Current developments in clinical trial design and conduct

Over 70 compounds have been evaluated by clinical studies, yet Riluzole is…

Words Lucie van Leeuwen.Published September 23, 2020
Current developments in clinical trial design and conduct

Over 70 compounds have been evaluated by clinical studies, yet Riluzole is the only available treatment for people with ALS in Europe. The reasons for this unsuccessful road of drug development are many, including flawed clinical trial design, poor bench-to-bedside translation and the need for more robust biomarkers. Researchers from our Dutch TRICALS Centre at UMC Utrecht have now reviewed the design and conduct of ongoing ALS trials, and published their findings in a scientific article.

To review current trials, they searched the clinical trial database ‘’ using the terms ‘motor neuron disease’ and ‘amyotrophic lateral sclerosis’. A total of 63 clinical trials were selected for review. These included:

  • 13 phase 1 trials. These are small trials investigating the safety and best dose of a drug.
  • 35 phase 2 trials. Phase 2 trials investigate how well a drug works and further confirm if it’s safe.
  • 15 phase 3 trials. These are large trials and are a definite assessment whether a drug works and if it can be used in the clinic.

Routes of administration

Most ALS trials investigate oral treatments. However, 30% of phase 2 and 3 studies administer their drugs via invasive injections (e.g. in the bloodstream or in the spinal canal). In this case, caution must be taken in randomised controlled trials. In randomised controlled trials, the active drug is compared against a ‘fake’ drug (placebo). Participants are not told if they receive the active drug or the placebo. This helps to rule out that the effectiveness and side-effects of a drug are due to a person’s conviction that the drug works (the placebo-effect). Invasive methods of administration, however, can be harmful for patients, irrespective of whether an active or placebo treatment is provided. This can make the comparison between the placebo treatment and the candidate drug less reliable and falsely suggest that a new treatment is working. In these settings, a possible solution could be to include an additional comparison, such as routine care or historical data.

Entry criteria

Entry criteria for people with ALS to participate in clinical trials, differ between studies. A large portion (41%) of studies uses the ‘El Escorial criteria’, which according to many scientists are too restrictive. In addition, more and more trials enrol patients based on disease progression rate. This means that patients who either progress too fast or too slow are denied participation. Not only does this take away hope from many people with ALS, it also makes results less representative. Entry criteria could be improved by using predictive modelling strategies (to predict a patients disease course) and biomarkers. Both are therefore key objectives in the strategy of TRICALS and have recently been endorsed by the EMA. At TRICALS, we aim to give every patient with ALS access to clinical trials, regardless of how fast they progress, their type of ALS or their disease duration. By doing so, we will speed up our search for new treatments.

Efficacy endpoints

Efficacy endpoints are measures to evaluate the effect of a drug. Currently, the main endpoints used in clinical studies are:

  • The ALSFRS-R scale. This scale measures a person’s ability to perform daily functions, such as walking, dressing, eating and drinking and sleeping.
  • Lung function
  • Survival time

Changes in cognition and ‘neurofilament’ levels – indicating nerve cell damage – are increasingly  measured to see if a drug is successful. Both give additional information about whether a drug works. Their implementation on a larger scale could therefore strengthen our ability to reliably determine if a drug works and will improve clinical trial design.


The FDA and other consensus guidelines urge clinical trials to verify if a drug extends survival of people with ALS. Worryingly, most phase 3 studies are not designed properly to detect even large survival benefits. This may affect whether promising drugs can enter the market, even after positive trial results. Not being able to notice that a drug prolongs survival has mainly to do with the short duration of most phase 3 trials. Hence, it is key for any phase 3 trial to make sure that a drug is provided for a long enough period to manifest its effect on survival time. By incorporating prediction models and choosing the right analytic strategies, the burden for patients can be minimised and the road to market authorisation of effective drugs shortened.

Platform trials

The design of ALS clinical trials is variable, making it hard to compare results between studies. A positive change is the arrival of ‘platform trials’. These innovative clinical trials offer a design that can be used again for new trials and enable the investigation of multiple treatments at the same time. Thereby, platform trials play an important role in harmonising the ALS clinical trial landscape. Recently TRICALS received endorsement from the European Medicines Agency for our very own platform trial: the MAGNET trial. At TRICALS we furthermore offer expert advice and support for an optimal design and conduct of clinical trials.

By further improving trial design we will accelerate our search for effective treatments for ALS.

The original review paper can be found here.


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