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Point/Counterpoint Editorials |

Point: Were Industry-Sponsored Roflumilast Trials Appropriate? YesRoflumilast Trials Appropriate? Yes 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):937-939. doi:10.1378/chest.14-0112
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The randomized controlled trial is the fundamental scientific design to obtain drug approval from regulatory agencies for either marketing purposes or for new indications. Although the pharmaceutical industry is obliged to run all preapproval trials, many postapproval trials are also industry sponsored, to investigate new outcomes, new indications, or safety issues. These postapproval trials have received a bad rap: It appears that a trial cannot be credible if it is industry sponsored.

The topic we were asked to discuss, namely “were industry-sponsored roflumilast trials appropriate?,” insinuates that even preapproval trials are now also being categorized as inferior “industry-sponsored” trials. This is rather surprising, after these study protocols and their findings were reviewed and approved by several entities, including scientific boards, regulatory agencies, and advisory committees and were generally peer reviewed and published in scientific journals.

The trials of the phosphodiesterase-4 inhibitor roflumilast were necessarily industry sponsored, because they were conducted with the goal of regulatory approval. We believe that an assessment of the validity of a trial should be based solely on its methods and conduct, independently of the origin of the sponsorship. In this article, we briefly review the trials and analyze some of the key methodological aspects of these trials necessary to assess their appropriateness.

The first large phase 3 clinical trial (trial 1) with roflumilast in patients with COPD involved 1,414 patients randomized to either receive 250 or 500 μg roflumilast or placebo for 24 weeks.1 FEV1 increased by 74 and 97 mL with the two doses against placebo, and St. George’s Respiratory Questionnaire also improved significantly. From these results it was cautiously speculated that roflumilast might be a promising candidate for the treatment of COPD. This conclusion was further fueled by the beneficial effect on the exacerbation rate, from 1.13 for those taking placebo to 1.03 and 0.75, respectively, for the two roflumilast doses. Since exacerbations were secondary end points, the European Medicines Agency appropriately decided not to count these data as sufficient support for the registration of roflumilast as a novel antiinflammatory agent for COPD, although it was ruled that roflumilast is a safe drug, despite the fact that more patients receiving roflumilast withdrew from the trial than those taking placebo.

A subsequent 1-year study (trial 2) was then conducted in a group of 1,513 patients with COPD, with exacerbations the primary end point in this trial.2 Roflumilast did not significantly reduce exacerbation frequency (rate ratio, 0.93; P = .45), although lung function improvements were recorded, similar to earlier trials. A post hoc analysis of these data, however, revealed that in a subgroup of patients with very severe disease, roflumilast did significantly reduce exacerbation frequency, with a rate ratio of 0.64 (P = .024). This patient group was characterized by very severe airflow limitation, frequent exacerbations, signs and symptoms of chronic bronchitis, and the need for oral steroid use.

The hypothesis of a benefit in more severe COPD formed the basis for the design of a phase 3b program, which, for the first time to our knowledge, tested the efficacy of a COPD drug on exacerbations in a subpopulation of patients.3 The first two identical placebo-controlled, double-blind, multicenter trials (trials 3 and 4) were conducted in > 3,000 patients with more severe COPD who were randomly assigned to oral roflumilast (500 μg once per day) or placebo for 52 weeks. The primary end point of prebronchodilator FEV1 increased significantly by 48 mL with roflumilast, and there was a significant 17% reduction in the exacerbation rate, the other primary end point (rate ratio, 0.83; P < .0003).

In the second set of studies, the effect of roflumilast on lung function was assessed in patients with COPD already treated with salmeterol or tiotropium (trials 5 and 6).4 Thus, in two separate trials, patients with moderate to severe COPD already treated with either salmeterol (933 patients) or tiotropium (743 patients) were randomly assigned to roflumilast or placebo. In both studies, roflumilast significantly improved prebronchodilator FEV1 by 49 mL in those treated with salmeterol and by 80 mL in those treated with tiotropium. Generally in all trials, adverse events, particularly nausea, diarrhea, and weight loss, were more frequent in patients in the roflumilast groups and were associated with higher rates of study withdrawal.

Some key methodological issues to assess the appropriateness of the trials involve the study question, entry treatment discontinuations, the intent-to-treat approach, and data analysis. The study questions posed in registration trials 3 to 6 were original in that they were scientifically and clinically oriented. Indeed, trials 3 and 4 studied the benefit of roflumilast in decreasing the frequency of exacerbations in the subpopulation of more severe COPD, a hypothesis generated by a subgroup analysis of trial 2. Trials 5 and 6 addressed clinical guideline questions of the effectiveness of adding roflumilast to patients treated with a first-line maintenance bronchodilator, namely salmeterol or tiotropium. These scientifically and clinically oriented questions contrast with that from the Towards a Revolution in COPD Health (TORCH) trial, the first large COPD trial, which evaluated the effect of a long-acting β-agonist (LABA) and inhaled corticosteroid (ICS) combination on mortality “as compared with usual care” in > 6,000 patients.5 The question was incongruent with the actual “usual care” comparison group devised in the study design. Indeed, 59% of the patients in the comparison “usual care” group had their usual maintenance therapy (LABA or ICS) discontinued at randomization and replaced by a placebo for the 3-year follow-up. In contrast, the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial, which assessed the effect of adding tiotropium to management “according to treatment guidelines,” included a placebo group wherein maintenance therapy was permitted to be continued at randomization and, thus, was quite representative of usual care with respect to maintenance therapy.6

