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The way that clinical trials are conducted doesn’t make much sense.
They take too long and a lot of resources to set up, they take a long time to be conducted, and we have to wait until they are finished before we get the results. And then on top of that we need to repeat the whole process everytime we want to make any further progress.
More efficient and adaptive models of clinical trials have been used in other medical conditions, and, thankfully, researchers are now asking if these could also be applied to Parkinson’s
In today’s post, we will discuss a recent review that explores the use of Multi-Arm Multi-Stage trial design, and asks how they could be applied to neurodegenerative conditions, like PD.
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“Mum’s the word” is a popular English idiom. It refers to not talking about a particular topic.
But where on Earth did the phrase come from?!?
In writing these blog posts, I like to try and devise clever (some might fairly say silly) titles to grab the attention of the reader. But these efforts often lead to distracting deviations of curiosity about the origins of certain quotes or titles.
“Mum’s the word” is a good example. I have used the phrase a lot in the past, but never questioned its origins. Until today that is.
The first time it appears in print is in A Walk Around London and Westminster – The Works of Mr. Thomas Brown, written in 1720 (“But Mum’s the Word – for who would speak their Mind among Tarrs and Commissioners“).
The phase, however, derives from the Latin “mimus” meaning “silent actor”, which evolved into ‘mummer’ in Old English. “Mummers” were artists who performed dances, games or plays in complete silence. Curiously this tradition is still maintained in the form of the Mummers Parade, which is held each New Year’s Day in Philadelphia:
Philadelphia Mummers Parade – doesn’t look very silent. Source: ABC
The word ‘mum’ in this context first appeared in print in William Langland’s Middle English poem “Piers Plowman” from the 1370s, and even Shakespeare has used the word ‘mum’ in his Henry VI (Part 2, Act 1, Scene 2: “Seal up your lips and give no words but mum”).
Interesting. But what has this got to do with Parkinson’s?
Like I said, it was just a silly attempt at making a cute title for this blog post.
And now, to business: Today we are going to discuss a new review exploring Multi-Arm Multi-Stage clinical trials and their potential use in Parkinson’s.
What does Multi-Arm Multi-Stage mean?
A Multi-Arm Multi-Stage (or MAMS) clinical trial is a study that allows for the assessment of several potential therapies at the same time. It also shifts participants seamlessly from a Phase II (safety and efficacy) study to a Phase III trial, by regular within study measures (or interim analyses).
Can we go back a moment please? Could you explain how clinical trials are currently conducted?
Here is how it currently work:
First, there is the setting up of the trial.
When it is determined (from a great deal of preclinical research) that “therapy A” is worthy of clinical testing in humans with Parkinson’s, investigators will begin to organise a study. They firstly need to find a sponsor (this is a research/medical institute that is prepared to accept the responsibility for ensuring that there are proper arrangements to manage and finance a research study).
Next, the researchers seek funding to conduct the study. And this is no easy task – trials cost a lot of money and applying for funding can take a long time. Funding applications are enormous and take a very long time to process (peer review opinions, etc). Once a sponsor and funding is in place, the researchers must still request ethical and regulatory approval for the study – in the UK all trials require approval by the Health Research Authority (HRA) which involves a review by a local Research Ethics Committee.
This first part of the clinical trial process can require years of work, and it takes place for every study (even when the same drug is being tested across two different studies, the same sequence must be followed – click here to read more about this process in the UK).
Second, there is the treatment part of the study (and we are skipping over a lot of other stuff here).
Once the green light is given for starting a clinical trial of ‘therapy A’, participants in a clinical study will typically be assessed and if they fit the inclusion criteria for the study, they will then be randomly assigned to one of multiple treatment groups (for example, the experimental treatment or the control group). Next, they will be followed and assessed over a fixed period of time (such as 12 months), at the end of which the researchers will pool together all of the results. Sometimes there is also a ‘washout’ period to see what happens to the participants in the absence of the treatment.
