Clinical research monitoring
Lead institution sponsor-investigators shall monitor the progress of all clinical investigations being conducted under its IND/IDE. (21 CFR § 312.56; 21 CFR § 812.46). FDA inspects sponsor-investigators. The FDA inspector findings common to sponsors, investigators, and sponsor-investigators are reported annually by FDA.
Common sponsor-investigator findings include failure to ensure proper monitoring, failure to submit an IND, adherence to the protocol, adequate records, drug accountability, patient-subject protection issues, consent issues, and failure to timely notify FDA of terminated investigators.
Goals of monitoring
- keeping participants safe and respecting their rights;
- having data we can trust;
- making sure the trial was run as it was meant to be;
- improving the way the trial is run; and
- preventing problems before they happen.
Study monitors may be tasked with spot-checking for inconsistencies or omissions, checking for completeness and consistency, source document verification and consistency between paper and electronic sources, identifying sites meriting further review, and the use of current consent and IRB documents.
Clinical studies in the US are overseen and may be audited by the Food and Drug Administration (FDA). Additionally, studies are overseen by the Institutional Review Board (IRB).
OVPRI provides monitoring services to all sponsor-investigator IND/IDE held studies throughout the course of the study that fulfills the FDA’s requirement for monitoring. Each study will have an individualized monitoring plan established at the start of the study. Monitoring frequency will vary based on complexity of the study and the rate of accrual.
If you have a study that you would like to have monitored on a routine basis, please contact indide@vcu.edu.
FDA regulations
- Responsibilities of sponsors and investigators including monitoring investigations - drugs
- Responsibilities of sponsors - devices
- Responsibilities of investigators - devices
- Monitoring investigations - devices
- Disqualification of a clinical investigator
FDA guidance
- Monitoring, questions and answers
- Monitoring, oversight of clinical investigations
- Establishment and operation of data monitoring committees
- Electronic source data in clinical investigations
- Good laboratory practice for nonclinical laboratory studies
- ISO 14971 Medical device risk management and standards
- ICH E6 R(3) Good clinical practice (GCP)
- Bioresearch monitoring (BIMO) annual report
Monitoring templates
FDA compliance programs are overseen by the product centers, e.g., Center for Biologics and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation & Research (CDER), who may trigger directed inspections. The Office of Bioresearch Monitoring Operations (OBIMO) receives assignments from the product centers, and tasks regional field inspectors. FDA publishes their bioresearch monitoring (BIMO) metrics annual report. Additionally, findings may be published in a warning letter.
FDA inspections may be followed by FDA communications.
FDA communications containing findings foreshadow a ten-year follow-on FDA visit frequency enhancement.
Because resources are limited for principal investigators and their study teams, it may be instructive to know the most common FDA findings. Protocol deviations, that is failure to follow the investigational plan, are consistently a common finding. Documentation issues together with failing to follow the protocol may account for as much as 75% of all FDA findings.
Other issues include accurate case history record, informed consent, investigational product accountability, 1572 statement adherence, safety reporting, and 21 CFR 56 (IRB) deficiencies.
FDA has three types of inspection findings: (1) NAI – No action indicated, (2) voluntary action indicated, and (3) involuntary or “official action” indicated. Forewarned with knowledge, Investigators can marshal resources to best protect the rights, safety, and welfare of participants in the clinical investigation and the integrity of data generated during the investigation.
While in practice a rare occurrence, a sponsor or sponsor-investigator who discovers that an investigator is not complying shall promptly either secure compliance, or terminate the investigator's participation.
Vehicles for monitoring include site visits, Data and Safety Monitoring Committee (DSMC) meetings, interim and closeout visits. Audits may include random and directed audits. Monitoring may include risk-based monitoring, routine, for cause, or in anticipation of marketing approval regulatory filings.
Risk-based monitoring attempts to better protect patients by monitoring higher risk studies more frequently and more completely. For example, a first in human study using a second or third drug in an old drug class presents less risk to patients than a first in human study with a first drug in a new drug class. By more closely monitoring higher risk studies, patients are better protected given the resourcing available.
For cause monitoring provides enhanced monitoring of previously identified issues. For-cause visits (FCVs) are conducted to address any unanticipated issues that arise which require training, remediation or other situations in which the site requires assistance. For-cause visits can be mandated by OVPRI, its designees, or can be requested by the site.