Study guide
9.1 Essential Documents (Pre-study, During, Post-study)
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1 Chapter 1: Scientific Concepts and Research Design
1.1 Protocol Elements 1.2 Study Design and Objectives 1.3 Study Endpoints and Biostatistics
2 Chapter 2: Ethical Principles and Guidelines
2.1 Ethical Principles (Declaration of Helsinki, Belmont Report) 2.2 Informed Consent Process and Documentation 2.3 Vulnerable Populations and Assent
3 Chapter 3: IRB/IEC Oversight and Participant Safety
3.1 IRB/IEC Functions and Oversight 3.2 Adverse Event Classification and Reporting 3.3 Safety Monitoring and Safety Reporting
4 Chapter 4: Participant Rights and Ethics
4.1 Participant Rights and Confidentiality (HIPAA/GDPR) 4.2 Conflicts of Interest 4.3 Ethical Scenarios in Clinical Trials
5 Chapter 5: Product Development and Regulatory Framework
5.1 Drug and Device Development Phases 5.2 U.S. and International Regulatory Frameworks 5.3 Investigational Product Investigator's Brochure (IB)
6 Chapter 6: Investigational Product Accountability
6.1 Investigational Product Labeling and Storage 6.2 Investigational Product Receipt, Dispensing, and Accountability 6.3 Investigational Product Return and Destruction
7 Chapter 7: Regulatory Submissions and Actions
7.1 Regulatory Submissions (IND, NDA, IDE, PMA) 7.2 Regulatory Actions and Compliance 7.3 Pharmacokinetics and Pharmacodynamics in Product Development
8 Chapter 8: Clinical Trial Operations and GCP Principles
8.1 Introduction to ICH E6 GCP Principles (including R3 updates) 8.2 Investigator Responsibilities under GCP 8.3 Sponsor Responsibilities and Oversight
9 Chapter 9: Essential Documents and Site Qualification
9.1 Essential Documents (Pre-study, During, Post-study) 9.2 Site Selection and Qualification 9.3 Quality Management and Standard Operating Procedures (SOPs)
10 Chapter 10: Protocol Deviations and Amendments
10.1 Protocol Adherence and Compliance 10.2 Protocol Deviations and Violations 10.3 Protocol Amendments and Version Control
11 Chapter 11: Monitoring Visits and Audits
11.1 Monitoring Preparation and Visit Types 11.2 Monitoring Visits (SIV, IMV, COV) 11.3 Regulatory Inspections and Site Audits
12 Chapter 12: Study and Site Management - Startup
12.1 Site Startup Operations 12.2 Site Budget and Contract Management 12.3 Site Staffing, Training, and Documentation
13 Chapter 13: Enrollment and Recruitment
13.1 Enrollment Management and Strategies 13.2 Participant Recruitment and Retention 13.3 Participant Compensation and Ethics
14 Chapter 14: Daily Trial Coordination
14.1 Visit Scheduling and Logistics 14.2 Equipment Maintenance and Calibration 14.3 Specimen Handling and Shipping (IATA/dangerous goods)
15 Chapter 15: Quality Improvement and Site Closeout
15.1 Participant Safety Management 15.2 Quality Improvement and Site Audits Preparation 15.3 Study and Site Closeout Procedures
16 Chapter 16: Source Documentation and Case Report Forms
16.1 Source Documentation Standards (ALCOA-C) 16.2 Case Report Forms and eCRF Completion 16.3 Electronic Data Capture (EDC) Systems
17 Chapter 17: Data Management and Queries
17.1 Data Management Processes 17.2 Data Queries and Discrepancy Resolution 17.3 Data Correction and Audit Trails
18 Chapter 18: Data Privacy and Records Retention
18.1 Data Privacy and Confidentiality 18.2 Records Retention and Archiving 18.3 Compliance in Clinical Trial Informatics
9.1 Essential Documents (Pre-study, During, Post-study)
Key Takeaways Explain This Topic AI
Essential documents demonstrate compliance with GCP and regulatory requirements.
Pre-study documents (1572, IRB approval, IB) must be in place before clinical activities start.
During the study, logs (DOA, screening) and source documents (ALCOA-C) ensure data integrity.
Post-study documents include IP return/destruction and the final report to the IRB.
ICH E6(R3) requires essential records to be kept for the required period under applicable regulations or until the sponsor says they are no longer needed, whichever is longest; US drug-trial rules add a 2-year minimum after approval or discontinuation.
Last updated: October 2026
9.1 Essential Documents (Pre-study, During, Post-study)
Quick Answer: ICH E6(R3) calls them essential records: the documents and data (with relevant metadata), in any format, that support the management of a trial and collectively allow evaluation of how it was conducted and whether its results are reliable. They show that the investigator, sponsor and monitor complied with Good Clinical Practice (GCP) and 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. ICH E6(R2) Section 8 grouped essential documents into three stages: before the clinical phase commences, during the clinical conduct, and after completion or termination of the trial. E6(R3), the version on ACRP exams since July 15, 2026, replaces that list with Appendix C: criteria for deciding which records are essential and an Essential Records Table, in which an asterisk marks the records that should generally be in place before the trial starts. The three stages below remain a practical way to organize the site file.
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 if its procedures require it. 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): Data acquisition tools designed to record the protocol-required information to be reported by the investigator to the sponsor on each trial participant.
Serious Adverse Event (SAE) Reports: Documentation of SAEs reported by the PI to the sponsor (immediately) and to the IRB/IEC as applicable requirements specify.
Data Management and Source Data
ICH E6(R3) (section 2.12.2) requires source records to be attributable, legible, contemporaneous, original, accurate and complete (often summarized as ALCOA-C). 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, it must be traceable and must not obscure the original: a single line through the error, the corrected value, initials and date, and a reason where it is not obvious.
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
Under ICH E6(R3) 2.12.12, the investigator/institution retains essential records for the required retention period under applicable regulatory requirements or until the sponsor informs them the records are no longer needed, whichever is the longest. In the US, 21 CFR 312.62(c) sets the drug-trial minimum: 2 years after a marketing application is approved for the drug for the indication being investigated, or, if no application is filed or approved, 2 years after the investigation is discontinued and FDA is notified. Sponsors and institutions often require longer.