Once the final participant finishes the treatment regime, the data will be ‘locked’ and the analysis of the results will begin.
Hang on a second, why do they wait till the end of the study to analyse the data?!?
You are stealing my thunder. Wait a moment, we will definitely be coming back to that.
Third, there is the data analysis and dissemination.
The data analysis can take several months and then the investigators will write a report which they will submit for publication in a medical journal. The peer-review process is a necessary part of the scientific process, but it can be a frustratingly long tale of woe – journal editors declaring that the study isn’t worthy of their prestigious journal (a business decision), peer reviewers using the anonymous system to attack competitors (in a bid to “improve the quality of the report”), etc. Big sigh!
Thankfully, now there are preprint databases such as MedRxiv which are being used by increasingly being used by researchers to make results available eariler as they go through the peer-review process (and kudos to the Parkinson Study Group NILO-PD investigators for posting a preprint of the Phase 2 Nilotinib in Parkinson’s clinical trial results – Click here to read more about this).
But the peer-review process can take a long time (6-12 months with all the back-and-forth of correspondence and edits/revisions), which delays the clinical trial process further. And this causes further frustration for the Parkinson’s community who would like to learn about the results (and see the whole process speed up).
And during this process of diseminating the results, the investigators will be deciding whether to further investigate the experimental therapy or not. If they chose to do so, they have to go through this entire process again – which can result in long delays between the phases of clinical trials.
RECAP #1: The current system of planning and conducting clinical trials for Parkinson’s is a long, slow, and costly exercise.
And once a trial is completed, the peer-review process slows the dissemination of the results.
What do you mean “phases” in the clinical trial process?
There are 5 Phases involved with getting a new treatment approved for clinical use:
To begin with, there is the long, labourious process of discovering and testing a new treatment/compound. This is the preclinical phase. Once a compound/treatment has been identified, validated in various preclinical models of a medical condition, and a basic phamacological profile has been established in animals (this involves determining if the treatment is toxic and investigating how long the treatment lasts in the body of a lab animal), then investigators will go through the process described above to organise a clinical study.
The first test is called a Phase I clinical trial.
The goal of Phase I trials is to determine if the drug is safe. Efforts will also be made to assess the ideal dose for further clinical testing. Phase I trials will often be in healthy individuals (perhaps 20-50 people), involve a single or multiple doses of the treatment, and they are usually very quick (think weeks or a few months).
If the treatment is found to be safe in Phase I, the investigative team will shift their efforts to a Phase II trial,… and again, they will need to go through the same long process for setting up a clinical trial that we described above – resulting in a delay between Phase 1 and Phase 2 of several months-years.
The goal of a Phase II clinical trial is to determine if the drug is safe in your patient population of interest and attempt to provide proof of efficacy (that is, try to provide evidence that the treatment is doing what it is supposed to). Phase II trials usually involve 50 – 100 individuals being on the treatment for a long period of time (they can last up to 12 months).
If the treatment is found to be safe in the cohort of interest and have an effect in Phase II clinical trials (an example in Parkinson’s of this is the Exenatide study – Click here and here to read more about this), the investigative team will then set up for a large Phase III clinical trial.
And again, this requires going through the same long process for setting up a clinical trial that we described above – resulting in a delay between Phase 2 and Phase 3 of several years (bigger trials take longer to set up and finance).
The goal of a Phase III trial is to determine efficacy in a large group of the patient population of interest (200-300+ participants). These are huge, expensive trials that will involve 1-2 years of treatment and assessments on average in the case of a slowly progressing condition like Parkinson’s.
There is also a Phase IV clinical trial which comes after a drug is approved by regulators. This involves companies/clinicians/researchers continually following the use of the treatment and collecting information in the clinical setting. This is outside of the scope of our interest here as it has nothing to do with getting treatments to the clinic.
As you can hopefully see, clinical trials are long, slow projects.
But this is crazy! Whose idea was this?
I’m not sure.
And I doubt many people would put up their hand to take credit for it.
