June 26, 2014

Recent Papers Highlight Difficulty of Studying Long-Term Impact on Progression of MS Disease-Modifying Therapies


Scores of research papers from well-controlled clinical trials demonstrate that the MS disease-modifying therapies significantly reduce MS relapses and disease progression, and improve quality of life. However, well-controlled research proving that these drugs can delay the progression of disability over the long term is lacking, which is illustrated in a recently reported British-based study. Other studies also point to challenges but provide additional important data regarding disease-modifying therapies.

In a study attempting to look at longer-term outcomes, Dr. George Ebers (Radcliffe Hospital, Oxford, UK) and international colleagues retrospectively traced outcomes of 260 out of 372 individuals who had originally participated in a clinical trial of interferon beta-1b (Betaseron, Bayer Schering Pharma) that began over 16 years ago. In their paper, the authors were unable to draw conclusions about differences in disability or MRI measures between those who started on placebo and those who were on therapy during the clinical trial. However, they did report that those on therapy appeared to have lower mortality rates than those originally on placebo. They concluded that outside of the original trial, many factors, such as changes in treatment, can intervene to make it difficult to find long-term differences between original study groups. The paper, published online in June 2010 (J Neurol Neurosurg Psychiatry), highlights the difficulties of tracking long-term outcomes of disease-modifying therapies without well-designed, long-term studies.
In the absence of lengthy, well-controlled trials, other methods have been used to investigate long-term effectiveness of the disease-modifying therapies with mixed results. For example:

  • Alarge-scale analysis published in 2007 suggested that disease-modifying drugs for MS (specifically, interferon beta-1a, interferon beta-1b or glatiramer acetate) were effective in reducing disability progression in people whose MS started with relapses. For that study (Neurology2007 Oct 9;69(15):1498-507), funded by Health Canada, the MS Society of Canada, Nova Scotia Health Research Foundation and others, Murray Brown, PhD, and colleagues used the Dalhousie MS Research Unit's database to track the course of 590 people with relapsing forms of MS. The database included 25 years of clinical data on people with MS, including up to six years of data on people whose three classes of DMDs were paid for by Nova Scotia's Department of Health from 1998 to 2004.

    Compared to estimated rates of progression before treatment, therapy was estimated to reduce progression in the EDSS by 90-105% over the course of the period studied in people with relapsing MS. The reduction in progression of the EDSS was 100-112% for patients with relapsing-remitting MS but only 8-22% for those with secondary-progressive MS. This study was based on clinical observations and not on a well-controlled clinical trial.
  • This group joined with Paul Veugelers, PhD (University of Alberta) to analyze data from 1752 MS patients seen between 1980 and 2004 at the regional MS Clinic that serves the entire population of Nova Scotia. They examined whether progression of neurologic disability in the clinic population - as measured by increases in the EDSS - before the DMD program existed was faster than after July 1998 when the DMD program came into effect. The investigators found a statistically significant reduction in disease progression following introduction of the program. Decreases in progression were statistically significant for people treated with all DMDs available at the time, except for a lower dose of Rebif (22 mcg). Fifty-six individuals who declined treatment with DMDs had the slowest progression prior to being offered treatment and their annual progression rate did not change once treatment was offered and declined. The authors conclude that studies with longer-follow up are necessary to determine whether these findings can be generalized to the MS population. (Multiple Sclerosis 2009;15:1286-94)
  • In a 2009 study of 2,570 people with relapsing-remitting MS, early treatment with interferon therapy was associated with a significant reduction in the risk of MS progression several years later. Maria Trojano, MD (University of Bari, Italy) and colleagues from 14 other Italian centers report their findings in Annals of Neurology (2009;66(4):513-520). The investigators recorded the dates of MS onset and treatment, and tracked disease progression using the EDSS scale, which measures physical disability on a rating scale of 0 to 10. Early treatment was defined as less than or equal to one year from disease onset, and delayed treatment was defined as more than one year from MS onset. After following individuals for a median of 4.5 years, the investigators found that early treatment significantly reduced the risk of progressing one point on the EDSS scale compared to those whose treatment was delayed.
  • Although not a long-term study, a recent study published in the British Medical Journal (2009 Dec 2;339:b4677) by Drs. Mike Boggild and colleagues in the UK and Germany attempted to determine the longer-term cost effectiveness of the use of MS disease modifying therapies in relapsing-remitting MS. They compared outcomes from 5583 individuals who began therapy in the UK from 2002 to 2005, focusing largely on 4749 individuals with relapsing-remitting MS who started treatment at different stages of disease duration, and were assessed for disability based on routine clinical assessments. With no randomized control group, their outcomes were compared to a historical database of patients followed before routine use of DMDs. This study has stimulated controversy for its methods and its findings that progression in disability was worse than that of the historical comparison group. The authors stated in their paper that "It is too early to reach any conclusion about the cost effectiveness of disease modifying treatments from this first interim analysis," and commentary about the study, also published in the journal, points out flaws in the study.
  • Joseph Herbert, MD (New York University) and colleagues in the New York State MS Consortium compared disease severity in people with MS in the DMD era to a cohort from pre-DMD era using Multiple Sclerosis Severity Scores (MSSS). The consortium is a group of 15 MS centers throughout New York State, organized to assess demographic and clinical characteristics of people with MS. The group evaluated 6238 people with MS; 57% were taking DMDs. There was a highly significant shift to lower MSSS in people examined in the DMD era versus those from before the DMD era. (Abstract #P05.07, AAN 2010).
Most Frequently Asked Questions

