ICH’s recent reflection paper “GCP Renovation” and the invitation to comment on the process laid out for modernising ICH-GCP and other related trial guidelines is to be welcomed. MoreTrials will send comments by the deadline of 11th March after we have discussed as a collaboration how we should respond.
What follows therefore is my own personal viewpoint having just read what ICH are proposing.
My starting point are the two long-standing related problems that need to be fixed. The first one is the ICH-GCP guideline, or more correctly as the ICH paper lays out the series of guidelines that relate to doing trials. The second one is ICH itself.
Fixing the ICH guidelines
Starting with the first problem. The proposal by ICH to start by updating ICH E8 which covers general consideration for doing trials seems logical. Using this guideline to reference the other related trial guidelines also sounds like a good idea.
One area that is worthy of mention are the various guidelines relating to safety reporting, covered in E2 on pharmacovigilance. Given the time, effort and money that goes into safety reporting this seems to be a key area to come up with new guidelines on how to do trials better.
Turning to ICH-GCP (E6). The update at the end of last year was just a “sticking-plaster” so ICH are right to point out that it now needs to be renovated.
I would go further though and say we don’t need to renovate E6 we need to demolish it and start again. Why do I say that?
ICH defended the confusion created by updating ICH-GCP last year by way of an addendum by insisting that the “original text was still correct.” It never was and never will be correct for it focuses on things that largely don’t matter at the expense of those few things that do matter when doing a randomised trial. The reflection paper also hints at times of a rather self-gratulatory tone by ICH, for example, on page-2 where it says ICH-GCP has supported the earlier submission of new drug applications “enabling earlier access to new medicines for patients who need them.”
What about the promising drugs that never get tested in phase-3 because the cost and related risk are too high?
Or the trials that are so complicated because of ICH-GCP that they never get completed falling in on themselves under their own weight?
Do ICH want to take credit for those as well? Drug development is in a mess. ICH-GCP is one of the major reasons for this.
And that leads on to next point, which is the starting point for the new-GCP is how to do a randomised trial well.
Not buried in an annex as the ICH paper proposes, but the starting point are those few key principles in doing a randomised trial that if you know and understand them guarantee the reliability of the result and the safety of the study participants. Throughout the document I get the sense that ICH, like many others, don’t really understand the unique value of having reliable evidence from randomised trials.
For example, on page-4 describing comparative effectiveness research (CER) it says,
For instance, observational studies of two approved therapies used to generate CER may not require the same level of documentation of informed consent, or it may be waived, as compared to a randomised controlled trial of an investigational agent.
Of course, instead, what we need ICH to promote are large simple randomised trials of commonly used treatments rather than studies with “real-world data” which will just give us bigger wrong answers. Ben Goldacre wrote about it this week in The Times how red-tape including ICH-GCP has killed off two such trials he has been involved with to compare different statins.
Everything I’ve written above can be solved by open, transparent dialogue between all parties involved in the conduct of trials. These are soluble problems.
And that brings me to what is the main problem that needs to be fixed, ICH itself.
The efforts by ICH over the last year to engage with us are positive signs and are appreciated. At various points in the paper there are indications that ICH is trying to become more open and transparent. It talks about more public consultation, taking forward all of this work with expert working groups whose membership could include experts from a mix of relevant disciplines.
All good signs, but then right at the end of the document, on page-9 it seems to me how ICH see this new way of working. They will write the concept papers for these new guidelines inviting comments from others in a 30 day window before the expert working groups start their work.
A better way of course would be to get everybody with relevant expertise to write the concept paper, put it out for consultation and then get everybody to look at the responses making all of the responses publicly available. ICH don’t publish the responses they receive to their public consultations, for example, the other responses to the update last year of ICH-GCP were never published. Why not?
The second worrying statement in the paper is the proposal to “Hold meetings with outside stakeholders at key guideline development milestones.”
Again, the intention is welcome, but it does not go nearly far enough. The model that ICH will do the work and then regularly check in with experts in trials to see if things are moving along the right lines won’t work. We can’t have ICH, regulators and industry meeting behind closed doors to come up with new guidelines and then getting input from experts “at key guideline development milestones.” This won’t work.
Instead, all of this work should be in the open, transparent with contribution from anybody who is interested. Open and transparent means just that. The names of those involved should be published, membership of the expert working groups should be agreed by all parties, along with all responses made openly available. Meetings should be held in public. If ICH and regulators are not able to do this, then the question once again is why not?
Overall, I’m left with the feeling that ICH are already busy “renovating” the house and I’m on the outside shouting to them through the safety fence,
Stop working! The foundations aren’t strong enough. You need to demolish it and build a new house instead. I know it’s only 20 years old, but it’s crap!
But, with all of the noise of a busy building site they can’t hear me and just carry on with their work………
Again, these are my own views from reading the ICH “renovation” paper and we will formally respond as a collaboration in the next few weeks.