Late last year, I wrote a post for Parkinson’s UK‘s excellent blog on Medium.
My piece was called the Dilemma of Success, and it explored a hypothetical situation that we may very well face in the not-so-distant future.
Optimistic as I am about the future of Parkinson’s research, I think this is a very serious issue – one which the Parkinson’s community needs to discuss and start planning for. I am re-posting it here today as I am keen for some thoughts/discussion on this matter.
Lord Robert Baden-Powell. Source: Utahscouts
My scout master looked around the horse shoe, making eye contact with each of us, before asking a simple question:
“When did Noah build the ark?”
My fellow scouts and I looked at each other. Some of us were wondering if the guy had completely lost the plot and somehow thought that it was Sunday morning and he was doing the sermon. Others seriously looked like they were trying to calculate an exact date.
He waited a moment for one of us to offer up some idiotic attempt at an answer, before he solemnly said:
“Before the rain”
It’s one of those childhood moments that didn’t make sense at the time, but comes back to haunt you whenever you can foresee certain troubles coming over the hill towards you.
The dilemma of success
It will be nice to have this problem, but it will still be a problem.
And we need to plan for it
Photo by Zac Durant on Unsplash
Most biomedical research focuses on developing a better understanding of the biology of diseases. The ultimate goal of this effort is the continual improvement of medical treatments for these conditions. But what happens when those ‘improvements’ start to block the process of developing new therapies?
A cure of Parkinson’s is going to require 3 components:
- A condition halting treatment to stop/slow progression
- A neuroprotective agent to nurture and protect the remaining cells
- Some form of cell replacement therapy to help restore lost function (for when Parkinson’s cannot be identified and stopped in the earliest stages)
While it is unlikely that just one treatment will be able to provide all three requirements in the near future, the good news is that a vast amount of research is being conducted on each of these components individually. And it is certainly very possible that significant achievements will be made in the near term, particularly in the area of a neuroprotective agent via repurposing clinically available drugs for Parkinson’s.
But success may actually bring with it new issues that need to be considered.
Hypothetical question: If a commercially available drug is found to have a neuroprotective effect on Parkinson’s in clinical trials in the next 12–24 months, what would be the consequences?
Upon first glance, the question is silly and answer is obvious: this event would represent a transformational moment for the Parkinson’s community. And following the huge media attention, everyone with Parkinson’s would naturally want to get their hands on the drug (let’s call it ‘Curetide’) ASAP.
But as the dust from the celebrations settles, the future of Parkinson’s research would become very complicated, very quickly.
You see, when the researchers get back to work after the celebrations, they would obviously want to start testing the next generation of new and improved experimental neuroprotective drugs. They would likely also start work on improving ‘Curetide’ itself. And, with this success under their belt, they would want to re-double their efforts to find ‘condition-halting’ and ‘cell replacement’ therapies — the 2 other components of a cure.
In order to test these novel therapies, new clinical trials would need to be organised. And here is where the problems would start.
Taking the ‘Curetide’ drug would need to be considered as an ‘exclusion criteria’ (that is, a factor that would prevent someone from being able to take part) in any future trials. This would be necessary because ‘Curetide’ could potentially affect the outcome of the new studies. To get accurate results, new therapies would be best tested on those who are not taking this hypothetical drug.
But if everyone is taking ‘Curetide’, then who will be left to take part in new clinical trials?
A neuroprotective dilemma
One proposed solution to this dilemma is to simply move the goal posts or change the aim of future clinical trials. In this scenerio, we would accept that everyone will be using ‘Curetide’ and continue on with the next trials regardless. The problem, however, is that the neuroprotective nature of ‘Curetide’ will hide the effect of new drugs. How can a new neuroprotective drug be tested on someone already taking a neuroprotective drug? Thus this ‘solution’ is a non-starter.
Another possible solution is to test all new neuroprotective drugs in recently diagnosed, drug-naive people. But this creates a terrible dilemma for these poor individuals. Perhaps they will want to be involved in the research, but they will be faced with a very difficult decision. When the neurologist explains to them that they have Parkinson’s, they would then be faced with a choice between taking ‘Curatide’ which will help them, or they could take part in a clinical trial for a new neuroprotective drug that needs to be tested. If they selflessly chose the latter, but the new experimental drug is not as effective as ‘Curetide’, they could be in a worse position in 12 months’ time.