The trial system (and industry surrounding it) was set up to make sure that treatments entering the medical usage are 1. safe, and 2. thoroughly characterised (ideally, they also provide some improved benefit on previous therapies, but this seems to be less important recently – click here to read more abot this).
One of the biggest problems, however, is that the current system of clinical trialling is not keeping up with the extremely rapid advances being made in the biomedical research field.
“With the ever increasing pace of research, including in vitro and in vivo screening systems, advances in virtual drug modelling and bioinformatics approaches, the number of suitable drug candidates for clinical evaluation as potential disease modifying therapies is on the rise” (Source: iospress)
The way we currently conduct clinical trials is too slow. An observer (I can’t recall who right now) once described the current system of clinical trials as being analogous to building a football stadium for just one game and then tearing it down again, before planning another stadium for a different game.
Building stadiums for a single game of football. Source: WWM
What we really need is a new way of conducting clinical trials that is more adapted to the current rapid progress of preclinical research. And this is where we come back to the idea of a Multi-Arm Multi-Stage (or MAMS) clinical trial.
RECAP #2: There are different phases in clinical trials – Phase 1 is an evaluation of safety of a new therapy in humans. Phase 2 is a longer and larger test of safety (and signs of efficacy) in your population of interest. Phase 3 is a very large study investigating the efficacy of the therapy.
Each trial is set up, conducted and analysed separately, and there can be long delays between phases.
So, to answer your question “What does Multi-Arm Multi-Stage mean?”, recently this review was published:
Title: Is It Possible to Conduct a Multi-Arm Multi-Stage Platform Trial in Parkinson’s Disease: Lessons Learned from Other Neurodegenerative Disorders and Cancer.
Authors: Zeissler ML, Li V, Parmar MKB, Carroll CB.
Journal: J Parkinsons Dis. 2020;10(2):413-428.
PMID: 32116263 (This report is OPEN ACCESS if you would like to read it)
In this review, the researchers explored the idea of clinical trials that can test multiple therapies at the same time (“Multi-Arm”) and allow for seamless transition between phases (“Multi-Stage”), and whether such trials could be useful for a condition like Parkinson’s.
The group of researchers who wrote this review were led by Dr Camille Carroll of Plymouth University:
Dr Camille Carroll. Source: Eurekalert
She is one of the young rockstars of the Parkinson’s research community.
Dr Carroll is an academic consultant neurologist and lead investigator on the UK-wide PD STAT clinical trial evaluating simvastatin in people with Parkinson’s (Click here to read a previous SoPD post on this topic).
In their review, the researchers first point out some of the issues with the current way clinical trials are conducted for Parkinson’s, for example:
“The development, financing and conducting of a clinical trial can take many years, creating a bottleneck for the clinical evaluation of potential therapies, particularly in the phase III setting. There is therefore a need to adopt an innovative and adaptive approach that allows for the seamless streamlining of trials and the testing of multiple hypotheses at once” (Source: iospress)
Then they discuss the advantages of the MAMS trial design, pointing out that:
“the multi-stage approach allows for the incorporation of phase II equivalent findings to be carried forward to the final phase III results without requiring the initiation of a separate trial” (Source: iospress)
This MAMS design provides a quicker and ultimately cheaper option than the conventional individual trial approach, but critically it requires interim analyses in order to determine which drugs are working.
Rather than waiting till the end of the study to find out whether a therapy actually work, the investigators must have the data being constantly assessed by an independent monitoring group which can tell them if an agent is demonstrating any signs of efficacy.
These regular assessments of the data as the trial is being conducted are needed so that decisions can be made about which therapies should be carried forward into Phase 3, and which should be stopped.
Below is an example from the review about how a MAMS study would function:
In the schematic provided above, 12 drugs (D1-D12) have been Phase 2 tested (or trial initiated) over the 5 year course of the study. Of these, eight have been determined to be having no effect and terminated (based on the interim analysis) while 2 (D1 and D8) have proceeded seamlessly into Phase 3 trials. Such a plan allows for 10 therapies to be Phase 2 tested in the span of 5 years.
