CONTINUING NON-COMPLIANCE

Transcription

1 CONTINUING NON-COMPLIANCE Kelley O Donoghue, MPH, CIP Associate VP for Human Subject Protection Kelly Unsworth, MS, CCRC, CIP Director, Research Education & Training 1

2 OUTLINE Introduction & Review of Definitions Case Study #1 Case Study #2 IRB Review Process 2

3 NON-COMPLIANCE Failure to follow the a) Federal, state or local regulations or laws governing the protection of human subjects in research; b) Institutional policies related to human subject research; or c) The requirements or determinations of the RSRB/Reviewing IRB with respect to the conduct of the research as approved. OHSP Policy 802 3

4 CONTINUING NON-COMPLIANCE OLD DEFINITION A pattern of non-compliance that continues despite identification by the RSRB, notice to the Investigator, or prior submission of a corrective action plan. This pattern may or may not result in increased risk to subjects. Although it may be due to a variety of factors, continuing noncompliance implies that an Investigator is either unwilling or unable to develop and apply successful corrective measures. 4

5 CONTINUING NON-COMPLIANCE OLD DEFINITION A pattern of non-compliance that continues despite identification by the RSRB, notice to the Investigator, or prior submission of a corrective action plan. This pattern may or may not result in increased risk to subjects. Although it may be due to a variety of factors, continuing noncompliance implies that an Investigator is either unwilling or unable to develop and apply successful corrective measures. 5

6 CONTINUING NON-COMPLIANCE OLD DEFINITION A pattern of non-compliance that continues despite identification by the RSRB, notice to the Investigator, or prior submission of a corrective action plan. This pattern may or may not result in increased risk to subjects. Although it may be due to a variety of factors, continuing noncompliance implies that an Investigator is either unwilling or unable to develop and apply successful corrective measures. 6

7 CONTINUING NON-COMPLIANCE OLD DEFINITION A pattern of non-compliance that continues despite identification by the RSRB, notice to the Investigator, or prior submission of a corrective action plan. This pattern may or may not result in increased risk to subjects. Although it may be due to a variety of factors, continuing noncompliance implies that an Investigator is either unwilling or unable to develop and apply successful corrective measures. 7

8 WHAT S OUR HISTORY? Since investigations opened - 8 Serious - 5 Continuing 5 determined not to meet the definition - 3 Serious - 2 Continuing 8

9 WHY THE REVISION? Some concern over inconsistency AAHRPP requirement for more documentation regarding non-compliance Will the pattern require more investigations to be opened? Will the current definition cause more determinations of continuing non-compliance, even though we really aren t concerned? 9

10 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

11 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

12 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

13 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

14 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

15 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

16 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

17 NEW/REVISED ELEMENTS 1. Removed the pattern Not necessarily same offense (e.g., lapsed approvals, consent issues, safety concerns) 2. Judgment of the convened board Clearly notes convened board determination Allows for a judgment call by the board 3. Evaluation by the convened board Both events must have board review 17

18 NEW/REVISED ELEMENTS 4. Lack of evidence of effective efforts towards resolution by the Investigator Is the Investigator putting in the effort? Are there extenuating circumstances? Allows for judgment call by the board More specific definition by also more flexibility 18

19 EXAMPLE ROUTINE OHSP-QI REVIEW Overenrolled by 20 Missing regulatory file docs Consent using incorrect version Un-watermarked consents POC did not sign/date Consent signature dates incongruent Consent by unapproved staff Consents with no letterhead Subject signatures/dates in pencil Missing eligibility documentation Enrollment log incomplete FOLLOW-UP OHSP-QI REVIEW Missing regulatory file docs Consent using incorrect version Consent signature dates incongruent Consent by unapproved staff 19

20 CASE STUDIES 20

21 CASE STUDY DISCLAIMERS Although inspired in part by true incidents, the following stories are fictional X 21

22 CASE STUDY #1 22

23 CASE STUDY #1: PROTOCOL SYNOPSIS Investigator-initiated, observational study of adults with planned travel to countries/territories with active Zika virus transmission Methods & Procedures 2 study visits 1 prior to travel and one within 10 days of their return - Includes physical exam, medical hx review, lumbar puncture and blood testing During travel subjects complete daily questionnaires - Mosquito exposure, insect repellent use, physical symptoms, safe sexual behaviors After post-travel study visit, subjects call once/month for 6 months to verify pregnancy status Subjects who become pregnant will be asked to enroll in an observational, minimal risk sub-study with a separate consent form - Female partners of males enrolled in the original study will be eligible 23

