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Chapter 6.13: Chronic Obstructive Pulmonary Disease

Priority Medicines for Europe and the World"A Public Health Approach to Innovation"

Background Paper

Chronic Obstructive Pulmonary Disease(COPD)

By Warren Kaplan

7 October 2004

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Table of Contents

Executive Summary....................................................................................31. Introduction........................................................................................42. What Are the Epidemiological Trends for Europe and the World?... .5

2.1 Genetic Risk Factors..............................................................................83. What is the Control Strategy? Is There an Effective Package of

Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?..................................................................9

4. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy?........................................................................104.1 Economic Burden.................................................................................11

4.1.1 Early Estimates of Economic Burden................................................114.1.2 Most Recent Estimates......................................................................11

5. Why Does the Disease Burden Persist?............................................136. What Can Be Learnt from Past/Current Research into

Pharmaceutical Interventions for this Condition?...........................146.1 Overview of the Medications................................................................14

6.1.1 Bronchodilators.................................................................................146.1.2 Glucocorticosteroids.........................................................................146.1.3 Other Pharmacologic Treatments.....................................................156.1.4 A substantial list of surgical interventions........................................16

6.2 Exacerbations of Symptoms in COPD..................................................177. What is the Current “Pipeline” of Products that Are to Be Used for

this Particular Condition?.................................................................177.1 Preclinical Development.......................................................................177.2 Clinical Development...........................................................................20

8. What is the Current Status of Institutions and Human Resources Available to Address the Disease?....................................................238.1 Private Sector.......................................................................................238.2 Public Funding.....................................................................................238.3 Sixth Framework Program...................................................................24

8.3.1 Global Allergy and Asthma European Network.................................249. Ways forward from a public health viewpoint with regard to Public

Funding.............................................................................................249.1 Gaps between current research and potential research issues which

could make a difference if eliminated..................................................249.2 What is the comparative advantage of the EU with regard to public

funding of pharmaceutical R&D for COPD?.........................................25References...........................................................................................................26

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Executive Summary COPD prevalence and morbidity data that are available probably greatly

underestimate the total burden of the disease because it is not usually recognized and diagnosed until it is clinically apparent and moderately advanced.

Estimates of prevalence, morbidity, and mortality vary appreciably across countries, but in all countries where data are available COPD is a significant health problem in both men and women.

The substantial increase in the global burden of COPD projected over the next twenty years reflects, in large part, the historical increase in tobacco use worldwide, and the changing age structure of populations in developing countries.

Medical expenditures for treating COPD and the indirect costs of morbidity represent a substantial economic and social burden for societies and public and private payers worldwide.

Respiratory diseases are the leading cause of death in Europe, and, indeed, worldwide, yet despite these statistics, these illnesses have a lower profile than many other disease areas such as heart disease.

The treatment options available to patients with COPD and their physicians are limited, and no pharmacologic therapy has demonstrated a reduction in the progressive loss of lung function that occurs. Smoking cessation slows the decline in lung function but sustained quit rates attained by intensive behavioral therapy is often quite low. Long-term oxygen therapy is the only other treatment that has been shown to improve survival.

No effective COPD-specific, comprehensive anti-inflammatory therapy currently exists.

Given the scale of their human and economic costs, managing lung diseases should become a high priority for all European countries.

The existing infrastructure of the Sixth Framework Program Global Allergy and Asthma European Network should be expanded to create an EU-wide consortium to study COPD.

As the outlook is poor in the short and medium term for development of emerging therapies to treat or reverse COPD, the overriding imperative in developing countries and in the expanded EU is to reduce the prevalence and incidence of smoking. At least 75% of deaths due to COPD in adults are directly attributable to smoking.1

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1. IntroductionChronic obstructive pulmonary disease (COPD) is a complex disease characterized by progressive and partly irreversible airway obstruction and ubiquitous chronic inflammation in the lung. COPD is the collective term describing two separate chronic lung conditions: emphysema and chronic bronchitis.i Initial clinical symptoms are shortness of breath and occasional cough. As the disease progresses difficulties in breathing becomes more pronounced, the cough more persistent and becomes associated with production of a clear sputum. In severe cases there are additional systemic complications.

The major risk factor for COPD is tobacco smoking so, in principle, COPD is preventable and a decrease in smoking would lead to a decline in COPD prevalence. Improved methods of decreasing tobacco use are the primary public-heath related measures for COPD control. However, smoking is only one cause of COPD . Not all smokers develop clinically significant COPD. Recent increases in the incidence of COPD have occurred mainly in older age groups, in non-smokers, and in females.

The public health situation with regard to COPD is, in broad outline, similar to other “preventable” chronic conditions such as alcoholic liver disease (See Chapter 6.14) where the relatively limited success of primary and secondary prevention of alcohol consumption is coupled with the notion that alcohol-induced liver disease is largely a self-inflicted disease.

Traditional treatments of COPD are useful in symptomatic control but do not prevent progression of the disease. Current therapies address the symptoms and range from bronchodilators, corticosteroids to oxygen. There are no effective cures and there is no single diagnostic test for COPD. Making a diagnosis relies on clinical judgment based on a combination of history, physical examination and confirmation of the presence of airflow obstruction using lung function testing (spirometry).

Although we know a great deal about the biology of extracellular matrix proteins, proteinases, and anti-proteinase, interest in, and funding for, COPD research has been woeful, and investigators have made no significant medical breakthroughs in the treatment of this disorder, which, unfortunately, is becoming epidemic worldwide. The World Health Organization (WHO) estimates that COPD will be among the top five factors affecting quality-of-life in industrialized countries by 2020. Nonethless, COPD is a disease that has a low level of public awareness. We believe this is changing as several recent reviews, treatment guidelines and monographs are bringing this important chronic condition to the attention of a wider audience. 2 3 4 5

i Definition: Chronic obstructive pulmonary disease (COPD) is characterised by airflow obstruction caused by chronic bronchitis, emphysema, or both. Emphysema is defined as abnormal permanent enlargement of the air spaces distal to the terminal bronchioles, accompanied by destruction of their walls and without obvious fibrosis. Chronic bronchitis is defined as chronic cough, mucus production, or both, for at least three months for at least two successive years where other causes of chronic cough have been excluded.1 The Health Consequences of Smoking: A Report of the Surgeon General 2004. May 27, 2004. CDC Office of Communication. Available online at: http://www.surgeongeneral.gov/ library/smokingconsequences/. Accessed June 7, 2004.

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http://mednet3.who.int/prioritymeds/report/background/alcohol.doc

http://mednet3.who.int/prioritymeds/report/background/alcohol.doc

http://www.surgeongeneral.gov/library/smokingconsequences


Smoking cessation will probably have the most important effects on COPD as a public health problem in Europe and the world. Nonetheless, this document is a summary of pharmacological interventions and approaches COPD from that viewpoint.

2. What Are the Epidemiological Trends for Europe and the World?In 1997 COPD was ranked as the sixth leading cause of death and the 12th leading cause of morbidity worldwide.6 In 2000, the World Health Organization estimated that chronic obstructive pulmonary disease was the fourth leading cause of death worldwide, with 2.74 million deaths in 2000.7 By the year 2020, COPD is expected to be the third leading cause of death and the fifth leading cause of disability.8 This substantial increase in the global burden of COPD projected over the next twenty years reflects, in large part, the increasing use of tobacco worldwide and the changing age structure of populations in developing countries. Overall, in developing countries chronic respiratory diseases generally represent a challenge to public health for a variety of factors that implicate all levels of the healthcare system (e.g., use of generic medicines, national anti-smoking programs, use of essential medicines).9

COPD is the only major chronic disease with an increasing death rate— a disparity all the more striking amid the dramatic decline in deaths from coronary artery disease, stroke, and other cardiovascular disorders.10

Most of the information available on COPD prevalence, morbidity, and mortality comes from developed countries. Even in these countries, it is difficult to collect accurate epidemiological data on COPD. Much of the epidemiological data underestimate the total burden of COPD because the disease is usually not diagnosed until it is clinically apparent and moderately advanced. Mortality data also underestimate COPD as a cause of death because the disease is more likely to be cited as a contributory than as an underlying cause of death, or may not be cited at all.11 Recent epidemiological surveys have used a variety of spirometric tests and the presence of airflow limitation as an accurate estimate of the true burden of COPD. In Spain, spirometrically confirmed COPD was present in 9·1 % of the population, 15% of smokers, 12·8% of ex-smokers and 4·1% in nonsmokers (cited in reference 2).

