Health benefits

— Are employers
getting the most
for their money?

Role of
pharmaceuticals
— How drugs
produce substantial
savings in both
direct and indirect
costs for the most
common chronic
illnesses seen in
the workplace

New medications
— Incremental
Pharmaceuticals and
pharmaceutical
improvements
Productivity:
substantially
improve workplace
productivity
An Investment in Human Capital
Keeping workers
healthy and
active
— Today’s drugs
help reduce
absenteeism
and improve job
performance

Pharmaceuticals
and disease
management
strategies
— Pharmaceutical
intervention
and drug-based
treatment protocols
can reduce health
care costs and
improve clinical
outcomes

N AT I O N A L P H A R M AC E U T I C A L CO U N C I L 2 0 0 1
TAB LE O F CO NTE NTS

Overview...........................................................................................................................1

What Are We Getting for Our Money? ...................................................................1

New Pharmaceuticals Save Both Direct and Indirect Costs............................3

Incremental Benefits of New Medications............................................................4

New Pharmaceuticals Reduce Treatment Costs

and Improve Workplace Productivity ......................................................................5

Disease Burden and Benefits of Drugs for

10 Diseases Prevalent in the Workplace................................................................6
Allergic Rhinitis ...............................................................................................8
Arthritis...............................................................................................................9
Asthma.............................................................................................................10
Diabetes ..........................................................................................................10
Depression ......................................................................................................11
Heart Failure ..................................................................................................13
Hypertension..................................................................................................14
Coronary Heart Disease (CHD)................................................................15
Migraine ..........................................................................................................16
Gastrointestinal Disorders .........................................................................17

Cost Savings Through Disease Management and

Practice Guidelines .....................................................................................................19

Conclusions ...................................................................................................................21

References .....................................................................................................................22
OVE R VI E W
New therapies have the potential to produce eco-
nomic savings and benefits both outside of the
health care system (indirect savings) and within the
system (direct savings). This report explores the ques-
tion of whether spending on pharmaceuticals has a
positive payoff. In short, do we get a good return on
our investment? The conclusions are as follows:
d Increases in drug expenditures have been off-
set by substantial improvements in health and
by direct savings associated with reductions in
the cost of illness. The benefits of new drugs
include increased longevity and quality of life,
and less use of hospitals, emergency rooms,
nursing homes, and other expensive services.
d New medications reduce the indirect costs of
illness, especially by improving workplace
productivity. This can be especially important
for employers because productivity can be
severely compromised by illness. Modern
drugs for major illnesses of employed persons
have been shown to reduce absenteeism and
to improve performance on the job.
d Disease management programs for asthma,
congestive heart failure, and diabetes that use
pharmaceutical intervention as a critical part
of their overall strategies have repeatedly
demonstrated effectiveness in reducing health
care costs and improving patient quality of life.
d Expenditures on medications by employers
are best viewed as an invest-
ment in improved
health and
productivity of
the work-
force.
| 1 |
What Are We Getting for Our Money?
Although still focused on cost management, employ-
ers are increasingly asking for hard information on
the return they are getting from their health care
expenditures, including those for pharmaceuticals.
Control of spiraling health care costs is a high prior-
ity for employers today, and pharmaceutical expen-
ditures are a prime cost-cutting target because they
are rising faster than many other health care costs.
A recent study addressed the question of what fac-
tors are driving the recent increase in drug expendi-
tures. Using large national claims databases covering
managed care plan enrollees and employees
covered by large employer-provided health plans,
researchers examined information on drug thera-
pies for seven common medical conditions (allergy,
asthma, depression, diabetes, gastrointestinal prob-
lems, high cholesterol, and hormone replacement).
It was found that for each condition, increased pre-
scription volume, not rising prices, accounted for
higher levels of spending.1 This increased volume
growth resulted from more patients, more prescrip-
tions per patient, and more days of therapy.
The main factors accounting for rising drug costs in
recent years include the following2,3:
d General inflation in all sectors of the economy,
including pharmaceuticals.
d Many new drugs available to patients today
are more effective than older drugs, such
as proton pump inhibitors, which have
replaced H2-receptor antago-
nists, and non-sedating
antihistamines,
which have
replaced older
sedating
therapies.
 d New therapies for previously untreatable
conditions, such as acquired immunodefi-
ciency syndrome, are now available.
d Patients are becoming more educated
about their health and are increasing
demand for certain brand name drugs as a
result of an increase in direct-to-consumer
marketing.
d New drugs for treating heart disease, can-
cer, and mental disorders are now replac-
ing more traditional medical treatments
that involve hospitalizations, surgery or
other invasive procedures.
In response to rising drug expenditures, some
employers and managed care organizations have
introduced cost-containment programs that
involve higher cost-sharing provisions for drug
benefits, multitier coinsurance arrangements that
favor generics and older therapies, and restricted
access to certain drugs through predetermined
formularies. But these blanket responses designed
Comparable Value of Pharmaceuticals: Relative Costs to Save One Year of Life
Home Smoke Detectors
Annual Mammography Age 55-64
Driver Airbag/Lap Belt
Drug Therapy for AIDS
Statin Cholesterol Drugs for Men 55-64
with Heart Disease
Beta Blockers for Heart Attack Survivors $850
$0
to control rising costs do not consider the full
value of many pharmaceutical treatments and
may ultimately cost employers more. The potential
impact of such programs on health outcomes and
employee productivity usually is not assessed
before such restrictions are imposed.
Drugs have helped increase the life expectancy of
Americans from 54 years in 1920 to more than
75 years today.4 In addition, medications have
reduced the overall cost of disease, because they
often replace more expensive surgeries and
medical treatments.
Many drugs save lives, and some are more
cost-effective than other nondrug life-saving
interventions. Figure 1 shows the costs of some
drugs compared with the costs of other important
health and safety interventions in saving one
year of human life.
In addition to their ability to save lives, pharma-
ceuticals may improve an employee’s health and
Figure 1
$210,000
$110,000
$42,000
$26,000
$20,000
$50,000 $100,000 $150,000 $200,000 $250,000
Source: Tengs et al, Risk Analysis, Vol. 15, No. 3,1995
| 2 |
well-being, and their cost may be offset by reduced costs? Dubois and colleagues1 posed the question:
hospital, emergency room, laboratory, or physician "If patients, for example, with milder and non-sui-
services, as observed for asthma. For example, cidal depression feel better on medication, or if
Figure 2 shows the correlation between the recent more expensive but less sedating antihistamines
increase in the use of asthma drugs and the improve concentration, are these gains worth the
decrease in the use of medical services. extra costs?" Often, the extra expenditures for
newer medications result in savings in other areas,
Figure 2 making the expenditures worthwhile.

