Download pdf - The COPD Biomarker Qualification Consortium (CBQC)

367

ORIGINAL RESEARCH

The COPD Biomarker Qualifi cation Consortium (CBQC)Richard Casaburi,1 Bartolome Celli,2 James Crapo,3 Gerard Criner,4 Thomas Croxton,5 Alasdair Gaw,6 Paul Jones,7 Nancy Kline-Leidy,8 David A. Lomas,9 Debora Merrill,10 Michael Polkey,11 Stephen Rennard,12 Frank Sciurba,13 Ruth Tal-Singer,14 Robert Stockley,15 Gerry Turino,16 Jorgen Vestbo,17 and John Walsh10

1Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, California, USA; 2Harvard University, Department of Internal Medicine, Boston, MA, USA; 3Harvard University, Department of Internal Medicine, Boston, MA, USA; 4Temple University, Philadelphia, Pennsylvania, USA; 5National Heart, Lung and Blood Institute, Rockville, MD, USA; 6Technology Strategy Board, Leicester, UK; 7Department of Internal Medicine, University of London, London, UK; 8United BioSource Corporation, Washington, DC, USA; 9Department of Internal Medicine, University of Cambridge, Cambridge, UK; 10COPD Foundation, Washington, DC, USA; 11Department of Internal Medicine, Royal Brompton & Harefi eld NHS, London, UK; 12Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA, 13Department of Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 14GlaxoSmithKline, Research Triangle Park, NC, USA; 15Department of Internal Medicine, University Hospital Birmingham, NHS Foundation, Birmingham, UK; 16Department of Internal Medicine, Columbia University, New York, NY, USA; 17Department of Internal Medicine, University of Manchester, Manchester, UK

The COPD Biomarker Qualifi cation Consortium (CBQC) is a collaborative project to develop new tools for the development and testing of treatments for Chronic Obstructive Pulmonary Disease. This report summarizes the origin, goals and current activities of the Consortium.

Keywords: biomarker, biomarker qualifi cation, CBQC, COPD Exacerbations, COPD foundation, desmosine, exercise, exhaled breath biomarkers, fi brinogen, imaging, patient-reported outcomes, St. George’s respiratory questionnaire, six-minute walk test, sputum measures

Correspondence to: Stephen I. Rennard, M.D., Pulmonary and Critical Care Medicine, 985910 Nebraska Medical Center, Omaha, Nebraska 68198-5910, phone: 402/559-7313, fax: 402/559-4878, email: [email protected]

Abstract

Knowledge about the pathogenesis and pathophysiology of chronic obstructive

pulmonary disease (COPD) has advanced dramatically over the last 30 years.

Unfortunately, this has had little impact in terms of new treatments. Over the

same time frame, only one new class of medication for COPD has been introduced.

Even worse, the rate at which new treatments are being developed is slowing.

The development of new tools for the assessment of new treatments has not kept

pace with understanding of the disease. In part, this is because drug development

tools require a regulatory review, and no interested party has been in a position to

undertake such a process. In order to facilitate the development of novel tools to

assess new treatments, the Food and Drug Administration, in collaboration with

the COPD Foundation, the National Heart Lung and Blood Institute and scientists

from the pharmaceutical industry and academia conducted a workshop to survey

the available information that could contribute to new tools. Based on this, a

collaborative project, the COPD Biomarkers Qualifi cation Consortium, was initiated.

The Consortium in now actively preparing integrated data sets from existing

resources that can address the problem of drug development tools for COPD.

COPD, 10:367–377, 2013ISSN: 1541-2555 print / 1541-2563 onlineCopyright © Informa Healthcare USA, Inc.DOI: 10.3109/15412555.2012.752807

Introduction

Chronic obstructive pulmonary disease (COPD) is a major public health problem. It is currently the third-leading cause of death in the United States, is a major cause of morbidity and is a major driver of health care costs. Recent advances in understanding the pathogenetic mechanisms that under-lie COPD have lead to the identifi cation of many novel therapeutic targets. As a result, a large number of agents have been explored as potential treat-ments, both at the preclinical and clinical levels. However, the tools used to assess treatments for COPD have been limited and better tools are needed, as the number of new drugs (new molecular entities) being approved to treat COPD is declining and attrition rate is high.

As discussed in the FDA draft guidance for industry, drug development for COPD can be aimed at diff erent aspects of the disease: improving air-fl ow, providing symptom relief, modifying or preventing exacerbations, altering the disease process, or modifying lung structure or treating extra-pulmonary manifestations. While there has been some success with drug therapies for the fi rst three of these disease aspects, it is in the most crucial areas of COPD treatment (i.e., altering the disease process, or modifying lung structure or treating extra-pulmonary manifestations) that eff ective therapies are lacking.

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368 Casaburi et al.

To date, the medications for the treatment of COPD have been FDA-approved primarily on the basis of improvements in lung function, i.e., FEV

1. Although

FEV1 may be adequate to evaluate treatments aimed at

improving lung function and the airways obstruction that is associated with COPD, FEV

1 (alone) may be inad-

equate to evaluate the effi cacy of novel therapies target-ing disease progression, lung structure or extrapulmo-nary manifestations of the disease. In the last four years, three U.S.-approved products: Advair ™250/50 (fl utica-sone propionate 250 mcg and salmeterol 50 mcg inhala-tion powder), Spiriva™ (tiotropium bromide inhalation powder) and Daliresp™ (rofl umilast) have obtained the claim of reduction in COPD exacerbations. However, the initial approved indication for two of these three products (improvement in lung function for Advair, and maintenance treatment of bronchospasm for Spiriva) was based on FEV

1.

