Introduction - World Health Organization

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Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
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1


Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"





Background Paper






Pharmaceuticals and the Elderly






By Marjolein Willemen, Dr. P.A.F. Jansen and Prof. Dr. H.G.M. Leufkens


7

October

2004







Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
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2


Table of Co
ntents


Summary
................................
................................
................................
................................
................

3

Introduction

................................
................................
................................
................................
...........

3

Size and Nature of Disease Burden

................................
................................
................................
...

4

Epidemiological Trends

................................
................................
................................
...................

4

What are the Current or Likely Future Factors that Impact on Disease Burden at the
Following Levels, and in What

Way Why:

................................
................................
...................

8

Individual, Community, Household

................................
................................
....................

9

Health Care Sector

................................
................................
................................
.................

13

N
on
-
Health Factors

................................
................................
................................
...............

13

Control Strategy

................................
................................
................................
................................
..

13

Individual Problems
................................
................................
................................
.......................

13

Genera
l

Problems

................................
................................
................................
...........................

14

How effective is it, or could it be?

................................
................................
................................

14

Why Does the Disease Burden Persist?

................................
................................
...........................

15

Past/Current Research into Pharmaceutical Interventions

................................
...........................

16

Current "Pipeline" of Products

................................
................................
................................
.........

17

Opportunities f
or Research into New Pharmaceutical Interventions

................................
.........

17

Conclusion

................................
................................
................................
................................
...........

20

References

................................
................................
................................
................................
............

20



Chapter 7.2: Cross
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7.2
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Summary

The numbe
r of elderly is increasing over the world. It is estimated that by the year 2020 the
proportion of people aged 60 and over will be 25% worldwide. The ageing process in Europe
is even at a higher level.
1, 2



The ageing of the society comes along with several specific problems. The increased frailty of
the elderly, the increasing prevalence of diseases (including co
-
morbidities) and the large
numbers of drugs used per patient have a
major impact on the health systems.
3, 4



The rate of adverse drug reactions in elderly is higher than in other parts of the society,
5

whereas about between 27.6 and 51% of the adverse drug reactions in elderly are
preventable.
5
-
7

The altered body
-
functions in older persons (e.g. changing body
-
composition,
renal function and liver m
etabolism) may require adapted dosages.
3, 8


Under
-

and overuse are also important problems that occur frequently among the elderly.
Underuse is often

not a well
-
recognised problem, but it may lead to unnecessary loss of
health. Underuse is caused by several reasons, ranging from poor access to health care to
practical problems with formulations (e.g. difficulties with opening medication containers).
On

the other hand polypharmacy is a well
-
recognised problem in the elderly. Numerous
studies have shown that elderly patients often continue using


sometimes obsolete
-

drugs
without indication.
9

To improve optimal pharmacotherapy and to provide the best possible
care,
there is a special need in developing adapted formulations for medications specially
used by the elderly and pharmaceutical care programs for elderly.
10
-
12


In the last decade, the awareness of the impact of the growing numbers of elderly has
increased. The ageing society has been one of the Key Actions of the 5
th

Framework Program
of the European Union. Within this program, much
attention is paid to effective and efficient
delivery of health and social care services to older people.
13

Despite the efforts made by the
5
th

FP, it is impor
tant to improve the knowledge of drug effects in the elderly by including
them in clinical trials. There is a need for special guidelines which stimulate the inclusion of
the people aged 70 and older in clinical trials.
4



As stated in the 5
th

FP, basic research is necessary to enhance the quality of life of the elderly,
and to keep them independent as long as possible, thereby reducing the burden on the
public health systems. If the u
nderlying processes of ageing and of the age
-
depended
disorders are known, it will be easier to develop therapies and to keep the elderly as healthy
as possible.
8

Introduction

In his key
-
note address to the International Society for Pharmacoepidemiology and
Risk Management in August 2003, Robert Califf from Duke University talked about
the elderly patient using a plethora of dr
ugs, having multiple morbidities and suffe
-
ring from renal or he
pa
tic failure as a Bermuda Triangle:
'you can get in, but......you
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
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4

never get out'
.
14

We can derive

an important message from this quote. The number of
elderly people is rising dramatically and is expected to continue rising even more in
the next couple of decades.
1

The boom in the ageing population will increase the
demand for efficacious, safe and affordable medicines enormously.
15

Although most
medications are prescribed to and used by patients aged over 60 years old, this does
not imply that innovation in pharma
cological knowledge related to drug usage in the
elderly has been developed propor
tionally.


The age
-
related problems were high on th
e agenda of the 5
th

Framework Programme
(FP) of the European Union (1999
-
2002). The aim of the 5
th

FP to sponsor research in
the areas that are related to the ageing of the society, both on individual (e.g. age
-
related illnesses) and society (e.g. health a
nd social care services) level. In the period
1999
-
2002 the European Union provided a total funding of €190,1 million for all
projects and actions considering the age
-
related disorders.
13



The proportion of t
he population aged 60 and over, is growing each year. By the year 2025,
the world will host 1.2 billion people aged 60 and over; rising to 1.9 billion older people in
2050.
1

People are living longer in relatively healthy condition and with less disability. The
ageing of the population will ha
ve a great impact on the size, organisa
tion, strategy and
economics of national health systems, since demands will increase, will change frequently
over time, and consumers will dictate more then ever in the health care arena.
15

An ageing
population is likely to l
ead to an increase in demand for medical technologies, care facilities,
physically impaired and disability support services, and tailored forms of housing and other
physical surroundings.
15


Although there are diseases that occur more frequently in and are typical
for the elderly (e.g.
cardiovascular diseases, dementia/Alzheimer's disease, diabetes, Parkin
son's disease, COPD,
depression and musculoskeletal disorders) the use of medicines in the elderly as a more
general, 'cross
-
cutting' issue requires careful atten
tion and ana
ly
sis
.
Virtually all
-
demanding
topics in the pharmaceutical marketplace (e.g. cost containment, patient safety, risk/benefit
balance, prioritising of health needs, long
-
term outcomes of the use of medical technologies)
show up in relation to
the frail section of our societies but with extreme amplification.
Moreover drug use in the elderly has a number of specifically relevant features as well.
16, 17

