Improving Performance and Reporting of RA Clinical Trials
Improving Performance and Reporting of RA Clinical Trials
A critical evaluation of many of the 'comparative effectiveness trials' in RA reveals a number of issues regarding study methodology. The important question is whether we are 'splitting hairs' with respect to raising these issues and, thus, questioning some of the conclusions in these peer-reviewed trials. Can a clinician correctly state: 'So what? The picture is still crystal clear. You cannot disqualify these important landmark trials that exactly describe how we should treat our RA patients'.
As experienced trialists, we are among the first to acknowledge how difficult it is to bring an investigator-initiated drug trial to successful conclusion, given the limitations in funding, the technical difficulties of many modern treatment designs (think of benchmark strategies), the dependence on volunteer clinical investigators, and the competition with available reimbursed treatments on the market, that requires a significant commitment for science from patients and investigators. This is also a reason why we have been, and will continue advocating, funding of investigator-initiated clinical trials with some success on national and European Union levels, as has meanwhile also been the case in the USA. We also readily acknowledge that industry-funded studies can have major limitations and may not address questions that are directly related to the usage of therapy in clinical practice.
We appreciate the value of 'comparative effectiveness research' in an effort to make progress in the treatment of RA: These trials address questions that will otherwise not be answered, and are advocated as part of the research agenda of the European League Against Rheumatism (EULAR) management recommendations for RA. We also accept that some variances in study methodology will be inherent in 'comparative effectiveness research' and that it is not reasonable to expect that all will be overcome.
However, we strongly feel that the methodological variations described in this Viewpoint article reduce evidence of 'comparative effectiveness research' to a level that does not allow firm conclusions to be drawn. By itself, this is not a disqualification. Needless to say, these articles have passed a thorough peer-review process, but investigators, authors, journal editors, members of guideline/recommendation committees and clinical rheumatologists must realise the limitations of the interpretations of 'comparative effectiveness research' in order to be able to use their results appropriately.
In our opinion, researchers and authors have major obligations. First, we should optimise methodology wherever possible, but further, we should scrutinise and report all variations and shortcomings of the trials, and describe how this deviates from the original plans, and we should also carefully mitigate the tone of the messages in the title, the abstract and the discussion of our manuscripts and in presentations in order to report only careful and valid conclusions: Not all 'randomised trials' are automatically 'level 1 evidence'.
All of us wish to see the funds of our healthcare systems used most prudently and cost effectively for treating patients. We would prefer to be able to endorse less expensive treatments as being as good as—or more effective than—costly therapies, if the data were clear and methodologically sound. As an example of that, the task force formulating the 2013 update of the EULAR recommendations on the management of RA has virtually abandoned the use of a biologic treatment before a first csDMARD strategy has been tried, which indeed is a recommendation that may save costs.
Our views in this Viewpoint are solely driven by looking into detail at the data presented by the authors of the investigator-initiated trials. Thus, the evidence that we see when we evaluate these trials may be at odds with the interpretations of the authors, as we have shown in numerous examples above.
Finally, we have summarised some points to consider when performing and presenting comparative effectiveness research in Table 1. These points to consider are intended to support providing a clearer picture of the full context and meaning of a clinical trial rather than a focus on one or two key messages of the trial. Many of these items are definitely not new, may not be complete, and call for further expansion by others.
Being convinced of the virtues of 'comparative effectiveness research', we strongly believe that readers of this important avenue of research should be able to see the entire picture in a clear fashion, because 'the tone of the music is in the entire music'.
Discussion and Orientation
A critical evaluation of many of the 'comparative effectiveness trials' in RA reveals a number of issues regarding study methodology. The important question is whether we are 'splitting hairs' with respect to raising these issues and, thus, questioning some of the conclusions in these peer-reviewed trials. Can a clinician correctly state: 'So what? The picture is still crystal clear. You cannot disqualify these important landmark trials that exactly describe how we should treat our RA patients'.
As experienced trialists, we are among the first to acknowledge how difficult it is to bring an investigator-initiated drug trial to successful conclusion, given the limitations in funding, the technical difficulties of many modern treatment designs (think of benchmark strategies), the dependence on volunteer clinical investigators, and the competition with available reimbursed treatments on the market, that requires a significant commitment for science from patients and investigators. This is also a reason why we have been, and will continue advocating, funding of investigator-initiated clinical trials with some success on national and European Union levels, as has meanwhile also been the case in the USA. We also readily acknowledge that industry-funded studies can have major limitations and may not address questions that are directly related to the usage of therapy in clinical practice.
We appreciate the value of 'comparative effectiveness research' in an effort to make progress in the treatment of RA: These trials address questions that will otherwise not be answered, and are advocated as part of the research agenda of the European League Against Rheumatism (EULAR) management recommendations for RA. We also accept that some variances in study methodology will be inherent in 'comparative effectiveness research' and that it is not reasonable to expect that all will be overcome.
However, we strongly feel that the methodological variations described in this Viewpoint article reduce evidence of 'comparative effectiveness research' to a level that does not allow firm conclusions to be drawn. By itself, this is not a disqualification. Needless to say, these articles have passed a thorough peer-review process, but investigators, authors, journal editors, members of guideline/recommendation committees and clinical rheumatologists must realise the limitations of the interpretations of 'comparative effectiveness research' in order to be able to use their results appropriately.
In our opinion, researchers and authors have major obligations. First, we should optimise methodology wherever possible, but further, we should scrutinise and report all variations and shortcomings of the trials, and describe how this deviates from the original plans, and we should also carefully mitigate the tone of the messages in the title, the abstract and the discussion of our manuscripts and in presentations in order to report only careful and valid conclusions: Not all 'randomised trials' are automatically 'level 1 evidence'.
All of us wish to see the funds of our healthcare systems used most prudently and cost effectively for treating patients. We would prefer to be able to endorse less expensive treatments as being as good as—or more effective than—costly therapies, if the data were clear and methodologically sound. As an example of that, the task force formulating the 2013 update of the EULAR recommendations on the management of RA has virtually abandoned the use of a biologic treatment before a first csDMARD strategy has been tried, which indeed is a recommendation that may save costs.
Our views in this Viewpoint are solely driven by looking into detail at the data presented by the authors of the investigator-initiated trials. Thus, the evidence that we see when we evaluate these trials may be at odds with the interpretations of the authors, as we have shown in numerous examples above.
Finally, we have summarised some points to consider when performing and presenting comparative effectiveness research in Table 1. These points to consider are intended to support providing a clearer picture of the full context and meaning of a clinical trial rather than a focus on one or two key messages of the trial. Many of these items are definitely not new, may not be complete, and call for further expansion by others.
Being convinced of the virtues of 'comparative effectiveness research', we strongly believe that readers of this important avenue of research should be able to see the entire picture in a clear fashion, because 'the tone of the music is in the entire music'.
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