This week’s research commentary post title is as about as mystical as it gets! Why are some things just the way they are? Why, for example, do ATMs (cash machines) return your card before giving you the actual cash? 

It turns out that it was only after the early rollout of the machines that banks observed many people took the dispensed cash and simply walked away leaving their cards, which were either taken back into the machine or lost/stolen. So the designers decided to address this behaviour by playing a psychological trick and presented their client with a task to complete before walking away with the cash, ie here’s your card. You then stand there, impatient, waiting for what you really want, ie the cash. It was a simple solution but unforeseen.

And that is today’s theme, the real complexity of things, or as Donald Rumsfeld once famously said

……. there are also unknown unknowns…..

We constantly learn from history, however, is it often forgotten and perhaps needs to be rediscovered?

Why the pheasants? It was a quote made on the radio that I was waking up to just the other day. In the programme, there was a seemingly pointless argument between two people on opposing sides of a debate. It was going absolutely no where. Then, one of the two protagonists made the comment about the pheasants. I think it sums up my musings today. Here’s hoping this discussion is written with the tone befitting of such an important subject, and that is:

The pressure, not unsurprisingly, from those with serious diseases for early access to unproven and unapproved drugs/treatments.

This is a demand which is certainly complex and controversial. I have sat on this post for a while considering what it’s value is, or not, to the wider MND/ALS community. I hope you find it thought provoking.

I have been, fortunately, around long enough to have observed some recurring themes here in the UK, the USA and around the globe. I write this, sitting here in the UK, watching the world whilst living with MND/ALS. So readers, I am indeed a very interested party! I don’t pretend to be an expert on the intricacies of worldwide legal and healthcare systems, but instead try to make some simple observations which I hope are useful when considering the subject.

First, I will just reiterate the important background as to why the demands for early access to treatments keep happening for diseases, and especially MND/ALS. It’s fairly obvious stuff, but worth restating……

We, with MND/ALS, are in a relatively unique position, in that our community is a revolving door of new members along with those, sadly, who leave at almost precisely the same rate! It is why the prevalence of the disease is relatively low. There is thus a repeating circle of disbelief, often anger, as to why a treatment hasn’t yet been found which often results in attacks on authorities with demands for access to experimental treatments.

What are the actual barriers put in the way of early access?

Drugs and treatments for all diseases are strictly controlled and regulated in most parts of the globe. In the USA it is the FDA (Food and Drugs Administration), in the UK the MHRA(Medical and Healthcare Products Regulatory Agency) /EMA and in Europe the EMA(European Medicines Agency). These organisations have developed over the last 100 years to provide consumer and patient safeguards. In some countries, there is yet a further hurdle, for example with NICE (National Institute for Clinical Excellence) here in the UK, who works with our government to regulate the actual delivery price of drugs which finally make it to our NHS. This is diametrically different to the USA in which there appears to be no obvious and apparent price regulation.

This is an important distinction that has far reaching consequences. Do these differing policies, perhaps, influence pharmaceutical companies?

Today, I will largely steer clear of this question of drug pricing/control and purely focus on drug efficacy and validation conditions.

Such approval processes are the result of one of the most amazing scientific achievements of the 20th century: randomised controlled trials (RCTs), building on successes, but just as importantly failures.

We need, perhaps, now, to place our MND/ALS disease challenge into a relative hierarchy compared to other diseases in terms of the “urgency” and “resource” to fix.

What Lee!? It’s urgent!

Of course, but we need to just move our mindsets outside of the MND/ALS world for a short moment and look out at other disease context, ie put ourselves in other people’s shoes. Although the premise of my blog is that MND/ALS is not rare, it is most certainly ‘minor’ compared to the numbers affected by cancer, for example. But it is, at the same time, far more common than a truly rare, 1 in a 10 million disease.

If one could relate to a disease as a “thinking” and “conscious” being, this would make MND/ALS really quite a cunning and devious entity, enabling it to almost completely avoid the limelight!

Why? Consider those very very rare diseases. They can quite understandably attract funding simply because of the sheer emotional push to for perhaps 1 or 2 media stories, often involving children. And if such diseases only affect 10 people a year, then spending $500k annually on each patient may very well be affordable? Ie it’s economically more viable in the short term, perhaps?

Hold on one tiny moment Lee! Do these very very rare diseases offer, therefore, another investigative pathway forward for us?