24 CASE STUDY #1: THE START OF OUR STORY At the time of Continuing Review #3, the specialist notes: All continuing reviews have been submitted to date have been submitted after the study s expiration date (all have resulted in lapses in approval) Last signed consent was not watermarked - Coordinators response: The sub-investigator who obtained consent from this subject was unaware that consent forms needed to be watermarked. One other subject was enrolled during this reporting period by this investigator with an un-watermarked form. I have reviewed this requirement with them. Board provided reminder to study teams re: timely review of CRs; no further follow-up required regarding consent issue Non-compliance? Continuing non-compliance? 24

25 CASE STUDY #1: CONTINUING REVIEW #4 Prior to the board meeting Specialist notes that the last signed consent indicates that consent was obtained by an unapproved study team member During the board meeting The Primary Reviewer reviews each of the last signed consents submitted with each of the previous Continuing Reviews - 1 st CR = no letterhead - 2 nd CR = ok - 3 rd CR = no watermark Non-compliance? Continuing non-compliance? 25

26 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

27 CASE STUDY #1: BOARD-DIRECTED OHSP-QI REVIEW Site reported 33 subjects enrolled Scope of Review = Random sample of 8 subject research charts reviewed Rating = Unacceptable 27

28 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 1. RSRB approval lapsed during the following time periods: 01JUL JUL2013; 01JUL JUL 2014; 01JUL JUL2015. No enrollment occurred during these time periods, however Subject 08FJ completed Visit 2 on 03JUL2014. Investigator s Response: This was completed in error. The resident conducting the study visit was unaware of the lapse. Investigator s Preventative Action Plan: Future continuing reviews will be submitted well in advance to prevent lapses in approval. 2. Multiple regulatory documents were not present in the regulatory file. The missing items represent 65% of the expected regulatory file contents. Investigator s Response: We were not aware that we need to maintain copies of approved documents beyond RSRB approval letters. Investigator s Preventative Action Plan: Moving forward, we will save copies of all RSRB approved documents. 28

29 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 3. The signed consent form was the correct version, but did not include the watermark for the following subjects: 01MP, 03NK, 08 FJ, 13MR & 15MS. Investigator s Response: The individuals who obtained consent for these subjects were unaware of the requirement concerning the watermark. They have since been made aware of the requirement. Investigator s Preventative Action Plan: Study team members will be reminded of the RSRB s consent requirements at future study team meetings. 4. The signed consent forms for the following subjects are not an original; a copy is in the subjects research chart: 03NK, 13MR & 15MS. Investigator s Response: These subjects were inadvertently provided the original signed consent instead of a copy, instead of retaining the original for ourselves. We ve documented this error in our files. Investigator s Preventative Action Plan: The study team has been reminded to keep the original copies of the signed consent forms, providing only copies of the document. 29

30 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 5. Consent was obtained by UR staff who were not RSRB-approved members of the study team for the following subjects: 18SW & 20AO. Investigator s Response: This was an error. Prior to enrolling Subject 18, we initiated the amendment to add the study team member who enrolled both of these subjects. Unfortunately, we failed to hit the submit button right away and the amendment was not approved until after the subject was enrolled. Investigator s Preventative Action Plan: The investigator will ensure that all new study team members are approved prior to permitting them to enroll subjects. 6. There was no documentation in the research chart to indicate that eligibility was confirmed for the following subjects: 05MJ & 15MS. Investigator s Response: Eligibility is always confirmed by either the Investigator or one of the co-investigators but it appears that the Inclusion/Exclusion Criteria Checklist was either not completed or was lost for these subjects. Investigator s Preventative Action Plan: This discrepancy was documented in a Note to File for Subject 05MJ (his participation is already complete). Eligibility will be re-confirmed and documented with Subject 15MS during his next monthly phone call. 30

31 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 7. There is no documentation to indicate that the protocol-defined telephone adverse event assessment was conducted following lumbar puncture procedures have been conducted. Investigator s Response: These were conducted (no adverse events were reported); they just weren t documented. Investigator s Preventative Action Plan: We have created a Telephone Log to document this procedure and all post-travel follow-up phone calls. Notes to file have been created and filed for all subjects with missing documentation of prior phone-related procedures. 8. There is no documentation to indicate that the post-travel telephone calls to verify pregnancy have been conducted. Investigator s Response: These were conducted using the telephone script approved by the RSRB; they just weren t documented. Any pregnancies that were reported were offered participation in the sub-study; agreement of which were documented via the sub-study consent form. Investigator s Preventative Action Plan: See above. 31

