- Email: [email protected]
External validity of trials should be taken into account before asthma drug candidates reach market authorisation
Comment
approved for the treatment of cough. In addition to this trial, two uncontrolled, observational therapeutic trials7,11 have assessed cough in patients with IPF. Oral administration of the antifibrotic agent interferon alfa for 12 months decreased cough in five of six patients; however, this agent is not commercially available.11 Likewise, 4 weeks of moderate doses of prednisolone decreased cough severity and sensitivity to capsaicin in six patients with severe IPF cough.7 However, steroid use in IPF is not without risk and is not recommended for IPF treatment. Of note, neither of the two drugs approved to treat IPF, pirfenidone or nintedanib, have been studied with cough as an outcome. Although a post-hoc analysis from a phase 3 trial of pirfenidone in IPF12 showed that a small subgroup of patients given high-dose pirfenidone (1800 mg per day) might have benefited from cough stability, the drug’s effect on quality of life is unknown. Of note, although gastro-oesophageal reflux has been suggested as a cause of both IPF and cough, in a study of 18 patients with IPF,6 no improvement in cough after acid suppression therapy was reported in patients with both cough and gastro-oesophageal reflux disease.13 In this study,6 although acid reflux was diminished with therapy, episodes of non-acid reflux increased, suggesting a potential role for non-acid reflux. Finally, although not tested for IPF cough, several drugs—eg, gabapentin, amitriptyline, and AF-219 (a P2X3 antagonist)—have been shown to have potential benefits in the treatment of idiopathic chronic cough, presumably by modulating the cough reflex or by decreasing the sensitivity of cough receptors on vagal afferents.14,15 These agents might be of benefit in patients with IPF, but further investigation in clinical trials is needed. In view of the substantial negative effects of cough on quality of life and disease progression in IPF, it
is time for studies to directly address the pathogenesis of IPF cough and to discover effective treatments for this devastating symptom. Christine L Vigeland, *Maureen R Horton Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA [email protected] We declare no competing interests. 1
2
3
4
5 6
7
8
9 10 11
12
13
14
15
Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med 1976; 85: 769–88. Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 2012; 157: 398–406. Lechtzin N, Hilliard ME, Horton MR. Validation of the Cough Quality-of-Life Questionnaire in patients with idiopathic pulmonary fibrosis. Chest 2013; 143: 1745–49. Ryerson CJ, Abbritti M, Ley B, Elicker BM, Jones KD, Collard HR. Cough predicts prognosis in idiopathic pulmonary fibrosis. Respirology 2011; 16: 969–75. Key AL, Holt K, Hamilton A, Smith JA, Earis JE. Objective cough frequency in idiopathic pulmonary fibrosis. Cough 2010; 6: 4. Kilduff CE, Counter MJ, Thomas GA, Harrison NK, Hope-Gill BD. Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study. Cough 2014; 10: 4. Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK. A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168: 995–1002. Jones RM, Hilldrup S, Hope-Gill BD, Eccles R, Harrison NK. Mechanical induction of cough in idiopathic pulmonary fibrosis. Cough 2011; 7: 2. Scholand MB, Wolff R, Crossno PF, et al. Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype. Cough 2014; 10: 3. Horton MR, Danoff SK, Lechtzin N. Thalidomide inhibits the intractable cough of idiopathic pulmonary fibrosis. Thorax 2008; 63: 749. Lutherer LO, Nugent KM, Schoettle BW, et al. Low-dose oral interferon alpha possibly retards the progression of idiopathic pulmonary fibrosis and alleviates associated cough in some patients. Thorax 2011; 66: 446–47. Azuma A, Taguchi Y, Ogura T, et al. Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment. Respir Res 2011; 12: 143. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: 136–42. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2015; 385: 1198–205. Niimi A, Chung KF. Evidence for neuropathic processes in chronic cough. Pulm Pharmacol Ther 2015; 35: 100–04.