Compare this to the current system which tests drugs individually.
You can see why MAMS is an attractive idea.
And beyond the testing of drugs, consider all of the data about Parkinson’s that would be collected along the way (clinical, genetic, brain imaging, biomarkers, etc data could be collected from very large cohorts).
And to emphasize the power of MAMS studies, the authors next discussed some of the MAMS trials that have been conducted for other medical conditions, such as the STAMPEDE trial.
What is the STAMPEDE trial?
This is Prof Mahesh ‘Max’ Parmar (another author of the MAMS review we are discussing today).
Prof Parmar. Source: Twitter
Prof Parmar is renowned in the world of clinical trials as he is intimately involved with the MAMS study for prostate cancer, known as the STAMPEDE trial.
Since opening in October 2005, the STAMPEDE trial has not only improved standard of care for prostate cancer by increasing life-expectancy, but it has also become a gold standard for researchers in other disease areas seeking to initiate MAMS trials.
The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial has involved more than 11,000 men with advanced prostate cancer thus far and it is still going.
Like Parkinson’s with levodopa, the main treatment for prostate cancer – long-term hormone therapy – was discovered in the middle of last century and since then there had been no new treatments for advanced prostate cancer. But since the start of STAMPEDE, the standard treatment for advanced prostate cancer (which is used in the placebo arm of STAMPEDE) has been improved 4 times (3 of those by research within the STAMPEDE trial itself!), improving the survival of men with advanced prostate cancer.
Not a bad output from this impressive project.
And the STAMPEDE MAMS platform aims to continue improve standard treatment for advanced prostate cancer until at least 2030.
RECAP #3: Multi-Arm Multi-Stage (or MAMS) trials involve multiple agents being tested at the same time within a single trial. Each therapy is tested in one group (or arm) of participants. Rather than waiting until the end of the study, data collected from the study is continously being analysed, allowing for the investigators to adapt the study as required (terminating treatments that are not working).
MAMS also allow for seamless transition between Phase 2 and Phase 3, thus speeding up the clinical trial process.
The STAMPEDE trial for advanced prostate cancer represents an amazing example of how MAMS trials can directly impact not only patient survival, but also improving clinical standard treatment.
Interesting. Has anyone ever tried MAMS for Parkinson’s before?
No, not that I am aware of.
The closest we get is the The Australian Parkinson’s Mission which is a clinical trial program built around multi arm studies, but they are not being designed to be multi stage (Click here to read a previous SoPD post on this topic).
In the first trial of the Australian Parkinson’s Mission project, there will be 300 individuals with Parkinson’s being recruited and randoms into four groups (3 of those groups will recieve one of 3 repurposed drugs while the fourth group will be administered a placebo treatment).
COVID-19 has delayed the start of this trial, but as lockdown is lifted in Australia, we hope to hear news of this project getting started soon.
Other neurodegenerative conditions are exploring MAMS platforms, particularly multiple sclerosis and motor neurone disease.
The MS Society in the UK has previously conducted a multi-arm trial – investigating 3 potentially disease modifying drugs – that was called the “MS-Secondary Progressive Multi-Arm Randomisation Trial” (or MS SMART).
The results of the MS SMART trial have now been published (Click here to read those). Despite not demonstrating a positive outcome, the MS SMART project has served as a foundation upon which the MS Society are now designing and building a clinical MAMS trial platform. They hope to start recruitment of trial participant in 2021.
The “Motor Neurone Disease Systematic Multi-Arm Adaptive Randomised Trial” (or MND SMART) is being sponsored by the University of Edinburgh and funded by a collection of charitable organisations (Click here to read more about this effort).
MND SMART has recently gained regulatory approval and should be starting soon. Interestingly, the project is taking advantage of Scotland’s CARE-MND integrated care and research programme, which aims to integrate “clinical care, audit, research and evaluation to provide ongoing comprehensive monitoring of every person living with MND in Scotland“.
