Electronic Documents Requiring Electronic Signatures: Understanding FDA Part 11 and Japan’s ER/ES Guidelines

Scope of Documents Requiring Electronic Signatures

Electronic Signatures under FDA 21 CFR Part 11

Under 21 CFR Part 11 issued by the FDA (U.S. Food and Drug Administration), documents requiring electronic signatures are limited to “records requiring legally binding signatures.” Specifically, this applies to documents submitted electronically to the FDA and electronic materials that serve as the basis for submitted documents.

If we consider documents submitted to the FDA as N-level data, then the supporting N-1 level data also falls within the scope of Part 11. A crucial point to understand is that not all electronic approvals are equivalent to electronic signatures. Electronic approval and electronic signature should not be confused with each other. Electronic signatures must meet specific requirements defined in Part 11 and are treated as legally binding acts by authenticated individuals.

Part 11 imposes the following requirements for electronic signatures:

• Use of at least two distinct identification components (such as ID and password)
• Uniqueness of electronic signatures (unique to each individual, non-reusable and non-reassignable)
• Documentation displaying the meaning of the signature, the signer’s name, and the date/time
• Permanent linking of signatures to records
• Prior certification that electronic signatures are legally equivalent to handwritten signatures

The 2003 FDA Guidance emphasized a risk-based approach to Part 11 application. Rather than imposing uniformly strict requirements on all electronic records, this approach requires appropriate controls based on the criticality and risk level of the records.

Electronic Signatures under Japan’s ER/ES Guidelines (Ministry of Health, Labour and Welfare Notification)

The Ministry of Health, Labour and Welfare issued “Guidance on the Use of Electronic Records and Electronic Signatures in Applications for Approval or Permission of Pharmaceuticals, etc.” (Notification No. 0401022, dated April 1, 2005), commonly known as the ER/ES Guidelines. These guidelines stipulate that when creating electronic records that require identification of the creator’s name, electronic signatures must be used.

The ER/ES Guidelines recognize two types of electronic signatures:

1. Digital signatures based on the Electronic Signature Law: Electronic signatures using public key cryptography authenticated by a certification authority
2. Signature acts equivalent to handwritten signatures on paper: Electronic signatures accompanied by identity verification through ID, password, etc.

Importantly, electronic signatures are not always required for documents subject to the ER/ES Guidelines. Hybrid systems are also permitted, where electronic records are printed on paper and signed with handwritten signatures or seals (hanko).

The ER/ES Guidelines apply to application materials submitted to the Pharmaceuticals and Medical Devices Agency (PMDA) or the Ministry of Health, Labour and Welfare, and to source documents inspected by regulatory authorities during audits when stored in electronic format. In other words, the primary focus is on “electronification of documents submitted to or presented to regulatory authorities.”

Electronic Signatures in EDC Systems and CRFs

Current State of Electronic Signatures in EDC Systems (2026)

EDC (Electronic Data Capture) systems are platforms used in clinical trials to create and manage Case Report Forms (CRFs) electronically. As of 2026, EDC systems have become the standard tool for clinical trials, with approximately 70% of global clinical trials utilizing EDC systems.

The EDC system market is projected to grow from USD 3.2 billion in 2024 to USD 8.5 billion by 2033, with a compound annual growth rate (CAGR) of 10.5-12.5%. This growth is driven by the following factors:

• Improved data quality and reduced data entry errors
• Real-time data access and monitoring
• Enhanced efficiency in regulatory authority inspections
• Shortened clinical trial timelines and reduced costs
• Support for Decentralized Clinical Trials (DCTs)

FDA Part 11 and EDC Systems

While the FDA does not mandate electronic signatures for CRF electronification, strict management of the following requirements is required when using EDC systems:

1. System Validation: Verification that the system operates accurately and reliably as intended
2. User ID and Password Management: Enforcement of unique user identification and access control
3. Audit Trail: Recording of all data entries, changes, and deletions (tracking who changed what, when, and why)
4. Ensuring Data Authenticity, Legibility, and Integrity: Compliance with data integrity principles (ALCOA+)

ALCOA+ Principles are fundamental principles for ensuring data integrity, encompassing:

• Attributable: Clear identification of data creators
• Legible: Data is readable
• Contemporaneous: Data is recorded at the time of creation
• Original: Data is original or a true copy
• Accurate: Data is accurate
• + includes Complete, Consistent, Enduring, Available, etc.

Most commercial EDC systems come equipped with features compliant with Part 11 requirements as standard, including electronic signature functionality, timestamped audit trails, role-based access control, and data encryption. When principal investigators enter data into eCRFs (electronic CRFs), it has become common practice to use electronic signature functions to finalize the data.