Th e natural history of COPD is generally that of pro-gressive deterioration of lung function and functional status, worsening quality of life, and, in many cases, demise. However, this progression is slow, occurring over years or decades, complicating interventional studies using these endpoints. In addition, COPD is extremely heterogeneous and while a number of attempts have been made to defi ne subsets of COPD, effi cient strate-gies to develop treatments targeting specifi c groups of COPD patients have yet to emerge. Th e extrapulmonary manifestations of COPD are becoming increasingly rec-ognized as substantial causes of morbidity and mortality that need timely characterization and treatment. Bio-markers have the potential to refl ect reliably the disease process and activity, and provide a better understanding of the COPD subtypes, especially the systemic or non-pulmonary manifestations.

Th us, biomarkers may allow for the development of therapies aimed at treating COPD using endpoints other than FEV

1. A large number of biomarkers have been

explored in this context. However, the use of biomark-ers in drug development requires rigorous evaluation of their utility. Recognizing the importance of biomarkers to advance the development of new treatments, the Food and Drug Administration (FDA) in the United States initiated a Biomarker Qualifi cation Process.

Biomarker qualifi cationTh e Biomarker Qualifi cation Process is part of the Drug Development Tools Qualifi cation program recently ini-tiated at the FDA. Th e Biomarker Qualifi cation process was established to support FDA’s work with external sci-entists and clinicians in developing biomarkers to serve as tools in clinical trials. Th e importance of this eff ort is evidenced by the FDA Critical Path initiative, which identifi es Biomarker qualifi cation as one of the Critical Path Opportunities (2). Furthermore, the importance of the Drug development Tools qualifi cation programs (including biomarker qualifi cation) is underscored by the recent (2010) publication of the draft guidance for

industry onthe Qualifi cation Process forDrug develop-ment Tools (3), andby the identifi cation of “Advancing Regulatory Science and Innovation” as one of the fi ve cross-cuttingareas to serve as FDA strategic priorities over the 5-year period 2011–2015 (4). Th e goal of the biomarker qualifi cation process is to qualify biomark-ers for specifi c contexts of use, which could impact drug development and may shorten the time necessary to develop a successful marketing application for regula-tory review. A context of use defi nes how a biomarker, once qualifi ed will be used in clinical or nonclinical decision-making. Some specifi c recognized contexts of use include but are not limited to: stratifi cation of patient populations, use in dose ranging and as outcome (effi cacy or safety) measures.

Th e reader is referred to the DDT guidance and the Agency’s website of biomarker qualifi cation located at: http://www.fda.gov/Drugs/DevelopmentApprovalPro-cess/DrugDevelopmentToolsQualificationProgram/ucm284076.htm for details on the biomarker qualifi ca-tion submission process.

Bethesda Workshop, 2010A pathway for qualifi cation of biomarkers as novel tools to aid drug development, therefore, has been defi ned. Th e process, necessarily, requires a substantial data set supported by a very careful analysis. Because of this, the process is likely to be expensive and time consuming. Th e resources required are likely to exceed those that could be justifi ed for any single pharmaceutical company or that would be likely to merit high priority in com-petitive public funded research. Although a rich body of information about biomarkers is already available as a result of industry and government research funded, in 2009, it was unclear whether suffi cient information was available to support qualifi cation of selected biomarkers for drug development in COPD.

Building on the initial enthusiasm for the Biomarker Qualifi cation process at the FDA and interest from phar-maceutical companies and academic research partners in sharing the scope of the data available, the “COPD Biomarkers Qualifi cation Workshop” was organized in Bethesda, MD under the auspices of the COPD Founda-tion on January 10, 2010. Th e Foundation was able to provide a neutral ground where representatives of the FDA, European Medicines Agency (EMA), Industry, Academia and the NIH could meet and discuss available data in an open forum. Th e format for the workshop consisted of a series of sessions in which various bio-markers and classes of biomarkers were discussed with regard to several specifi c questions (Table 1).

Participants from government, academia and indus-try presented and led discussions (Table 2) and were extremely open in sharing specifi c fi ndings relevant to individual biomarkers from unpublished data sets. Th is was followed by straw votes on whether the various biomarkers were of interest and had suffi cient data to merit consideration for qualifi cation. Biomarkers in fi ve

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COPD Biomarker Consortium 369

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general areas were felt to have a rich body of data avail-able that might be suffi cient to support qualifi cation. In addition, several were felt to be of signifi cant interest, but additional work was likely to be needed. One bio-marker was noted to be in the process of review.

COPD Exacerbations: Candidate Drug Development ToolsTh e EXACT-PRO (Exacerbations of Chronic Pulmonary Disease Tool – Patient-Reported Outcome) Initiative is a multi-sponsor project involving clinical, research, methodology, and regulatory experts in the develop-ment of a standardized PRO instrument to measure the frequency, severity, and duration of exacerbations in clinical trials of COPD. Phase I included focus groups and 1:1 interviews with 83 patients with COPD, and two expert panels to inform instrument content and struc-ture. Phase II involved a two-group observational study of 222 patients with a clinician-confi rmed exacerba-tion who completed the daily diary via personal digital

Table 1. Questions relevant for each biomarker

• Why was the biomarker selected for study?• Why is the biomarker relevant?• What is the biomarker’s clinical relevance?• Is the biomarker responsive to intervention over the short and/or long

term?• What was the population or subtype or segment for which the biomarker

is relevant?• Is the biomarker currently qualifi ed?• Are the results reproducible and appropriately sensitive?

assistant (PDA) on Days 1–28 of their exacerbation and Days 60-67.

