Solid foundations are crucial in all aspects of our world and lives. I never fail to notice that when a new housing area is under development there is an inordinate amount of time where nothing appears to be actually happening. There is, however, lot of digging and work is going on below ground with mud, dirt and mess!

Suddenly an acceleration occurs; much like that performed by a 100 metre sprinter. The walls pop up and rooms appear.

This is not unlike scientific research, including the complicated and pioneering field of complex neurological diseases, where the essential core science takes a long time and requires many talented people.

This is my final devil is in the detail series post in 2019. I write this just after the end of the Worldwide ALS/MND Research Symposium. This amazing and ever growing event was held on the edge of the Australian desert in Perth.

My chain of commentaries has been trying to give exposure in, I hope, easy to read articles about the really challenging background that our truly dedicated scientists and regulators work with everyday with our difficult disease.

If you want to read more about the symposium, or even see the detail of, literally, hundreds of scientific abstracts, just click on the marvellous Periodic table of MND Research image below to link to the MND Association website. It’s a really nice tool for exploring the agenda and collateral.

MND Foundational Research has dominated the knowledge accumulation over the last two decades. Digging deep, finding issues with the ground, restarting, facing bad weather and perhaps, occasionally, accidentally mixing the mortar a bit too quickly, all in an attempt to build what we need! But now…

In December 2019, have those foundations begun to settle? Are we starting to see the building site being cleared? Are we ready for the walls to start to go up?

I have been specifically covering the genuine difficulties faced by researchers in running and interpreting clinical trials for our disease that perhaps the wider community have not been exposed to. I have discussed the following vital foundation stones:

  1. The need for placebo cases.
  2. The statistics used and how they should and should not be interpreted.
  3. The choice of the most appropriate candidates for trials.
  4. The need to ensure proper oversight before drugs/treatments are released to the community.

Today I thought I would explore some of the thoughts now ongoing to potentially make these difficult trial processes more efficient. After examining the abstracts of the presentations that were to presented at the symposium, it was evident that clinical trial optimisation was clearly woven into the fabric of the conference.

The symposium week started off on Monday 3rd December with an Ask the Experts session streamed live in a pre-conference meeting. It is well worth a watch. The last hour was the traditional Q and A section. Trial optimisation was mentioned by all members of the panel as a key area of focus.

The highly desirable aim to reduce the numbers of people who receive placebo, and other efficiency considerations, have led researchers to start investigations into a concept now used in some cancer trials, known as platform trials. The basic premise of platform trials, or as they are often known, adaptive protocols, is that several drugs/treatments can be tested at the same time rather than just 1, every patient is administered each drug in turn and a placebo all using the same methodology and protocol. You might have also heard such trials referred to as ‘crossover’. The promises of such trial methodologies are manyfold:

1) More drugs might be processed/screened in a shorter time than if processed sequentially in separate trials.

2) Every participant could receive at least one real drug as well as a placebo rather than potentially no real drug at all.

3) Trials could be designed to be ended early in the case of negative or highly promising early results.

This sounds amazing, doesn’t it?

The techniques are most certainly not new and have been considered for many years in a number of diseases, all the way back to the 1980s. But yet it has been only recently that they have started to be used in some cancers. Why has there been, apparently, a slow move to the attractive benefits of such protocols?

This wouldn’t be a devil is in the detail post without delving into such challenging issues. In one sentence; platform trials have typically been not been utilised because of their sheer operational complexity. However, MND/ALS research groups have performed some trials utilising adaptive protocols, but specifically only with symptom control drugs. One of the key complexities is that to constructively use with a potentially disease altering drug, that might only show a marginal effect over many many months, they pose very real logistical difficulties. Many cancers lend themselves more naturally to adaptive protocols for several reasons, including the fact that a precise disease measurement can be carried out and a shorter time is typically needed to reveal a beneficial effect. For example, a tumour’s precise size can be measured, and shrinkage can be observed.

As I discussed in the series so far, ALS/MND is not yet a quantifiably precisely measurable disease. We are, sadly, currently without any repeated trial proven biomarkers and are thus forced to run longer trials, typically with a quite a large number of participants and with subjective measures. Add to this the difficulty of weaving in and out of different treatments for our disease. In fact it could make statistically for far more expensive trials as well as longer ones! And there are other challenges…

What about drug interactions? Both good and bad.
How long is each phase for?

Is it long enough to detect an effect or not?

