Downloaded from ard.bmj.com on September 26, 2014 - Published by group.bmj.com
Correspondence
When is it not ethical to withhold treatment for rheumatoid arthritis? I read with interest the study by Takeuchi et al1 looking at the role of monotherapy golimumab in Japanese rheumatoid arthritis (RA) patients, who had active disease despite diseasemodifying anti-rheumatic drug (DMARD) therapy. Inclusion criteria for the study stipulated that patients have two out of three criteria which were elevated inflammatory markers, erosions on radiograph or positive serology, in addition to more than six swollen and tender joints despite DMARD therapy for at least 3 months. They had mean disease duration of close to 9 years and mean swollen and tender joint counts of roughly 16 and 13. They were then randomised to placebo, golimumab 50 or golimumab 100 mg injections. Primary efficacy outcome was at 14 weeks, as the authors state “due to ethical concerns about the potential for an inadequate response to placebo”. At 14 weeks, both golimumab doses showed better efficacy than placebo. In the Introduction section, the justification for looking into monotherapy was explained as “some patients cannot tolerate MTX treatment; therefore, it is clinically relevant to evaluate the safety and efficacy of monotherapy…”. In the discussion, authors state that 100 mg golimumab was studied as monotherapy in a previous publication2 but in that study primary endpoint was not reached by this monotherapy arm. Various reasons are presented to possibly explain this difference. However, in the current study this time the 50 mg monotherapy did not show any significant difference in radiographic inhibition from placebo and neither did the 100 mg until post hoc adjustments were made and the data were reanalysed. There are several serious methodological and ethical issues with this study that are not addressed in the paper. First, the trial was registered at the clinicaltrials.gov site in October 2008. It is unclear to me how the ethical justification of withholding active treatment for up to 4 months, including the 4 weeks of washout before the study medication was administered, from patients with RA who were failing their current therapy and were at risk for destructive disease as reflected by the inclusion criteria (high joint counts, serological or radiographic evidence for higher risk for erosions) was made. In 2008, there is no more equipoise about how patients fare when they are not given DMARDs, biologics or combinations of these agents. Authors state, as mentioned previously, that “due to ethical concerns about the potential for an inadequate response to placebo” they were analysed at 14 weeks and switched to active drug at 16 weeks. What is meant by “potential for an inadequate response to placebo”? Is it only a potential or a near certainty? How is it that authors truly believe this is not a resolved issue in this day and age of RA treatment, that active RA patients need treatment not placebo and how is that any institutional review board would think this to be ethical? It would be of interest to see what the informed consent document actually read and how the information that despite available active medications that the patients could have been switched to including other biologic agents, instead of enrolling in this trial, treatment was withheld
Ann Rheum Dis May 2014 Vol 73 No 5
for over 4 months (including the 4 weeks of washout before the study medication was administered), when overwhelming published data suggest early and aggressive treatment is the best way to get RA under control. The second issue is that even though the similar intervention was tried in an earlier study,2 the need to try again was felt. This time there were some differences that suggest golimumab 100 mg has radiographic (no such benefit was seen with 50 mg, the approved dose in the USA) and clinical benefits but who is to say the reasons listed by the authors that affected the first trial results in one way, did not affect the results of the second trial in the other direction? Which one is the ‘true’ study? This is now the second study where radiographic benefit was not demonstrated with golimumab until post hoc analysis of the data was done. Several explanations for this state of affairs come to mind: (1) either radiographic progression is not a clinically important outcome, as was argued previously,3 since the actual differences are so small to have clinical relevance; (2) golimumab does not work as well as some other biologics, which have shown effects on radiographic progression as a primary outcome with no need for post hoc analysis or (3) the authors would like to think and are trying to prove golimumab is no different than any other biologic, despite what the data show. None of these are good reasons for withholding treatment from active RA patients for close to 4 months in the guise of scientific experimentation. Yusuf Yazici Correspondence to Dr Yusuf Yazici, NYU Hospital for Joint Diseases, 333 East 38th Street, New York, NY 10016 USA; [email protected] Competing interests YY: consultant for Abbvie, Bristol-Myers Squibb, Celgene, Genentech, Pfizer, Samumed, UCB. Provenance and peer review Not commissioned; internally peer reviewed. To cite Yazici Y. Ann Rheum Dis 2014;73:e25. Received 8 December 2013 Accepted 9 December 2013 Published Online First 24 December 2013
▸ http://dx.doi.org/10.1136/annrheumdis-2013-205042 Ann Rheum Dis 2014;73:e25. doi:10.1136/annrheumdis-2013-205033
REFERENCES 1
2
3
Takeuchi T, Harigai M, Tanaka Y, et al. Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicenter, randomized, double-blind, placebo-controlled GO-MONO study through 24 weeks. Ann Rheum Dis 2013;72:1488–95. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789–96. Yazici Y, Yazici H. Tumor necrosis factor alpha inhibitors, methotrexate or both? An inquiry into the formal evidence for when they are to be used in rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:449–52.