Figure 6.13.1 plots the burden of disease per capita for COPD for various regions. COPD is not confined to developing countries, as inferred from the much higher global per capita burden COPD as compared to Europe. At this level of analysis, gender differences in COPD burden can be seen .

Figure 6.13.2 shows COPD as a fraction of all DALYs (both acute and chronic conditions) for different age groups. The global burden of COPD approaches 9% of the total global disease burden in the elderly as the burden continues to increase across all ages. The burden of COPD in EU15 as a fraction of all DALYs in the EU15 approaches 5% .

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COPD (DALYs per 1000 persons in age group)

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

EU10-MEU10-FEU15-MEU15-FWorld-MWorld-F

Figure 6.13.1Source: World Health Organization Global Burden of Disease Study

COPD (Percentage of ALL DALYs across age groups)

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

7.00%

8.00%

9.00%

10.00%

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

EU10-MEU15-MWorld-MWorld-F

Figure 6.13.2Source: World Health Organization Global Burden of Disease Study

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Until recently, most population-based studies in developed countries showed a much greater prevalence and mortality of COPD among men compared to women.12, 13, 14 See Figures 6.13.1 and 6.13.2. This is probably due to gender-related differences in exposure to risk factors, mostly cigarette smoking. This pattern is changing and some studies show that women now are as affected as men (notwithstanding the “macro”-level estimates in Figures 6.13.1 and 6.13.2). In developing countries, some studies report a slightly higher prevalence of COPD in women than men. This is probably due to exposure to indoor air pollution from cooking and heating fuels (greater among women).15, 16,

17, 18

In the UK the General Practice Research Database (http://www.gprd.com) provides population-based data on physician-diagnosed COPD . In 1997, the prevalence of COPD was 1.7% among men and 1.4% among women. Between 1990 and 1997, the prevalence increased by 25% in men and 69% in women. The prevalence of COPD among men plateaued in the mid-1990s, but continued to increase among women, reaching in 1997 the level observed in men in 1990.19

The General Practice Research Database includes all ages and thus underestimates the true impact of COPD on older adults.

Table 6.13.1 is taken from the WHO Global Burden of Disease Study (1990)20

Region or country COPD prevalence per 1000Males/Females (all ages)

Established Market EconomiesFormerly Soviet Economies of EuropeIndiaOther Asia and IslandsSub-saharan AfricaLatin American and Caribbean

6.9/3.87.3/3.44.4/3.42.6/1.84.4/2.53.3/2.7

12 Buist AS, Vollmer WM. Smoking and other risk factors. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. Philadelphia: WB Saunders Co.; 1994. p. 1259-87.13 Thom TJ. International comparisons in COPD mortality. Am Rev Respir Dis 1989; 140:S27-34.14 Xu X, Weiss ST, Rijcken B, Schouten JP. Smoking, changes in smoking habits, and rate of decline in FEV1: new insight into gender differences. Eur Respir J 1994; 7:1056-61.15 Chen JC, Mannino MD. Worldwide epidemiology of chronic obstructive pulmonary disease. Current Opinion in Pulmonary Medicine 1999; 5:93-9.16 Dennis R, Maldonado D, Norman S, Baena E, Martinez G. Woodsmoke exposure and risk for obstructive airways disease among women. Chest 1996; 109:115-9.17 Amoli K. Bronchopulmonary disease in Iranian housewives chronically exposed to indoor smoke. Eur Respir J 1998; 11:659-63.18 Samet JM, Marbury M, Spengler J. Health effects and sources of indoor air pollution. Am Rev Respir Dis 1987; 136:1486-508.19 Soriano et al., Validation of general practitioner-diagnosed COPD in the UK General Practice Research Database.Eur J Epidemiol. 2001;17(12):1075-80.

20 WHO Burden of Disease study Murray CJL, Lopez AD, eds. The global burden of disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge, MA: Harvard University Press; 1996.

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http://www.gprd.com/


Middle East 2.7/2.8

ChinaThe WHO Global Burden of Disease study reported a higher prevalence of COPD in China (26.20/1,000 among men and 23.70/1,000 among women). A more recent survey conducted in three regions of China (Northern: Beijing; Northeast: Liao-Ning; and South-Mid: HuBei) in persons older than 15 years estimated the prevalence of COPD at 4.21/1,000 among men and 1.84/1,000 among women.21

There is a lack of population-based data on COPD prevalence in many countries of the world.. The prevalence of COPD is highest in countries where cigarette smoking has been, or still is, very common, while the prevalence is lowest in countries where smoking is less common, or total tobacco consumption per capita is still low. The lowest COPD prevalence among men (2.69/1,000) was found in the Middle East (which includes countries in Northern Africa) and the lowest prevalence among women (1.79/1,000) was found in the region referred to as "Other Asia and Islands" (a group of 49 countries and islands, the largest of which is Indonesia and which includes Papua New Guinea, Nepal, Vietnam, Korea, Hong Kong, and many small island countries). Except in the Middle East, the prevalence of COPD is higher among men than among women.

Of all of the descriptive epidemiological data for COPD, mortality data are the most readily available, and probably the most reliable. Diagnostic criteria of COPD usually pose problems in population studies because COPD and chronic airflow limitation, which includes bronchial asthma, may not be differentiated.22

There are observed variations in mortality across developed countries for both genders,23 but differences between countries in death certification, diagnostic practices, the structure of health care systems, and life expectancy impact reported mortality rates.

The European White Book on Lung Disease, published in 2003 by the European Respiratory Society and the European Lung Foundation,24 reviewed the epidemiological data for the full spectrum of lung diseases collected from all European countries for the first time. It provides a detailed overview of the evolution of lung diseases in Europe, including data on morbidity, mortality, and costs. The estimates of prevalence of COPD range from 2,000 per 100,000 inhabitants to more than 10,000, with mortality rates varying between 25 to 75 per 100,000. The death rate from respiratory diseases (including, but not limited to COPD) in the UK is 105 per 100,000 people, which is twice the EU average. The only countries with a higher rate are former Soviet Union countries - Kyrgyzstan, Kazakhstan, Turkmenistan and Uzbekistan – and Ireland.

2.1 Genetic Risk FactorsCOPD is a major public health problem whose risk factors, in particular genetic risk factors, are poorly understood. COPD typically occurs insidiously in individuals with a long history of cigarette smoking, which usually begins at about age 15. Who will, and who will not, develop COPD cannot usually be ascertained until middle age, and an additional 15 years may pass between the onset of detectable disease and physician diagnosis of COPD. Only about 15% of chronic smokers develop clinically significant COPD, and fewer than 15% of these are diagnosed with emphysema.25

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The only proven genetic risk factor for COPD is severe alpha-1-antitrypsin deficiency, which increases the risk of developing COPD in a small percentage of the population. Patients with severe alpha-1-antitrypsin deficiency—most commonly, protease inhibitor (PI) type Z—are at increased risk for severe, early-onset COPD.26

Specifically, severe congenital deficiency for alpha1-antitrypsin (AAT) is associated with the early onset of emphysema, usually by the third decade of life. One approach to correct this deficiency is though replacement with alpha1-antitrypsin (referred to as alpha1-proteinase (A1Pi) inhibitor in its purified form). An intravenous preparation of A1Pi concentrate was produced from human plasma by Cutter Biological, a division of Miles, Inc., Berkeley, California. This preparation had been evaluated in a clinical study for its safety and biochemical efficacy. Based on the augmentation of its levels in the lung upon intravenous administration, the A1Pi preparation was licensed by the Food and Drug Administration for replacement therapy to treat individuals with severe congenital deficiency and impaired lung function. Slow progression of emphysema and lack of an adequate control group have made it difficult to evaluate this proteinase inhibitor through a controlled clinical trial.27

The true prevalence of this genetic deficiency has been hard to determine because of differences in genetic characteristics and ethnic backgrounds of the populations. The highest prevalence appears to be in Scandinavia; it is estimated that in Sweden 1 in 1,600 people has homozygous AAT deficiency. In contrast, in the United States the best estimates are that it may be about 1 in 3000, and in some other parts of the world the condition is extremely rare.28

Recently, researchers in the Netherlands have found that a Tumor Necrosis Factor-α gene polymorphism is associated with chronic obstructive pulmonary disease.29

Table 6.13.2: List of the candidate genes that have been associated with COPD in case–control studies

PI MZ alpha1-antitrypsin deficiencyTumour necrosis factor alphaMicrosomal epoxide hydrolaseGlutathione S1-transferaseHeme Oxygenase-1Taq-1 polymorphism of alpha1-antitrypsin

Alpha1-antichymotrypsinVitamin D binding proteinABO Blood GroupABH Secretor StatusCystic fibrosis transmembrane regulatorHLACytochrome P450

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For most of these loci, some studies have supported a significant association while other studies have refuted the association. Candidate genes for which there is the strongest supporting evidence are shown in bold 30, although the results in different populations are not consistent. 3

3. What is the Control Strategy? Is There an Effective Package of Control Methods Assembled into a “Control Strategy” for Most Epidemiological Settings?The overall approach to managing stable COPD should be characterized by a stepwise increase in treatment, depending on the severity of the disease. These fall into three broad areas: prevention of disease, progression, management of stable disease, and management of exacerbations. For a review of these issues, see references 2 and 3.

