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
Table of ContentsExecutive Summary 3
1. Introduction 4
2. What Are the Epidemiological Trends for Europe and the World? 5
2.1 Genetic Risk Factors 8
3. 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? 10
4.1 Economic Burden 11
4.1.1 Early Estimates of Economic Burden 11
4.1.2 Most Recent Estimates 11
5. Why Does the Disease Burden Persist? 13
6. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition? 14
6.1 Overview of the Medications 14
6.1.1 Bronchodilators 14
6.1.2 Glucocorticosteroids 14
6.1.3 Other Pharmacologic Treatments 15
6.1.4 A substantial list of surgical interventions 16
6.2 Exacerbations of Symptoms in COPD 17
7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular Condition? 17
7.1 Preclinical Development 17
7.2 Clinical Development 20
8. What is the Current Status of Institutions and Human Resources Available to Address the Disease? 23
8.1 Private Sector 23
8.2 Public Funding 23
8.3 Sixth Framework Program 24
8.3.1 Global Allergy and Asthma European Network 24
9. Ways forward from a public health viewpoint with regard to Public Funding 24
9.1 Gaps between current research and potential research issues which could make a difference if eliminated. 24
9.2 What is the comparative advantage of the EU with regard to public funding of pharmaceutical R&D for COPD? 25
References 26
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]
1. Introduction
Chronic 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]
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 2.74million 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 reference2).
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% .
Figure 6.13.1
Source: World Health Organization Global Burden of Disease Study
Figure 6.13.2
Source: World Health Organization Global Burden of Disease Study
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 Economies
Formerly Soviet Economies of Europe
India
Other Asia and Islands
Sub-saharan Africa
Latin American and Caribbean
Middle East / 6.9/3.8
7.3/3.4
4.4/3.4
2.6/1.8
4.4/2.5
3.3/2.7
2.7/2.8
China
The 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 Factors
COPD 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]
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]