CRSO QA Monitoring SOP

Introduction and Purpose

The sponsor of a clinical research study is responsible for providing monitoring oversight for the study per the Code of Federal Regulations (21 CFR 312.53(d)) and Good Clinical Practice (ICH GCP) guidelines. The purpose of monitoring is to ensure the study is conducted according to the investigational plan and complies with institutional policy, local law, and federal regulations; that the rights, safety, and welfare of subjects are being protected; and that data integrity are maintained.

The Quality Assurance Group within the Clinical Research Support Office (CRSO QA) was established to provide monitoring oversight for clinical research conducted at the University of Utah. The primary focus of the group is to monitor Investigator-Initiated Trials (IITs) where University faculty are acting as sponsor-investigators with an active Investigational New Drug (IND) or Investigational Device Exemption (IDE) application with the U.S. Food and Drug Administration (FDA). However, ALL studies conducted at the University of Utah may utilize CRSO QA services, and are subject to monitoring as described in this SOP (exempting studies conducted at the Huntsman Cancer Institute (HCI)).

The CRSO QA team is housed within the Clinical & Translational Science Institute (CTSI) and operates under the direction and authority of the Associate Dean of Clinical Research and the CRSO Medical Director.

Definitions & Acronyms

Clinical Research: Clinical research includes all research involving human participants. It does not include secondary studies using existing biological specimens or data collected without identifiers or data that are publicly available.

Clinical Trial: Clinical trials are clinical research studies involving human participants assigned to an intervention in which the study is designed to evaluate the effect(s) of the intervention on the participant and the effect being evaluated is a health-related biomedical or behavioral outcome.

Sponsor: A person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, primate organization, or others.

Investigator: An individual who actually conducts a clinical investigation (i.e., under whose immediate direction study procedures are performed, and/or drug or other intervention is administered or dispensed to a subject).

Sponsor-Investigator: An individual who both initiates and conducts an investigation, and under whose immediate direction the investigational drug or device is administered or dispensed. The term does not include any person other than an individual. A sponsor-investigator maintains the responsibilities of both a sponsor and an investigator.

CAPA: Corrective and Preventative Action Plan
CFR: Code of Federal Regulations
CRSO: Clinical Research Support Office
CRSO QA: Clinical Research Support Office Quality Assurance Group
CTSI: Clinical & Translational Science Institute
DSCC: Data and Safety Consultation Committee
EMA: European Medicines Agency
ERICA: Electronic Research Integrity and Compliance Administration
FDA: United States Food and Drug Administration
GCP: Good Clinical Practice
HCI: Huntsman Cancer Institute
HIPAA: Health Insurance Portability and Accountability Act
ICH: International Council on Harmonization
IDS: Investigational Drug Service
IIT: Investigator-Initiated Trial
IRB: Institutional Review Board
OQC: Office of Quality Compliance
PCH: Primary Children’s Hospital
PI: Principal Investigator
SOP: Standard Operating Procedure

Procedure

1. Selection of Studies for Monitoring
1.1. Studies conducted at the University of Utah may be identified for monitoring by a variety of methods, including but not limited to:
1.1.1. Currently active sponsor-investigator IITs without routine monitoring oversight will be identified by the CRSO QA team, who will contact the PI and study team to arrange monitoring.
1.1.1.1. IITs that are only in data analysis or are near IRB closure may be exempt from monitoring, at the discretion of the QA team.

1.1.2. New sponsor-investigator IITs that are submitted to the IRB will receive an automated message via ERICA informing the study team that monitoring by the CRSO QA team is mandatory, and directs them to complete an intake form through the CTSI’s ProTrackS system.

1.1.3. The Office of Quality Compliance (OQC), as part of its review and oversight process, may suggest or require study teams to be monitored by CRSO QA, either ad-hoc or ongoing for the duration of the study.

1.1.4. Any study at the University of Utah that is notified of an FDA inspection will be required to receive pre-inspection audit prep/monitoring from CRSO QA, who will participate in the inspection process with OQC (further described in Section 6 of this SOP).
1.1.4.1. Studies that are being audited or inspected by other groups or regulatory agencies (sponsor, IRB, OHRP, EMA, etc.) may request audit prep/monitoring services from CRSO QA, which will be approved on a case-by-case basis.

1.1.5. Other clinical research or trials not otherwise subject to CRSO QA oversight may request monitoring services through the CTSI’s ProTrackS system, which will be approved on a case-by-case basis.

2. Scheduling a Monitoring Visit

2.1. When a study has been identified for monitoring, the CRSO QA team will contact the PI and study team to arrange the monitoring visit.

