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
6.13-1
Chapter 6.13: Chronic Obstructive Pulmonary Disease
Table of Contents
Executive 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
4.1.2
5.
6.
Why Does the Disease Burden Persist? ............................................................................... 13
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
6.1.2
6.1.3
6.1.4
7.
8.
Early Estimates of Economic Burden ....................................................................... 11
Most Recent Estimates ............................................................................................... 11
Bronchodilators ........................................................................................................... 14
Glucocorticosteroids ................................................................................................... 14
Other Pharmacologic Treatments ............................................................................. 15
A substantial list of surgical interventions .............................................................. 16
6.2 Exacerbations of Symptoms in COPD ......................................................................... 17
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
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
6.13-2
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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. Longterm 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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Chapter 6.13: Chronic Obstructive Pulmonary Disease
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
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.
i
6.13-4
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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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Chapter 6.13: Chronic Obstructive Pulmonary Disease
COPD (DALYs per 1000 persons in age group)
35.0
30.0
25.0
EU10-M
EU10-F
EU15-M
EU15-F
World-M
World-F
20.0
15.0
10.0
5.0
0.0
0-4
5-14
15-29
30-44 45-59
60-69
70-79
80+
Figure 6.13.1
Source: World Health Organization Global Burden of Disease Study
COPD (Percentage of ALL DALYs across age groups)
10.00%
9.00%
8.00%
7.00%
6.00%
EU10-M
EU15-M
World-M
World-F
5.00%
4.00%
3.00%
2.00%
1.00%
0.00%
0-4
5-14
15-29 30-44 45-59 60-69 70-79
Figure 6.13.2
Source: World Health Organization Global Burden of Disease Study
6.13-6
80+
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 1000
Males/Females (all ages)
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
Established Market Economies
Formerly Soviet Economies of Europe
India
Other Asia and Islands
Sub-saharan Africa
Latin American and Caribbean
Middle East
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.
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Chapter 6.13: Chronic Obstructive Pulmonary Disease
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
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
6.13-8
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 deficiency
Tumour necrosis factor alpha
Microsomal epoxide hydrolase
Glutathione S1-transferase
Heme Oxygenase-1
Taq-1 polymorphism of alpha1-antitrypsin
Alpha1-antichymotrypsin
Vitamin D binding protein
ABO Blood Group
ABH Secretor Status
Cystic fibrosis transmembrane regulator
HLA
Cytochrome P450
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
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Chapter 6.13: Chronic Obstructive Pulmonary Disease









Improve health status
Prevent and treat complications
Prevent and treat exacerbations
Reduce mortality
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 ß2agonists 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-torisk 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.
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.
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
6.13-10
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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.
4.1
Economic Burden
COPD 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 COPDrelated 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
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
6.13-11
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 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
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Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 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.
6.13-13
Chapter 6.13: Chronic Obstructive Pulmonary Disease
6.
What Can Be Learnt from Past/Current Research into
Pharmaceutical Interventions for this Condition?
6.1
Overview of the Medications
Pharmacologic 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 hyperinflation, 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 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
6.13-14
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 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
6.13-15
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 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
6.13-16
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 Development
The 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.
6.13-17
Chapter 6.13: Chronic Obstructive Pulmonary Disease
Table 6.13.3 Potential Targets and Therapeutics for COPD
Potential Target for
Therapy/Mode of
Action
Reactive oxygen
species/antioxidants
Potential Therapeutic
N-acetylcysteine
Stable glutathione compounds
Comments
in clinical trials
Superoxide dismutase analogues
Selenium-based antioxidants
Resveratrol
phenolic 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/CD18
inhibitors of E-selectin
Chemokines/CXC family
inhibitors
Cytokines/cytokine
inhibitors
antibodies to interleukin-8
human mab in clinical trials
CXCR2 antagonists
CCR2 antagonists
CXCR3 antagonists
small molecule inhibitors in trials
small molecule inhibitors in trials
various anti-tumor necrosis factor
antagonists
TACE inhibitors
general anti-inflammatory drugs
antibodies to TNF alpha and
TNF receptor
Interleukin-10
phosphodiesterase inhibitors
IL-10 has anti-inflammatory
properties
Phosphodiesterases/PDE
inhibitors
PDE4 antagonists
cilomilast and roflumilastlimited by side effects
Kinases and transcription
factors/Inhibitors
NFkappa(B) antagonists
p38MAPK antagonists
P13K gamma/delta antagonists
PPAR agonists
6.13-18
small molecule antagonists in
development
small molecule antagonists in
development
small molecule antagonists in
development
Some PPAR subtypes are antiinflammatory
Chapter 6.13: Chronic Obstructive Pulmonary Disease
Potential Target for
Therapy/Mode of
Action
Mucus producing structural
cells
Potential Therapeutic
neutrophil antagonists
epidermal growth factor (EGF)
antagonists
CACC inhibitors
Comments
small molecule inhibitors of EGF
receptor kinase
inhibitors of neural stimulation
niflumic acid
K+ channel openers; tachykininreceptor antagonists
Structural proteins/fibrosis
inhibitors
inhibition of transforming growth
factor beta1 (TGFß1)
small molecule antagonists in
development
Structural
proteins/proteinase
inhibitors
endogenous anti-proteinases
small molecule inhibitors of proteinases
Lung tissue/regenerating
agents
large amounts of protein are
required
NE, cysteine proteinase, MMP
inhibitors
retinoic acid
retinoic acid receptor agonists
stem 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 metalloproteinases, 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.
6.13-19
Chapter 6.13: Chronic Obstructive Pulmonary Disease



7.2
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 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.
Clinical Development
The 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, oncea-day anticholinergic agent that is administered as a dry powder aerosol . It is being comarketed 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 beta2agonist/corticosteroid combinations.
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
6.13-20
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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 .
6.13-21
Chapter 6.13: Chronic Obstructive Pulmonary Disease
Table 6.13.4
Sponsor
Intervention
Centocor
Infliximab (monclonal antibody)
Sepracor Inc.
(R,R)-formoterol
Sepracor Inc.
(R,R)-formoterol
I
II
X
Pfizer/Altana Pharm. "new IND"
Abgenix
III
humab anti IL-8
225
X
Multi
750
X
Multi
800
X
Multi
X
NHLBI
retinoic acid
GlaxoSmithKline
beta 2 agonist TD3327
GlaxoSmithKline
274150 (selective iNOS inhibitor,
oral)
GlaxoSmithKline
beta 2 agonist 597901
GlaxoSmithKline
842470 (PDE IV inhibitor)
Novartis
Pharmaceuticals
none / formoterol fumarate
X
ICOS
no name
X
Patients
Multi
X
Pfizer/Altana Pharm. Roflumilast
Sites
CA
150
CA
1100
X
X
X
X
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.
6.13-22
Chapter 6.13: Chronic Obstructive Pulmonary Disease
8.
What is the Current Status of Institutions and Human Resources
Available to Address the Disease?
8.1
Private Sector
Some 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 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) 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 COPDrelated topics.ii Their total funding since 2001, including that for therapeutic and non
therapeutic interventions, and basic biology, is about $1.7 million.82
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).
ii
6.13-23
Chapter 6.13: Chronic Obstructive Pulmonary Disease
8.3
Sixth Framework Program
8.3.1
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 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.







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.
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 nonmedical 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
6.13-24
Chapter 6.13: Chronic Obstructive Pulmonary Disease

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.
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.
6.13-25
Chapter 6.13: Chronic Obstructive Pulmonary Disease
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