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This monograph explains that small incremental improvements within drug classes provide important health benefits, especially for elderly patients. The monograph illustrates therapeutic advantages of these newer drugs in a class including: fewer side effects, improved safety and greater effectiveness; easier use, which facilitates compliance with prescribed regimens; and better tailoring to fit individual patient needs.
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The Value ofIncremental
PharmaceuticalInnovation
for OlderAmericans
by
Albert Wertheimer, PhD, MBADirector, Center for Pharmaceutical
Health Services Research, Temple University School of Pharmacy
Thomas W. O’Connor, Jr., PharmD, MBADirector, Continuing Professional Education,
Temple University School of Pharmacy
Richard Levy, PhDVice President, Scientific Affairs, National Pharmaceutical Council
© 2001 Temple University
..
The Value ofIncremental
PharmaceuticalInnovation for
Older Americansby
Albert Wertheimer, PhD, MBA
Thomas W. O’Connor, Jr., PharmD, MBA
Richard Levy, PhD
Published byTemple University
Center for Pharmaceutical Health Services ResearchPhiladelphia, PA 19140
( 2 1 5 ) 707 – 7 787www.temple.edu/tuhs
■
Temple’s School of Pharmacy is located on the Temple University Health Sciences Campus and is recog-
nized for its high standards in research innovation and education. It is becoming known for the Center for
Pharmaceutical Health Services Research, which conducts externally-funded and academic research in the
areas of pharmacoeconomics, outcomes research, and health policy analysis. One year old, the Center has
already attracted research support from a number of multi-national pharmaceutical companies, trade asso-
ciations, professional societies, marketing research and advertising agencies
■
Since 1953 the National Pharmaceutical Council (NPC) has sponsored and conducted scientific, evidence-
based analyses of the appropriate use of pharmaceuticals and the clinical and economic value of pharma-
ceutical innovation. NPC provides educational resources to a variety of health care stakeholders, including
patients, clinicians, payers and policy makers. More than 20 research-based pharmaceutical companies are
members of the NPC.
■
The Value of Incremental Pharmaceutical Innovation for Older Americans 1
Incremental advances, rather than “breakthrough” discov-eries, constitute the basic mechanism of all technologicalinnovation. Newer drugs in a therapeutic class often have
fewer side effects, improved drug safety and effectiveness,and greater ease of use which facilitates compliance with prescribed therapeutic regimens. Product alternatives permittreatments to be better tailored to individual patient needs.In addition, new uses for existing agents are continually discovered and bring significant benefits to patients. Theseimprovements and discoveries are especially important foroptimal treatment of elderly patients, because their diverseresponse to medications requires individualized care. Abroad range of medicines provides physicians with a “toolchest” to treat each patient with precision and providesoptions when particular agents are ineffective or poorly toler-ated. New, incremental innovations are often less expensivethan existing agents in a therapeutic category, and some havebeen shown to save overall healthcare costs. Policies that fos-ter the development of agents representing incrementaladvances serve to stimulate research and broaden access toimportant therapies, while enhancing market competition.
Abstract
..
Understanding PharmaceuticalInnovationThe current policy debate over drug benefit reform
and improved access to needed medicines for seniors
has generated considerable confusion and mispercep-
tions regarding the nature and value of incremental
pharmaceutical innovation. For example, some critics
have suggested that since a majority of the new drug
applications approved by the FDA do not represent
“breakthrough” innovations, the value of these “incre-
mental” drugs is questionable, if not negligible.
In fact, incremental pharmaceutical improvements
provide important benefits to patients:
■ Fewer side effects
■ Improved drug safety and effectiveness
■ Greater ease of use, facilitating compliance
with prescribed therapeutic regimens
■ Product alternatives that permit treat-
ments to be better tailored to individual
patient needs
Incremental Advances andPharmaceutical InnovationThe process of continuous incremental improvement
is the predominant mechanism of technological inno-
vation and product development in most manufac-
turing and high technology industries. Incremental
innovation has been an especially important source of
progress in the pharmaceutical industry. The vast
majority of clinically important drugs developed over
the last 50 years have resulted from an evolutionary
process, involving multiple, small, successive
improvements within a pharmacological class.
Incrementally innovative medicines have a molecular
structure or method of action similar to that the first
drug to be approved in a given therapeutic class.
Another type of incremental innovation occurs when
the FDA approves a previously introduced com-
pound for a new clinical use. The benefits of these
medicines are striking because a broad class of drugs
enables physicians to treat with greater precision the
individual needs of diverse patients. In addition,
patients who fail to respond to one drug will often
respond to another agent of that class.