For patients with COPD, health education can play a role in improving skills, ability to cope with illness, and health status. It is effective in accomplishing certain goals, including smoking cessation.

None of the existing medications for COPD has been shown to modify the long-term decline in lung function that is the hallmark of this disease. Therefore, pharmacotherapy for COPD is used to alleviate symptoms and/or complications. While disease prevention is the ultimate goal, once COPD has been diagnosed, effective management should be aimed at the following goals:

Prevent disease progression Relieve symptoms Improve exercise tolerance Improve health status Prevent and treat complications Prevent and treat exacerbations Reduce mortality

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Bronchodilator medications are central to the symptomatic management of COPD. They are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. The principal bronchodilator treatments are short and long-acting ß2-agonists and anticholinergics, theophylline, and a combination of these drugs.

Inhaled corticosteroids improve lung function and reduce the number of exacerbations. The improvement of lung function appears to be more important and more rapid than reduction in exacerbations when these agents are used in combination with long-acting beta-agonists.

Chronic treatment with systemic glucocorticosteroids has an unfavorable benefit-to-risk ratio.

All COPD patients benefit from exercise training programs, improving with respect to both exercise tolerance and symptoms of shortness of breath and fatigue.

The long-term administration of oxygen (> 15 hours per day) to patients with chronic respiratory failure has been shown to increase survival.

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Various guidelines have been developed, and in the past not all of them have been consistent.31, 32 Recent guidelines, prepared with advice from the United States (NHLBI) and the WHO, were designed to provide a more uniform set.33

Guidelines from the Global Initiative in Obstructive Lung Disease (GOLD) were updated in 2003. 34 The National Institute for Clinical Excellence (NICE) published a guideline earlier this year. 35 The most recent set of guidelines are the ATS/ERS COPD guidelines (May 2004) and are generally consistent with that of the NHLBI/WHO.

In principle, therefore, treatment should be directed at increasing survival, improving symptoms, preventing complications, and accelerating recovery when exacerbations occur. Airway obstruction is generally not reversible in chronic obstructive pulmonary disease.36

Only two interventions have been shown to increase survival of smokers who develop chronic obstructive pulmonary disease. The first is stopping smoking, which is beneficial at all stages of the disease. Nicotine patches roughly double success rates and have a lower cost per quality adjusted life year gained than other widely used preventive measures.37 The second is long term oxygen therapy, which increases life expectancy of patients with chronic respiratory failure.

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4. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy?COPD treatment, particularly in the elderly, has been expensive because of the high rate and length of hospital admissions in elderly patients.38, 39 It must also be noted that current therapies, however, are limited in important ways. The bronchodilators that were developed originally for the treatment of asthma, exploit the small degrees of smooth muscle tone that are present in COPD patients. By inducing smooth muscle relaxation, airflow can be improved, but only very modestly. These small gains, perhaps surprisingly, can be exceedingly meaningful for some COPD patients. While current therapies can clearly be beneficial in treating the symptoms of COPD, new treatments are needed. In particular, the development of novel drugs that ameliorate the inflammatory and abnormal airway secretory responses initiated in response to chronic irritation from inhaled tobacco smoke may provide useful steps toward reduction of the ongoing destruction of the lung tissue and the progressive, relentless deterioration in pulmonary function that culminates in respiratory failure and death. This is the “holy grail” of therapy in patients with COPD.

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4.1 Economic BurdenCOPD is a progressive and debilitating disease, in its severe form, is not very responsive to therapy, COPD symptoms limit exercise tolerance and impair patients’ ability to work.40

4.1.1 Early Estimates of Economic Burden

4.1.1.1 United Kingdom. In 1996, the total direct cost of COPD in the UK was approximately £846 million (about US $1.393 billion) or £1,154 (about US $1,900) per patient per year, according to data from the National Health Service (NHS).41 Pharmaceutical expenditures for COPD and allied conditions in 1996 accounted for 11.0% of the total expenditures for prescription medications. Only 2% of total primary care expenditures were for COPD-related visits. In 1996, lost work productivity, disability, and premature mortality from COPD in the UK was estimated at £600 million (about US $960 million) for attendance and disability living allowance and £1.5 billion (about US $2.4 billion) to employers for work absence and reduced productivity.42

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4.1.1.2 The Netherlands. In 1993, the direct cost of COPD in the Netherlands was estimated to exceed US $256 million, or US $813 per patient per year. Assuming constant costs and treatment patterns, the total direct cost is expected to reach US $410 million per year by 2010. In 1993, inpatient hospitalizations accounted for 57% of the total direct cost of COPD, and medications accounted for an additional 23%. The indirect cost of COPD in the Netherlands was not available. The increase in health care costs in the Netherlands between 1993 and 2010 might be as high as 60%, at constant prices.43

4.1.1.3 United States: Direct costs for COPD in 1999 were estimated to be over $18 billion annually in the US.44 Total lost productivity due to COPD in 1994 was approximately $9.9 billion.37

4.1.2 Most Recent Estimates

We note that the total annual financial burden of respiratory diseases in Europe is currently approximately €100 billion, with COPD accounting for almost half of the total, followed by asthma, pneumonia, lung cancer, and TB. Perhaps surprisingly, the annual number of hospital days for respiratory diseases (including, but not limited to COPD) is higher in Western Europe than in Central and Eastern Europe (11.1 versus 7.2 per 100,000 population), while average daily hospital costs in Western Europe are almost ten times higher (€310 versus €32). The largest single cost of respiratory diseases, and by inference due largely to COPD, is lost worker productivity, estimated at €48.3 billion.

An economic analysis of data from a large-scale international survey was conducted in seven countries (Canada, France, Italy, The Netherlands, Spain, the U.K and the U.S.A.), to investigate the burden of COPD. The results demonstrated the high economic impact of COPD on the healthcare system and society in each country.45

The mean annual direct costs of COPD were particularly high in the U.S.A. ($4119 per patient) and Spain ($3196 per patient) but relatively low in The Netherlands ($606) and France ($522). The total societal cost of COPD per patient ranged from over $5646 in the U.S.A. to $1023 in The Netherlands. In five out of seven countries, the majority (52-84%) of direct costs associated with COPD were due to inpatient hospitalizations. Acute exacerbations of COPD are a key driver of secondary care costs. In all of the participating countries, COPD was underdiagnosed and undertreated. Between 9% and 30% of patients were undiagnosed despite having symptoms consistent with COPD, and up to 65% of patients did not receive regular prescribed medication.

Patients reported poor symptom control and considerable use of healthcare resources. The survey also demonstrated that the societal costs of COPD were 4-17 times higher in patients with severe COPD than in patients with mild COPD. Patients with comorbid conditions (accounting for 30-57% of patients in each country) were also particularly costly to society.45

In Italy, an estimated 2.6 million men and women presently have COPD, and the disease causes around 18 000 deaths each year. In addition to mortality, morbidity from COPD results in substantial use of secondary healthcare resources. The mean annual cost of COPD to the Italian healthcare system was about $1200 per patient. Indirect costs were estimated at about $50 per

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patient. Three-quarters of the direct per patient cost of COPD in Italy were accounted for by inpatient hospitalizations.46

In the Netherlands, the annual cost per patient of managing COPD is almost 3 times as high as that of asthma.47 Together, the two respiratory conditions cost the Dutch healthcare system $US346 million for direct medical costs in 1993, amounting to 1.3% of the total healthcare budget. The burden of COPD is expected to increase considerably in the future, reflecting the previous smoking habits of an aging population. Even if the current decline in the prevalence of smoking continues, by 2015 there will be a 76% increase in the prevalence of COPD (with the increase higher among women than men), compared with the prevalence in 1994.47 This will need to be considered by decision-makers allocating funds to healthcare services. It also further underlines the need to maximize the value gained from limited resources available to manage asthma and COPD.