Which path would you take?
In addition, many of those recently diagnosed people will not necessarily be psychologically ready to partake in an experimental drug trial. And relying solely on the newly diagnosed would also severely limit the number of potential participants for all the clinical trials that are currently being planned.
Are you starting to see the dilemma that comes with success?
Many people within the Parkinson’s community may not be concerned by this issue. Understandably, they simply want a neuroprotective drug ASAP. And if one drug is found to work, why would we need another? It is not a problem.
But unfortunately, it is.
This situation is going to hinder many future clinical trials, including those not focused on neuroprotection, such as in the development of cell replacement therapies. How will researchers be able to accurately measure the effect of a cell transplantation procedure if some of the recipients are also taking ‘Curetide’? And this situation will only become more complicated as subsequent neuroprotective drugs are found. Researchers will be excluding people from future clinical trials because they will be taking one of potentially multiple drugs like ‘Curatide’.
Now, before this hypothetical situation becomes overly negative, we should note that other medical conditions have dealt with similar dilemmas, and the development of marvellous new therapies has not slowed the pace of innovation. Let’s explore how the research community focusing on other conditions have dealt with this problem.
Since 1989, the number of people who have survived breast cancer has steadily increased to an average 5-year survival rate of 90% (Source: CRUK). This shift has been largely due to both early detection and new therapeutic drugs. And it has not stopped the development and testing of new anti-cancer drugs. Similarly, cholesterol reducing drugs called statins were first approved for clinical use by the Food and Drug Administration (FDA) in the US in September 1987, but their success has not slowed the development and testing of new statin-based therapies.
One key difference between these other medical conditions and Parkinson’s is the degree to which they can be accurately measured and assessed. For example, tumour biopsies can be taken and genetically analysed, providing a relatively accurate picture of what is happening inside the cancerous growth. Similarly, blood tests can clearly determine an individual’s cholesterol levels.
Photo by patricia serna on Unsplash
Thus, part of the answer to this ‘dilemma of success’ could be found in the methods of testing and tracking Parkinson’s. There is certainly an urgent need for improvements in this area and for validated biomarkers that can help to track the condition. Currently, most clinical trials rely on the observations and subjective assessment skills of the clinicians (for example, using criteria like the MDS-UPDRS) and brain imaging techniques. More sophisticated tools may allow for outcomes to be measured independently of drugs like ‘Curetide’. And this would allow people with Parkinson’s to benefit from a drug like ‘Curetide’ while still helping to advance novel therapies.
Responders vs non-responders
Another likely scenario is that, similar to cancer, not everyone with Parkinson’s will respond to a single drug like ‘Curetide’. This is very possible given the high level of variability of symptoms within the Parkinson’s community. Some people with Parkinson’s may find no benefits whatsoever in taking this hypothetical drug. These ‘non-responders’ could become the participants in future clinical trials of experimental neuroprotective drugs, and as such would be a vital resource to overcome the dilemma of success.
But to identify non-responders, changes must be made to how clinical trials are undertaken that would allow researchers to identify and make the most of the non-responder phenomenon.
Historically, obtaining clinical trial results that were reliable and valid required participants to be randomly allocated into different groups and ‘blindly’ treated with either the experimental treatment or a placebo. The studies also required the conditions to remain constant until the end of the trial when the results would be determined. As such researchers would have to wait 12–24 months to find out the results.
However, there is an alternative approach: adaptive clinical trials.
Here, the data being collected is frequently analysed while the trial is being conducted. It guides the course of the study and makes the trial more dynamic. By analysing data as the trial proceeds, researchers can determine which participants are benefiting the most from a particular drug. The results of each individual within a treatment group can be looked at as opposed to looking at the group as a whole. In this way, some non-responders to a drug like ‘Curetide’, could be identified, shifted off the drug during the clinical trial and started on another novel therapy.