Incremental innovations in a therapeutic category are
often priced at a discount, since they must compete
with their predecessors for market share. The result is
less expensive alternatives long before generic copies
enter the market when the patent on the first-in-class
drug expires. In addition, incremental improvements
have been shown to save overall healthcare costs.
Incremental Improvements EnableIndividualized Treatment of theElderlyThe availability of multiple, similar agents in a drug
class is of particular value to the elderly. Variation in
response to medications is common among the elder-
ly, resulting in part from wide differences in numbers
and patterns of coexisting conditions, organ function,
frailty, cognitive ability, and capacity to perform
activities of daily living. Compared with younger
patients, the elderly are more likely to experience
atypical, enhanced, or adverse drug effects.
Individual physical and medical differences increase
as people age. As a result, multiple drug options are
necessary for safe, effective, and individualized thera-
py, especially for our fastest growing elderly popula-
tion—the oldest-old, age 86+ years. Therapeutic
options within classes of medications offer the elderly
needed choices among similar agents with somewhat
different pharmacological properties and side effect
profiles. Even choices of dosage form (tablets, cap-
sules, liquids) can benefit certain elderly patients,
such as those with stroke or Parkinson’s disease, who
may have difficulty chewing, swallowing, and meas-
uring or pouring liquids.
Controlled-release formulations, which have a long
duration of action and are taken only once or twice
Executive Summary
The Value of Incremental Pharmaceutical Innovation for Older Americans 3
4 The Value of Incremental Pharmaceutical Innovation for Older Americans
daily, offer many benefits for older patients. The
steady-state drug levels achieved by these formula-
tions reduce side effects while maintaining efficacy,
and the simplified regimen improves general compli-
ance. These advanced technology dosage forms can
allow greater independence for elderly residents in
long-term care facilities, who are often extremely frail
and predisposed to adverse drug effects.
Matching Patients’ Needs: MultipleAgents Provide PharmacologicalVariability and ChoiceOver the past decade, growing numbers of older
Americans have benefited enormously from incre-
mental improvements in medicines used to treat a
variety of chronic diseases. The advantages of these
agents, and of “pharmacodiversity” within therapeutic
categories, are illustrated by examples from the fol-
lowing important diseases and conditions.
Cardiovascular ConditionsThe many beta-blockers used to treat hypertension
and a variety of other cardiovascular conditions illus-
trate the advantages of a fully developed class of
drugs. These agents differ in potency, effects on the
nervous system, appropriateness for patients with
impaired kidney or liver function, potential for drug
interactions, efficacy in specific ethnic groups, com-
plexity of dosing, adverse effect profiles, and other
features. This array of differences enables customized
prescribing according to the patient’s specific needs.
Calcium channel blockers have rapidly gained impor-
tance in the treatment of hypertension, angina, cardiac
dysrhythmias, heart failure, cardiomyopathy, stroke,
and other cardiovascular conditions. Physicians choose
the most appropriate agent for an individual patient.
Advanced dosage forms and delivery systems for car-
diovascular agents can provide considerable thera-
peutic advantage, especially for elderly patients.
Controlled-release dosage forms often impart
improved efficacy, safety, or compliance benefits.
Although tissue plasminogen activator (t-PA) is fre-
quently a lifesaver for heart attack victims, time is of the
essence in preventing damage to the heart and t-PA
administration can require up to 90 minutes. An
improved, second-generation clot-buster called
tenecteplase was introduced in 2000, which can be
administered in a single 5-second injection.
Subsequent to its acceptance as a therapy for heart
attack, t-PA was found to be effective, and cost-effec-
tive in the treatment of stroke. A National Institute
for Neurological Diseases and Stroke study found
that hospital costs for patients treated with t-PA
increased by $1700 per patient, but rehabilitation
and nursing home costs were reduced by $6200, for
a net savings of $4500. In addition to this decline in
costs, quality of life also improved.
The low-molecular-weight heparins are smaller pieces
of the heparin molecule and are a major advance over
unfractionated heparin in the treatment and preven-
tion of blood clots in the deep veins after surgeries
common in the elderly, such as hip fracture repair or
joint replacement. These agents are as effective as
unfractionated heparin, but can be administered once
daily by subcutaneous injection without subsequent
monitoring or dose adjustment, and they cause less
bleeding and fewer complications. Hospital stays
have been reported to be 60% to 70% shorter, and
the average cost of treating a patient with deep vein
clots was reduced by up to $8000. The properties of
these agents also enable their use in nursing home
settings, with consequent cost savings due to reduced
need for hospitalization.