32 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 9. The following subjects completed post-travel study visits at a time point greater than the protocol-specified window (within 10 days of travel return): 01MP, 05MJ, 08FJ, 15MS & 18SW. Investigator s Response: We have had trouble scheduling subjects for their post-travel study visit within the protocol-defined window. We ve documented these in a Protocol Deviation Log. Investigator s Preventative Action Plan: The protocol will be amended to extend the post-travel study visit window. 10.Subject 08FJ: There is no documentation to indicate that the pre-travel study visit (i.e. baseline) was completed. Investigator s Response: Subjects 08 and 09 completed pre-travel visits on the same day. After the review was conducted, pre-travel study visit documentation was located in Subject 09 s research chart. Investigator s Preventative Action Plan: N/A. 32

33 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS 11. Subject 13MR: There is no documentation of sub-study consent, however a sub-study visits were completed on 15NOV2014, 21AUG2015 & 05JAN2016. Investigator s Response: Sub-study consent was obtained from this subject prior to conducting study procedures, however it appears that the document has been misplaced. Re-consent from this subject will be obtained via mail and the error documented in a Note to File. Investigator s Preventative Action Plan: N/A. 33

34 CASE STUDY #1: BOARD-DIRECTED REVIEW FINDINGS SUMMARY Lapse in approval (x3), with a study visit conducted during 2 nd lapse Missing regulatory file documentation (65%) Consents with no watermark (5 subjects) No original consents kept, only copies (3 subjects) Unapproved personnel obtained consent (2 subjects) No documentation confirming eligibility (2 subjects) No documentation of post-lumbar puncture telephone call (all subjects) No documentation of post-travel monthly phone calls (all subjects) Post-travel study visits out of window (5 subjects) Missing documentation of pre-travel study visit (1 subject) Missing sub-study consent (1 subject) Continuing non-compliance? 34

35 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

36 CASE STUDY #1: PREVENTATIVE ACTIONS We will Submit CRs in a timely manner Ensure study personnel are added prior to obtaining consent Document post-travel calls in Telephone Log Amend the protocol to extend post-travel visit window Remind (re-train?) staff on Consent requirements N/A 36

37 CASE STUDY #1:BOARD-DIRECTED 6 MONTH OHSP-QI RE-REVIEW Site reported 10 additional subjects enrolled since the previous OHSP-QI review Scope of Review = Random sample of 6 subject research charts reviewed Rating = Acceptable with Follow-Up 37

38 CASE STUDY #1: 6 MONTH RE-REVIEW FINDINGS 1. Multiple regulatory documents were not present in the regulatory file. This missing items represent 20% of the expected regulatory file contents. Investigator s Response: We inadvertently forgot to download and file the recruitment flyer that was rewatermarked with the last continuing review and amendment. This has since been done. Investigator s Preventative Action Plan: Moving forward, the study coordinator is going to QA the regulatory file once a year at the time of continuing review to ensure that all documents are appropriately downloaded and filed. 38

39 CASE STUDY #1: 6 MONTH RE-REVIEW FINDINGS 2. An incorrect version of the consent form was used to consent Subjects 32PS and 38JK. There was one modification regarding subject payment between the two documents. Investigator s Response: The study file containing blank consent forms for enrollment was not updated following the amendment that revised the subject payment. We reviewed our remaining consent forms and found that Subjects 31 and were also consented using the wrong form. We will re-consent these individuals via mail. Investigator s Preventative Action Plan: We will no longer maintain a file of blank consent forms for use, instead study members will print current, watermarked consent forms directly from ROSS for use. 39

40 CASE STUDY #1: 6 MONTH RE-REVIEW FINDINGS 3. The following subjects completed post-travel study visits at a time point greater than the protocol-specified window (within 10 days of travel return): 29MB and 41DH. Both incidents were documented in the Protocol Deviation Log. Investigator s Response: Extending the study visit window has helped ensure appropriately scheduling of post-travel study visits, however it is not perfect. Regarding the subjects listed above, we knew ahead of time that Subject 29MB would be out of the window because he was ill and had to postpone the visit and Subject 41DH was simply a mistake (though we realized the error after the fact and documented it). Investigator s Preventative Action Plan: The study coordinator has inserted visit window field into her subject tracking sheet. The fields are automatically calculated based on concrete data entered in other cells within the spreadsheet. Utilizing this should help eliminate the errors we ve experienced in scheduling. 40

41 CASE STUDY #1: 6 MONTH RE-REVIEW FINDINGS 4. Subject 27BB: The signature and date lines for Investigator were incomplete on the Inclusion/Exclusion Criteria Checklist. Investigator s Response: This was just an oversight. Investigator s Preventative Action Plan: The coordinator will review documentation for completeness following each in-person study visit, regardless of who conducts the visit (be that an investigator, co-investigator, etc). In an effort to improve this process, she will create a checklist to aid the review of these forms. 41

