HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Correspondence to:

ARTICLES: M. Daumer, A. Neuhaus, S. Morrissey, R. Hintzen, and G. C. Ebers MRI as an outcome in multiple sclerosis clinical trials Neurology 2009; 72: 705-711 [Abstract] [Full text] [PDF]

Correspondence: Submit a response to this article

Correspondence published:

MRI as an outcome in multiple sclerosis clinical trials

Richard B. Tenser   (22 June 2009)

Reply from the authors

Prof. George C. Ebers, Martin Daumer   (22 June 2009)

MRI as an outcome in multiple sclerosis clinical trials

Maria Pia Sormani, Massimo Filippi (Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute, Milan, Italy) and Nicola De Stefano (Quantitative Neuroimaging Lab, Dept. of Neurological & Behavioral Sciences, University of Siena, Siena, Italy)   (26 May 2009)

Reply from the author

George Ebers, Martin Daumer,Technical University of Munich, Ludwig Maximilian University and the Sylvia Lawry Centre, Munich, Germany   (26 May 2009)

MRI as an outcome in multiple sclerosis clinical trials 22 June 2009
Richard B. Tenser, Penn State University College of Medicine 30 Hope Dr. Hershey, PA 17033 Send Correspondence to journal: Re: MRI as an outcome in multiple sclerosis clinical trials rtenser{at}psu.edu Richard B. Tenser	Daumer et al. found that brain MRI is not a good surrogate marker of medication efficacy and that gadolinium enhancement is not a predictor of relapses in MS. [1] The authors also noted that other studies found either no or weak correlation between disability and MRI change. While brain MRI is invaluable in helping diagnose MS, this study should lead to consideration of the value of the clinical practice of repeated following of the brain MRI, particularly in stable MS patients. It seems that the MRI should be helpful in following established MS patients, but the data from Daumer et al. [1] and others [2-4] dispute this. While some investigators have been more sanguine about the value of the MRI in following established MS patients, they have also noted that there is a paradox of modest correlation between the MRI and relapses at the individual level and better correlation at the trial level. [5] This would seem to support the conclusion that in the clinical practice of caring for the individual patient, following the MRI is of limited value. Evidence-based medicine is the basis for considering MS treatment, and now that medical costs are an important issue, evidence-based medicine should also be the basis for laboratory testing. While cost is not everything, it is suggested that physicians should be more critical in evaluating the use of resources. It is possible that new MRI techniques will correlate with MS clinical course or medication efficacy and therefore be important in following established patients. However, the current data does not support the practice of performing repeated conventional brain MRI studies in the stable MS patient. References 1. Daumer M, Neuhaus A, Morrissey S, Hintzen GC. MRI as an outcome in multiple sclerosis clinical trials. Neurology 2009;72:705-711. 2. Filippi M, Grossman RI. MRI techniques to monitor MS evolution. Neurology 2002;58:1147-1153. 3. Pettkau J, Reingold S, Held U, et al. Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses. Mult Scler. 2008;14:770-778. 4. Held U, Heigenhauser L, Shang C, Kappos L, Polman C. Predictors of relapse rate in MS clinical trials. Neurology 2005;65:1769-1773. 5. Arnold DL, Goodin DS. Magnetic resonance imaging as a surrogate for treatment effect on multiple sclerosis relapses. Ann Neurol 2009;65:237-238. Disclosures: Dr. Tenser has received honoraria from Biogen idec, Bayer, Merck, Pfizer and Teva pharmaceutical companies.
Reply from the authors 22 June 2009