External validity of trials should be taken into account before asthma drug candidates reach market authorisation Substantial advances in asthma treatment have been made in the past decade; however, concerns have been raised about the validity of trial results with respect to the entire asthma population because of the considerable heterogeneity of subgroups of patients www.thelancet.com/respiratory Vol 4 August 2016
with asthma and the short duration of trials.1,2 A basic reason for questioning the general applicability of asthma therapeutics is that participants of randomised controlled trials often represent only 5% of the asthma population because of strict eligibility
Published Online May 27, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30118-7
601
Comment
Exploratory
Explanatory
Confirmatory
High internal validity
High internal validity
High external validity
Pharmacokinetic–pharmacodynamic relationship, initial dose selection, proof of concept
Efficacy and safety
Real-life effectiveness and real-life safety
Population enhancement at interim point
Figure: Trial design incorporating external validity
criteria.3 Since the risk–benefit profile of new drugs can be unpredictable for most patients with asthma, we need to re-examine the issue of external validity of trial results. Several groups of patients are under-represented in randomised controlled trials. Patients prone to small airway disease (eg, refractory asthma, nocturnal asthma, exercise-induced asthma, smokers, and those with coexisting allergic rhinitis)4 are often excluded from trials. Yet, these groups of patients are likely to show a different response to inhaled corticosteroid treatment depending on the particle size of the formulation.5 Despite the fact that patients with uncontrolled asthma can develop fixed airway obstruction, irreversible bronchoconstriction is often set as an exclusion criterion and disqualifies roughly 75% of asthma trial participants.3 Additionally, patients with a smoking history of more than 10 packyears are often excluded, even though 25% of patients with asthma in Europe are estimated to be smokers6 and smoking is associated with impaired therapeutic response to corticosteroids. Moreover, although substantial comorbidity is present in roughly a third of patients with asthma, more than half of randomised controlled trials exclude patients with comorbidities.7,8 If all the groups mentioned above are excluded from trial participation, it is very likely to result in uncertainty on the use of drugs in real-life clinical settings. Therefore, it is clear that alternative trial design that incorporates external validity should be developed. In this way, we could avoid the debatable approval of drugs that apply to a small proportion of patients and address the seemingly unavoidable efficacy– effectiveness gap.9 To establish high external validity of trials as a requirement for drug approval, generalisability needs to be quantified in an objective manner. A useful tool to assess this could be the Pragmatic–Explanatory 602
Continuum Indicator Summary (PRECIS-2),10 which was originally created to assist with trial design. PRECIS-2 evaluates, on a numerical scale, the parts of a trial design that relate to applicability, including the eligibility criteria, recruitment process, trial setting, resources and expertise needed for the treatment, flexibility and adherence of treatment, follow-up of patients, relevance of outcomes, and extent of analysis. Therefore, it can be used to assess the generalisability of trials in an objective and reproducible way. More specifically, we propose that external validity could be established by a specific adaptive trial design composed of three phases (figure). An initial exploratory phase would be characterised by strict eligibility criteria, controlled settings, and follow-up to study the pharmacokinetic–pharmacodynamic relationship and determine the proposed dose. In a subsequent explanatory phase, efficacy and safety would initially be assessed in a controlled and tightly defined patient population so that efficacy can be demonstrated. After confirmation of the risk–benefit profile, the study population will be enhanced at an interim point. Population enhancement can be done in two ways, either by broadening eligibility criteria of the pre-existing groups or by adding additional groups with broader eligibility criteria. The second method would enable the parallel study of efficacy and safety in highly selected populations and in so-called real-world patients, generating data with both high internal and external validity at the same time, and thus increasing generalisability of results and precision in patient subgroups. We conclude that regulatory authorities need to request the submission of confirmatory data that show the generalisability and predictability of results to the whole patient population for whom the drug will finally be prescribed. Moreover, we propose to integrate external validity to randomised trials of asthma drugs by developing novel trials that are characterised by an adaptive trial design and population enhancement at an interim point. *Orestis Briasoulis, Ross Breckenridge, Andrew Nunn Division of Medicine (OB, RB) and MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology (AN), University College London, London WC1E 6BT, UK [email protected] We declare no competing interests.
www.thelancet.com/respiratory Vol 4 August 2016
Comment
1
2
3
4
5
Butler MG, Zhou EH, Zhang F, et al. Changing patterns of asthma medication use related to US Food and Drug Administration long-acting beta2-agonist regulation from 2005–2011. J Allergy Clin Immunol 2016; 137: 710–17. Kew KM, Evans DJ, Allison DE, Boyter AC. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma. Cochrane Database Syst Rev 2015; 6: CD011438. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007; 62: 219–23. Bonini M, Usmani OS. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis 2015; 9: 281–93. Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: does it matter? J Allergy Clin Immunol 2009; 124 (6 Suppl): S88–93.
