TMF and GCP Compliance

Are your practices for handling TMFs compliant with the new GCP requirements from ICH E6 (R2) coming into effect June 14?

Background for ICH E6 (R2)

The ICH GCP E6 regulation was introduced in 1996 when clinical trials were largely run on paper. Since then, the following trends have significantly increased:

• the scale, complexity, and cost of clinical trials
• the degree of outsourcing for clinical trials
• the sophistication of risk management practices
• the sophistication and use of technology within clinical trials

Due to the above-mentioned factors, there was a recognition within ICH and across major HAs that a revision of the GCP Guideline was needed to reflect best practices in clinical trial design, conduct, oversight, recording, and reporting, all of which have evolved over the 21 years since the release of the initial ICH GCP Guideline.

For more than 20 years, ICH E6 (R1) has been the Gold Standard for Good Clinical Practice (GCP) internationally. ICH E6 (R2) is the most significant revision to Good Clinical Practice for two decades, addressing key findings from GCP inspections across the industry.

The Implications of ICH E6 (R2) for TMF Management

So what are the implications of ICH E6 (R2) on TMF management? From a sponsor Trial Master File (TMF) management perspective, new requirements surface in the following key areas:

1. Risk-Based Quality Management
2. Monitoring
3. Essential Documents
4. Trial Management, Data Handling, and Record Keeping

Let’s have a closer look at each of these four areas and how TMF management practices will be impacted by considering: 1) ICH E6 (R2) definitions, 2) ICH E6 (R2) requirements and 3) Key questions relevant to TMF management.


1. Risk-Based Quality Management 

ICH E6 (R2) Definition

Interestingly enough, the term Quality Management is not defined, but could logically be assumed to cover at least Quality Control and Quality Assurance as defined.

ICH E6 (R2) Requirements

“The sponsor should implement a system to manage quality throughout all stages of the trial process. … Quality Management includes…the collection of information that is essential to decision making. … The quality management system should use a risk-based approach.”

Questions that come to mind pertaining to TMF management:

  • Does your current Quality Management System (QMS) provide comprehensive and adequate procedures, and working instructions for TMF management?
  • Do you currently have a formal process for identifying, evaluating, and controlling risks at the system level, i.e., related to the system(s) and procedures used for TMF management and at the individual trial level?


2. Monitoring

ICH E6 (R2) Definition

The act of overseeing the progress of a clinical trial and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

ICH E6 (R2) Requirements

“The sponsor should develop a systemic, prioritized, risk-based approach to monitoring clinical trials. … The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring or where justified, centralized monitoring.”

Questions that come to mind pertaining to TMF management:

  • Is your current monitoring approach risk-based and are you leveraging your TMF content and metadata for monitoring activities?
  • Do you currently have an electronic Trial Master File (eTMF) that can be used for combined or centralized monitoring?
  • Are you actively using your eTMF for site monitoring during trial conduct?
  • Do you have a formal process for assessing sites and/or processes to be targeted for on-site monitoring based on documentation and reporting from your eTMF?


3. Essential Documents

ICH E6 (R2) Definition

Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data produced (see point 8. Essential Documents for the Conduct of a Clinical Trial).

Let’s take a look at the new requirements regarding location and content of TMFs before we look at the new requirements for storing essential documents and handling copies of original documents.

a. TMF Location and Content

ICH E6 (R2) Requirements

“The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents, including source documents. Essential documents for the trial should be supplemented or may be reduced where justified based on the importance and relevance of the specific documents to the trial.”

Questions that come to mind pertaining to TMF management:

  • Do you currently have a record of the location of your essential documents across all your trials and service providers?
  • Do you have a formal process for assessing which documents are considered essential per trial or are you collecting the same documents across all trials?
  • Are you including all documents needed to reconstruct the trial, including those not labeled as essential documents in ICH E6 (R2), such as QP certifications, regulatory green light to release and ship IMP, and database lock documentation?

b. TMF Storage and Handling of Copies

ICH E6 (R2) Requirements

“The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document identification, version history, search, and retrieval. … When a copy is used to replace an original document (e.g. source documents, CRF), the copy should fulfill the requirements for certified copies.”

Questions that come to mind pertaining to TMF management:

  • Can you identify individual essential documents, including confirming their uniqueness within the TMF?
  • Do you have a formal process for creating certified copies of original documents?
  • Does it cover destruction of paper originals?
  • Do you have a TMF archive that: a) makes the TMF easily available if needed and b) ensures that no changes are made to the actual content of the TMF?
  • How efficient is your TMF archiving and restoring process?


4. Trial Management, Data Handling and Record Keeping

ICH E6 (R2) Definition

No definitions provided.

ICH E6 (R2) Requirements

ICH E6 (R1) already required sponsors to validate any systems used for electronic trial data handling. With E6 (R2), the sponsor should now base the validation on a risk-based approach.

Likewise, ICH E6 (R1) required sponsors to maintain SOPs for such systems. With E6 (R2), it has now been specified that these SOPs should describe the following: system validation and functionality testing, data collection and handling, system maintenance, system security, change control, data backup and recovery, as well as contingency planning and decommissioning. Lastly, all relevant users should be trained on these SOPs.

Furthermore, a requirement for ensuring the integrity of the data, including any data that describes context, content, and structure (i.e. metadata), has been added, stressing the particular importance of this requirement when changes such as system upgrades or data migrations are made.

Questions that come to mind pertaining to TMF management:

  • Is your current computer systems validation methodology risk-based?
  • Do you have all of the above-mentioned SOPS pertaining to your TMF? In addition, is it documented and are all relevant users trained?
  • Does your current TMF system leverage metadata and is the metadata applied in a consistent way across trials?
  • If you already migrated TMF data, did you include the metadata?
  • If you are planning on migrating TMF data, are you planning on migrating the metadata as well?


With the implementation of ICH E6 (R2) GCP Guideline, the compliance bar has been raised another notch. Is that a bad thing? Not at all. E6 (R2) provides the industry with clarifications on a number of topics where current practices have overtaken E6 (R1).

In addition, the implementation of ICH E6 (R2) will further mature the digitization of GCP and TMF management. If you haven’t already implemented an eTMF, E6 (R2) should compel you to consider this seriously and if you have, you should do your due diligence to see if all requirements are met.

Needless to say, we would be pleased to continue the dialogue with you on how to manage TMFs in 2017 in compliance with ICH E6 (R2).