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Abstract
The COPD Foundation Biomarker Qualification Consortium (CBQC) is a unique public–private partnership established in 2010 between the COPD Foundation, the pharmaceutical industry, and academic chronic obstructive pulmonary disease (COPD) experts with advisors from the U.S. NHLBI and the Food and Drug Administration (FDA). This was a direct response to the 2009 publication of a guidance on qualification of drug development tools by the FDA. Although data were believed to be available from publicly funded and industry-funded studies that could support qualification of several tools, the necessary data resided in disparate databases. The initial intent of the CBQC was to integrate these data and submit a dossier for the qualification. This led to the FDA qualification of plasma fibrinogen as a prognostic or enrichment biomarker for all-cause mortality and COPD exacerbations in July 2015. It is the first biomarker drug development tool qualified for use in COPD under the FDA’s drug development tool qualification program. This perspective summarizes the FDA’s qualification process, the formation of the CBQC, and the effort that led to a successful outcome for plasma fibrinogen and discusses implications for future biomarker qualification efforts.
Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and the second leading cause of disability in the United States; its prevalence and impact are rising (1, 2). Despite the fact that COPD has been a major public health problem for decades, only one new class of medication has been approved to manage COPD in the last 25 years (3). No therapy has been demonstrated to improve survival. Lack of novel treatments is not due to a shortage of potential therapeutic targets or novel agents. The “pipeline” for potential new treatments is extremely rich (4, 5). Furthermore, the recognized heterogeneity of COPD (6, 7) creates an ideal opportunity for precision or personalized medicine. Development of novel medications that can achieve these goals will require strategies for patient segmentation that will support regulatory approval and clinical application.
Clinical trials using currently approvable outcomes, such as COPD exacerbations or mortality, enroll hundreds to thousands of subjects, including individuals who are unlikely to experience the outcome of interest during the trial period. For example, in recent COPD exacerbation studies ∼50% of clinical trial participants randomized to placebo (standard of care/reference therapy) did not experience an event (8–10). Exclusion of subjects who do not contribute events would decrease the cost of a trial, increasing the number of new agents that could be tested. Furthermore, exclusion of patients who will not benefit from a medication will decrease healthcare costs and reduce exposure to potential side effects. Recognizing these challenges, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have developed guidance documents to support the qualification of drug development tools (DDTs) that are applicable to clinical outcome assessments and biomarkers (11–13).
This perspective focuses on the FDA Biomarker Qualification process and its first tangible result for COPD, the qualification of plasma fibrinogen as a prognostic biomarker for subject enrichment in COPD exacerbation and mortality trials (14).
New drug development is a long and expensive process. The Tufts Center for the Study of Drug Development reported in 2014 that the average cost for developing a new drug from discovery to market approval was $2.6 billion and required 10 or more years to complete (15). In addition, only about 1 in 10 drugs that enter human trials achieve marketing approval (16). Although there are many reasons to account for the cost and complexity of new drug development, an important component of the challenge is the lack of accepted tools to identify and select subjects most likely to benefit from a new treatment. In many diseases, the typical approach for pivotal trials has been to include “all comers.” A result of inclusion of subjects who will not benefit is large trials to provide the appropriate statistical power to assess the endpoints of interest. In recent years, the application of precision medicine treating only those who will benefit has been touted as a means to help facilitate both drug development and the use of drugs in routine clinical practice. However, the successful implementation of precision medicine in diseases such as COPD will require the identification of biomarkers and other assessments that allow for the identification of important subgroups of patients.
Regulatory qualification of DDTs offers the potential to help expedite the drug development process. Central to the qualification process is what the FDA has defined as the Context of Use: “a complete and precise statement that describes the appropriate use of the DDT and how the qualified DDT is applied” (12). The FDA Drug Development Tool Guidance Document, recognizes several contexts of use for which a tool can be qualified: (1) enrichment (of patients), (2) predictive (i.e., predicts response to a treatment), (3) pharmacodynamic (measures biological response to a treatment), and (4) surrogate endpoint (intended to substitute for a clinical endpoint). Although not a requirement for use in drug development, qualification does provide a regulatory position on the use of the DDT to support its application within the defined context of use in multiple drug development programs and avoids having to seek FDA agreement for use in each individual study.
