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Core Outcomes for Clinical Trials: Moving Ahead
EDITORIAL
Core Outcomes for Clinical Trials: Moving Ahead Timothy Rowe, MB BS, FRCSC Editor-in-Chief
O
ne of the nice things about being Editor-in-Chief of JOGC is getting to meet and talk with fascinating and stimulating people. For the most part, these people are our authors and reviewers, and although I may not actually meet or interact with each one regularly, our exchanges are invariably thought-provoking. We share the worthy goal of wanting to add to the sum of medical knowledge, and authors, reviewers, editors, and publishers try to do this efficiently and collegially. But adding to what we know is not always straightforward. At the recent World Congress of the Royal College of Obstetricians and Gynaecologists in Liverpool, I met Professor Khalid Khan, the Editor-in-Chief of the British Journal of Obstetrics and Gynaecology. We had an amicable discussion about the present and future concerns of publishing in our specialty (he’s a big fan of Twitter, by the way), but one subject of discussion resonated and continues to do so. It was the subject of clinical outcomes for studies submitted to journals of obstetrics, gynaecology, and reproductive medicine, and how the heterogeneity of the outcomes of RCTs makes comparison between and combination of results across studies difficult–and sometimes impossible. It was perhaps telling that we met initially in Liverpool, because much of the groundwork related to defining core outcomes in clinical trials across the medical spectrum has originated in Liverpool.1-4 The idea of having a “core outcomes set” for achieving clinical progress was the foundation for the COMET (Core Outcome Measures in Effectiveness Trials) Initiative,5 which began in 2010 in Liverpool and has spread since then, hosted by the BMJ group. The COMET Initiative is intended to develop agreed standardized sets of outcomes, comprising the minimum that should be measured in clinical trials, practice audits, and other forms of research for a specific condition. These core outcomes sets would not necessarily be the only outcomes measured in these studies, but would be a required minimum so that individual studies could be
compared meaningfully or the findings of different studies could be easily aggregated. Individual investigators would be able to add whatever other outcomes they wished to measure to the core outcomes set. The COMET Initiative has been gathering momentum, but it has a very broad mandate (currently there are 267 references to planned, current, or completed projects in the COMET database) and arguably has no means of requiring or enforcing the use of core outcomes sets by investigators. Enter the journals of obstetrics and gynaecology cavalry. Spearheaded by Professor Khan, a large and growing number of editors of journals in the fields of obstetrics, gynaecology, women’s health, and reproductive health (including JOGC) have agreed to work towards defining a core outcomes set for studies in these fields. Manuscripts derived from these studies and submitted to the participating journals will ultimately be required to have covered and reported on the core outcomes for the field of study. Once the core outcomes sets for each area (examples being preterm birth, preeclampsia, intrauterine growth restriction) have been identified and agreed to, it will obviously take time for these to become embedded in study designs. Thus, short-term change is not likely, but in the longer term the availability of study reports that always contain the core outcomes, together with mandatory registration of trials (theoretically negating publication bias), will give the potential for much more rapid and meaningful comparisons of studies or aggregation of results. Potentially, this activity goes beyond facilitating the comparison of effectiveness studies or pooling of results. Having core outcomes sets will facilitate practice audits, so that identifying abnormal patterns of practice would then be less arbitrary and more objective. Our worry, of course, is that as journal editors we see this as desirable and logical, but that authors and investigators may dispute the selection and definition of specific core J Obstet Gynaecol Can 2013;35(10):877–878
OCTOBER JOGC OCTOBRE 2013 l 877
Editorial
outcomes. How the core outcomes sets are selected might be seen as imperious. So it will be important—critical, in fact—to inform and underpin the choice of outcomes with the best possible research and to publish this alongside the core outcomes lists. The COMET Initiative leaders emphasize the importance of having a consumer perspective in developing core outcomes sets, pointing out that patients have more than once identified an outcome of a clinical trial that was important to them but that might not have been considered if the outcome set was developed by investigators alone.5 Having the perspective of patients for identifying core outcomes in specific areas of obstetrics and gynaecology is clearly critical too.6 There are still some kinks to iron out, of course. We have to have clear definitions of target conditions, and, importantly, we need a snappy acronym for the initiative. Nevertheless, the initiative has the potential to catalyze our harnessing of “big data”; focusing on outcomes seems to be a natural extension of the CONSORT statement.7 Stay tuned, because this promises to be an exciting development. On a related note, this issue of the Journal contains the first of a four-part series from Motherisk, on fetal pharmacotherapy.8 This first article, by Shirin NamouzHaddad and Gideon Koren, is a review of the use of prenatal glucocorticoids; I’m sure you’re aware that the 1990 meta-analysis of the use of these agents for the
prevention of respiratory distress syndrome is the source of the logo for the Cochrane Collaboration.9 Outcomes, again; what goes around, comes around. REFERENCES 1. Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E, et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 2008;3(8):e3081. 2. Sinha I, Jones L, Smyth RL, Williamson PR. A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children. PLoS Med 2008:5(4):e96. 3. Williamson PR, Altman DG, Blazeby JM, Clarke M, Devane D, Gargon E, et al. Developing core outcome sets for clinical trials: issues to consider. Trials 2012;13:132. 4. Williamson P, Clarke M. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative: its role in improving Cochrane reviews. Cochrane Database Syst Rev 2012;5:ED000041. 5. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative. Available at http://www.comet-initiative.org. Accessed August 12, 2013. 6. Parker-Autry CY, Barber MD, Kenton K, Richter HE. Measuring outcomes in urogynecological surgery: “perspective is everything”. Int Urogynecol J 2013;24:15–25. 7. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276:637–9. 8. Namouz-Haddad S, Koren G. Fetal pharmacotherapy 1: prenatal glucocorticoids. J Obstet Gynaecol Can 2013;35(10):920–2. 9. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11–25.
