VOL 188



Feasibility and Ethics

From the Authors:

To the Editor:

We thank Dr. Oba for his interest in and comments on the revised document of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) (1). We acknowledge that there are limits to the evidence base for roflumilast, but find that there is sufficient evidence for improvement in lung function and reduction of exacerbations, as stated in the document. However, as the evidence is weaker than for other drug classes, and because of the less favorable side effect profile, we do not recommend roflumilast as a firstchoice therapy but rather as one of several alternative choices. The GOLD document also lists all the adverse effects of roflumilast mentioned by Dr. Oba. We are somewhat less encouraged by the effects of theophylline than Dr. Oba, but do list theophylline as another possible treatment, and to a broader range of patients. We also thank Dr. West for pointing out the limitations of using FEV1 alone and not considering the underlying pathophysiology leading to chronic bronchitis and/or emphysema—there is a significant proportion of patients with both. However, as we have no treatments aimed specifically at either of these disorders, we do not think a global document gains from “splitting” rather than “lumping” for management. We disagree with the statement that only subjects with reversible airway obstruction (at least measured as FEV1 reversibility) will benefit from bronchodilator treatment, and we therefore recommend a treatment trial with bronchodilators in patients with symptoms. As in medicine in general, this needs to be followed up, and patients who do not feel any benefit should of course not continue for symptomatic purposes alone. We believe that on a global scale, exposures other than smoking matter for the development of persistent airflow limitation, and we do not see any reason to highlight smoking here. And is chronic obstructive pulmonary disease (COPD) treatable? Yes, as treatment includes symptom management; not least, nonpharmacological treatment, such as pulmonary rehabilitation, has a major impact on symptoms and quality of life. Dr. Tzouvelekis and colleagues turn our attention to combined pulmonary fibrosis and emphysema. We also find the topic very interesting but find that our current knowledge on this entity does not warrant specific focus on combined pulmonary fibrosis and emphysema in the executive summary of a global COPD document. We hope that current and future research will enable us to better understand and manage this subgroup of patients with COPD.

We read with interest Dr. Albert’s essay arguing for the superiority of randomized controlled trials (RCTs) over observational studies to answer treatment-related questions (1). We contend that the key question is not whether RCTs or observational studies represent the “ideal design,” but how these complementary approaches can optimize therapeutic research efficiency and, through their role in cost-effectiveness evaluations, how they can help to clear the fourth hurdle in the regulatory approval and usage of interventions. Consistent scientific evidence demonstrates that RCTs and observational studies should be viewed as complementary components of the research framework because they answer different questions (2). In general, “classical” (i.e., other than pragmatic) RCTs deal with efficacy, whereas observational studies deal with effectiveness. The exploratory utility of observational therapeutic studies is notable (1) for evaluating treatment effectiveness and treatment safety in broader populations (to complement efficacy evaluations conducted in controlled RCT settings and in tightly selected patient populations), and (2) for evaluating treatment effects beyond RCT-proven indications, thus generating new hypotheses. One example of the latter role of observational studies is that of statin use in chronic obstructive pulmonary disease, where observational studies suggested potential respiratory benefits (3), and several RCTs are now underway (4). There are many scenarios where observational studies can answer questions unevaluable in RCTs and where they can strengthen the dictum primum non nocere. First, observational studies capture the dimensions of real patient and physician activity (e.g., behavior and preference) in a way that is difficult to achieve in classic RCTs. Indeed, adherence might be greater in RCTs than real-life patients. Similarly, in RCTs involving inhalation therapies, inhalation technique is checked and patients are educated, yet in routine care (“real life”), there is frequent inhaler misuse and doctors often offer insufficient education (5). Thus, RCTs are more “rigid” and observational studies are more “real life.” Both provide important information. Second, although RCTs can be designed to include naturalistic populations, they seldom do due to financial constraints, commercial strategies, or regulatory requirements. As such, populations are relatively small and evaluation periods are relatively short. Strategic commercial decisions, as well as limited academic research funds, result in few head-to-head RCTs of different treatment strategies. In such scenarios, observational studies offer an affordable means of testing or generating clinical hypotheses. Importantly, they are also the only way to practically evaluate the prevalence of rare adverse events and, by linking clinical datasets, of powering effectiveness and safety evaluations of small, yet significant, patient subgroups (e.g., pediatrics). Observational studies are also useful when seeking to evaluate the cost-effectiveness of interventions; models relying on RCT evidence alone are often plagued by the same limitations as RCTs. These are exemplars of scenarios where observational studies can complement RCTs. We believe it is time to move away from

Author disclosures are available with the text of this letter at www.atsjournals.org.

Jørgen Vestbo, D.M.Sc. University of Manchester Manchester, United Kingdom and University of Southern Denmark Odense, Denmark Marc Decramer, Ph.D. Katholieke Universiteit Leuven Leuven, Belgium Reference 1. Vestbo J, Hurd SS, Agustí AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013;187:347–365. Copyright ª 2013 by the American Thoracic Society

Supported by The Respiratory Effectiveness Group. A full list of Respiratory Effectiveness Group (REG) collaborators who pledge their support to this letter can be found in the online supplement. This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org

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