Prof. George C. Ebers, University of Oxford John Radcliffe Hospital Oxford OX39DU, United Kingdom, Martin Daumer Send Correspondence to journal: Re: Reply from the authors george.ebers{at}clneuro.ox.ac.uk Prof. George C. Ebers, et al.	We agree with Dr. Tenser’s comments about stable MS patients and we cannot support with evidence the clinical decisions about therapy made on the basis of unvalidated surrogates. This is highlighted when therapies carry significant risk. Dialogue with patients should reflect what is known and not what is hoped for, unless this is explicitly stated. The strong attraction of MRI both visually and conceptually has to be complemented by the hard work of showing that change in an MRI measure independently correlates with the key outcome of unremitting disability. If it is not independent and not related to the key outcome, the cost and time spent by patients for MRI cannot be justified. Furthermore, demonstrating correlation is not enough and it is required that treatment-related suppression of that MRI change translates into suppression of this key outcome. We have previously assessed the clinical trial utilization of disability measures and have similar reservations. The key outcomes are surely the prevention of or delay in onset of progressive disease and the slowing of its progress when it occurs. Progressive disability, often in the absence of relapses, dwarfs any other outcome in importance and this should be the target of surrogate validation and treatment alike. This formidable and as yet undefeated foe is what patients and physicians most dread. Disclosures: Prof Ebers received funding from Roche for participation in a meeting and from UCB Pharma for consulting, has received grant support from Bayer Schering Pharma for a natural history study and prepared 4 medico-legal reports. Dr. Daumer, Scientific Director of the Sylvia Lawry Centre for Multiple Sclerosis Research e.V. and Managing Director of Trium Analysis Online GmbH serves on the Editorial Board of MedNous,holds patents Patent 10 2007 044 705.3-35., German patent and trade mark office 307 19 449.3/09. The Sylvia Lawry Centre received honoraria for interviews of Dr. Daumer with Propagate Pharma Limited, Deerfield Research LLC, is Medical Advisor of the German Multiple Sclerosis Society, serves as consultant for the following commercial entities Hoffmann-La Roche, Biopartners, Novartis, EISAI Limited, Böhringer-Ingelheim; received research grants from the following gonvernmental entities Federal Ministry of Education and Research, Mayo Clinic Rochester, European Union (for SLC and Trium) Grant No 215820, European Union (for SLC) Grant No 223865, Federal Ministry of Economics and Technology. Grant No KF0564001KF7, University of Oxford, Technical University of Munich, Hertie Foundation and others Grant No 1.01.1/07/015, Bavarian Research Foundation, National Multiple Sclerosis Society (NMSS), Porticus Foundation Grant No 900.50578, European Union Grant No LSHM-CT-2006-03759, University of Rochester, Medical Center, European Union Grant No LSHM-CT-2004-503485.
MRI as an outcome in multiple sclerosis clinical trials 26 May 2009
Maria Pia Sormani, Biostatistics Unit, Department of Health Sciences University of Genoa, Genoa, Italy, Massimo Filippi (Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute, Milan, Italy) and Nicola De Stefano (Quantitative Neuroimaging Lab, Dept. of Neurological & Behavioral Sciences, University of Siena, Siena, Italy) Send Correspondence to journal: Re: MRI as an outcome in multiple sclerosis clinical trials m.filippi{at}hsr.it Maria Pia Sormani, et al.	We read with interest the retrospective study of Daumer et al. who analyzed the placebo arms of several randomized clinical trials (RCTs) to establish the relationship of T2-weighted and gadolinium-enhanced T1- weighted MRI lesions with clinical endpoints. [1] The results showed no correlation between clinical and MRI markers and were interpreted as an indication that MRI adds little, if anything, to clinical measures. If confirmed, this should lead us to reconsider the use of MRI measures as surrogates of clinical endpoints in MS clinical trials. However, we believe that the study has important methodological flaws, which limit the validity of the results and the consequent conclusions. The concept of clinical surrogacy should always be related to a treatment effect. Indeed, the Prentice criteria have been developed to validate surrogate markers in the context of individual RCTs or meta-analysis of several complete RCTs. The clinical/MRI correlation performed by Daumer et al. using only placebo arms of different trials does not meet an established validation procedure and might be misleading. In contrast, a previous analysis of complete data sets of RCTs revealed that a clinical/MRI correlation does exist providing