A second group of 188 patients considered clinically stable completed the diary over seven days. Th e fi nal 14 items comprising the EXACT include assessments of shortness of breath, chest congestion, cough, sputum, chest discomfort, feeling weak or tired, sleep distur-bances, and concern or worry. Scores on the instrument exhibited strong evidence of reliability (internal consis-tency and reproducibility in stable patients) and validity, including responsiveness to change over time in acutely ill patients, correlation with the St. George’s Respiratory Questionnaire (SGRQ), clinician and patient ratings of severity, and diff erentiation of responders and non-responders from Day 1 to 10 of the event.

Th ese results suggested the instrument was ready for use in prospective clinical trials. Methods and results of the development and validation of the EXACT were summarized in a PRO Evidence Dossier submitted to the FDA to qualify the instrument for use in clinical tri-als testing the eff ect of treatment on frequency, severity and/or duration of exacerbations of COPD.

Th e discussion of the EXACT-PRO development process, which represented a collaboration among a number of pharmaceutical and academic collaborators with active participation of the FDA, was felt to be a suc-cessful paradigm for biomarker development.

Additional biomarkers for assessing COPD exacerba-tions were also discussed. Raised serum C-reactive pro-tein (CRP) (5) and plasma fi brinogen (6) are associated

Table 2. Meeting agenda

Session 1: Background

FDA Biomarker Qualifi cation Process Frederico GoodsaidFDA PRO Tool Qualifi cation Process Laurie BurkeRedefi ning COPD as a Multi-component Disease: Emerging knowledge of the pathophysiology of COPD Thomas CroxtonSession 1: PROs Overview-Symptoms and Health Status Questionnaires EXACT PRO Nancy LeidySGRQ, SGRQ-C, CAT, EQ-5D Paul Jones

Session 2: Candidate Biomarkers for Use as Intermediates in Drug Development in COPD –linking Phase II endpoints to Phase III outcomes, Part 1: Biochemical markers

Desmosine/isodesmosine in blood and urine Alasdair GawExhaled breath biomarkers Ruth Tal-SingerBlood biomarkers-stable disease David LomasBlood biomarkers-COPD exacerbation Chris Brightling and Jorgen VestboSputum biomarkers Robert Stockley and Ian KiltyDiscussion Leonardo Fabbri

Part 2: Physiology and Performance Outcomes

Assessment of lung mechanics/physiology: data from cohort studies Gerard CrinerAssessment of lung mechanics/physiology: data from intervention studies Dennis O’DonnellFunctional Performance: 6-minute walk Frank SciurbaFunctional Performance: Shuttle walk Michael PolkeyFunctional Performance: Activity monitoring and strength testing Richard CasaburiImaging for patient selection Edwin Silverman

Session 3: Panel Discussions

Panel discussion on Multidimensional index or indices Bartolome Celli and Edwin SilvermanPanel discussion on Candidate Biomarkers for Qualifi cation Stephen RennardView From the Meeting Chairpersons and Closing Remarks Lydia Gilbert-McClain and James Kiley

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370 Casaburi et al.

with future risk of exacerbations and management strat-egies directed at normalizing sputum eosinophil counts have yielded reductions in exacerbation frequency (7). However, the application of biomarkers to distinguish exacerbation and stable events in the same subjects has been disappointing. Although CRP in combination with a major symptom (8) and serum amyloid A (9) promise to identify exacerbations, their sensitivity and specifi city was felt to be insuffi cient for widespread clinical utiliza-tion. Th us, no biochemical measures for exacerbations were considered ready for qualifi cation.

Blood biomarkersBlood biomarkers have attracted considerable interest and were discussed in detail. Several relatively novel biomarkers that may refl ect lung specifi c activity were discussed. Blood levels of the lung specifi c biomarkers Clara Cell protein (CC)-16 (10) and surfactant protein-D (11) are signifi cantly diff erent in individuals with COPD when compared to smoker controls without airfl ow obstruction. As well as being associated with disease, serum surfactant protein-D is sensitive to the adminis-tration of both inhaled (12) and oral corticosteroids (11) in COPD. However, the clinical implication of raised or reduced levels of CC-16 and surfactant protein-D is uncertain and additional work is needed to determine their value in following disease progression and as inter-mediate endpoints in clinical studies.

Th e systemic component of COPD may also be refl ected by raised mean values of blood fi brinogen, C-reactive protein (CRP) and IL-6. CRP and fi brinogen are associated with GOLD stage of disease and are ele-vated during COPD exacerbations of COPD. Elevated levels of CRP and fi brinogen have also been associated with increased risk for hospitalization and death from this disease (13,14). CRP shows signifi cant variability in COPD while fi brinogen is much more stable. Moreover blood fi brinogen is sensitive to intervention with inhibi-tors of p38 MAP kinase (dilmapimod [15] and losamapi-mod [16]) in COPD. Because of its stability, association with COPD-related outcomes (exacerbation, hospital-ization and death) and sensitivity to intervention, fi brin-ogen was felt to be a very promising biomarker.

Health statusHealth status/health-related quality of life measures are designed to provide a summative measure of the overall impact of COPD on health, regardless of phenotype. Th ey are also designed to measure the overall benefi t of treatment regardless of mechanism or site of action. Th e most widely used measure is the 50-item St. George’s Respiratory Questionnaire (SGRQ). It has proven dis-criminative and evaluative properties and predictive validity. Much experience has been gained from its use in all pivotal trials in COPD over the last decade.

It uses empirical patient-derived weights to provide a valid overall measure of health impairment. Th is methodology has not found wide use because of its

complexity and need for computerized scoring algo-rithms. Recent FDA guidance places great weight on deriving candidate PRO items directly from patients. A new instrument, the COPD Assessment Test (CAT) has done this and coupled it with modern mathematical techniques to ensure that it had very reliable measure-ment properties. Th is instrument only has 8 items and a simple 6-point scale. Studies in United States, Europe and China have shown a very strong correlation (> 0.8) with SGRQ. Th e strength of this association, between two instruments designed to measure the same con-struct but developed and structured in very diff erent ways, provides powerful evidence that the SGRQ does measure impaired health in COPD. Th is, combined with the very rich data set available, led to a strong con-sensus that the SGRQ would be an excellent candidate biomarker for qualifi cation.

