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• Response to Dr Yazici's eLetter: Ethical issue of withholding treatment from patients with active rheumatoid arthritis
  Tsutomu Takeuchi
  Published on: 13 April 2016
• When is it not ethical to withhold treatment for rheumatoid arthritis?
  Yusuf Yazici
  Published on: 13 April 2016

• Published on: 13 April 2016

  Response to Dr Yazici's eLetter: Ethical issue of withholding treatment from patients with active rheumatoid arthritis

  • Tsutomu Takeuchi, Professor
  • Other Contributors:
    • Masayoshi Harigai, Yoshiya Tanaka, Hisashi Yamanaka, Naoki Ishiguro, Kazuhiko Yamamoto, Nobuyuki Miyasaka, Takao Koike, Minoru Kanazawa, Takuya Oba, Toru Yshinari, Daniel Baker and the GO-MONO study group

  Dear Editor,

  The ethical consideration in placebo-controlled studies of antirheumatic drugs is of primary importance. We thank Dr Yazici for his questions regarding the ethical aspect of our study.

  The GO-MONO study was designed to have placebo crossover to methotrexate (MTX) at Week 16, as a Registration Study to Japan Health Authority, following the MHLW Guideline for the Clinical Study and Evaluat...

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  Dear Editor,

  The ethical consideration in placebo-controlled studies of antirheumatic drugs is of primary importance. We thank Dr Yazici for his questions regarding the ethical aspect of our study.

  The GO-MONO study was designed to have placebo crossover to methotrexate (MTX) at Week 16, as a Registration Study to Japan Health Authority, following the MHLW Guideline for the Clinical Study and Evaluation of Drugs for Rheumatoid Arthritis, which is similar to the US Food and Drug Administration's Guidance for Industry Rheumatoid Arthritis (1). The US guidance recommends sponsors to limit the use of placebo as a control and consider the use of an active comparator as the control or the escape to rescue treatment in studies longer than 12 weeks. In the event of aggravation of rheumatoid arthritis (RA) symptoms, subjects were to be withdrawn from study immediately and receive appropriate rescue treatment, which was explicitly written in the informed consent. The investigators and IRBs of the participating medical institutions and the Japanese health authorities considered that the GO-MONO study had adequate ethical considerations. Twelve or 24-week placebo-controlled studies were conducted in the clinical development of recently approved antirheumatic drugs in Japan after the golimumab studies without being questioned about the ethical conduct (2,3,4). Even allowing for the disadvantages in subjects receiving placebo, conducting a placebo-controlled study of golimumab monotherapy was thought to be imperative not only because it would meet the requirement by the Japanese health authorities to demonstrate the true efficacy of an antirheumatic drug in a placebo-controlled study, but because the approval of golimumab monotherapy provide an alternative treatment option to MTX- intolerable patients with active RA.

  The second issue Dr Yazici raises is the credibility of the data from our studies based on the different results for the effect on radiographic progression between the studies.

  As we discussed in the paper describing our earlier 2 studies of golimumab (5), subjects in all treatment groups of the GO-FORWARD study had lower disease activity and less radiographic progression at baseline than those in the earlier studies of TNF-? inhibitors in patients with an inadequate response to MTX (6,7,8), and this may have resulted in the lack of statistically significant differences between treatment groups. The GO- FORWARD study failed to adequately assess the effects of golimumab on radiographic progression in patients with established disease, In the GO- MONO study, however, subjects had more active RA inflammation at baseline than those in the GO-FORWARD study, and golimumab showed a significantly greater effect of preventing radiographic progression. This result is consistent with the results in our other studies of golimumab, the GO- FORTH study (9) and the GO-BEFORE study (10). A similar relationship was seen between the radiographic progression and response to certolizumab in patients with active RA despite MTX (11). Dr Yazici points out that radiographic benefit was not demonstrated with golimumab until post hoc analysis of the data was done. As explained in the literature of the GO-MONO study, the post hoc analysis using normalized data was appropriate for radiographic analyses because the radiographic change scores were not normally distributed. For instance, the median of the golimumab 100 mg group was skewed because of a single outlier. Data normalization is the standard statistical analysis technique used in the literature and for Health Authority submissions. Significantly less radiographic progression than placebo was noted when the data were analyzed post hoc using normalized scores. The 100 mg dose was associated with better clinical outcome than the 50 mg dose (not statistical comparison) as measured using the American College of Rheumatology criteria and Disease Activity Scores. The effect of the 100 mg dose for the use in golimumab monotherapy was appropriately evaluated and approved by the Japanese health authorities.

  References

  1. Guidance for Industry Rheumatoid Arthritis: Developing Drug Products for Treatment (Draft guidance). :http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM354468.pdf

  2. Fleischmann R et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis 2009;68:805-11

  3. Yamamoto K, Takeuchi T, Yamanaka H, Ishiguro N, Tanaka Y, Eguchi K, et al. Efficacy and safety of certolizumab pegol without MTX co- administration in Japanese patients with active rheumatoid arthritis: the HIKARI randomized, placebo-controlled trial. Mod Rheumatol 2013 Nov 1.

  4. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose- ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum 2012; 64:617-29.

  5. Emery P, Fleischmann R, van der Heijde D, et al. The effects of golimumab on radiographic progression in rheumatoid arthritis: results of randomized controlled studies of golimumab before methotrexate therapy and golimumab after methotrexate therapy. Arthritis Rheum 2011;63:1200-10.

  6. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789-96.

  7. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594-602.

  8. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 2004;50: 1400-11.

  9. Tanaka Y, Harigai M, Takeuchi T, et al. Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study. Ann Rheum Dis 2012;71:817-24.

  10. Emery P, Fleischmann RM, Moreland LW, at al. Golimumab, a human anti-tumor necrosis factor ? monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 2009;60:2272-83.

  11. Keystone E, Heijde Dv, Mason D Jr, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum 2008;58:3319-29.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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• Published on: 13 April 2016

  When is it not ethical to withhold treatment for rheumatoid arthritis?

  • Yusuf Yazici, MD

  Dear Editor

  I read with interest the study by Takeuchi et al (1) looking at the role of monotherapy golimumab in Japanese rheumatoid arthritis (RA) patients, who had active disease despite disease modifying anti-rheumatic drug (DMARD) therapy. Inclusion criteria for the study stipulated that patients have 2/3 criteria which were: elevated inflammatory markers, erosions on radiograph or positive serology, in additio...

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  Dear Editor

  I read with interest the study by Takeuchi et al (1) looking at the role of monotherapy golimumab in Japanese rheumatoid arthritis (RA) patients, who had active disease despite disease modifying anti-rheumatic drug (DMARD) therapy. Inclusion criteria for the study stipulated that patients have 2/3 criteria which were: elevated inflammatory markers, erosions on radiograph or positive serology, in addition to more than 6 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 randomized 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 publication (2) but in that study primary end point 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 reanalyzed.
  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 from patients with RA, for up to 4 months, including the 4 weeks of washout before the study medication was administered, 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 analyzed 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 IRB 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 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 US) and clinical benefit but who is to say the reasons listed by the authors that affected the first trials 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 posthoc 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.

  References

  1. 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.

  2. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor ? given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study. Ann Rheum Dis 2009;68:789-96.

  3. 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.

  Conflict of Interest:

  None declared

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  Conflict of Interest:
  None declared.

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