Some examples of the use of drug development tools include:
| • | Prognostic or enrichment tools intended to help identify individuals at risk for events that can be prevented. | ||||
| • | A tool to facilitate dose ranging for interventions that impact long-term outcomes. COPD progresses over years to decades. Studies of that duration are unfeasible for dose ranging, and intermediate or surrogate assessments are needed. | ||||
| • | Outcome measures to evaluate treatment efficacy. | ||||
The DDT qualification process consists of several discrete stages: (1) initiation, (2) consultation and advice, and (3) review (12) (Figure 1). At the initiation stage, the submitter provides a letter of intent (LOI) to the FDA describing the drug development tool, proposed context(s) of use, and available data to support qualification to allow the FDA to make a decision whether or not to accept the proposed DDT into the qualification program. After acceptance of the LOI, the submitter prepares an initial briefing package. The briefing package provides the framework for how the submitter intends the DDT to be used. The briefing package should contain relevant background information describing the DDT and available supporting data. Perhaps most importantly, the briefing package should clearly define and describe the proposed context(s) of use (COU) and articulate how the DDT will improve drug development over currently available approaches. As discussed above, the proposed COU will have a significant impact on how the FDA views the DDT, in particular the extent of data required to support qualification. After FDA review of the briefing package, additional information may be requested from the submitter. On satisfactorily addressing FDA questions and comments, the submitter will prepare a final qualification package, which the FDA will use to render a qualification decision. Once approved, a draft guidance is posted on the FDA Guidance web page and in the Federal Register, at which time a public comment period begins. The FDA will then consider any comments that are received before issuing the final qualification recommendation. The draft guidance document for the Exacerbations of Chronic Pulmonary Disease Tool (EXACT), a patient-reported outcome measure for use in COPD trials, is an example of this process as it has been applied to clinical outcome assessments (17).
Figure 1. U.S. Food and Drug Administration’s biomarker qualification process and timeline. Adapted by permission from Reference 36. FR = Federal Register; LOI = letter of intent.
[More] [Minimize]Many COPD studies conducted by industry and academia have included assessments of potential biomarkers. These studies have raised the possibility that sufficient data may already exist to support the qualification of some novel drug development tools. However, until the formation of the COPD Biomarker Qualification Consortium (CBQC), there has been no mechanism for the COPD community to collaborate to use the available data for this purpose.
In 2010, the COPD Foundation sponsored a workshop to bring together key contributors to COPD drug development. Participants included representatives from the FDA, the EMA, the National Institutes of Health, the pharmaceutical industry, academic researchers, and the COPD patient community (18). The workshop provided a “neutral ground,” where industry, academia, and government representatives reviewed published and unpublished data. Available data and the willingness of the various parties to cooperate in the development of new tools to assess treatments for COPD were discussed. The potential biomarker candidates were ranked for their potential to improve the drug development process for COPD and for the availability of data sufficient to support qualification. A strong sense emerged that several potentially useful biomarkers might be appropriate for qualification. However, there was no mechanism that would allow interested parties to collaborate toward this end. As a result, the COPD Foundation created the CBQC. This unique public–private partnership was established to facilitate open exchange of data by industry and academic researchers with the aim to work together with regulators to progress the qualification of new drug development tools, including biomarkers (18).
Five pharmaceutical companies—AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Pfizer—committed initial financial support for the CBQC. The CBQC enlisted participation of a number of leading academic investigators and industry scientists, regulatory experts, and patient representatives. The work of the CBQC was organized into a steering committee and six working groups, each centered around a candidate biomarker or other drug development tool. Each working group was cochaired by an academic expert and an industry representative.