6
7
8
9
10
Cerveri I, Cazzoletti L, Corsico AG, et al. The impact of cigarette smoking on asthma: a population-based international cohort study. Int Arch Allergy Immunol 2012; 158: 175–83. Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA 2007; 297: 1233–40. Herland K, Akselsen JP, Skjonsberg OH, Bjermer L. How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir Med 2005; 99: 11–19. Eichler HG, Abadie E, Breckenridge A, et al. Bridging the efficacy– effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat Rev Drug Discov 2011; 10: 495–506. Zuidgeest MG, Goetz I, Grobbee DE, WP3 of the GetReal Consortium. PRECIS-2 in perspective: what is next for pragmatic trials? J Clin Epidemiol 2016; published online March 6. DOI:10.1016/j.jclinepi.2016.02.027.
The air we breathe: differentials in global air quality monitoring Air pollution is a severe problem worldwide, causing more than 7 million deaths every year. On May 12, 2016, WHO released its most recent report1 on urban air pollution. Compared with the last report released in 2014, the number of cities with air quality monitoring data available almost doubled, reaching 3000 cities in 103 countries. According to this new report,1 low-income and middle-income countries have the highest particulate matter (PM) levels: Onitsha, Nigeria, is the most polluted city in the world, followed by other cities in Nigeria, Pakistan, Iran, Afghanistan, and India in the top ten. The annual mean levels of PM10 (ie, PM with a diameter of less than 10 μm) in the ten most polluted cities range from 329 μg/m³ to 594 μg/m³, 16–30 times higher than WHO-recommended limits (annual mean 20 μg/m³). Many of the 100 most polluted cities, all of which have annual mean PM10 levels above 130 μg/m³, are in India, China, and other countries in Africa, southeast Asia, and the Middle East. 98% of cities with a population larger than 100 000 in low-income and middle-income countries have PM10 levels above WHO-recommended annual limits, compared with 56% of such cities in high-income countries. The WHO report1 covers thousands of cities that have air quality monitoring; however, many cities still do not monitor air quality. Here, we analyse data from the WHO Report1 and other sources2–12 to compare air quality monitoring coverage in 2012–14, adjusting for population sizes and land area, in different countries www.thelancet.com/respiratory Vol 4 August 2016
and regions of the world (table). In general, highincome countries have the best air quality monitoring in terms of the number of monitoring stations relative to population size or land area. Despite many efforts by the governments of several countries, most low-income and middle-income countries still have insufficient air quality monitoring.
Published Online July 13, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30180-1 See News page 609
Number of stations per 10 000 km²
Number of air monitoring stations
Number of Population* Area* (million) (km²) cities monitored
Number of stations per 1 000 000 population
USA3
4916
1639
318·9
9 833 517
15·42
5·00
Japan5
1934
887
127·1
364 560
15·22
53·05
Europe4
6099
2833
508·0
4 933 469
12·01
12·36
198
79
17·8
743 532
11·12
2·66 0·13
Chile11
99
54
23·5
7 682 300
4·21
South Africa9
145
27
54·0
1 213 090
2·69
1·20
South America1,11,12
540
208
414·4
17 457 742
1·30
0·31 0·30
Australia
10
Brazil12
252
95
206·1
8 358 140
1·22
China2
1436
338
1364·3
9 388 211
1·05
1·53
Egypt1
61
2†
89·6
995 450
0·68
0·61
India6
342
127
1295·3
2 973 190
0·26
1·15
Russia1,8
38
2
143·8
16 376 870
0·26
0·02
Africa1,9
252
65
1155·2
30 000 061
0·22
0·08
Nigeria1
13
12
177·5
910 770
0·07
0·14
Indonesia1,7
10
8
254·5
1 811 570
0·04
0·06
Pakistan1,7
6
5
185·0
770 880
0·03
0·08
*Data from World Bank, 2014. †This number is underestimated because it represents only cities in the Greater Cairo and Delta regions, and actual numbers are not publicly available.
