Can placebo trials ever be justified for terminal illness diseases……?

Hi readers, onein300 here with my latest MND Research commentary post.

The title is a question I see occasionally posed on social media, disease community discussion groups and in the wider news. It most certainly is a conundrum. Jumping to that immediate emotional conclusion is hard to avoid, I know. Before you read on I want to point out that this subject is one of great controversy and causes much anger. Therefore I have opened myself up for some attack, I admit! But please, grant me a listen.

This is the first of a new series of posts which could have the sub-title of the “devil is in the detail! “

I hope you enjoy the background, find the format stimulating and the content brings a wider understanding of the challenges facing our dedicated and talented researchers in the search for a treatment for MND and other neurological diseases.

For our “no cure as yet” disease, media “sound bites” are often used accidentally, mostly by well meaning people, but sadly also for deliberate distraction by some. For me, being lumbered with this disease, all my writings on research are centred around one single principle…..

Such respect is not limited to just those with the disease and their families, but for all who are endeavouring to help us, be they regulators, researchers, drug companies etc.

I see a lot of authority and other group bashing on social media made with short simple emotive statements. To be honest, it makes me feel upset and uneasy. Such comments not only apply to our disease plight. The “attack culture” seems to have perpetrated all aspects of information dissemination in the modern world in the last few years.

I cannot be alone in thinking….

• What must it be like to be on the receiving side of some of these statements?
• How would it make make me feel?
• Why are they shouting at me?
• I am only trying to help!

My mantra, readers, is “don’t upset the good guys unless you don’t want their help!”

The reason for this rather long winded introduction is to explain myself.

Now, let me continue.

The use of placebo and control groups is a long established, scientifically demanding principle of efficacy testing, and more specifically proof of a new treatment’s worthiness. It is considered one of the most important scientific breakthroughs in experimental design.

Why are such groups needed?

They are to eliminate bias caused by the observer and patient in evaluating a drug.

“But Lee, how can it ever be ethical to submit a terminally ill person to participate in a trial and potentially for him/her to receive a placebo?”

Clinical trials are very precise pieces of technology. They are comparable to the design of the most complex electronic devices and rocket science.

So, readers, I will use a few short stories to illustrate that the answer to my post’s posed question is, at the current moment in history, a most resounding “yes it can be.”

Mini Story 1 – But what actually is the placebo effect?

I need to describe the “placebo effect” and it’s dramatic implications on drug trials.

Literally meaning, I shall please, the phenomenon of the placebo can be so immensely powerful that faith healers use it to their advantage in fooling people into believing their apparent powers. The frenzied excitement created at such events promotes the release of adrenaline. This can have short lived “wellness” feelings.

Another well documented piece of information is that statistically any patient involved in a trial, whether taking a real drug or dummy, appears to benefit. The very act of being involved in a trial has some apparent or real wellness effect.

It is this separation of short lived, unassociated or “perceived” benefit from the actual drug/treatment effect that is central to control testing.

Mini Story 2 – “They are banned in Cancer trials, aren’t they?”

An uttering I have recently heard and made by some campaigners is

“Placebo trials are banned in cancer now”.

This statement is simply NOT true, and at best is a blurring of the situation. Cancer trials do, however, give us an excellent way of presenting the challenges we face with neurological diseases. Placebo trials are NOT actually banned in cancer drug trials.

The FDA (in the USA) stated in August 2018 (updated 2019) that placebos are not necessarily required. This is where the blurring of the truth starts, ie that devil detail! But what is necessary?

The ethics of placebo testing are perhaps best summarised by the one sentence:

”No patient should be caused undue harm, or be denied a best alternative treatment, and placebos should be kept to an absolute minimum”.

For many cancers there are now effective treatments. Therefore, ethically, the control arm of any trial for a new treatment should ideally use patients who receive the best known alternative treatment PLUS placebo versus new treatment.

MND has no real effective treatment. This is what makes using even pure placebo ethical.

I do emphasise currently however. More on that later.

But, I hear critics screaming…….

“hold on, why, if a drug has obvious effects?!”

Mini Story 3 – The marginal effectAnd herein lies another good, probably the vital, reason for the placebo arm of a trial. Most drugs trialled only have a marginal effect in pre-clinical testing. However, even a marginal effect, if proved, is still potentially worth taking a drug forward.