Asthma-related Hospital and

New Pharmaceuticals Save Both Direct and
ER Use Decreased as
Indirect Costs
Asthma Drug Use Increased
The higher costs associated with new pharmaceuti-
450
cals often are offset by reductions in other direct
400
1995 costs (e.g., hospitalization) and by reductions in indi-
350 424 1998
393 rect costs (e.g., improved worker productivity).
Rate per 1,000 Asthmatics

300
250
200
Benefits of New Pharmaceuticals
150
100 163 d Reduced hospitalization
128
50 d Improved side effect profiles
0
ER Hospitalizations
d Reduced patient visits
($450 each) ($11,037 each) d Expanded formulary choices
Source: Protocare Sciences
d Reduced worksite injuries
d Enhanced patient adherence
Savvy health care purchasers need to ask the d Reduced absenteeism
following questions when faced with increases in d Enhanced longevity
drug costs: d Reduced expensive treatments
d Is the added expense of a drug worth it in d Enhanced quality of life
terms of the drug’s ability to improve health d Reduced invasive treatments
and reduce overall spending? d Enhanced workplace performance
d Does the drug enhance or hamper employ-
ee productivity?
The reverse is also true. Research shows that cut-
d Do the answers to these questions differ for
backs in drug spending can raise utilization in
newer, higher priced drugs compared with
other parts of the health care budget—notably,
older agents?
hospital admissions, emergency mental health
The core question for employers is: Compared with facilities and nursing home admissions.5,6,7,8 Some
drug or nondrug alternatives, are the benefits of managed care plans have begun to move away
newer, more expensive drugs worth their added from restrictive formularies and are implementing

| 3 |
 pharmaceutical Incremental Benefits of New Medications
management
The need for multiple agents that are similar to
programs that are
existing medications is often questioned. It is
based on an inte-
assumed that drugs with similar pharmacological
grated approach to
actions are essentially identical. This is a misconcep-
health care. HealthNet,
tion. The process of incremental innovation pro-
in California, has report-
duces a diverse class of drugs, enabling physicians
ed cost savings and quality
to tailor drug therapy to individual patients. New
improvement by investing in new
agents resulting from this process can offer advan-
drugs that are often more expensive
tages in the form of improved effectiveness, fewer
than older agents.9 Formularies are increasingly
side effects, better patient satisfaction and compli-
being evaluated for their impact on overall disease
ance, and greater cost-effectiveness.
management and not just drug budget costs.10 This
evaluation is welcomed by most employers.
These gradual improvements do not necessarily
increase the cost of pharmaceuticals, because the
new drugs must compete with their predecessors for
Employees Perceptions About
market share. Analysis of drug pricing indicates that
Medications
most new drugs are launched at discounts relative
A 2001 survey of employees by Harris to existing drugs in the same class.12 Thus, the more
Interactive11 revealed the following percep- recently introduced cholesterol medications are
tions about the value of medications: more cost-effective than earlier ones in elderly
patients,13,14 though not in lower-risk patients.15
d Seventy-nine percent of survey respon-
dents said prescription medications
Because they often have fewer side effects and are
enhanced productivity at work for them
easier to take, newer medications can facilitate
or someone they care about.
adherence to treatment regimens. Patients who do
d Eighty percent said that medications have not take their medications as directed may fail to
helped them or someone they care about improve, worsen, or relapse. Each of these negative
return to work more quickly after an illness. outcomes has an economic effect on the entire
d Eighty percent said that medications health care system. The costs of hospitalization and
have helped to keep them or someone physician visits caused by relapse owing to nonad-
they care about alive. herence are estimated at $8.5 billion in otherwise
unnecessary spending.16 Other effects of nonadher-
d Eighty-seven percent credit prescription
ence are huge indirect costs, one of which is lost
medications with keeping an ailment
workdays, which increases the cost of manufactur-
in check.
ing.16 Table 1 lists the negative economic conse-
d Ninety-three percent of respondents with quences of nonadherence.
private prescription drug coverage believe
that prescription drugs are an "essential
part" of their health coverage.

| 4 |

Table 1.— Economic Burden of
Nonadherence with Medications.16
d Need for additional medical treatment;
d Need for additional medications;
d Additional hospital/nursing home admis-
sions or readmissions;
d Absenteeism or reduced productivity at
work; and
d Mortality costs (including direct and indirect
costs associated with lost earnings).
Pharmaceutical companies are responding to the
need for better patient adherence by developing
new medications or new forms of existing
medications with improved side effect profiles, less
frequent dosing requirements, or both. For example,
patients with osteoporosis used to take alendronate
(FosamaxF) each morning upon rising. They were
instructed to have nothing to eat or drink for a half
hour, nor could they lie down during that period.
Now the product is available in a preparation to be
taken (with the same restrictions) once weekly. It is
anticipated that this streamlined dosage schedule
will foster greater adherence. Similarly, in February
2001, a once-weekly dosage form of fluoxetine
(ProzacF) was approved by the Food and Drug
Administration. These and other improved dosage
forms can improve patient adherence to medication
regimens, improve treatment outcomes and thereby
increase workforce productivity.
New Pharmaceuticals Reduce Treatment Costs
and Improve Workplace Productivity
A healthy and productive workforce can provide a
strong competitive advantage for companies operat-
ing in today’s business world. Some corporate leaders
| 5 |
are beginning to look at the health status of their
workforce from a new perspective — as an investment.
It is becoming clear that improved drug therapies for
ill workers can substantially improve productivity
and therefore the bottom line of employers (see
Table 2). There is a growing trend by employers to fac-
tor productivity goals into health benefit decisions.17
Innovative employers across America are producing
definitive data on the ways health, illness, and med-
ical treatment affect productivity.
Table 2.—Causes of Reduced Worker
Productivity Due to Illness.
d Loss of optimal efficiency
d Use of sick days
d Lost time in caring for ill child or dependent
d Work-related injury or disability resulting
from illness
New medications offer the potential to reduce over-
all health care costs by replacing more expensive
and invasive medical treatments. A recent study by
Columbia University economist Frank Lichtenberg18
used large public databases containing individual
patient records on use and costs of health care serv-
ices to ask the question, "Are the benefits of these
newer drugs worth their cost?" He found that peo-
ple consuming newer medicines in 1996 experi-
enced fewer deaths and fewer work-loss days than
people consuming older medications. The use of
newer drugs tended to lower all types of nondrug
medical spending, resulting in a net reduction in
the total cost of treating a given condition. The
overall reduction in medical expenditures from
using a newer drug was found to be about four
times greater than the added cost of that drug.
The prevalence and annual cost burden of the leading illnesses (excluding work-related injuries) that compro-
mise workplace productivity and contribute to lost wages are listed in Table 3. These diseases account for at least
$422 billion annually in total health care costs.