In Spain, for a representative sample of the overall Spanish population between 40 and 69 years of age the cost per person of severe COPD was more than 3 times that of moderate COPD and more than 7 times that of mild COPD. The estimated annual cost of COPD in Spain in 1997 was about 238 million Euros.48

Individuals with COPD frequently receive professional medical care in their homes. In some countries, national health insurance plans provide coverage for oxygen therapy, visiting nursing services, rehabilitation, and even mechanical ventilation in the home, although coverage for specific services varies from country to country.49 Any estimate of direct medical expenditures for home care under-represents the true cost of home care to society, because it ignores the economic value of the care provided to those with COPD by family members. In developing countries especially, direct medical costs may be less important than the impact of COPD on workplace and home productivity. Because the health care sector might not provide long-term care for severely disabled individuals, COPD may force two individuals to leave the workplace - the affected individual and a family member who must now stay home to care for the disabled relative. Since human capital is often the most important national asset for developing countries, COPD may represent a serious threat to their economies.

A number of obstacles in developing countries prevent asthma and COPD guidelines from being effectively implemented, including the availability and affordability of inhaled drugs, availability of equipment, and difficulty of implementing a new health intervention in poorly functioning services.9

5. Why Does the Disease Burden Persist?There is presently no cure for COPD. Most significantly, its etiology is confounded with the culture of tobacco, smoking and poverty. The prevalence of chronic obstructive pulmonary disease is greatest in socio-economically deprived people; the differential effect between higher and lower social groups is perhaps greater for chronic obstructive pulmonary disease than for any other chronic disease.50

Furthermore, chronic obstructive pulmonary disease is under-diagnosed and under-treated partly because many people do not consult their physicians or health care practitioners or do not reveal all their symptoms unless specifically asked. Similarly, many physicians are not proactive with patients with an

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inhaled exposure pattern to tobacco smoke or other irritants. Patients often regard their symptoms as a result of age or lack of fitness and do not seek treatment, or they perceive treatment to be ineffective. In the United States one estimate is that only 14- 46% of all cases are diagnosed.51 At least in the United States, there has been a statistically significant decrease in the proportion of persons younger than 55 years who have evidence of mild or moderate COPD on pulmonary function tests and this might be due to smoking prevention programs that started in the mid-1960s.42

At least for the UK, a recent publication52 suggested that, despite the considerable burden imposed on patients, the health service and society, respiratory diseases are not currently a priority in the UK national strategy for health, and there is no national service framework (NSF) to guide those responsible for commissioning and providing respiratory services. We believe COPD is not currently a priority for most health systems.

6. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition?

6.1 Overview of the MedicationsPharmacologic therapy is used to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. None of the existing medications for COPD has been shown to conclusively modify the long-term decline in lung function that is the hallmark of this disease. The medications are presented in the order in which they would normally be introduced in patient care, based on the level of disease severity.

6.1.1 Bronchodilators

Medications that increase lung function usually by altering airway smooth muscle tone, are termed bronchodilators, since the improvements in expiratory flow reflect widening of the airways rather than changes in lung elasticity. Regular bronchodilation with drugs that act primarily on airway smooth muscle does not modify the decline of function in mild COPD and, by inference, the prognosis of the disease . Bronchodilator medications are central to the symptomatic management of COPD.53, 54 The side effects of bronchodilator therapy are pharmacologically predictable. However, COPD patients tend to be older than asthma patients and more likely to have comorbidities, so their risk of developing side effects is greater.

6.1.1.1 ß2-agonists. Long-acting B2-agonists improve lung function, reduce dynamic hyper-inflation, reduce dyspnea, improve health status and reduce exacerbations. Oral therapy is slower in onset and has more side effects than inhaled treatment. 55

6.1.1.2 Anticholinergics. The bronchodilating effect of short-acting inhaled anticholinergics is well demonstrated and is comparable to long-acting b-2 agonists. Anticholinergic drugs, such as ipratropium bromide, are poorly absorbed. This class of agents appears to be generally safe.

6.1.1.3 Methylxanthines. Controversy remains about the exact effects of xanthine derivatives. Data on duration of action for conventional, or even slow-release, xanthine preparations are limited in COPD. Theophylline is effective in

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COPD but toxicity is dose related. 56 Unlike the other bronchodilator classes, xanthine derivatives may involve a risk of overdose (either intentional or accidental).

6.1.2 Glucocorticosteroids

Their role in the management of stable COPD is limited to very specific indications. Inhaled corticosteroids improve lung function and reduce the number of exacerbations but there is some controversy about the clinical merits of using inhaled corticosteroids in COPD but the reader is referred to the published literature.5 57 What appears not debatable at present is that improvement of lung function appears to be more important and more rapid when these agents are used in combination with long-acting beta-agonists as is the reduction in exacerbations.

6.1.2.1 Oral glucocorticosteroids. Many existing COPD guidelines recommend the use of a short course (two weeks) of oral glucocorticosteroids to identify COPD patients who might benefit from long-term treatment with oral or inhaled glucocorticosteroids. A short course of oral glucocorticosteroids is a poor predictor of the long-term response to inhaled glucocorticosteroids in COPD.58

6.1.2.2 Oral glucocorticosteroids - long-term. Based on the lack of evidence of benefit, and the large body of evidence on side effects, long-term treatment with oral glucocorticosteroids is not recommended.

6.1.2.3 Inhaled glucocorticosteroids. Meta analysis has shown that, in patients with clearly defined moderately severe COPD, relatively high daily doses of inhaled corticosteroids improve lung function.59 Other meta-analysis have demonstrated that on other important clinical outcomes, like exacerbations of COPD, or hospital admissions, they also seem to have an important effect. No important side-effects has been demonstrated.

6.1.2.4. Combination therapy (inhaled corticosteriods + long acting beta agonists). Combination therapy with long-acting b-adrenoceptor agonists and inhaled corticosteroids are an established therapeutic option for asthma in patients with moderate and severe disease. Such combinations also appear to improve lung function in COPD, improve quality of life and delay the time to a first exacerbation. These effects are more pronounced with the combination therapy than in either component alone.60 Published studies support the view that combination therapy with inhaled steroids and long-acting beta-adrenoceptor agonists should be reserved for COPD patients with advanced disease and a history of frequent (more than one) exacerbation per year

6.1.3 Other Pharmacologic Treatments

6.1.3.1 Vaccines. Influenza vaccines can reduce serious illness and death in COPD patients by about 50%. A pneumococcal vaccine containing 23 virulent serotypes has been used, but sufficient data to support its general use in COPD patients are lacking.61

6.1.3.2 Alpha-1 antitrypsin augmentation therapy. Alpha-1 antitrypsin augmentation therapy is very expensive, and is not recommended for patients

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with COPD that is unrelated to alpha-1 antitrypsin deficiency but is clearly beneficial in patients with Alpha1 anti-trypsin defeciency.

6.1.3.3 Antibiotics. In several large-scale controlled studies done many years ago62, 63 prophylactic, continuous use of antibiotics was shown to have no effect on the frequency of acute exacerbations in COPD.

6.1.3.4 Mucolytic (mucokinetic, mucoregulator) agents (ambroxol, erdosteine, carbocysteine, iodinated glycerol). Most studies showed no effect of mucolytics on lung function or symptoms, although some have reported a reduction in the frequency of acute exacerbations.64 , 65, 66

6.1.3.5 Antioxidant agents. Antioxidants, in particular N-acetylcysteine, are the subject of some debate and may reduce the frequency of exacerbations.

6.1.4 A substantial list of surgical interventions have also been attempted during the last hundred years in attempts to help patients with emphysema.67

Only two are effective and none are in widespread use.

