What’s New: EMA Guideline on GCP Compliance (Inspection Readiness)

April 25, 2017

  • eTMF Guidelines

On 31 March 2017, the European Medicines Agency released a “Guideline on GCP Compliance in relation to trial master file (paper and/or electronic) for content, management, archiving, audit and inspection of clinical trials“.

This document contains the following important note:

“A revised version of the reflection paper on TMF, considering comments collected during the public consultation (01 February – 30 April 2013), have been incorporated into this guideline, which has been prepared as part of the work related to the implementation of the new Clinical Trial Regulation (EU) 536/2014.”

In providing this guidance, the EMA re-organized, re-wrote and re-worded the entire body of information that had been included in the Reflection Paper. As a result, it’s not an easy task to grasp the differences between the Reflection Paper and the Guideline.

I decided to start with the Inspection Readiness part of the Guidance. This section is repeated verbatim below, with new elements in red. At the end, I have summarized what I think are the key differences between the old and new guidance.

7.1. Inspection readiness of TMF

Article 57 states “the clinical trial master file shall at all times contain the essential documents relating to that clinical trial which allow verification of the conduct of the clinical trial and the quality of the data generated”. Sponsors and investigators are expected to keep the TMF up to date and ensure that it is complete at the end of the trial. About the TMF Articles 57 (and of the Regulation also state that “it shall be readily available and directly accessible, upon request, to (the competent authorities of) the Member States.”. The sponsor is recommended to undertake routine quality assurance activities of the TMF processes to ensure this.

Prior to the inspection, the inspector will usually discuss with the sponsor and investigator(s) the logistics of making the TMF available to the inspectors. A paper TMF (or e-TMF stored on media archived elsewhere) or certified copies relevant to the inspection site should be available for the inspection upon reasonable notice, whereas, access to e-TMFs (live and archived on servers) would be expected by inspectors to be essentially immediate (time only required to set up inspector access to the trials requested by the inspectors).

With reference to Article 57 of the Regulation, direct access to the TMF is expected. The inspectors should have read only access, without any restriction (e.g. to final documents), to the entire TMF for inspection during preparation and conduct of the trial, which means that they can review the same TMF as used by the staff conducting the trial. Direct access includes all the systems that comprise the TMF as defined by the sponsor, however, due to the technical nature of some of these systems, for example those containing data rather than documents, these may require the direct access to be assisted by a representative of the sponsor familiar with the system. Organisations should be aware that GCP inspectors may have rights to seize original trial documentation if circumstances arise that require it. GCP inspectors can always request copies or print outs and can retain some or all of these. The GCP inspectors’ expectation is that an e-TMF should adequately replicate the paper based system that it is replacing and provide for suitable document identification, search, prompt retrieval and marking for future reference/copying. The e-TMF should allow review in an efficient manner, analogous to that possible with paper TMFs. Such a review should not take longer to be undertaken than for a paper TMF and should allow efficient, straightforward navigation and opening of documents permitting searching and browsing (analogous to leafing through a paper file). This would include:

  • a folder structure to allow easy identification of TMF sections;
  • a folder/file naming convention that readily identifies what each file/document is, so inspectors/auditors do not have to open numerous documents to locate those they need;
  • the ability to open more than one document at a time to allow comparison (so size of screens or double screens important);
  • the ability to provide access to the same type of document across all studies/sponsors/product etc. (i.e. if inspector needs to review documents for all/some selected studies/sites);
  • the system is recommended to have an efficient speed of access and ideally not require the use of a nomenclature document or require time spent opening non self-evident named files to determine their content. It is acknowledged that inspectors may need to familiarise themselves with an e-TMF. Any training should be an option for the inspector to choose and is anticipated to be very brief (taking no more than an hour). The e-TMF will need the use of suitable equipment, to be provided by the organisation, for the inspector to view the documents. This equipment is recommended to facilitate the presentation of the documents at actual size.

Key Changes

  1. The EMA emphasizes that the sponsor needs to undertake routine QA in order to keep the TMF up to date – it’s necessary but not sufficient just to file documents promptly.
  2. The organization should be able to provide “essentially immediate” inspector access to an eTMF.
  3. Direct access to systems containing data (e.g., safety, EDC, etc.) could be provided by assistance from a representative of the sponsor familiar with the system and need not be provided by direct access to an inspector.
  4. “Organisations should be aware that GCP inspectors may have rights to seize original trial documentation if circumstances arise that require it.” – I think this was probably true, but it has been specifically called out here.
  5. “GCP inspectors can always request copies or print outs and can retain some or all of these.” – same.
  6. A requirement to present documents in a folder structure.
  7. A requirement for a sound naming convention so that inspectors don’t have to open documents to discern the contents. (This problem was alluded to in the reflection paper but the solution was not defined).
  8. The ability to search for a specific document type across studies, countries or sites.

A few items were dropped as well:

  1. “The organisation is responsible for providing suitable equipment to view the eTMF.” – could this be a prelude to inspectors using their own equipment on-site or remotely?
  2. “The system and equipment would ideally be akin to flipping the pages of a book”

If you anticipate an EMA/MHRA inspection, a review of the updated guidance and check of your eTMF system for compliance would be well-advised.