Despite available therapies for chronic obstructive pulmonary disease (COPD), significant unmet treatment needs remain because most patients with COPD experience chronic respiratory symptoms and limitations to their daily lives (1, 2). These include chest tightness and shortness of breath, chronic cough and excessive mucus, activity and exercise limitations, impaired physical functioning, poor sleep, and low energy, all of which contribute to frequent feelings of anxiety and depression (Figure 1). Together with these chronic symptoms, acute exacerbations are perceived by patients with COPD as the most important negative consequence of their disease (3). Hence, it is imperative for patients with COPD, their healthcare providers, payers, and researchers in the field to be armed with tools to develop new medications and strategies for management and monitoring of COPD symptoms and impact. Until a cure that restores lung function to normal is available, reducing the symptomatic burden of disease is of critical importance. The COPD Assessment Test (CAT) was developed according to the Food and Drug Administration (FDA) patient-reported outcome development guidance (4) with the aim to provide an accurate and readily usable tool that measures the burden of COPD and thus could serve as a clinical trial endpoint when studying novel interventions in addition to being a clinical assessment tool.
Figure 1.
COPD Foundation patient reports representing the patient’s perspective. COPD = chronic obstructive pulmonary disease.
Addressing COPD Symptomatic Burden and Functional Limitation in the Context of Drug Development
Given the multifaceted nature of COPD, drug development can be aimed at many different characteristics of the disease, including 1) improved lung capacity, 2) symptom relief, 3) modification of the course and/or prevention of exacerbations, 4) alteration of the underlying pathophysiological abnormalities or modification of lung architecture, and 5) treatment of extrapulmonary manifestations. Although measurement tools are available to quantify some of these categories, they are limited in number and scope and often require considerable time to complete, thus creating a burden that makes them impractical for many applications (5). To date, treatments for COPD have been approved by the FDA primarily on the basis of improvements in lung function (FEV1) and reduction in risk of exacerbations. Additional benefits, described in U.S. labeling as improvements in health-related quality of life (HRQoL), have also been recognized but have not been accepted as the primary basis for approval. Although FEV1 may be adequate to evaluate treatments aimed at improving expiratory airflow and is routinely used as a primary outcome in clinical trials, it is insufficient for interventions that affect other disease components, including cough, sputum production, and fatigue, that may be impacted independently of expiratory flow. Short-term improvements in FEV1 may not be associated with improved disease progression or preservation of lung structure. Moreover, although it is an objective measure, FEV1 does not fully reflect the symptomatic burden of COPD and correlates only modestly with HRQoL as assessed by the St. George’s Respiratory Questionnaire (SGRQ) (r = −0.28 in intervention studies and −0.53 in observational studies) (6).
Role of COPD Biomarker Qualification Consortium in Qualification of Novel Drug Development Tools, Including CAT
In recognition of the importance of clinical outcome assessments (COAs) to advancing the development of new treatments, in the early 2000s, the FDA initiated the biomarker and COA qualification process to support new tool development. In 2010, the COPD Biomarker Qualification Consortium (CBQC) was formed to undertake the qualification of new drug development tools (DDTs) consistent with these processes. The focus of its initial efforts was on qualification of plasma fibrinogen as a stratification tool (7) and qualification of the SGRQ as an endpoint. In 2016, the FDA recognized the SGRQ in its draft guidance for COPD studies as a COA for the measurement of HRQoL, appropriate for use as a coprimary or lower-order endpoint demonstrating efficacy in clinical development. Although this was a major step forward, the CBQC believes that a wider range of tools, some of which have been developed according to new regulatory standards, are important to patients and can be easier to implement electronically in clinical trials. The CAT is a simple tool reflecting a patient’s current experience, thus requiring no recall time. It is already widely used in disease management digital applications and accepted by patients with COPD and healthcare providers as a reliable, easy-to-use, and rapidly completed tool to assess the severity of disease and overall HRQoL. Its inclusion in product labeling as clinical trials develop evidence supporting the approval of new therapies can provide a direct and familiar link for practicing clinicians between the formal product label and a tool they use in their own clinical practice.
This article summarizes the use of the CAT in clinical practice for the management of patients with COPD and use by patients themselves in self-management of their condition. It also provides details on the development and measurement properties of the CAT to support its use as a measure of efficacy and provides recommendations for its application in randomized clinical trials, as well as in real-world and observational studies. Finally, it describes the COA regulatory framework into which CAT fits and the unmet need it addresses.