Japan’s ER/ES Guidelines and EDC Systems

When using EDC systems in Japan, the following methods can be selected when principal investigators create eCRFs electronically:

1. Using Electronic Signatures: Implementing electronic signature functionality compliant with ER/ES Guidelines to achieve fully paperless operations
2. Hybrid System: Printing eCRFs on paper and having principal investigators apply handwritten signatures or seals

As of 2026, the use of electronic signatures in EDC systems for clinical trials in Japan is increasing due to the following reasons:

• Standardization of operations in global trials
• Necessity for remote support due to the proliferation of Decentralized Clinical Trials (DCTs)
• Acceleration of contactless and remote support following the COVID-19 pandemic
• Strengthening of data integrity requirements
• Demand for trial acceleration and increased efficiency

However, when implementing electronic signatures, attention must be paid to the following points:

• Appropriate issuance and management of IDs, passwords, etc.
• Limitation of electronic signature implementers and ensuring verifiability
• Implementation of functions to detect and verify changes or unauthorized modifications to electronic records
• Conducting CSV (Computer System Validation) of the system

The “Commentary on ER/ES Guidelines” (2024 revised edition) by the Japan Association of Clinical Research Organizations provides detailed explanations of recent technological trends, including support for eConsent (electronic consent acquisition), CDISC standards, and DCTs (Decentralized Clinical Trials), indicating that the industry as a whole is advancing toward electronification.

Importance of Data Integrity

In recent years, regulatory authorities have increasingly focused on data integrity to ensure the completeness, accuracy, and reliability of electronic records. Reports indicate that approximately 80% of FDA warning letters cite data integrity issues.

Ensuring data integrity requires not only technical measures but also organizational management systems, proper standard operating procedures, and staff training. While implementing electronic signature systems is an important element for ensuring data integrity, it alone is insufficient; a comprehensive data governance strategy is required.

Global Harmonization and Future Outlook

Although FDA Part 11, Japan’s ER/ES Guidelines, and Europe’s EudraLex Annex 11 are different regulations, their basic requirements (validation, access management, audit trails, backups, legibility, record retention, electronic signatures, etc.) are common across the three regions. Therefore, proper compliance with requirements in one region is likely to cover most requirements in other regions.

Beyond 2026, EDC systems are expected to evolve in the following directions:

• Integration of AI and Machine Learning: Advanced automated detection of data patterns, predictive analytics, and risk assessment
• Full Support for Decentralized Clinical Trials (DCTs): Home monitoring, direct data capture from wearable devices
• Enhanced Interoperability: Seamless integration with Electronic Health Records (EHR), ePRO, IRT, eConsent, etc.
• Standardization of Cloud-Based Solutions: Improved global access, scalability, and cost efficiency
• Improved User Experience: Enhanced usability for Clinical Research Coordinators (CRCs) and principal investigators

Summary

Electronic signatures are a critical technology for ensuring the authenticity and reliability of electronic records. FDA Part 11 and Japan’s ER/ES Guidelines take different approaches but share the common goal of ensuring data integrity.

As of 2026, EDC systems have become standard tools in clinical trials, and electronic signature functionality is widely adopted. Security measures (user ID and password management, access control) and audit trails are essential requirements in electronic record systems.

Pharmaceutical companies and CROs can conduct efficient and compliant clinical trials by understanding global regulatory requirements and selecting and managing appropriate systems. With technological evolution, the importance of electronic signatures and data integrity continues to grow, requiring continuous learning and adaptation.

Key Regulatory Requirements Comparison Table

Requirement	FDA 21 CFR Part 11	Japan ER/ES Guidelines	EU Annex 11
System Validation	Required	Required	Required
Access Control	Required	Required	Required
Audit Trail	Required (timestamped)	Required	Required
Data Backup	Required	Required	Required
Legibility/Readability	Required	Required (見読性)	Required
Record Retention	Required	Required (保存性)	Required
Electronic Signature Requirements	2-factor authentication minimum	Electronic Signature Law or equivalent	Qualified electronic signature
Authenticity	Required	Required (真正性)	Required
Data Integrity Principles	ALCOA+	ALCOA+ equivalent	ALCOA+

EDC System Adoption and Market Growth

Year	Global EDC Market Size (USD)	Clinical Trial EDC Adoption Rate
2020	~2.0 billion	~50-60%
2024	3.2 billion	~70%
2026 (projected)	~4.0 billion	~75-80%
2033 (projected)	8.5 billion	~85-90%

CAGR 2024-2033: 10.5-12.5%

Essential Features of Modern EDC Systems

Modern EDC systems in 2026 typically include the following capabilities:

Core Compliance Features:

• 21 CFR Part 11 and GxP compliance
• Electronic signature functionality with dual authentication
• Timestamped, tamper-evident audit trails
• Role-based access control (RBAC)
• Data encryption (at rest and in transit)
• System validation documentation (IQ/OQ/PQ)

Advanced Functionality:

• Real-time data validation and edit checks
• Automated query management
• Integration with ePRO, eConsent, IRT systems
• Support for remote and decentralized trials
• Mobile and tablet accessibility
• AI-powered data quality monitoring
• Direct data capture from wearable devices and sensors
• CDISC standard compliance (CDASH, SDTM, ADaM)
• Cloud-based architecture with 99.9%+ uptime

Inspection Readiness:

• Complete audit trail reporting
• Source data verification (SDV) support
• Electronic regulatory binder
• Export to regulatory submission formats
• Inspection-ready documentation packages

This comprehensive approach to EDC implementation ensures that clinical trials meet the highest standards of data quality, regulatory compliance, and operational efficiency in the evolving landscape of clinical research.