The European Medicines Agency (EMA) published its Guideline on Content, Management and Archiving of Clinical Trial Master File (paper and/or electronic) to address the usage of both paper and electronic document management for sponsors, clinical investigator and other participants in the clinical trials process. The guidance document introduces other ecosystem participants such as contract research organizations and third-party vendors offering portals.

The Guidance timeline:

  • GCP Inspectors Working Group (GCP IWG) 30 January 2017
  • Start of public consultation 12 April 2017
  • End of consultation (deadline for comments) 11 July 2017
  • Final revised document after comments received from public consultation adopted by GCP Inspectors Working Group (GCP IWG) 06 December 2018
  • Legal Effective Date 18 June 2019

Executive Summary

EMA initiates with its’ executive summary noting that the trial master file (TMF) plays a key role in the successful management of a trial by the investigator/institutions and sponsors. The essential documents and data records stored in the TMF enable the operational staff as well as monitors, auditors and inspectors to evaluate compliance with the protocol, the trial’s safe conduct and the quality of the data obtained.

They declare their guideline is intended to assist the sponsors and investigators/institutions in complying with the requirements of the current legislation (Directive 2001/20/EC and Directive 2005/28/EC), as well as ICH E6 Good Clinical Practice (GCP) Guideline (‘ICH GCP guideline’), regarding the structure, content, management and archiving of the clinical trial master file (TMF). The guidance also applies to the legal representatives and contract research organization (CROs), which according to the ICH GCP guideline, includes any third party such as vendors and service providers to the extent of their assumed sponsor trial-related duties and functions.

The ICH GCP guideline provides information in relation to essential documents to be collected during the conduct of a clinical trial. The risk-based approach to quality management also has an impact on the content of the TMF. To ensure continued guidance once the Clinical Trials Regulation (EU) No. 536/2014 (‘Regulation’) comes into application, this guidance already prospectively considers the specific requirements of the Regulation with respect to the TMF.

Introduction

In EMA’s introduction, they declare that a TMF is the collection of essential documents that is used by sponsors, CROs and investigators/institutions for the management of the trial and by monitors, auditors and inspectors to review and verify whether the sponsor and the investigators/institutions have conducted the trial in life with the applicable regulatory requirements and the principles and standards of GCP.

They note the legislation doesn’t differentiate between paper and electronic TMFs (eTMFs). Consequently, all basic requirements are the same for both formats or when used in combination as a hybrid TMF. EMA introduces Article 57 of the Clinical Trial Regulation that conveys “The clinical trial master file shall at all times contain the essential documents relating to that clinical trial.”

Furthermore, Article 20 of Directive 2005/28/EC and Article 58 of the Regulation, according to EMA, also demand that after archiving “Any alteration to the content of the trial master file shall be traceable.”  EMA posits that the TMF should provide for document identification, version history, search and retrieval; also they note, as stated in both Directive 2005/28/EC (Article 17) and Regulation (Articles 57 and 58) it shall be archived in a way that ensures that it is readily available and directly accessible upon request, to the competent authorities of the Member States.

The sponsor’s and any CRO’s quality management system should have procedures (e.g. SOPs) in place to manage all aspects of the TMF to ensure the TMF is complete, legible, and accurate.

The investigator/institution should also ensure the TMF is managed to achieve the same outcome. The TMF documentation should be sufficient to adequately reconstruct the activities undertaken in conducting the trial, along with decisions and justifications made concerning the trial. Documents and records in the TMF should collectively permit confirmation of compliance with the protocol and GCP and the integrity of data collected without the need for additional explanation from the sponsor, CRO, or investigator/institution staff. Per the EMA, the document offers guidance for implementing and maintaining a TMF that complies with the regulatory requirements.

EMA delineates the following sections:

Section 3                                  Trial Master File Structure and Contents

Section 4                                  Security and Control of Trial Master File

Section 5                                  Scanning or Transfers to other Media

Section 6                                  Archiving and Retention of Trial Master File

Section 7                                  References

As TrialSite News focused on the research (clinical) investigator site we provide a brief summary of Section 4 and specifically how this guidance applies to investigative sites.  Under 4.1.3 “Investigator Electronic Trial Master File.

First in 4.1.3 “Investigator TMF” EMA continues “may be electronic, paper or hybrid format. When an investigator/institution eTMF is used the following requirements should be taken into consideration:

  • A complete investigator TMF should be available before, during and after the trial, and accessible under the control of the investigator/institution, independent from the sponsor.

