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.

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:

1. A condition halting treatment to stop/slow progression

2. A neuroprotective agent to nurture and protect the remaining cells

3. 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.

Measuring success

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.

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.


Simon is a post-doctoral researcher at the University of Cambridge. He writes about the latest research results in the field of Parkinson’s on his own blog at scienceofparkinsons.com.