6.1 Investigator Responsibilities & Delegation (ICH E6 4.0 / 21 CFR 312.60)

Investigator Responsibilities & Delegation (ICH E6 4.0 / 21 CFR 312.60)

In clinical trials, the clinical investigator (often referred to as the Principal Investigator or PI) is the individual responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator is the responsible leader of the team and may be called the Principal Investigator. The regulatory obligations of the investigator are codified in United States (U.S.) federal law under 21 CFR Part 312.60 (for investigational drugs) and further elaborated in the International Council for Harmonisation (ICH) E6 Good Clinical Practice (GCP) Section 4.0. Understanding the investigator's responsibilities, commitments under Form FDA 1572, the principles of delegation, and the requirements for supervision and protocol adherence is fundamental for any clinical research professional.

Form FDA 1572: Statement of Investigator

The Form FDA 1572 is a legally binding contract between the clinical investigator and the U.S. Food and Drug Administration (FDA) required for clinical trials conducted under an Investigational New Drug (IND) application. By signing this form, the investigator provides the sponsor with essential information about their qualifications and the site, and makes nine specific commitments to the FDA.

The nine commitments outlined in Section 9 of Form FDA 1572 require the investigator to:

1. Conduct the study in accordance with the current protocol and only make changes after obtaining sponsor and Institutional Review Board (IRB) approval, except when necessary to protect the safety, rights, or welfare of subjects.
2. Personally conduct or supervise the described clinical investigation.
3. Inform subjects that the drugs are being used for investigational purposes, and ensure that the requirements relating to obtaining informed consent (21 CFR Part 50) and IRB review and approval (21 CFR Part 56) are met.
4. Report to the sponsor adverse experiences that occur in the course of the investigation in accordance with 21 CFR 312.64.
5. Read and understand the information in the Investigator's Brochure (IB), including the potential risks and side effects of the drug.
6. Ensure that all associates, colleagues, and employees assisting in the conduct of the investigation are informed about their obligations in meeting the commitments.
7. Maintain adequate and accurate records in accordance with 21 CFR 312.62 (including drug disposition and case histories) and make them available for inspection in accordance with 21 CFR 312.68.
8. Ensure that an IRB complying with 21 CFR Part 56 is responsible for the initial and continuing review and approval of the study, and report all changes in research activity and unanticipated problems involving risks to subjects.
9. Comply with all other investigator obligations and requirements under 21 CFR Part 312.

Delegation of Authority and the DoA Log

While the investigator is permitted to delegate specific trial-related tasks to qualified sub-investigators and study staff, the investigator cannot delegate the ultimate responsibility for the trial. The investigator remains personally responsible for the conduct of the study and the safety of the subjects at their site.

To document the delegation of tasks, sites maintain a Delegation of Authority (DoA) Log (sometimes called the Delegation of Log or Site Signature Log). The DoA log is a critical regulatory document that must contain:

• The printed names and signatures of all staff members performing study-related tasks.
• The specific tasks delegated to each individual (using predefined task codes).
• The initials of each staff member.
• The start and end dates of the delegation for each individual.
• The Principal Investigator's signature and date, verifying approval of the delegation before the staff member performs any study tasks.

Appropriateness of Delegation

Investigators must ensure that tasks are only delegated to individuals who are qualified by education, training, and experience (as required by ICH E6 4.2.4). Delegating clinical tasks to unqualified personnel is a frequent finding in FDA inspections.

• Medical Decisions: Tasks requiring medical judgment, such as performing physical examinations, assessing eligibility criteria, evaluating lab results, grading adverse event (AE) severity, and determining AE relationship to the investigational product, must only be delegated to licensed medical professionals (e.g., physicians, or nurse practitioners/physician assistants where permitted by state licensing laws).
• Administrative/Technical Tasks: Tasks such as scheduling visits, entering data into the case report forms (CRFs), shipping laboratory samples, and filing documents in the regulatory binder can be delegated to Clinical Research Coordinators (CRCs) or administrative assistants.

Investigator Supervision and Training

In October 2009, the FDA issued its final guidance titled Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects. This guidance clarifies the FDA’s expectations for adequate investigator supervision. The FDA evaluates several factors to determine whether an investigator has maintained sufficient oversight of a delegated trial:

• Qualifications of Delegated Staff: Whether the investigator delegated tasks only to individuals who have the appropriate credentials, licensing, and expertise.
• Training: Whether the staff received protocol-specific and study-agent-specific training. This must be documented on a training log.
• Oversight Mechanisms: Whether the investigator has a clear plan for supervising the study. This includes hosting regular staff meetings to discuss trial progress, reviewing study data and source documents in a timely manner, and implementing a plan to identify and correct errors.
• Addressing Performance Issues: Whether the investigator took prompt corrective action when staff performance issues or protocol deviations were identified.

Protocol Adherence and Deviations

The investigator must conduct the trial in strict compliance with the approved protocol. Protocol adherence is crucial for ensuring subject safety and the scientific validity of the trial data.

• Prior Approval: Under ICH E6 4.5.2, the investigator should not implement any deviation from or change to the protocol without agreement by the sponsor and prior documented approval/favorable opinion from the IRB, except where necessary to eliminate an immediate hazard to trial subjects.
• Emergency Deviations: If a protocol deviation is implemented to eliminate an immediate hazard (e.g., stopping a study drug due to a life-threatening reaction), the investigator must document the deviation and submit it to the sponsor and the IRB as soon as possible, in accordance with institutional and regulatory timelines.
• Documentation: All protocol deviations must be fully documented in the subject's source documents and reported to the sponsor and the IRB according to their respective guidelines. Frequent or systematic protocol deviations are indicative of poor investigator supervision and can lead to regulatory action.

Records Maintenance and Drug Accountability

The investigator is responsible for maintaining complete, accurate, and legible study records.

• Drug Accountability: Under 21 CFR 312.62(a), the investigator must maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. Every unit of investigational product must be accounted for (from receipt to dispensing, return, or destruction).
• Case Histories: Under 21 CFR 312.62(b), the investigator must maintain adequate and accurate case histories of all individuals administered the investigational drug or employed as controls in the study. This includes signed consent forms, medical records, and CRFs.
• Record Retention: In the U.S., records must be retained for at least 2 years following the date on which a marketing application (NDA/BLA) is approved; or, if no application is filed or if the application is not approved, 2 years after the investigation is discontinued and the FDA is notified. Note that ICH E6 4.9.7 may require a longer retention period depending on local regulations or sponsor contracts.