Table 3.— Prevalent and Costly Illnesses*

Disease Prevalence Direct Cost Indirect Cost Total Cost

(million) ($ billion) ($ billion) ($ billion)
Allergic rhinitis 20-40 5.9 4.6 10.5
Arthritis 43 15 50 65
Asthma 14 5.1 2.7 7.8
Diabetes 16 44 54 98
Depression 18.8 12.4 31.3 43.7
Heart failure 2-3 19.4 32.6 52
Hypertension 50 17 7 24
Coronary heart disease 12.4 53.4 47.4 100.8
Migraine 11-18 1 13 14
Peptic ulcer disease 27 5 1 6
*See below for further discussion and references.

For many of the diseases listed in Table 3, the indirect costs of lost productivity due to absenteeism, disability, pre-
mature mortality, and lost wages are substantial and in some cases exceed the direct costs of treatment (Figure 3).

Figure 3

Direct and Indirect Costs of Major Illness in the Workplace*

100% —
Percentage of Total Costs

50% —

0% —
Migraine

Arthritis

Depression

Diabetes

Coronary Heart
Disease

Allergic Rhinitis

Asthma

Hypertension

Peptic Ulcer
Disease

Indirect costs: Costs of lost productivity due to absenteeism, disability, premature mortality, lost wages
Direct costs: Health care costs including hospitalizations, physicians, drugs, etc.
*See following for further discussion and references.

| 6 |
For individuals with cardiovascular disease, the drug costs are often far lower than the productivity and health
costs. The relative proportions of these costs for several cardiovascular diseases are illustrated in Figure 4.

Figure 4

Drug Costs, Health Care Costs, and Productivity Costs

of Cardiovascular Diseases

$120 —
100 — Drugs
Billions of Dollars

80 — Health Care
60 — Productivity
40 —
20 —
Source: American Heart Association Heart and Stroke 2000
0— Statistical Update: www.americanheart.org/statistics/economic
Coronary Heart Stroke Hypertension Congestive
Disease Heart Failure

The use of prescription medicines has the potential to improve worker productivity by reducing the direct and
indirect costs of major illnesses. In a 1996 study using nationally representative data from 1987 government
surveys, Rizzo and colleagues19 estimated the effects of prescription medicines on hourly wages and on days lost
from work for workers with hypertension, heart disease, type 2 diabetes, and depression. The net benefits to
employers from having workers take prescription medications for these chronic diseases were substantial.
Assuming average rates of compliance with medication regimens, the annual net savings amounted to $286
per hypertensive employee, $633 per employee with heart disease, $822 per depressed employee, and $1475
per employee with diabetes. The authors concluded: "These estimated net benefits accrue because prescription
medicines substantially lower absenteeism among chronically ill workers."

Importantly, Rizzo and colleagues19 found that "for all chronic conditions examined, estimated employer costs for
prescription medications were outweighed by increased revenues resulting from enhanced employee productivity."

Similarly, a Massachusetts Institute of Technology study of depression,

anxiety, migraine, and hypertension in individuals employed
as insurance claims processors showed that for each
of these diseases the number of hours worked in
a 2-week interval increased after pharmaceu-
tical treatment.20 In addition, the number of
claims processed by these claims proces-
sors (i.e., productivity) also went up after
treatment (see Figure 5).

| 7 |
 Figure 5

Pharmaceuticals Improve Productivity

70
Hours worked over 2 week period
68
66
64
62
60
58
Depression Anxiety Migraine Hypertension
Pre-Treatment Post-Treatment
Source: Ernie Berndt, "Illness and Productivity: Objective Workplace Evidence," MIT Working Paper, May 1997

Newer drugs can reduce the cost of illness and to indirect costs.23 A poll by Louis Harris &
result in productivity gains. Ten diseases preva- Associates for USA Today (August 7, 1999) found
lent in the workplace are discussed below (see that over half of adults reported suffering from a
Table 3). In each case, therapy with medications, related disorder (sinus problems); 34% of sufferers
especially newer medications can significantly said the condition affects work performance.
improve the health and productivity of ill employees.
Benefits of drugs.
Allergic rhinitis The first-generation and some second-generation
Disease burden. antihistamine preparations used for these condi-
Seasonal allergic rhinitis (hay fever) affects an tions cause sedation, variously described as
estimated 13 million working adults and causes drowsiness, fatigue, and altered cognitive and
absenteeism and diminished work productivity.21 psychomotor function. The new, less sedating
Estimates of at-work productivity losses range antihistamines avoid these central nervous
from $2.4 to $4.6 billion,22 much of which comes system side effects because they do not cross the
not from absence due to allergies but from lost blood-brain barrier.
productivity due to the sedating effects of the
older medications used to treat them. Compared with nonsedating agents, sedating anti-
histamines have been linked to more workplace
When patients self-manage allergic rhinitis with accidents and injuries21 as well as to impaired work
older, more sedating antihistamines, lost produc- performance.24,25 A study of productivity in clerical
tivity and missed workdays add $3.8 billion yearly workers (insurance claims processors) with aller-