So if others are doing it, what are the challenges with starting a MAMS trial for Parkinson’s?
In their review, Dr Carroll and colleagues list some of the issues that need to be addressed if a MAMS trial is going to be considered for Parkinson’s:
1. Drug selection – selecting the right experimental therapies is important. The authors believe that MAMS trials should investigate drugs that are mechanistically as divergent as possible, avoiding direct competition between drugs which will ultimately make a MAMS platform more appealing to industry (they might not be interested in a MAMS trial of four GLP1 agonists, they there is a chance that their drug would be found to be the weakest).
The authors also discuss programmes like the international Linked Clinical Trial committee as a good example of drug selection efforts (Click here to read a previous SoPD post on this topic).
2. Outcome measures – choosing the right measures of efficacy will also be critical, and the authors list aspects of Parkinson’s research investigating this (such as motor progression, cognition, time to event measures, non-motor symptoms, quality of life measures, biomarkers, and digital health technologies).
In this section there is also a good discussion on “shaping future outcomes”, which explores how other neurodegenerative conditions are tackling the issue of assessing neuroprotective therapies. Most interesting here is the production of composite scores to better reflect the range of issues a typical person with a neurodegenerative condition may exhibit (we will be exploring the issue of composite scores in an upcoming SoPD post).
3. Trial design – there are many important aspects to consider here as well (including things like inclusion/exclusion criteria, stratification methology, etc). The MAMS trial arms should also be statistically powered to compare active arms to placebo only.
Ultimately, the authors conclude that in order to establish a MAMS trial platform consensus will have to be reached on four key issues: 1) drug selection, 2) an appropriate patient population for study, 3) methodology for identifying disease modification and 4) effective and relevant outcome measures.
How do you determine consensus?
The authors discussed the use of a “Delphi process”.
What is a Delphi process?
A Delphi process is a method for structuring a group communication process to build a consensus. It typically involves multiple rounds of questionnaires being sent to a panel of experts, and the anonymous responses are aggregated and shared with the group after each round. In this fashion, multiple points of view can help to build estimates on the likelihood and outcome of future events (such as whether a MAMS trial platform should be set up for Parkinson’s).
A Delphi process is currently being developed to help build consensus around what a MAMS platform for Parkinson’s might look like.
We will hopefully hear more about this in the near future.
So what does it all mean?
We humans are strange creatures.
Falling into routine and habit all too easily, and extremely reluctant to change our ways once we form our habits. Even when stuff doesn’t really work, it is always easier to simply say “We’ve always done it this way“.
MAMS platforms represents a new way of doing clinical trials that the Parkinson’s community should explore. One aspect that was not discussed in this post was the set up cost, which is likely to be significant. But it will certainly be less expensive over the long term, compared to continuously setting up new individual trials (remember the idea of building stadiums for one game of football).
In addition, with interim analyses being conducted throughout the trial, we will be able to stop studies that do not show signs of efficicacy – not wasting time or money. And on top of all of this, the seamless shift from Phase 2 to Phase 3 will surely speed up the clinical trial process. Yet another reason for change.
My write up here really doesn’t do justice to the review that Dr Carroll and colleagues wrote on the idea of a MAMS platform for Parkinson’s. For those interested in the topic, I highly recommend reading it – it is a good read (Click here to read it).
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EDITOR’S NOTE: The author of this post is an employee of the Cure Parkinson’s Trust which was the funder of the research report discussed in this post and aiding in the ongoing Delphi process.
The Cure Parkinson’s Trust is also funding the PD-STAT clinical trial (along with the Van Andel Institute and the JP Moulton Charitable Foundation) and supporting the ‘The Australian Parkinson’s Mission‘. The Trust has not asked for this post to be written. This post has been written by the author solely for the purpose of sharing what the author considers interesting information.
The banner for today’s post was sourced from Eupati