6.1.4.1 Lung volume reduction surgery (LVRS). LVRS is a surgical procedure in which parts of the lung are resected to reduce hyperinflation, making respiratory muscles more effective pressure generators by improving their mechanical efficiency. LVRS appears to improve exercise capacity as well as quality of life in some patients. There are reports of these effects lasting more than one year. 68, 69 Hospital costs associated with LVRS in 52 consecutive patients ranged from $11,712 to $121,829 (US). Hospital charges in 23 consecutive patients admitted for LVRS at a single institution ranged from $20,032 to $75,561 with a median charge of $26,669 (US).70 A small number of individuals incurred extraordinary costs because of complications. LVRS is still an experimental procedure.6.1.4.2 Lung transplantation. In appropriately selected patients with very advanced COPD, lung transplantation has been shown to improve quality of life and functional capacity although the Joint United Network for Organ Sharing in 1998 found that lung transplantation does not confer a survival benefit in patients with end-stage emphysema after two years.71 Common complications seen in COPD patients after lung transplantation, apart from operative mortality, are acute rejection and CMV, other opportunistic fungal (Candida, Aspergillus, Cryptococcus, Carini) or bacterial (Pseudomonas, Staphylococcus species) infections, lymphoproliferative disease, and lymphomas.72 Another limitation of lung transplantation is its cost. Hospitalization costs associated with lung transplantation have ranged from $110,000 to well over $200,000 (US). Costs remain elevated for months to years after surgery due to the high cost of complications and the immunosuppressive regimens that must be initiated after surgery.73 , 74

KEY POINTS:

To date, only two interventions—smoking cessation and long term treatment with oxygen (in people with hypoxaemia)—have been found to alter the long term course of chronic obstructive pulmonary disease.

RCTs found short term benefits (as opposed to long term effects on progression) from: anticholinergic drugs, beta2 agonists, inhaled corticosteroids (alone and in combinations with LABAs); oral steroids. The effects of anticholinergic drugs and beta 2 agonists are not seen in all

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people with chronic obstructive pulmonary disease, and the two agents combined are slightly more effective than either alone.

Adverse effects and the need for frequent monitoring of blood concentrations limit the usefulness of theophyllines.

It is not clear that anticholinergic agents affect decline in lung function; mucolytics have been shown to reduce the frequency of exacerbations but with a possible deleterious effect on lung function; beta 2 agonists, oral corticosteroids, and antibiotics have not yet been evaluated for their long term effects.

6.2 Exacerbations of Symptoms in COPD KEY POINTS

Exacerbations of respiratory symptoms requiring medical intervention are important clinical events in COPD.

The most common causes of an exacerbation are infection of the tracheobronchial tree and air pollution, but the cause of about one-third of severe exacerbations cannot be identified.

Inhaled bronchodilators (particularly inhaled ß2-agonists and/or anticholinergics), theophylline, and systemic, preferably oral, glucocorticosteroids are effective treatments for acute exacerbations of COPD.

Patients experiencing COPD exacerbations with clinical signs of airway infection (e.g., increased volume and change of color of sputum, and/or fever) may benefit from antibiotic treatment.

Noninvasive intermittent positive pressure ventilation (NIPPV) in acute exacerbations improves blood gases and pH, reduces in-hospital mortality, decreases the need for invasive mechanical ventilation and intubation, and decreases the length of hospital stay.

7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular Condition?

7.1 Preclinical DevelopmentThe benefits from current COPD treatments are modest. Progress in COPD treatment may require the development of entirely new therapies, in part based upon the pathological inflammatory processes that underlie lung tissue destruction. Several approaches are possible. The following Table 6.13.3 is adapted from the recent review by Barnes and Hansel (reference 80 and papers cited therein) and points to the varied number of potential targets for COPD therapeutics.

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Table 6.13.3 Potential Targets and Therapeutics for COPD

Potential Target for Therapy/Mode of

Action Potential Therapeutic Comments

Reactive oxygen species/antioxidants N-acetylcysteine in clinical trials

Stable glutathione compoundsSuperoxide dismutase analoguesSelenium-based antioxidants

Resveratrolphenolic component of red wine

Peroxynitrite formation/inhibition of iNOS

Prodrug of L-N6-(1-imminoethyl)lysine reduces NO concentration

Leukotrienes/leukotriene receptor antagonists

Various leukotriene B4 receptor antagonists

Leukotriene B4 inhibitors have not been successful

Adhesion molecules/inhibitors of recruitment sialyl-Lewis X mimic

antibodies to CD11/CD18inhibitors of E-selectin

Chemokines/CXC family inhibitors antibodies to interleukin-8 human mab in clinical trials

CXCR2 antagonistssmall molecule inhibitors in trials

CCR2 antagonistssmall molecule inhibitors in trials

CXCR3 antagonists

Cytokines/cytokine inhibitors

various anti-tumor necrosis factor antagonists

antibodies to TNF alpha and TNF receptor

TACE inhibitorsgeneral anti-inflammatory drugs phosphodiesterase inhibitors

Interleukin-10IL-10 has anti-inflammatory properties

Phosphodiesterases/PDE inhibitors PDE4 antagonists

cilomilast and roflumilast- limited by side effects

Kinases and transcription factors/Inhibitors NFkappa(B) antagonists

small molecule antagonists in development

p38MAPK antagonistssmall molecule antagonists in development

P13K gamma/delta antagonistssmall molecule antagonists in development

PPAR agonistsSome PPAR subtypes are anti-inflammatory

Mucus producing structural cells neutrophil antagonists

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Potential Target for Therapy/Mode of

Action Potential Therapeutic Commentsepidermal growth factor (EGF) antagonists

small molecule inhibitors of EGF receptor kinase

CACC inhibitors niflumic acid

inhibitors of neural stimulation

K+ channel openers; tachykinin-receptor antagonists

Structural proteins/fibrosis inhibitors

inhibition of transforming growth factor beta1 (TGFß1)

small molecule antagonists in development

Structural proteins/proteinase inhibitors endogenous anti-proteinases

large amounts of protein are required

small molecule inhibitors of proteinases

NE, cysteine proteinase, MMP inhibitors

Lung tissue/regenerating agents retinoic acid

retinoic acid receptor agonistsstem cells

The following points are of note:

Cellular matrix metalloproteinases may be important in the pathogenesis of COPD.75 In principle, inhibiting specific metalloproteinases, inhibiting serine proteases that inactivate inhibitors of the matrix metal-loproteinases, or reducing production of matrix metalloproteinases might be useful to limit the development or progression of COPD.

It might be possible to enhance the synthesis, assembly, or stability of elastic fibers in the lung.76

Another approach may be to inhibit recruitment of inflammatory cells to the lung. Attention has largely focused on mediators involved in recruitment and activation of neutrophils, and reactive oxygen species. In this category are the LTB4 antagonists, lipoxygenase inhibitors, chemokine inhibitors, and TNF- inhibitors. One needs to understand the inflammatory process throughout the natural history of COPD, identification of factors that exaggerate the inflammatory process and development of selective drugs that target relevant inflammatory pathways or cells.

There needs to be a clear biological distinction between stable disease and exacerbations where the inflammatory patterns are clearly different. Novel types of nonsteroidal anti-inflammatory treatment may be needed. There are several new approaches to anti-inflammatory treatment in COPD including, for example, phosphodiesterase inhibitors, transcription factor NF- B inhibitors, and adhesion molecule blockers.

In principle, although still unproven, interventions could be developed to enhance the antioxidant capabilities of the lung.77 Prospective data are needed to determine if exogenous antioxidants can prevent COPD or slow its progression. Oxidative stress is increased in patients with COPD, particularly during exacerbations. Oxidants are present in cigarette

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smoke and are produced endogenously by activated inflammatory cells, including neutrophils and alveolar macrophages, suggesting that antioxidants may be of use in therapy for COPD.

Based on several observations on death of pulmonary endothelial cells in experimental animals, pharmacologic inhibition of programmed cell death (apoptosis) might prevent loss of alveoli. The use of retinoids to stimulate alveoli development is a related approach The molecular mechanisms involved and whether this can be extrapolated to humans are not yet known. Several retinoic acid receptor subtype agonists have now been developed that may have a greater selectivity for this effect. Hepatocyte growth factor (HGF) has a major effect on the growth of alveoli in the fetal lung, and it is possible that in the future drugs might be developed that switch on responsiveness to HGF in adult lung or mimic the action of HGF.

Another approach would be to decrease the production of mucus by regulation of glandular mucous cells. There are several types of mucoregulatory drugs including tachykinin antagonists, sensory neuropeptide inhibitors, mediator and enzyme inhibitors, mucin gene suppressors, mucolytic agents, macrolide antibiotics, and purinoceptor blockers.