Adaptive clinical trials are currently being used in other medical conditions, such as cancer (for example the I-SPY trials). Perhaps it is time we start to consider applying this approach to Parkinson’s in order to help us deal with the dilemma of success.
We live in an incredible age in which there is the very real possibility of neuroprotective drugs being available in the not so distant future. But these exciting new developments will bring new issues and challenges that we will have to deal with, and the Parkinson’s community may well be the first neurodegenerative group to face them. It is important for us to start a discussion now about how to handle some of the foreseeable issues that we will face, and to begin preparing the tools and strategies to deal with them.
Special thanks to Dr Beckie Port at Parkinson’s UK for her help with the production of the original version of this post.
I would be interested in any thoughts readers may have on this matter.
The banner for today’s post was sourced from Jason Blackeye on Unsplash
17 thoughts on “The dilemma of success”
Great thought provoking post. Falls under the “good problem to have” category I think. I wonder if the generic name for “Curetide” is Isradipine? Although your example is the only word in English that rhymes with exenatide…
Are there any parallels to the development of the present HIV cocktail? It seems that they would suffer from the same dilemma?
Here’s hoping the fist “curatide” discovery lights a fire in the industry and R/D money flows in to the neurodegenerative disease field. It worries me that if nothing takes that many will loose interest.
Thanks for the comment. Unfortunately it is already a problem: we have a lot of folks involved in studies in our PD research clinic, and they will turn up for an assessment session & announce that they have started taking drug X (or supplement X) based on something they read online (seriously, blogs like this are our worst enemy!). And this is actually the good side of the issue – at least we are aware of the additional variable in the study. Consider the bigger problem – those folks who start taking some new treatment and don’t declare it to a study co-ordinator for fear that they will be dropped from the study. The whole situation leads me to only one conclusion – clinical drug studies can no longer be about the drug, they must rather be about the patient. But for this to be the case, our methods of assessment need to be expanded and refined.
The HIV angle is a good one. I have recently been reading up on their activism in the late 80s/early 90s (e.g. the ACT UP campaign – thank you Mr Jones). I will have a look at how the HIV researchers handled this situation. That is a good idea.
And I honestly don’t think any of the pharma industry will turn their backs on neurodegeneration. They will make a big show of licking their wounds to appease their shareholders, but they are all desperate to get ‘market share’ here. This sector of medicine is one of the few that still offers them serious growth opportunities (wow, listen to me! I’m wasted on this science blogging malarkey, I should be an investment advisor). They would be foolish to turn their back on neurodegeneration and walk away (and yes, I’m looking at you Pfizer).
Thanks again for the comment.
interesting inference, double, that isradipine may be found neuroprotective. i’m guessing if it is, it will be something like rasagiline almost was, with a modest effect. one of the researchers, surmeier, said as the isradipine trial was beginning that he thought it might become like a low-dose aspirin, a pill to take every day to prevent parkinson’s – or that it might extend the effective window for levodopa by a few years. since it is cheap, it would be easy for everyone to jump on the bandwagon. i’m guessing that, like rasagiline, it would be more effective for some than others. for me, if it were in that modest-effect category, i would be willing to hold out for something better, and that’s in part because of this blog and the realization that research is on the cusp of amazing. on the other hand, i worry a lot about cost, so maybe something like isradipine would be the only affordable option. i’m not willing to bankrupt the family even for a cure — since levodopa is a reasonable backup.
Thanks for the interesting comment. A lot of thought provoking ideas there (e.g. bankruptcy vs cure). Isradipine is going to be discussed in an upcoming blog post so I won’t comment here on it (for readers unfamiliar with this drug, there is a phase III clinical trial of this calcium channel blocker medication in Parkinson’s called the STEADY-PD trial (https://clinicaltrials.gov/ct2/show/NCT02168842). It is set to finish late 2018/early 2019). I agree, however, that we are unlikely to initially see some wonder drug (like ‘Curetide’) that will fix things by itself. Rather a combination of beneficial agents will be used and they will need to be individually balanced for each person. While this will be fantastic for the PD affected community, it will not make the dilemma discussed above any easier. More than ever we need better methods of assessment.
p.s. the scoutmaster sounds awesome!
