans 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 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

30. Take Home Points… Follow the IRB approved protocol Follow the IRB approved protocol Develop and implement mechanisms such as checklists, SOPs, and Notes-to-File to maximize compliance and minimize deviations 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 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 Make sure to check the IRB’s website regularly for updates and changes to policies and guidances Maintain Transparency Maintain Transparency

31. Contact 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: jschulc1@jhmi.edu rghodga1@jhmi.edu fluthar1@jhmi.edu Regulatory questions concerning recordkeeping requirements may be directed to: Regulatory Affairs Specialists or the Assistant Dean for Human Subjects Research.