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Rebuttal From Drs Suissa and RabeRebuttal From Drs Suissa and Rabe FREE TO VIEW

Samy Suissa, PhD; Klaus F. Rabe, MD, PhD
Author and Funding Information

From the Centre for Clinical Epidemiology (Dr Suissa), Jewish General Hospital, Department of Epidemiology and Biostatistics, McGill University; and LungenClinic Grosshansdorf and Department of Medicine (Dr Rabe), University Kiel, member of the German Center for Lung Research (DZL).

Correspondence to: Samy Suissa, PhD, Centre for Clinical Epidemiology, Jewish General Hospital, 3755 Cote Ste-Catherine, H4.61, Montreal, QC, H3T 1E2, Canada; e-mail: samy.suissa@mcgill.ca


Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Suissa attended an advisory meeting for a clinical trial involving roflumilast, the drug discussed in this paper, for Nycomed AG and participated in an expert panel meeting for Forest Laboratories, Inc. Dr Rabe has been and is still involved in several clinical trials involving roflumilast, has presented data on behalf of the sponsoring companies Nycomed AG and Takeda Pharmaceutical Company Limited, received financial compensation for talking at scientific meetings and taking part in the expert panels at European Medicines Agency and the US Food and Drug Administration, by Forest Laboratories, Inc, Nycomed AG, and Takeda Pharmaceutical Company Limited. Drs Suissa and Rabe hold no interest or stocks in any of the companies listed above.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(5):942-943. doi:10.1378/chest.14-0113
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Dr Rho and colleagues1 claim that “an appropriate study must answer only one question: Does this drug improve quality or quantity of life beyond the best available therapy?” The authors deem that studies of roflumilast “do not meet this mark.” On the other hand, the Towards a Revolution in COPD Health (TORCH) trial of the fluticasone/salmeterol inhaler is presented as an example of such an appropriate study. We show below that this is not so; had the authorization of this combination inhaler been based on such a mark for the TORCH trial, the drug would simply not have been approved. Indeed, the trial does not satisfy the three criteria set down by Dr Rho and colleagues, namely, quality of life, quantity of life, and best available therapy.

First, quality of life as measured by St. George’s Respiratory Questionnaire determined a mean change score of 4 units was needed to establish the treatment to be slightly efficacious, 8 for moderately efficacious, and 12 for very efficacious.2 The TORCH trial found a difference of only 3.1 units with the study treatment, which, although statistically significant, does not even reach the clinically significant threshold of 4 determined by patients for a slightly efficacious treatment. Second, quantity of life is not significantly improved with the fluticasone/salmeterol combination inhaler, though the effect was on the border of statistical significance. Further analyses of these data, using the full 2 × 2 factorial design of the trial, confirmed that the effect on mortality was entirely due to the bronchodilator component of the combination and statistically significant, whereas the inhaled corticosteroid component was associated with no effect on mortality whatsoever.3-5 Third, whether the improvements are “beyond the best available therapy” is, in fact, the major weakness of the TORCH trial. Indeed, at least 60% of the patients in the comparison group who were on usual maintenance therapy of corticosteroids, inhaled long-acting bronchodilators, or both at the time of randomization discontinued their treatment and replaced it with a placebo for the 3-year follow-up, hardly the best available therapy for COPD.

Additionally, a major adverse side effect of roflumilast is diarrhea, whereas for the fluticasone/salmeterol combination it is pneumonia. The number needed to treat is a useful measure to compare these adverse effects.6 The TORCH trial data arrive at 16 patients needed to be treated with fluticasone/salmeterol for 3 years for one to develop pneumonia.6 The two identical 1-year trials of roflumilast (trials 3 and 4) involving > 3,000 patients arrived at around 20 patients needing to be treated with roflumilast for 1 year for one to develop with diarrhea.7

In all, we agree that trials of new drugs must demonstrate clinically meaningful effects. It is, however, unreasonable to expect that mortality benefits be established initially for a drug to be approved for use by regulatory agencies. No drug would ever be on the market. There are several COPD outcomes other than mortality that can provide valuable information on clinical benefits of drugs and can be used for regulatory approval purposes. Once the drug is on the market, it is then imperative that industry sponsor real-life mega-trials of major outcomes, as advocated by Ioannidis.8

References

Rho J, Ho N, Prasad V. Counterpoint: were industry-sponsored roflumilast trials appropriate? No. Chest. 2014;145(5):939-942.
 
Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002;19(3):398-404. [CrossRef] [PubMed]
 
Rabe KF. Treating COPD—the TORCH trial, P values, and the dodo. N Engl J Med. 2007;356(8):851-854. [CrossRef] [PubMed]
 
La Vecchia C, Fabbri LM. Prevention of death in COPD. N Engl J Med. 2007;356(21):2211-2212. [CrossRef] [PubMed]
 
Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J. 2008;31(5):927-933. [CrossRef] [PubMed]
 
Suissa S. Number needed to treat in COPD: exacerbations versus pneumonias. Thorax. 2013;68(6):540-543. [CrossRef] [PubMed]
 
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694. [CrossRef] [PubMed]
 
Ioannidis JP. Mega-trials for blockbusters. JAMA. 2013;309(3):239-240. [CrossRef] [PubMed]
 

Figures

Tables

References

Rho J, Ho N, Prasad V. Counterpoint: were industry-sponsored roflumilast trials appropriate? No. Chest. 2014;145(5):939-942.
 
Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002;19(3):398-404. [CrossRef] [PubMed]
 
Rabe KF. Treating COPD—the TORCH trial, P values, and the dodo. N Engl J Med. 2007;356(8):851-854. [CrossRef] [PubMed]
 
La Vecchia C, Fabbri LM. Prevention of death in COPD. N Engl J Med. 2007;356(21):2211-2212. [CrossRef] [PubMed]
 
Suissa S, Ernst P, Vandemheen KL, Aaron SD. Methodological issues in therapeutic trials of COPD. Eur Respir J. 2008;31(5):927-933. [CrossRef] [PubMed]
 
Suissa S. Number needed to treat in COPD: exacerbations versus pneumonias. Thorax. 2013;68(6):540-543. [CrossRef] [PubMed]
 
Calverley PM, Rabe KF, Goehring UM, Kristiansen S, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694. [CrossRef] [PubMed]
 
Ioannidis JP. Mega-trials for blockbusters. JAMA. 2013;309(3):239-240. [CrossRef] [PubMed]
 
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