| 8 |
gies found that the productivity of workers using
sedating antihistamines was 13% lower than the
productivity or workers using nonsedating antihista-
mines.24 This lost productivity was calculated to cost
the employer $9.00 daily for each employee taking
sedating antihistamines. Assuming a greater daily
cost of up to $1.50 for nonsedating antihistamines,
this translates to a favorable cost/benefit ratio.25
Similarly, the William M. Mercer employee benefits
consultant company used an actuarial model to cal-
culate that many employers can realize a net finan-
cial gain of $2.00 to $4.00 for every $1.00 spent
when allergy sufferers use nonsedating instead of
sedating treatments.26 The savings result from a
combination of productivity gain, fewer accidents
and disability claims, and less sick leave.
Arthritis
Disease burden.
In the United States, arthritis and related conditions
affect nearly 43 million individuals and are a major
cause of disability.27 The total annual cost for arthri-
tis is estimated at $65 billion each year; $15 billion
in direct costs and $50 billion in indirect costs,
largely resulting from lost wages.28
Benefits of drugs.
Treatment for the various types of arthritis
(osteoarthritis, fibromyalgia, and rheumatoid arthritis
are the leading forms) has been centered around
the use of nonsteroidal anti-inflammatory drugs
(NSAIDs), either alone or com-
bined with disease-modi-
fying anti-rheumatic
drugs for rheuma-
toid arthritis.
One of the
drawbacks to
long-term
| 9 |
treatment with NSAIDs is the potential for damage
to the stomach lining.
A relatively new class of NSAIDs has emerged: the
cyclo-oxygenase-2 (COX-2) inhibitors. These agents
relieve the pain and inflammation of osteoarthritis
and rheumatoid arthritis, while largely avoiding
gastrointestinal toxicity. These agents also have
potential positive and negative cardiovascular
effects, but more research is needed to clarify the
clinical significance of these actions.
A study was undertaken to model the economic effi-
ciency of nonselective (i.e., conventional) NSAIDs used
in combination with gastroprotective agents with the
economic efficiency of a selective COX-2 inhibitor
alone, in the treatment of arthritis.29 The investigators
found that the COX-2 inhibitor had significant tolera-
bility and safety advantages compared with nonselec-
tive NSAIDs. The risk of gastrointestinal adverse events
with the COX-2 inhibitor was similar to or less than
that observed when nonselective NSAIDs were given
in combination with gastroprotective agents. The
investigators concluded that use of the selective
COX-2 inhibitor is expected to significantly reduce the
economic costs of treating arthritis by reducing
gastrointestinal toxicity and its associated morbidity.
In terms of work loss and productivity, a great deal
can be gained by keeping patients free from the
serious gastrointestinal injury associated with older
antiarthritic drugs. Those who have had to limit
their use of arthritis medications
to avoid side effects can
now seek relief
from con-
straining or
incapaci-
tating
pain.30

