Patient centered outcome measurements in rare disease trials: Challenges and potential solutions

Co organizers and session chairs:

Hanneke van der Lee, MD, PhD, Academic Medical Center, Amsterdam, Netherlands.

Prof dr Kit Roes, University Medical Center Utrecht, Netherlands.

Outcome measurement in rare disease clinical trials is a challenge because generic instruments are usually not responsive, and no disease-specific instruments are available. The development of disease-specific instruments is further hampered by the heterogeneity among rare disease patients. Disease progression may vary, and more importantly, disease manifestations may be different. For clinical trial designs within these small populations this poses an additional challenge for the size of trials: If trials need to be focused on more homogeneous subgroups, this becomes unfeasible and an opportunity to evaluate the shared underlying disease mechanisms in the same trial is missed.

In this session we explore potential solutions for these challenges from different perspectives, including those of patients and clinicians.

The problem of developing new treatments for a (very) heterogeneous disease cluster with a shared underlying mechanism is sketched for the case of mitochondrial diseases. New drug treatments are being developed that, based on their mechanism, have the potential to be effective across a range of disease manifestations. Subgrouping on specific disease manifestations renders clinical trials unfeasible, hence it is of utmost importance to define outcomes that matter to patients and capture treatment effect across manifestations.

The patient perspective on measuring outcomes that truly express benefit is increasingly taken into account in trial design. This perspective will be sketched, specifically for rare diseases – as well as how patients and/or their caretakers would prefer to be involved in designing trials, and more specifically in deciding on major trial outcome measures.

A potential direction forward is to develop an individualized patient-relevant measurement instrument that can deal with this heterogeneity in the study population, whilst retaining (or possibly improving) efficiency because its elements are affected by the underlying mechanistic response to treatment.  An existing instrument, Goal Attainment Scaling (GAS), will be introduced – as well as a review of its application and basic characteristics. Furthermore, it will be described how this is implemented in an actual clinical trial and first results are shared.

Whilst it can be concluded that this could be a useful approach, the validity of GAS has hardly been investigated, and the statistical analysis methods are not well developed. They are not specifically geared towards the situation that goals are set, whilst trying to assess a potential underlying treatment mechanism aimed at helping patients improve. Therefore a solid statistical approach to model these individualized scores was developed. Based on this, appropriate analysis to compare treatment groups can be established as well as recommendations for practice on how to set these individualized goals. Thus, some advice can be given on the number of goals, their likely association and the appropriate weighting for statistical efficiency. The modeling approach could very well be used for other individualized approaches.

Finally, for implementation in drug development for rare diseases, the regulatory perspective is essential. Also regulators are prioritizing the involvement of patients and their perspective on new treatments in general, and the development of patient-centered outcomes more specifically. This perspective is sketched, and it is indicated what would be needed in terms of quality and validation of patient-centered outcomes to make them contribute optimally to the regulatory review process.




  1. The need for new approaches for patient centered outcome measurement: the case of mitochondrial diseases.

Speaker:  Prof. dr. J. Smeitink, Radboud University Medical Center, Nijmegen, Netherlands and Khondrion (to be confirmed)


  1. Outcome measurement in rare diseases: The patient perspective.

Speaker: Alex Johnson, Duchenne UK (to be confirmed)


  1. A potential way forward: Goal Attainment scaling.

Speaker:  C. Gaasterland, Academic Medical Center Amsterdam, Netherlands (confirmed)


  1. Statistical and methodological basis to allow proper inference.

Speaker: S. Urach, Medical University Vienna, Austria (confirmed)



  1. Regulatory perspective on new approaches to patient centered outcome measurement.

EMA Speaker to be confirmed.

Published on 5 October 2017

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