Size and Nature

of Disease Burden

Epidemiological Trends


Ageing

People aged 60 and older are a growing part of both western and global communities (see
Figure
7.2.
1). In 2000, about 20% of the population worldwide was aged 60 and over. By the
year 2020, this proportion
of people aged 60 years and over will be 25%. In Europe, this
process of ageing is more pronounced. By the year 2020, fore
casts say that the percentage of
people aged 60 and over will be about 50%.
1, 2

Interestingly, while the overall trend is
Chapter 7.2: Cross
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Cutting Issues: Elderly





7.2
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5

virtually similar in all countries, there is considerable variation between individual countries,
and between Europe and the rest of the world with respect to the slope and speed of these
dev
elopments.
2



Fig
ure 7.2.1:

Population distribution: recent history and next decades

(Data from

World P
opulation Prospects, The 2002 revision database,

UN Population division)
2

World
0
5
10
15
20
25
30
35
40
0-4
5-14
15-24
25-59
60-64
65-79
80 +
Age groups
% of total population
2000
2005
2010
2015
2020

Europe
0
5
10
15
20
25
30
35
0-4
5-14
15-24
25-59
60-64
65-79
80+
Age groups
% of total population
2000
2005
2010
2015
2020


Diseases which Occur More

Frequent Among the Elderly

This section discusses the nature of the disease burden of a number of geriatric diseases in
more detail. The sample presented is not intended to be complete but the purpose is to give
an impression of the most relevant topics r
elated to geriatric medicine and possible
implications for pharmacotherapy in the elderly (Table
7.2.
1).


Table
7.2.
1: Summary of the burden of some geriatric diseases


Cardiovascular
diseases

Dementia (incl.
Alzheimer's
disease)

Parkinson's
disease

CO
PD

Depression

Musculoskeletal
disorders

Surge in
hospital
admissions

High societal
burden

Unknown
aetiology

High burden

Under
-
diagnosed

Hospital
admissions

High mortality

Co
-
morbidities

Drug
-
induced
parkinsonism

Hospital
admissions

High burden

Disabili
ty

Disability

Great demands
health systems

Threat to
quality of life

High
mortality

Co
-
morbidities

High costs

Polypharmacy

High costs


Disability


Drug
-
induced
osteoporosis

High costs




High costs







Co
-
morbidities




Cardiovascular Diseases (Hype
rtension, Heart Failure)

The prevalence of cardiovascular diseases increases dramatically with age.
18

The prevalence
of hypertension in the elderly (mean age 80 years) is estimated around 60%.
Hypertension is
Chapter 7.2: Cross
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7.2
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6

an import
ant risk factor for the occurrence of other cardiovascular disorders such as
myocardial infarction and stroke.
19
,

20

I
n many western societies, an epide
mic of heart failure
has emerged. This is partly a result of the ageing population, but also because of the success
in applying modern technologies to treat patients immediately after they have suffered a
myocardial infarction. Nowadays, the prevalence of heart failure is about 3% in people aged
45
-
64 and increases up to 10% in people aged >75 years.
21

Heart failure is one of the leading
causes of hospital admissions
in the elderly, also being responsible for high mortality rates,
disabilities and costs.
22

Pharma
co
logical prevention of cardiovas
cular diseases deals essen
-
tially with lowering blood pressure, the cholesterol
-
lipid balance and/or antithrombotic

medicines, three strate
gies from which the very elder
ly (85 years and older) are often
excluded because of lack of evidence in this age group.
23

These preventive strategies need to
be addressed, if indicated, already in people's 40's or 50's of age.
23

Moreover, pharma
-
cological treatment of heart failure can be improved. Patients with decreased left ventricular
function and manifest heart failure often do not receive drugs with

proven effects on
morbidity and mortality (such as ACE
-
inhibitors and beta
-
blockers).
22


Dementia (Including Alzheimer's Disease)

Dementia is a term that covers different forms of neurological diseases. It includes
Alzheimer's disease, but also va
scular dementia, dementia with Lewy bodies, front temporal
dementia and dementia secondary to another disease process (e.g. stroke).
24

In Europe and
North America, Alzheimer's disease is seen to be the more prevalent than vascula
r dementia.
The overall prevalence of dementia in the elderly is 5
-
10%.
24

It is estimated that the
prevalence increases exponentially with age: the established prevalence of dementia doubles
every five years (in people aged 65 an
d older), up to a prevalence of 30 to 40% in people aged
between 90 and 95.
25, 26

Dementia is at the top of virtually every assessment of burden of
disease in the very old, mainly because of the large number affected by the disease and the
relative young age at onset of

the disease. Unless the pharmaceutical industry spends an
enormous amount of money in research on dementia, the aetiology of dementia is still
unknown. The existing therapies do not stop or reverse the illness, only delay the onset and
provides symptomati
c relief for a short period of time (six to eighteen months) People with
diagnosed dementia may continue to live for 20 years or longer thereby suffering from
severe disabilities and having a great need for comprehensive care and support. Dementia
weighs h
eavily to the societal disease burden because it relatively affects most family or
other directly involved communities.
27, 28


Parkinson's Disease (PD)

Although basic research is adding tremendously to a better understanding of Parkin
son’s
disease,
it’s aetiology is still unknown. Because of the increasing numbers of people affected
with PD, it is important to continue investing in unravelling the under
lying processes of the
disease, as this strategy is most likely the most successful one finding ap
propriate therapy.
29

Before the age of 60, the incidence rates of PD are low, but increase in people aged 60 years
and over.
29

A study by Twelves, who reviewed several incidence studies on PD, shows that
the incidence in the age group 50
-
59 years ranges between 16 and 20/100,000/year. These
rates increase in the age group 60
-
69 up to 30
-
90/100,000/year. In people aged between 70
-
79,
the incidence rates increases up to 60 and 200/100,000/year.
29, 30

Although in terms of
aetiology a diffe
rent disease, drug
-
induced parkinsonism should be
mentioned as well in
Chapter 7.2: Cross
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7.2
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this section. Many of the drugs which can induce parkinsonism are commonly used by
elderly patients (e.g. antidepres
sants, antipsychotics).
31