Is there a disease measuring scale precise enough to facilitate such trials?
These are just some the critical issues that need to be addressed with platform trials.

Certainly to achieve the premature exit capability from trials, for either futility or, more optimistically, early detection of benefit, more trial patients would be required to maintain statistical significance, and not less! Is this a desirable trade off? It might just be.

So despite the community buzz around such platforms, they are most definitely in their infancy for our disease and they may not yet suit subtle disease slowing drugs until we discover repeatable bio-markers. New consensus will need to be found, and ‘trial trials’ will need to be performed to establish whether they really can benefit our fight. At the symposium there were several presentations on platform trial concepts. It will be very interesting to hear how these challenges were addressed. If they can, such a trial protocol could bring major improvements and speed up the search for a long hoped for treatment(s).

I am certainly more confident they could certainly be useful in early stage trials to screen more drugs before investing big in a full Phase 2 or Phase 3. But also, don’t be surprised to see such trials being more used in processing quickly ‘symptom’ control drugs as opposed to disease ‘modifying’ drugs. Symptoms can be measured very easily.

One hugely pressing aspect of desperately needed trial improvement, whether in adaptive or traditional designs, is choosing the ‘best’ patients to be included. Because of the wide and varied presentation of the disease and progression, there has always been a drive to have an homogenous batch of patients as possible so that a drug effect could be more confidently detected. Have we been precise enough so far in trials?

There have been a number of research projects examining how truly homogenous existing trials have really been and some characteristics have started to float to the surface. For example, as noted in Ruben Van Eijk’s recent papers, MND/ALS trials have a large over-representation of younger, slower progression male candidates.


Younger slower progressing patients are far more likely to physically be able travel to trials and even simply contemplate their involvement.

If you then consider the fact that slower progression patients are, by their nature, more likely to have apparent plateaus of disease you can see that there could be some very nasty implications for conclusions in short trials!

And why are there more males in trials? This is a more complex observation to explain. There is some evidence to show that females are maybe less inclined to be medically tested. That is probably a bit controversial, I am aware.

But one thing is for sure. This unintentional bias skews results and may mean we are missing effective drugs and, equally as bad, seeing false positives!

The typical end aim measure of a trial is ‘significant improvement’ of a treatment group versus placebo. If we have not got a homogenous group there will be issues. There are at least two ways to correct this. For example, the homogeneity of the trial could be improved or on the other hand we could predict with better precision each participant’s disease progress without the trial treatment intervention. Some good work has been been made on the latter, which I mentioned in my earlier devil detail post, Narrowing and widening the search. Bringing such changes together might just make adaptive protocols even more possible.

Whether adaptive or traditional trials are used, one trend that will help us move forward is the continuing improvement of pre-clinical science, and this is very obvious from the depth and quality of the science presented. In short, this should lead to only the more promising treatments making through to human tests. A lot of the failure of human trials over the last 20 years has been, to be quite straight talking, due to really quite weak drug candidates being tested.

I will write a symposium follow up post from what I have learnt and gleaned from those who attended the conference, written reports and social media. By all events, it seems to have been a great success.

The absolute highlight for me, watching from afar I admit, was the presentation of the gene therapy (SOD1 gene) early trial data. I mentioned this trial in my recent Stratification post. With its very narrow prognosis stratification (specific SOD1 aggressive mutations), and even with only a few cases, the signals can hold much greater promise than a trial without such a participant profile, This appears to be working its way from “promising” to ”highly likely” to be a future viable treatment. I can sense a quiet confidence, but researchers and the owning Pharmaceutical company are being quite rightly cautious. I believe the Phase 3 is now in progress. Very very exciting for our community indeed.

The other highlights, for me, were the developing focus on anti-inflamantory disease research, and also anti-viral drug research in the light of reports of endogenous retro viruses being flagged in some people with MND.

But readers, I am very aware that I am doing the hundreds of scientists who attended and presented a huge disservice by simply mentioning these few highlights for me. All the work presented is vital core science and the coverage of the disease from pathology to care at the symposium just shows how far we have come in the last 20 years.

Finally, I was going to write about the concept of ‘n of 1’ trials which I mentioned briefly in my last post. However, I am going to hold this subject for a while until a future post.

I definitely believe the bricks in the wall are piling up nicely. But, unlike Pink Floyd’s song from the 1980s, they are most certainly…

Not “Just another brick in the wall”