In many COPD trials, the drug under study is already on the market, so that some study patients entering the study are instructed to stop this treatment prior to randomization. For example, in the TORCH trial, nearly 60% of the study patients were already using an ICS or LABA and had to stop the use of these medications prior to randomization. Such discontinuation of medications taken by the patient at the time of randomization becomes an inherent component of the intervention but is never considered as such. The Canadian Optimal Therapy of COPD Trial (OPTIMAL) showed that the overall hazard ratio of exacerbation associated with ICSs relative to bronchodilators, estimated as 0.79, was in fact 0.71 among the patients already using ICSs who had to discontinue their use at randomization and 1.11 among those who had not used ICSs prior to randomization.7,8 In the roflumilast trials, however, this is not an issue, because no patient was on roflumilast at the time of randomization, although patients had to stop ICS use in all trials. In this case, cessation of ICSs or other drugs at randomization should be expected to have a similar effect in both the roflumilast and placebo groups and thus not cause such a bias.

The intent-to-treat principle is fundamental in randomized trials, since it provides a clean scientific evaluation of the effect of the drug. Regrettably, no trial to date has collected data on FEV1 or exacerbations after treatment discontinuation, including the roflumilast trials as well as the TORCH and UPLIFT trials, which only did so for mortality. Consequently, analyzing end point data only until discontinuation of study drugs can lead to bias if the reasons for discontinuation are associated with the outcome and differ between treatments.9,10 Moreover, data analysis of the roflumilast trials included proper techniques, such as accounting for between-patient variability when computing rate ratios of exacerbation and using repeated measures analysis of covariance for FEV1.11

Finally, roflumilast is admittedly a drug with rather frequent side effects, which have led to significant premature discontinuations in clinical trials. The published study reports, however, have been transparent and proactive in relation to these data and, consequently, observations from these trials have indeed led to clinically interesting and novel observations.12,13

In all, we find that the industry-sponsored roflumilast trials were indeed appropriate. Its development involved excellent randomized trial methodology that included scientifically and clinically oriented study questions as well as rigorous study design and statistical analyses that permitted avoiding the biases seen with other trials in COPD. Although roflumilast may not have remarkable effects on COPD, the methodology used in the trials, which should be the primary basis for evaluating the benefit-risk of a drug, was sound and the reporting transparent. That these trials were industry sponsored is evident, and this should not play any role in its approval by regulatory agencies.

FDA

US Food and Drug Administration

ICS

inhaled corticosteroid

LABA

long-acting β-agonist

REACT

Roflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment

TORCH

Towards a Revolution in COPD Health

Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563-571. [CrossRef] [PubMed]
 
Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161. [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]
 
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Aaron SD, Vandemheen KL, Fergusson D, et al; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555. [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]
 
Kesten S, Plautz M, Piquette CA, Habib MP, Niewoehner DE. Premature discontinuation of patients: a potential bias in COPD clinical trials. Eur Respir J. 2007;30(5):898-906. [CrossRef] [PubMed]
 
Suissa S. Lung function decline in COPD trials: bias from regression to the mean. Eur Respir J. 2008;32(4):829-831. [CrossRef] [PubMed]
 
Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(8):842-846. [CrossRef] [PubMed]
 
Wouters EF, Bredenbröker D, Teichmann P, et al. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(9):E1720-E1725. [CrossRef] [PubMed]
 
White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758-765. [CrossRef] [PubMed]
 

Figures

Tables

References

Rabe KF, Bateman ED, O’Donnell D, Witte S, Bredenbröker D, Bethke TD. Roflumilast—an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2005;366(9485):563-571. [CrossRef] [PubMed]
 
Calverley PM, Sanchez-Toril F, McIvor A, Teichmann P, Bredenbroeker D, Fabbri LM. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;176(2):154-161. [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]
 
Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374(9691):695-703. [CrossRef] [PubMed]
 
Calverley PM, Anderson JA, Celli B, et al; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356(8):775-789. [CrossRef] [PubMed]
 
Tashkin DP, Celli B, Senn S, et al; UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543-1554. [CrossRef] [PubMed]
 
Aaron SD, Vandemheen KL, Fergusson D, et al; Canadian Thoracic Society/Canadian Respiratory Clinical Research Consortium. Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med. 2007;146(8):545-555. [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]
 
Kesten S, Plautz M, Piquette CA, Habib MP, Niewoehner DE. Premature discontinuation of patients: a potential bias in COPD clinical trials. Eur Respir J. 2007;30(5):898-906. [CrossRef] [PubMed]
 
Suissa S. Lung function decline in COPD trials: bias from regression to the mean. Eur Respir J. 2008;32(4):829-831. [CrossRef] [PubMed]
 
Suissa S. Statistical treatment of exacerbations in therapeutic trials of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2006;173(8):842-846. [CrossRef] [PubMed]
 
Wouters EF, Bredenbröker D, Teichmann P, et al. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012;97(9):E1720-E1725. [CrossRef] [PubMed]
 
White WB, Cooke GE, Kowey PR, et al. Cardiovascular safety in patients receiving roflumilast for the treatment of COPD. Chest. 2013;144(3):758-765. [CrossRef] [PubMed]
 
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