COPD

Chronic Obstru
ctive Pulmonary Diseases (COPD) is a very common disease, but is
essentially preven
table
-

up to 80% of COPD is attributable to smoking
-

and affects
dramatically the quality of life and life expectancy.
32

Moreover, the disease is costly because
of heavy burden on the health care system, heavy demands for health care, and wor
sening of
quality of life.
33

The prevalence increases rapidly with age, especially in smokers. Because of
the progressive nature of the disease, diagn
osis is often late, and at a moment when preven
-
tive strategies are virtually meaningless.
32

There are no pharmacological therapies available
that reduce or reverse the loss of lung function. The prevalence of COPD in people aged 40
-
59 years is about 1% and this number increases up to 13
-
23% in people aged 65
-
84 years
old.
34

Patients with COPD show frequently concur
rent diseases suffering from heart failure.
This pattern of co
-
occurrence of two severe diseases in the elderly represents a major and
typical cate
gory of geriatric morbidity, frequently also leading to a cascade and clustering of
other diseases (e.g. co
-
occur
rence of pneumonia, steroid induced osteoporosis, hip fractures
and the like).
35

It is of great importance to pay attention to smoking cessa
tion programs in
patients of younger age top to prevent them from developing COPD.


Depression

There is still a poor understanding of the underlying mechanisms of mental disorders. This
leads to difficulties in developing effective and safe medicines, but
also to underdiagnosis
and undertreatment of the disorder in the elderly. The treat
ment is important because
depression is associated with other morbidities (e.g. more difficult recovering after myo
-
cardial infarction, greater risk to fall).
18

For a long time the seriousness (in terms of
prevalence, effects on quality of life and societal costs) of this disorder in the elderly was not
well recognized and understood. The preva
lence of depression varies in different stu
dies;
dependent on whether the clinical condition or the symptomatology is studied.
36

In the
community, the prevalence of elderly people with depressive symptoms is estimat
ed to be
around 15%, while the prevalence of a major depressive disorder ranges between 1
-
3%.
37

In
the ambulatory setting, the rates are much higher: about 20% of the elderly has depre
ssive
symp
toms and the prevalence of a major depressive disorder is 10
-
12%.
36

These prevalences
are doubled and sometimes tripled in patients with severe somatic morbiditi
es (e.g. cancer)
or severe expressions of chronic diseases (e.g. arthritis, diabetes, post
-
myocardial infarction).
Depression as a co
-
morbidity represents a heavy burden also because affects negatively
management of the somatic disease (e.g. non
-
compliance
, etc).
18, 37



Musculoskeletal Disorders (MSDs)

Diseases affecting the joints and bones (MSDs) are at the top of virtually every listing on
disease burden in the elderly, both fro
m the numbers perspective and the implications for
quality of life and economic costs.
38

The most important MSDs are rheumatoid arthritis,
osteoarthritis (OA) and osteoporosis.
39

The first one counts because of disease severity, the
two other because of numbers. MSDs are

associated with high levels of pain and disability.
Rheumatoid arthritis, a disease where severe and erratic inflammation is the main concern, is
Chapter 7.2: Cross
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Cutting Issues: Elderly





7.2
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8

relatively rare (<1% of the population).
40

OA on the other hand is a common disease of the
aged and frail. It is estimated that about 9.6% of men and about 18% of women aged 60 and
over, have symptomatic OA.
38

The treatment of MSDs is sym
ptomatic; there are no
treatments available which can cure the diseases. Osteo
porosis has two other important
dimensions. Very often the disease is drug induced (e.g. corticosteroids) and is thereby
associated with diseases where heavy steroid use is prev
alent (e.g. asthma, COPD and
rheumatic disorders), and the most important signature of the disease burden is osteoporosis
as a risk factor for fracture, particularly the hip.
41

The prevalence of osteoporosis increases
with age, and women are much more affected than men. The prevalence rises from 5% in
women aged 50, up to 50%

in women aged 85 years. In men, the prevalence is 2.4%
(50
years) up to 20% (85 years).
38


What are the Current or Likely Future Factors that Impact on Disease Burden at the
Following Levels, and in What Way Why:


In the 19th and 20th century, improvements in socio
-
economic and environmental con
ditions
have con
tributed significantly to increase of life expectancy in most parts of the western
world. These improvements included better hygiene, drinking water and nutrition, better
housing and more physical exercise.
17

Wealth in general, in com
bination with improved
preventive (e.g. vaccines) and direct medical care, has drama
tically increased life expecta
ncy
during the last century (see Figure
7.2.
2).

This factor together with a decreas
e in fertility
(below replacement level in more developed countries, see Figure
7.2.
3) is an important
driver behind the trend that the proportion of elderly in community is

growing steadily. In
the next decade, the baby
-
boom genera
tion (born between 1946 and 1964) will reach the age
of 60. This growing proportion of older people will have enormous impact on the whole
society, both medically, socially and in terms of economi
cs.
2, 17


Figure
7.2.
2: Life expectancy over time

Figure
7.2.
3: Fertility rate over time

(Data from

World Population Prospects, The 2002 revision database, UN Population
division)
2

Life expectancy
0
10
20
30
40
50
60
70
80
90
1950
1960
1970
1980
1990
2000
2010
2020
2030
2040
Year
Age
World
More developed countries
Less developed countries
Least developed countries

Fertility

rate
0
1
2
3
4
5
6
7
1980-1985
1990-1995
2000-2005
2010-2015
2020-2025
2030-2035
2040-2045
Year
Fertility rate
World
More developed countries
Less developed countries
Least developed countries


Chapter 7.2: Cross
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Cutting Issues: Elderly





7.2
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9

Individual, Community, Household

Among older people the prevalence of almost all diseases increases.
3

Therefore, older people
are using more h
ealth care technologies, care, drugs, etc. than younger people.
4

It is studied
that the number of drugs used increases almost linearly with age.
42

Several studies in
different settings have shown that the elderly use an average of 2
-
6 prescribe
d medications
and 1
-
3 non
-
prescribed medications.
43

At least 80% of the people aged 60+ are usi
ng one or
more drugs on prescription.
6, 44, 45

More than 40% of the elderly are us
ing 5 or more drugs
each week.
4, 6

The process of ageing, the hig
h prevalence of co
-
morbidity of diseases, the
large numbers of drugs used, and complexities related to the use of medicines in this section
of the population, cause a plethora of problems.