TSN Interpretation: The clinical research site must maintain a comprehensive and complete trial master file throughout the trial and always under the control of the investigator/institution. As in the electronic world there are hybrid scenarios where sponsor or CRO may share access for trial -based document sharing the strict interpretation means when it comes to TMF each entity should maintain its own comprehensive and controlled TMF (eTMF)– no sharing between sponsor (or CRO) and site when it comes to eTMF. Site truly needs its own, independent, eTMF if electronic.

  • The documentation in the investigator TMF includes some source documents containing personal data that enable the data subjects to be directly identified (i.e. direct identifiers of trial subjects); for example, subject identification code list, subject-related source documents and signed consent forms, which would remain under the sole control of the investigator/institution due to data privacy requirements. In general, information (data/documents) shared with the sponsor/CRO or uploaded into a database or filing system that is managed by the sponsor/CRO, should only contain data of trial subjects, which has been pseudonymized. The documents containing direct identifiers of trial subjects, such as the subject medical files, the identification code list and informed consent forms, should be maintained separately by and under the control of the investigator/institution.

TSN Interpretation: At all times a best practice necessitates that key source documentation must always remain within the control of the investigator/institution.  Although EMA is allowing for some exchange and collaboration (electronically) between sponsor (CRO) and site, they are defining the rules for what the site/institution can share with the sponsor and what the site cannot share with the sponsor.

  • The uploading of any investigator/institution-generated essential documents onto a sponsor/CRO maintained eTMF system bears the risk that the investigator has no control of and no continuous access to its documents. If an eTMF is to be used for such documents, the contractual arrangements for the system and the hosting of the data should identify the investigator/institution, as owner of/responsible party of these document.

TSN Interpretation: Of interest, many commercial electronic trial master file vendors may facilitate the uploading of an investigator/institution essential document onto the sponsor-side eTMF (many have a portal or site exchange feature).  EMA is allowing for this electronic exchange to occur however they explicitly declare that the contract between the eTMF vendor and the sponsor should also legally delineate and “identify” the investigator/institution as owner of/responsible party of the relevant documents.  We are not sure if this has been a standard practice with eTMF vendors hence they will have to review their client base and perhaps update practices and legal terms not to mention through review of workflows, etc.

  • The investigator/institution is responsible for the suitability of the investigator TMF. Regardless of what arrangements are put in place for an eTMF, these should ensure that this responsibility can be fulfilled and that they investigator/institution  maintains continuous access to and control of the files and their documents. When a third party eTMF is used, there should be assurance that the investigator/institution can fulfill their responsibility.

TSN Interpretation: eTMF vendors must have the ability to cordon off and ensure that investigator/institution has full access and controls in place. Investigators/institutions must include full legal/regulatory requirements in the service level agreements.  This ability to exert control cannot just be theoretical but must be validated in real terms.

  • Many documents within the investigator TMF are those provided by the sponsor (e.g. protocol, IB, procedural manuals, etc.). Access to these documents in a part of the sponsor eTMF could be undertaken by the investigator’s/institution’s access to a web portal, or by the sponsor uploading these in the investigator/institution’s eTMF directly.  In this situation there should be procedures and controls in place that demonstrate at all times when versions of documents were made available to the investigator/institution and when these documents were accessed (e.g. through an audit trail) and implemented by the investigator/institution

TSN Interpretation: EMA is offering flexibility and supporting the facilitation of secure essential document exchange via sponsor portal or a sponsor monitor-based concierge service uploading sponsor-originated essential documents directly into investigator/institution’s eTMF directly.  Tight and seamless policies, procedures and work records need to be in place demonstrating that all guidance and rules followed. Also third party vendor must offer granular rules, workflows and security provisioning, not to mention versioning for exchange of essential artifacts—all validated for fit for purpose.

  • All agreements should include provisions for the situation that any of the parties mentioned above are going out of business and how the integrity and accessibility of the complete investigator TMF will be maintained throughout the required archiving period.

TSN Interpretation: Contracts with vendors or between sponsor and site/institution need to incorporate the provisions of the guidance in addition to how the integrity of the eTMF shall be maintained.

  • Remote access by sponsor or CRO personnel to the investigator TMF should only be possible to the documents where personal data that enable the data subjects to be directly identified (i.e. direct identifiers of trial subjects) is not present or had been pseudonymized.

TSN Integration: If the investigator/site eTMF or by extension eTMF and portal does not systematically segment data based on rules (e.g. system that includes directly identified subject is not accessible unless pseudonymized) then there should be no sponsor or CRO access.  eTMF (site or sponsor side) vendors should include purpose-built rules engines to support enforcement of the systematic policies and procedures necessitated by the guidance.

Source: EMA Europa EU

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