He was (and his scout pack were pretty cool too)
Hi Simon – an excellent perspective on a true dilemma. Part of this is the inherent nature of Parkinson’s – variability from person to person, from day to day, from symptom to symptom etc. I think the focus should be on turning the subjective to the objective, with biomarkers and objective assessment of motor and non-motor symptoms, in order to get a clearer baseline to assess the performance of new drugs. It’s also crucial to get a better handle on the true number of sub-types of Parkinson’s.
While I understand that each PwP should make their own decision about entering clinical trials without taking Curetide, it may not be up to them, as ethics committees may not approve the protocol.
A heterogeneous response, where a new therapy works very well for only a proportion of PwP, may actually be good news, especially If it works for a distinct sub-type of Parkinson’s.
Perhaps the worst-case scenario is a therapy that produces a statistically significant result; but one which is modest, and homogeneous amongst all PwP. It may then be obligatory in future trials, but will dial down the differential, meaning that future therapies would need to be particularly effective, and trial numbers large, to reach statistical significance. It would also disrupt the outcome of an adaptive trial.
What about exercise? On a n=1 basis, my consultant believes that the amount of exercise I do is providing a protective benefit. Looking at the evidence, she’s probably right. Should I stop exercising in order to join a clinical trial? (rhetorical question…)
This topic will run and run…..
Thanks for your comment and thoughtful insights.
I have long wondered if filtering drug responses from PwPs would better highlight subpopulations. See who in a group responds to the drug and then look at what shared characteristics that have. This is also a better approach to finding biomarkers, as opposed to the current “take a group of PwPs and look in their blood for particular proteins” approach. In the breath analysis study, we are applying a biased approach (eg. groupings based on time since diagnosis), but also an unbiased approach (eg. what characteristics of PD do PwPs with high levels of 2-ethylhexanol in their breath share).
Indeed the worse case scenerio is a treatment that creates a “modest, and homogeneous amongst all PwP”. There would be the very real risk of the rest of the world saying “Well, we’ve sorted Parkinson’s, what next?” and abandoning the community (research funding cuts, etc) with a modest treatment. This was another potential outcome that I didn’t want to suggest in the post. One dilemma at at time.
A behemoth post on exercise is still coming. Maybe over Easter I’ll get some time to finish it. It’s already a beast. But I really like the idea of exercise as there are many measurable variables that can be assessed over time. Definitely a N=1 situation, but what can we learn from exercise that could be applied to other areas of PD treatment? This topic will definitely run and run (I liked the pun).
Like many, I see the world through the lense I’ve shaped through my work and social life over the years. And it’s not in the health fields. I work in an industry where we manufacture billions of units a year. Each product we ship has dozens of parameters tested to insure that we’re giving our customers a quality product that will work when it’s integrated into their product alongside various other simalry screened products that comprise the rest of their system.
To your point Simon about making trials about the patient, there is incredible power in a well taken data set. Manufacturing tools exist to easily analyze data across any number of variables to look for statically significant trends. This is much easier of course when you get data on a million units taken with an automated screening process in a single factory… it wou be great to have that data set on a million Parkinson’s patients factoring every supplement, drug, hour of sleep, minute of exercise correlated to a robotic UDPRS measurement. I’d recommend all these patients be clones of me because god only knows how this would work on on someone else’s genetics and how the trends would change :). What a mess you have to figure out Simon.
To your comment on patients taking what they hope will work: From the patient perspective, I understand the desire to take what might help. It’s a classic “nothing to loose” scenario. Unfortunately the language in trial exclusions can be intimidating and I’d argue is a contributing factor to patients withholding information. This could be helped with some simple statements that say it’s ok to share what you are taking and you won’t be excluded.
I think a bigger problem is the vast untapped group of patients that are not engaged. I believe 90% of people with Parkinson’s get standard playbook care that is 10-20 years behind the best available, take no supplements, aren’t exercising and aren’t aware of any research. These people might gladly join a study without the cloud of off label drugs or supplements influencing data. It seems to me that there two types of Parkinson’s patients: Those who take the fight to the desease and those that do what their less than informed doctors do.