Q: What about reports I've seen that the disease

modifying drugs are ineffective?

A: More than thirty research papers from

well-controlled clinical trials show that the MS disease-modifying

therapies significantly reduce MS relapses and disease progression

and improve quality of life. This research led to the Society

issuing an Expert Opinion paper on Disease Management recommending

that treatment with an FDA approved disease modifying therapy

should be considered as soon as possible following a definite

diagnosis of MS. There is not at this time, however,

well-controlled long-term research proving that these medications

can delay the progression of disability.

Q: If there is no conclusive proof that the disease

modifying therapies delay progression of disability, should I

begin, or maintain, the use of one of the seven FDA approved

disease modifying therapies?

A: To date, the studies that have looked at

the issue of slowing disability progression have had mixed rather

than uniformly negative results, with some providing evidence for

effectiveness while others not. However, even the studies

that raise questions concerning the issue of whether the disease

modifying drugs delay progression of disability, report mixed

findings and the need for more long-term well-designed

studies. It is important for individuals on any therapy to

have that therapy monitored for long-term effectiveness by their

health care providers. There are a variety of treatment

options available to people with MS and more on the way based on

recent FDA advisories and research reports.

Q: What about a popular study done in Canada last year,

whose lead investigator was PJ Veugelers, comparing how long

it took a group of individuals both on DMDs and not on DMDs to

progress to level 6 on the Expanded Disability Status Scale (EDSS)

disability scale and seemed to show that there was no difference in

time to reach level 6?

A: That's not actually what the study showed. The

study compared time to progression (as measured by time to reach

EDSS 6) before and after the introduction of a province-wide

program that provided the disease modifying drugs to residents of

Nova Scotia. Using a widely accepted statistical technique

known as "proportional hazards regression," the authors showed that

there was a statistically significant difference in time to

progression after the introduction of the program. Following

introduction of the program, time to progression in the MS

population was significantly longer than it had been before the

disease modifying drugs were available. In evaluating the

significance of the study, there has been some confusion over how

"confidence intervals" - which indicate the likelihood that the

true value of a measurement falls within certain limits - affect

the validity of the findings. However, the analysis that resulted

in determining statistically significant differences actually took

these confidence intervals into account and therefore provided

statistically significant evidence supporting the idea that the

disease modifying drugs slow progression.

Adapted from National MS Society Website

National Research and Programs