Lung mechanicsFor over 150 years, spirometry has been the pre-dominant tool used in COPD to assess the presence and severity of airways obstruction and measure the response to therapy. FEV

1, or changes in FEV

1, have been

used to predict mortality, characterize patients as sur-gical candidates (e.g., lung cancer resectional surgery, lung volume reduction surgery), approve medications for clinical use and designate patients as legally handi-capped or disabled from gainful employment. However, recent data show that FEV

1 does not correlate well with

patient reported outcomes such as quality of life, degree of breathlessness, extent of exercise performance or bronchodilator responsiveness in those most severely obstructed (i.e., GOLD Stages III–IV).

Conversely, measurements of lung hyperinfl ation (RV, RV/TLV, IC, IC/TLC, and EELV) have been found to be superior to FEV

1 in assessing dyspnea, exercise

capability, ability to wean from mechanical ventilation and even survival. Casanova demonstrated in patients with mild to severe COPD that an Inspiratory Capacity (IC) to Total Lung Capacity (TLC) ratio (IC/TLC) ≤ 0.25 was associated with a two-fold increase in mortality over a 4-year follow-up period compared to patients with an IC/TLC > 0.25.

Recent data from the ECLIPSE cohort in 1162 COPD subjects shows that hyperinfl ation is present in all stages and worsens with increasingly more severe airfl ow obstruction (RV % pred vs. FEV

1 % pred, r = –0.645,

p < 0.001) (17). Moreover, RV % predicted correlated directly with complaints of breathlessness (p < 0.001), more impaired overall health status (r = 0.492, p < 0.001) and inversely with 6 MWD (r = –0.211, p < 0.001). Physi-ological measurement of hyperinfl ation is an important marker of lung mechanics that is valuable in character-izing COPD patients and assessing their response to therapy. Based on the discussions and the potentially rich data set available, a measure of lung infl ation, and in particular of hyperinfl ation, was felt to be a potential biomarker worth further consideration.

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Lung imagingChest CT scans have become extremely valuable tools in the assessment of COPD, because, among other virtues, the degree of emphysema can be accurately and non-invasively quantifi ed (18). Both qualitative (radiologist scoring) and quantitative (computerized image analysis) approaches have been used to analyze the severity and distribution of emphysema. Quantitative emphysema assessments are often based on determining the per-centage of lung voxels below a specifi c threshold, such as -910 or -950 HU (19,20). Measurements of airway wall dimensions have been more challenging, and many diff erent approaches have been used.

Hasegawa and colleagues reported an approach (curved multiplanar reconstruction) to obtain longitudi-nal airway reconstructions and accurate measurements of airway wall area with airways as small as 2 mm in lumenal diameter (21). Of interest, they found stronger correlations of FEV

1 with airway wall area measurements

with smaller, rather than larger airways. Th is work indi-cates the potential value of airway wall measurements in dissecting the heterogeneity of COPD, as well as the importance of studying small airways in such analyses. Several studies have shown that quantitative CT mea-sures of emphysema and airway disease are signifi cant and independent predictors of airfl ow obstruction (22).

Change in chest CT lung density has been assessed as an outcome for the eff ect of alpha-1 antitrypsin (AAT) augmentation therapy in two studies of AAT-defi cient subjects (23,24); in both cases, the CT density outcome was of borderline statistical signifi cance. Applying quan-titative chest CT assessments in clinical trials requires careful quality control. Understanding of the impact of CT scanner brand, model, and reconstruction kernel is required. Standardized approaches to measurements to be used in clinical trials would be benefi cial. Chest CT scans can have been used eff ectively for subject stratifi cation. For example, the National Emphysema Treatment Trial (NETT) identifi ed a benefi t from lung volume reduction surgery for subjects with upper lobe predominant emphysema (25). CT scans engender a non-trivial radiation exposure; the appropriate radiation dosage to balance subject risk and quantitative imaging data quality remains to be determined.

ExerciseSeveral measures of exercise were considered. Peak oxy-gen uptake is a predictor of survival (26,27) and constant or incremental work rate cardiopulmonary exercise testing provides rigorous assessment of performance, but both require specialized equipment and methods, making studies in large groups of subjects problematic. Th e 6-minute walk test (6MWT) is attractive because it has been performed in large cohorts and is predictive of long-term outcomes on its own (26,28) or as part of the widely used BODE index (29).

Th ere is great experience in the use of 6MWT, partic-ularly in North America, and it is accepted for labeling

claims in other conditions (e.g., pulmonary hyperten-sion) by the FDA. Th e incremental shuttle walk test (ISWT), more popular in Europe, has the advantage of being externally paced and reproducible and captures improvements conferred by treatments of known effi -cacy such as pulmonary rehabilitation. Areas of concern for both tests include a ceiling eff ect so that they are less responsive in individuals with mild exercise intolerance. A practice walk increases precision and can reduce sample size. For the 6MWT, new analyses suggest the minimal clinically important diff erence (MCID) may be closer to 25 m rather than 54 m for a variety of disorders (30–32) and this is being reassessed in COPD.

Quadriceps strength measurement has mostly been confi ned to small studies although values in a larger cohort have recently become available (33) and it is known that weakness is associated with increased mor-tality (34). Physical activity is an independent predictor of long-term outcome (35); it can be assessed by ques-tionnaire or electronic device (36,37). A joint European Union-pharma funded initiative between the industry and academia in Europe (the PROactive project) has the goal of developing a patient reported outcome tool by combining physical activity monitoring with a question-naire developed from qualitative research with patients. Activity monitoring technology is advancing rapidly, but standardization of measurement methodology cru-cial, and this is presently being established as part of PROactive.