42 CASE STUDY #1: 6 MONTH RE-REVIEW FINDINGS 5. Subject 32PS: The date the subject signed the consent form is blank; therefore, it cannot be determined if the subject signed the consent form prior to study procedures being conducted. Investigator s Response: The research assistant who enrolled this subject verified that consent was obtained prior to conducting procedures; she didn t realize the document was not dated. We will document this error in a Note to File. Investigator s Preventative Action Plan: Given the issues that have been identified concerning consent both with this review, as well as the previous review, the PI is going to dedicate an upcoming study team meeting to the topic to review expectations. Personnel that are unable to attend will have to meet with the PI and/or study coordinator individually. 42

43 CASE STUDY #1: RE-REVIEW FINDINGS SUMMARY Missing regulatory file documentation (20%) QA regulatory file Incorrect version of consent (2 subjects) Printing blank consents directly from ROSS Post-travel study visits out of window (2 visits) Added field visit windows into tracking spreadsheet Missing Investigator signature on eligibility checklist (1 subject) Reviewing for completeness & creating checklist to do so Missing subject signature date (1 subject) Dedicated study team meeting to review Investigator responses? Continuing non-compliance? 43

44 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

45 WHAT IF Findings looked more like this: More lapses in approval Missing regulatory document >20% Wrong version of consent for all subjects after amendment, with no watermark More missing eligibility forms More missed post-travel phone follow-up More visits out of window 45

46 CASE STUDY #2 46

47 CASE STUDY #2: PROTOCOL SYNOPSIS Multi-center, randomized, placebo-controlled study of SupplementWIN on exercise performance and muscle recovery in competitive athletes aged Methods & Procedures = 1 year of study drug intervention with: Regular physical examinations, clinical labs, speed, endurance, strength and agility testing Daily study diaries that collect information pertaining to: workout schedules, study drug compliance, adverse events, and physical signs/symptoms (e.g., muscle soreness) Optional blood draws (stored for future use) collected at baseline, 6 months and 1 year. Exclusion Criteria: high blood pressure medications, anticoagulants, pregnancy, prior/current use of anabolic steroids and elevated kidney and/or liver function levels IND is held by the PI of the coordinating center at the University of Athletes; the UR is an enrolling site only Locally, the study team is expected to enroll 20 subjects 47

48 CASE STUDY #2: THE START OF OUR STORY Routine OHSP-QI Review Conducted approximately 2 months following RSRB approval Site reported 4 subjects enrolled at the time of the review Scope of Review: - All signed consent forms were reviewed - Random sample of 3 subject research charts reviewed Rating = Acceptable with Follow-Up 48

49 CASE STUDY #2: ROUTINE REVIEW FINDINGS 1. Documentation of signatures and initials of study personnel authorized to make entries and/or corrections on data collection forms was not present in the regulatory file (often referred to as a Signature Log). Investigator s Response: The data collection forms used for this study were created by, and provided to enrolling sites, by the coordinating center at the University of Athletes. As a signature log was not included with these forms, we incorrectly assumed it was not required for this study. We ve since created a Signature Log, in collaboration with the coordinating center, and have completed it accordingly. Investigator s Preventative Action Plan: All new study personnel will be added to the Signature Log accordingly, as part of our onboarding procedures. With future FDA-regulated research, we will utilize the OHSP Study Start-Up Consultation Service prior to study initiation to ensure we have adequately planned for our study documentation. 49

50 CASE STUDY #2: ROUTINE REVIEW FINDINGS 2. A list of study personnel to whom the investigator has delegated significant trialrelated duties was not present in the regulatory file (often referred to as a Delegation of Authority Log). Investigator s Response: As above, this documentation was not provided by the coordinating center. We ve since created a Delegation of Authority Log and have completed it accordingly. Investigator s Preventative Action Plan: As above, all new study personnel will be added to the Delegation of Authority Log, as part of our onboarding procedures. 3. Documentation of the location and identification of retained blood samples for future research was not present in the regulatory file (often referred to as a Specimen Tracking Log). Investigator s Response: Same as above. We ve since created a Future Use Specimen Tracking Log, in collaboration with the coordinating center, and have completed it accordingly. Investigator s Preventative Action Plan: Same as above re: OHSP Study Start- Up Consultations. 50