Arthritis and OsteoporosisNonsteroidal anti-inflammatory drugs (NSAIDs) often
provide relief from arthritis pain and inflammation in
older patients. Although the NSAIDs all have similar
effectiveness and side effect profiles, it is difficult to
predict a patient’s response to a particular agent; and
Executive Summary
tolerance and clinical response to a given NSAID vary
widely. Studies of prescribing patterns indicate that
physicians utilize the full range of available agents;
and regardless of which NSAID is used initially, a sec-
ond or third agent must often be tried before finding
one that produces an optimal effect, with an accept-
able level of side effects.
Hormone replacement therapy (HRT) is the standard
prevention for osteoporosis, which results in a decline
in bone mass at menopause. HRT is now available in
many natural and synthetic forms. In addition,
women who cannot or will not take HRT now have
other treatment avenues to prevent bone loss, often
available in user-friendly formulations. One choice is
calcitonin, a hormone that regulates calcium levels in
the blood and inhibits bone loss. Treatment with cal-
citonin became much easier with the introduction of a
nasal spray in 1996.
Urinary IncontinenceUrinary incontinence is a significant cause of disabili-
ty and dependence among the elderly. Although oxy-
butynin has been the mainstay of therapy for several
decades, its utility is limited by its significant side
effects (dry mouth, constipation, blurred vision, con-
fusion and drowsiness). A new once-daily, con-
trolled-release formulation of oxybutynin maintains
consistent release of medication over 24 hours, with
an improved side effects profile as a result.
Tolterodine, a newer agent in the same family and
having a similar mechanism of action, is as effective
as oxybutynin but has an improved side effect pro-
file. An extended release, once-daily form of toltero-
dine is now available.
Diabetes New oral agents and insulin analogs developed in the
mid-1990s have contributed substantially to our ability
to tighten control of glucose levels by targeting insulin
resistance and impaired insulin production as well as
by targeting both fasting and postprandial blood glu-
cose levels with minimal risk for hypoglycemia.
The sulfonylurea agents, which cause the release of
more insulin, are a mainstay in the management of
diabetes. These agents differ widely in potency, dura-
tion of action, range of available dosages, metabolism,
side effects, convenience, and potential for interaction
with other drugs. This variety of characteristics
enables the matching of an agent to an elderly
patient’s nutritional status and dietary habits, age,
concomitant medications, and other medical condi-
tions.
The insulin molecule has been manipulated exten-
sively to produce a range of insulin products that
vary in their time of onset and duration of action.
Intensive treatment regimens often utilize several
types of insulin, injected at different times of the day.
Premixed preparations of insulins with different onset
and duration times offer added convenience,
improved compliance, greater dosage accuracy, and
reduced risk of hypoglycemia. These mixtures are
especially useful for elderly or physically impaired
patients who have difficulty preparing an insulin
injection from two vials.
Technical improvements in insulin delivery have led
to continuous subcutaneous insulin infusion and
convenient pen-type, multiple-dose injection devices.
Pulmonary, nasal, and oral administration methods
are in various stages of development.
CancerAlthough the aromatase inhibitor drugs, which block
estrogen synthesis, have been used in breast cancer
treatment, their shortcomings (weak action, nonspe-
cific effects, substantial toxicity) have limited their
role. Recently, several new-generation aromatase
inhibitors have been developed that are far more spe-
cific and powerful than their predecessors. These
agents are now considered first-line therapy for breast
cancers in postmenopausal women.
A new, long-duration testosterone suppression thera-
py for the palliative treatment of advanced prostate
Executive Summary
The Value of Incremental Pharmaceutical Innovation for Older Americans 5
6 The Value of Incremental Pharmaceutical Innovation for Older Americans
cancer was introduced in 2000. The product is
implanted under the skin under the upper arm to
deliver continuous treatment for an entire year.
Chronic Obstructive Pulmonary Disease(COPD) Bronchodilators drugs are the mainstay of treatment
of COPD, the fourth leading cause of death in the
U.S. These agents are used in inhaled, metered-dose
formulations and differ in potency, selectivity of
action in the lung, duration of action, and side
effects. The short-acting agent albuterol is now being
manufactured in its purer, single-isomer form, which
appears to be more potent. Since it requires a lower
dose to achieve its therapeutic effect, fewer side
effects are experienced.
Policy ImplicationsThe examples above underscore the importance of
incremental pharmaceutical innovation, as well as the
need for policies ensuring patient access and choice
among alternative drug treatments. The adequacy of
drug benefit programs for the elderly and other
chronic care patients depends on the extent to which
they cover the range of drug therapies necessary for
appropriate care.
