9.1 Essential Documents (Pre-study, During, Post-study)

9.1 Essential Documents (Pre-study, During, Post-study)

Quick Answer: Essential documents are those that individually and collectively permit evaluation of the conduct of a trial and the quality of the data produced. They serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of Good Clinical Practice (GCP) and with all applicable regulatory requirements.

The Trial Master File (TMF) and the Investigator Site File (ISF) form the backbone of clinical trial documentation. The TMF is maintained by the sponsor, while the ISF is kept at the investigator's site. According to ICH GCP E6(R2) Section 8, essential documents are grouped into three distinct stages of the trial: before the clinical phase commences, during the clinical conduct, and after completion or termination of the trial.

1. Before the Clinical Phase Commences (Pre-Study)

Before any subject is enrolled or any study-specific procedures are performed, the site must compile a robust set of regulatory documents. These ensure that the site is qualified and that all ethical and regulatory approvals are in place.

Key Pre-Study Documents

• Investigator's Brochure (IB): A compilation of the clinical and nonclinical data on the investigational product(s) relevant to the study in human subjects.
• Protocol and Amendments: The document describing the objective(s), design, methodology, statistical considerations, and organization of a trial. It must be signed by the Principal Investigator (PI) and the sponsor.
• Informed Consent Form (ICF): The IRB/IEC-approved document used to consent subjects. It must contain all required elements of informed consent.
• Form FDA 1572 (Statement of Investigator): For US IND studies, this form is a legally binding agreement where the PI commits to following the protocol, FDA regulations, and GCP. It lists sub-investigators, research facilities, and the IRB.
• Curriculum Vitae (CV) and Medical Licenses: Updated and signed CVs for the PI and all sub-investigators to document their qualifications.
• Financial Disclosure Forms (FDF): To document any financial arrangements that could introduce bias, completed by the PI and sub-investigators.
• IRB/IEC Approval: Documented approval for the protocol, ICF, subject recruitment materials (e.g., advertisements), and any other written information provided to subjects.

Real-World Example

In a Phase 3 oncology trial, the site coordinator (CRC) must ensure the Form FDA 1572 is accurate before the Site Initiation Visit (SIV). If a new sub-investigator joins the site, the CRC cannot simply let them see patients. The PI must update the 1572, the new sub-I must sign an FDF, provide a CV, and the IRB must be notified. Only after these essential documents are filed in the ISF and sent to the sponsor can the sub-I begin study-related duties.

2. During the Clinical Conduct of the Trial

As the trial progresses, the essential documents serve to demonstrate that the study is being conducted properly and that data is being collected accurately.

Key Documents During the Study

• Updated IB, Protocol, and ICFs: Any amendments or updates must be documented, approved by the IRB (if applicable), and filed.
• Monitoring Visit Reports: Provided by the Clinical Research Associate (CRA) after each visit to document site progress and compliance.
• Subject Screening and Enrollment Logs: To document identification of subjects who entered pre-trial screening and those who actually enrolled.
• Delegation of Authority (DOA) Log: A crucial document where the PI delegates specific study-related tasks to appropriately qualified site staff.
• Investigational Product (IP) Accountability Records: Documents detailing the receipt, dispensing, return, and destruction of the study drug. These must perfectly match the patient dispensing records.
• Source Documents: Original documents, data, and records (e.g., hospital records, clinical and office charts, laboratory notes).
• Case Report Forms (CRFs): Printed, optical, or electronic documents designed to record all protocol-required information for each trial subject.
• Severe Adverse Event (SAE) Reports: Documentation of SAEs reported by the PI to the sponsor and the IRB/IEC within the required timeframes.

Data Management and Source Data

The FDA's ALCOA-C standard applies to all source documentation: Attributable, Legible, Contemporaneous, Original, Accurate, and Complete. For example, if a CRC takes blood pressure, they must immediately document it in the electronic medical record (EMR) or paper source chart, sign, and date it. If a correction is needed, a single line through the error, corrected value, initial, date, and reason for change must be applied.

3. After Completion or Termination of the Trial

Once all subjects have completed the study and the database is locked, the site enters the close-out phase. Documentation during this phase proves that all close-out activities were performed appropriately.

Key Post-Study Documents

• Investigational Product Destruction or Return Records: Final documentation showing that all unused study drugs were either returned to the sponsor or destroyed on site according to SOPs.
• Final Report to IRB/IEC: The PI must submit a final summary of the trial's outcome to the IRB/IEC.
• Clinical Study Report (CSR): The sponsor provides a comprehensive report of the clinical trial's results.
• Close-Out Monitoring Report: A report from the CRA documenting that all close-out procedures have been completed, IP is accounted for, and site files are complete.

Retention of Records

According to FDA regulations (21 CFR 312), investigators must retain essential documents for a minimum of two years after the last approval of a marketing application, or until two years have elapsed since the formal discontinuation of clinical development of the investigational product. However, sponsors or institutional policies often require longer retention periods (e.g., 15-25 years in some international jurisdictions).