Table: Air quality monitoring coverage in 2012–14, by country and world region
603
approved for the treatment of cough. In addition to this trial, two uncontrolled, observational therapeutic trials7,11 have assessed cough in patients with IPF. Oral administration of the antifibrotic agent interferon alfa for 12 months decreased cough in five of six patients; however, this agent is not commercially available.11 Likewise, 4 weeks of moderate doses of prednisolone decreased cough severity and sensitivity to capsaicin in six patients with severe IPF cough.7 However, steroid use in IPF is not without risk and is not recommended for IPF treatment. Of note, neither of the two drugs approved to treat IPF, pirfenidone or nintedanib, have been studied with cough as an outcome. Although a post-hoc analysis from a phase 3 trial of pirfenidone in IPF12 showed that a small subgroup of patients given high-dose pirfenidone (1800 mg per day) might have benefited from cough stability, the drug’s effect on quality of life is unknown. Of note, although gastro-oesophageal reflux has been suggested as a cause of both IPF and cough, in a study of 18 patients with IPF,6 no improvement in cough after acid suppression therapy was reported in patients with both cough and gastro-oesophageal reflux disease.13 In this study,6 although acid reflux was diminished with therapy, episodes of non-acid reflux increased, suggesting a potential role for non-acid reflux. Finally, although not tested for IPF cough, several drugs—eg, gabapentin, amitriptyline, and AF-219 (a P2X3 antagonist)—have been shown to have potential benefits in the treatment of idiopathic chronic cough, presumably by modulating the cough reflex or by decreasing the sensitivity of cough receptors on vagal afferents.14,15 These agents might be of benefit in patients with IPF, but further investigation in clinical trials is needed. In view of the substantial negative effects of cough on quality of life and disease progression in IPF, it
is time for studies to directly address the pathogenesis of IPF cough and to discover effective treatments for this devastating symptom. Christine L Vigeland, *Maureen R Horton Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA [email protected] We declare no competing interests. 1
2
3
4
5 6
7
8
9 10 11
12
13
14
15
Crystal RG, Fulmer JD, Roberts WC, Moss ML, Line BR, Reynolds HY. Idiopathic pulmonary fibrosis. Clinical, histologic, radiographic, physiologic, scintigraphic, cytologic, and biochemical aspects. Ann Intern Med 1976; 85: 769–88. Horton MR, Santopietro V, Mathew L, et al. Thalidomide for the treatment of cough in idiopathic pulmonary fibrosis: a randomized trial. Ann Intern Med 2012; 157: 398–406. Lechtzin N, Hilliard ME, Horton MR. Validation of the Cough Quality-of-Life Questionnaire in patients with idiopathic pulmonary fibrosis. Chest 2013; 143: 1745–49. Ryerson CJ, Abbritti M, Ley B, Elicker BM, Jones KD, Collard HR. Cough predicts prognosis in idiopathic pulmonary fibrosis. Respirology 2011; 16: 969–75. Key AL, Holt K, Hamilton A, Smith JA, Earis JE. Objective cough frequency in idiopathic pulmonary fibrosis. Cough 2010; 6: 4. Kilduff CE, Counter MJ, Thomas GA, Harrison NK, Hope-Gill BD. Effect of acid suppression therapy on gastroesophageal reflux and cough in idiopathic pulmonary fibrosis: an intervention study. Cough 2014; 10: 4. Hope-Gill BD, Hilldrup S, Davies C, Newton RP, Harrison NK. A study of the cough reflex in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168: 995–1002. Jones RM, Hilldrup S, Hope-Gill BD, Eccles R, Harrison NK. Mechanical induction of cough in idiopathic pulmonary fibrosis. Cough 2011; 7: 2. Scholand MB, Wolff R, Crossno PF, et al. Severity of cough in idiopathic pulmonary fibrosis is associated with MUC5 B genotype. Cough 2014; 10: 3. Horton MR, Danoff SK, Lechtzin N. Thalidomide inhibits the intractable cough of idiopathic pulmonary fibrosis. Thorax 2008; 63: 749. Lutherer LO, Nugent KM, Schoettle BW, et al. Low-dose oral interferon alpha possibly retards the progression of idiopathic pulmonary fibrosis and alleviates associated cough in some patients. Thorax 2011; 66: 446–47. Azuma A, Taguchi Y, Ogura T, et al. Exploratory analysis of a phase III trial of pirfenidone identifies a subpopulation of patients with idiopathic pulmonary fibrosis as benefiting from treatment. Respir Res 2011; 12: 143. Raghu G, Freudenberger TD, Yang S, et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: 136–42. Abdulqawi R, Dockry R, Holt K, et al. P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 2015; 385: 1198–205. Niimi A, Chung KF. Evidence for neuropathic processes in chronic cough. Pulm Pharmacol Ther 2015; 35: 100–04.
