Noncompliance: Deviations, Solutions and Corrective Actions

1. 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

2. 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

3. 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

4. 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

5. COMMON DEVIATIONS #9Not following Departmental or Internal Standard Operating Procedures (SOPs) Best Practice: • Be familiar with your department SOPs/internal policies (as applicable)

6. COMMON DEVIATIONS #8Late 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…”

7. 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: • adversely affect the rights and welfare of participants; • 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; • compromise the integrity or validity of the research; or • result from willful or knowing misconduct on the part of the investigator(s) or study staff.”

8. 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.”

9. #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

10. COMMON DEVIATIONS #7CONSENT, 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 IRB-approved version • Consenting is a PROCESS (IRB consent and HIPAA authorization), not just a signature.

11. COMMON DEVIATIONS #6MORE 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.

12. 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.

13. COMMON DEVIATIONS #4 Not reconsentingsubjects 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

14. COMMON DEVIATIONS #3Not 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

15. COMMON DEVIATIONS #2Poor/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

16. COMMON DEVIATIONS #1Enrolling 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.

17. 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.

18. 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.

19. 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)

20. 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.

21. Case Scenarios

22. 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.

23. Case Scenario#1: What would be an acceptable CAPA for this deviation? • 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. • 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. • As provided by the PI, a CAPA is not necessary for this deviation.

24. 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.

25. Case Scenario# 2: What action is missing from the provided CAPA? • 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.

26. 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).

27. Case Scenario#3: How could this deviation have been prevented? • 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.

28. 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.

29. Case scenario#4: How could this deviation have been prevented? • 5 and 7 months is still an acceptable time frame to submit protocol amendments to the IRB. • 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. • Once the study was closed to enrollment,the study was no longer obligated to promptly submit amendments to the IRB.

30. 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.

31. Case Scenario # 5 How could this deviation have been prevented? • 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. • 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 4-6). 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. • 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.

32. Questions?