This study examined the extent to which the psychometric properties of the most important instruments to assess disease progression in MS – EDSS and MSFC – meet the methodological standards and what value they have as outcome measures in clinical trials.
In a systematic literature review of 120 relevant full-text publications, we found that while the EDSS is the most widely used instrument in clinical trials assessing the effectiveness of therapeutic interventions, the MSFC is becoming increasingly important.
Single methodological characteristics of the two instruments have been investigated in numerous studies. The EDSS has some documented weaknesses in reliability and sensitivity to change. Although the MSFC was developed rigorously, its weaknesses include interpreting the z-scores (which are used to calculate the summary score from the three components), the learning effects of the PASAT, low acceptance by patients and lack of a visual dimension. However, the MSFC has better sensitivity and reliability compared to EDSS. The methodological quality criterion of validity is sufficiently met by both instruments.
Despite the criticisms, in particular the EDSS could be classified as an important endpoint. In neither publication, the EDSS (or MSFC) are discussed as a surrogate parameter (in contrast to MRI measurements). Cohen et al.  emphasized in their review of clinical outcome parameters, the general acceptance of the EDSS as an endpoint by different authorities. In contrast, the MSFC is usually used as a secondary endpoint.
The importance of the instruments is also reflected in our evaluation of clinical trials: in 50 of 66 identified relevant phase-III and phase-IV studies, disease progression as measured by EDSS was used as primary (27 studies) or secondary outcome (23 studies). The MSFC was used in eight studies as a secondary endpoint and only one study as a primary endpoint.
In summary, both instruments are acceptable outcome criteria to assess the effectiveness of clinical interventions and to monitor disease progression. When using the EDSS, its limited inter-and intra-rater reliability should be considered. All possibilities to increase reliability should be used, including training of investigators, assessment by the same doctor/neurologist during the study, specified times of detection, standardized protocols for neurological examination and a precise definition of all requirements. When using the MSFC, the learning effects of the PASAT and 9HPT should be considered and controlled (e.g. using control groups).
Concerning the natural history of MS, Weinshenker and colleagues  observed an average change of 0.5 points on the EDSS scale in a year. A clear recommendation on interpreting changes in EDSS and MSFC values does not yet exist. EDSS changes by 1.0 points from a baseline EDSS less than or equal to 5.5 and 0.5 points over a baseline 5.5 are commonly recognized as a clinically increase in disability. However, it is now understood that it is more accurate to define disability change as a sustained change for 12 weeks or, even more reliably, for 24 weeks.
For the MSFC, changes by 20% in the individual components are considered to be clinically relevant. However, it is difficult for a clinician to understand what a 20% change in MSFC subscores is while a significant EDSS change is more intuitively understood.
Overall, the literature reveals that the EDSS is the most widely used and best-known instrument to assess disease progression in MS. The advantages and disadvantages of EDSS and MSFC have been investigated frequently. The great advantage of the EDSS is its international acceptance (including the EMA) as a primary endpoint in clinical trials. Because it is so commonly used, studies that use the EDSS can easily compare results to other findings. Following the current literature, we can conclude that the importance of the EDSS will be unabated in future. Major changes of the EDSS are not recommended, as not to jeopardize its advantage.
In addition, the use of other measurements as clinical trial endpoints (e.g. the MSFC) is recommended to provide information on dimensions no covered in the EDSS, such as upper limb function or cognitive skills.