External validity of trials should be taken into account before asthma drug candidates reach market authorisation Substantial advances in asthma treatment have been made in the past decade; however, concerns have been raised about the validity of trial results with respect to the entire asthma population because of the considerable heterogeneity of subgroups of patients www.thelancet.com/respiratory Vol 4 August 2016
with asthma and the short duration of trials.1,2 A basic reason for questioning the general applicability of asthma therapeutics is that participants of randomised controlled trials often represent only 5% of the asthma population because of strict eligibility
Published Online May 27, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30118-7
601
Comment
Exploratory
Explanatory
Confirmatory
High internal validity
High internal validity
High external validity
Pharmacokinetic–pharmacodynamic relationship, initial dose selection, proof of concept
Efficacy and safety
Real-life effectiveness and real-life safety
Population enhancement at interim point
Figure: Trial design incorporating external validity
criteria.3 Since the risk–benefit profile of new drugs can be unpredictable for most patients with asthma, we need to re-examine the issue of external validity of trial results. Several groups of patients are under-represented in randomised controlled trials. Patients prone to small airway disease (eg, refractory asthma, nocturnal asthma, exercise-induced asthma, smokers, and those with coexisting allergic rhinitis)4 are often excluded from trials. Yet, these groups of patients are likely to show a different response to inhaled corticosteroid treatment depending on the particle size of the formulation.5 Despite the fact that patients with uncontrolled asthma can develop fixed airway obstruction, irreversible bronchoconstriction is often set as an exclusion criterion and disqualifies roughly 75% of asthma trial participants.3 Additionally, patients with a smoking history of more than 10 packyears are often excluded, even though 25% of patients with asthma in Europe are estimated to be smokers6 and smoking is associated with impaired therapeutic response to corticosteroids. Moreover, although substantial comorbidity is present in roughly a third of patients with asthma, more than half of randomised controlled trials exclude patients with comorbidities.7,8 If all the groups mentioned above are excluded from trial participation, it is very likely to result in uncertainty on the use of drugs in real-life clinical settings. Therefore, it is clear that alternative trial design that incorporates external validity should be developed. In this way, we could avoid the debatable approval of drugs that apply to a small proportion of patients and address the seemingly unavoidable efficacy– effectiveness gap.9 To establish high external validity of trials as a requirement for drug approval, generalisability needs to be quantified in an objective manner. A useful tool to assess this could be the Pragmatic–Explanatory 602
Continuum Indicator Summary (PRECIS-2),10 which was originally created to assist with trial design. PRECIS-2 evaluates, on a numerical scale, the parts of a trial design that relate to applicability, including the eligibility criteria, recruitment process, trial setting, resources and expertise needed for the treatment, flexibility and adherence of treatment, follow-up of patients, relevance of outcomes, and extent of analysis. Therefore, it can be used to assess the generalisability of trials in an objective and reproducible way. More specifically, we propose that external validity could be established by a specific adaptive trial design composed of three phases (figure). An initial exploratory phase would be characterised by strict eligibility criteria, controlled settings, and follow-up to study the pharmacokinetic–pharmacodynamic relationship and determine the proposed dose. In a subsequent explanatory phase, efficacy and safety would initially be assessed in a controlled and tightly defined patient population so that efficacy can be demonstrated. After confirmation of the risk–benefit profile, the study population will be enhanced at an interim point. Population enhancement can be done in two ways, either by broadening eligibility criteria of the pre-existing groups or by adding additional groups with broader eligibility criteria. The second method would enable the parallel study of efficacy and safety in highly selected populations and in so-called real-world patients, generating data with both high internal and external validity at the same time, and thus increasing generalisability of results and precision in patient subgroups. We conclude that regulatory authorities need to request the submission of confirmatory data that show the generalisability and predictability of results to the whole patient population for whom the drug will finally be prescribed. Moreover, we propose to integrate external validity to randomised trials of asthma drugs by developing novel trials that are characterised by an adaptive trial design and population enhancement at an interim point. *Orestis Briasoulis, Ross Breckenridge, Andrew Nunn Division of Medicine (OB, RB) and MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology (AN), University College London, London WC1E 6BT, UK [email protected] We declare no competing interests.
www.thelancet.com/respiratory Vol 4 August 2016
Comment
1
2
3
4
5
Butler MG, Zhou EH, Zhang F, et al. Changing patterns of asthma medication use related to US Food and Drug Administration long-acting beta2-agonist regulation from 2005–2011. J Allergy Clin Immunol 2016; 137: 710–17. Kew KM, Evans DJ, Allison DE, Boyter AC. Long-acting muscarinic antagonists (LAMA) added to inhaled corticosteroids (ICS) versus addition of long-acting beta2-agonists (LABA) for adults with asthma. Cochrane Database Syst Rev 2015; 6: CD011438. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007; 62: 219–23. Bonini M, Usmani OS. The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis 2015; 9: 281–93. Leach C, Colice GL, Luskin A. Particle size of inhaled corticosteroids: does it matter? J Allergy Clin Immunol 2009; 124 (6 Suppl): S88–93.
