Using Observational Data to Complement RCT Results – Examples Based on Multiple Sclerosis

A common scenario in modern research arises when a long-term treatment has been evaluated in RCTs, but with only limited follow-up. Not surprisingly patients do not want to continue to take medicines in the long-term that have been shown to be inferior in the shorter-term. Such was the case with the first generation of multiple sclerosis (MS) drugs, and so I found myself chairing the scientific advisory committee for a long-term observational study based on the MS Risk Sharing scheme. ‘Risk sharing’ because the tax payer and pharmaceutical companies shared the risk that the medicines would appear more or less successful in the longer-term than had been estimated in the RCTs (all of which were of 2-3 years duration). This study is now closed and the resulting paper has been submitted for publication.

In the meantime, new treatments have been developed for the treatment of MS. One class of treatments involves autologous bone marrow cell transplantation.[1] This treatment, unlike drugs used in the MS Risk Sharing scheme, is suitable only for patients with rapidly progressing disease, because it is an aggressive treatment with a mortality of about 2%, and a long-term cancer risk of about 1%. As with the first generation drugs, benefits in the short-term (about two years) had been well-established, but long-term effects were unknown. So a long-term study was conducted. In the case of the MS Risk Sharing scheme, progression on treatment was compared to a control population recruited in British Columbia before use of drugs became widespread. Patients recruited to this Canadian study therefore constituted a natural history control cohort for patients in the Risk Sharing scheme. In contrast, long-term follow-up was uncontrolled in the autologous bone marrow cell transplant study. Nevertheless, the authors rely on the large observed effect size to conclude that bone marrow cell therapy was effective over a mean of six years follow-up. The biological mechanism is a little unclear, but the agreement with short-term RCT outcomes (clinical progression and surrogate markers on MRI), along with the large apparent benefit, suggests that this treatment is worth its costs, in terms of money and side-effects, in people with aggressive disease.

— Richard Lilford, CLAHRC WM Director


  1. Muraro PA, Pasquini M, Atkins HL, et al. Long-term Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Sclerosis. JAMA Neurol. 2017; 74(4): 459-69.

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