Development and Measurement Properties of the CAT
The CAT was developed in line with FDA guidance for the development of patient-reported outcome measures for use in labeling, representative of best practice at the time of development (4, 8). In brief, a qualitative study, based on interviews and focus groups with patients with COPD supported by interviews with community physicians and pulmonologists, generated 21 relevant items (4). Psychometric analyses, including Rasch analysis, identified eight items fitting a unidimensional model to form the CAT. Based on data from six countries, these items were tested for differential functioning between countries with excellent internal consistency. Test–retest reliability in stable patients was very good (intraclass correlation coefficient, 0.8). In the sample from the United States, the correlation with the COPD-specific version of the SGRQ was 0.80 (4) (Figure 2). The instrument’s score range is 0–40, and patients respond to each question using a 0–5 scale based on their current perceptions. During its development and in subsequent clinical studies, the CAT demonstrated measurement properties very similar to those of the SGRQ across a broad COPD population with a wide range of lung function impairment, including patients experiencing and recovering from exacerbations (8–14).
Figure 2.
Pearson’s correlations between scores in the chronic obstructive pulmonary disease (COPD)–specific version of the St. George’s Respiratory Questionnaire (SGRQ-C) and the COPD Assessment Test (CAT) in 229 stable patients from the United States. Reprinted by permission from Reference 4.
Longitudinal measurement properties (construct validity and ability to detect change) and guidelines for interpretation of treatment benefit were also reported and demonstrated the high value of the CAT as an HRQoL instrument (15). The most widely accepted estimate of the minimum clinically important difference, reflecting an individual patient CAT score change from baseline with clinical significance, is between 1.2 and 2.8. For the purposes of responder analysis, a minimum clinically important difference value of 2 is an appropriate cut point defining a response because individual CAT scores can only change by integer values (15).
The CAT has been demonstrated to have convergent validity in both stable and exacerbating patients with COPD. The CAT discriminated between stable and exacerbating patients, as well as between patients with different levels of airflow limitation and dyspnea (12). Furthermore, researchers have demonstrated that the CAT possesses discriminant ability for risk of and detection of exacerbation frequency. Patients who experience a higher frequency of exacerbations have higher CAT scores than patients who experience a low frequency of exacerbations or have not experienced exacerbations (16–19), including patients in one large clinical trial in which the higher CAT score category (≥20) was associated with higher exacerbation risk across all interventions (20). The CAT has also been shown to meaningfully change before and during exacerbations of COPD (12, 14). Furthermore, it was shown to be responsive to change during the initial recovery phase from a severe hospitalized exacerbation (12, 21, 22). Change over time in the CAT score is also predictive of exacerbation risk, with a 1-point increase associated with an 8% increase in the risk of exacerbations (23).
The responsiveness of the CAT has been demonstrated in patients with COPD taking part in a pulmonary rehabilitation program and in response to exacerbation onset and recovery (21). The CAT score improves (lower score) in response to pulmonary rehabilitation and remains improved at the end of 6 months (9, 11). The change in the CAT score is predictive of outcomes of COPD (24), including risk of exacerbation, depression, acute deterioration in HRQoL, and mortality (25).
Overall, these studies have shown that the CAT scores can reliably detect changes in HRQoL in patients with COPD (14). These changes reflect the multidimensional nature of COPD, making the CAT a reliable, simple, and effective clinical outcome assessment tool applicable in clinical practice and clinical development, including digital health. Over the last few years, the CAT has also been used in other chronic lung diseases, including asthma, interstitial pulmonary fibrosis, and bronchiectasis (26–28).
The CAT was developed as a COPD-specific measure; however, some of the individual items have relevance in other chronic illnesses. Comorbidities most consistently reported as impacting CAT scores include anxiety and depression, gastroesophageal reflux disease, and cardiovascular disease (29–32). In particular, the presence of cardiovascular disease has been shown to increase CAT scores, though the change over time does not seem to be impacted, and the measure remains sensitive to respiratory treatments in populations with a significant burden of comorbidities (20, 32). There are several areas in which further evidence generation about the utility of the CAT is needed. First, little is known about the predictive value of the CAT in populations less frequently included in clinical trials or prospective observational prospective studies, such as patients with COPD younger than 50 or older than 80 years of age or in current or former smokers who do not have airflow limitation but do have radiographic emphysema or symptoms of chronic bronchitis. In addition, the performance of the measure has not been evaluated in patients with very severe or uncontrolled comorbidities or in those with major disability and activity limitation. There is also a need for more information about the long-term changes in CAT scores (i.e., >5 yr), which would allow determination of average rates of worsening over time and a better understanding of the clinical implications of rapid and slow progressor phenotypes.