Polypharmacy

The term 'polypharmacy' is used in two different mea
nings. If one speaks about
polypharmacy as 'using multiple drugs' it does not appoint polypharmacy as a bad event.
Less medication does not necessarily mean better treatment for the patient, and more
attention has to be paid to ap
pro
priate prescribing in
stead of less prescribing.
42, 46

The
tr
eatment and prevention of cardiovascular disease is a good example of appropriate
polypharmacy. To obtain optimal pharmacotherapy, the use of several different drugs is
required (e.g. antiplatelet therapy, cholesterol
-
lowering drugs and blood pressure lowe
ring
drugs).
47

However it is not yet clear what the additi
onal risk reduction is of combining
several preventive drugs. For many physicians, appro
priate prescribing is not that easy. To
obtain optimal prescription, it is necessary that physi
cians have a good understanding of the
pathophysiology of the disease,
the changes of pharmacology with increasing age
8

and in the
pharmacology of the drugs. Several studies show that inappropria
te prescribing occurs
frequently among the elderly and that it is often related to polypharmacy.
48
-
50


Despite the advantages of polypharmacy in some specific cases, polypharmacy is not
favourable in all cases. If polypharmacy is seen as the 'administration of more medications
than are clinically indicated', a negative event which has

to be avoided, occurs. It is studied
that in the elderly the percentage of medication without indication or a less than optimal
indication, ranges between 55 and 59% of the prescriptions.
51, 52

This kind of polypharmacy is
problematic especially in the elderly because it increases unnecessary the risks of adverse
drug reactions, geriatric syndromes (like cogn
itive impairment and delirium) and the health
care costs.
9


Many patients are treated by different physicians, who often do not know about the other
medication a patient is using, prescribed by other doctors. In most countries, people do not
have a regular pharma
cist
or a family doctor who can review all patients' medication.
Moreover, many people do not only use medicines on prescription, but also a large amount
of 'over the counter' (OTC) drugs. These OTC
-
medicines include NSAIDs, antihistamines but
also vitamins, mi
nerals and herbals. Most patients do not realize that the OTC
-
medications
they are using can also influence their therapy, for example by interacting with their
prescribed medications. Many patients are not aware that OTC
-
medicines can have similar
actions

as prescription drugs (e.g. NSAIDs and antihistamines). Because of this ignorance,
most patients do not report the use of OTC
-
medications.
45

Chapter 7.2: Cross
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7.2
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10


Adverse Drug Reactions

The risk of adverse drug reactions (ADRs) increases with the number of individual drugs
patients are using. Because elderly are using more drugs in comparison with the younger
population, it is likely that more adverse dr
ug reactions occur in people aged 65 and over.
53

The incidence of ADRs in elderly was found to be about 5%, whe
reas the incidence of ADRs
in non
-
elderly was about half of this.
5

A meta
-
analysis suggests that adverse

drug reactions
rank between the fourth and sixth cause of death in hospitalized patients.
54


ADRs are responsible for unnecessary hospital admiss
ions, which cause an unneces
sary loss
of health and an unnecessary waste of money. In several studies, the percen
tage of hospital
admissions due to adverse drugs reactions ranges from 4.1% in young people, up to 16.6% in
the elderly.
55

It is important to realize that many adverse drug reactions are preventable: the
percentage of preventable ADRs in the elderly ranges between 27.6% and 51%.
5
-
7

Therefore,
if it is possible to prevent unnecessary ADRs, it will yield an enormous improvemen
t of
health and it will save a large amount of money. In several studies the costs of hospital
admissions

due to adverse drug reactions have been calculated. The amounts ranges
between €182,927 per year (29
-
bed ward of general medicine)
56

to €261,220 per year (23
-
bed
ward of gene
r
al medicine).
57

Therefore, these costs are cons
iderable, certainly at a (inter)
-
national level.


Next to the adverse drug reactions, other drug
-
related problems like drug
-
drug interactions
and contra
-
indications cause problems in the elderly. These medication errors are also
associated with hospital ad
missions, high burden of disease and considerable costs.
58, 59

As
with the adverse drug reactions, a large number of these other drug
-
related problems can be
prevented.
59



Co
-
Morbidity

The incidence of diseases increases with age. Many elderly have several different disorders
at the same time. This re
-
occurrence of diseases can lead to problems.
3, 60

There is too little
knowledge of the int
erference of different diseases, so this will be an important domain for
research by industry and academics in the near future. In the case of re
-
occurrence of several
disorders, therapy must also be adapted. For most patients, only the disease with the hi
ghest
risk on events, or with the greatest impact on life, is treated.
60

To structure the care of the
elderly, and thereby providing the best care possible, it is necessary that the physicians not
only treat one org
an (e.g. for mental disorders a psychiatrist and cardiovascular diseases the
cardiologist), but one physician (e.g. specialized in geriatrics) who treats the patient as a
whole.


Altered Body Functions
3, 8

In older persons, body functions change. Almost all parts of the body show deterioration in
structure and/or function with increasing age. In healthy elderly, this might not be problem,
but it may b
e more difficult or take more time for an elderly person to recover from illness. It
is also more likely for elderly to be left with perma
nent disability after illness. Changes in
pharmacokinetics and pharmaco
dynamics can influence the metabolism and/or
excretion of
Chapter 7.2: Cross
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7.2
-
11

medicines. Prescribers must be aware of the risk of altered body functions, because it may
cause unexpectedly higher or lower drug levels. This can result in preventable adverse drug
reactions, and, on the other side, in little or no effect of

therapy.


Change in Body Composition
3

With advancing age, the body composition alters. Because of a reduction in body water and
lean body mass, body fat relatively increases. This can induce a different partition of a drug
in the body. Polar d
rugs will have decreased distribution volumes, which result in higher
serum levels. Non
-
polar drugs will have increased partition volumes, thereby resulting in
prolonged half
-
lives. This can be important to know to obtain an accurate dosage and dosage
regi
me, especially in drugs with a narrow therapeutic range.


