SOPs in Europe: Required for GCPs?


SOP Europe requirements

SOPs for Clinical Trials in Europe

What are the differences in SOPs for clinical trials in Europe and the United States? Despite the fact that FDA and the European Medicines Agency are increasing their cooperation and collaboration there are still some formidable obstacles. One is the difference in regulations. The other is how much influence ICH E6: Good Clinical Practice: Consolidated Guidance has in different parts of the world. Today we have a Guest Commentary from The SOP Doctor, Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB, a clinical scientist and trainer from the United Kingdom. She is here to give us a European perspective on SOPs. In 1996, Marie established McKenzie Mills Partnership (MMP), providing consultancy services including training, medical information, medical writing, and clinical research.

I will be publishing a post in Marie’s blog this weekend. Trans-Atlantic Cooperation!

Also: Please take the survey at the bottom of the post!

Guest Commentary

Is there a legal requirement to have SOPs for GCP in Europe?

by Dr Marie McKenzie Mills MICR, CSci, CBiol, MSB

Back in January, in his post “reflecting on the TMF”, Carl mentioned that the ICH Topic E6 Guideline for GCP may not appear to receive the same emphasis from some regulatory authorities as in the past. His post raised a flag about whether there’s a GCP standard other than ICH E6 GCP, which got me thinking. In Europe, a similar concern often pops up along the lines of: which GCP should we be following? So here goes with my answer, particularly for those of us affected by European legislation, with a wee bit of context to explain it.

In Europe, ICH GCP was adopted in July 1996, and became operational in January 1997. Despite having no uniform legal framework for implementation, it was largely adhered to within the European Community (EC) as a set of 13 internationally recognised principles for conducting clinical trials, founded in the bioethical principles that were established in the Declaration of Helsinki. But, its adoption as a regulatory standard was neither complete nor uniform.

SOP Europe

Does the Clinical Trials Directive Require SOPs?

In 2001, Directive 2001/20/EC – legislation known as the Clinical Trials Directive – eventually provided a common legal framework across Member States for monitoring and enforcing GCP standards applicable to clinical research implementation. However, Directives have to be transposed into national law, in each Member State (within three years of their publication). This created scope for differing interpretations of the intended regulatory requirements, somewhat at odds with the goal of harmonisation. Even so, ICH GCP is the cornerstone standard within both the Clinical Trial Directive (Article 1 (3)), and the GCP Directive (Directive 2005/28/EC: Introduction, points 1 and 8; Chapter 1, Article 1 (1a)). So, far from receiving less emphasis, its principles have been adopted in both Directives, where it provides a basic standard for the conduct of clinical trials in a “set of internationally recognised ethical and scientific quality requirements, which must be observed for designing, recording and reporting trials that involve the participation of human subjects”.

This then brings me to the question about requirements for SOPs. Even if this requirement isn’t explicitly stated in European legislation, the burden to satisfy it exists nonetheless, particularly for sponsors because, according to ICH GCP 5.1.1, they’re responsible for “QA and QC systems with written SOPs to ensure that trials are conducted in compliance with the protocol, GCP, and the applicable regulatory requirement(s)”. Likewise, IRBs or IECs – as they’re better known across Europe – also need to have SOPs for their functions (ICH GCP 3.2.2).

Europe SOPs require?

Requirements for EU
Member States

As it turns out, in the GCP Directive, the requirement for SOPs is emphasised less for sponsors, and more for Member States, since their inspectors need appropriate tools for verifying GCP compliance (Chapter 6, Inspection Procedures, Article 26: “Member States shall establish the relevant procedures for verification of good clinical practice compliance. The procedures shall include the modalities for examining both the study management procedures and the conditions under which clinical trials are planned, performed, monitored and recorded, as well as follow-up measures”.

So there you have it: SOPs are required tools for sponsors to ensure GCP compliance; and, for inspectors they’re required tools for verifying compliance. As an all-encompassing requirement in the GCP Directive it often seems to escape everyone’s notice, perhaps because it appears understated. But, it’s there in Chapter 2, entitled Good Clinical Practice for the design, conduct, recording and reporting of clinical trials in Section 1, Article 2 (4): “The necessary procedures to secure the quality of every aspect of the trials shall be complied with.” I don’t know about you, but I think that’s all about SOPs. What do you think?

Links to the Clinical Trials Directive, GCP Directive and the ICH GCP guideline can all be found on the European Medicines Agency website on the link below.

European Medicines Agency (EMA)

EMA GCP Inspections

Marie’s Blog on the Difference between ICH and WHO GCPs

Carl’s Guest Post on Marie’s Blog on Differences Between FDA & EMA Sponsor/CRO Requirements

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For more information about Europe you can read:

Applied Clinical Trials, View From Brussels by Peter O’Donnell
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Jobs in Clinical Research? The April issue of the Journal of Clinical Research Best Practices just arrived on my doorstep (actually my email inbox) with a review by editor Norm Goldfarb on a new book, “Careers Opportunities in Clinical Drug Research” by Rebecca J. Anderson. At $59.00 it is a bit pricey but reading Norm’s journal always gives you a spectrum of information on clinical trials. You should consider an introductory Free Subscription to the Journal.
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4 Responses to SOPs in Europe: Required for GCPs?

  1. Shirley Hallam says:

    It is misleading to describe ICH GCP as the cornerstone of the European directives (2001/20/EC and 2005/28/EC). 2001/20/EC does not mention ICH GCP at all. The reference you cite mentions “good clinical practice” without further qualification. 2005/28/EC makes one reference to ICH-GCP in introductory paragraph 8, where it describes ICH GCP as a “concensus paper” which “should be taken into account”.
    However, contrary to your assertion, the requirement for SOPs is clearly stated in European legislation, in 2005/28/EC section 1, article 2, para 4: “The necessary procedures to secure the quality of every
    aspect of the trials shall be complied with”.

  2. GxP Perspectives says:

    Shirley brings a different perspective. I am not an expert on the clinical trials directive and would welcome more comments on this topic.

  3. Hi Shirley,
    Thanks for opening up discussion: are we talking letter versus spirit of the law interpretation?

    As you state, the Clinical Trials Directive (2001/20/EC) does not explicitly mention ICH-GCP. However, aren’t both the Clinical Trials Directive and the GCP Directive (2005/28/EC)the implementing Directives for GCP in the EU, where since its adoption in 1996, ICH-GCP was the recognized regulatory standard? As I mentioned in my post, because its adoption as a regulatory standard was inconsistent, a legislative framework was needed to monitor and enforce GCP standards.

    Therefore, I’m not sure how it’s misleading to describe ICH-GCP as the cornerstone of the two EU Directives that are pivotal to implementing its principles. Aren’t both Directives founded on the principles of good clinical practice as laid down in the community guideline: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) (the consensus paper referred to in paragraph 8 of 2001/28/EC)?

    In effect, Article 1(2)of the Clinical Trials Directive (2001/20/EC) establishes ICH-GCP standards as requirements, “which must be observed”, thus providing the statutory basis for implementing Good Clinical Practice in the conduct of clinical trials. There’s no need then to further qualify what’s meant by GCP in Article 1(3). However, to give a complete picture, I should perhaps have also listed Article 1(2).

    Finally, I’m glad you agree the requirement for SOPs is clearly stated. My point: not everyone may appreciate where it’s stated, or that this statement is in fact the expression of the requirement for SOPs. That’s the problem with interpreting law, can’t always see the wood for the trees.

    Marie aka Dr M | The SOP Doc

  4. FDA 483s says:

    Carl, thanks for the mention. Dr. M and Shirley – thanks for sharing your great perspectives. -Tony

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