Use of the CAT for Evaluation of Efficacy or Effectiveness of Interventions to Treat COPD
Many recent COPD drug development programs used the SGRQ as a measure of HRQoL (33, 34). This instrument is long (40 questions for the COPD-specific version) and complex, places a significant respondent burden on patients and staff (∼10-min completion time), and relies on patients’ recall. The short CAT was developed as a simpler real-time measure of HRQoL, with practical application for patients and clinicians, and it is also suitable for remote electronic capture.
Since its launch as a new tool in 2009, the CAT has been widely used globally, with more than 90 approved and linguistically validated translations. Several clinical and observational studies have included the CAT as a measure of HRQoL (14, 25). Multiple recent randomized clinical trials employed the CAT as a measure of the clinical efficacy of pharmacological intervention across a variety of interventions and patient severity levels. These trials demonstrated that effective therapies, as assessed with change in FEV1, reduction of COPD exacerbations, or improvement in other HRQoL measures (e.g., SGRQ), also result in clinically meaningful improvement in the CAT scores with a statistically significantly higher proportion of responders (35–45) (Table 1). Moreover, the CAT was incorporated into the European Medicines Agency’s summary of product characteristics for the inhaled triple combination of fluticasone furoate/umeclidinium/vilanterol dry powder inhaler (46).
Table 1.
Responsiveness of the COPD Assessment Test to Pharmacological Interventions in Patients with COPD
| Study | Treatment Arms | Patients (N) | Duration | Baseline CAT Score [Mean (SD) or Range] | CAT Change from Baseline/Treatment Difference [Mean (SD)] | CAT Responders [% (n) or OR (95% CI)] |
|---|---|---|---|---|---|---|
| Decramer et al., 2014 (35) | UMEC 125 μg/VI 25 μg, UMEC 62.5 μg/VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2) | Study 1: 208, 209, 214, and 212 | 24 wk | Study 1: 17.19–18.95 | Change from baseline in study 1: −2.83 (7.447); −2.45 (6.954); −3.07 (7.032); −2.67 (6.839) | Not reported |
| Study 2: 215, 222, 215, and 217 | Study 2: 16.96–17.76 | Change from baseline in study 2: −3.46 (6.711); −3.18 (7.178); −2.32 (6.980); −3.02 (7.212) | ||||
| Zhong et al., 2015 (36); LANTERN | IND/GLY 110/50 μg once daily | 343 | 26 wk | 13.7 (5.94) | Week 12: LSM (SE) IND/GLY, 11.7 (0.43); treatment difference vs. SFC, 0.3 (−0.4 to 0.9) | Not reported |
| Week 26: LSM (SE) IND/GLY, 11.1 (0.46); treatment difference vs. SFC, −0.2 (−0.9 to 0.6) | ||||||
| SFC 50/500 μg | 333 | 13.8 (6.78) | Week 12: LSM (SE) SFC, 11.5 (0.42) | |||
| Week 26: LSM (SE) SFC, 11.2 (0.46) | ||||||
| Siler et al., 2016 (37); two studies | 12 wk | Change from baseline: | Not reported | |||
| Study 1 | PBO + FP/SAL 250/50 μg | 179 | 18.16 (7.02) | −0.77 (5.697) | ||
| UMEC 62.5 + FP/SAL 250/50 μg | 190 | 17.79 (7.40) | −0.81 (5.543) | |||
| UMEC 125 + FP/SAL 250/50 μg | 185 | 18.71 (6.92) | −0.92 (5.112) | |||
| Study 2 | PBO + FP/SAL 250/50 μg | 172 | 18.08 (7.43) | 0.41 (5.445) | ||
| UMEC 62.5 + FP/SAL 250/50 μg | 180 | 18.12 (7.35) | −1.31 (7.182) | |||
| UMEC 125 + FP/SAL 250/50 μg | 184 | 17.02 (7.08) | −1.42 (5.880) | |||