Hold that thought until the very end of this post, perhaps they might just do…..?

Returning to our disease, which is scientifically extremely complicated, apparently has no hope, with 2000 new patients diagnosed a year in the UK (6000 approximately in the USA). It is far harder to justify a larger investment or spend when looking at that share of limited resources, especially in the face of the bigger picture. Obviously we ask for more funds, but it is tough, very tough. However, as I have learnt, it’s probably the singular most valuable thing we can do as advocates.

What my garbled paragraph, or so, is trying to achieve, is to set the scene and background for the rest of this post and the importance of drug regulation and control which has literally ‘evolved’ across the entire human health and disease spectrum.

If anyone is in any doubt of the need for regulation, you only have to take a read of the history of the FDA, why it was formed, and how it has changed. It contains a quite horrific series of events, even including items like worthless cures for diabetes back in the 1920s, which strangely enough still even raise their heads into today’s internet world! And just read some of the absolutely shocking products allowed to hit the human body before regulation! There have also been some unintended consequences of actual formal approvals, and you don’t have to look much further than the current opioid crisis that is encasing both the USA and UK alike. The FDA is having to respond with new regulations.

How are drugs actually approved?

A basic drug approval pathway is broadly structured in the same manner in both the UK and the USA in that any treatment must pass a series of escalating tests. Phase 1, 2 and, more often or not, Phase 3 clinical trials are needed to be considered for approval and eventual general availability.

Historically, due to the length of this process of approval through such evidential proof, there has been pressure to grant early access to experimental, unproven drugs/treatments for diseases that are so serious and have an, as yet, unmet need.

In response, in the USA, for example, the FDA, in conjunction with patient groups and others, has developed a number of programs such as the expanded access route and the more recent controversial right to try act. Most of these programs have strictly focused on reducing the bureaucratic processes, and importantly NOT the scientific aspects. In the UK the closest we have is the Accelerated Access Collaborative, but it does NOT provide any access to a drug without full trial success.

Just why has the right to try act been so controversial in the USA? And what exactly is it?

It is complicated, but in one short line, it is considered a dangerous path by many, for although it speeds the process, it potentially totally removes FDA involvement (oversight), and effectively grants any patient access to a drug, if the pharmaceutical company is willing to sell it to him/her and provided that drug has passed a Phase 1 Trial*. All earlier access programs have retained that stronger level of evidential oversight.

*Please note that I do NOT state “Passed the safety trial of Phase 1”. Please read on for precisely why. It’s very important and one reason why the program is highly controversial amongst many experienced clinicians.

I must say right now, I believe everyone should have the right to try an experimental drug, and should be able to. After all I can’t argue against it when “we” have no option! But, there are huge BUTs which we should be aware of when making such requests.

On taking a closer look at what the passed right to try act actually is, things start to creep out and absolutely smack you in the face!

For example, under right to try it is illegal in the USA to sell an unapproved treatment for anything more than an “acceptable” cost price. Some have commented that this inability to make even a small profit is hindering right to try and even stopping it working.

I see it as a double edged sword as yes it would quite clearly stop even perhaps a large pharmaceutical company offering a substantial number of expensive treatments (as we have seen with MND/ALS). But just consider if they were allowed to make a profit? Where exactly do you draw the line? Does the size of the company affect their ability to offer right to try, and could a large company perhaps benefit inordinately? This does beg the question should “incentives” be aimed at innovative companies? This might jump out as an obvious reaction, but we must be very careful to not simply equate ‘innovative’ with ‘effective’. Solid science has to rise above all. I suspect market forces would avail in some form or another.

The subject of drug/treatment cost is critical, but I am well aware that many may see cost as irrelevant in the game of life. But, sadly, it is.

Consider the following:

Are all experimental drugs/treatments equal?

They are clearly not. Imagine either a cheap drug or a drug already approved elsewhere for another disease, that’s perhaps well used and safety has been time proven. Such a treatment could be relatively easy to obtain access to for a different disease under early access programs. However, a new pioneering treatment, possibly involving vast costs to scale, and perhaps involving a large patient burden to process/administer does bring two big dilemmas at least:

1) The pharmaceutical or sponsor financial risk – this is not, of course, at the forefront of a patient’s mind!

2) The exposure of patients to an unproven treatment – Most certainly not at the forefront, but…..

