Here is the News for Wednesday 30th November, 2016

ICH adopted their update to ICH-GCP on 30th November, 2016. The updated addendum can be found here.

This is the first time it has been updated since it was first created in 1996. That’s big news, but there’s more.

The update includes MoreTrials two fixes on the draft document, first, we asked to make it clear that the new text takes priority over the original text (Solution #1 above and the highlighted text from the update shown below).

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Second, we asked that it should cross-reference other ICH guidelines that are about the conduct of trials (Solution #2 above and highlighted text from the update shown below).

ICH have also announced long-term plans for a major overhaul of ICH-GCP and will be seeking views from all stakeholders going forward. The highlighted text from their Osaka press release is here on the right.

We need to see the details when they come out next year, but our analysis is that they’ve taken on board all four of our requests to them in Lisbon back in June.

Most people involved in trials will recognise the monumental significance of this, if you do you don’t need to read on, but, if you don’t, here’s a bit of the history which will hopefully show you why we think this might be a big deal.

The backstory of the randomised trial in medicine.

1950s-1990s

Back in the 1950s, the randomised trial is created as the most reliable way to test the things we do in medicine to see if they are any good or not. Well conducted trials demonstrate what actually works. Examples emerge where lives could have been saved if effective treatments had been tested properly in trials earlier, but also treatments that were routinely used but good trials went on to show they actually caused more harm than good. In the next few decades more things got tested in randomised trials and medicine became evidence-based. It was even given a name, Evidence Based Medicine.

Other areas of life lagged behind, for example, schools every few years were told by the latest new, shiny politician how to teach because they just knew what worked. They didn’t need to see evidence. Teachers never knew about the randomised trial.

These trials were first done on drugs, but other things got tested, even surgeons started doing trials. Trials were done on things like different types of wound dressings (it matters), sending letters to family doctors to tell them they prescribe a lot of antibiotics (they reduce their prescribing), even giving overweight football fans the chance to run around at their local club emulating their heroes (they lose weight). Randomised trials even showed that if you give someone a dummy pill and tell them it will work in some people it actually does work. We call this the “placebo effect” and it nicely demonstrates why we need reliable evidence from randomised trials.

But what really mattered was that when you stacked the results of all of these trials on top of each other there were big gains for human health……

most children now live after cancer……

most people now survive a heart attack………..

more women now live after breast cancer……….

These randomised trials were done by lots of different people, academics in universities, by the pharmaceutical industry to develop new drugs. These trials were at first done in the developed world, but also increasingly more trials were done in the developing world.

1990s-2010:

Then in 1996, a few of the drug regulators and the pharmaceutical industry decided we needed regulation on how do trials and ICH-GCP was born. It’s starting point was sensible. The world 20 years ago was becoming global and companies wanted to do a trial of a new drug in one part of the world and use the data from that trial to get the drug approved in many other parts of the world. It’s called “harmonisation” and, again it’s sensible.

But what was not sensible was that experts in both universities and industry who knew how to do randomised trials well were never asked to be involved in writing ICH-GCP. These experts knew that to do a trial well, to conduct an experiment that reliably answers the question at hand and keeps participants safe requires knowing and understanding a few key principles. If you get these right your trial will be a good trial. Because these experts weren’t involved, the resulting ICH-GCP guideline focused on things that largely don’t matter at the expense of those few key principles that do matter when doing a trial.

In the ten years or so after 1996, as a result of ICH-GCP, the complexity and cost of randomised trials increased enormously. Today, we hear about the half a billion dollar trial. We then started to hear about the crises in pharmaceutical R&D, “broken pipelines”, companies went out of business, development failed because the risk of a “late-stage failure” was just too high.

Trialists in universities and also some in industry started to call for better, sensible, more proportionate regulation of trials. ICH and drug regulators ignored these calls for change.