Because of the wealth of experience available, its cur-rent use by the FDA and acceptance in the clinical com-munity, the 6MWT was felt to be the activity measure with the best available data set for qualifi cation. Other measures including physical activity and quadriceps strength were considered of interest for further research and are currently being evaluated by a U.K. government-funded consortium, COPD MAP.

Other biomarkersAs noted above, a number of other biomarkers were discussed that were not felt to be likely candidates for qualifi cation based on existing data sets. Two, however, were felt to be of considerable promise and were the subject of active ongoing research programs.

DesmosineElastin degradation products can be eff ective biomarkers in COPD (38,39). Lung elastin undergoes degradation in COPD related to smoke exposure or genetically deter-mined alpha-1 antitrypsin defi ciency (AATD) (40,41). Elastin degradation is detectable by measurements of specifi c amino acids, desmosine and isodesmosine (DI), which occur only in elastin. Recent methods have improved accuracy and sensitivity of measurements of DI in all body fl uids (42,43), including sputum. Accumu-lating data suggest that desmosine refl ects disease sever-ity, may refl ect disease activity and may be sensitive to change, thus giving it great potential a biomarker.

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Plasma levels of DI are increased in COPD (44), are higher in AATD (44) and increase with progression of disease (45). Measurements of DI in urine correlate with COPD severity (38). Healthy non-smokers have the lowest levels of DI excretion, which are progressively increased in smokers with normal lung function, in patients with stable COPD, and in patients with COPD during exacerbations. Th e highest levels have been observed in. Measurements of DI in urine and plasma in patients from the Swedish Twin Registry in 115 subjects with COPD demonstrated correlations with all lung function measurements after adjustments for age, gen-der, height, body mass index (BMI) and smoking.

Plasma desmosine values were uniformly correlated with FEV

1 and DLCO (46). Urinary desmosine values

were signifi cantly correlated with all lung function measurements after adjustments for age, gender, height, body mass index (BMI) and smoking. Finally, plasma and sputum levels of DI were lowered following treatment with tiotropium in although whether this is related to long term progression of emphysema is not known (47). Desmosine, therefore, has great potential as a biomarker as it directly relates to disease pathogenesis.

Sputum measuresTh e collection of biological specimens from the airways involves either spontaneous or (more recently) induced sputum that provides a means to directly sample the lung, and is very appealing as a means to access poten-tial biomarkers. Th ese samples contain a multitude of infl ammatory mediators that are associated with the disease process in COPD patients. However, sample processing and analyte measurements in a non-plasma matrix require considerable validation including spike recovery, which has not always been done. In addition, issues relating to the eff ect of variable dilution during the collection process and the presence or absence of spon-taneous sputum, bacterial colonization, smoking habit and therapy need to be considered. As these have not generally been performed, sputum measures were not felt to be ready, at the present time, for qualifi cation.

Exhaled breath biomarkers have the potential to sample the lung in a non-invasive manner. Sampling methodologies are well-tolerated, allowing repeated assessments of airway lining fl uid in the clinic or at home using commercially available devices. Th ere is a signifi cant body of literature that supports the applica-tion of exhaled breath condensate (EBC) and exhaled breath volatiles in COPD drug development (48, 49). However, there are currently several key issues that limit the potential for any exhaled breath biomarker for qualifi cation (50,51). Markers that have been explored included CO

2, pH, NO, CO, metabolites, leukotrienes,

prostanoids, hydrogen peroxide, cytokines, and alde-hydes. Issues that remain to be resolved for these biomarkers include: (i) variability in sample collection methods, (ii) lack of standard assay methodology leading to variability in reported levels of biomarkers, (iii) lack

of reproducibility data, (iv) dilution of EBC limits assay accuracy with currently available methodologies, (v) inconsistent associations with clinical measures based on data obtained from small numbers of subjects and (vi) diffi culty in publishing negative studies.

Follow-upAt the conclusion of the Bethesda workshop, there was considerable enthusiasm on three fronts. First, it was felt that for several biomarkers suffi cient data may exist in the form of completed studies to support a dossier for qualifi cation. Second, it was clear that there was willingness of many parties, including pharmaceutical companies, to collaborate in an eff ort to prepare dos-siers for qualifi cation of biomarkers, including sharing unpublished proprietary data. Finally, the COPD Foun-dation seemed an ideal organization to provide a “neu-tral” platform that could facilitate a collaborative eff ort based on pooled existing data.

With this background, the COPD Foundation embarked on the creation of the COPD Biomarkers Qualifi cation Consortium (CBQC). Th e Consortium would be supported by member pharmaceutical compa-nies, each of which would contribute fi nancial support, data and expertise. Th e consortium would also include experts from academia with the FDA, EMA and NHLBI in an advisory role.

Concurrent with the organizational eff orts, fi ve ad hoc working groups, refl ecting the biomarkers that had the highest enthusiasm at the Bethesda workshop, met informally on a number of occasions during 2010. Th ese groups conducted more detailed discussions on the merits and limitations of candidate biomarkers and conducted a more detailed survey of available data.

Based on the discussions of these groups, it was felt that three biomarkers would merit highest consideration for qualifi cation: fi brinogen for stratifi cation of subjects at risk for hospitalization and mortality, 6-minute walk distance for stratifi cation of subjects at risk for mortality and SGRQ for subject stratifi cation and as an outcome measure. Imaging was felt to be a very promising bio-marker. However, a parallel eff ort for qualifi cation of CT Scanning was currently in progress through the Society of Th oracic Radiology, so action on this biomarker was deferred. Measurement of lung volumes as a biomarker was felt to be promising, but a number of issues and concerns were raised which required further evaluation of available data and review of methods of quality con-trol used on various studies.

