A regulatory binder is crucial for managing clinical trial documents, ensuring compliance with regulations, and supporting audits. It organizes essential documents, providing easy access for trial monitors, auditors, and regulatory authorities, while also serving as a reference for the research team. While not legally required, maintaining a regulatory binder is strongly recommended for all intervention trials. This checklist provides a comprehensive framework for efficiently managing all necessary documents.
Notes
Terms Used Synonymously
- Study binder
- Investigator binder
- Administrative binder
- Regulatory files
- Investigator’s study files
Guidance Documents
These documents are necessary to demonstrate the investigator’s, sponsor’s, and monitor’s compliance with GCP and regulatory requirements.
- The ICH GCP E6 Section 8 outlines the essential documents needed for clinical trials, which is in line with the documentation requirements under the EU Clinical Trials Regulation. These documents ensure transparency and compliance with both GCP and regulatory standards in the EU.
- ICH GCP E6 4.9.4 provides guidelines on maintaining trial documents to prevent accidental or premature destruction, which is also relevant to the EU Clinical Trials Regulation. The regulation emphasizes the importance of proper documentation retention for the integrity of the trial and the protection of participants.
Essential Documents of a Regulatory Binder (Based on European Regulations)
These documents are essential to demonstrate compliance with Good Clinical Practice (GCP) and European regulatory requirements for clinical trials.
1. Protocol and Amendments
- Purpose: To document revisions of trial-related documents during the trial.
- Documents:
- Log of protocol changes
- IRB-approved protocol with PI signature page
- IRB-approved case report forms
- IRB-approved advertisements and participant information sheets
- Protocol amendments
2. Informed Consent Documents
- Purpose: To document the informed consent process.
- Documents:
- Log of informed consent versions
- IRB-approved informed consents
3. IRB Documentation
- Purpose: To document that the trial has been reviewed and approved by an independent ethics committee (IEC).
- Documents:
- IRB/IEC approval letters
- Submissions and correspondence (initial review, continuing review, advertisements, subject compensation, etc.)
- Ethics Committee roster and membership
- Declaration of compliance with European Clinical Trial regulations (EU CTR No. 536/2014)
4. Investigator Qualification Documentation
- Purpose: To document the qualifications and eligibility of the investigator.
- Documents:
- Updated investigator CVs (signed/dated within two years)
- Clinical licenses for PI and co-investigators
- Training certificates (GCP, human subject protection)
5. Clinical Investigator’s Brochure
- Purpose: To provide relevant and current scientific information for the investigational product.
- Documents:
- Investigator’s brochure or package insert for approved medications
6. European Regulatory Documents
- Purpose: To document compliance with European regulatory requirements for clinical trials.
- Documents:
- Clinical Trial Application (CTA): Submitted to the relevant national competent authority (NCA) in EU member states (e.g., the Dutch Medicines Evaluation Board (CBG-MEB), BfArM in Germany, ANSM in France, etc.)
- EMA (European Medicines Agency) documents where applicable
- EU Trial Master File (TMF) compliance documentation
- Declaration of compliance with the Clinical Trials Regulation (EU) No 536/2014
- Investigator’s Declaration of compliance with European regulations
7. Financial Disclosure Forms
- Purpose: To document compliance with regulations regarding financial interests.
- Documents:
- Signed forms for PI and co-investigators
8. Study Communication
- Purpose: To document important decisions and agreements.
- Documents:
- Confidentiality agreements, data sharing agreements, material transfer agreements
- Signed agreements between sponsors and investigators
- Important decisions or notes to the study file
9. Delegation of Authority Log
- Purpose: To document which study-related tasks the PI has delegated.
- Documents:
- Delegation of authority log
- Signature form
10. Clinical Research and Study Training
- Purpose: To document adequate training for all staff participating in the study.
- Documents:
- Documentation of training (e.g., human subject protection, GCP, EU-specific clinical trial regulations)
11. Screening/Enrollment Log
- Purpose: To document the identification of subjects who entered pre-trial screening and those who were enrolled.
- Documents:
- Log of screened subjects (without identifying information)
- Subject identification code list (kept separately)
12. Signed Consent Documents
- Purpose: To document informed consent.
- Documents:
- Signed informed consent documents
13. Study Product Records
- Purpose: To document the disposition and accountability of study products.
- Documents:
- Documentation of study product disposition and accountability
14. Laboratory Certification
- Purpose: To document the competence of the facility performing protocol-specific tests.
- Documents:
- CLIA, CAP, or other certifications
- Updated normal-range values for reference labs
15. Specimen Tracking Log
- Purpose: To document the tracking and handling of specimens.
- Documents:
- Specimen tracking logs
16. Serious Adverse Events (SAEs)/Unanticipated Problem Documents
- Purpose: To document that the sponsor was notified of all SAEs and related reports.
- Documents:
- SAE report forms
- Unanticipated problem forms
- Clinical Trial Regulation (EU) No 536/2014 safety reporting
17. Protocol Deviation Form or Memo
- Purpose: To document any deviations from the protocol.
- Documents:
- Protocol deviation forms or memos
18. Clinical Site Monitoring Visits
- Purpose: To document site visits and monitor findings.
- Documents:
- Site visit log
- Reports and correspondence
19. Sponsor Correspondence
- Purpose: To document agreements or significant discussions regarding trial administration.
- Documents:
- Sponsor correspondence
20. Data and Safety Monitoring Documents
- Purpose: To document compliance and actions related to safety monitoring.
- Documents:
- Data and safety monitoring plan
- Reports generated for independent safety monitors
- Safety monitor meeting minutes
21. Other Documents
- Purpose: To document additional relevant information and procedures.
- Documents:
- Unmasking procedures for blinded trials
- Certificate(s) of confidentiality
These documents ensure compliance with European Union Clinical Trial Regulations (EU CTR No. 536/2014), including the Clinical Trial Application (CTA) and Trial Master File (TMF) requirements. They also help ensure the trial meets the European Medicines Agency (EMA) guidelines, ensuring patient safety, scientific integrity, and regulatory compliance throughout the clinical trial lifecycle.
Keywords: Informed Consent, Research Compliance, Clinical Operations, compliance, institutions, regulatory, sites
References
- International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ICH Harmonised Guideline: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2). 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
- European Medicines Agency. EU Clinical Trials Regulation (Regulation (EU) No 536/2014). 2014. https://ec.europa.eu/health/human-use/clinical-trials/regulation_en
- U.S. Food and Drug Administration. Investigator Responsibilities – FDA. 2023. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigator-responsibilities
- World Health Organization. Handbook for Good Clinical Research Practice (GCP): Guidance for Implementation. 2005. https://www.who.int/medicines/areas/quality_safety/safety_efficacy/gcp1.pdf
- European Commission. Clinical Trial Application (CTA) in the European Union: Guidance Document. 2021. https://ec.europa.eu/health/system/files/2021-09/ct_reg_guidance_en_0.pdf
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