Feasibility and Ethics - ATS Journals

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bined pulmonary fibrosis and emphysema. We also find the topic very ... on this entity does not warrant specific focus on combined pul- monary fibrosis and ...
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AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

VOL 188

2013

Reply

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

Correspondence

the traditional hierarchical view of evidence toward a more continuous, integrated approach to evidence reviews. It is the role of observational studies as qualifiers and interpreters of RCTs that professional societies, medical professionals, payers, and drug manufacturers are increasingly recognizing (6). In a world of budgetary constraints and availability of many (equal or noninferior) treatment options, observational studies can help guide informed prescribing decisions. The challenge is to optimize the design of observational studies and RCTs—observational studies so that they involve high-quality data collection and analyses, and RCTs so that they are not compromised by excessively narrow selection criteria and unrepresentative standards of care. In this way, for a given investment, both efficacy and effectiveness can be thoroughly explored. Author disclosures are available with the text of this letter at www.atsjournals.org.

David Price, M.D. University of Aberdeen Aberdeen, United Kingdom and Respiratory Effectiveness Group Cambridge, United Kingdom Nicolas Roche, M.D., Ph.D. Service de Pneumologie AP-HP, Hôpitaux Universitaires Paris Centre Paris, France and Respiratory Effectiveness Group Cambridge, United Kingdom Richard Martin, M.D. National Jewish Health Denver, Colorado and Respiratory Effectiveness Group Cambridge, United Kingdom Alison Chisholm, M.Sc. Respiratory Effectiveness Group Cambridge, United Kingdom O N BEHALF OF THE R ESPIRATORY E FFECTIVENESS G ROUP C OLLABORATORS References 1. Albert RK. “Lies, damned lies ...” and observational studies in comparative effectiveness research. Am J Respir Crit Care Med 2013;187: 1173–1177. 2. Krishnan JA, Schatz M, Apter AJ. A call for action: comparative effectiveness research in asthma. J Allergy Clin Immunol 2011;127:123–127. 3. Janda S, Park K, FitzGerald JM, Etminan M, Swiston J. Statins in COPD: a systematic review. Chest 2009;136:734–743. 4. Simvastatin Therapy for Moderate and Severe COPD (STATCOPE). ClinicalTrials.gov identifier NCT01061671. 2010 [updated 2013 Oct 21; accessed 2013 Oct]. Available from: http://clinicaltrials.gov/ct2/show/NCT01061671? term¼STATCOPE&rank¼1 5. Giraud V, Allaert F-A, Roche N. Inhaler technique and asthma: feasability and acceptability of training by pharmacists. Respir Med 2011; 105:1815–1822. 6. Lieu TA, Au D, Krishnan JA, Moss M, Selker H, Harabin A, Taggart V, Connors A; Comparative Effectiveness Research in Lung Diseases Workshop Panel. Comparative effectiveness research in lung diseases and sleep disorders: recommendations from the National Heart, Lung, and Blood Institute workshop. Am J Respir Crit Care Med 2011;184: 848–856. Copyright ª 2013 by the American Thoracic Society

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Reply From the Author: Price and colleagues suggest that randomized controlled trials (RCTs) and observational studies answer different questions. I agree, but the question under consideration in my essay (1) is comparative effectiveness. Observational studies can provide interesting information and suggest potentially important clinical associations, but they cannot answer the question of whether treatment A is better or worse than treatment B. Price and colleagues cite the standard “efficacy versus effectiveness” argument in support of observational studies; but with respect to comparative effectiveness, the concerns in question are comparative efficacy and comparative effectiveness. Accordingly, as noted by the data cited and the clinical researchers’ and statisticians’ opinions quoted in my essay (1), these questions are much more likely to be answered accurately by the results of RCTs. Price and colleagues refer to the “exploratory utility” of observational studies and their ability to generate new hypotheses. As a clinical investigator who has published a number of observational studies, I completely agree, but would note that neither of these functions deals with determining comparative effectiveness. Price and colleagues reiterate the argument that observational studies can answer questions that are “unevaluable” in RCTs, capturing the “dimensions of real patient and physician activity.” As delineated in my essay, real patient and physician activity can be nicely captured in RCTs while preserving the critical requirement for randomized treatment allocation. Price and colleagues acknowledge that RCTs can be designed to incorporate the benefits attributed to observational studies but note that they seldom are. I agree, but this is a poor rationale for resorting to observational studies. A far better approach would be to design the RCTs to include these benefits, thereby preserving the ability to randomize patients. Inhalational techniques are frequently checked in the course of RCTs, and patients are frequently educated, but, as indicated in my essay, RCTs can certainly be designed without incorporating either of these features. RCTs can be as “real life” as the study designers wish to make them. Price and colleagues contend that observational studies are useful for evaluating rare adverse events. Will more observational studies answer the question of whether long-term b-agonist use increases mortality in asthma? Observational studies can be used to determine cost-effectiveness, but without a randomly allocated control group, such studies cannot accurately compare the costeffectiveness of various treatments. I agree that “financial constraints” and “limitations of academic funds” presently limit the ability to conduct RCTs, but, as noted in my essay, RCTs can be done far less expensively than they are, and, as opposed to observational studies, welldesigned RCTs will answer the question of whether treatment A is better or worse than treatment B. Also, as noted in my essay, the cost of RCTs should take into account far more than the financial outlay required. Price and colleagues cite regulatory requirements and commercial strategies in support of the need for doing observational studies. The points raised in my essay deal with clinical science and cost-effectiveness, not capitalism. Price and colleagues believe it is time to “move away from the hierarchical view of evidence to an integrated approach.” Why? The clinical researchers and statisticians who developed these hierarchical grading schemata are leaders in their field. Were they all wrong? Are there data indicating that integrated approaches generate more reliable data? As indicated in my essay, many card-carrying clinical researchers and statisticians believe quite the opposite.