“The study coordinator (SC) takes care of all of that stuff, right? I just have to sign what the SC tells me to sign.”
“Aren’t those FDA inspections like IRS audits? They only happen to other people. If I happen to be audited and did something wrong, I’ll just have to pay a little fine and move on.”
Not so fast.
When you agree to be an investigator, you are obligated to do more than sign where someone tells you to sign. There are federal regulations, ethical responsibilities, and clinical obligations that are yours and yours alone as the principal investigator.
The Principal Investigator (PI) is the leader of the local clinical research team and assumes responsibility for the safe and successful execution of the clinical research protocol. This includes a number of responsibilities and duties that can be accomplished only when the PI is an active and engaged leader in the local conduct of the trial. (21 CFR 312) (ICH E6 4.0)
It is the PI’s responsibility to ensure that there are adequate resources and facilities to perform the work necessary to successfully participate in the clinical study. It is important that the PI have regular and active communication with the local study team throughout the duration of the study, including with personnel added due to increased workload or turnover. (ICH E6 4.2)
The PI should consider the following critical areas when developing their local oversight plan:
1) Protocol Knowledge.
The PI must be well versed in all details of the study protocol and should ensure that the key local study team members receive adequate training on the study responsibilities delegated to them by the PI. (21 CFR 312.60) (ICH E6 4.5)
2) Patient Consent.
The PI is responsible for overseeing the informed consent process. This includes ensuring that anyone who has been delegated the responsibility of conducting informed consent has been trained and carries out these responsibilities according to study requirements and good clinical practice (GCP). The PI must oversee the consent process on an ongoing basis, not just at the time of enrollment but throughout the study. (21 CFR 50.20) (ICH E6 4.8)
Patient Randomization. The PI must ensure that the randomization process follows the protocol-specified requirements. The PI is ultimately responsible for ensuring that each enrolled patient meets the protocol-specified eligibility criteria. (ICH E6 4.7)
3) Trial Follow-up, Study Drug Compliance, and Patient Retention Procedures.
The PI is responsible for ensuring that:
- Each randomized participant completes the protocol-specified follow-up procedures and visits
- All study data is entered into the data collection (case report) form
- Any queries concerning that data are answered within the study-required timeframe
- Randomized patients receive any needed support to remain on the randomized study drug
- Contact is maintained with all randomized patients until the completion of the study
(21 CFR 312.62) (ICH E6 4.5)
In addition, if the protocol requires dose adjustments or has specific requirements for discontinuing study drug, it is the PI’s responsibility to follow these procedures as outlined in the protocol. (ICH E6 4.6)
Situations requiring rapid intervention by the PI
- When a participant unexpectedly misses an appointment
- When a participant is perceived to be at risk for discontinuing study drug, withdrawing consent, or becoming lost to follow-up
- When a participant may require a dose adjustment, discontinuation of study drug (based on protocol requirements), or is not taking the study drug as prescribed
4) Complete Ascertainment of Suspected Trial Endpoints and Adverse Events.
The PI should establish a systematic process that allows collecting and reporting of all primary and secondary endpoints as well as all adverse events (as required by the study protocol). It is important that the PI not only assure the process is in place but that it is carried out throughout the conduct of the study. (ICH E6 4.11) (21 CFR 312.64)
It is important that the PI establish a local process that ensures all relevant source documents (including electronic health records, paper records, records from other facilities, etc.) are available and reviewed throughout the conduct of the study. All adverse events must be appropriately reported in the case report form (as required by the study protocol) within the required timelines (e.g., within 24 hours for serious adverse events [SAEs]). (21 CFR 312.62) (ICH E6 4.9)
The PI should assure that he/she is aware of any reported hospitalizations (from any source) and that endpoint or safety reporting is completed based on review of the hospitalization record including those that occur remote from the local practice. (21 CFR 312.64) (ICH E6 4.11)
5) Local Institutional Review Board (IRB) Reporting.
The PI is responsible for meeting all local IRB requirements (i.e., renewals, reporting of SAEs, regular updates). The PI is responsible for understanding any differences in local IRB vs. study-specific reporting of events. (21 CFR 312.66) (ICH E6 4.4)
6) Reporting of Significant GCP Issues.
The PI is responsible for quickly and appropriately reporting and resolving any significant GCP issues, including reports to the ARO/Sponsor and the responsible IRB. The PI should establish processes to minimize reoccurrence of the issue. (21 CFR 312.66) (ICH E6 4.1.3)
7) Resolution of Corrective Action Plans (CAPs).
When the ARO/Sponsor establishes a CAP due to issues identified during the conduct of a study, it is the PI’s responsibility to respond to the CAP in a timely manner, and to put in place and manage corrective actions for the duration of the trial.
8) Participation in Monitoring Activities.
It is important that the PI be an active participant in both on-site and central monitoring activities. This includes being available to clinical research associates (CRAs)/monitors to address any concerns or follow-up items. (21 CFR 312.68) (ICH E6 4.9.7)