| Pavord et al., 2017 (38); METREO/METREX | 52 wk | |||||
| METREX mITT* | Mepolizumab 100 mg | 233 | 18.5 (7.8) | Change from baseline: −0.8 (0.5) | ||
| Difference vs. placebo: −0.8 (95% CI, −2.0 to 0.5) | ||||||
| Placebo | 229 | 19.6 (7.7) | Change from baseline: 0.0 (0.5) | |||
| Population with an eosinophilic phenotype† | Mepolizumab 100 mg | 417 | 18.6 (7.6) | Change from baseline: −1.0 (0.3) | MEPO: 37% | |
| Difference vs. placebo: −0.6 (95% CI, −1.5 to 0.4) | MEPO vs. PBO: OR, 1.21 (95% CI, 0.80 to 1.82) | |||||
| Placebo | 419 | 19.1 (7.7) | Change from baseline: −0.4 (0.4) | PBO: 35% | ||
| METREO mITT population* | Mepolizumab 100 mg | 223 | 18.7 (7.4) | Change from baseline: −1.6 (0.42) | MEPO 100: 42% | |
| Difference vs. placebo: −1.1 (95% CI, −2.3 to 0.0) | MEPO 100 vs. PBO: OR, 1.66 (95% CI, 1.10 to 2.50) | |||||
| Mepolizumab 300 mg | 225 | 19.4 (7.8) | Change from baseline: −0.8 (0.42) | MEPO 300: 41% | ||
| Difference vs. placebo: −0.4 (95% CI, −1.5 to 0.8) | MEPO 300 vs. PBO: OR, 1.58 (95% CI, 1.05 to 2.37) | |||||
| Placebo | 226 | 19.4 (7.5) | Change from baseline: −0.4 (0.42) | PBO: 32% | ||
| Tabberer et al., 2018 (39); FULFIL | ||||||
| ITT population | FF/UMEC/VI 100/62.5/25 μg | 5,911 | 24 wk | 17.6 (6.43) | Change from baseline: FF/UMEC/VI: Week 4, −1.7; Week 24, −2.7 | Week 24: |
| FF/UMEC/VI: 53% | ||||||
| BUD/FOR: 45% | ||||||
| FF/UMEC/VI vs. BUD/FOR: OR, 1.44 | ||||||
| BUD/FOR 400/12 μg | 5,899 | 17.8 (6.24) | Change from baseline: BUD/FOR: Week 4, −1.4; Week 24, −1.7 | |||
| Treatment differences at Weeks 4 and 24: −0.7 and −0.9 units | ||||||
| EXT population | FF/UMEC/VI 100/62.5/25 μg | 5,210 | 52 wk | 18.1 (6.29) | Treatment differences at Week 52: −0.2 | Week 52: FF/UMEC/VI: 44% BUD/FOR: 35%; FF/UMEC/VI vs. BUD/FOR: OR, 1.50 |
| BUD/FOR 400/12 μg | 5,220 | 17.7 (5.93) | ||||
| Tamási et al., 2018 (56); RWE study | Dose/regimens per physician decision | 12 wk | Not reported | |||
| BUD/FOR: COPD 2 × 2 inhalations per day of either 160/4.5 μg or 320/9 μg | 778 | 24.2 (5.7) | Mean (SD) at 12 wk: 18.2 (5.1) | |||
| ACO treated in accordance with GINA | 99 | 23.7 (6.5) | Mean (SD) at 12 wk: 18.3 (4.7) | |||
| Kostikas et al., 2018 (57); CRYSTAL | IND/GLY 110/50 μg or GLY 50 μg | 4,324 | 12 wk | 13.2 (6.50) | Not reported | 36.7% (1,585) |
| Riley et al., 2018 (41) | UMEC/VI 62.5/25 μg or PBO (crossover) | 198/198 | 12 wk | Not reported | Treatment difference: −1.07 (95% CI, −2.09 to −0.05) | Not reported |
| Lipson et al., 2018 (20); IMPACT | 10,355 | 52 wk | Not reported | Change from baseline: | FF/UMEC/VI vs. FF/VI: OR, 1.24 (95% CI, 1.14 to 1.36) | |
| FF/UMEC/VI 100/62.5/25 μg | −2.0 | |||||
| FF/VI 100/25 μg | −1.5 | |||||
| UMEC/VI 62.5/25 μg | −1.6 | FF/UMEC/VI vs. UMEC/VI: OR, 1.28 (95% CI, 1.15 to 1.43) | ||||
| Kardos et al., 2018 (44); DACOTA/DINO | Roflumilast as per local label | 24 wk | Change from baseline: | |||
| DINO | 5,375 | 26.8 (7.0) | −9.0 | 85.8% | ||
| DACOTA | 3,597 | 25.4 (6.9) | −6.4 | 72.8% | ||
| Frith et al., 2018 (42); FLASH | IND/GLY 110/50 μg and placebo for SFC | 248 | 12 wk | 17.9 (5.59) | Week 12: mean (SD), 13.4 | Not reported |
| SFC 50/500 μg twice daily and placebo for IND/GLY | 250 | 17.8 (6.09) | Week 12: mean (SD), 13.8 | |||
| Treatment difference: −0.4 (95% CI, −1.3 to 0.4) | ||||||
