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Quality of life reporting in multiple sclerosis clinical trials: enough quality? Alessandra Solari Mult Scler 2012 18: 1668 DOI: 10.1177/1352458512447595 The online version of this article can be found at: http://msj.sagepub.com/content/18/12/1668

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MSJ181210.1177/1352458512447595SolariMultiple Sclerosis Journal

MULTIPLE SCLEROSIS MSJ JOURNAL

Editorial

Quality of life reporting in multiple sclerosis clinical trials: enough quality?

Because they evaluate the effects of treatments on physical, psychological and social dimensions of health from the unique perspective of the patient, health-related quality of life (HRQOL) instruments have become major outcome measures in randomized clinical trials (RCTs).1,2 Over the past two decades, HRQOL has become an established outcome measure in clinical research on multiple sclerosis (MS), with the first disease-specific inventories being published from 1995 on.3 HRQOL endpoints are important in trials of MS disease-modifying drugs as they make it possible to better understand the efficacy and tolerability of these medications which must be integrated with the information provided by the other outcome measures. For nonpharmacological and symptomatic treatments, HRQOL and other patient-reported outcomes are clearly of paramount importance. In this issue of the Multiple Sclerosis Journal, Kuspinar et al. publish a systematic review of the effects of non-disease-modifying interventions on HRQOL in people with MS.4 Their quantitative review of 39 RCTs and 6 intervention categories found pooled effect sizes (ESs) that ranged from negligible (7 RCTs, ES 0.16, 95% confidence interval [CI] –0.08 to 0.40) for complementary and alternative medicines, to moderate (3 RCTs, ES 0.69, 95% CI 0.45–0.91) for psychological interventions on mood symptoms, which provided useful indications of the clinical significance of these types of intervention, and importantly suggested sample sizes for future trials. Kuspinar and colleague’s qualitative review presented a ‘risk of bias’ rating based on five items comprising randomization (two items), blinding (two items) and method of analysis. They found that only 49% of trials provided information on allocation concealment, while 69% reported that outcome assessment was blinded. Figures were better for allocation sequence generation (80%), intention-to-treat analysis (85%) and participant and personnel blinding (100% of pharmacologic trials). However, a number of important aspects of the HRQOL instruments themselves were not systematically evaluated by Kuspinar and colleagues in their otherwise excellent study. For example, the criteria used to evaluate, report and interpret HRQOL data were not analysed.5 Although all but two of the trials were published after 2000, only a third employed MS-specific instruments. Half employed generic inventories, and the rest employed a disparate assortment

Multiple Sclerosis Journal 18(12) 1668­–1669 © The Author(s) 2012 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458512447595 msj.sagepub.com

of instruments ranging through global assessment, ad hoc, domain-specific (one study) and utility-focused (EuroQol-5D, one study) inventories. Choosing a validated instrument that addresses the pertinent HRQOL domains, together with an appropriate prospective analysis plan, are crucial for good trial design. For the 13 trials that used HRQOL as primary (n = 8) or co-primary (n = 5) endpoint, it seems essential to assess how many provided a clear rationale for the HRQOL measure they employed, how many reported an a priori study hypothesis, and how many pre-specified statistical endpoints and analyses in order to avoid multiple statistical comparisons, selective reporting of results and data mining (particularly important with multidimensional instruments).5 Citing evidence of an instrument’s clinimetric properties (chiefly reliability and responsiveness), particularly those pertinent to the specific context or study population, is also essential. Furthermore a linguistically validated version of the instrument should be used, and administered correctly.3,5 It is also important that the timing of administration of the HRQOL is appropriate: there must be sufficient time from intervention to outcome assessment (so that HRQOL changes can take place) and adequate follow up (to assess the sustainability of effects). Finally, HRQOL findings should be interpreted in the context of the other trial outcomes.5 It is noteworthy that over 80% of the RCTs included in Kuspinar et al.’s review were on non-pharmacologic treatments, a wide range of which were covered. Particular issues of non-pharmacologic RCTs include documentation of the theory at the base of the intervention, adequate description of content and care provider expertise. Moreover, participant and personnel blinding is often impossible or unethical.6 To conclude, Kuspinar et al.’s study highlights the reality that HRQOL measures are now established in MS trials; however, careful analysis also reveals that choosing the appropriate instrument for a particular trial objective is still an unresolved problem, and that the current standard of reporting is less than ideal. The assessment of HRQOL in MS trials is time-consuming and costly: inadequate conception, management, analysis and reporting devalue HRQOL evidence and compromise its ability to inform clinical decision-making, patient counselling, practice guidelines and health policies. A CONSORT extension of criteria for HRQOL trial reporting is currently being

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Solari developed.7 In the meantime, HRQOL quality reporting criteria originally devised for trials on other medical conditions could usefully be applied to MS.8,9 It would also be useful to apply these criteria to systematic reviews on the effects of MS disease-modifying treatments on HRQOL: such reviews are at present conspicuous by their absence.10 Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement The author declares that there were no conflicts of interest in preparing this article.

References 1. Acquadro C, Berzon R, Dubois D, et al. Incorporating the patient’s perspective into drug development and communication: an Ad Hoc Task Force Report of the Patient-Reported Outcomes (PRO) Harmonization Group Meeting at the Food and Drug Administration, February 16, 2001. Value Health 2003; 6: 522–531. 2. Reflection paper on the regulatory guidance for the use of health related quality of life (HRQL) measures in the evaluation of medicinal products. European Medicines Agency preauthorisation evaluation of medicines for human use. EMEA 2005. Doc. Ref. EMEA/CHMP/EWP/139391/2004 [cited 2012 10 April]; available at:www.ispor.org/workpaper/emeahrql-guidance.pdf. 3. Solari A. Role of health-related quality of life measures in the routine care of people with multiple sclerosis. Health Qual Life Outcomes 2005; 3: 16; DOI: 10.1186/1477-7525-3-16.

4. Kuspinar A, Rodriguez AM and Mayo NE. The effects of clinical interventions on health-related quality of life in multiple sclerosis: a meta-analysis. Mult Scler J 2012; in press. 5. Brundage M, Bass B, Davidson J, et al. Patterns of reporting health-related quality of life outcomes in randomised clinical trials: implications for clinicians and quality of life researchers. Qual Life Res 2011; 20: 653–664. 6. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P; CONSORT Group. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: explanation and elaboration. Ann Intern Med 2008; 148: 295–309. 7. Calvert M, Blazeby J, Revicki D, Moher D and Brundage M. Reporting quality of life in clinical trials: a CONSORT extension. Lancet 2011; 378: 1684–1685. 8. Efficace F, Bottomley A, Osoba D, et al. Beyond the development of health-related quality-of-life (HRQOL) measures: a checklist for evaluating HRQOL outcomes in cancer clinical trials — does HRQOL evaluation in prostate cancer research inform clinical decision making? J Clin Oncol 2003; 21: 3502–3511. 9. Chang S, Davidson PM, Newton PJ, Krum H, Salamonson Y and MacDonald P. What is the methodological and reporting quality of health related quality of life in chronic heart failure clinical trials? Int J Cardiol 2012; DOI: 10.1016/j. icard.2012.01.019. 10. Heesen C, Solari A, Giordano A, Kasper J and Köpke S. Decisions on multiple sclerosis immunotherapy: New treatment complexities urge patient engagement. J Neurol Sci 2011; 306: 192–197.

Corresponding author: Dr Alessandra Solari, Foundation IRCCS Neurological Institute C. Besta, Epidemiology, Unit Via Celoria 11, Milan 20133, Italy. Email: [email protected]

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