What is an eTMF?

Clinical research demands meticulous document management to ensure quality and regulatory compliance. An electronic Trial Master File (eTMF) meets this need by digitizing and centralizing all study documentation. This enhances workflow efficiency and provides better oversight throughout the trial process. But how do you determine which eTMF system is best for your clinical (multicenter) study?

The requirements of a mid-sized biotech company differ significantly from those of academic research centers, large pharmaceutical organizations, or emerging CROs. This guide outlines key selection criteria to help you make the right choice.

Key Selection Criteria for an eTMF Platform

1.  Compliance
   1. Certification
   2. Audit trail
   3. Data Security
   4. Data Storage
2. Document & Version Control
3. Validated eSignature Functionality
4. Scalability
5. Pricing Model
6. Onboarding
   1. Implementation
   2. Support

A reliable eTMF platform must comply with international regulations and standards. Therefore, the first step is to check whether an eTMF complies with the laws and regulations in your country. If it does not, then the eTMF system is not suitable.

Certification

An eTMF platform must meet relevant certifications for clinical research. The exact certifications required depend on the location where the study is being conducted.

• ISO 27001: Ensures structured information security and continuous improvement

• ISO 14155: Applies to clinical investigations of medical devices

• GCP Compliance: Ensures adherence to ethical and scientific quality standards

• 21 CFR Part 11: U.S. FDA rule for trustworthy electronic records and signatures

• GDPR/AVG (Europe): Data privacy regulations for processing personal data

• HIPAA (USA): Regulates protection of personal health information

• NEN 7510 (Netherlands): Dutch healthcare information security standard

• ISO 9001: (Preferred) Global standard for quality management systems

Audit trail

“When selecting the best eTMF platform for an organization, the audit trail functionality plays a crucial role. A comprehensive audit trail enables organizations to provide full transparency of all actions within the eTMF during audits and internal or external inspections. This is essential for achieving and maintaining certifications and complying with regulations in clinical research. 

An effective audit trail should include:

• Comprehensive logging of all system activity

• Detailed user account activity (logins, password changes, role assignments)

• Immutable records that cannot be altered retrospectively

• Automatic documentation of who made changes, when, and what was changed

• Customizable requirement for change justifications

• Practical tools to view, export, and print audit logs

Related resource: “How Does an eTMF Contribute to Efficient Audits and GCP Compliance?“

Data Storage

The location of data storage is an important selection criterion, especially for international multi-site studies, as each research site must comply with its own local regulations. Depending on local laws and organizational preferences, regional cloud services may offer the best fit. This brings two key advantages:

1. Data is stored and processed within the jurisdiction of the respective country — for example, in the U.S., Canada, Australia, Japan, or a European country.

2. Processing complies with local security and compliance standards.

Data Security

Access Management and Security

A reliable eTMF system is characterized by advanced security features that ensure safe and controlled access to research data.

Essential security features include:

1. A role-based access control (RBAC) system

2. Research sites have access only to their own documentation via RBAC

3. Single Sign-On (SSO) capability through Security Assertion Markup Language (SAML)

4. Two-Factor Authentication (2FA) using username, password, and verification code

5. Permissions that can be configured at various levels, such as application, tool, study, site, and patient

6. Ability to enforce password strength

7. Configurable password change policies

Penetration Testing

When selecting an eTMF platform, it is crucial to understand how its security is tested and maintained. A provider may conduct so-called penetration tests (pentests). During a pentest, ethical hackers search for vulnerabilities in the eTMF system to identify potential weaknesses that malicious hackers could exploit. The results of a pentest allow developers to strengthen security and reduce risks.

 2. Document & Version Control

Document management is, of course, central when choosing an eTMF system. The best eTMF platform—especially for large studies—stands out with extensive document and version management capabilities. This ensures more efficient workflows and that every team member is always working with the most up-to-date document.

When comparing eTMF systems, pay attention to the following features:

1. Digital workflows with built-in processes and deadlines

2. Automatic deadline notifications to relevant stakeholders

3. Document versions are logged automatically to avoid confusion and ensure everyone works with the latest version

4. Advanced filtering options by country, region, research site, and document name

5. A flexible folder structure is advantageous compared to a rigid structure imposed by the provider

6. All communication takes place within the eTMF system, preventing important information from being lost in email threads

7. Comprehensive audit trails for tracking and logging changes

8. Electronic Investigator Site File (eISF) functionality for multicenter studies

9. It is legally required to store data for 15 years. Does the eTMF provider support this? And can data be stored in a country of your choice?

3. Validated eSignature Functionality

A good eTMF system is characterized by a validated eSign functionality. This streamlines workflows, accelerates approvals, and enables faster decision-making—ultimately improving the efficiency of the research process.