| Papi et al., 2018 (45); TRIBUTE | BDP/FF/GLY 87/5/9 μg | 764 | 26 wk | Not reported | Changes from baseline: −0.8 | Not reported |
| IND/GLY 85/43 μg | 768 | 52 wk | Changes from baseline: −0.6 | |||
| Calverley et al., 2018 (43); DYNAGITO | TIO/OLO 5/5 μg | 3,939 | 52 wk | 18.8 (7.4) | Treatment difference TIO/OLO vs. TIO over 52 wk varied between −0.4 (SE 0.15) and −0.7 (0.13) | TIO/OLO vs. TIO: OR, 1.17 (95% CI, 1.06 to 1.28) |
| TIO 5 μg | 3,941 | 18.4 (7.4) | ||||
| Kaplan et al., 2018 (58); POWER | IND/GLY 110/50 μg | IND/GLY from TIO: 248 | 4 and 16 wk | IND/GLY from TIO: 18.1 (6.1) | Change from baseline: | Not reported |
| IND/GLY from SFC: 21.1 (6.9) | Week 4: | |||||
| IND/GLY from SFC: 87 | All IND/GLY: 18.9 (6.4) | IND/GLY from TIO: −4.7 (95% CI, −5.4 to −3.9) | ||||
| IND/GLY from SFC FDC: −5.9 (95% CI, −7.6 to −4.2) | ||||||
| All IND/GLY: 338 | Week 16: | |||||
| IND/GLY from TIO: −5.9 (95% CI, −6.7 to −5.1) | ||||||
| IND/GLY from SFC FDC: −8.2 (95% CI, −10.0 to −6.4) | ||||||
| All IND/GLY: −6.5 (95% CI, −7.3 to −5.7) |
Definition of abbreviations: BDP = beclomethasone dipropionate; BUD = budesonide; CI = confidence interval; CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; FDC = fixed-dose combination; FF = fluticasone furoate; FOR = formoterol; FP = fluticasone propionate; GINA = Global Initiative for Asthma; GLY = glycopyrronium; IND = indacaterol; LSM = least-squares means; mITT = modified intention to treat; OLO = olodaterol; OR = odds ratio; PBO = placebo; SAL = salmeterol; SFC = salmeterol–fluticasone combination; TIO = tiotropium; UMEC = umeclidinium; VI = vilanterol.
The METREX mITT population included patients who received at least one dose of mepolizumab or placebo.
The METREX mITT population with an eosinophilic phenotype included patients who received at least one dose of mepolizumab or placebo and had an eosinophil count greater than or equal to 150 cells/mm3 at screening or greater than or equal to 300 cells/mm3 within the previous year.
The studies summarized in Table 1 demonstrate that the CAT is a well-established and broadly used outcome measure for COPD trials. It is sensitive to change after treatment, and its measurement properties allow comparisons between treatment groups. Importantly, it has a defined minimal clinically important difference, which allows treatment effects to be placed into a meaningful perspective, particularly in terms of proportion of patients who have a clinically significant response to therapy. All these features support an important role for the CAT in drug development.
Use of the CAT in Clinical Practice to Manage COPD
There is a critical need to measure symptoms of COPD in clinical practice to better understand their severity to optimize treatment. Though lung function has been the traditional metric used predominantly by pulmonary medicine specialists to assess disease severity, COPD symptoms are more closely related to overall HRQoL, and, as the current Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease (47) suggests, these should be assessed routinely. It is also important to recognize that patients routinely underestimate the severity of their disease and that there is often a significant discrepancy between physicians’ and patients’ perceptions of patients’ quality of life.