51 CASE STUDY #2: ROUTINE REVIEW FINDINGS 4. Per the study protocol, the PI will assure the appropriate training relevant to study procedures is given to all study personnel involved in the investigation. Documentation of this training is not present in the regulatory file. Investigator s Response: This training was completed by the coordinating center prior to study initiation and we continue to have quarterly teleconferences with the project manager. We have obtained documentation to demonstrate this and, going forward, will save copies of the meeting minutes from our quarterly teleconferences in our regulatory file. Investigator s Preventative Action Plan: Same as above re: OHSP Study Start-Up Consultations. 51

52 CASE STUDY #2: ROUTINE REVIEW FINDINGS 5. Documentation identifying subjects who enrolled in the study is incomplete; Subject 004/JE is not listed (consent signed 16APR2015) on the Screening/Enrollment Log. Investigator s Response: This was an oversight. All remaining subjects were promptly entered into the Screening/Enrollment Log. Investigator s Preventative Action Plan: Given the administrative burden of onboarding newly enrolled subjects, the study coordinator has created a Subject Enrollment Checklist. This checklist, which includes entering subjects on the Screening/Enrollment Log, will be completed for all newly enrolled subjects. 52

53 CASE STUDY #2: ROUTINE REVIEW FINDINGS 6. The reviewer did not find documentation of the subjects study participation in the electronic health record which is inconsistent with IRB-approval. Investigator s Response: This was an oversight. Electronic health records for all enrolled subjects have now been updated to reflect study participation (i.e., patient records have been flagged and scanned copies of the signed consent form have been uploaded into the record). Investigator s Preventative Action Plan: Flagging enrolled subjects and uploading scanned copies of the consent form into the electronic health record has been added to the Subject Enrollment Checklist listed above. 53

54 CASE STUDY #2: ROUTINE REVIEW FINDINGS 7. Documentation to indicate protocol-specified laboratory assessments were completed was not present in any reviewed subjects research charts. Investigator s Response: All clinical laboratories are sent to a central laboratory, the results of which are ed to the principal investigator and study coordinator. This documentation has been maintained electronically and can be provided to the reviewer, if necessary. No results were clinically significant. Investigator s Preventative Action Plan: All laboratory results will be printed and filed in the subjects research chart going forward. 54

55 CASE STUDY #2: ROUTINE REVIEW FINDINGS 8. Subject 001/AW: correspondence with the study coordinator was present in the subject s research chart, however a Research Subject Consent Form was not present in the study files. Investigator s Response: The study team does not routinely subjects and was unaware that this was required. We will obtain Research Subject Consent from this subject at her next visit. Investigator s Preventative Action Plan: Going forward, Research Subject Consent will be obtained prior to ing any subjects who wish to communicate electronically. 55

56 CASE STUDY #2: ROUTINE REVIEW FINDINGS 8. Subject 001/AW (Continued): The Visit 2 Case Report Form is incomplete; the checkbox confirming that the Concomitant Medication Log was reviewed with the subject was not completed. Investigator s Response: This was an oversight this was completed but we missed checking the box (the subject had no changes). The coordinating center identified this error remotely once the visit s data had been entered in the electronic data capture system. We have printed a copy of this notification and our response to the coordinating center to document the error in our source documentation. Investigator s Preventative Action Plan: The study coordinator will review case report forms for completeness following each study visit and document any discrepancies accordingly. 56

57 CASE STUDY #2: ROUTINE REVIEW FINDINGS 9. Subject 003/BM: The date of the subject s signature on the consent form (31MAR2015) and the date of the person obtaining consent s signature (05APR2015) are not congruent. The RSRB-approved consent process indicates consent will be obtained by study staff in person, therefore it is expected that the dates would be the same. Investigator s Response: This subject was mailed the consent form prior to his screening visit for review (prior to which the study was reviewed with him verbally over the telephone with the study coordinator). He then arrived to the screening visit with the form already signed. After further review of the study with the subject, prior to conducting screening visit procedures, the study coordinator signed and dated the form. Investigator s Preventative Action Plan: The appropriate process, based on the approved protocol, and RSRB expectations were reviewed with the OHSP-QI reviewer during the PI meeting; this information has since been reviewed with the remainder of the study team. Going forward, if potential subjects arrive to screening visits with a signed/dated consent a new consent form will be completed. 57