ERRATUM
Riggin L, Frankel Z, Moretti M, Pupco A, Koren G. The fetal safety of fluoxetine: a systematic review and meta-analysis. J Obstet Gynaecol Can 2013;35(4):362–9. The authors have noted an error in Figure 4, which shows odds ratios for cardiac malformations associated with fluoxetine in case–control studies. The denominator in the Alwan study was 9622, representing all malformations, rather than 4268, which represents cardiac-only malformations. The odds ratio of 0.48 for the Alwan study, overall OR of 0.63, and P value of 0.07 were therefore erroneous. The new calculation reveals an odds ratio of 1.09 for this study, and the overall odds ratio is 0.91 with a P value of 0.59 for the case–control cardiac malformations meta-analysis. This does not change the overall direction of the results. The Journal of Obstetrics and Gynaecology Canada regrets this error and any inconvenience or distress it may have caused.
878 l OCTOBER JOGC OCTOBRE 2013
Core Outcomes for Clinical Trials: Moving Ahead Timothy Rowe, MB BS, FRCSC Editor-in-Chief
O
ne of the nice things about being Editor-in-Chief of JOGC is getting to meet and talk with fascinating and stimulating people. For the most part, these people are our authors and reviewers, and although I may not actually meet or interact with each one regularly, our exchanges are invariably thought-provoking. We share the worthy goal of wanting to add to the sum of medical knowledge, and authors, reviewers, editors, and publishers try to do this efficiently and collegially. But adding to what we know is not always straightforward. At the recent World Congress of the Royal College of Obstetricians and Gynaecologists in Liverpool, I met Professor Khalid Khan, the Editor-in-Chief of the British Journal of Obstetrics and Gynaecology. We had an amicable discussion about the present and future concerns of publishing in our specialty (he’s a big fan of Twitter, by the way), but one subject of discussion resonated and continues to do so. It was the subject of clinical outcomes for studies submitted to journals of obstetrics, gynaecology, and reproductive medicine, and how the heterogeneity of the outcomes of RCTs makes comparison between and combination of results across studies difficult–and sometimes impossible. It was perhaps telling that we met initially in Liverpool, because much of the groundwork related to defining core outcomes in clinical trials across the medical spectrum has originated in Liverpool.1-4 The idea of having a “core outcomes set” for achieving clinical progress was the foundation for the COMET (Core Outcome Measures in Effectiveness Trials) Initiative,5 which began in 2010 in Liverpool and has spread since then, hosted by the BMJ group. The COMET Initiative is intended to develop agreed standardized sets of outcomes, comprising the minimum that should be measured in clinical trials, practice audits, and other forms of research for a specific condition. These core outcomes sets would not necessarily be the only outcomes measured in these studies, but would be a required minimum so that individual studies could be
compared meaningfully or the findings of different studies could be easily aggregated. Individual investigators would be able to add whatever other outcomes they wished to measure to the core outcomes set. The COMET Initiative has been gathering momentum, but it has a very broad mandate (currently there are 267 references to planned, current, or completed projects in the COMET database) and arguably has no means of requiring or enforcing the use of core outcomes sets by investigators. Enter the journals of obstetrics and gynaecology cavalry. Spearheaded by Professor Khan, a large and growing number of editors of journals in the fields of obstetrics, gynaecology, women’s health, and reproductive health (including JOGC) have agreed to work towards defining a core outcomes set for studies in these fields. Manuscripts derived from these studies and submitted to the participating journals will ultimately be required to have covered and reported on the core outcomes for the field of study. Once the core outcomes sets for each area (examples being preterm birth, preeclampsia, intrauterine growth restriction) have been identified and agreed to, it will obviously take time for these to become embedded in study designs. Thus, short-term change is not likely, but in the longer term the availability of study reports that always contain the core outcomes, together with mandatory registration of trials (theoretically negating publication bias), will give the potential for much more rapid and meaningful comparisons of studies or aggregation of results. Potentially, this activity goes beyond facilitating the comparison of effectiveness studies or pooling of results. Having core outcomes sets will facilitate practice audits, so that identifying abnormal patterns of practice would then be less arbitrary and more objective. Our worry, of course, is that as journal editors we see this as desirable and logical, but that authors and investigators may dispute the selection and definition of specific core J Obstet Gynaecol Can 2013;35(10):877–878