COPD symptoms are varied, and though dyspnea is the most common reason patients with COPD seek medical attention, it is often underestimated because of withdrawal from activity and thus is inadequate to represent overall COPD burden when assessed in isolation. The CAT captures dyspnea as well as key COPD symptoms and impacts, including cough and sputum production, sleep disturbance, energy level, confidence in leaving home, and activity limitation. The questionnaire can be completed in less than 2 minutes, is sensitive to treatment, and correlates well with more detailed and comprehensive measures of HRQoL, including the SGRQ, which, because of its length, is not suitable for real-world clinical management of COPD.
Routine assessment of the CAT at every office visit is feasible in routine clinical practice, can improve the efficiency of those encounters, and aids the identification of troublesome symptoms more objectively than clinical questioning (48, 49). Patients can complete the CAT before the office visit, and, when used in conjunction with an additional assessment of exacerbation risk such as prior history of exacerbations, a more complete profile of a patient’s clinical phenotype can be obtained, which may directly inform decisions about treatment. The CAT is also readily incorporated into electronic medical record systems, allowing it to be readily tracked over time.
The use of the CAT in routine clinical care has been advocated by multiple professional bodies and has been incorporated into a number of electronic health record systems, including in the Mid Yorkshire Hospitals NHS Trust in the United Kingdom and the Geisinger Health System, Mayo Clinic, and University of Pittsburgh Lung Center in the United States. The CAT has also been incorporated into various digital health tracking applications, including the Propeller Health app and the COPD Foundation’s COPD Pocket Consultant Guide for healthcare providers. Furthermore, the CAT has been electronically completed by approximately 6,100 patients to date as part of the COPD Foundation’s Patient-Powered Research Network. The use of the CAT to assess disease impact and target precise therapeutics is also consistent with the goals of the recently released COPD National Action Plan supported by the NIH and others.
Use of the CAT by Patients in Management of Their Condition
In the context of today’s patient-focused environment, the design of the CAT is well suited for patient use. The 0–5 scoring scale for each question is simple and provides an opportunity for patients to establish a baseline (either with a physician or independently) and to track changes in the impact of their COPD over time. The eight questions are easy to understand and target cardinal symptoms and other disease indicators that have significant effects on daily life, including cough, mucus production, chest tightness, breathlessness with exertion, activity limitations, confidence in leaving home independently, sleeping soundly, and energy level. Patients can use changes in individual question scores as well as total CAT score as measures of disease activity (50, 51). Because the CAT has been incorporated into apps as well as self-management and educational tools, it can be applied in a number of patient-centric settings (52–54).
Regulatory Considerations for the CAT as a DDT
Several ongoing and recently implemented important legislative initiatives reinforce the importance of new tools in supporting clinical research and assessing patient outcomes. The 21st Century Cures Act (Cures Act), signed into law on December 13, 2016, is designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently. The law builds on FDA’s ongoing work to incorporate the perspectives of patients into the development of drugs, biological products, and devices in the FDA’s decision-making process. The Cures Act is aimed at enhancing the ability to modernize clinical trial designs and COA, ultimately speeding the development and review of novel medical products.
In testimony to the Subcommittee on Health, Committee on Energy and Commerce, U.S. House of Representatives, on July 25, 2018, Scott Gottlieb, M.D., former commissioner of the FDA, noted that encouraging the identification and use of reliable DDTs can significantly advance development of new safe and effective drugs and biologics. The Cures Act revised and codified the FDA’s qualification process to expedite the development of publicly available DDTs, including biomarkers and COA. Once qualified, a DDT can be widely used across multiple drug and biologic development programs, facilitating efficient development of important new therapies for patients. Without formal qualification, a given tool can be used on a case-by-case basis, but including an unqualified tool as a primary or coprimary outcome measure creates risk and uncertainty because the tool itself may be subject to criticism during regulatory review. This can impede a sponsor’s confidence in moving forward with otherwise meaningful clinical trials. As described in the present article, the CBQC consider the CAT to be a tool that meets these goals. Moreover, this tool is aligned with the Framework for FDA’s Real-World Evidence Program issued in December 2018. To date, we have submitted to the FDA a Drug Master File, an integrated data summary supporting the validation of the CAT for the purposes of supporting efficacy claims in regulatory submissions of medicines for treatment of COPD.