58 CASE STUDY #2: ROUTINE REVIEW FINDINGS 10. Subject 004/JE: The consent form option section regarding blood specimen retention for future use was not completed. Given the subject did not provide permission to collect or retain this sample, the sample should not have been collected. The reviewer was unable to determine if the sample was collected. Investigator s Response: This blood sample was collected and retained; however at the time of collection the study subject was agreeable to completing the procedure and storing the specimen. Failing to note that the checkbox was incomplete to begin with and then neglecting to review the information at the time of the blood draw (which occurs 1 visit following enrollment, at the Baseline Visit, as opposed to at the time of enrollment [the Screening Visit]) was an error on the part of the study team. Investigator s Preventative Action Plan: The study coordinator has included reviewing checkbox options on signed consent forms on the Subject Enrollment Checklist referenced above. In the event a subject either leaves the box blank or indicates that they do not wish to complete the procedure, the study coordinator will flag this procedure for the following visit (the Baseline Visit) and either reconsent the subject, ensuring the checkbox option is complete, or ensure the blood draw is not completed. 58

59 CASE STUDY #2: REVIEW FINDINGS SUMMARY FINDINGS Missing regulatory file docs Incomplete enrollment log No documentation in EHR Lab results not in subject charts No consent (1 subject) Incomplete CRF (1 subject) Incongruent consent signature dates (1 subject) Incomplete checkbox options (1 subject) PREVENTATIVE ACTIONS OHSP Study Start-Up for FDAregulated research Subject Enrollment Checklist for new subject onboarding Printing/filing lab results Obtaining consent Reviewing CRFs for completeness Re-training study team on consent signature dates Reviewing checkbox options & flagging future use specimens Continuing non-compliance? 59

60 CASE STUDY #2: REPORTABLE EVENT #1 Incident of non-compliance Submitted ~10 months after study approval 1 subject who should have failed screening was inadvertently enrolled - Subject self-reported a daily aspirin regimen (due to a prior deep vein thrombosis) at screening (REMINDER: EXCLUSION INCLUDES ANTICOAGULANTS) - Subject received only 2 weeks of intervention, therefore the likelihood that the subject s risk of thrombosis increased due to study participation is low 60

61 CASE STUDY #2: REPORTABLE EVENT #1 (CONT )..this was an oversight on part the part of the study coordinator as it was not clear on the eligibility form that aspirin was a disallowed medication. Error identified by study monitor during routine monitoring visit At the time of the visit, the monitor met with the PI and study coordinator to review the incident, current enrollment practices & requirements concerning eligibility verification by PI Continuing non-compliance? 61

62 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

63 CASE STUDY #2: CONTINUING REVIEW #1 8 of 20 requested subjects have been enrolled 6 currently undergoing intervention 1 self-withdrew due to ongoing symptoms of nausea 1 withdrawn by study team due to ineligibility (RE #1) Last signed consent is in order 63

64 CASE STUDY #2: CONTINUING REVIEW #1 (CONT D) Monitoring Report (dated 6 months prior): Cites the following areas of concern: - Multiple protocol deviations (5 of 8 subjects have had study visits out of window & at multiple time points either the strength, speed or agility testing were not completed) - Untimely review by PI of safety lab reports, subject diaries (specifically, the signs/symptoms reported within them) and adverse events - Untimely and inaccurate submission of study data by the study team to the coordinating center Includes CAPA agreed upon at visit Follow-up monitoring visit scheduled in 6 months Continuing non-compliance? 64

65 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

66 CASE STUDY #2: BOARD-DIRECTED OHSP-QI REVIEW Site reported 8 subjects enrolled since the previous OHSP-QI review (total of 12) Scope of Review: All 8 signed consent forms were reviewed Random sample of 5 subject research charts reviewed Rating = Unacceptable 66

67 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 1. The following documents approved with Continuing Review #1 were not present in the regulatory file: RSRB Approval Letter, Watermarked Consent Form, Recruitment Flyer, Recruitment Brochure. Investigator s Response: The OHSP-QI review occurred within a week of RSRB re-approval. The study team did not have time to update the regulatory file; this has since been completed. Investigator s Preventative Action Plan: As we ve previously done, the study coordinator will continue to update the regulatory file as approvals are provided. 2. The Future Use Specimen Tracking Log is incomplete; Subjects 006/DD and 011/MJ agreed to, and completed blood draws, but their specimens are not listed. Investigator s Response: This was an error on the part of the study coordinator. These samples have now been entered into the log. Investigator s Preventative Action Plan: N/A 67