One other interesting development at this time was that one response of the pharmaceutical industry was to “outsource” the conduct of their trials to others. Ignoring the maxim “if you want something done well do it yourself”, these so called “CROs”, Contract Research Organisations, were created around the time that ICH-GCP first appeared and are now a very big global business, estimated to be worth around $25 billion a year.

Things got so bad that even the European Commission started to call for change saying that their 2001 trials directive which had incorporated ICH-GCP into law rather than promoting the conduct of more trials in Europe, which it was created to do, had actually made it more difficult.

Academic trialists and others again called for change, but again ICH ignored them.

Trialists even wondered whether ICH really existed or might be some mythical beast, like the “Loch Ness Monster.”
Another thing that happened in the last 10-15 years was that how trials were done fundamentally changed with the arrival of computers and the internet.

Why put somebody on a plane to go to a hospital to check the trial data when you could do it from the comfort of your office?

One reason is that ICH-GCP says you need to go to the site to do monitoring (“in general, there is a need for on-site monitoring, before, during and after the trial”). The other reason could be if you make a large part of your profit from sending your staff out to the site to check the data. Of course, that last muse is just a maybe.

Academic trialists in particular started getting louder. They even put together a group to try to engage ICH and regulators. The group was started in 2007 and was called “The Sensible Guidelines for the Conduct of Clinical Trials Forum”. The hint was in the name, but ICH ignored it, some regulators listened and one, the FDA took action and set up CTTI, which has been one of the main driving forces in improving how trials are done, but has also shown that it is possible to bring everybody together to make things better. CTTI continue to do great work and many of the good things in the update to ICH-GCP, like risk-proportionate monitoring, are the result of the work that they’ve done over the last few years.

2010-2016:

But, the biggest change in trials in the last decade wasn’t created by anybody in the trial community. No, it was the result of a small charity in London, called Sense About Science starting the AllTrials campaign.

It’s main message was not a new one in medicine, namely that around half of the trials that get done don’t get published, but the difference was that they made it a public campaign, with a simple solution, all trials that get done should be registered and all trials should report their results.
And in the space of a couple of years everybody involved in the regulation and governance of trials was falling over themselves to address “transparency” as it came to be called.

Interesting. Speak directly to regulators and governments and they ignore you. Get the public to speak to them and everything changes very quickly.

The other big change is that other areas of life started doing randomised trials. That online holiday you’re booking, that flight, that book, chances are you’re in a randomised trial. We also see the emergence of “evidence-based policy”, where
randomised trials are being done in diverse areas, such as education, tax collection and crime reduction. One of the best examples of this whole area of “behavioural economics” is the work of the affectionately called “Nudge Unit” at the heart of the British government in Whitehall. The interesting part is that all of these areas have inherited most of the key principles from medicine of how to do a trial well, for example, randomise large numbers, without taking all of the regulations and other red-tape that gets in the way of doing trials in medicine well. Again, interesting.

2016:

Now, to the present and the start of 2016.

MoreTrials was created on 1st January and to date we’ve gone from a handful of trialists in Oxford to over 200 trialists from around 30 countries signed up to the campaign along with the support of a number of research organisations.

Our first letter to the EMA and ICH back in January pointed out the many problems with the proposed update to ICH-GCP as well as the problems with ICH itself. We expected it to be ignored, it wasn’t.

What happened next though surprised everybody. We got an invite for 6 of us from MoreTrials to attend the ICH meeting in Lisbon back in June to discuss our concerns.

We went to Lisbon, we presented our 4 problems and proposed 4 solutions shown at the top of this page. We expected these to be ignored, but on 30 November, 2016 ICH announced the adoption of the proposed update to ICH-GCP and their intention next year to start the process of fundamentally reviewing ICH-GCP.

What next?

So, it looks like the answer to our question back in June, “Is the door to ICH opening?” might be, I think, “yes.”

Before that back in January when we started MoreTrials the point we made was, “This might not work.” My response now remains “this might not work.”

So, 2016 has been the year of surprises, Brexit, Trump, Germany not winning the Euros, not all of them good surprises, but the news from ICH is very good news indeed, I think!