Changes in (Liver) Metabolism
3, 8

Many drugs are metabolised in liver (first
-
pass metabolism
), either to be excreted more
easily or to be activated (pro
-
drugs). In elderly people, there is a reduced blood flow to the
liver and the mass of the liver decreases. This implicates that first
-
pass metabolism results in
higher bioavailability for drugs t
hat are metabolised for excretion. On the other hand, the
bioavailability of pro
-
drugs will be decreased.


Changes in Renal Function
8

In the elderly, a reduction of renal function is common. This kind of reduction decreases the
clearance of mainly water
-
soluble drugs and glucuronised metabolites. Whether or not this
might be a problem, is dependent on the toxicity and therapeu
tic range of the drug.
8


Underuse of Medication

Underuse of medication in the elderly is an under
-
estimated problem, but it
occurs
frequently among elder patients. As described above, overuse (polypharmacy) receives
much attention from policy makers, while it is not unfavourable in all cases (e.g.
cardiovascular diseases). Underuse is also a problem among the elderly, but polic
y makers
are not familiar with it.
4

It is important to realize underuse can cause harm to patients and
therefore results in high costs. Underuse of medication can be explained in seve
ral ways.
Many older people and their family hesitate to contact a physician. Many health problems
are signs of ageing, and people think they just have to accept these problems. This is not true
in all cases, because nowadays there is a wide range of thera
pies and medications available.
Many of these medications are effective and have little adverse effects, but, as described
above, not for all disorders effective and safe treatments are available.


Not only do patients hesitate to ask for therapies and/or
medication, underuse can also be
caused by underprescription by physicians. In the past, "the less medications the better" was
a common opinion. In the last few years, this opinion is changing. Less medication is not the
main pursuit. More important is app
ropriate prescribing. In this point of view, early
intervention can prevent more serious illness, which is likely, especially in the elderly, who
recover less easily from illness than younger people.
46, 61

Un
deruse due to underprescription
by physicians can be caused by the tendency of physicians to treat first the disease with
highest burden, and the disease with less impact on the patients well
-
being is pushed into
the background.
60

Economic barriers can also cause underuse. In many countries, seniors
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
12

with low incomes have little or no access to health care in general or insurance for
medications.
45

Many elderly do not have enough income to pay for their medications.
Because of that, people decide not to use the medications which they are prescribed.
4, 45


Another reason for underuse is poor adherence to medication regimes.
4, 45

Elderly are in
general not less adherent than younger patients. However elderly with depression and/or
cognitive problems

(like dementia) are likely to have poorer adherence. This will be
especially important if there is also a lack of social support. Because of extensive ageing, the
numbers of elderly living alone is increasing also. People living together help each other
r
emember important things like taking medica
tion. Therefore, living alone is a risk factor for
non
-
adherence.
62


Even uncomplicated problems with formulations such as difficulties to break scored tablets,
hamper adherence to the drug
-
regimen and can make taking medications a discom
forting
experience for patients. It is expected this interferes with adherence and causes non
-
compliance.
10

It is therefore needed to stimulate the pharmaceutical industry to develop
special formulations for th
e elderly.


Underuse is mainly seen with medication for primary prevention (e.g. hypercholesterolemia,
hypertension), because patients do not directly benefit.
4

To help patients adhe
re to their
medications, it is important that physicians and pharmacists explain the need for the use of
medications, and possible drug related problems (like side effects); all adapted to the
patient's intellectual capacity.
61

It

is important to diminish the underuse of medications
because it can lead to serious adverse consequences, which will raise the overall costs of
medical care.
4, 45



Drug Formulations

Specifically tailored formulations for medications explicitly used in the elderly are rare.
There is a special need for these formulations, because dosage used in the
elderly can be
different from dosage in younger populations. Special formulations are also needed because
of practical problems.


Mainly due to poor vision of many elderly but also because of impaired physical and
cognitive function,
63

problems with opening pill boxes occur frequently among the elderly.
11,
12

Other problems with formulations include too large pills to s
wallow; difficulties in reading
drug monographs or pills which need to be broken.
45

Un
equal breaking of scored tablets can
be prob
lematic, especially when drugs have a narrow therapeutic range.
10


The pharma
ceutical industry does not pay much attention to this problem, but it is likely that
adapted formulations will increase the sale of
their medications: elderly are a growing part
of society, and they use

a great amount of medications. Problems with formulations can
cause a discomforting experience for patients, and therefore interfere with adherence and
causes non
-
compliance.
10
-
12



Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
13

Health Care Sector

Ageing is followed by an increase of frailty and an increase in the use of medical faci
lities.
The increasing

number of elderly will have major impact on the health systems. To avoid an
excessive impact of the elderly on the health systems, resulting in unaccep
table high costs for
society, policy makers should realize that planning and evidence
-
based policy deci
sions are
the only way to cope with the growing proportion of elderly people. Health care systems
must be organized effectively, avoiding too many medical interventions, too long hospital
stays and inappropriate use of high cost technologies.
15, 17

It is important to pay attention at
the prevention of chronic diseases. Many risk factors for chronic diseases (e.g. hyper
choles
-
terolemia, smokin
g, over
weight) can be prevented by early informa
tion, health education
and other lifestyle interventions.
4, 45, 64


Non
-
Health Fac
tors

Economic burden will increase with the ageing of society. In developed countries, the
working part of society, aged between 20 and 60 years old, is getting smaller (see Fig. 1). The
maintenance of the social services, in the way they exist in many cou
ntries, can give
problems. The smaller, working part of the society has to pay relatively more to maintain the
welfare state, so there will be a higher economic burden on fewer people.
64

Control Strategy

There are several problems related to drug developme
nt and use in our ageing society. As
described above, these problems can be divided into 'individual' problems (e.g. problems
with medication) and 'general' problems (e.g. impact of the elderly on the health systems).