Consider Asthma drug trials. There is almost a constant stream of new treatment combinations. Data has shown that in these trials the placebo effect is as much as 50% of the apparent measured improvement! It is even higher in trials for antidepressant drugs. Up to 75%!!!

Another interesting trial that powerfully shows the sheer strength of the placebo effect involved a new heart pacemaker.

In the early testing trials for the new pacemaker there was no placebo group. The research simply compared the new surgically installed pacemaker with a non-surgical treatment. The small trial showed positive indications for the new pacemaker. However, the lack of a placebo group might have skewed the findings. When a larger study was completed with a placebo, (the insertion of a pacemaker that did nothing) versus the actual pacemaker, no difference in the results was found!! Hence, the new pacemaker was not recommended. If the original trial had used a placebo less patients would have been exposed to potentially harmful surgery for an eventually disproved treatment!

Mini Story 4 – The current point in history 

The lack of treatment for MND and several characteristics of our disease align in a perfect storm to make it absolutely critical, and for the greater good, that patients are perhaps willing to potentially be exposed to placebos.

These characteristics are:

1) We have no effective current treatment.

2) We have no way of measuring the progress of disease, only highly subjective and un-related observations and patient feedback. An apparent positive effect can be hugely influenced by the participating patient. Any new and original biomarkers to be measured cannot be validated if there is no true placebo arm.

3) The time factor for the progression of the disease, ie the progression is often over months, and is highly variable and can have natural plateaus of weeks, months and even years!

4) Most drugs are NOT miracle drugs, but marginal effect drugs at best as previously mentioned.

I will tackle the last point first as it is definitely one that could override and change all aspects of the first three.

Imagine a drug, which if ingested, stopped a disease in its tracks, perhaps even reversed it.

Imagine further that a trial on 20 people with the typical disease showed within 2 weeks they were running around when they were previously paralysed!

Of course, this would be a game changer. Any such drug would emerge as a priority to fast track and the need for placebos would be removed. In fact, if any company had made such a discovery, in only a few cases, in an early trial, they would be all over it. Those with MND should be fully assured that there are existing protocols in place to detect such changes in trials.

This has simply NOT happened yet (but it might). Despite every now and then a drug making some form of waves, no current drug is in that situation. Today (May 2019) there are 3 or 4 drugs that raise their heads on social media, and other channels, that campaigners are pushing for access to before trial completion. Not one of these drugs has shown anything other than a statistically marginal indication of effects in early small trials, and even these effects are possibly false statistical indicators due to post analysis of earlier trials.

Phase 2 and 3 trials are still needed to show whether there is real statistical evidence.

“Statistics, statistics, they can say anything, so what…?”

This will be the subject of my second post later this month. The correct Interpretation of statistics. I will explain the concept of confirmatory trials, detecting small effects, and why early apparent detected effects may be just through pure chance. In addition, I will discuss what the statistics are actually stating there is significance of.

My working title for this upcoming post is:

’There is a 50% chance of rain today’

So in summary, the answer is yes, placebo trials are currently vital, despite the immediate emotional response. Otherwise we risk crying wolf for a treatment that has no discernible effect.

Francis Barlow’s illustration of the fable – The Boy who Cried Wolf

Before anyone says “Lee, you are so negative” let’s look at how things may change…..

As time moves forward, trial design will be able to change as effective treatments emerge and biomarkers appear.  There is now a potential use of historical control data to supplement the active trial arm. This so called e-placebo data faces a lot of challenges, but intuitively will be made possible by stringent data collecting, advances in bio-informatics and wide spread collaboration. It won’t, however, remove the full need for placebos due to new data that might need collecting, such as the new unrecorded biomarkers I touched on above.

The use of placebos will then be reduced just as in Cancer therapy trials. But we are not there yet.

To finish the post, I have one final story to add to the challenges of trial design.

Mini Story 5 – “Jeesh that’s spooky!”

An interesting counter to the placebo is a mysterious reaction known as the Nocebo effect. In trials, the issues this intriging artefact can cause is best illustrated by the following example.

A potential new treatment often has side effects. Sometimes quite serious. All participants are told of these effects. It is well documented that often a statistically significant number of placebo takers experience the same side effects! This is the Nocebo effect, meaning “to cause harm”. I have previously written about another example of this effect in an old post – You only live twice – which you may want to read. It’s almost horror film-ish!

The devil is most truly in the Detail!