I would contend, currently, the former is probably the main barrier now. The second dilemma is, to be brutal, a potential mute point. I say mute, but yet again there are still significant implications, often overlooked, which I will touch on later.

Why would a reputable company scale up production etc if it hasn’t proven effectiveness? It might all come tumbling down. Add to this the very real possibility of another product from another vendor potentially totally destroying their market!

So unless a government compels a sponsor to provide a drug, which they never will (and right to try certainly doesn’t) widespread access to expensive experimental drugs will always certainly be highly limited. I do also worry about who exactly would be able to access, especially in the USA, for those without insurance. It certainly appears, on the surface, a rich man’s game. Although, I could envisage low cost unproven drugs as an interesting conundrum right now.

But let’s dig even further, perhaps lifting the lid more slightly off of Pandora’s box.

Pandora – John William Waterhouse 1896 – public domain

Specifically with MND/ALS there have been 10s of treatments that have produced calls for early approval/access. There are some right now, here in 2019.

We should examine some of the currently known pitfalls, those kettles of fish (or pheasants!), that are inherent in the process of early access to drugs without formal oversight.

But before I do that, it is vitally important to clarify some items surrounding clinical trials. There are many misunderstandings, perhaps inevitable, with clinical trials that I thought I’d briefly summarise the precise purpose of the 3 phases and what passing each stage actually means and, more importantly, does not:

Phase 1 – To investigate the initial safety and potentially appropriate dosage for Phase 2 and 3.

Passing phase 1 does not mean safety is proven. Far, far from it. It will have, at best, proven safety only for the time period of the phase 1. Safety will be continually assessed in both Phase 2 and Phase 3. Too many drugs to name have been stopped in early phase 2 because of emerging safety, for example, due to the longer exposure to the drug and unforeseen (unknown unknowns) issues.

I have seen this misunderstanding all over the internet and in the media. In fact, I do regard this as the slightly already lifted lid on Pandora’s box in the right to try act.

To add to this, the size of a Phase 1 is very small and although efficacy could be hinted at, the sizing of the trial is never large enough to be statistically significant in anything but miracle drugs. Remember those? I wrote about them in – Can Placebos ever be…. There are no such miracle drugs, yet, for MND.

Phase 2 – A larger study designed to further investigate safety but also test for efficacy with perhaps the dose levels identified in phase 1. Some, but not all, Phase 2 trials also often start to ‘hone’ the target of the treatment to those who might most benefit (Stratification).

Again, this is typically a phase that is still too small to prove efficacy and is generally for too short a time period.

Phase 3 – This is where the rubber hits the road, and efficacy is the focus. The huge investment that a pharma will have to make is robustly tested in 100s, or even 1000s of people to really see if the drug really works.

So one way to look at the right to try act, is that it appears to effectively grant access to drugs, not safety proven, with little or no proof of effectiveness? This fills me with deep unease, but not total objection.

What would be the potential known adverse implications of access before time? History gives us some clues:

  • What if the treatment is not effective as hinted at, or not effective at all?
  • What if the treatment actually causes harm to those who have received it in large numbers in the advocated community? This may seem an illogical concept in a life threatening disease, but what if it accelerated the disease or even worse made progress rapid in those with slower disease? There are numerous historical examples of such treatments in other diseases.
  • Could the focus on such an early access drug remove advocate associations attentions away from other promising treatments?
  • Would this not lead to the control of drugs effectively being partially handed over to pharmaceutical companies? Or as they say, careful what you wish for.
  • Why would someone, or an organisation, potentially invest their time in the phase 2 and phase 3 path for example when a shorter route is available? Apparently it’s already happened with participants deliberately dropping out of trials and applying for right to try in some diseases!
  • If provided early, before proven, how do you decide who gets the drug? How is this economically viable when sponsors might have to build production/infrastructure only for it to be torn down if not successful and/or another treatment makes it redundant? There are very real financial concerns here? And if a sponsor says ok, we will fund 200, how do you choose?
  • The dilemmas just keep mounting up.

And these are only some of the potential implications we do know!