Individual Problems


Clinical trials

A main strategy of solving problems with medication in the elderly is to improve the
participation of elderly in clinical trials. It is necessary to test new medications in the group
who will use those most. Nowadays, people aged 65 and over are often exc
luded, because of
several reasons. The existence of co
-
morbidity, poly
phar
macy and the frailty of the elderly
make researchers hesitate about the partici
pation of these patients. Next to that, also practical
problems like the transport of seniors to res
earch centres can be an obstacle for the inclusion
of elderly in clinical trials.
4, 45

Despite
this, it is really important to include represen
tative
samples of elderly into clinical trials which study medications used by elderly. The inclusion
of elderly into clinical trials may provide us with important information about dosage,
efficacy, long
-
t
erm effects, dosage regimes and safety of drugs. As described above, in elder
people there occur pharmacokinetic and pharmacodynamic changes. This occurs mainly in
the very old people, aged 70 and older. So, also very old people need to participate in tria
ls
in order to obtain impor
tant knowledge about the effects of drugs.
8


Comprehensive Monitoring of the Drug Use Process in

the Elderly

A relative great part of the problems in drug prescription in the elderly is due to the lack of
oversight on all therapies a patient is involved with. Many patients are treated by multiple
physicians, who are specialized in single 'organ medic
ine'. To avoid problems it is necessary
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
14

that physicians see and treat a patient as a whole, thereby linking problems and trying by
multidisciplinary consultations with the different physicians and pharmacists involved in
the treatment of the elderly, to im
prove the treatment of a patient.
45

One way of coping with
this problem is to organise multi
disci
plinary team assessments. All me
dical professionals
involved in a patient's treatment (e.g. physicians and pharmacists) adjust their therapy to
each other. In this way, the optimal therapy a patients needs, will be obtained.
53

Advanced
information technology (IT) (e.g. individual electronic patient dossiers, EPD) is a resource to
address this problem. But successful comprehensive monitoring requi
res more than
introducing new technologies. A systems approach is needed to implement the best mixture
of medical, managerial, technological and behavioural strategies.
4, 65


General

Problems


At national and at international level, attention must be paid to the access of elderly to health
care. Cost
-
containment in
health care is a major concern in virtually all societies.
15

Indepen
-
dent of whatever social, political or economic system exists, governments, insurers and other
decision makers struggle with the ever
-
increasing demand for health care. To cope with the
ageing part

of society, it is increasingly recognised that the governments need to revise their
health systems. Economic experts tell us that there is no way out of a dramatic transfor
ma
-
tion of our health care systems: they should be organized more effectively, avo
iding
unnecessary medical interventions and inappropriate use of high cost technologies, and
putting more the interest of the elderly patient first instead of letting bureaucrats or
technologies drive development.
4, 64

I
t is very important to insure access to health care for the
elderly. With a good health system, thereby providing possibilities of quality care to all
people, it is possible to prevent the increase of disorders and provide early intervention for
diseases.
45


European Union: 5th Framework Program
13

The European Union is promoting all different types of research by Framework Programs
(FP). The 5th Framework Program (1999
-
2002) pays much attention to the issues related to
the ageing society in the Key Action 6:
The ageing population and their
disabilities
. A wide
range of issues considering the ageing society were included and €190.1 million of funding
had been divided between different research projects. The aim of the 5th FP is to improve the
knowledge of the process of ageing and the age
-
related disorde
rs, and to lighten the burden
on the public health systems.


The 5th FP, Key Action 6, includes research in all parts of the ageing process, ranging from
the underlying cellular and molecular mechanisms of ageing, to the age
-
related disorders
(pathophysio
logy of Alzheimer's or Parkinson's disease). Also the epidemiological trends
and the impact of the ageing society on the health services are studied.


How effective is it, or could it be?


Reducing Adverse Drug Reactions (ADRs)

Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
15

As stated above, many ADRs
occur due to several reasons. The percentage of hospital
admissions due to adverse drug reactions varied from 0.2% to 41.3%.
55

Several studies show
that the incidence of fatal adverse drug reactions in hospital pat
ients ranges between 0.2 and
0.7%.
6, 7, 54

Next to this, these
studies also show that the more serious adverse effects are more
likely to be preventable. Two studies by Gurwitz et al show that the percentage of preven
-
table, life
-
threatening ADRs ranges between 42.2 and 72%, whereas the percentage of
significant ADRs
which are judged to be preventable, ranges between 18.7 and 34%.
6, 7

These
percentages are shocking and are coupled with high rates of m
orbidity and mortality.
Adverse drug reactions induce also an unnecessary loss of health especially in the elderly. As
stated before, elderly persons recover less easily from illnesses than younger people do and
by preventing hospital admissions, morbidity

and mortality will be largely reduced.


Stimulating Appropriate Prescribing and Drug Use

By stimulating appropriate prescribing by physicians, preventing underuse, guarantee access
to health care for all patients and development of adapted formulations fo
r the elderly,
optimal treatment will be achieved and the health of the older patient will be sustained.
45, 66

A si
gnificant reduction of adverse drug reactions could be achieved by enhancing
streamlining of and continuity in the drug use process and better appli
cation of modern
information technologies like electronic patient dossier

(EPD).
67

It is well recognised that the
in
troduction of information technology implies a considerable financial investment, but is
also expected to give major health returns and even financial profits in the long term.
67

Electronic records can alert and thereby prevent medication errors, resulting in a bet
ter
prescribing, less adverse drug reactions and fewer unnecessary laboratory costs.
67

Why Does the Disease Burden Persist?

Because of an increase in socio
-
economic and environmental conditions, expanded
knowledge of the human body and medical care, more people ar
e getting older than ever.
The ageing of the society will bring several problems. They cannot be prevented yet, but
there are possibilities to cope with the problems, which come along with the growing
proportion of elderly in society.


Exclusion of the El
derly from Clinical Trials

Many of the problems are caused by the historical exclusion of special groups (e.g. children,
women, elderly) from clinical trials because of ethical objections and practical problems.
Because of the exclusion, there is little k
nowledge of the process of ageing, the physical
changes in elderly people and difficulties, which can occur in case of re
-
occurrence of
diseases or using large amounts of different medications at the same time.
3, 4

This seems to be
very contradictory, because the people aged 60 and over are using large amounts of
medicines and they are the largest growing proportion of the population. So, for pharma
-
ceutical industry the elderly should be an attractive group to

develop new medicines for.