68 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 3. correspondence with the study coordinator was present; however Research Subject Consent Forms were not present in the study files for the following subjects: 005/CL, 009/CA, 011/MJ, and 012/GL. Investigator s Response: The current study coordinator was unaware of this requirement (the coordinator that was present for the initial routine review of this study has since left the department). In follow-up, Research Subject Consent has been obtained from Subject 005/CJ and will be obtained from Subject 009/CA, 011/MJ & 012/GL at their next visit. Investigator s Preventative Action Plan: Obtaining Research Subject Consent from subjects at the time of enrollment has been added to the Subject Enrollment Checklist. Subjects who refuse to provide consent will not have their address collected on demographics form. 4. The signature and date lines for Investigator were incomplete on the Eligibility Checklist for the following subjects: 005/CL and 012/GL. Investigator s Response: This was an oversight. Either the PI or Co-Investigator are present at each Screening visit and verify enrollment. In these cases, the signature was simply missed. Investigator s Preventative Action Plan: The study coordinator will review all forms for completeness at the end of each study visit. 68

69 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 5. The Study Drug Accountability Log indicates that Subjects 0011/MJ and 012/GL were dispensed incorrect study drug kits per the Randomization Log. Subject 011/MJ received Kit2L and should have received Kit2K; Subject 012/GL received Kit2K and should have received Kit2L. Investigator s Response: All study drug kits are provided by the coordinating center and maintained in a locked cabinet in the study coordinator s office. When Subject 011/MJ completed her baseline visit and study drug was dispensed, a back-up coordinator was covering for the primary coordinator; he inadvertently grabbed the wrong kit. The unused kit that should have gone to Subject 011/MJ was then dispensed to the following subject (Subject 012/GL). Investigator s Preventative Action Plan: The coordinating center has been notified of this deviation. Drug dispensing and accountability practices were reviewed at the last study team meeting to prevent future errors. 69

70 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 6. The following study visits were conducted at a time point greater than the protocol-specified window (ten days before or after the expected visit date): Subject 006/DD Subject 009/CA Subject 012/GL Visit 2 (3 days out of window) Visit 2 (5 days out of window) Visit 3 (3 days out of window) Visit 3 (1 day out of window) Visit 4 (2 days out of window) Investigator s Response: Based on training and work schedules, it is occasionally difficult to get subjects in for visits within the specified time frame. Subjects also often have to reschedule study visits due to last minute conflicts, which sometimes pushes re-scheduled visit outside of the visit window. The incidents listed above were only marginally outside of the visit window (a maximum of 5 days). Investigator s Preventative Action Plan: The study coordinators will provide reminder phone calls to subjects at least 5 days prior to study visits, in an effort to potential identify conflicts and re-schedule visits in a timelier manner 70

71 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 7. Documentation to indicate the following protocol-specified procedures were completed was not present in the subjects research charts. Subject 006/DD Subject 009/CA Subject 011/MJ Subject 012/GL Visit 2 Agility Testing Visit 3 Speed Testing Visit 3 Strength Testing Visit 3 Agility Testing Visit 6 Strength Testing Visit 3 Strength Testing Visit 4 Strength Testing Investigator s Response: As mentioned above, subject scheduling can be difficult based on the time commitment. In some cases, subjects have requested to skip certain procedures in order to shorten the study visit. We also experienced a calibration issue with our Biodex testing system (the machine used to complete the strength testing). Once we identified the issue, strength testing was suspended until the machine was fixed. Investigator s Preventative Action Plan: In the future we ll document when and why procedures aren t completed. 71

72 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 8. The following laboratory assessments were reviewed outside of the protocol-specified window of two weeks after receipt by the Investigator. Subject 005/CL Subject 006/DD Subject 011/MJ Subject 012/GL Visit 3 (2 days out of window) Visit 6 (10 days out of window) Visit 3 (10 days out of window) Visit 6 (21 days out of window) Visit 2 (14 days out of window) Visit 5 (8 days out of window) Visit 2 (32 days out of window) Visit 4 (17 days out of window) Investigator s Response: Due to heavy workload and/or travel, the review of these laboratory reports were not completed in a timely manner. Nor did we realize there was a protocol-specified window for completing this review. Investigator s Preventative Action Plan: Rather than providing these reports to the Investigator s secretary to pass off to the PI to review, the coordinator will ensure timely manner by bringing reports with her and requesting sign-off at in-person meetings with the PI. 72

73 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 9. Subject 005/CL: The consent form option section regarding blood specimen retention for future use was indicated no, however a specimen is documented as collected and retained in the Future Use Specimen Log. Given the subject did not provide permission to collect or retain this sample, the sample should not have been collected. Investigator s Response: This blood sample was collected and retained in error. The specimen has been destroyed. Investigator s Preventative Action Plan: Consent will be verified prior to conducting the Baseline Study Visit, when the blood draw is conducted. There was no documentation of an adverse event; the AST laboratory assessment at Visit 8 meets the definition of a clinically significant abnormality as defined by the study protocol. Investigator s Response: This lab value was flagged by the central laboratory and reviewed, but we did not feel it was clinically significant. Per discussion with the OHSP-QI reviewer, we recognize that, aside from our assessment this should have been reported per the study protocol. This event has since been reported to the coordinating center Investigator s Preventative Action Plan: All future clinically significant events will be reported as described in the study protocol. 73