Asthma
Disease burden.
More than 14 million individuals in the United
States are affected by asthma.31 The prevalence of
and morbidity and mortality from asthma have
increased over the past 20 years for reasons that
are not clear.32 The direct and indirect costs attrib-
uted to asthma also are rising. In the United States,
these costs were estimated at $6.2 billion in 1990.33
They rose to $7.8 billion in 1994.34 The indirect
medical costs (missed work or school and restricted
activity) were estimated at $2.7 billion. The remain-
ing $5.1 billion was attributed to direct medical
costs (ambulatory care visits, hospital outpatient
and inpatient services, emergency department visits,
physician fees, and prescription medications).
Asthma is one of the few medical conditions in which
direct medical costs are greater than indirect costs.
Benefits of drugs.
For years, asthma was attributed to airway constric-
tion (bronchospasm) that led to airway obstruction,
and bronchodilators were the agents of choice. Now,
the disease is considered primarily an inflammatory
disease, and anti-inflammatory agents are preferred
for long-term control. Inhaled corticosteroids are
| 10 |
recommended for moderate to severe disease.
Donahue and associates35 found that inhaled corti-
costeroids protect against exacerbations of asthma
that lead to hospitalization. A Saskatchewan study36
determined that the regular use of low-dose, inhaled
corticosteroids is associated with a decreased risk of
death from asthma. Balkrishnan and colleagues37
reported a 50 percent decrease in hospitalization rates
and a 26 percent decrease in outpatient visits and
concluded that the introduction of inhaled corticos-
teroids reduced total health care costs by 24 percent.
A study by Ozminkowski and coworkers38 suggested
that using inhaled corticosteroids, cromoglycate, or
nedocromil to control airway inflammation is a less
costly approach than using other drugs to control
asthma. They noted that asthma-related expendi-
tures would be higher if inhaled anti-inflammatory
medications were used, but total health care costs
would be reduced by nearly $950 per patient per
year. Since these studies were completed, newer
drug treatments for asthma have emerged, such as
leukotriene antagonists and more potent inhaled
corticosteroids, which may further reduce the use of
other more costly services.
Diabetes
Disease burden.
It is estimated that 16 million Americans have dia-
betes, with nearly 800,000 cases diagnosed annually;
about 10 million Americans have the disease and do
not know it.39 Diabetes is the nation’s seventh leading
killer and accounts for $98 billion in direct and
indirect medical costs and lost productivity
each year.40 In 1997, $44 billion was spent
on direct medical costs for diabetes; the
remaining $54 billion was allocated to
indirect medical costs (disability, work
loss, and premature mortality).41
A study42 was conducted that measured labor force
participation, hours of work lost, and the economic
value of those lost work hours in employed persons
with diabetes. The researchers found that loss of
yearly earnings, on average, amounted to about a
one-third reduction in earnings.
The authors of a 1998 Harvard study on the bene-
fits of glucose control through drugs and dietary
treatment43 observed that "lost productivity,
increased absenteeism, and increased use of health
resources associated with poor glycemic control
should provide a strong incentive for demanding
more comprehensive management from the health
care provider organization than what is currently
offered." Specific findings are shown below.
Economic and Quality-of-Life Benefits
of Glucose Control with Diet and
Drug Therapy43
d Higher retained employment
(97% vs. 85% with no treatment)
d More stay fully productive
(99% vs. 87% with no treatment)
d Lower absenteeism
($90 monthly savings/worker)
d Fewer bed days
($300 savings/1000 person days)
d Fewer restricted activity days
($1600 savings/1000 person days)
Benefits of drugs.
Today, there are six classes of diabetes drugs that
act through different mechanisms: insulin, sulfony-
lureas, biguanides, alpha-glucosidase inhibitors,
meglitinides, and thiazolidinediones. One study,
| 11 |
using two of the
newer agents for
type 2 diabetes
(metformin and
troglitazone),
showed distinct
advantages were
achieved by combin-
ing these drugs, which
are from different classes.44
One drug acts by decreasing the
body’s production of glucose and the
other by increasing the rate at which glucose is
removed from the blood stream and delivered to
body tissues, where it is needed. Although the thia-
zolidinedione, troglitazone, has been withdrawn
from the market because of serious problems with
liver toxicity, two other drugs in this class with sim-
ilar beneficial effects but a reduced likelihood of
adverse effects are now available.
The second-generation sulfonylurea agent glipizide
is now available in an extended-release formulation
for the treatment of diabetes. Monthly productivity
losses related to absenteeism improved slightly or
did not change significantly in patients receiving
extended-release glipizide, and differences in direct
health care costs among patients receiving conven-
tional glipizide, metformin, or acarbose were
small.45 The extended-release glipizide formulation
provided more stable plasma drug concentrations
than the conventional formulation, and the once-
daily regimen may improve patient adherence.
Depression
Disease burden.
Major depression is a leading cause of disability in
the United States.46 An estimated 9.5 percent of
Americans 18 years of age and older suffer from
depression in any given year. In 1998, some 18.8
million people were believed to have depression.
Nearly twice as many women (12%) as men (7%) are
affected by a depressive disorder.
In one study,47 the average duration of disability and
the disability relapse rates were greater for depres-
sive disorders than for other common chronic
medical conditions. Depression is the costliest
modifiable risk factor for increased health care
expenditures. Goetzel and colleagues48 reported that
among 10 modifiable health risks, depression had
the greatest impact on employee medical expendi-
tures. But depression is a largely treatable disorder;
more than 80 percent of patients improve when
they receive appropriate treatment.
Estimates have been developed for three major cost
categories of depression49: (1) direct costs of med-
ical, psychiatric, and pharmacologic care; (2) mortal-
ity costs arising from depression-related suicides;
and (3) morbidity costs associated with depression
in the workplace. These researchers estimated that
the annual cost of depression in the United States in
1990 was approximately $43.7 billion, including
$12.4 billion (28%) in direct, treatment-related
costs; $7.5 billion (17%) in suicide-related costs;
and $23.8 billion (55%) for excess absenteeism and
reduced productive capacity while at work during
episodes of depression.
Kessler and Frank50 reported that the effects of psy-
chiatric disorders on work loss are similar across all
occupations, while effects on work cutback are
greater among professional workers than those in
other occupations. The investigators found that
major depression was by far the most prevalent
psychiatric disorder.
Benefits of drugs.
Antidepressant medications influence the function-
ing of brain neurotransmitters. Newer drugs, includ-
| 12 |
ing selective serotonin reuptake inhibitors (SSRIs)
and agents that influence reuptake of norepineph-
rine and dopamine, tend to have fewer side effects
than older drugs, which include tricyclic antidepres-
sants (TCAs) and monoamine oxidase inhibitors.
Newer and older antidepressants are all effective in
relieving depression. However, some individuals
respond to one type of drug, but not to another.
Therefore, newer medications should be additions
to, not replacements for, older medications in
formularies. Other types of antidepressants are
currently in development.
In a real-world study on treatment costs for SSRIs
versus TCAs,51 the researchers made sophisticated
econometric adjustments for factors that influence
drug choice and expenditures. Once these adjust-
ments were made, they found that total direct
health care expenditures were significantly lower
for SSRI users than expenditures for users of the
older medications.
A study on the effects of chronic depression and its
treatment on workplace performance52 found that
the more severe the depression, the lower the level
of perceived at-work performance. In addition, the
researchers found that a reduction in depressive
severity improves the patient’s perceived work per-
formance. The researchers noted that after imple-
mentation of treatment, improvement in work per-
formance was rapid, with two thirds of the change
occurring by the fourth week of treatment.
The relationship between depression and work per-
formance was studied in a large clinical trial.53
Eighty-six percent of patients treated with
antidepressant medications reported some
improvement after 4 weeks. The extent of work per-
formance improvement correlated highly with the
improvement in depressive symptoms.
Compared with older medications, SSRIs have been
found to make greater contributions to improved
productivity; and twice as many patients on older
medicines discontinued treatment. SSRIs have a
better side effect profile, leading to more continu-
ous use and better patterns of adherence to clinical
practice guidelines for depression care.54,55 This in
turn may lead to more cost-effective care.
Heart Failure
Disease burden.
Some 2 to 3 million Americans have heart failure,
and 400,000 new cases are diagnosed each year.56
Heart failure causes 39,000 deaths a year and is a
contributing factor in another 225,000 deaths.
Mortality due to heart failure is more common
among men than women and is twice as high for
African Americans than for whites in all age groups.
The risk of heart failure increases with age. More
people are living and working longer so heart fail-
ure has a growing impact on worker productivity.
The total cost of heart failure in the United States is
estimated at $52 billion per year.57
The presence of coronary disease is among the great-
est risk factors for heart failure. Although a
single risk factor may be sufficient to cause heart fail-
ure, a combination of factors dramatically increases
the risk. Common risk factors are coronary disease,
irregular heartbeat, high blood pressure, elevated
blood cholesterol, tobacco use, physical inactivity,
poor nutrition, obesity, and diabetes.58
An analysis of a proprietary claims database of
3.1 million insured individuals was per-
formed to examine the indirect costs of
ischemic heart disease, a condition in
which there is coronary artery block-
age.59 The conclusions of this report,
published in 2001, are that the
| 13 |
total indirect cost of ischemic heart disease to
employers in private industry was $182.74 per
enrollee, and 95 percent of this indirect cost was the
consequence of work loss due to morbidity, rather
than mortality.
Benefits of drugs.
In most cases, a cure for heart failure is not possible.
Lifestyle modifications and drug therapy are used
to manage symptoms and prolong life. A treatment
program for heart failure usually requires rest, prop-
er diet, modified daily activities, and medications
that include angiotensin-converting enzyme (ACE)
inhibitors, beta-blockers, digitalis, diuretics, or
vasodilators.
The various medicines for heart failure have differ-
ent functions. ACE inhibitors and vasodilators dilate
(expand) blood vessels and decrease resistance,
permitting blood to flow more easily and thus mak-
ing the heart’s pumping action easier and more effi-
cient. These medications have been shown to
reduce mortality from heart failure, delay the pro-
gression of the disease, improve functional status,
and decrease the need for hospitalization.60,61 Beta-
blockers, once used with care in patients with heart
failure, have been shown to slow the progression of
heart failure and reduce hospitalization and mor-
tality.62,63 Digitalis increases the force of the heart’s
contractions, helping to improve circulation.
Diuretics help reduce the amount of fluid in the
body and are helpful for patients with fluid reten-
tion and hypertension.
Because heart failure can be managed (but not
cured) using a combination of drugs from several
different classes, it is important that a variety of
drugs be carried on formularies, with particular
attention being paid to new drugs, especially those
in the ACE inhibitor and beta-blocker classes. New
research has shown that patients with congestive
heart failure who received a new beta-blocker plus
standard treatment were 35% less likely to die than
those who received just standard treatment.64
Hypertension
Disease burden.
Hypertension (high blood pressure) is an extremely
common disorder that affects about 50 million peo-
ple in America.65 The total cost of hypertension in
the United States is estimat-
ed to be $24 billion
annually, of which
$17 billion are
direct costs
and $7 bil-
lion are
indirect
costs.66
| 14 |
Hypertension is more common as people grow older,
and it is more serious among African Americans.
Nine out of every 10 people with hypertension have
no identifiable cause. Often called the "silent killer,"
hypertension can lead to serious health problems (or
even death) without causing symptoms. People with
untreated hypertension are much more likely than
those with normal blood pressure to die from or be
disabled by cardiovascular complications such as
strokes, heart attacks, heart failure, irregular heart-
beat, and kidney failure.
A 19-year follow-up study,67 begun in 1972, linked
10,284 normotensive (diastolic blood pressure
[DBP] less than 95 mm Hg), mildly hypertensive
(DBP 95—104 mm Hg), and severely hypertensive
(DPB greater than 104 mm Hg) individuals in
Finland with national registries covering hospital
admissions, use of major drugs, absence due to sick-
ness, disability pensions, and deaths. The mean
undiscounted total costs (in U.S. dollars at 1992
prices) were $132,400 among normotensive men,
$146,400 among mildly hypertensive men, and
$219,300 among severely hypertensive men. More
than 90 percent of total costs were indirect produc-
tivity losses. If these results were extrapolated to
the entire U.S. population with hypertension (50
million people), the costs would be staggering.
Benefits of drugs.
Only one in four patients with hypertension receives
treatment,68 yet this disease can be treated success-
fully. A wide variety of medications are available for
the treatment of hypertension. It is a matter of find-
ing the specific drug that will best suit an individual
patient (see Table 4).
A recent report by the American Heart Association69
points out that with so many antihypertensive agents
to choose from, those that provide benefits beyond
decreasing blood pressure will become the preferred therapies. The American Heart Association states that angiotensin
II receptor antagonists have a very favorable side effect profile, and that "these drugs may become the preferred
agents of physicians who factor indirect costs – less morbidity and greater productivity – into their selection of an anti-
hypertensive therapy."

