In this post I complete my brief “Survivor’s guide” started last week. You might wish to reprise before continuing? But, grab a coffee first.
First up, lets start with the disease measures used within a trial. That is, how is our disease progression tracked, objectively, to help distinguish any differences between patients?
Which disease measure was used?
The most commonly used is an absolute clinical interpretation of function, the ALSFRS-R rating. However, a trend seen recently is to use a second degree measurement, as I described in detail in the post I thought the weather report said it would rain! The particular example I used is the concept of a ‘responder’ threshold, ie a patient might be counted in an assessment if improvement is over x points. There are numerous issues with such a concept.
Is the patient cohort uniform?
Homogeneity, or the uniformity, of patients within a trial might be important depending on the measures used. Historically the approach has been to recruit as similar a group as possible because of the simple assessments we have. This is still largely the case, but statistical and patient prognosis prediction techniques, now emerging, are helping facilitate more inclusive trials. Biomarker measures are also starting to appear and I am very hopeful that trial protocols will be refined to take advantage.
The varying natural history of our disease is, however, something that if not taken into account or planned for can seriously adversely affect trial interpretation and so much so that a new trial(s) might be needed.
You might find the following paper from 2015 an interesting read on the much higher than perceived natural plateaus with our disease, and even partial reversals.
How common are ALS plateaus and reversals?
This very recent paper from China lends further weight to these earlier findings with quite striking data for limb onset patients, especially over a short period of time. How might such variance reveal itself in treatment studies, especially short duration trials?
What are the side effects and burden?
During my editing of this two part post I had pondered with which subjects I should terminate the discussion on. After a bit of deliberation I decided that these two areas are in fact two giant ones.
Side effects are often overlooked by us, the desperate patients, and certainly burden can easily pass us by when we read press articles, in particular.
Side, or more precisely, adverse effects are a key element of a trial protocol, and there are strict reporting protocols for examining deaths/serious reactions. One aspect of a good length 18 month trial is that longer term use safety starts to emerge.
I often hear that safety is not uppermost in the minds of MND/ALS patients because “what is worse than a near 100% fatal disease?” I have to disagree with this and the impact and implications of potential serious side effects are nearly always underestimated. A treatment which, for example, leaves a patient in permanent pain, blind, or other non fatal effect could have a devastating impact in an individual and the larger community. In addition, despite MND/ALS being typically fatal in 3 years, today with multi-displicinary care and the wide spread natural history of the disease, some of us can live for 5, 6, 7, 10 or even 20 years.
Treatment burden barely makes a ripple in trial reports. Simply put, we should consider the implications on daily life caused by a treatment. This can range from very little, in the case of a daily pill, to being hooked up daily to an IV to an extreme burden of regular travel to a centre to receive complicated and painful treatment. Even a relatively low to medium burden could have much greater impact on early disease patients, perhaps? I’ll leave the reader to consider the wider potential implications, but I do urge you to take a fresh read of any prospective treatment to get behind this important facet.
The implications of any approved treatment, that has doubt, risk or burden are not in the forefront of advocates minds. But just imagine a highly publicised experimental treatment being suddenly approved in the 24 hour social media world of today. The rush and demand would be huge. We’d better be sure of side effects, real, targeted measurable effectiveness, the wider societal and economic costs, and burden before embarking on such an event.
I do hope these two short posts have helped you, and will again in the future, to start to understand the difficulties our scientists and regulators face, and perhaps be more understanding of, what can often appear at first sight, unduly negative comments.
What about that trial, which compound or treatment was it?
Before I conclude this two part post I do need to answer the question about this trial that I included in Part 1.
Well it is in fact ……., wait for it…..
…..a completely fictional example with results as yet unseen in any MND/ALS trial. This chart shows a hypothetical drug/treatment that has clearly, almost blindly obvious, beneficial, dramatic, and disease halting (not just slowing) characteristics.
Let’s look at some key points which you might now look for in real trials for that ‘hint’ of whether an effect is real, significant enough but also to help you understand the trial data. Compare the chart to those you might have seen in actual trial results. There have been none so far like this but it is what we all need and are eagerly looking for! We are, however, closing in.
Thats all for now, folks, and I hope you have enjoyed the last two posts.
And remember, the devil is in the detail, as always!