Know Your Regs: A TMF Regulatory Overview

Part 2: MHRA Gray Guide

As part of a recent webinar series, LMK Clinical Research Consulting was lucky enough to host Marie-Christine Poisson-Carvajal, Head of TMF & Registry Operations at Pfizer, to discuss the main regulations that predicate the trial master file. During the webinar, Marie-Christine outlined the four most common relevant regulatory authorities and their associated TMF regulations: ICH GCP, EMA Clinical Trial Regulation and Guidance, the MHRA Gray Guide, and FDA 21 CFR Part 11. Marie-Christine established that these regulations are the foundation of every TMF and that the TMF is the foundation of every clinical trial.

To learn more about these essential TMF regulations and best practices for applying them to your TMF business processes, watch the recording of Marie-Christine’s webinar, or read on, as we cover an often misunderstood and underutilized resource, the MHRA Gray Guide. Check back regularly to catch the next post in this multi-part series and gain the regulatory knowledgebase necessary to achieve TMF health!


What is MHRA?

The Medicines and Healthcare Products Regulatory Agency (MHRA) is the government agency that regulates pharmaceuticals, blood establishments, advanced therapy medical products, and medical devices in the United Kingdom. The MHRA is the competent authority (one who is legally delegated authority from the European Medicines Agency, or EMA) of the UK which grants product licensing for new treatments in the UK. More plainly, the MHRA is the UK’s equivalent to the FDA, although because of the interplay between EMA and MHRA, the regulatory environment is more complex.


What is the Gray Guide?

As discussed in the last post in this series, ICH GCP is a guideline produced by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and is a nongovernmental initiative. Different regions and regulators must choose to implement ICH GCP as part of their regulations. Despite the mission of ICH to harmonize all aspects of the novel treatment development process, regulators choosing to adopt ICH GCP can have different interpretations. The Gray Guide is MHRA’s comprehensive guidance on their interpretation of ICH GCP. In Chapter 10 it also contains one of the most modern and complete explanation of eTMF expectations published by any regulator. For this reason it is considered a valuable and forward-thinking resource for clinical research professionals. The guide is only available in paperback format (ISBN 9780117081079).


When do I need to follow the Gray Guide?

Your clinical trial needs to follow the Gray Guide when your study “counts as a medicinal product” and “counts as a clinical trial within the scope of the relevant EU directive”, per REGULATION (EU) No 536/2014. Meeting these requirements makes your study fall under SI 2004/1031, the UK’s adoption of the EU regulations. According to Annex I, point 8 of the Directive 2001/83/EC, when “clinical trials are conducted outside the EU, but submitted for marketing authorisation in the EU, they have to follow similar principles to the provisions of the Clinical Trials Directive”. This means that the TMF of a trial with sites in the US (or elsewhere) conducted by a Sponsor for a UK marketing submission (thus falling under EU clinical trial regulation) can be inspected by the MHRA. The situation can become even more complicated when a Sponsor’s responsibilities are delegated to a party in the UK, especially for international trials. Therefore, careful consideration should be taken to determine whether a trial falls under MHRA’s clinical trial legislation.


What parts of the Gray Guide apply specifically to my TMF?

If your TMF fall under MHRA’s regulation, it is important to keep in mind that FDA’s GCP interpretation can differ from MHRA’s interpretation. Many consider MHRA’s TMF expectations to be higher than FDA’s, therefore an FDA GCP compliant TMF can be considered a good starting point. Compared to FDA GCP, the Gray Guide is detailed and authoritative, specifically calling for comprehensive planning and risk management strategies. Here are another few Gray Guide essentials to keep in mind:

  • Different repositories are acceptable. The TMF ‘does not necessarily need to be in the same location, but it must be clear as to where it is held from TMF procedures or indexes.’
  • Creation of a TMF plan is a mandatory.
  • MHRA clearly states that ICH GCP and EudraLex Volume 10 should not be considered a checklist/table of contents for TMF.
  • Duplication of documents within the TMF is to be avoided and is a common inspection finding.
  • Inspectors will require “direct access” to the live eTMF system (not a copy).
  • Your retention strategy must account for format changes and other retrieval barriers.

An MHRA inspection of a TMF is a formidable process; an inspector will require over-the-shoulder access to the TMF and will scrutinize the audit history and metadata of documents. The MHRA will leverage eTMF functionality to gain a holistic view of the trial in time, not just on the day of inspection. They will also expect a foundation of well documented roles and responsibilities and clearly defined processes to support the TMF. Preparing a TMF for an MHRA inspection must begin well before the start of a clinical trial.


Contact LMK Clinical Research Consulting today for a complementary GCP essential document gap analysis and ensure your TMF meets all regional regulatory expectations.