Table 4. — Types of Drugs Used to Manage Hypertension68

Therapeutic Class Effects of Drugs in Class

Diuretics Increased urination to reduce salt and water retention and lower
blood volume
Beta-blockers Slowing of heart rate and lowering of cardiac output
Angiotensin-converting enzyme Blockade of production of angiotensin II, the hormone that causes
inhibitors arteries to contract; stimulation of release of another hormone that
causes kidneys to retain water
Angiotensin II receptor Relaxation of blood vessels by blocking the vasoconstrictive action of
antagonists angiotensin
Calcium channel blockers Expansion of blood vessels by slowing the entry of calcium into cells;
some agents in this class increase heart rate somewhat, whereas
others slow it a little
Alpha-1 blockers Blockade of the effect of constricting hormones such as norepinephrine
Alpha-2 agonists Decreased action of the nervous system in constricting blood vessels;
works in the brain
Direct vasodilators Relaxation of artery walls
Sympathetic nerve blockers Prevention of nerves from constricting blood vessels

Coronary heart disease (CHD)

Disease burden.
Coronary heart disease (CHD), which includes myocardial infarction and angina pectoris, afflicts 12.4 million
Americans and is the leading cause of premature, permanent disability in the workforce.69 Total estimated
expenditures for CHD in 2001 are $100.8 billion; direct costs are $53.4 billion, with pharmaceuticals accounting
for only 6% of these costs. Lost productivity due to morbidity and mortality from CHD will cost employers $47.4
billion.69 Studies show overwhelmingly that the risk of developing CHD is related to elevated levels of total
cholesterol and low-density lipoprotein cholesterol (LDL-C or "bad cholesterol"). High cholesterol is the most
prevalent condition among American workers, affecting about 30% of the workforce.70 Cholesterol levels are
uncontrolled in 67% of these individuals, although levels can generally be modified with diet, exercise, and
medications.