Thanks for your thoughts.
What are the key features of “a well taken data set”. There are some very big data sets around now. For example, 23andMe and PredictPD have recently been releasing some of their data from huge datasets. But if big data was the answer, wouldn’t we be in a better situation now?
Your comment regarding “the language in trial exclusions can be intimidating” and “I’d argue is a contributing factor to patients withholding information” is rather eye-opening. I have to be honest and admit that this is one aspect of clinical study design that I have never really considered before. Exclusions are simply ‘the rules’ that stipulate who can and can’t be involved; consultation with the affected community can help with regards to which are do-able and which isn’t, but those consultations are usually conducted on usually experienced, well-informed individuals. The psychology of the study participant would be a really interesting area of research.
There is a very human side to all this clinical trial malarky, which I fully appreciate. If roles were reversed, I could imagine myself going mad trying everything under the sun. This only strengthens the argument for N=1 studies I guess. This also gets around that engagement issue you mentioned – 90% sounds about right to me, but it is a very personal choice being involved in a clinical trial. Not one to be taken lightly.
Yes, it’s a mess, but we are going to figure it out.
Diana, my hope is that isradipine becomes one of the ingredients in an effective cocktail 🍹. Maybe vermouth? :). It doesn’t sound like it will be earth shattering, but I’ll take any positive news. Here’s hoping!
Kevin, very articulate an informative reply.
Simon, thanks for fighting the fight for us.
This is a very well thought out article indeed! You have given us a look at some potential research futures and I would venture to guess that many (if not all) of those who read your works may be able to come up further scenarios that are not convenient to the process of trying to produce outcomes which are reproducible and accurate. It is logical to expect a degree of difficulty when living and dealing with a chronic illness.
Sometimes, when resistance is low in the early hours of yet another morning awake when I should be asleep, I consider notions that would seem to be unscientific and are dismissed as such when later arrives. Those who suffer with restless leg syndrome may be able to imagine what it is like with restless body syndrome: Raise the recliner, get up, wander around very slowly and unsteadily, have to sit down again. Five minutes later the tormenting feeling inside makes me raise the recliner, get up etc. etc. etc. (did the real king of Siam really talk like that?). This little dance can go on for hours until exhaustion finally treats me to sleep for an hour or two. String together enough nights like that and even the dumbest ideas start to inspire thoughts like ‘could it help?’ or ‘ It would not hurt to try a bit of x or y or z, even though I am on a drug trial already. I can’t stand any more nights without sleep – but I won’t tell the doctors or I will be in trouble!’
There you go – but I don’t want sympathy, I just want this body to stop tormenting me. However, I cannot tell a lie father, it was not me that covertly experimented and screwed the drug trials up BUT I easily understand anyone else doing so.
Simon, I realize this comment is of no use to even hint at a different way of doing things but perhaps it could help to explain to normal people why so many Parky people are on the lookout for something (anything!) that can make life more comfortable. Your article nails down all the reasons why selfish action is not good, so on behalf of those I represent (to be fair, a grand total of one!) lets help the researchers and stick to their protocols when we join their studies.
Thanks for sharing. Your recliner situation very much provides ‘normal’ folks with an example of the reason for desperate experimentalism. I said above that I fully appreciate the human side to these clinical trials, but I realise now that such words are only easy to write. I have to be careful not to pretend to understand things that really I don’t. I recently read “Man’s Search for Meaning” by Viktor Frankl (based on a recommendation by one Martin Taylor – read his post on the book here: https://granderouge.wordpress.com/2018/03/16/the-delusion-of-reprieve/?fb_action_ids=10155437184035003&fb_action_types=news.publishes). It gives a remarkable insight into life in the concentration camps of WWII. But I’m sure that reading hundreds of these types of books, wouldn’t let me ‘fully appreciate’ what the experience was actually like. I should be more careful what I write. Feel free to share your experiences whenever you want Lionel.
Oh, and I would like to state that before Beckie Port at Parkinson’s UK looked at this article, it was a very badly ‘thought out article indeed’! A lot of credit belongs with her.