Does the eTMF include an eSign feature? If so, consider the following:

• The electronic signature must be legally valid

• Full traceability of the signing process (who, when, where)

• Flexible configuration of digital approval processes:
       – Built-in workflows with deadlines per research site
       – Configurable signing order among responsible officials
       – Possibility to phase approval processes across different research sites

4. Scalability

When selecting the best eTMF system for an organization, it is important to look ahead to future growth. Choosing a system with limited scalability can lead to constraints as the organization or number of studies expands. A scalable system avoids this limitation and evolves with the organization’s needs.

A future-proof eTMF platform offers:

• Seamless integration with CTMS and other research tools via APIs

• Flexible expansion of functionalities

• Support for an increasing number of studies and users

• Support for multicenter studies through an Electronic Investigator Site File (eISF)

• Expandability with additional modules, such as EDC (Electronic Data Capture), ePRO (Electronic Patient-Reported Outcomes), RTSM (Randomization and Trial Supply Management), CTMS (Clinical Trial Management System), RIMS (Regulatory Information Management System), and LIMS (Laboratory Information Management System)

• Adaptability to specific research processes such as Phase I, II, III, IV, or Pivotal/Pilot/Post-Market Surveillance (PMS) studies

• Integration with existing systems via APIs, such as Single Sign-On (SSO), financial software, HR software, and business intelligence tools

5. Pricing Model

eTMF system providers use various pricing models. The best eTMF offers a flexible pricing structure that aligns with the number of studies and users within an organization. A well-adjusted pricing model prevents unnecessary costs by avoiding mandatory purchases of unused studies and functionalities.

Type of Organization

First, verify if the provider suits the size of the organization, such as:

• Large pharmaceutical companies

• Mid-sized biotech companies

• Start-up CROs

• Academic research centers

• Hospitals with only a few studies per year

• Academic hospitals with hundreds of studies per year

Pricing Structure

Pay attention to these aspects in the pricing model:

• Mandatory purchase of a minimum number of users

• Fixed costs per study versus costs per user

• Access to only the necessary modules

• Ability to start small and scale up later

• Possibility for licensing fees to start only when the study begins

• Implementation and training costs

• Support costs within the Service Level Agreement (SLA)

6. Onboarding & Implementation

The onboarding and implementation process is a key factor in the practical success of an eTMF system. The best eTMF platforms stand out through a well-designed onboarding strategy with extensive support during the implementation phase.

Implementation

The complexity of the organisation and the type of studies determine the implementation approach. A start-up or mid-sized CRO can often be operational within just a few days using a standard implementation, without high start-up or licensing costs. For more complex organisations—with multiple research sites, diverse study types, or extensive workflows—a customised implementation process averaging two to three months is required.

User Adoption

User adoption determines how efficiently staff can work within the eTMF platform. Key considerations include:

• Flexible configuration options provide benefits, but may require a longer learning curve if you plan to set them up internally

• An intuitive interface that aligns with existing workflows accelerates adoption

• The platform should include clear, logical workflows tailored to each user type and process

• If programming knowledge is required to customise forms and reports, you’ll need internal expertise or accept the need to hire the vendor for customisation

• Built-in training modules and user manuals for various knowledge levels and user groups are a strong advantage

Support

Professional support is a crucial pillar during both implementation and daily use of an eTMF platform. The best systems offer a combination of functional, technical, and strategic support tailored to the needs of different user groups and types of organisations.

Helpdesk

A professional helpdesk is the backbone of effective eTMF support:

• Direct access to experienced specialists

• A standard or custom service level agreement (SLA) with clear guarantees

• Options for tailored support services

• A comprehensive knowledge base with manuals

• Training programmes for various user roles

• Proactive monitoring and support in case of technical issues

Technical Support

Continuous monitoring and proactive system management form the foundation of professional technical support from the vendor:

• Daily performance checks

• Monitoring of data integrity

• Verification of backup procedures

• Review of system logs

• Rapid response to technical issues

Vendor Evaluation

The quality of an eTMF platform also depends on the expertise and reliability of the vendor. Focus on these key points:

• Demonstrated implementation experience in similar research organisations

• Availability of domain experts in clinical research

• Proven track record in system and service improvements

• Commitment to long-term strategic collaboration

• Global support infrastructure for international studies

Conclusion: The Best eTMF Depends on Your Organization

When selecting an eTMF platform, organizational-specific needs play a crucial role. The best eTMF system stands out through scalability and future-proofing, ensuring that both current and future research processes are effectively supported. A careful consideration of all selection criteria results in an eTMF platform that seamlessly aligns with the unique characteristics of the research organization.

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