9/28/2021
Photo by Agence Olloweb on Unsplash
The US Food and Drug Administration (FDA) released an updated Compliance Program Guidance Manual (CPGM) for sponsors in September 2021. CPGMs are used to guide FDA inspectors when conducting an inspection for subject protection and data quality and integrity as part of FDA's Bioresearch Monitoring Program (BIMO). Part III, Inspectional, is vastly expanded in line with the current way clinical trials are conducted, including remote monitoring, sponsor’s outsourcing of clinical trial activities, and clinical trials conducted outside the United States. The CPGM increases scrutiny of sponsor processes and procedures related to selection of investigators, electronic systems, and CRO oversight. The following are selected highlights of the changes.
Under the “Selection and Monitoring of Clinical Investigators” section, the following inspection items were added:
if an investigator conducted a non-IND trial outside the US
list of investigators placed on enrollment hold and the reason
list of changes to the investigator and the reason
criteria for selection of investigators, including if the sponsor considers the FDA Debarment List and previous administrative and regulatory actions against the investigator
if the sponsor provided adequate training to the investigator prior to initiation of and during the clinical trial so they can adequately conduct the trial and that it is documented. Includes:
Protocol
Electronic systems needed (EDC, ePRO, etc.)
Labeling or Investigator’s Brochure (IB)
for study termination:
if the sponsor has a plan for site termination and subject transfer
what happened to the subjects after termination (participation ended versus transferred to another site)
that required notifications occurred (e.g., IRB notified of an investigator’s termination, or if IP poses unreasonable risk that IRB, FDA, and investigators were notified, etc.)
A new section “Outsourced Services” was added related to the sponsor’s oversight of vendors, including determining or reviewing:
if the sponsor has processes and procedures in place for selection of a CRO including determining that the CRO will follow GCP and regulations
written agreements between the sponsor and CRO, including:
where roles, tasks, and responsibilities of the sponsor and CRO are defined
where who has the decision-making authority for study activities is documented
qualifications of the CRO personnel
SOPs for audits, communication plans, escalation plans, and contingency plans
if there were deviations, what impact assessment and CAPA were performed
sponsor communication with the CRO in terms of frequency, purpose, and if they were documented
protocol-specific training provided to the CRO
oversight plans and any audits that occurred, including their scope
Under “Selection of Monitors”, a part about the sponsor assigning responsibilities for multiple monitors that provide different functions, such as remote monitor versus onsite, was added.
The “Monitoring Procedures and Activities” section explains that a risk-based approach to selecting monitoring activities means that methods may differ between clinical trials. Some changes in the new CPGM include:
increased focus on written monitoring plan (before mentioned guidelines and SOPs), if it was followed, and if it had to be modified
expanded the review to remote monitoring processes
increased scrutiny of monitoring activities, including specifically mentioning assurances that IRB approval and informed consent were obtained
focus on how remote monitoring accesses site files and assures the security and confidentiality of the records (e.g., direct access to EMR)
There were two added sections on “Data and Safety Monitoring Board/Data Monitoring Committee” and “Progress Reporting.”
A section was added on “Safety Oversight” including determining:
if the sponsor had a risk management plan and if it was followed
processes and procedures for use of safety data
if any SAEs were endpoints or safety events per the protocol
The section on “Data Collection and Handling” was expanded to include inspection of:
data management plans and SOPs for data collection, handling, and management procedures
if there are processes and procedures for data modifications or corrections and that they create an audit trail
electronic systems data integrity, security controls, validation, and their documentation
whether the sponsor or vendor provides the electronic system
data flow (creation to reporting) and transmission procedures
assurance that only authorized users have access
training on the systems was provided by qualified individuals
data retention procedures and disaster recovery plans
The section on “Electronic Records and Electronic Signatures” was expanded to include inspection of:
electronic systems that are used to manage critical data and study procedures
processes or methods for electronically signing documents
The updated sponsor CPGM shows there will be an increase in scrutiny for electronic systems used for critical data or study procedures, sponsor’s oversight of CROs and other vendors, sponsors providing adequate training to sites and CROs, increased diversity in monitoring including remote access of EHR or centralized monitoring, and investigators who may be conducting a non-IND clinical trial outside the US. The modernization of the CPGM reflects other recent guidance released by the FDA. For example, the FDA released a draft guidance earlier this year, “Frequently Asked Questions: Statement of Investigator” that answers a question about investigators outside the US conducting a non-IND clinical trial. Read our blog about it HERE.
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- The Clinical Pathways Team
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