Is MRI is ready for prime time? #MSBlog #MSResearch
Epub: Sormani and Bruzzi. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013 Jun 3.
Epub: Sormani and Bruzzi. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013 Jun 3.
BACKGROUND: A meta-analysis of randomised trials in relapsing-remitting multiple sclerosis published in 2009 showed a quantitative relation between the treatment effects detected on MRI lesions and clinical relapses. Sormani and Bruzzi aimed to validate that relation using data from a large and independent set of clinical trials in MS.
METHODS: They searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting MS published from Sept 1, 2008, to Oct 31, 2012. They extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R2 value was estimated to quantify the strength of the correlation. They used an interaction test to test for a difference in slope from the previously estimated equation. They also ran several sensitivity analyses.
FINDINGS: They identified 31 eligible trials, which provided data for 18 901 RRMSers. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R2=0·71), much the same as was previously estimated (p interaction=0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials.
INTERPRETATION: These findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for MS can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults.
METHODS: They searched Medline for clinical trials that assessed disease-modifying drugs for relapsing-remitting MS published from Sept 1, 2008, to Oct 31, 2012. They extracted data for the treatment effects on MRI lesions and on relapses from each trial, and the correlation of log transformed relative measures of these treatment effects was assessed with a weighted linear regression analysis. The R2 value was estimated to quantify the strength of the correlation. They used an interaction test to test for a difference in slope from the previously estimated equation. They also ran several sensitivity analyses.
FINDINGS: They identified 31 eligible trials, which provided data for 18 901 RRMSers. The regression equation derived using data from these studies showed a relation between the concurrent treatment effects on MRI lesions and relapses (slope=0·52; R2=0·71), much the same as was previously estimated (p interaction=0·45). Analysis of trials that tested the same drugs in phase 2 and phase 3 studies showed that the effects on MRI lesions over short follow-up periods (6-9 months) can also predict the effects on relapses over longer follow-up periods (12-24 months), with reported effects on relapses that were within the 95% prediction intervals in eight of nine trials.
INTERPRETATION: These findings indicate that the effect of a treatment on relapses can be accurately predicted by the effect of that therapy on MRI lesions, implying that the use of MRI markers as primary endpoints in future clinical trials of treatments for MS can be considered, in specific situations, such as in trials testing generics or biosimilars of drugs with a well known mechanism of action or in paediatric trials testing drugs already approved for adults.
"Will the regulators, i.e. the EMA and FDA, accept this meta-analysis and allow drugs to be licensed using MRI as a surrogate marker?"
EMA = European Medicine Agency
FDA = Food and Drug Administration
Meta-analysis = combining data from a large number of studies into one trial
Surrogate marker = the use of MRI as a proxy for relapse rate
"I will be surprised if the FDA and EMA are ready to move in this direction with novel or new drugs. They may allow MRI outcomes to be used for biosimilars. Will Industry like the lowering of this bar? No. Why should the accept competition gaining access to the market with a lower burden of proof. It will kill their cash cows. In addition, biosimilars will need to have data on immunogenicity; i..e neutralising antibodies. These latter studies take 2 years to do and need relatively large numbers of MSers to complete. So I can't see things changing in Europe of the US for some time despite the evidence to the contrary."