The COPD Biomarkers Qualifi cation ConsortiumAn organizational structure was created and arrange-ments made (Figure 1), and the CBQC was offi cially launched on October 4th, 2010. Founding members included GlaxoSmithKline, BoehringerIngelheim, AstraZeneca and Pfi zer. Novartis joined in October, 2011. Th e consortium is supported by restricted funds contributed by participating pharmaceutical companies.

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All intellectual property resulting from the CBQC eff orts will be owned by the COPD Foundation and will be made freely available to all, thus facilitating the devel-opment of new treatments. Th e consortium is governed by a Steering committee with elected representatives for each partner as well as specifi c working groups (e.g., exercise, biochemical biomarkers, PROs, lung function, and two expert support groups: Regulatory and Data Management).

A data analysis structure was created, and, after soliciting bids, a contract was awarded to INC Research who will assemble a database pooling data provided by collaborators from industry, government and academic sources. Th is structure allowed sharing of anonymized clinical trials data in a pre-competitive setting, a key component for Public-Private-Partnerships.

Formal working groups for fi brinogen, SGRQ, 6-min-ute walk distance and lung volumes were constituted. Because it was given a lower priority, work on lung vol-umes was deferred. Th e other working groups then con-ducted a series of assessments confi rming the viability

of these biomarkers and collecting a set of data from specifi c studies that could support a dossier (Figure 2). Based on these reviews, letters of intent to submit a dos-sier for qualifi cation of each these biomarkers were then submitted to the FDA. Th is led to a meeting with the FDA to discuss the overall process. Th e FDA expressed enthusiasm for the development of biomarkers to aid as tools in drug development. Specifi c comments were also made regarding the three letters of intent. Th e letter of intent for fi brinogen was accepted and the Biomarker Qualifi cation Review Team (BQRT) has been created.

Th e response to the SGRQ and the 6-minute walk measures, however, was diff erent. Th e FDA clarifi ed that measures such as the SGRQ and the 6-minute walk were not considered as biomarkers, but rather as clinical assessments. Th e FDAalso indicatedthat the SGRQwas already used in clinical trials for COPD and did not need to go through thequalifi cation process. Th e FDA also explained that the 6-minute walk could be used in clinical trials for stratifi cation via direct interaction with the review Division without qualifi cation. However, the

Figure 2. Number of studies and subjects that will be included in the analysis of the initial biomarker targets by the Consortium.

Figure 1. Structure of the COPD Biomarkers Qualifi cation Consortium.

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Consortium was also encouraged by the FDA to con-sider the 6-minute walk as an outcome for which the Agency would be willing to engage in the process of qualifi cation. Although FDA currently accepts the use of the SGRQ in clinical trials and will accept the 6-min-ute walk as a stratifi cation tool for patient enrollment, careful review of these measures is still necessary for rigorous study design.

In particular, if a measure is used during a drug development program, there must be confi dence that the measure itself will be acceptable to regulators. Th e analyses provided by the Consortium will provide clear delineation of the cut points used for stratifi cation and evidence based estimates of sample size needed for clin-ical trials. General acceptance of these aspects of these measures is essential to facilitate drug development. To these ends, assembly and analysis of the data equivalent to that required for a dossier remain necessary, even if FDA review would not be required. Th e results from these eff orts should be prepared as white papers which would be available for public comment. Th e working groups for the SGRQ and 6-minute walk distance were charged to meet these goals.

OutputA key part of the FDA review process is publication of the data submitted in the dossier. In this context, “pub-lication” means make public. Th is is essential both for there to be public review and comment and for the data and analyses to be widely usable. It is the intent of the CBQC to publish the analyses and summaries of the combined data sets as white papers. It is anticipated that these will be online publications in the Journal of COPD, which is the offi cial journal of the COPD Foundation.

At present, three such publications are expected, one each for fi brinogen, SGRQ and 6-minute walk distance. It is also anticipated that, as these data and analyses are completed, that they will contribute to future guidance prepared by the FDA relating to drug development in COPD. Of the three biomarkers that are being reviewed, it is currently anticipated that a formal regulatory appli-cation for fi brinogen, supporting a subject stratifi cation context of use, will be submitted. SGRQ and 6-minute walk distance, which have already been used in applica-tions approved by the FDA, will be supported by White Papers that will defi ne their measurement characteris-tics, as well as their use in clinical trials as stratifi cation tools and outcome measures. Finally, it is hoped that the process pioneered by these eff orts will represent a para-digm for the development of additional biomarkers that can serve as tools to facilitate the development of new treatments for COPD.

Acknowledgements

CBQC Steering Committee: Cerasoli, Frank, Pfi zer; Compton, Christopher, Novartis; Disse, Ber-nard, Boehringer-Ingelheim; Goldmann, Mitchell,

AstraZeneca; Lomas, David, Cambridge University; Martin, Ubaldo, AstraZeneca; Merrill, Debora, COPD Foundation; Tal-Singer, Ruth, GlaxoSmithKline (co-chair); Rennard, Stephen, University of Nebraska, (co-chair); Tetzlaff , Kay, Boehringer-Ingelheim; Th om-ashaw, Byron, Columbia University; Walsh, John, Alpha-1 Foundation and COPD Foundation; Liaison – NHLBI.