2.2. Monitoring visits should be scheduled with at least 4 weeks’ notice, except in cases of impending audit/inspection, or if the monitoring is requested or required for-cause.

2.3. The CRSO QA team will request information from the study team to help inform the conduct of the monitoring visit, which may include:

•  Current study status (i.e. active, closed to recruitment, study procedures complete)
• Number of participants enrolled.
• The electronic systems used to house study records, if applicable. (e.g. eReg, REDCap, uBox, etc.)
• The location of physical study records, if applicable. (e.g. participant charts, regulatory binders, etc.)
• Whether the University of Utah (UU) or Primary Children’s (PCH) Investigational Drug Service (IDS) are involved and are managing study drug. If the trial is IDS-exempt, then the identity of the group or individual delegated to manage drug.
• For device studies, the identity of the group or individual delegated manage the device.

2.4. Depending on the nature and disposition of study records, a remote or in-person visit may be requested.
2.4.1. For remote visits, CRSO QA must be granted access to all electronic systems used to house study records; or, records must be uploaded and made available via a mutually accepted, HIPAA-compliant system (e.g. uBox, eReg)
2.4.2. For in-person visits, all physical study records must be made available. In addition, adequate accommodations should be provided to conduct the monitoring visit. (e.g. office space, conference room, Wi-Fi, etc.)

2.5. Once the scope and nature of the monitoring visit is determined, the CRSO QA team will work with the study team to schedule time for the visit. In general, a full week will be requested; however, more or less time may be required based on the needs of the study.
2.5.1. If the trial involves pharmacy, the CRSO QA team will schedule monitoring with the pharmacy (e.g. IDS) directly via their established practices, ideally within the same timeframe as the primary monitoring visit. If the trial is blinded, an unblinded monitor will be assigned.
2.5.2. If the trial involves a device, the CRSO QA team will schedule monitoring with the group or individual managing the device, ideally within the same timeframe as the primary monitoring visit.

2.6. Once scheduling is complete, CRSO QA will provide a formal notice of monitoring via a Monitoring Notification Letter, which will be sent via email to the PI, study team, and pharmacy (if applicable). The monitoring letter will include:

• The name and IRB number of the study being monitored.
• The date(s) that the monitoring visit will occur.
• The specific records that will be reviewed during the visit.

3. Conducting a Monitoring Visit

3.1. At the beginning of a monitoring visit, either in-person or remote, the CRSO QA team may meet with the study team to discuss the scope of the monitoring, ask questions about the study and its conduct, and ensure that all requested records are available for review.

3.2. The review of records may occur in any order, but will traditionally begin with Regulatory/IRB review, followed by participant records. If the trial is blinded, the unblinded monitor will exclusively review pharmacy records.

3.3. Common examples of documents to be reviewed during monitoring include, but are not limited to:
3.3.1. Regulatory:

• IRB submissions, approvals, and correspondence
• Signature pages (protocol, Investigator’s Brochure, etc.)
• FDA forms, submissions, approvals, and correspondence
• Study team qualifications, training, and delegated authority

3.3.2. Participant charts:

• Informed Consent
• Eligibility criteria
• Treatment records, pertinent medical records, and investigational product accountability
• Safety reporting and (serious) adverse event documentation
• Protocol violations or deviations

3.3.3. Investigational Product:

• Investigational product accountability
• Investigational product storage and temperature logs
• Investigational product preparation, dispensation, return, and destruction records

3.4. The review may involve a comprehensive review of ALL provided participant records; alternatively, a risk-based approach may be utilized. The scope of monitoring will be determined by the monitor and based on a variety of factors, including but not limited to: risk level and phase of the trial, number of participants enrolled, complexity of the trial procedures, level of experience of the PI and study team, and results of prior monitoring.
3.4.1. The scope of monitoring may be dynamic throughout the life of the trial. The nature, frequency, or severity of findings may necessitate an increase in the scope of the review; alternatively, a risk-based approach may be considered if minimal findings are identified in prior reviews.

3.5. During the monitoring visit, the study team should be available to answer any questions that arise during review, and to provide additional documentation if any are missing from the study records.

3.6. The CRSO QA team may request additional records not initially identified for review based on the nature or severity of findings during the review. Additional records should be provided by the study team within a reasonable timeframe.

3.7. Queries will be generated during the review based on observations and findings in the study records. Informational queries that do not require direct or immediate action may be included and will be indicated as such.

3.8. At the conclusion of the monitoring visit, a meeting will be requested with the study team (lead coordinator and/or regulatory coordinator) to discuss the review and any findings. Any significant or major findings will be brought to the attention of the team.
3.8.1. If the study is blinded, the unblinded monitor will meet with pharmacy staff separately.

