Submission to Taylor & Francis Online: Peer Reviewed Journals
Andrew Darke PhD and Cali Orsulak BSc Pharm
A recent paper by Boddy et al (2025)1 advanced the argument that new drugs for ALS should only be considered to be effective if they demonstrate a separation from placebo in total ALSFRS-R score of 3.8 points, over 3 months of treatment. As a person living with ALS (pALS) and a caregiver (cALS) for a loved one who succumbed to this disease, we respectfully disagree with this proposal. We believe that it could be a significant barrier to the availability of much needed new drugs for ALS, if it were to become a benchmark for regulatory decision makers. Patients and their caregivers are limited in treatment options to only two drugs that have been assessed as having adequate clinical and statistical evidence of efficacy in non-familial ALS, to justify market approval. We are under no illusions about the imminent availability of a cure, or even a drug that will halt the rate of loss of function. Our most immediate and realistic need is for new drugs with a comparable level of evidence to the two previously approved drugs, that they slow disease progression. There are approximately 192 drugs for ALS listed in the clinical trial database of the US National Library of Medicine (clintrials.gov). This level of research activity brings a vital measure of hope to those battling this disease. We are very concerned that the results of these trials will be considered to be inadequate, if this overly conservative criterion were to become a regulatory requirement for market approval, without further analysis and confirmation of its validity by the academic community.
The study of Boddy et al was designed to relate changes in total ALSFRS-R scores during 5 visits at 3 month intervals over 12 months, to an estimate of quality of life (QOL), with the objective of defining the minimal important difference (MID) from the patient’s perspective. However, the QOL assessment was a simple global rating of change question, for which only 3 responses were possible (“worse”, “about the same” and “better”). As an unvalidated instrument for assessment of QOL, which is not specific to ALS, it does not provide the patient with what Simmons (20152) described as a platform by which to perform a structured, item-by-item analysis of their QOL. As the authors acknowledged because of these deficiencies, the MID should be estimated in future studies using one of the more detailed, and validated, ALS-specific QOL instruments, such as the various versions of the ASQOL (Felgoise et al 20183). They further stated that interviewing participants about the change in their symptoms may have provided more granularity about the extent of the change in their QOL. The lack of such information therefore limits the applicability of their study, and until further validation is completed, we believe it would be premature to invoke the MID estimated in this study, as a required criterion to be satisfied in evaluations of drug efficacy.
Although the ALSFRS-R is a conventional outcome measure in many clinical trials in ALS, it is well understood to have deficient biometric properties, and its replacement has been strongly advocated by ALS experts (Fournier et al 20204 ) who have proposed an alternative – the Rasch-built Overall Disability Rating Scale (ROADS) – which has greater sensitivity to disease progression. Nevertheless, clinical trials on a limited number of drugs have demonstrated an adequate clinical and statistical basis for approval for marketing, and/or for proposed progression to a phase 3 clinical trial, based on the ALSFRS-R as the primary outcome measure. The differences from placebo in mean ALSFRS-R score at 6 months in clinical trials of Albrioza, PrimeC and Radicava, were substantially less (2.2–2.5 points) than the proposed MID of 3.8 points after 3 months. In contrast, the recently approved drug (Qalsody), for ALS associated with a SOD1 gene mutation, only demonstrated a 1.2 point difference from placebo in ALSFRS-R score at 6 months, but is widely regarded as a breakthrough in ALS treatment. It is therefore currently unrealistic to expect that any new drug demonstrating statistically significant efficacy in slowing disease progression, based on ALSFRS-R scores at 6 months or 12 months, will achieve a separation from placebo of 3.8 points at 3 months. Moreover, based on the clinical benefit evident during long term treatment with Qalsody, failure to achieve a 3.8 point separation from placebo in ALSFRS-R score at 3 months, cannot be regarded as a valid efficacy criterion.
We also note that there is a related term, the minimal clinically important difference (MCID), which has been confounded with MID, but ideally uses clinically measured factors that are specific to the particular disease and its severity (Fournier et al 20235 ). A previous estimate of MCID in ALS was based on a survey of 65 expert ALS clinicians (Castrillo-Viguera et al 20106). This concluded that an appropriate estimate of MCID would be a 20-25% difference in the slope of the ALSFRS-R time relationship. This has become a generally accepted benchmark for clinical trial design. Importantly, the differences from placebo demonstrated in the 6 month studies of the ALS drugs noted above, were greater than 25%, even though they are substantially lower than the 3.8 points separation at 3 months, proposed by Boddy et al.
Speaking from our experience as pALS and cALS, we believe that QOL needs to be assessed with a comprehensive validated instrument, that at minimum encompasses the functional domains of the ALSFR-R, and is not based on a simple 3 point global rating of change.We also do not regard a 3.8 point separation between active and placebo treatment after 3 months as an appropriate estimate of MID, since a one point decrease in score on any single functional item, occurring at any time during the course of treatment, could represent an important loss of functional ability for a particular pALS. Our perspective is supported by a detailed analysis of the clinical and methological problems with use of MID estimates to interpret the significance of ALSFRS-R data in clinical trials (Vazquez-Costa 20247). Moreover, even if 3.8 points were to be taken as the MID, and such separation did not occur until after 12 months of treatment, it would still mean that the active treatment had achieved that minimal important difference.
As members of the ALS patient and caregiver community we would consider it extremely disheartening if the proposal in this paper were to become accepted as an efficacy criterion for clinical trials, or be entrenched as policy by regulatory agencies. This should be of concern, not just for patients, but also for their neurologists, clinical trial methodologists and commercial sponsors, as it could lead to significant restrictions for the foreseeable future on the approval of the large number of drugs currently in clincal trials.
References
1. Boddy SL, Simpson RM, Walters SJ, Bamford H, Walsh W, McDermott CJ, et al. Estimating the minimum important difference in the ALSFRS-R-instrument in people living with MND. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2025; 26: 249–258.
2. Simmons Z. Patient-Perceived Outcomes and Quality of Life in ALS. Neurotherapeutics (2015) 12:394–402.
3. Felgoise SH, Feinberg R, Stephens HE, Barkhaus P, Boylan K, Caress J, lora l.Clawson LL, Elman L, Goutman SA, Mccluskey L, Russell J, Tiryaki E, Weiss M, and Simmons Z. Amyotrophic Lateral Sclerosis–specific quality of life–short form (ALSSQOL-SF): a brief, reliable, and valid version of the ALSSQOL-R. Muscle Nerve 58:646–654, 2018
4. Fournier CN, Bedlack R, Quinn C, Russell J, Beckwith D, Kaminski KH, et al. Development and validation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). JAMA Neurol. 2020;77:480
5. Fournier CN, James V, Glass JD. Clinically meaningful change: evaluation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) and the ALSFRS-R. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2023; 24: 311–316
6. Castrillo-Viguera C, Grasso DL, Simpson E, Shefner J, Cudkowicz ME. Clinical significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler. 2010;11: 178-80
7. Vazquez-Costa JF. Do we really need to calculate a minimal important difference for ALSFRS-R?: A letter in response to ‘Clinically meaningful change:evaluation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) and the ALSFRS-R’ published in Vol.24(3–4), pp. 311–316. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2024; 25:214-215