Plasma fibrinogen was deemed appropriate for the initial submission of a complete dossier for qualification and was accepted into the biomarker qualification program.
Fibrinogen is a soluble glycoprotein primarily synthesized in the liver by hepatocytes. Circulating fibrinogen is a major protein component of blood (the major circulating coagulation protein by mass) and the primary determinant of blood viscosity. Fibrinogen is a key component of the coagulation cascade (via thrombin-mediated conversion of fibrinogen to fibrin). Fibrinogen is also a major acute-phase reactant, its synthesis being up-regulated in response to inflammatory mediators (e.g., IL-6) (19). Elevated concentrations of plasma fibrinogen are observed in subjects with several chronic diseases that have inflammation as an underlying component. These include cardiovascular disease, rheumatoid arthritis, diabetes, and COPD. Plasma fibrinogen concentration is also influenced by several demographic characteristics, including age, sex, smoking status, body mass index, and physical activity (20). Several marketed and investigational pharmaceutical agents have been reported to influence plasma fibrinogen concentration (21).
For several reasons, plasma fibrinogen is highly suitable for use in clinical trials. These include: (1) well-defined protocols for sample collection and processing; (2) well-established, standardized, controlled, reproducible, and widely available testing methods for determining plasma fibrinogen concentration in most clinical laboratories; (3) relative stability and reproducibility of plasma fibrinogen concentration in stable disease; and (4) evidence from numerous prospective and retrospective studies demonstrating associations between elevated plasma fibrinogen and adverse clinical outcomes in COPD (i.e., COPD exacerbations, COPD-related hospitalizations, and mortality) (22–24).
Furthermore, there is a plausible mechanism for fibrinogen predicting risk in COPD. Specifically, systemic inflammation (as reflected by blood biomarkers such as IL-6, C-reactive protein, fibrinogen, and circulating leukocytes) has long been considered a hallmark of COPD and is associated with many of the pulmonary and extrapulmonary manifestations of COPD. Moreover, elevated concentrations of biomarkers of systemic inflammation have been found to be associated with poor clinical outcomes in patients with COPD, including COPD exacerbations and mortality (24–26). However, although subjects with COPD, on average, have elevated concentrations of circulating biomarkers of inflammation, not all subjects with COPD have evidence of systemic inflammation (25, 26). Those with persistent measures of systemic inflammation may constitute a distinct subgroup or phenotype. Fibrinogen, perhaps because it is an acute-phase reactant driven by diverse inflammatory processes, could serve as a biomarker to identify this group of patients who are potentially at high risk.
In the original LOI submitted to the FDA, the CBQC proposed plasma fibrinogen for two COUs in drug development: (1) as an enrichment factor for subjects with COPD more likely to experience a COPD exacerbation and (2) as an enrichment factor for subjects with COPD at higher risk for all-cause mortality. Plasma fibrinogen is intended to be used along with other important clinical characteristics for selection of trial subjects.
To support the qualification of plasma fibrinogen as a drug development tool, the CBQC first conducted an extensive literature review to identify appropriate studies that could be used to build an integrated dataset to support the proposed COUs (full details of the selection process and studies considered are in the online supplement). Five studies were determined to be appropriate for inclusion:
| • | NHANES III (The National Health and Nutrition Examination Survey III) (27) | ||||
| • | Framingham Heart Study Offspring Cohort (28) | ||||
| • | CHS (Cardiovascular Health Study) (29) | ||||
| • | ARIC (Atherosclerosis Risk in Communities Study) (30) | ||||
| • | ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) (31) | ||||
After standardizing variables to a common format appropriate for regulatory submissions (Clinical Data Interchange Standards Consortium [CDISC]; Study Data Tabulation Model [SDTM]), an integrated dataset was constructed by an independent contractor (INC Research). This allowed for studies to be analyzed individually and as a combined dataset. The data were transferred to another independent contractor, Evidera, and a statistical analysis plan was developed to evaluate the relationships between plasma fibrinogen and the two events of interest (i.e., COPD exacerbations and all-cause mortality). This analysis demonstrated that fibrinogen could predict risk. Figure 2 is a Kaplan-Meier plot showing differences in all-cause mortality when subjects are separated using a plasma fibrinogen threshold of 350 mg/dl; subjects with plasma fibrinogen greater than or equal to 350 mg/dl had nearly a twofold increased risk of death from any cause over 3 years (hazard ratio, 1.94; 95% confidence interval, 1.62–2.31). Figure 3 is a Kaplan-Meier plot of time to first exacerbation in the ECLIPSE study using both exacerbation history and a plasma fibrinogen threshold of 350 mg/dl to classify subjects showing the improved recognition of individuals at risk using fibrinogen. Complete details and the full set of results used to support the plasma fibrinogen qualification are provided in the online supplement.
Figure 2. Kaplan-Meier plot of all cause-mortality within 36 months in the integrated database. High plasma fibrinogen was defined as a plasma fibrinogen concentration greater than or equal to 350 mg/dl at enrollment. Reprinted by permission from Reference 22.
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Figure 3. Kaplan-Meier plot of time to first chronic obstructive pulmonary disease exacerbations within 12 months in the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study. High plasma fibrinogen was defined as a plasma fibrinogen concentration greater than or equal to 350 mg/dl at enrollment. Reprinted by permission from Reference 22.
[More] [Minimize]The final qualification package was submitted to the FDA in August 2013. During the review stage, an iterative process took place; the FDA submitted questions and comments to the CBQC and the CBQC provided responses back to the FDA. This process continued until July 2015, with the FDA issuing its draft guidance with the qualified context of use for plasma fibrinogen as a DDT: “Plasma fibrinogen can be used as an enrichment factor, in addition to standard inclusion/exclusion criteria, in COPD clinical trials with endpoints of COPD exacerbation and/or all-cause mortality” (14). Figure 4 summarizes the complete process and timeline for the plasma fibrinogen qualification.
Figure 4. Plasma fibrinogen qualification timeline. The graphic depicts the events and timeline from submission of the initial letter of intent (LOI) through issuance of the draft qualification guidance by the U.S. Food and Drug Administration (FDA). mtg = meeting; telecons = teleconferences.
[More] [Minimize]The use of plasma fibrinogen as a biomarker for COPD exacerbation and mortality studies will help facilitate enrollment of subjects more likely to experience the important clinical outcomes of COPD exacerbations and/or all-cause mortality, making the drug development process more efficient. It is important to note that the qualification of the plasma fibrinogen biomarker, although a meaningful advance, is a modest gain. Plasma fibrinogen is the first of several biomarkers that may assist in the development of novel treatments for COPD. Given the heterogeneity of COPD, it is likely that multiple prognostic or enrichment tools will be needed to facilitate the development of the rich pipeline of pathway-specific agents currently under investigation. The qualification of plasma fibrinogen provides a template and road map for other biomarkers to follow.
For future DDT qualifications, it is important to recognize that considerable financial and human resources were required for the CBQC’s qualification activities. The CBQC invested approximately $1.4 million for costs related to data acquisition, construction of the integrated database, data analysis, and preparation of the initial briefing package and the final qualification package. Over the course of nearly 4.5 years from LOI submission to the issuance of the draft qualification guidance, a core multidisciplinary team of academic and industry scientists provided on average about 5% of their total work time, with some individuals contributing substantially more, to support the plasma fibrinogen working group. Throughout, the COPD Foundation provided program management, administrative support, and oversight.
It also should be noted that data from thousands of subjects followed for many years using a validated clinical laboratory assay were available to qualify fibrinogen, which highlights the importance of the large, longitudinal observational studies with sample biobanks (e.g., ECLIPSE [31], SPIROMICS [Subpopulations and Intermediate Outcomes in COPD Study] [32], COPDGene [Genetic Epidemiology of COPD] [33]) that will allow generation of robust data with novel clinical assays.
The FDA’s establishment of a defined process and commitment of resources to support the evaluation of new drug development tools will facilitate more focused approaches to drug development in COPD and other complex diseases. The successful qualification of plasma fibrinogen as a prognostic biomarker for use in COPD drug development is itself an important step. Plasma fibrinogen is currently being used as one of the enrollment criteria in at least two interventional studies with COPD subjects: (1) an interventional study with an oral p38 inhibitor, losmapimod, funded by a grant from Innovate UK (NCT01541852) (34); and (2) a first time in patient study with an oral CXCR2 antagonist, danirixin (NCT02130193, GSK Study No. 200163). In addition, it demonstrates the value of a public–private partnership working together with regulators.
The FDA has recently encouraged the submission of additional biomarkers for potential qualification (35, 36). The Biomarker Qualification process at the FDA (and the EMA) is expected to become more active and more important in the coming years, especially with the recent focus on application of precision medicine approaches (37). The CBQC expects to remain an active participant in this process. Specifically, white papers for the 6-minute-walk test and the St. George’s Respiratory Questionnaire are nearing completion and are expected to provide support and clarification of their use in drug development. Working groups have been organized to develop qualification packages for constant work-rate exercise tests as outcome measures in COPD and for lung imaging to stratify subjects for enrollment in clinical trials and as an outcome measure of therapeutic response. Other biomarkers under consideration for COPD include soluble receptor for advanced glycation end products (sRAGE) (38) to help identify subjects at risk for emphysema progression and blood eosinophils to identify subjects more likely to respond to inhaled corticosteroids (39). Potential outcome measures, in addition to the EXACT and the Evaluating Respiratory Symptoms in COPD (E-RS:COPD) tools (40), include methods for evaluating physical activity (41, 42) and development of a combined measure of disease activity. Understanding the requirements and the process for regulatory qualification, which has been demonstrated with the pioneering work on plasma fibrinogen, will facilitate acquisition of data and qualification of additional biomarkers and other drug development tools.
| 1. | Miniño AM, Murphy SL, Xu J, Kochanek KD. Deaths: final data for 2008. Natl Vital Stat Rep 2011;59:1–126. |
| 2. | Yach D, Hawkes C, Gould CL, Hofman KJ. The global burden of chronic diseases: overcoming impediments to prevention and control. JAMA 2004;291:2616–2622. |
| 3. | Oba Y, Lone NA. Efficacy and safety of roflumilast in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis. Ther Adv Respir Dis 2013;7:13–24. |
| 4. | Mushtaq Y. The COPD pipeline. Nat Rev Drug Discov 2014;13:253–254. |
| 5. | Loukides S, Bartziokas K, Vestbo J, Singh D. Novel anti-inflammatory agents in COPD: targeting lung and systemic inflammation. Curr Drug Targets 2013;14:235–245. |
| 6. | Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010;11:122–135. |
| 7. | Rennard SI, Vestbo J. The many “small COPDs”: COPD should be an orphan disease. Chest 2008;134:623–627. |
| 8. | Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM; POET-COPD Investigators. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364:1093–1103. |
| 9. | Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, D’Andrea P, Arrasate C, Chen H, Banerji D. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Lancet Respir Med 2013;1:199–209. |
| 10. | Dransfield MT, Bourbeau J, Jones PW, Hanania NA, Mahler DA, Vestbo J, Wachtel A, Martinez FJ, Barnhart F, Sanford L, et al. Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 2013;1:210–223. |
| 11. | U.S. Food and Drug Administration. Innovation/stagnation: challenge and opportunity on the critical path to new medicinal products. 2004 [accessed 2016 Feb 15]. Available from: http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm113411.pdf |
| 12. | U.S. Food and Drug Administration. Qualification process for drug development tools: guidance for industry and FDA staff. 2014 [accessed 2015 Aug 10]. Available from: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm230597.pdf |
| 13. | European Medicines Agency. Qualification of novel methodologies for drug development: guidance to applicants. 2014 [accessed 2015 Aug 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2009/10/WC500004201.pdf |
| 14. | U.S. Food and Drug Administration. Qualification of biomarker—plasma fibrinogen in studies examining exacerbations and/or all-cause mortality in patients with chronic obstructive pulmonary disease: draft guidance for industry. 2015 [accessed 2015 Aug 10]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM453496.pdf |
| 15. | DiMasi JA, Grabowksi HG, Hansen RW. Innovation in the pharmaceutical industry: new estimates of R&D costs. 2014 [accessed 2015 Aug 10]. Available from: http://csdd.tufts.edu/files/uploads/Tufts_CSDD_briefing_on_RD_cost_study_-_Nov_18,_2014..pdf |
| 16. | Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Clinical development success rates for investigational drugs. Nat Biotechnol 2014;32:40–51. |
| 17. | U.S. Food and Drug Administration. Qualification of exacerbations of chronic pulmonary disease tool for measurement of symptoms of acute bacterial exacerbation of chronic bronchitis in patients with chronic obstructive pulmonary disease. Draft guidance for industry. 2014 [accessed 2015 Aug 14]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM380961.pdf |
| 18. | Casaburi R, Celli B, Crapo J, Criner G, Croxton T, Gaw A, Jones P, Kline-Leidy N, Lomas DA, Merrill D, et al. The COPD Biomarker Qualification Consortium (CBQC). COPD 2013;10:367–377. |
| 19. | Lowe GDO, Rumley A, Mackie IJ. Plasma fibrinogen. Ann Clin Biochem 2004;41:430–440. |
| 20. | Duvoix A, Dickens J, Haq I, Mannino D, Miller B, Tal-Singer R, Lomas DA. Blood fibrinogen as a biomarker of chronic obstructive pulmonary disease. Thorax 2013;68:670–676. |
| 21. | de Maat MPM. Effects of diet, drugs, and genes on plasma fibrinogen levels. Ann N Y Acad Sci 2001;936:509–521. |
| 22. | Mannino DM, Tal-Singer R, Lomas DA, Vestbo J, Graham Barr R, Tetzlaff K, Lowings M, Rennard SI, Snyder J, Goldman M, et al. Plasma fibrinogen as a biomarker of mortality and hospitalized exacerbations in people with COPD. Chronic Obstr Pulm Dis (Miami) 2015;2:23–34. |
| 23. | Valvi D, Mannino DM, Müllerova H, Tal-Singer R. Fibrinogen, chronic obstructive pulmonary disease (COPD) and outcomes in two United States cohorts. Int J Chron Obstruct Pulmon Dis 2012;7:173–182. |
| 24. | Celli BR, Locantore N, Yates J, Tal-Singer R, Miller BE, Bakke P, Calverley P, Coxson H, Crim C, Edwards LD, et al.; ECLIPSE Investigators. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012;185:1065–1072. |
| 25. | Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, et al.; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. Plos One 2012;7:e37483. |
| 26. | Gan WQ, Man SF, Senthilselvan A, Sin DD. Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 2004;59:574–580. |
