Vital status at the 21-year LTF
The primary aim of the 21-year LTF was to determine the vital status of participants from the original BETAFERON pivotal study. Vital status was determined for 98.4% (366/372) of the study participants (see figure). The relative risk of death was reduced by 46.8% in patients randomized 21 years earlier to receive BETAFERON compared with initial placebo treatment (p = 0.0173) . Death due to MS-related causes was reported in 78.3% (54/69) of patient .
The findings of the 21-year LTF resonated throughout the neurological community. The study was selected as the most important MS study of 2012 by both the Editorial Advisory Board of Neurology  and the Editor for Controversies in Multiple Sclerosis . It was also recognized for its remarkably high ascertainment rate (all but six of the original 372 study patients (98%) were included) [3,4]. The study observed markedly improved survival in patients who initiated treatment 3.3 years earlier compared to placebo, and demonstrated that treatment with BETAFERON may translate into not only short-term but also longer term benefits .
In the 21-year LTF, vital status was determined for 98.4% (366/372) of study participants: Patients originally randomized to BETAFERON had a higher likelihood of being alive than those randomized to placebo 
Registry data from Canada and France (N=5,989) also reported a survival advantage for interferon beta-exposed RRMS patients vs. matched controls . In another Canadian registry study (N=35,894), the survival advantage was more pronounced with early exposure than with later exposure to interferon beta treatment . Survival can be considered as an integrated measure (comprised of a treatment’s underlying safety and effectiveness) of long-term outcomes .
Predictive validity of NEDA in the 16- and 21-year LTF from the pivotal trial of BETAFERON 
No evidence of disease activity (NEDA) has become a popular therapeutic target in the management of patients with MS. Long-term follow-up studies from randomized, placebo-controlled clinical trials are useful for validating short-term NEDA outcomes over the long run. Datasets from the 16- and the 21-year LTF studies were used as a basis to assess the predictive validity for negative disability outcomes such as death, need for wheelchair, EDSS ≥6, or progressive MS. Data from 245 and 371 patients were evaluated at 16 and 21 years, respectively.
Clinical NEDA, defined as no relapses or EDSS progression from baseline to year 2, predicted long-term disability outcome. However, expanding the definition of NEDA to include on-therapy changes in MRI variables like T2 burden of disease and brain atrophy did not improve upon the predictive capacity of clinical NEDA alone. These findings are in contrast with NEDA studies from shorter-term studies. Whether newer MRI techniques will contribute to outcome prediction over the long-term remains an open and unanswered question.
EDSS: Expanded Disability Status Scale
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