Policies that foster the availability of unique, incre-
mental pharmaceutical innovations along with break-
through drug discoveries can have important implica-
tions for treatment outcomes, patients’ quality of life,
cost containment, and ongoing research investment
in newer and more effective medicines. Such policies
increase diversity and variability within drug classes
and thereby enable differentiated, individualized
therapy. The availability of a wide range of choices is
especially important for elderly patients, who have
the greatest need for individualized care and are at
greatest risk for compromised outcomes if choices are
overly circumscribed.
Policy makers need to grapple with the short-term
risks and benefits associated with current drug bene-
fit reform proposals, intellectual property protection,
and related issues. These policy decisions can have
long-term consequences for the availability of both
breakthrough and incremental pharmaceutical inno-
vations.
Executive Summary
Understanding PharmaceuticalInnovation
According to a recent Johns Hopkins
University study, 125 million Americans suf-
fered from chronic illnesses in 2000 (20 mil-
lion more than had been forecast by a landmark
1996 study). This figure is expected to reach 157
million in 2020, at which time 25 percent of all
Americans will be living with multiple chronic condi-
tions.1
The increasing prevalence of chronic illnesses and
conditions, particularly among older Americans,
underscores the importance of continued medical
innovation aimed at preventing, treating and hopeful-
ly curing these costly, life threatening diseases. Over
the past decade, growing numbers of patients and
families have benefited enormously from innovative
new medicines that address an ever-wider range of
acute and chronic diseases.
In 2000 almost 700 new medicines were in the
pipeline to treat diseases of aging, including treat-
ments for heart disease, cancer, stroke, Alzheimer’s
disease, diabetes, depression, arthritis, osteoporosis,
Parkinson’s disease, and others.2 The innovative track
record of U.S. research-based pharmaceutical and
biotechnology companies has made the industry a
world leader. Many observers attribute this success in
no small way to public policies that (1) support basic
research; (2) promote market incentives and rewards
for the huge, high-risk private sector investment
needed to research and develop innovative products;
and (3) ensure intellectual property protection for the
results of that investment.3
However, the current policy debate over drug benefit
reform and improved access to needed medicines for
seniors has generated considerable confusion.
Misleading claims have been made about the nature
and value of incremental pharmaceutical innovation.
Some critics, for example, have suggested that since a
majority of the new drug applications approved by the
FDA do not represent “breakthrough” innovations, the
value of these drugs is questionable or minimal at
best.4
Incrementally innovative medicines have a molecular
structure or method of action similar to that of the
first drug approved in a therapeutic class. Another
type of incremental innovation occurs when the FDA
approves a previously introduced compound for a
new use. Common misperceptions about pharmaceu-
tical innovation are well illustrated by the following
viewpoint quoted in the Financial Times of London:
The debate about pharmaceutical pric-
ing and innovation should focus on
how many companies provide real
breakthrough benefit for consumers.
The answer is: depressingly few. The
vast majority of drugs are simply bet-
ter or worse me-too copies of products
that went before them.5
In fact, as will be illustrated in subsequent sections of
this paper, incremental pharmaceutical improve-
ments provide important benefits:
■ Fewer side effects
■ Improved drug safety and effectiveness
■ Greater ease of use, which facilitates com-
pliance with prescribed therapeutic regi-
mens
■ Product alternatives that permit treat-
ments to be better tailored to individual
patient needs
Understanding the nature of technological innovation
in general and the value of incremental pharmaceuti-
cal improvements in particular (especially for the eld-
erly), is not an academic question. Public policies
can have a critical influence in either encouraging or
discouraging pharmaceutical innovation. For that
reason, it is essential that policy makers and the pub-
lic appreciate the importance of both incremental
pharmaceutical improvements and breakthrough
innovations for individual and public health.
The Value of Incremental Pharmaceutical Innovation for Older Americans 7
8 The Value of Incremental Pharmaceutical Innovation for Older Americans
Incremental Improvement is theBasic Mechanism of TechnologicalInnovationThe process of continuous incremental improvement
is the predominant mechanism of technological inno-
vation and product development in most manufac-
turing and high-technology industries.6 Small incre-
mental steps rather than sudden large jumps in tech-
nology through breakthrough discoveries usually
underlie progress. Over time, a succession of small
wins adds up to a big advance. According to experts
on the innovation process:
The cumulative effect of numerous
minor incremental innovations can
sometimes be more transforming and
have more economic impact than a
few radical innovations or ‘technologi-
cal breakthroughs.7
In the last 20 years the number of bits
on a [computer] chip has gone from
one to one million. Incremental
improvement has also given us better
resolution screens and quieter, better
quality printers, . . . jet engines with
double the thrust per unit weight of
two decades ago, plastics that can be
used at temperatures twice as high as
a decade ago, and incandescent light
bulbs that are 15 times as efficient as
Edison’s; in short, an array of prod-
ucts across the entire spectrum of
modern industry that are much better,
and often less costly, than those of an
earlier era.8
Most competition within an industry is
between variants of the same product
type, for example, automobile vs.