| 27. | National Center for Health Statistics. Analytic and reporting guidelines: the Third National Health and Nutrition Examination Survey, NHANES III (1988-94). Hyattsville, MD: Centers for Disease Control and Prevention. 1996 [accessed 2015 Aug 10]. Available from: http://www.cdc.gov/nchs/data/nhanes/nhanes3/nh3gui.pdf |
| 28. | Feinleib M, Kannel WB, Garrison RJ, McNamara PM, Castelli WP. The Framingham Offspring Study: design and preliminary data. Prev Med 1975;4:518–525. |
| 29. | Fried LP, Borhani NO, Enright P, Furberg CD, Gardin JM, Kronmal RA, Kuller LH, Manolio TA, Mittelmark MB, Newman A, et al. The Cardiovascular Health Study: design and rationale. Ann Epidemiol 1991;1:263–276. |
| 30. | The ARIC Investigators. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. The ARIC investigators. Am J Epidemiol 1989;129:687–702. |
| 31. | Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G, Knobil K, Lomas DA, MacNee W, et al.; ECLIPSE investigators. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 2008;31:869–873. |
| 32. | Couper D, LaVange LM, Han M, Barr RG, Bleecker E, Hoffman EA, Kanner R, Kleerup E, Martinez FJ, Woodruff PG, et al.; SPIROMICS Research Group. Design of the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS). Thorax 2014;69:491–494. |
| 33. | Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, Curran-Everett D, Silverman EK, Crapo JD. Genetic epidemiology of COPD (COPDGene) study design. COPD 2010;7:32–43. |
| 34. | Fisk M, Mohan D, Cheriyan J, Yang L, Fuld J, McEniery CM, Tal-Singer R, Polkey MI, Wilkinson IB. Evaluation of losmapimod in patients with chronic obstructive pulmonary disease (COPD) with systemic inflammation stratified using fibrinogen (‘EVOLUTION’): rationale and protocol. Artery Res 2014;8:24–34. |
| 35. | U.S. Food and Drug Administration. Identifying potential biomarkers for qualification and describing contexts of use to address areas important to drug development: request for comments. Fed Regist 2015;80:8089-8091 [accessed 2015 Aug 10]. Available from: https://www.federalregister.gov/articles/2015/02/13/2015-02976/identifying-potential-biomarkers-for-qualification-and-describing-contexts-of-use-to-address-areas |
| 36. | Amur SG, Sanyal S, Chakravarty AG, Noone MH, Kaiser J, McCune S, Buckman-Garner SY. Building a roadmap to biomarker qualification: challenges and opportunities. Biomarkers Med 2015;9:1095–1105. |
| 37. | Rooney C, Sethi T. Biomarkers for precision medicine in airways disease. Ann N Y Acad Sci 2015;1346:18–32. |
| 38. | Yonchuk JG, Silverman EK, Bowler R, Agusti A, Lomas DA, Miller BE, Tal-Singer R, Mayer RJ. Circulating soluble receptor for advanced glycation end products (sRAGE) as a biomarker of emphysema and the RAGE axis in the lung. Am J Respir Crit Care Med 2015;192:785–792. |
| 39. | Pascoe S, Locantore N, Dransfield MT, Barnes NC, Pavord ID. Blood eosinophil counts, exacerbations, and response to the addition of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015;3:435–442. |
| 40. | Leidy NK, Murray LT. Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS. COPD 2013;10:393–398. |
| 41. | Donaire-Gonzalez D, Gimeno-Santos E, Balcells E, Rodríguez DA, Farrero E, de Batlle J, Benet M, Ferrer A, Barberà JA, Gea J, et al. Physical activity in COPD patients: patterns and bouts. Eur Respir J 2013;42:993–1002. |
| 42. | Gimeno-Santos E, Raste Y, Demeyer H, Louvaris Z, de Jong C, Rabinovich RA, Hopkinson NS, Polkey MI, Vogiatzis I, Tabberer M, et al.; PROactive consortium. The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease. Eur Respir J 2015;46:988–1000. |
Author Contributions: All authors contributed to the conception and design of the work and interpretation of data and critically reviewed the manuscript for intellectual content. All authors provided approval of the final version of the manuscript.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201509-1722PP on January 8, 2016
Author disclosures are available with the text of this article at www.atsjournals.org.