One of the problems of the participation of elderly in clinical trials is the large amount of
drugs the elder people are using. This can occur in higher rates of adverse effects or even in a
higher co
-
morbidity.
3

It

is understandable that the pharmaceutical industries prefer to
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
16

exclude the group of seniors that are difficult to study. In addition to the problem of the
drug
-
drug interactions there is the problem of higher rates of re
-
occur
rence of disease in the
elde
rly. Different diseases can interfere which each other and with medications; the effects
are unknown. In order to avoid a high noise to signal level, people who have different
diseases (often elder people) are excluded.
4

In the last decade, the proportion of elderly
involved in clinical trials is increasing. This is partly due to the development of govern
-
mental guidelines, which require the inclusion of special groups into clinical tr
ials (not only
elderly
68

but also children
69

and women
70
-
72
).


In spite of this, it is important to realise that the elderly who are participating in clinical
trials, often are younger and fitter than the general population of older adults.
4


Adverse Drug Reactions

The higher rate of adverse drug reactions in the elderly causes a higher amount of hospital
admissions.
55

Because of the increased frailty of the elder people, hospital admissions

can
more easily result in disability among the elderly in comparison with the younger. The
higher incidence of ADRs in the elderly has different reasons. One of the important reasons
is inappropriate prescribing of medications by physicians. The inappropr
iate prescribing is
caused by a lack of knowledge of physicians about the pathophysiology and pharmacology
of disorders and medicines.
61

One other explanation for the higher rate of adverse drug
reactions is the use of a large num
ber of medications by seniors, without a good survey of all
medications (including OTC
-
medications) a patient is using.
42


Survey of Therapies

Several physicians, due to the re
-
occurrence of different diseases, treat many elderly patients
and do not have an accurate survey of the large amounts of drugs the elderly t
ake. In many
countries, there is no accurate overview of all (drug) therapies a patient gets. This is
estimated to result in medication errors (e.g. due to interactions or dose errors), which can be
prevented by an accurate overview of the therapies.


Uneq
ual Access to Health Care
45

In many countries, retired seniors do not have fixed incomes. When there are little or no
social servic
es, it is very difficult for those people to make ends meet every month. Due to
this unequal access to health care, many seniors decide not to use all medica
tions prescribed.
In the short term, this allows considerable savings for the patient. Over the lo
nger term, costs
for health care will be much higher. For example, a person who is not taking his prescribed
lipid
-
lowering statins, saves a considerable amount of money every month. At the same
time, his cholesterol is increasing to dangerous values and t
wo years later, he gets a heart
attack and needs to be admitted in hospital for at least one week. The hospital admission
costs a lot more than a daily statin therapy.

Past/Current Research into Pharmaceutical Interventions

Stimulating Participation of Eld
erly in Clinical Research

In 1993, EMEA developed a Note for Guidance on the participation of elderly in clinical
trials. This Note did not contain obligations, only recommendations are made.
68

Despite this
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
17

guidance, there were several studies published which showed that a large number of clinical
trials tend to use
unjustifiable

age limits.
73, 74



It is seen that despite the guidance of EMEA
68

the participation of elderly (especially the
elderly aged > 75 years old) almost did not increase.
73, 74

Therefore, it may be helpful to insert
obligations in this guidance, just like the Best Pharmaceuticals for Children Act (BPCA) did
in the U.S
.A. (2002).
75



The exclusion of participation into clinical trials is not a problem specifically for the elderly.
It is also a problem in other vulnerable groups, like children and women. The part
icipation
of children and women in clinical trials is also negligible, caused by the same reasons as in
the elderly. These reasons include practical problems e.g. different pharmacokinetic, and
-
dynamic properties and large differences between age groups i
n children.
76

In children and
women in the reproductive age, also ethical considerations play an important role in the
decision of the exclusion of clinical research.
77

Therefore, off
-
label and unlicensed drug use is
not an acceptable situation in these groups. I
n order to stimulate the pharmaceutical
industries to perform research also in children, in the U.S.A. the Best Pharmaceuticals For
Children Act was passed. Next to the obligations this law contains, there is also an prolonged
market exclusivity of 6 month
s for industries who get a license for paediatric use.
76

In the
European Union, EMEA provided guidelines to improve the paediatric labelling. These
guidelines do not include obligations but only recommendations.
78



The guidelines and laws recently developed for research in children and women are
a good example of the laws and guidelines necessary for research in the elderly.
Policy makers should learn from the experience of the current policy in the
participation of women and children in research and improve the participation of the
elderly in cli
nical trials by including obligations in the guidelines.

Current "Pipeline" of Products

Prevention and Management of Adverse Drug Reactions and Medication Errors

There are several ways to detect and prevent adverse drug reactions. In the past, voluntary
re
porting was often used.
59

Nowadays, there is much attention to electronic medical records,
which point out adverse d
rug reactions and medication errors, thereby reducing disabilities
and saving considerable amounts of money.
58, 59

It is seen that the number of computer
-
detected adverse reactions is much higher than the voluntary reported ADRs. Despite these
promising features, the electronic medical record

is yet not widely used.
79


Opportunities for Research into New Pharmaceutical Intervention
s

There is still a lack of basic knowledge about the process of ageing. Little is known about the
origins of changes in pharmacokinetics and
-
dynamics, the changes in body composition,
deterioration of structure and function of organs.
8

In order to under
stand the ageing process
and to develop medications that can reverse or halt the ageing process, it is necessary to
produce k
nowledge of the underlying basic principles. Next to that, the development of
Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
18

medications for diseases, which occur more common in the elderly, is of significant interest.
With the ageing of society, the prevalence of several diseases will increase. Nowada
ys, many
companies are doing research in these areas and the need for suitable medication will
increase in the future.
80


In patients with dementia, not only medication for prevention, reversion or stopping the
disease is needed. There is also a great need for medication that treats the symptoms of these
disorders, because there is hardly any treatment available. Patients w
ith dementia often have
behavioural disorders, (for example they may behave aggressively), which are very tedious
for the patient and his relatives and caregivers.