7.2 Clinical DevelopmentThe COPD market is complex, as at the moment, many drugs of various types are used in the treatment of the condition. Some of these drugs are also used for asthma, another condition that requires brochodilation. The privately-owned German pharmaceutical company Boehringer Ingelheim makes two of the older standard treatments: Atrovent® (ipratropium bromide), an anticholinergic and Combivent® (ipratropium/salbutamol), an anticholinergic/beta2-agonist combination. These must be taken several times a day and offer only limited symptomatic relief.

Boehringer Ingelheim launched Spiriva® (tiotropium bromide) in 2002, a long-acting, once-a-day anticholinergic agent that is administered as a dry powder aerosol . It is being co-marketed by Pfizer. Spiriva® was first launched in the Netherlands, and has since been introduced in Europe, North America and in a number of other countries.78

GlaxoSmithKline's Advair/Seretide® (flucatisone/salmeterol), was introduced for COPD (it has previously been available for asthma) around the world , and AstraZeneca's Symbicort® (formoterol/budesonide), which has been approved in Europe and in several other countries but not in the United States for COPD Both Advair/Seretide® and Symbicort® are beta2-agonist/corticosteroid combinations.

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AstraZeneca, Schering-Plough and Novartis, announced that they would collaborate on the development of a beta2-agonist/corticosteroid combination product for asthma and COPD, based on Schering-Plough's Asmanex® (mometasone furoate) and Novartis' formoterol product Foradil®; both products are currently approved for use in asthma, and Foradil® is approved for COPD.

Recent laboratory data have shown that all-trans-retinoic acid, a derivative of vitamin A, can regenerate lung alveoli in animal models of emphysema. Intra peritoneal injection of retinoic acid in rats increased alveolar surface area. The U.S. government is sponsoring a clinical trial with retinoic acid.79 See Tables 6.13.3 and 6.13.4 (below).

Further up the pipeline, the main focus is on a new class of drugs known as phosphodiesterase-IV inhibitors. No PDE-IV drug has yet been approved for COPD (or asthma), however, and candidates have been hindered by safety problems. Even so, companies have stated that this class shows promise although in April 2003, Merck & Co discontinued development of Celltech's PDE-IV inhibitor, citing safety concerns. Celltech later said one patient had developed colitis. Merck said it would continue to investigate its earlier-stage PDE-IV inhibitors.

As of 2003, notable pipeline products for COPD include:

Ariflo® (cilomilast): an oral PDE-IV inhibitor from GSK, has received an “approvable” letter for use of Ariflo® in maintenance of lung function in COPD patients poorly responsive to salbutamol Before issuing final approval, the FDA has requested additional efficacy and safety data.

Roflumilast®: another oral PDE-IV inhibitor, in Phase III trials, originated by Altana and being co-developed with Pfizer (with Tanabe in Japan). See Table 3.

ONO 6126: a PDE-IV inhibitor from Ono, in Phase II trials. We have no information with regard to US trials.

842470/AWD 12281: originally developed by the European company Viatris, this PDE-IV inhibitor is being developed by Elbion, which granted GSK worldwide development and commercialisation rights in July 2002. Phase I trials in COPD are underway This compound is probably “842470 “ in Table 3.

IC 485: Phase II trials are scheduled for the third quarter of 2003 for this PDE-IV inhibitor, in development with Icos (See Table 3).

CP 671305: a PDE-IV inhibitor in Phase I trials with Pfizer for COPD . We find no counterpart in Table 3.

For a relatively recent review of drugs for COPD, see reference 80 .

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Table 6.13.4Sponsor Intervention I II III Sites Patients

Centocor Infliximab (monclonal antibody)

X Multi 225

Sepracor Inc. (R,R)-formoterol X Multi 750

Sepracor Inc. (R,R)-formoterol X Multi 800

Pfizer/Altana Pharm.

"new IND" X Multi

Abgenix humab anti IL-8 X CA 150

Pfizer/Altana Pharm.

Roflumilast X CA 1100

NHLBI retinoic acid X

GlaxoSmithKline beta 2 agonist TD3327 X

GlaxoSmithKline 274150 (selective iNOS inhibitor, oral)

X

GlaxoSmithKline beta 2 agonist 597901 X

GlaxoSmithKline 842470 (PDE IV inhibitor) X

Novartis Pharmaceuticals

none / formoterol fumarate X

ICOS no name X

Milkhaus Laboratory

ML-03 X

Schering Plough PDE IV inhibitor X

Genaera no information X

There are 45 COPD-related clinical trials listed in the international database of clinical trials (http://www.controlled-trials.com/ ). Of these, 19 (42%) are directed to various therapeutic interventions and of nineteen, 8 are sponsored by the UK National Health Service, the remainder being funded by the National Institutes of Health.

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http://www.controlled-trials.com/


8. What is the Current Status of Institutions and Human Resources Available to Address the Disease?

8.1 Private SectorSome of the largest pharmaceutical companies in the world (Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Schering Plough) are involved on R&D directed to respiratory conditions, including COPD. They understand that, because of its chronic and progressive nature, COPD represents a massive and growing burden, both in direct and indirect costs. In developing countries where smoking continues to be extremely prevalent, COPD is on the increase. There is obviously a lack of purchasing power in most less developed countries, and one can only 2 Pauwels, RA, Rabe, KF. 2004. Burden and clinical features of chronic obstructivepulmonary disease (COPD) Lancet 364: 613–620.3 Calverley PMA, Walker P. 2003. Chronic obstructive pulmonary disease, Lancet 362: 1053–1061.

4 Chronic Obstructive Pulmonary Disease: National Clinical Guideline for Management of Chronic Obstructive Pulmonary Disease in Adults in Primary and Secondary care. Produced on behalf of the National Institute for Clinical Excellence by the National Collaborating Centre for Chronic Conditions at the Royal College of Physicians, 2004.

5 Barnes PJ. 2000. Chronic obstructive pulmonary disease. N Engl J Med. 343:269-280.

6 Murray CJ, Lopez AD. 1997. Global morality, disability and the contribution of risk factors: global burden of disease study. Lancet 349:1436–14427 National Heart Lung and Blood Institute. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Bethesda, ML: NHLBI ,2001.8 Murray CJ, Lopez AD. 1997. Alternative projection of mortality by cause 1990–2020: global burden of disease study. Lancet 349:1498–1504.9 Aıt-Khaled N, Enarson D, & Bousquet J , 2001. Chronic respiratory diseases in developing countries: the burden and strategies for prevention and management, Bulletin of the World Health Organization, 79: 971–979.10 Mannino DM. 2003. Chronic obstructive pulmonary disease: definition and epidemiology. Respir Care 48:1185-1191.11 Mannino DM, Brown C, Giovino GA. 1997. Obstructive lung disease deaths in the United States from 1979 through 1993. An analysis using multiple-cause mortality data. Am J Respir Crit Care Med 156:814-8.21 Xian Sheng Chen. Analysis of basic data of the study on prevention and treatment of COPD. Chin J Tuber Respiratory Dis 1998; 21:749-52.22 Sobradillo Pena V, Miravitlles M, Gabriel R, Jimenez-Ruiz CA, Villasante C, Masa JC, Viejo J, and Fernandez-Fau L, 2000. Geographic Variations in Prevalence and Underdiagnosis of COPD CHEST 118:981–989.23 Incalzi RA, Fuso L, De Rosa M, Forastiere F, Rapiti E, Nardecchia B, et al. 1997. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J 10:2794-800.24 European Respiratory Society, 2003, press release, at http://www.ersnet.org/ers/show/default.aspx25 Croxton TL, Weinmann GG, Senior RM, Wise RA, Crapo JD, & Buist, AS, 2003. Clinical Research in Chronic Obstructive Pulmonary Disease Needs and Opportunities,

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hope that COPD does not become a “neglected” chronic disease in these regions.

It is difficult to ascertain exactly how much private sector R&D is relegated to COPD, as the available information (usually in the form of annual reports or SEC filings) usually do not parse out R&D expenses into specific disease conditions.