6
7
8
9
10
Cerveri I, Cazzoletti L, Corsico AG, et al. The impact of cigarette smoking on asthma: a population-based international cohort study. Int Arch Allergy Immunol 2012; 158: 175–83. Van Spall HG, Toren A, Kiss A, Fowler RA. Eligibility criteria of randomized controlled trials published in high-impact general medical journals: a systematic sampling review. JAMA 2007; 297: 1233–40. Herland K, Akselsen JP, Skjonsberg OH, Bjermer L. How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir Med 2005; 99: 11–19. Eichler HG, Abadie E, Breckenridge A, et al. Bridging the efficacy– effectiveness gap: a regulator’s perspective on addressing variability of drug response. Nat Rev Drug Discov 2011; 10: 495–506. Zuidgeest MG, Goetz I, Grobbee DE, WP3 of the GetReal Consortium. PRECIS-2 in perspective: what is next for pragmatic trials? J Clin Epidemiol 2016; published online March 6. DOI:10.1016/j.jclinepi.2016.02.027.
The air we breathe: differentials in global air quality monitoring Air pollution is a severe problem worldwide, causing more than 7 million deaths every year. On May 12, 2016, WHO released its most recent report1 on urban air pollution. Compared with the last report released in 2014, the number of cities with air quality monitoring data available almost doubled, reaching 3000 cities in 103 countries. According to this new report,1 low-income and middle-income countries have the highest particulate matter (PM) levels: Onitsha, Nigeria, is the most polluted city in the world, followed by other cities in Nigeria, Pakistan, Iran, Afghanistan, and India in the top ten. The annual mean levels of PM10 (ie, PM with a diameter of less than 10 μm) in the ten most polluted cities range from 329 μg/m³ to 594 μg/m³, 16–30 times higher than WHO-recommended limits (annual mean 20 μg/m³). Many of the 100 most polluted cities, all of which have annual mean PM10 levels above 130 μg/m³, are in India, China, and other countries in Africa, southeast Asia, and the Middle East. 98% of cities with a population larger than 100 000 in low-income and middle-income countries have PM10 levels above WHO-recommended annual limits, compared with 56% of such cities in high-income countries. The WHO report1 covers thousands of cities that have air quality monitoring; however, many cities still do not monitor air quality. Here, we analyse data from the WHO Report1 and other sources2–12 to compare air quality monitoring coverage in 2012–14, adjusting for population sizes and land area, in different countries www.thelancet.com/respiratory Vol 4 August 2016
and regions of the world (table). In general, highincome countries have the best air quality monitoring in terms of the number of monitoring stations relative to population size or land area. Despite many efforts by the governments of several countries, most low-income and middle-income countries still have insufficient air quality monitoring.
Published Online July 13, 2016 http://dx.doi.org/10.1016/ S2213-2600(16)30180-1 See News page 609
Number of stations per 10 000 km²
Number of air monitoring stations
Number of Population* Area* (million) (km²) cities monitored
Number of stations per 1 000 000 population
USA3
4916
1639
318·9
9 833 517
15·42
5·00
Japan5
1934
887
127·1
364 560
15·22
53·05
Europe4
6099
2833
508·0
4 933 469
12·01
12·36
198
79
17·8
743 532
11·12
2·66 0·13
Chile11
99
54
23·5
7 682 300
4·21
South Africa9
145
27
54·0
1 213 090
2·69
1·20
South America1,11,12
540
208
414·4
17 457 742
1·30
0·31 0·30
Australia
10
Brazil12
252
95
206·1
8 358 140
1·22
China2
1436
338
1364·3
9 388 211
1·05
1·53
Egypt1
61
2†
89·6
995 450
0·68
0·61
India6
342
127
1295·3
2 973 190
0·26
1·15
Russia1,8
38
2
143·8
16 376 870
0·26
0·02
Africa1,9
252
65
1155·2
30 000 061
0·22
0·08
Nigeria1
13
12
177·5
910 770
0·07
0·14
Indonesia1,7
10
8
254·5
1 811 570
0·04
0·06
Pakistan1,7
6
5
185·0
770 880
0·03
0·08
*Data from World Bank, 2014. †This number is underestimated because it represents only cities in the Greater Cairo and Delta regions, and actual numbers are not publicly available.
Table: Air quality monitoring coverage in 2012–14, by country and world region
603