3.9. A comprehensive list of queries will be compiled and forwarded to the study team. Any queries that are resolved by the study team prior to the final monitoring letter being sent will be marked as “closed” in the final query report; however, study teams are not expected or required to resolve queries during this time.
3.9.1. If the study is blinded, pharmacy queries will still be included in the final query report; however, only queries that do not have the potential to unblind will be included. Major or significant findings may be redacted or otherwise reworded to allow incorporation in the final query report and monitoring letter.

4. Monitoring Visit Follow-Up

4.1. When all other aspects of the monitoring visit are concluded, the CRSO QA team will request a meeting with the PI. This meeting should ideally occur within a week of the conclusion of the monitoring visit.

4.2. During this meeting, significant results, findings, or observations will be brought to the attention of the PI. The CRSO QA team may suggest corrective action to the PI, but resolution is ultimately the responsibility of the PI.
4.2.1. If no significant or major findings are identified during the review, the PI may be apprised of this; it may also be appropriate to only follow up with the PI via email.

4.3. The outcome of the monitoring visit and any significant findings will be summarized in the final monitoring letter. This letter, as well as the final query report and any supporting documentation, will be sent to the PI via email with key study team members cc’d (and pharmacy staff, if applicable).

4.4. Subsequent monitoring visits will be scheduled according to the CRSO QA Oversight Plan, the frequency of which will be specified in the final monitoring letter. Frequency of follow-up visits will be determined according to the study’s determined risk level; the nature, frequency, and severity of findings; study enrollment; and other factors as described in the Oversight Plan.

4.5. The CRSO QA team will set an appropriate timeframe for the study team to address queries from the monitoring visit. Routine queries are generally given a window of 2 weeks for resolution, while significant or major findings may require more immediate resolution.
4.5.1. Study teams may request additional time to address queries, which will be approved on a case-by-case basis by the CRSO QA team.

4.6. Documentation of query resolution should be provided to the CRSO QA team within the established timeframe. Query resolution may also be verified by reviewing the study records electronically, or physically at the next monitoring visit.

4.7. Depending on the nature and severity of monitoring findings, the CRSO QA team may request additional corrective action, such as submitting a report form to the IRB or implementing a CAPA. Findings may also be brought to the Data and Safety Consultation Committee (DSCC), who may provide additional oversight or suggest corrective action.

5. Closeout Monitoring Visits

5.1. For studies that are actively monitored by the CRSO QA team, a closeout monitoring visit may be scheduled once all study procedures are complete and IRB closeout has occurred or is imminent.

5.2. During this visit, regulatory and subject records will be reviewed to ensure all previous monitoring findings have been adequately addressed, and any final study procedures were completed appropriately.

5.3. For studies involving an investigational product (drug or device), a closeout visit may be scheduled once all aspects of investigational product administration, return, and/or destruction have been completed.

5.4. At the conclusion of the closeout visit, any final queries or outstanding issues will be addressed with the study team and included in the final monitoring letter and query report. A meeting with the PI may be scheduled, but is not required.
5.4.1. Depending on the nature and severity of pending queries at the completion of this visit, CRSO QA may delay closeout until appropriate resolution is provided. In such instances, the final query report will be provided to the team at the conclusion of the visit, but the final monitoring letter will not be sent until resolution is provided.

5.5. Once closeout has occurred, no further monitoring visits for the trial will take place, excepting cases of impending audit or inspection.

6. FDA Audits and Prep

6.1. Once notification of an impending FDA audit is received, CRSO QA will work with OQC to prepare, educate, and assist study teams with the audit process.

6.2. CRSO QA will conduct a pre-audit monitoring visit of all study records identified for inspection (regulatory and participant, investigational product if applicable).
6.2.1. OQC may assist with pre-audit monitoring, as needed.
6.2.2. A query report will be prepared and sent to the study team as part of the pre-audit monitoring visit; however, no monitoring letter is required to be sent with the query report.

6.3. At the initiation of the audit, members of CRSO QA and OQC will attend the opening meeting with the study team.

6.4. During the audit process, CRSO QA will attend the daily meetings, when available, in conjunction with OQC.

6.5. At the conclusion of the audit, members of CRSO QA and OQC will attend the closeout meeting with the study team.

6.6. If an FDA Form 483 is issued, CRSO QA may assist with the initial draft of the CAPA and response letter to FDA, in conjunction with OQC, as needed.
6.6.1. All further edits, responses, and follow-up pertaining to the response letter, and the CAPA and its implementation, will be managed by OQC.

Materials Required

• Monitoring Notification Letter
• Monitoring Checklist
• Query Report
• Final Monitoring Letter

References

• 21 CFR 312
• 21 CFR 50
• CRSO QA Oversight Plan