preliminary evidence of the validity of MRI surrogates. [2-3] Another recent study confirmed this by demonstrating that the reduction in MRI lesions across different treatment trials correlated with the effect of reducing relapses. [4] Using the same database, it was shown that the main source of variability of MRI lesion counts in placebo arms of different RCTs is the MRI center where data were analyzed. [5] Therefore, reporting the correlation of MRI lesions and clinical endpoints using individual data from different trials necessarily dilutes the correlation. In a highly variable disease such as MS, the low individual level of correlation between MRI markers and clinical variables is likely due to the high variability of both measures rather than to the lack of a biologically meaningful relationship. The well documented capability of the brain to reorganize after tissue injury makes this relationship even more difficult to prove with the authors’ simplified approach. In addition, the known limitations of any retrospective analysis based on data from old and heterogeneously evaluated trials should prompt a more cautious interpretation of the results. References 1. Daumer M, Neuhaus A, Morrissey S, Hintzen R, Ebers GC. MRI as an outcome in multiple sclerosis clinical trials. Neurology 2008 (e-pub ahead of print). 2. Sormani MP, Bruzzi P, Comi G, Filippi M. MRI metrics as surrogate markers for clinical relapse rate in relapsing-remitting MS patients. Neurology 2002;58:417-421. 3. Sormani MP, Bruzzi P, Beckmann K, et al. MRI metrics as surrogate endpoints for EDSS progression in SPMS patients treated with IFN beta-1b. Neurology 2003;60:1462-1466. 4. Sormani MP, Bonzano L, Roccatagliata L, Cutter GR, Mancardi GL, Bruzzi P. Magnetic resonance imaging as a potential surrogate for relapses in multiple sclerosis: a meta-analytic approach. Ann Neurol 2009;65:268-275. 5. Schach S, Scholz M, Wolinsky JS, Kappos L. Pooled historical MRI data as a basis for research in multiple sclerosis. A statistical evaluation. Mult Scler 2007;13:509-516. *The MAGNIMS Steering Commettee Chairs: F Barkhof (Amsterdam, The Netherlands) and X Montalban (Barcelona, Spain) Members: F Fazekas (Graz, Austria), J Frederiksen (Copenhagen, Denmark), L Kappos (Basel, Switzerland), DH Miller (London, United Kingdom), J Palace (Oxford, United Kingdom), CH Polman (Amsterdam, The Netherlands), MA Rocca (Milan, Italy), M Rovaris (Milan, Italy), A Rovira (Barcelona, Spain), T Yousry (London, United Kingdom) Disclosures: Dr. M. Filippi has received honoraria for lectures and travel expenses, and consulting fees as an investigator in previous and current treatment trials from Teva, Merck-Serono, Bayer-Schering, Biogen-Dompè, and Genmab. Dr. Filippi reports 100% effort of his clinical practice on MRI procedures and has received fees from Teva, Merck-Serono, Bayer-Schering, Biogen-Dompè, and Genmab for consultation regarding performing MRIs. Dr M. Pia Sormani received honoraria for lectures and travel expenses, and consulting fees as Teva, Merck-Serono, Biogen-Idec, Actelion. Dr. N. De Stefano has received honoraria for lectures and travel expenses, and consulting fees as an investigator in previous and current treatment trials from Teva, Merck-Serono, Bayer-Schering and Biogen-Dompè.
Reply from the author 26 May 2009
George Ebers, University of Oxford Oxford, United Kingdom, Martin Daumer,Technical University of Munich, Ludwig Maximilian University and the Sylvia Lawry Centre, Munich, Germany Send Correspondence to journal: Re: Reply from the author George.Ebers{at}clneuro.ox.ac.uk George Ebers, et al.	Sormani et al.’s letter invites clarification of MRI monitoring of MS treatment effects. We addressed the value of change in MRI measures in predicting subsequent disability, given that many important therapeutic decisions in clinical practice are influenced by trial MRI activity. Claims that “MRI is the disease” and that “clinical features are poor surrogates for MRI” provide context for the lack of validation. Scopus lists more than 4,000 MS papers with MRI in the title. Simple correlations dominate this literature. Among them it is difficult to find papers quantitating the independent contribution of MRI change to clinical outcomes. It is inevitable that MRI spots or atrophy correlate with