ICH GCP and the Declaration of Helsinki

A relationship gone south?

ICH GCP will have it’s 20th anniversary this year, with the first real update in advanced stages of preparation. It’s aimed at being adopted in November this year1
. Where GCP in it’s introduction states that the principles ‘have their origin in the Declaration of Helsinki’, the Declaration (DoH) has evolved significantly in the past 20 years and not without controversy. So where does ICH, and for that matter some of their official parties, stand on the current DoH?

How it all started

It all started so great. ICH, the International Conference on Harmonisation, has worked hard to establish internationally accepted guidelines for clinical research. Originally ICH provides a unified standard for the EU, US and Japan, facilitating the mutual acceptance of clinical data by the regulatory authorities of those jurisdictions. The upcoming revision of the E6 guideline (GCP) aims to extend the reach of that guideline to include Canada and Switzerland as well. The ICH Steering Committee is contained of representation from regulatory authorities and the research-based industry2. The medical society, the investigators, are not represented within the ICH organisation. However, by basing their principles squarely on the principles of the DoH upon creation ICH fully accepted the ethical principles outlined by the World Medical Association (WMA) in their Declaration, and built upon those.

ICH doesn’t state that the DoH needs to be observed when generating clinical trial data, nor does it specify the version of the DoH from which their principles originate. At the time of the creation of GCP the fourth (1989) version was current, however the fifth (1996) version was in preparation.

The evolution of the DoH

With four revisions over the first 32 years of the declaration’s existence, only the first being an extensive revision, the DoH entered a more rocky period in the 17 years after. The 1996 version was the start of the controversy surrounding the declaration, which led to 3 revisions and 2 notes of clarification, bringing it to the current, 2013 version3.

Without going too much into the details of what caused the controversy, the core lies in the specification for the first time in the 1996 version that “the use of inert placebo” is only acceptable “in studies where no proven diagnostic or therapeutic method exists”4.

ICH in response to the DoH revisions

ICH has been eerily quiet on the whole controversy over the Declaration of Helsinki. The only thing that can be said is that, now that it’s preparing the first real update of their E6 GCP guideline it’s not considering updating the principles of ICH GCP to reflect the revisions in the DoH. It still reads however that “clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki”5.

So if ICH is not responding to the revisions and the controversy, let’s explore how the two largest jurisdictions of ICH have responded.

The EU and the Declaration of Helsinki

The position of the EU towards the DoH has historically been an interesting one. After ICH GCP was finalised, the EU started creating it’s legal framework around this guideline, leading to the 2001 Clinical Trial Directive (EU-CTD 2001/10/EC6). In this EU-CTD it states that “the accepted basis for the conduct of clinical trials in humans is founded in the protection of human rights and the dignity of the human being (…), as for instance reflected in the 1996 version of the Helsinki Declaration”. This is interesting for two reasons. Firstly the EU seems to accept that the WMA feels that placebo controlled research should only be done if no proven treatment exists. In the meantime continuing to ask for precisely such research. Secondly the EU blatantly ignores the then current version of the DoH, the 2000 revision! In the 2000 revision the WMA reworded their declaration significantly on the topic of placebo controlled research and removed the distinction between “therapeutic” and “non-therapeutic” research. Apparently unacceptable for the EU.

When the EU in 2005 released their GCP-Directive (2005/28/EC7) it re-enforced their position by again referring to the 1996 revision: “Clinical trials shall be conducted in accordance with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects, adopted by the General Assembly of the World Medical Association (1996).”. At this point, the WMA has already added their 2002 and 2004 Notes of Clarification to the 2000 revision. This however seemed not to please the EU. They stuck to their guns and made the 1996 version law in the EU.

USEUBut what of the newly created Clinical Trial Regulation? This Regulation (536/20148 will be replacing the 2001 EU-CTD when it becomes effective. The full text has been adopted in 2014 already and implementation is currently expected in 2018.

The Clinical Trial Regulation surprisingly states that “this Regulation is in line with the major international guidance documents on clinical trials, such as the 2008 revision of the World Medical Association’s Declaration of Helsinki (…)“. Totally ignoring the 2013 revision, which the WMA says “is the only official one”9.

I am yet to find out what caused the EU to skip the current version and opt to refer to the 2008 version, with which it’s contradicting it’s own 2005 GCP-directive. This still refers to the 1996 version and is not rescinded by the Regulation. If and when I find out more I’ll make sure to share that information. I invite all who have thoughts about this to leave them in the comments.

The US and the Declaration of Helsinki

The position of the US towards the DoH has been more outspoken than that of the EU. The FDA in 1996 already decided to stick with the 1989 version after the first explicit mentioning of placebo as being only acceptable where no proven treatment exists. And it never improved after that.

The 2000 revision, 2002 and 2004 notes of clarification did nothing to persuade the FDA to move to the current version of the DoH. And in 2008, even before the 2008 revision was adopted, the FDA abandoned the use of the Declaration of Helsinki, specifying that, for foreign data not being generated under an investigational new drug application, the requirement of that data to be generated in accordance with the Declaration of Helsinki was no longer applicable, replacing that with the need to adhere to GCP. This was stated in their final rule, which took effect on October 27, 2008, is codified at 21 CFR 312.12010.

So where does that leave us?

As the above demonstrates, the Declaration of Helsinki is not unchallenged. In their article The 50th Anniversary of the Declaration of Helsinki – Progress but Many Remaining Challenges 11, the authors skilfully outline the current challenges of the Declaration of Helsinki.

With the frequency of revisions of the Declaration of Helsinki, it is probably not reasonable to expect ICH to refer to any particular version in their guidelines. And so it doesn’t. However, nor has it seen fit to incorporate any of the more recent points of the Declaration in their upcoming update. That leaves it up to the regulatory authorities to determine our minimally required standards.

Best the rest of us in the clinical research world can do is to make sure that there is never any doubt about out efforts to work according to the highest possible ethical and scientific standards in everything we do. Don’t ignore the Declaration of Helsinki. Where possible, take it into account and where needed use common sense. Keep in mind that the authors of the Declaration also have the best interest of our trial subjects as well as future patients in mind. I wish all involved the wisdom to come together and soon see eye to eye.

Your GCP Nerd

GCP Nerd is a blog about ICH GCP in particular and related clinical research topics. If there are any topics or questions you’d like Your GCP Nerd to address, feel free to mail them to: GCP Nerd

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