automobile, not automobile vs. truck,
and “where the United States has not
been competitive, we have lost, usually
not to radical new technology, but to
better refinements. . . . 9
It is by no means certain that the
increase in productivity over a longer
period of time is chiefly due to the
great inventors and their inventions. It
may well be true that the sum total of
all minor improvements, each too
small to be called an invention, has
contributed to the increase in produc-
tivity more than the great inventions
have.10
The value of incremental innovation in medical tech-
nology is illustrated by the case of computerized
tomography (CT) scanning technology. A detailed
economic analysis of the diffusion and use of succes-
sively improved CT scanners in U.S. medical facilities
estimated a social rate of return of about 270%.11
These gains accruing to consumers from successive
innovations in scanning technology greatly exceed
the amount paid for services.
Though the spotlight typically focuses on break-
through drugs, incremental innovation also has been
an important source of progress in the pharmaceuti-
cal industry. The vast majority of clinically important
drugs developed over the last 50 years have resulted
from an evolutionary process, involving multiple,
small, successive improvements within a pharmaco-
logical class.
Incremental Advances andPharmaceutical InnovationGreat strides in pharmacology and therapeutics have
resulted from small variations in the chemistry of
active molecules and the discovery of new indications
for previously introduced compounds.12 In fact, the
history of pharmacology is characterized by incre-
mental improvements in the safety, efficacy, selectivi-
ty, and utility of drugs within a given therapeutic
class. As a result, many pharmacological classes now
contain numerous agents. Although these agents are
molecularly similar, their therapeutic properties are
often substantially different. The benefits are striking
because a broad class of drugs enables physicians to
The Value of Incremental Pharmaceutical Innovation for Older Americans 9
treat with greater precision the individual needs of
diverse patients. The importance of gradual improve-
ments is often underestimated.
Incremental advances* have generally resulted either
from molecular modification of existing products or
from independent attempts by drug companies to
develop agents with a given pharmacological action.
Incremental innovations are often the unintentional
result of simultaneous research by several companies
on breakthrough products based on a new mecha-
nism of action; only one can be first to market and
the others become follow-on products.
Casual dismissal of new agents in a class as merely
me-too drugs assumes that these agents are essentially
identical. This is a misconception. The process of
incremental innovation is evolutionary, not duplica-
tive. The new agents resulting from this process can
offer advantages in terms of improved efficacy, better
patient satisfaction and compliance, and in some cases
greater cost-effectiveness.
To best treat individual patients, a wide range of
choices is required that includes both new and older
agents. One important reason for having multiple
drugs within the same pharmacologic class is that
patients who fail to respond to one drug will often
respond to another agent of that class.13
Since incremental innovations in a therapeutic class
must compete with their predecessors for market
share, they often are priced at a discount. The result
is less expensive alternatives long before generic
copies enter the market when the patent on the first-
in-class drug expires. For example, when follow-on
SSRI antidepressant medications and cholesterol-low-
ering statins were introduced in the mid-1990s, they
cost only about half as much as the pioneer products
in these classes did when they were first introduced
in the late 1980s.
A study by the Tufts Center for the Study of Drug
Development has shown that new drugs in a class are
often priced lower than existing agents within that
class14 (Figure 1). This study examined the pricing of
new entrants to drug classes and subclasses in eight
therapeutic categories, five of which represent com-
mon ailments of the elderly. The majority of new
drugs were launched at discounts relative to both the
class price leader and the average price in the class.
Six of the 20 drugs examined were priced at dis-
counts of 30% or more, and 13 were discounted by
at least 5%. Five of the drugs were introduced essen-
tially at parity with existing prices. Only two drugs
entered the market at a premium, but they were still
discounted relative to the price leader.15
Evolution of Drug TherapiesThe development of drug product classes is analo-
gous to the evolution of biological species.
Breakthrough therapies are analogous to new species,
and these are eventually replaced by improved relat-
ed compounds that have “evolved” to become more
effective, more selective and better tolerated. Most of
the top 10 prescription drugs sold in the United
States in 1999 represent incremental improvements.16
The advantages of diversity within groups of pharma-
ceutical products are similar to the advantages of bio-
diversity. “Pharmacodiversity” ensures the stability
and viability of the drug group. