What are the major problems with the ICH-GCP guideline?
Along with other trialists, we have repeatedly pointed out the major problems with the ICH-GCP guideline, which in summary are:
- Focuses on the wrong things: the ICH-GCP guideline emphasises many aspects of trial conduct (e.g. excessive data checking, source document verification, individual adverse event reporting) that are not important at the expense of those few critical things (e.g. sufficiently large sample size with proper randomisation and blinding along with proportionate monitoring) that really matter to the success of the trial in reliably answering the study question and keeping participants safe.
- One-size-fits-all: the ICH-GCP guideline is inflexible emphasising a one-size-fits-all approach which ignores the fact the conduct of a trial, particularly aspects such as monitoring and safety reporting, should be proportionate to the risks of the trial, which to a large extent depends upon the treatments being tested (e.g. a new drug in development would require much more intensive monitoring and safety review compared to a vitamin or over-the-counter product which has been in use for many years).
- Lack of harmonisation: since the ICH-GCP guideline was introduced 20 years ago, many other guidelines and regulations related to trial conduct have been created. Unfortunately, these have not been harmonised across different countries and region making the conduct of global studies overly complex and more costly than they need to be. Obviously, when the organisation responsible for bringing everything together has “harmonisation” in its name, this is slightly surprising.
Other problems with the ICH-GCP guideline include the emphasis on safety assessments that rely on reports of individual adverse events, the requirements for the training of site staff, the checking of site documents that the ICH-GCP guidelines regards as “essential”, a look into those things that the ICH-GCP regard as “serious breaches” and many others problems.
These fundamental problems with the ICH-GCP guideline are not just a problem for industry developing new drugs
However, things are much worse for over the last two decades the ICH-GCP guideline has expanded massively in scope to cover all randomised trials (and even many other forms of health research). Keep in mind that most trials that get done are not done by companies to get approval for a new drug. The reasons for this massive expansion in the scope of the ICH-GCP guideline are not entirely clear, but one reason is the absence of an alternative and the assumption that if drug regulators are behind it then it must be good, right? The problem is that the fundamental flaws mean that it is not good and calls from us and others to correct this have been largely ignored by ICH and drug regulators. We’ve seen questionnaire surveys of hospital staff, family doctors prescribing common licensed drugs and studies in low-income countries not getting done, all because they’re research so are required to follow the ICH-GCP guideline. Yes, it’s all a bit bonkers.
In June 2015 ICH finally acknowledge for the first time the problems with their ICH-GCP guideline
Having said all of that, in June 2015 we were both surprised and pleased to hear about the ICH’s plan to update the ICH-GCP guideline. In particular, we were pleased to see that ICH for the first time acknowledged the problems the ICH-GCP guideline had created. The following text is taken from ICH’s introduction to the draft update (E6 is the reference number for the the ICH-GCP guideline):
“Although ICH E6 generally can be interpreted as providing sponsors flexibility to implement innovative approaches, it has been misinterpreted and implemented in ways that impede innovation by, for example, emphasising less important aspects of trials (e.g., focusing on the completeness and accuracy of every piece of data) at the expense of critical aspects (e.g., carefully managing risks to the integrity of key outcome data).”
You can read the draft update on the ICH website.
ICH says that the the ICH-GCP guidelines “original text is still correct”
However, as you can read in our recent letter to the EMA, ICH have not revised in any respect the original text, which they themselves acknowledge is fundamentally flawed, but have rather dropped in a few sections of new text by way of an addendum. We queried this with ICH and they responded by saying that the original text in their ICH-GCP guideline was not being revised because the “original text is still correct.”
How can something that even ICH itself acknowledges is fundamentally flawed still be correct?
Further, the proposed changes proposed in the update from ICH merely mention some of the modern concepts, like risk-proportionate monitoring, that came out of the work of CTTI, but they just pay lip-service to them, without providing any new guidance on how they might be implemented. These proposed changes are clearly not going to correct the fundamental problems with the ICH-GCP guideline, but worse, it introduces all sorts of confusions and contradictions that could even make matters worse. So, the problems with the ICH-GCP guideline persist.
All of the above leads us to conclude that we have a twofold problem here: #1 the ICH-GCP guideline; #2 ICH itself.