8.2 Public Funding The extent of public funding for COPD-related R&D in Europe is also difficult to estimate, although we have some limited information. In general, the amounts are far less than public funding in the United States. The total National Health Lung and Blood Institute (the primary NIH Institute for pulmonary diseases)

Am J Respir Crit Care Med Vol 167. 1142–1149.26 Silverman, EK, Chapman HA, Drazen JM, Weiss S, Rosner B, Campbell EJ, O’Donnel WJ , Reilly JJ, Ginns L, Mentzer S, Wain J & Speizer FE. 1998. Genetic Epidemiology of Severe, Early-onset Chronic Obstructive Pulmonary Disease Risk to Relatives for Airflow Obstruction and Chronic Bronchitis, Am J Respir Crit Care Med Vol 157. 1770–1778. 27 Pierson DJ, 2004. 2004. Translating New Understanding Into Better Care for the Patient With Chronic Obstructive Pulmonary Disease, Respiratory Care, 49: 99-109.28 Rennard SI, Farmer SG. 2002. COPD in 2001 A Major Challenge for Medicine, the Pharmaceutical Industry, and Society Chest, 121:113S–115S.29 Küçükaycan M, Van Krugten M, Pennings, H-J, Huizing, TWJ, Buurman WA, Dentener, MA & Emiel FM. 2002. Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease. Respir Res 2002, 3:29, at http://respiratory-research.com/content/3/1/2930 Lomas DA & Silverman EK. 2001. Review The genetics of chronic obstructive pulmonary disease

Respir Res 2:20–26, at http://respiratory-research.com/content/2/1/020.31 Fabbri L, Caramori G, Beghe B, Papi A, & Ciaccia A. 1998. Chronic obstructive pulmonary disease international guidelines. Curr Opin Pulm Med 4: 76–84.32 Lacasse Y, Ferreira I, Brooks D, Newman T, & Goldstein RS. 2001. Critical appraisal of clinical practice guidelines targeting chronic obstructive pulmonary disease. Arch Intern Med 161: 69–74.33 Pauwels RA, Buist AS, Calverley PM, Jenkins CR, & Hurd SS. 2001. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 163: 1256–1276.34 Fabbri LM, Hurd SS. Global strategy for the diagnosis and managementand prevention of COPD. 2003 Update. Eur Respir J 2003;22:1-2.

35 National Collaborating Centre for Chronic Conditions. 2004. Chronic obstructive pulmonary disease. National clinical guideline on management of chronic obstructive pulmonary disease in adults in primary and secondary care. Thorax ;59(suppl 1):1-232.

36 Roche N. 1999. Recent advances Pulmonary medicine BMJ 318 : 171-176.37 Fiscella K, Franks P. 1996. Costeffectiveness of the transdermal nicotine patch as an adjunct to physicians' smoking cessation counseling. JAMA 275:124751. 38 Cydulka RK, McFadden ER, Jr, Emerman CL, Sivinski LD, Pisanelli W, & Rimm AA. 1997. Patterns of hospitalization in elderly patients with asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 156:180712.

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http://respiratory-research.com/content/2/1/020

http://respiratory-research.com/content/3/1/29


appropriation for fiscal year (FY) 2001 was over $2 billion. In the United Kingdom (April 2002 to March 2003), the Medical Research Council (MRC) spent a total of £200.7m (£180.3m resource and £20.4m capital) to fund its own research centers. Grants to researchers in universities and medical schools, including training awards for post-graduate students and fellows, amounted to another £194.9m.81

The British Lung Foundation is the only charity in the UK that funds research into COPD-related topics.ii Their total funding since 2001, including that for therapeutic and non therapeutic interventions, and basic biology, is about $1.7 million.82

ii Throughout Europe there are many organizations directed to providing educational and training materials related to COPD and therapeutic guidelines. Such organizations include the Alpha-1 Association ( http://alpha1.org); Alpha-1 Foundation (more than $15million has been funded in Alpha-1 research http://www.alphaone.org); British Lung Foundation (http://www.lunguk.org); Global Initiative for Chronic Obstructive Lung Disease (GOLD) (define treatments; increase awareness and prevention of COPD worldwide http://www.goldcopd.com); EFA is the European Federation of Allergy and Airways Diseases Patients' Associations, an alliance of 41 organizations in 23 different countries across Europe http://www.efanet.org).

39 Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. 1995. Am. J. Respir. Crit. Care Med.152:S77–S120.40 Sin DD, Stafinski T, Chu Ng Y, Bell NR & Jacobs P. 2002. The Impact of Chronic Obstructive Pulmonary Diseaseon Work Loss in the United States . Am J Respir Crit Care Med. 165. 704–707, 2002.41 D Price and M. Duerden, BMJ 2003;326:1046–742 Calverley PMA. 1998. Chronic obstructive pulmonary disease: the key facts. London: British Lung Foundation43 Rutten-van Molken MP, Postma MJ, Joore MA, Van Genugten ML, Leidl R, Jager JC. 1999. Current and future medical costs of asthma and chronic obstructive pulmonary disease in the Netherlands. Respir Med 93:779-87.44 Sullivan SD, Ramsey SD, Lee TA. 2000. The economic burden of COPD. Chest 117(2 Suppl):5S–9S. 45 Wouters EF. 2003. Economic analysis of the Confronting COPD survey: an overview of results. Respir Med. 97 Suppl C:S3-14. 46 Dal Negro R, Rossi A, Cerveri . 2003.The burden of COPD in Italy: results from the Confronting COPD survey. Respir Med. 97 Suppl C:S43-50. 47 Rutten van-Molken MP, Feenstra TL. 2001. The burden of asthma and chronic obstructive pulmonary disease: data from The Netherlands. Pharmacoeconomics. 19 Suppl 2:1-6.48 Masa JF, Sobradillo V, Villasante C, Jimenez-Ruiz CA, Fernandez-Fau L, Viejo JL, Miravitlles M., 2004, Costs of chronic obstructive pulmonary disease in Spain. Estimation from a population-based study, Arch Bronconeumol. 40:72-9 (article in Spanish).

49 Fauroux B, Howard P, Muir JF. 1994. Home treatment for chronic respiratory insufficiency: the situation in Europe in 1992. The European Working Group on Home Treatment for Chronic Respiratory Insufficiency. Eur Respir J 7:1721-6.50 .Prescott E, Vestbo J. Socioeconomic status and chronic obstructive pulmonary disease. 1999. Thorax ;54:737-41

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http://www.goldcopd.com/

http://www.lunguk.org/

http://www.alphaone.org/

http://alpha1.org/


8.3 Sixth Framework Program8.3.1 Global Allergy and Asthma European Network

This is a Europe-wide consortium of research organizations with greater than 25 partners making up an EU-backed ‘network of excellence’ under the European Union’s umbrella research program – the Sixth Framework Program (FP6) This Network of Excellence will study allergy and asthma and will establish an international network that will conduct specific integrated multidisciplinary research. The network would like to build a permanent structure that will be

51 Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971-2000. MMWR Morb Mortal Wkly Rep. 2002;51:1-16 52 General Practice Airways Group, University of Aberdeen, UK http://www.gpiag.org/news/Bridging-the-gap-(final).pdf, last accessed 5 June 2004.53 Vathenen AS, Britton JR, Ebden P, Cookson JB, Wharrad HJ, & Tattersfield AE. 1988. High-dose inhaled albuterol in severe chronic airflow limitation. Am Rev Respir Dis 138:850-5.54 Gross NJ, Petty TL, Friedman M, Skorodin MS, Silvers GW, & Donohue JF. 1989. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am Rev Respir Dis 139:1188-91.55 Shim CS, Williams MH Jr. 1983. Bronchodilator response to oral aminophylline and terbutaline versus aerosol albuterol in patients with chronic obstructive pulmonary disease. Am J Med 75:697-701.56 Murciano D, Auclair MH, Pariente R, Aubier M. 1989. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 320:1521-5.57 Pauwels R. Inhaled glucocorticosteroids and chronic obstructive pulmonary disease. How full is the glass? Am J Respir Crit Care Med 2002;165:1579-1580.

58 Callahan CM, Dittus RS, Katz BP. 1991. Oral corticosteroid therapy for patients with stable chronic obstructive pulmonary disease. A meta-analysis. Ann Intern Med 114:216-23.59 PM van Grunsven et al. Long term effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a meta-analysis. Thorax 1999 54: 7-14. 60 Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S,Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J 2003; 22: 912–919.

