Ineligible Subjects: Common Causes and Tips for Prevention Human Research Protection Program (HRPP) HRPP Compliance and Quality Team Yale University

Agenda Yale IRB Policy and the Enrollment of Ineligible Subjects Why is it so important to enroll subjects that meet study criteria? Procedure for Single Subject Protocol Modification/Deviation Examples of Ineligible Subject Deviations FDA 483 Finding based on the Enrollment of Ineligible Subjects Tips to Help Prevent the Enrollment of Ineligible Subjects

Yale IRB Policy and the Enrollment of Ineligible Subjects

HRPP Policy 700: Noncompliance, Suspension and Termination 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: 1. adversely affect the rights and welfare of participants; 2. harm or pose an increased risk of substantive harm to a research participant; 3. result in a detrimental change to a participant’s clinical or emotional condition or status; 4. compromise the integrity or validity of the research; or 5. result from willful or knowing misconduct on the part of the investigator(s) or study staff Serious Noncompliance example includes: “Enrolling participants who fail to meet the inclusion or exclusion criteria in a protocol that involves greater than minimal risk and that in the opinion of the IRB Chair, designee, or convened IRB, places the participant(s) at greater risk”

Question: Do Eligibility Waivers Require Prospective IRB Approval?

Answer: Yes! Eligibility exceptions/waivers require IRB review AND approval before a prospective participant, who does not meet protocol inclusion/exclusion criteria, can be enrolled.

700. PR6 Procedure for Single Subject Protocol Modification/Deviation FOR ONE-TIME REQUEST ONLY http://www.yale.edu/hrpp/policies/index.html

Single Subject Protocol Modification/Deviation Procedure Highlights The IND regulations at 21 CFR 312.66 require that the Investigator not make any changes in the research without IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.  If there is to be a planned deviation relating to eligibility or significant changes to the protocol, an MOD accompanied by a letter of concurrence from the sponsor, must be submitted in IRES IRB then acknowledged by an HIC Chairperson PRIOR to implementation. Upon receipt of the request for a single subject protocol modification/deviation, an HIC Chairperson will review the request and respond to the Investigator in writing. Every effort will be made to respond to each request with 24-48 hours.

Single Subject Protocol Modification/Deviation Procedure Process Submit the request as a modification (MOD) in IRES IRB. It is also recommended that you also call the IRB to notify them of the submission. If the modification is approved, you will get an email notification. If you do not hear back by the requested date, call your IRB regulatory analyst. If the IRB is unable to review and approve the request, DO NOT proceed with the change. It will be considered a deviation, which might be a serious non-compliance.

Single Subject Protocol Modification/Deviation Procedure Caveats The MOD cannot be used for more than ONE subject (an amendment to the study must be submitted instead). The MOD cannot be used for routine, non-significant reporting of issues (such as out-of- window or rescheduled visits). If the investigator is also the sponsor (as in an investigator-initiated trial), a MOD may NOT be used. An amendment to the study must be submitted instead. An investigator must receive both Sponsor and IRB approval before initiating any change to the research unless the change is intended to eliminate an apparent immediate hazard to subjects, in which case it may be implemented immediately provided the IRB is subsequently notified in accordance with 21 CFR 56.104(c). In this case, the change should be reported to the HIC as a deviation (RNI in IRES). Important Note: The IRB will not consider a request for modification unless the Sponsor has provided written approval.

Ineligible Subject Deviations Reported to the Yale IRB and Common Deviation Causes

Case Example 1 During a recent monitoring visit of HIC #123, a study monitor noted that subject “ET” was not eligible for the study. Inclusion criteria #2 states: “Participants must have traveled to a country affected by the Zika virus within 120 days of being enrolled.” The subject was consented into this study on February 17, 2016. The subject traveled to Brazil and returned to the US on November 13, 2014. Root Cause Analysis: When the subject was consented for this study the person obtaining consent did not clarify the year of travel with Subject ET when he responded “November 13th” and assumed it was 2015. The coordinator counted 3 months for this subject’s return to the US (Dec, Jan, Feb). However, even if the date was November 13, 2015, this date would still have been out of window making the subject ineligible for the study. Corrective and Preventative Action (CAPA) plan: Retraining on consenting and eligibility requirements for all study staff (PI too), document training and attendance in the team meeting minutes. The eligibility checklist was revised to better outline, capture and detail dates of travel, with a prompt counting backwards to the last potential day that the subject could have been eligible.

Case Example 2 A new coordinator took over HIC # 789. While reviewing paperwork she noticed that subject “TR” did not appear to have been eligible. Study exclusion criteria includes: “Treatment with more than one chemotherapy agent for kidney cancer.” This subject had received 3 previous chemotherapy agents for kidney cancer prior to enrollment. This was missed by the study team (CRCs and a Sub- Investigator) when reviewing eligibility and by the sponsor when conducting the final review of eligibility. The subject has been on study and receiving drug since April 2015 as part of the protocol. The subject has stable disease. Root Cause Analysis: Even though there was an eligibility workflow in place, it was not properly adhered to. Only one research coordinator signed the eligibility packet prior to investigator review (instead of two coordinators). The prior cancer treatments were given before the implementation of EPIC, and were overlooked at the time of the eligibility review. Corrective and Preventative Action (CAPA) plan: Retraining of the entire study team was conducted by the Lead Clinical Research Coordinator and the Principal Investigator on the eligibility workflow process. The PI will now also personally review and confirm eligibility of all subjects on the trial. PI attests that the team will strictly adhere to the current eligibility workflow process when confirming eligibility.