One final interesting aspect of the right to try act is that doctors and pharmaceuticals are protected by law if any adverse reaction might occur. Further the same act instructs that if such an adverse reaction occurs it must not influence the potential approval in the long run. This looks and sounds attractive doesn’t it? It means that there is greater willingness to help? That’s certainly one view. But despite what the law says, what if a serious adverse reaction occurred, perhaps because of early and rushed drug formulation issues, might an investor not be influenced, negatively, to continue funding? Now please do not think I am denying anyone access, I am just raising valid concerns. If early access ever caused a “promising” drug to be prematurely curtailed because it was accelerated too fast, just how would the wider community feel then? As recently noted by Ken Menkhaus, in his essays on advocacy, those of us who advocate are probably in the minority of our community, with there being a significant silent majority not advocating. We need to be responsible to them as well.

Readers, I don’t pretend that some of the completely ‘quack’ treatments, those of the most tenuous claims kind, would be promoted by organisations or individuals actually prepared to complete a full Phase 1 Trial. It is actually pretty darn tough and expensive. But that lid is lifting.

So is the the right to try act fundamentally flawed? Some have commented it is ‘a right to ask above anything else.

Regulation and ‘compelling’ scientific evidential proof is key to our systems, It means that safe treatments are founded for the many in the most responsive time possible. I have not yet seen a model that can be described that is better, or even financially viable, than the classic protocol. Now, I have to say that doesn’t mean this will always be the same. New technology, technique repetition and success will perhaps reveal new ways forward.

The key to me is not reduced oversight, but more efficient oversight.

One aspect of early drug access which I have to admit I am rather undecided on is the access/prescription of drugs that are relatively cheap, approved elsewhere globally (perhaps for other conditions) for those with unmet needs. There are literally 100s of these, and 10s that are acquired by MND/ALS sufferers. In the UK, for example you can legally import any drug for personal use, as long as it is not controlled. Also, a UK doctor can prescribe an unapproved drug under certain circumstances. The advantage of this is that you can probably acquire from a more reputable source. However, so few UK doctors do this, for I believe the simple reason that there so many drugs. Such importation happens though and quite regularly. Of course it costs. I have no problem with these imports. Whether I would do it would be based on detailed analysis of the drug. So far, nothing has yet convinced me. But of course, it’s not a route open to all.

We are all aware that today’s internet world can lead to a mass of claims presented in short sound bites for every subject under the sun. There has always been some chatter, for example, quoting anecdotal evidence for certain drugs over the years, long before full trial completion and final data analysis. Although I clearly understand the well intended motivations of those presenting such information, it is indeed not as simple as it appears. To give you a feel for the challenges faced by our scientists in identifying solid drug effects for MND/ALS, I strongly encourage those of you close to MND/ALS to read just this one single research paper. It’s not too long, and you only need to read the abstract if you are short on time.

Have you read it? If not please consider doing so before you continue.

Surprised? Contrary to huge popular belief, MND/ALS illness plateaus and even minor improvements do actually occur in the natural untreated history of the disease and they are very common (up to 25% of all cases!) and for the sort of time duration of trials and longer!

It is against this extremely diverse background data that the need for full trials to complete is necessary for ‘compelling’ evidence, or not, to be realised. It is truly complex and we all should be very careful of sound bites.

I am nearing the end of this commentary. “Thank goodness”, I hear you cry!

I earlier mentioned the very rare diseases and potential implications for MND/ALS? Yes, a concept of “Trials of 1” may help us. I will discuss these in my final “devil is in the detail” post where I will also comment on some other emerging and exciting ideas that hope to speed up full trials, perhaps in conjunction with advancing discoveries, and honing our target.

In fact I firmly believe the solution to accelerating effective new drugs is not by removing oversight, as in right to try, but by streamlining evidential processes and retaining hard data proof.

Finally in summary:

Our community should be totally reassured that with ‘compelling’ scientific, data driven, evidence of effectiveness the authorities and powers that be will act. I firmly believe this. I feel very uneasy for the community that any drug should ever be approved for widespread use without such data. And make no mistake about it, some not so well intentioned people are peeking into that dusty opening lid of Pandora’s box to see if they can exploit us.

The more we talk, advocate, inform government and healthcare representatives of our need and the disease reality the faster we will get there. The greatest value that we as advocates can provide is to keep the disease on the radar of these decision makers but all with solid scientific backing and rationale.

We must not forget, it’s a 1 in 300 lifetime risk, thats 3 children in every school today who will be diagnosed in their life with MND/ALS unless…..

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