61 Williams JH, Jr., Moser KM. 1986. Pneumococcal vaccine and patients with chronic lung disease. Ann Intern Med 104:106-9.62 Francis RS, May JR, Spicer CC. 1961. Chemotherapy of bronchitis: influence of penicillin and tetracylcline administered daily, or intermittently for exacerbations. BMJ 2:979-85.63 Francis RS, Spicer CC. 1960. Chemotherapy in chronic bronchitis: influence of daily penicillin and tetracycline on exacerbations and their cost. A report to the research committee of the British Tuberculosis Assoication by their Chronic Bronchitis Subcommittee. BMJ 1:297-303.64 Guyatt GH, Townsend M, Kazim F, Newhouse MT. 1987. A controlled trial of ambroxol in chronic bronchitis. Chest 92:618-20.

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financially independent after EU support ends. The EC is likely to commit €14.3 million with the consortium putting up an equal amount.83.

9. Ways forward from a public health viewpoint with regard to Public Funding

9.1 Gaps between current research and potential research issues which could make a difference if eliminated.

65 Petty TL. 1990. The National Mucolytic Study. Results of a randomized, double-blind, placebo-controlled study of iodinated glycerol in chronic obstructive bronchitis. Chest 97:75-83.66 Poole PJ, Black PN. 2000. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2: Available from: URL: www.update-software.com or www.updatusa.com67 Benditt JO. 2004. Surgical therapies for chronic obstructive pulmonary disease. Respir Care 49:53-61.68 Cooper JD, Patterson GA, Sundaresan RS, Trulock EP, Yusen RD, Pohl MS, et al. 1996. Results of 150 consecutive bilateral lung volume reduction procedures in patients with severe emphysema. J Thorac Cardiovasc Surg 112:1319-29.69 Russi EW, Stammberger U, Weder W. 1997. Lung volume reduction surgery for emphysema. Eur Respir J 10:208-18.70 Elpern EH, Behner KG, Klontz B, Warren WH, Szidon JP, Kesten S. 1998. Lung volume reduction surgery: an analysis of hospital costs. Chest 113:896-9.71 Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. 1998. The registry of the International Society for Heart and Lung Transplantation: fifteenth official report - 1998. J Heart Lung Transplant 17:656-68. 72 Theodore J, Lewiston N. 1990. Lung transplantation comes of age. N Engl J Med 322:772-4.73 Ramsey SD, Patrick DL, Albert RK, Larson EB, Wood DE, Raghu G. 1995. The cost effectiveness of lung transplantation. A pilot study. University of Washington Medical Center Lung Transplant Study Group. Chest 108:1594-601.74 van Enckevort PJ, Koopmanschap MA, Tenvergert EM, Geertsma A, van der Bij W, de Boer WJ, et al. 1997. Lifetime costs of lung transplantation: estimation of incremental costs. Health Econ 6:479-89.75 Hautamaki RD, Kobayashi DK, Senior RM, Shapiro SD. 1997. Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277:2002-2004. 76 Yanagisawa H, Davis EC, Starcher BC, Ouchi T, Yanagisawa M, Richard-son JA, Olson EN. 2002. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415:168-17177 MacNee W. 2000. Oxidants/antioxidants and COPD. Chest 117:303S-317S. 78 COPD: a new market emerges, IMS-health, at http://www.ims-global.com/insight/news_story/0305/news_story_030509.htm.79 Massaro, GD and Massaro D. 1997. Retinoic Acid Treatment Abrogates Elastase-induced Pulmonary Emphysema in Rats. Nature Med 3:675-677.

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While new treatment initiatives have come from information on the physiology of COPD, not a single new therapy has come from information on pathogenic inflammatory processes.

A better understanding of the molecular and cellular pathogenic mechanisms of COPD should lead to many new directions for both basic and clinical investigations.

Surrogate markers of inflammation, possibly derived from the analysis of sputum (cells, mediators, enzymes) or exhaled condensates (lipid mediators, reactive oxygen species, cytokines), that may predict the clinical usefulness of new management and prevention strategies for COPD need to be developed.

80 New Drugs for Asthma, Allergy and COPD, in Progress in Respiratory Research v. 31, (ed. C. Bollinger, T. Hansel & P. Barnes) Karger Publishing, 2001; Barnes PJ & Hansel TT. 2004. Prospects for new drugs for chronic obstructive pulmonary disease, Lancet 364: 985-996.

81 MRC Annual report, 2002, at http://www.mrc.ac.uk/index/publications/publications-annual_reports/publications-annual_reports-2.htm, last accessed 5 June 2004.82 British lung foundation, www. britishlungfoundation .org , last accessed 5 June 2004.83 Global Allergy and Asthma European Network, at http://europa.eu.int/comm/research/press/2004/pr0502en.html, last accessed 12 June 2004.

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http://www.britishlungfoundation.org/

http://www.mrc.ac.uk/index/publications/publications-annual_reports/publications-annual_reports-2.htm

http://www.mrc.ac.uk/index/publications/publications-annual_reports/publications-annual_reports-2.htm


New clinical end points are needed to assess the impact of different COPD interventions. The cornerstone of clinical assessment has been a reduction in the decline of the forced expiration volume (FEV1) of the lung for inhaled corticosteroids and an improvement of FEV1 with brochodilators. Both measures fail to take into account the multi-component nature of COPD. Rehabilitation therapy would have failed these tests despite its clear beneficial impact.

Standardized methods for tracking trends in COPD prevalence, morbidity, and mortality over time need to be developed so that countries can plan for future increases in the need for health care services in view of predicted increases in COPD. This need is especially urgent in developing countries with limited health care resources.

Data are needed on the use, cost, and relative distribution of medical and non-medical resources for COPD, especially in countries where smoking and other risk factors are prevalent. These data are likely to have some impact on health policy and resource allocation decisions.

Since COPD is not fully reversible (with current therapies) and slowly progressive, it will become ever more important to identify early cases as more effective therapies emerge. Consensus on standard methods for detection and definition of early disease need to be developed.

Research is required to gauge the impact and reduce the risk from increasing air pollution, urbanization, recurrent childhood infections, occupational exposures, and use of local cigarette equivalents. Programs designed to reduce exposure to biomass fuel in countries where this is used for cooking and domestic heating should be explored in an effort to reduce exposure and improve ventilation in homes.

9.2 What is the comparative advantage of the EU with regard to public funding of pharmaceutical R&D for COPD?

Given the scale of their human and economic costs, managing lung diseases should become a high priority for all European countries. The pharmaceutical industry is beginning to recognize this and it is probable that new and more effective therapies will become available, although not in the short term.

If properly appreciated, the “White Book on Lung Disease”, published last year, should signal an increasing awareness of the burden of such conditions on the European healthcare system and this might offer a comparative advantage in a public health context. We suggest that, going forward, there is an opportunity to use this increasing awareness in conjunction with expansion of the existing Sixth Framework Network of Excellence Global Allergy and Asthma European Network.

The existing infrastructure of this Network of Excellence should be expanded to create an EU-wide consortium to study COPD as there may be reasonable “spillovers” from the Global Allergy and Asthma network. While both diseases have components of variable airflow obstruction, there are significant differences between the two conditions, i.e., asthmatics respond more frequently and to a greater extent to bronchodilators than do patients with COPD.84 The inflammatory process in COPD is very different from that in asthma, with different inflammatory cells, mediators, inflammatory effects, and response to therapy. 85 The eosinophilic inflammation in asthma is markedly suppressed by corticosteroids, but they have no appreciable effect on the inflammation in COPD.

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Nonetheless, there is an opportunity for advances in our understanding of the basic biology of COPD by expansion of this Network. In proportion to the total amounts spent on COPD R&D (indeed for most pharmaceutical R&D) very little is spent to identify truly effective therapies. Expansion of the Network into COPD should be predicated on allowance for communication between basic and clinical scientists to efficiently produce novel therapies. The strongest comparative advantage in COPD would be to coordinate efforts by advocacy groups, academia and industry to educate the public and the government of the need for novel and effective therapies.

As the outlook is poor in the short and medium term for development of emerging therapies to treat or reverse COPD, the overriding imperative in developing countries and in the expanded EU is to reduce the prevalence and incidence of smoking. At least 75% of deaths due to COPD in adults are directly attributable to smoking.

References

84 Donohue, JF & Ohar JA. Inflammation and Treatment of Asthma and COPD, American College of Chest Physicians at FCCPhttp://www.chestnet.org/education/online/pccu/vol16/lessons19_20/index.php.85 Peter J. Barnes, (CHEST 2000; 117:10S–14S) Mechanisms in COPD Differences From Asthma

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