CBQC Working groups: Fibrinogen: Barr, Graham, Columbia University; Compton, Christopher, Novartis; Goldmann, Mitchell, AstraZeneca; Lomas, David, Cambridge University; Lowings, Michael, Glaxo-SmithKline; Mannino, David, University of Kentucky (co-chair); Miller, Bruce, GlaxoSmithKline (co-chair); Merrill, Debora, COPD Foundation; Rennard, Stephen, University of Nebraska; Snyder, Jeff rey, Boehringer-Ingelheim; Tal-Singer, Ruth, GlaxoSmithKline; Tetzlaff , Kay, Boehringer-Ingelheim; Vestbo, Jorgen, University of Manchester; SGRQ: Glendenning, Alastair, Novartis; Goldmann, Mitchell, AstraZeneca; Jones, Paul, University of London (co-chair); Karlsson, Niklas, AstraZeneca; Menjoge, Shailendra, Boeh-ringer-Ingelheim; Merrill, Debora, COPD Foundation; Muellerova, Hana, GlaxoSmithKline; Rudell, Katja, Pfi zer; Rennard, Stephen, University of Nebraska; Tabberer, Margaret, GlaxoSmithKline (co-chair); 6-minute Walk: Celli, Bartolome, Harvard University (co-chair); Casaburi, Richard, LA BioMed; Cerasoli, Franklin Jr., Pfi zer; Compton, Christopher, Novartis; Criner, Gerard, Temple University; Croxton, Th omas, NHLBI; Goldmann, Mitchell, AstraZeneca; Locantore, Nicholas, GlaxoSmithKline; McLoughlin, Katrina, GlaxoSmithKline; Merrill, Debora, COPD Foundation; Polkey, Michael, Royal Brompton; Rennard, Stephen, University of Nebraska; Sciurba, Frank, University of Pittsburgh; Tal-Singer, Ruth, GlaxoSmithKline; Tetzlaff , Kay, Boehringer-Ingelheim (co-chair); Weisman, Idelle, Novartis; Lung Volumes: Casaburi, Richard (Co-Chair), LA BioMed; Cerasoli, Franklin Jr. (Co-Chair) Pfi zer;, Goldman, Mitchell, AstraZeneca; Lazaar, Aili, Glaxo-SmithKline; Kesten, Steven, Boehringer-Ingelheim; Tetzlaff , Kay, Boehringer-Ingelheim, Rennard, Stephen, University of Nebraska, Gomes, Joe, Roche; Mattes, William, COPD Foundation; Walsh, John, Alpha-1 Foundation and COPD Foundation; CBQC Data committee: Locantore, Nicholas, Glaxo SmithKline; Menjoge, Shailendra, Boehringer-Ingelheim; Peppe, Dennis, Boehringer-Ingelheim; Sutradhar, Santosh, Pfi zer; Walsh, Simon, Novartis; CBQC Regulatory Com-mittee: Aprile, Peter, Pfi zer; Lowings, Michael, Glaxo-SmithKline; McLoughlin, Katrina, GlaxoSmithKline; Snyder, Jeff , Boehringer-Ingelheim; Staff : Jamie Lamson Sullivan, COPD Foundation; and the COPD Founda-tion Biomarkers Workshop chairs: Gilbert McClain, Lydia, FDA; Kiley, James, NHLBI; Presenters: Bright-ling, Christopher, Leicester University; Burke, Laurie, FDA; Casaburi, Richard, LA BioMed; Celli, Bartolome, Harvard University; Criner, Gerald, Temple University;

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Croxton, Th omas, NHLBI; Fabbri, Leo, University of Modena & Reggio Emilia; Gaw, Alastair, AstraZeneca; Gilbert McClain, Lydia, FDA; Goodsaid, Frederico, FDA; Jones, Paul, University of London; Kilty, Ian, Pfi zer; Leidy, Nancy, United BioSource Corporation; Kiley, James, NHLBI; Lomas, David, Cambridge Uni-versity; O’Donnell, Dennis, Queen’s University; Polkey, Michael, Royal Brompton Hospital; Rennard, Stephen, University of Nebraska; Sciurba, Frank, University of Pittsburgh; Silverman, Edwin, Harvard University; Stockley, Robert, University Hospital Birmingham, NHS Foundation Trust; Tal-Singer, Ruth, GlaxoSmith-Kline; Vestbo, Jorgen, University of Manchester; and Participants: Anderson, Wayne, GlaxoSmithKline; Aprile, Peter, Pfi zer; Bao, Warren, Pfi zer; Baribaud, Fred, Johnson & Johnson; Barnathan, Elliot, Johnson & John-son; Barr, Graham, Columbia University; Bode, Fred, Sepracor; Boshoff , Chris, NIH; Brightling, Christopher, Leicester University; Burke, Laurie, FDA; Casaburi, Richard, UCLA; Celli, Bartolome, Harvard University; Cerasoli, Franklin, Pfi zer; Chowdhury, Badrul, FDA; Compton, Christopher, Novartis; Coyle, Anthony, Med-immune; Crapo, James, National Jewish Health; Criner, Gerald, Temple University; Croxton, Th omas, NHLBI; Cruz, Cristina, Talecris; Disse, Bernard, Boehringer-Ingelheim; Donohue, Christine, CSL Behring; Dorney Koppel, Grace Ann; Drone, C. Alison, NIH; Fabbri, Leo, Unimore. it; Fan, Ying, FDA; Fernandes, Peter, Novar-tis; Finn, Symma, NIH; Forsman-Semb, Kristina, Astra-Zeneca; Gaw, Alasdair, AstraZeneca; Gervais, Francois, Merck; Glendenning, Alastair, Novartis; Goldmann, Mitchell, AstraZeneca; Goodsaid, Federico, FDA; Han, MeiLan K., University of Michigan; Herrie, Myra, Novartis; Hitchcock, Chris, Pfi zer; Jhingran, Priti M., GlaxoSmithKline; Ji, Ping, FDA; Jones, Paul, University of London; Karlsson, Niklas, AstraZeneca; Kesten, Ste-ven, Boehringer-Ingelheim; Kilty, Iain, Pfi zer; Kramer, Benjamin, Novartis; Lamson, Jamie, COPD Founda-tion; Lipson, David A., GlaxoSmithKline; Locantore, Nichloas, GlaxoSmithKline; Lomas, David, Cambridge University; Lowings, Mike G., GlaxoSmithKline; Loza, Matt, Johnson & Johnson; Lyons, David, Irish Medicines Board; Ma, Shuren, Columbia University; MacMillan, Christine, CSL Behring; Mannino, David, University of Kentucky; Martin, Ubaldo, AstraZeneca; Martinez, Fernando, University of Michigan; Mascelli, MaryAnn, Medimmune; McLoughlin, Katrina, GlaxoSmithKline; Shailendra, Menjoge, Boehringer-Ingelheim; Merrill, Debora, COPD Foundation; Michele, Th eresa, FDA; Miller, Bruce E., GlaxoSmithKline; Miller, Douglas, Wyeth/Pfi zer; Molfi no, Nestor, Medimmune; Mulle-rova, Hana, GlaxoSmithKline; Mummaneni, Padmaja, FDA; Leidy, Nancy, United BioSource Corporation; Newbold, Paul, AstraZeneca; Nocka, Karl, Pfi zer; Noone, Marianne, FDA; O’Donnell, Denis, Quenn’s University; Pariser, Anne, FDA; Peppe, Dennis, Boeh-ringer-Ingelheim; Pillaj, Sreekumar, Roche; Polkey, Michael, Royal Brompton & Harefi eld NHS; Punturieri,