| 15 |
 Benefits of drugs.
Four classes of drugs are
used to treat elevated
levels of cholesterol:
statins, niacin, bile
acid resins, and
fibrates. The statins,
which reduce choles-
terol synthesis by
inhibiting HMG CoA-
reductase (an enzyme
associated with cholesterol
production), have proven to
be highly effective in lowering
cholesterol levels. The cholesterol-
lowering effects of the statins are asso-
ciated with large decreases in LDL levels, deaths
from CHD, and nonfatal myocardial infarctions.71,72
The statins provide an example of the benefits of grad-
ual improvements in a drug class. The newer statins
are considerably more potent than the earlier ones in
reducing serum LDL-C and are an effective treatment
for patients with severe hypercholesterolemia. The ear-
lier, less potent statins may nevertheless be adequate
for individuals who have mildly elevated serum cho-
lesterol and are at low risk of coronary heart disease.
The statins vary in price and in their effects on high-
density lipoprotein cholesterol (HDL-C) and serum
triglycerides. Thus, the availability of a range of statins
enables physicians to treat the individual patient with
precision and at the lowest cost.
Despite the general public awareness about the dan-
gers of high cholesterol and CHD risk, many patients
still are not receiving and following the recommended
treatment. Although 17 million Americans are candi-
dates for drug therapy for CHD, it is estimated that
only 5.3 million actually receive therapy.73 In addition,
it has been estimated that 50 percent of patients using
| 16 |
lipid-lowering medications stop taking the drug within
the first year. After two years, compliance falls to
25 percent.74 Data from studies attribute treatment
failure rates to inadequate physician treatment and
lack of implementation of current cholesterol programs.
Migraine
Disease burden.
In the United States, an estimated 11 to 18 million
individuals, most of them women, suffer from
migraine disease.75 There is no known cure for
migraine, only treatments for symptoms.
Migraine disease has many symptoms, including nau-
sea, vomiting, auras (light spots), sensitivity to light
and sound, numbness, difficulty in speech, and severe
semihemispherical head pain; a migraine attack can
last for 8 hours to (in severe cases) several days, even
weeks. Migraine is caused when a physiological trig-
ger or triggers cause vasodilation (expansion) of the
cranial blood vessels. Controllable triggers include
bright light, aspartame, alcohol, and some foods such
as fish and aged cheese. Uncontrollable triggers
include weather patterns and menstrual cycles.
Migraine costs U.S. employers about $13 billion a
year due to missed workdays and impaired work
function.76 Close to $8 billion of that cost is directly
due to missed workdays. Annual direct medical costs
for migraine are about $1 billion, making the overall
health care cost $14 billion. One study77 determined
that work effectiveness was reduced 41 percent for
people with migraine headaches and 24 percent for
people with other types of headaches. Some $100 is
spent per diagnosed patient, and physician office vis-
its account for about 60 percent of all direct costs.
Benefits of drugs.
Recently introduced drugs are reported to be effec-
tive against migraine headaches. Sixty-eight percent
of patients with migraine responded to treatment Gastrointestinal Disorders
with sumatriptan, a new drug that works on the
Peptic ulcer disease (PUD) and gastroesophageal
neurotransmitter serotonin.78 A study of the bene-
reflux disorder (GERD) are two of the most
fit/cost ratio of sumatriptan for the treatment of
common and costly gastrointestinal disorders.
migraine found that that the benefits (i.e., the reduc-
Pharmaceutical advances have led to the develop-
tion in labor costs and decrease in lost productivity)
ment of the proton pump inhibitors (PPIs), a class of
exceeded the costs by 10-fold (see Figure 6).
highly effective prescription medications that control
stomach acid and promote healing for both disorders.
Figure 6
Nonprescription drugs are widely used for heartburn
and other symptoms of GERD and peptic ulcers.
Migraine Medication Reduces
However, the greater effectiveness of prescription
Employers’ Labor Costs and Decreases
medications and the cost-effectiveness of PPI treat-
Lost Productivity
ment even for mild cases of GERD suggest that using
$500 —
prescription rather than nonprescription therapies
may result in savings.
$400 — $435
PUD disease burden.
Cost per Employee per Month

$300 — At least once in a lifetime, 1 in 10 Americans suffers

from PUD.81 Annual health care costs have been
estimated at nearly $6 billion: $5 billion in direct
$200 —
costs ($3 billion in hospitalization costs, $2 billion
in physician office visits) and $1 billion in
$100 — decreased productivity and increased absenteeism.
Every year there are some 500,000 to 850,000 new
$44 cases of PUD in the United States, and more than
$0 —
Cost of Drug Treatment Reduction in Labor Costs
for Migraine and Decrease in Lost
one million hospitalizations.
Productivity

Source: Legg RF, et al., "Cost Benefit of Sumatriptan to an Employer," In the past 20 years, we have learned that 9 out
Journal of Occupational and Environmental Medicine, Vol. 39, No. 7, July 1997.
of 10 peptic ulcers are caused by an infection
with the microorganism Helicobacter pylori (H.
A study by Schulman and associates79 placed dollar
pylori), a spiral-shaped bacterium found in the
figures on the effectiveness of sumatriptan admin-
stomach. In the United States, H. pylori is seen
istered to migraineurs in the workplace. The authors
more often in older adults, African Americans,
found that there was a labor savings of $600 per
Hispanics, and persons in lower socioeconomic
patient per year. Similarly, in a placebo-controlled
groups. H. pylori infection can cause chronic
trial examining patients with four moderate to
active, chronic persistent, and atrophic gastritis
severe migraine attacks, those receiving the
in adults and children.82 Infected individuals
migraine drug rizatriptan reported 0.7 fewer hours
have a two- to sixfold increased risk of develop-
of paid work missed due to absenteeism and 0.4
ing gastric cancer.
fewer hours of productive time lost on the job.80

| 17 |
Benefits of drugs for PUD.
Before the discovery of H. pylori in 1982, spicy
food, acid, stress, and lifestyle were considered the
major causes of ulcers. Most patients were pre-
scribed acid-suppressing medications such as his-
tamine-H2 receptor blockers or PPIs on a long-term
basis. These drugs relieved ulcer symptoms and
healed gastric mucosal inflammation. Sometimes
they healed the ulcer, but they did not treat the
infection. When acid suppression is stopped, the
majority of ulcers recur, especially those caused by
H. pylori. H. pylori infection can usually be cured
with a short course of antibiotics. With this treat-
ment, the ulcer is cured and does not recur in more
than 80 percent of patients.81
Therapy for H. pylori infection consists of 10 days
to 2 weeks of one or two effective antibiotics,
such as amoxicillin, tetracycline, metronidazole, or
clarithromycin, as well as ranitidine bismuth cit-
rate, bismuth subsalicylate, or a PPI.82 Longer dura-
tions of treatment (14 days versus 10 days) provide
better eradication rates, as do triple-drug regimens
compared with two-drug regimens or monotherapy.
As of February 2001, the Food and Drug
Administration had approved eight treatment
options for the eradication of H. pylori infection.82
H. pylori eradication therapy has been shown to be
cost-effective in a managed care setting. A study
undertaken in a large HMO by Levin and col-
leagues83 reported that total 12-month costs in a
group treated with antibiotics for H. pylori infec-
tion were $285 per person less than the costs in
untreated patients. The eradication of H. pylori
in patients with PUD resulted in decreased use
of outpatient services and decreased cost of
follow-up care.
| 18 |
GERD disease burden.
GERD is a common, chronic, relapsing condition
where gastric acid irritates and often damages the
esophagus. It is estimated that 18.6 to 21 million
adults suffer from GERD. The main symptom of this
disease is heartburn, and it is estimated that 60
million Americans suffer heartburn at least on a
monthly basis.84 One large HMO found the direct
cost of medical treatment for GERD to be $471 per
adult, not including over-the-counter medications,
among those receiving drug therapy.85 If untreated
(or treated inappropriately with over-the-counter
medications), GERD may lead to recurring heart-
burn, significant chest pain, and a higher likeli-
hood of esophageal cancer.
Benefits of drugs for GERD.
Until recently, treatment for GERD usually
involved a combination of over-the-counter
antacids and the use of H2-receptor antagonists
such as cimetidine or ranitidine to control stomach
acid. In recent years, however, PPIs have been
widely used because they are substantially more
effective at controlling stomach acid, leading to
faster healing of the esophagus, better symptom
relief for all grades of esophagitis, and longer
periods between relapse.86
Although more expensive than the older H2-recep-
tor agents, in most circumstances PPIs are often
more cost-effective because of their superior ability
to relieve symptoms.87,88,89,90,91 One study of pre-
scribing strategies for treating moderate to severe
GERD found that the most cost-effective plan was
initial treatment with PPIs followed by additional
PPI therapy as symptoms recur. This strategy
achieved cost savings by substantially reducing the
need for the diagnostic endoscopies that other
management strategies require before a PPI can
be prescribed.92
Cost Savings through Disease Management and
Practice Guidelines
Disease management is a multidisciplinary,
continuum-based approach to health care delivery
that evolved from a failed experiment in cost
control: health care component management (e.g.,
limiting formulary choices, reducing the number of
diseases covered). Disease management programs
proactively identify populations with, or at risk for,
chronic medical conditions. They are designed specif-
ically to target populations with high-cost conditions
for which a substantial gap exists between the imple-
mentation of guidelines for care and how patient care
is actually provided.93,94 They focus on both quality of
care and costs.95,96
Pharmaceutical intervention is the keystone of any dis-
ease management program. Even though medication
use may increase, disease management programs con-
trol costs through improved clinical outcomes.
Examination of three common medical conditions —
asthma, diabetes, and congestive heart failure —
shows the benefits of disease management. In all three
cases, optimal use of pharmaceutical agents is crucial
to both improving outcomes and controlling costs.
Asthma. By encouraging the appropriate use of med-
ications in patients with asthma in Georgia and
Florida, CIGNA HealthCare reported a 23 percent
reduction in hospital admissions and a 15 percent
improvement in appropriate medication usage.97 The
Virginia Health Outcomes Partnership (VHOP), the
first disease management program for Medicaid
patients, incorporated disease management interven-
tion and trained physicians in the appropriate use of
state-of-the-art asthma therapy. VHOP also trained
health care providers in methods for teaching patients
how to effectively control their asthma.97 It was
estimated that the program would have saved
| 19 |
$1.2
million
in emergency
claims had it been
implemented statewide.
Congestive heart failure. A congestive heart failure
management program in Sacramento, California,
reduced hospital admissions and readmissions by 80
percent.98 The Northeast Ohio office of United Health
Care of Ohio Inc. is receiving encouraging results in
its congestive heart failure disease management pro-
gram, reporting a 52 percent reduction in hospital-
izations. A study of a heart failure outpatient man-
agement program in Portland, Oregon, demonstrated
that total hospital admissions for cardiovascular
causes decreased by 59 percent and total emergency
room visits decreased by 77 percent.99
Disease management programs for diabetes are
under way across the country.100 In Arizona, a review
of a random sample of patients in six Medicare
managed care plans that comprise 40 percent of
the Medicare population determined that the mean
number of physician office visits fell 13 percent
after disease management intervention that
included use of pharmaceuticals.101
There are many ways to manage health plan
costs without merely restricting access to new medi-
cines. According to a report in Disease Management
News, PacifiCare of Colorado achieved striking
results with its low-cost disease management
 Figure 7

Impacts of Disease Management on Congestive Heart Failure Patients —

Net Savings: $2900 per patient102
30% — 27%
20% — 18%

10% — Rate of Avg. Length of

Hospitalization Hospital Stay
0% —
Use of ACE Use of Diuretics
-10% — Inhibitors
-20% —
-30% —
-40% — -36.1% -33.7%

program for patients with congestive heart failure. productivity and avoided sick wages saved in 2001
By focusing on extensive use of clinical guidelines, (see Figure 8).104 Optimal drug treatment protocols
case management, and patient counseling, the pro- were an integral element of these HEDIS measures.
gram reduced both the rate of hospitalization and
the length of hospital stay, and achieved a net sav-
Figure 8
ings of $2900 per patient (see Figure 7).102
Productivity dividends resulting from
In addition to savings in health care costs, produc- adherence to seven key
tivity improvements can also result when pharma- HEDIS measures in 2001
ceuticals are used according to currently accepted
standards endorsed by clinicians and quality review Sick/unproductive Wages saved
organizations. The National Committee for Quality days avoided ($ millions)
Assurance (NCQA) report State of Managed Care Heart disease 2,900,000 $501
Quality, 2001 makes it clear that high-quality health
Asthma 1,970,000 $337
care, including pharmaceutical therapy, returns eco-
nomic benefits in the form of less absenteeism and Hypertension 1,000,000 $171
improved productivity.103 Using its Health Employer Chicken Pox 948,000 $163
Data and Information Set (HEDIS) measures of qual-
Depression 640,000 $110
ity treatment for specific diseases, NCQA noted that
over the past several years there has been an Diabetes 575,000 $99
improvement in the treatment of employees having
Smoking 147,000 $25
seven key diseases . As a result, U.S. employers will
enjoy an annual productivity dividend of 8 million Total 8,180,000 $1,406
sick days avoided and $1.4 billion in improved Source: NCQA104

| 20 |
CO N C LU S I O N S Accordingly, benefit plans should be designed to
include enough drugs in each therapeutic class to
Maintenance of the health status of a compa-
better match therapy to patient needs. Individual
ny’s workforce is an investment in human
patients can differ greatly in their response to
capital. Because pharmaceuticals are generally
medicines due to variations in physiology, age,
the most effective means for improving health
gender, ethnic background, and other factors.
status, programs that make state-of-the-art
Improved versions of medicines usually provide
medications available to employees represent
advantages over existing agents, including greater
an essential strategy. Drug therapies can bring
effectiveness, safety, and dosage convenience.
the benefits of increased productivity, individual-
ized and optimized patient care, savings in over-
The test of the value of new pharmaceutical prod-
all health care costs, and improved quality of life
ucts should be whether they help keep people
and satisfaction for employees.
healthy and active. This translates to greater
productivity for individuals in the workforce.
Evidence reveals that new drugs should be made
Disease management programs have the poten-
available to individuals covered by health care
tial to produce increased savings and improved
plans because such drugs may decrease productiv-
health outcomes.
ity losses and may lower total health care costs.

The National Pharmaceutical Council (NPC) is supported by more than 20 of the nation’s major research-based pharmaceutical
companies. NPC sponsors a variety of research and education projects aimed at demonstrating that the appropriate use of
pharmaceuticals improves both patient treatment outcomes and the cost effective delivery of overall health care services.

| 21 |
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