74 CASE STUDY #2: BOARD-DIRECTED REVIEW FINDINGS 10. Subject 006/DD: There was no documentation to indicate that the Visit 6 pregnancy test was completed. Investigator s Response: Per the study coordinator, at Visit 6 the subject selfreported amenorrhea for the previous year and indicated that she did not want to complete the test, therefore the test was not completed. The subject agreed to report when and if she experiences break through bleeding or menstruation in the future, so that testing can be completed accordingly. Investigator s Preventative Action Plan: Going forward, all pregnancy testing will be completed as defined by the study protocol. 11. Subject 011/MJ: The exclusion criterion concerning prior use of anabolic steroids is crossed out on the Eligibility Checklist with no indication of who crossed it out or why. Investigator s Response: During screening, this subject initially denied prior use of anabolic steroids so the checkbox was marked. She then changed her answer, so the criterion was crossed out. Upon further discussion, we determined that she was referencing a supplement, not the use of anabolic steroid. In retrospect, our documentation concerning this exclusion criterion should have been more clear. Investigator s Preventative Action Plan: A Note to File has been placed in the subject s file to clarify the discrepancy. 74

75 CASE STUDY #2: REVIEW FINDINGS SUMMARY Missing regulatory files (all from CR#1) Specimen Log incomplete No consent (4 subjects) Missing Investigator sign-off on eligibility (2 subjects) Incorrect dispensing of study drug (2 subjects flip-flopped) Study visits out of window (5 visits) No documentation of study procedures (7 procedures) Untimely lab review (8 lab reports) Collection/storage of blood without consent (1 subject) Missing AE documentation (1 subject) Missing pregnancy test (1 subject) Exclusion criterion cross-out (1 subject) Continuing non-compliance? Anything else?? 75

76 CONTINUING NON-COMPLIANCE REVISED DEFINITION (OHSP POLICY 802 V2.0) Non-compliance that, in the judgment of the convened board, persists when there is: a) evaluation by the convened board, b) notice to the Investigator, c) prior submission of a corrective action plan(s), and d) lack of evidence of effective efforts towards resolution by the Investigator. These events may or may not result in increased risk to subjects and may be due to a variety of factors. The non-compliance might imply that an Investigator is either unwilling or unable to develop and apply successful corrective measures. OHSP Policy

77 IRB REVIEW 77

78 RSRB REVIEW PROCESS Notification If Yes: Potentially Serious or Continuing? Review by Board Chair & Board Specialist: Basis in fact? Credible? If No: No Further Action If Yes: Full Board Review If No: Chair, Specialist Review CAPA Exception: All OHSP-QI undergo FB review OHSP Policy 802 OHSP Guideline for RSRB Review of Allegations of Non-Compliance 78

79 FULL BOARD REVIEW PROCESS Referral to Board: Potentially Serious or Continuing? If Yes, Open an Investigation Notify Investigator, Opportunity to Respond If No, Review CAPA Compile Additional Documentation, Consult with Office of Counsel Board Meeting, Vote on Determination OHSP Policy 802; OHSP Guideline for RSRB Review of Allegations of Non-Compliance 79

80 IRB REPORTING REQUIREMENTS Determinations of serious or continuing noncompliance (or suspension/ termination) require reporting to: Institutional officials IO (Senior VP for Research), Dept Chair, Legal Regulatory authorities OHSP, FDA Study sponsors OHSP Policy 403; OHSP Policy 802; OHSP Guideline for RSRB Review of Allegations of Non-Compliance 80

81 LESSONS LEARNED Continuing non-compliance can stem from multiple sources, across multiple studies Thoughtful CAPAs are a MUST Are you investigating the root cause and responding accordingly or are you brushing it under the carpet? Is the plan something you can/will follow through with? Don t neglect bigger picture issues Other risk areas: Staff turnover, onboarding new staff Enrolling sites participating in multi-site research 81

82 QUESTIONS? Cartoonist: Don Mayne ( References Office for Human Subject Protection Policy 802 Non-Compliance in Human Subject Research. (2016, August 1). Retrieved November 18, 2016, from Office for Human Subject Protection Guideline for RSRB Review of Allegations of Non-Compliance. (2016, August 1). Retrieved November 18, 2016 from 82