Summarizing the Rationale for Application of the CAT in Clinical Development and in Clinical Practice
The CAT is a brief and reliable assessment tool for measuring COPD-specific HRQoL. It is available to the healthcare and research communities at no charge with validated translations at the website (https://www.copdfoundation.org/Research/COPD-Biomarker-Qualification-Consortium/Learn-More.aspx), which is managed under the auspices of an international multidisciplinary governance board. It is employed and accepted in global clinical practice as an easy-to-use and reliable tool to assess the severity of disease and overall HRQoL of patients with COPD.
The CAT was developed following FDA guidance on the development of patient-reported outcome measures supporting product labeling. During development and in subsequent clinical studies, the CAT has demonstrated measurement properties very similar to those of the SGRQ across a broad COPD population with a wide range of lung impairment. Advantages of the CAT compared with the SGRQ include its shorter length and immediate recall period. Its inclusion in product labeling can provide a direct and familiar link for practicing clinicians between the label indication and their clinical practice, and the CAT has been accepted by the European Medicines Agency as an outcome measure supporting product registration (55). Its ease of use enables improved disease management by patients and their healthcare providers and allows for incorporation into electronic medical record systems. This further facilitates its use in clinical study designs requiring low intervention, such as pragmatic randomized trials using e-data collection tools, as well as in traditional trials. The CAT has also been evaluated and validated across a spectrum of chronic respiratory diseases (e.g., interstitial pulmonary fibrosis, bronchiectasis, and asthma) (26–28). The authors therefore endorse the CAT as a candidate for FDA qualification as a DDT in clinical trials assessing the impact of interventions on HRQoL in patients with COPD and other chronic respiratory diseases.
Supplementary Material
Acknowledgments
Acknowledgment
The COPD Biomarker Qualification Consortium (CBQC) is a collaborative public–private partnership aiming to undertake regulatory qualification of emerging biomarkers and clinical assessments to facilitate the development and approval of novel treatments for COPD. The CBQC was created to help fast track research for better treatment and medicines that will help improve the lives of those with COPD.
Current CBQC member companies: AstraZeneca, Boehringer Ingelheim, Chiesi, and GlaxoSmithKline.
Global Initiative for Chronic Obstructive Lung Disease Scientific Committee Chair: Claus Vogelmeier, Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps University of Marburg, member of the German Center for Lung Research (DZL), Marburg, Germany.
COPD Foundation Working Group Consortium Chair: Mark T. Dransfield, Lung Health Center, Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham and Birmingham VA Medical Center, Birmingham, Alabama.
CAT Governance Board:
Independent chair: Michael Polkey, National Institute for Health Research Respiratory Biomedical Research Unit at the Royal Brompton and Harefield Foundation NHS Trust and Imperial College London, London, United Kingdom.
Academic research user: Toru Oga, Department of Respiratory Medicine, Kawasaki Medical School, Okayama, Japan.
Industry research users: Ruth Tal-Singer, formerly VP of Medical Innovation, Value Evidence and Outcomes, GlaxoSmithKline, Collegeville, Pennsylvania (currently COPD Foundation representative); Stephen Rennard, University of Nebraska Medical Center, Omaha, Nebraska, and SVP, Early Development and Clinical Pharmacology, AstraZeneca.
Scientific adviser: Maggie Tabberer, Patient-Centered Outcomes, Value Evidence and Outcomes, GlaxoSmithKline, Uxbridge, United Kingdom.
Foundation chair: Paul W. Jones, Institute of Infection and Immunity, St. George’s University of London, and Global Medical Expert, GlaxoSmithKline, Brentford, United Kingdom.
Footnotes
Funding for this COPD Biomarkers Qualification Consortium working group was provided by AstraZeneca, Boehringer-Ingelheim, and GlaxoSmithKline.
Author Contributions: All authors contributed to the conception and design of the work and to the interpretation of data and critically reviewed the manuscript for intellectual content. All authors provided approval of the final version of the manuscript.
Originally Published in Press as DOI: 10.1164/rccm.201907-1369PP on December 9, 2019
Author disclosures are available with the text of this article at www.atsjournals.org.
Contributor Information
Collaborators: on behalf of the COPD Biomarker Qualification Consortium and the CAT Governance Board
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