disability. No MRI measure achieves the criterion to start the process of validation [1,6]—an independent correlation with the key clinically relevant measure—unremitting disability. Sormani et al. dismiss the results as “retrospective” yet they are no more retrospective than the analysis of MRI data at the end of major pivotal trials. Data collected prospectively, much by MAGNIMS members, were blended with disability scores to determine the independent contribution from MRI to disability. The MAGNIMS signatories can answer why they had not done these analyses themselves. Sormani et al. also state that our results need confirmation bestowing null hypothesis status on their unproven belief. This upends time-honored approaches to proving hypotheses (validating MRI), a strategy used by others whose conclusions were challenged. Paraphrasing from Foster and Huber’s illustrative example – ‘you have to prove homeopathy does not work’ rather than ‘we have to prove that it does’. [7] The MRI field’s evident discomfort with the results highlights the delay in validation. Papers debating the ethics of placebo trials recall the rhetorical device of enjoining a debate on the number of angels on the head of a pin thereby forcing concession that angels exist. What about the ethics of enrolling patients in trials with unvalidated outcomes? We had placebo arms only but the key clinical determinant of treatment efficacy in these trials was placebo arm worsening—in no trial did treatment make MS better. Clinical or MRI efficacy claims hinge on placebo worsening for clinical or MRI measures. This is what we studied. [1] We are nonplussed that Sormani et al. mention Schach et al. [5] Center to center variation in MRI surpassed the treatment effects in the trials examined. We fail to see how this helps their argument. It was not a given that widely used MRI measures would be validated, the visually compelling nature of imaging notwithstanding. Axonal loss in MS spinal cords is tract and fiber size-specific. Small fibers disappear, leaving large ones intact microns away. [8] A large initial safety factor can be assumed and symptoms may not begin until the majority of axons are lost. If subsequent loss of relatively small numbers accounts for most unremitting disability, detection could be beyond MRI resolution. We would be pleased to see MRI fulfill initial promises but more work is needed. References 6. Prentice RL. Surrogate endpoints in clinical trials: Definition and operational criteria. Statistics in Medicine 2006;8:431–440. 7. P Huber, KR Foster. Judging Science: Scientific Knowledge and the Federal Courts.Cambridge,MA: MIT Press; 1997. Pages 37-68. 8. DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: A pathological survey of the corticospinal and sensory tracts. Brain 2004;127:1009-1018. Disclosures: Prof Ebers received funding from Roche for participation in a meeting and from UCB Pharma for consulting, has received grant support from Bayer Schering Pharma for a natural history study and prepared 4 medico-legal reports. Dr. Daumer, Scientific Director of the Sylvia Lawry Centre for Multiple Sclerosis Research e.V. and Managing Director of Trium Analysis Online GmbH serves on the Editorial Board of MedNous,holds patents Patent 10 2007 044 705.3-35., German patent and trade mark office 307 19 449.3/09. The Sylvia Lawry Centre received honoraria for interviews of Dr. Daumer with Propagate Pharma Limited, Deerfield Research LLC, is Medical Advisor of the German Multiple Sclerosis Society, serves as consultant for the following commercial entities Hoffmann-La Roche, Biopartners, Novartis, EISAI Limited, Böhringer-Ingelheim; received research grants from the following gonvernmental entities Federal Ministry of Education and Research, Mayo Clinic Rochester, European Union (for SLC and Trium) Grant No 215820, European Union (for SLC) Grant No 223865, Federal Ministry of Economics and Technology. Grant No KF0564001KF7, University of Oxford, Technical University of Munich, Hertie Foundation and others Grant No 1.01.1/07/015, Bavarian Research Foundation, National Multiple Sclerosis Society (NMSS), Porticus Foundation Grant No 900.50578, European Union Grant No LSHM-CT-2006-03759, University of Rochester, Medical Center, European Union Grant No LSHM-CT-2004-503485.