OCTOBER JOGC OCTOBRE 2013 l 877
Editorial
outcomes. How the core outcomes sets are selected might be seen as imperious. So it will be important—critical, in fact—to inform and underpin the choice of outcomes with the best possible research and to publish this alongside the core outcomes lists. The COMET Initiative leaders emphasize the importance of having a consumer perspective in developing core outcomes sets, pointing out that patients have more than once identified an outcome of a clinical trial that was important to them but that might not have been considered if the outcome set was developed by investigators alone.5 Having the perspective of patients for identifying core outcomes in specific areas of obstetrics and gynaecology is clearly critical too.6 There are still some kinks to iron out, of course. We have to have clear definitions of target conditions, and, importantly, we need a snappy acronym for the initiative. Nevertheless, the initiative has the potential to catalyze our harnessing of “big data”; focusing on outcomes seems to be a natural extension of the CONSORT statement.7 Stay tuned, because this promises to be an exciting development. On a related note, this issue of the Journal contains the first of a four-part series from Motherisk, on fetal pharmacotherapy.8 This first article, by Shirin NamouzHaddad and Gideon Koren, is a review of the use of prenatal glucocorticoids; I’m sure you’re aware that the 1990 meta-analysis of the use of these agents for the
prevention of respiratory distress syndrome is the source of the logo for the Cochrane Collaboration.9 Outcomes, again; what goes around, comes around. REFERENCES 1. Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E, et al. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PLoS One 2008;3(8):e3081. 2. Sinha I, Jones L, Smyth RL, Williamson PR. A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children. PLoS Med 2008:5(4):e96. 3. Williamson PR, Altman DG, Blazeby JM, Clarke M, Devane D, Gargon E, et al. Developing core outcome sets for clinical trials: issues to consider. Trials 2012;13:132. 4. Williamson P, Clarke M. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative: its role in improving Cochrane reviews. Cochrane Database Syst Rev 2012;5:ED000041. 5. The COMET (Core Outcome Measures in Effectiveness Trials) Initiative. Available at http://www.comet-initiative.org. Accessed August 12, 2013. 6. Parker-Autry CY, Barber MD, Kenton K, Richter HE. Measuring outcomes in urogynecological surgery: “perspective is everything”. Int Urogynecol J 2013;24:15–25. 7. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276:637–9. 8. Namouz-Haddad S, Koren G. Fetal pharmacotherapy 1: prenatal glucocorticoids. J Obstet Gynaecol Can 2013;35(10):920–2. 9. Crowley P, Chalmers I, Keirse MJ. The effects of corticosteroid administration before preterm delivery: an overview of the evidence from controlled trials. Br J Obstet Gynaecol 1990;97:11–25.
ERRATUM
Riggin L, Frankel Z, Moretti M, Pupco A, Koren G. The fetal safety of fluoxetine: a systematic review and meta-analysis. J Obstet Gynaecol Can 2013;35(4):362–9. The authors have noted an error in Figure 4, which shows odds ratios for cardiac malformations associated with fluoxetine in case–control studies. The denominator in the Alwan study was 9622, representing all malformations, rather than 4268, which represents cardiac-only malformations. The odds ratio of 0.48 for the Alwan study, overall OR of 0.63, and P value of 0.07 were therefore erroneous. The new calculation reveals an odds ratio of 1.09 for this study, and the overall odds ratio is 0.91 with a P value of 0.59 for the case–control cardiac malformations meta-analysis. This does not change the overall direction of the results. The Journal of Obstetrics and Gynaecology Canada regrets this error and any inconvenience or distress it may have caused.
878 l OCTOBER JOGC OCTOBRE 2013