Case Example 3 During a not for cause review of HIC #039, the auditor had concerns that Subject “MJ” was ineligible as he had a history of diabetes. The subject met exclusion criteria #3 “No active systemic disease.” The subject was consented, enrolled and randomized on to this study and began treatment in January 2016. According to the study team, the subject’s diabetes has been well controlled for many years and, with the exception of the prostate cancer he had just been diagnosed with (the reason for enrollment into study HIC #039) he was otherwise healthy. The auditor noted that there was no record of this deviation having been reported to or approved by the study sponsor or the Yale IRB. Root Cause Analysis: There was a misinterpretation of an exclusion criteria (#3) amongst the study team. The team did not understand that diabetes was a systemic disease and thought that being under control regardless, it would not be considered active. Corrective and Preventative Action (CAPA) plan: The study team and PI were re-trained regarding inclusion/exclusion criteria of this study. If questions arise regarding criteria, questions should be directed to the PI. Training also included a review of the Prospective Single Subject Protocol Modification/Deviation via IRES MOD. Attendance was required and recorded. All currently enrolled subjects were re-reviewed to confirm eligibility. All prospectively enrolled subjects eligibility packets are reviewed/approved by the PI prior to enrollment.

Case Example 4 During an internal not for cause review of investigator-initiated trial HIC # 956, it was discovered that one subject failed to meet inclusion criteria #7 “An MRI must be completed within 2 weeks of placement of the study device.” The subject had an MRI 4 weeks prior to placement of the study device. There was evidence in the subject record that the sponsor had granted a waiver for this criteria for this subject, however, the Yale IRB had not been informed or approved of the deviation. Root Cause Analysis: At the time of the deviation, there was no formal eligibility criteria checklist in place for subjects this trial. Study team members relied on their previous review of the protocol and only referenced it as necessary throughout the trial. Study coordinators also changed around the time of the deviation and it was believed this deviation was initiated when coordinator 1 was leaving but before coordinator 2 assumed the role. The new study team was unaware of the waiver approval requirements. Corrective and Preventative Action (CAPA) plan: An eligibility checklist was implemented. The entire/current study team (and PI) were retrained regarding study criteria (eligibility and ineligibility) and use of the checklist. All study team members attest to use of the new form for all subjects screened/enrolled. The PI implemented regular team meetings. It is hoped that this will ensure a smooth transition during future changes in staff.

FDA 483 Finding Based on the Enrollment of Ineligible Subjects

FDA 483 Citation: “You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].   As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plans for Protocol ___ required that you to ensure that subjects met all inclusion and exclusion criteria prior to randomization. Specifically: ...”

Tips to Help Prevent the Enrollment of Ineligible Subjects

“Protocol 101” Get Back to Protocol Basics Re-review the IRB application and protocol Focus on specific sections: inclusion and exclusion criteria and the recruitment of subjects. Are all current staff listed on the HIC application that are engaged in research? Get and stay familiar with study criteria… but rely on your study screening form Both should be congruent with one another! Develop and maintain a screening log. Regularly communicate with all active study team members (and the PI) Talk about the study issues, protocol changes, and challenges in the study

Strive for Optimal Organization Clearly label all documents and folders, create version numbers, footers, dates Ensure study team members (and the PI) know where documents are located Keep documents central to study staff Each inclusion/exclusion criteria must be supported with source documentation Look for and retain ORIGINAL documentation Lack of documentation equals NO documentation If a sponsor provides an inclusion/exclusion checklist you may need to make notes so that it makes sense to you! (make sure everyone on the study team is interpreting criteria in the same manner). Be cautious of screening windows Know your timelines and windows!

Think Outside of the Box Create your own inclusion/exclusion list Create an advertisement that captures all criteria as a quick reference Approach the eligibility packet with the mindset that the patient is NOT eligible. Unclear exclusion/inclusion criteria? Get clarification from the source! Create a Past Medical History worksheet to log previous adverse events Note length of time, start/stop dates

Other Tips Complete the screening document in the presence of the subject, if possible Have a third party who does not know the patient review the eligibility packet, if possible In a multiple verification process, ALL staff who sign the packet are equally responsible Be cautious of data that needs manipulating or calculations to be made. Ensure the entire study team stays up to date on study changes/amendments

Other Tips Be mindful of additional departmental requirements regarding eligibility confirmation A CAPA across a department or group is great-but make sure all parties approve and are on board. If the CAPA is not implemented correctly others can be noncompliant (without knowing it!) and can lead to continuing non-compliance! Make study meetings effective: talk about the issues you DON’T feel comfortable talking about (i.e., a deviation that transpired, a line/section that seems vague in the protocol).

Questions?