Another important area of research is that of formulations for the elderly. Formulations,
which are suitable for middle
-
aged people, are not automatically suitable for the elderly.
More attention must be paid to the development of formulations which are suitable for the
elderly, thereby improving adherence.
10, 45


What are the gaps between current research and potential research issues which could
make a difference are affordable and could be carried out in a) 5 y
ears or b) in the longer
term? For which of these gaps are there opportunities for pharmaceutical research?


The pharmaceutical industry is doing much research on specific diseases for the elderly
(Alzheimer’s disease, Parkinson’s disease and others). All
big pharmaceutical com
panies are
doing research in these areas, and have potential drugs in their pipelines.
80


For nat
ional governments and international institutions like the European Union, it seems
not to be a logical step to support this type of research. The big pharmaceutical companies
are spending such an enormous amount of money on research; it will not be possibl
e for
governmental organisations to accomplish a break
-
through by the investment of limited
public money.


The basic research of the principles of the ageing process can be supported by governments.
There is still a lack of knowledge of the underlying mech
anisms whereas an accurate
understanding of these principles would made it easier to understand the pathophysiology
of diseases, which occur specific among the elderly. This basic research could occur in the
state
-
subsidized universities. Within the univer
sities there is knowledge and with financial
support of the governments, they can do much work in disentangling the process of ageing.


Another area, which needs financial support on short term, is the research about the best
way to organise the health sy
stems. With the ageing of population, the demands of the
health systems increase in a comparable way. To ensure the access to health care for all
people, it is really necessary to study on the best way to organise the health systems.
15


There are other areas in whi
ch great efforts are needed to improve the health care for elderly.


Clinical Trials

Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
19

As discussed in this paper, the exclusion of the elderly in clinical trials leads to a lack of
knowledge on the use of drugs in elderly.
3, 81

There is little information about issues like
doses, administration regimes and adverse d
rug reactions.
45

This may lead to inaccurate
treatment of elder patients, resulting in increasing morbidity and higher costs.
4

By improving
the participation of elderly in clinical trials, these problems might be solved. Despite the
guidance of EMEA (1995),
68

elderly are still excluded from clinical trials, mainly for
unjustifiable reasons.
73


By developing laws and guidelines which include obligations towards the partici
pa
tion of
the elderly, government could improve the knowledge of drug effects in the elderly, thereby
providing more accurate health
care and preventing medication errors.
4

To improve the
participation of the elderly in clinical trials, a cooperation between pharmaceutical industry
and governments is warranted.
45

Together it is possible to develop guidelines and recom
-
men
dations to carry out clinical research in elderly in an ethical way, wit
h sufficient num
-
bers of elderly patients participating and with practical problems to be solved more easily.
81



Drug Formulations

After marketing of a new drug, changes in doses are often seen.
82

As discussed before, these
changes are often due to altered body functions in the elderly.
3, 8

Because of t
he lack of
knowledge about the drug effects in elderly, these adaptations are mainly educated guesses.
4

Appropriate dosing is the key to successful drug development and dosing in the
elderly is an
Achilles' heel of drug innovation. Next to adapted doses for the elderly, special formulations
might be required. Due to physical or cognitive impairment, problems (e.g. difficulties with
opening medication containers, too large pills to swal
low or problems with reading drug
monographs) might occur. By developing special formulations for the elderly, adherence can
be improved and taking medications will be a less discomforting experience.


Monitoring of Safety of Drug Use in the Elderly

Adve
rse drug reactions and medication errors occur frequently in the elderly.
83, 84

Most

of
these events are preventable.
6, 7

Therefore by providing a system which can monitor all
therapies a patient is involved with, adverse drug reactions and other medication errors
might be prevented.
67

This may result in reduced hospital admissions, increasing quality of
li
fe and considerable savings.
57



The introducti
on of these monitoring systems comes with considerable costs.
67

With
governmental support, either by financial support or by practical support, it may be easier
for health services to introduce advanced moni
toring systems.
85


Appropriate Prescribing

By stimulating appropriate prescribing by physicians underuse but also polypharmacy
might be prevented. Thereby the optimal ther
apy for the patient can be obtained.
42, 61

A significant reduction of ad
verse drug reactions could be achieved by improving drug
prescribing, thereby reducing costs and increasing quality of life.
4, 42


Chapter 7.2: Cross
-
Cutting Issues: Elderly





7.2
-
20

Access to Health Care

Many elderly can not afford the health care they need. This may lead to a sub optimal use of
health care.
45

For example blood pressure in patients with hypertension is only controlled
adequately in a minority of the elder patients. This is partly due to a poo
r access to health
care in the elderly.
45

This unequal access to health care may therefore lead to less benefit of
existing therapi
es, which may lead to increasing morbidity and increasing costs.
4


Conclusion

The number of elderly is increasing dramatically in virtually all regions in the world.
The ageing societ
y comes along with several specific problems.
2

The frailty of the
elderly, the increasing prevalence of diseases (including co
-
morbidities) and the large
numbers of drugs used per patient have a major impact on the health systems.
3, 4

Therefore patient safety, a key public health issue particularly in this population,
should be at the top of our menu.


In the last decade, the awareness of the impact of the growing numbers of elderly has
increased. The ageing so
ciety has been one of the Key Actions of the 5
th

Framework
Program of the European Union. Within this program, much attention is paid to
effective and efficient delivery of health and social care services to elder people.
13


Despite the efforts made by the 5
th

FP, it is important to improve the knowledge of
the basic principles of the ageing process. Beside that, it is important to gain know
-
ledge about the drug

effects in the elderly. Therefore it is necessary to include them
in clinical trials. There is a special need for guidelines which stimulate the inclusion
of the people aged 70 and older in clinical trials.
4


References

1.

World Population Prospects: The 2002 Revision, Highlights. New York: United Nations
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http://www.un.org/esa/population/unpop.htm
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Crome P. What's different about older people. Toxicology 2003;192(1):49
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9.

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Rodenhuis N BD, de Smet PAGM.
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