e25
Downloaded from ard.bmj.com on September 26, 2014 - Published by group.bmj.com
When is it not ethical to withhold treatment for rheumatoid arthritis? Yusuf Yazici Ann Rheum Dis 2014 73: e25 originally published online December 24, 2013
doi: 10.1136/annrheumdis-2013-205033
Updated information and services can be found at: http://ard.bmj.com/content/73/5/e25.full.html
These include:
References
This article cites 3 articles, 2 of which can be accessed free at: http://ard.bmj.com/content/73/5/e25.full.html#ref-list-1
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Correspondence
When is it not ethical to withhold treatment for rheumatoid arthritis? I read with interest the study by Takeuchi et al1 looking at the role of monotherapy golimumab in Japanese rheumatoid arthritis (RA) patients, who had active disease despite diseasemodifying anti-rheumatic drug (DMARD) therapy. Inclusion criteria for the study stipulated that patients have two out of three criteria which were elevated inflammatory markers, erosions on radiograph or positive serology, in addition to more than six swollen and tender joints despite DMARD therapy for at least 3 months. They had mean disease duration of close to 9 years and mean swollen and tender joint counts of roughly 16 and 13. They were then randomised to placebo, golimumab 50 or golimumab 100 mg injections. Primary efficacy outcome was at 14 weeks, as the authors state “due to ethical concerns about the potential for an inadequate response to placebo”. At 14 weeks, both golimumab doses showed better efficacy than placebo. In the Introduction section, the justification for looking into monotherapy was explained as “some patients cannot tolerate MTX treatment; therefore, it is clinically relevant to evaluate the safety and efficacy of monotherapy…”. In the discussion, authors state that 100 mg golimumab was studied as monotherapy in a previous publication2 but in that study primary endpoint was not reached by this monotherapy arm. Various reasons are presented to possibly explain this difference. However, in the current study this time the 50 mg monotherapy did not show any significant difference in radiographic inhibition from placebo and neither did the 100 mg until post hoc adjustments were made and the data were reanalysed. There are several serious methodological and ethical issues with this study that are not addressed in the paper. First, the trial was registered at the clinicaltrials.gov site in October 2008. It is unclear to me how the ethical justification of withholding active treatment for up to 4 months, including the 4 weeks of washout before the study medication was administered, from patients with RA who were failing their current therapy and were at risk for destructive disease as reflected by the inclusion criteria (high joint counts, serological or radiographic evidence for higher risk for erosions) was made. In 2008, there is no more equipoise about how patients fare when they are not given DMARDs, biologics or combinations of these agents. Authors state, as mentioned previously, that “due to ethical concerns about the potential for an inadequate response to placebo” they were analysed at 14 weeks and switched to active drug at 16 weeks. What is meant by “potential for an inadequate response to placebo”? Is it only a potential or a near certainty? How is it that authors truly believe this is not a resolved issue in this day and age of RA treatment, that active RA patients need treatment not placebo and how is that any institutional review board would think this to be ethical? It would be of interest to see what the informed consent document actually read and how the information that despite available active medications that the patients could have been switched to including other biologic agents, instead of enrolling in this trial, treatment was withheld
Ann Rheum Dis May 2014 Vol 73 No 5
for over 4 months (including the 4 weeks of washout before the study medication was administered), when overwhelming published data suggest early and aggressive treatment is the best way to get RA under control. The second issue is that even though the similar intervention was tried in an earlier study,2 the need to try again was felt. This time there were some differences that suggest golimumab 100 mg has radiographic (no such benefit was seen with 50 mg, the approved dose in the USA) and clinical benefits but who is to say the reasons listed by the authors that affected the first trial results in one way, did not affect the results of the second trial in the other direction? Which one is the ‘true’ study? This is now the second study where radiographic benefit was not demonstrated with golimumab until post hoc analysis of the data was done. Several explanations for this state of affairs come to mind: (1) either radiographic progression is not a clinically important outcome, as was argued previously,3 since the actual differences are so small to have clinical relevance; (2) golimumab does not work as well as some other biologics, which have shown effects on radiographic progression as a primary outcome with no need for post hoc analysis or (3) the authors would like to think and are trying to prove golimumab is no different than any other biologic, despite what the data show. None of these are good reasons for withholding treatment from active RA patients for close to 4 months in the guise of scientific experimentation. Yusuf Yazici Correspondence to Dr Yusuf Yazici, NYU Hospital for Joint Diseases, 333 East 38th Street, New York, NY 10016 USA; [email protected] Competing interests YY: consultant for Abbvie, Bristol-Myers Squibb, Celgene, Genentech, Pfizer, Samumed, UCB. Provenance and peer review Not commissioned; internally peer reviewed. To cite Yazici Y. Ann Rheum Dis 2014;73:e25. Received 8 December 2013 Accepted 9 December 2013 Published Online First 24 December 2013
▸ http://dx.doi.org/10.1136/annrheumdis-2013-205042 Ann Rheum Dis 2014;73:e25. doi:10.1136/annrheumdis-2013-205033
REFERENCES 1
2
3
Takeuchi T, Harigai M, Tanaka Y, et al. Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicenter, randomized, double-blind, placebo-controlled GO-MONO study through 24 weeks. Ann Rheum Dis 2013;72:1488–95. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789–96. Yazici Y, Yazici H. Tumor necrosis factor alpha inhibitors, methotrexate or both? An inquiry into the formal evidence for when they are to be used in rheumatoid arthritis. Clin Exp Rheumatol. 2008;26:449–52.
e25
Downloaded from ard.bmj.com on September 26, 2014 - Published by group.bmj.com
When is it not ethical to withhold treatment for rheumatoid arthritis? Yusuf Yazici Ann Rheum Dis 2014 73: e25 originally published online December 24, 2013
doi: 10.1136/annrheumdis-2013-205033
Updated information and services can be found at: http://ard.bmj.com/content/73/5/e25.full.html
These include:
References
This article cites 3 articles, 2 of which can be accessed free at: http://ard.bmj.com/content/73/5/e25.full.html#ref-list-1
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