Antonello, NHLBI; Rennard, Stephen, University of Nebraska; Rudell, Katja, Pfi zer; Sahajwalla, Chandrahas, FDA; Sandhaus, Robert, Alpha-1 Foundation; Sciurba, Frank, UPMC; Seymour, Sally, FDA; Silberstein, David, AstraZeneca; Silverman, Edwin, Harvard; Snyder, Jef-frey, Boehringer-Ingeelheim; Stockley, Robert, BHAM; Stringer, Clive, AstraZeneca; Sutradhar, Santosh, Pfi zer; Swensen, Andrine, Novartis; Tabberer, Margaret, GlaxoSmithKline; Tal-Singer, Ruth, GlaxoSmithKline; Tan, Keith, Pfi zer; Tetzlaff , Kay, Boehringer-Ingelheim; Th omashaw, Byron, Columbia University; Turino, Gerard, Columbia University; Vestbo, Jorgen, Man-chester; Walsh, John, COPD Foundation; Walsh, Simon, Novartis; Walton, Marc, FDA; Waltz, David, Novartis; Ward, Christine, Medimmune; Weinmann, Gail, NIH; Weisman, Idelle, Novartis; Whittaker, Paul, Novartis; Wire, Patrick D., GlaxoSmithKline; Wolf-Rodda, Julie, NIH; Wolford, Eric, Talecris; Woodruff , Prescott G., University of California, San Francisco; Yao, Yihong, Medimmune; Yates, Julie C., GlaxoSmithKline; Zeldin, Robert, Novartis; Zhang, Jie, Novartis.

Declaration of Interest Statement

SR received honoraria for lectures from AARC, Alm-irall, Am Col Osteopathic Physicians, Asan Medical Center, American Th oracic Society, California Society of Allergy, CME Incite, COPD Foundation, Creative Edu-cational Concepts, Dey, Duke University, Forest, France Foundation, HSC Medical Education, Information TV, Lung Association, Novartis (Horsham, Nycomed, Otsuka, PeerVoice, Pfi zer, Shaw Science, University of Washington, University of Alabama Birmingham, VA Sioux Falls.

SR received honorarium for consulting with the following: ABIM, Able Associates, Adelphi Research, Align2Acton, Almirall/Prescott, APT Pharma/Britnall, Astra-Zeneca, American Th oracic Society Beilenson, Boehringer Ingelheim, Boehringer Ingelheim (ACCP), BoomCom, Britnall and Nicolini, Capital Research, Chiesi, Clarus Acuity, CommonHealth, Complete Medical Group, Consult Complete, COPDForum, DataMonitor, Decision Resources, Dunn Group, Easton Associates, Equinox, Forest, Frankel Group, Fulcrum, Gerson Lehman, Globe Life Sciences, Guidepoint, Health Advanced, Hoff man LaRoche, Informed, Insyght, KOL Connection, Leerink Swan, M. Pankove, McKin-sey, MDRxFinancial, Medimmune, Merck, Novartis, Nycomed, Oriel, Osterman, Peal, Penn Technology, Pennside, Pfi zer, PharmaVentures, Pharmaxis, Prescott, Price Waterhouse, Propagate, Pulmonary Reviews, Pulmatrix, Reckner Associates, Recruiting Resource, Roche, Sankyo, Schering, Schlesinger Medical, Scimed, Smith Research, Sudler and Hennessey, Summer Street Research, Talecris, Th ink Equity, UBC, Uptake Medical, Vantage Point Management.

RT-S is an employee and shareholder of GlaxoSmith-Kline.

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MP discloses receiving personally fees for lectur-ing or consultancy from Portaero, Broncus, GSK, AZ, Chiesi, & Novartis. His institutions have held or hold funding on his behalf from AZ, GSK, Lilly, the MRC, the EU, the Wellcome Trust and the Technology Strategy Board. His contribution to this project was funded by the NIHR Respiratory Biomedical research unit at the Royal Brompton and Harefi eld Foundation NHS Trust and Imperial College who part fund his salary.

Th e authors alone are responsible for the content and writing of the paper.

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