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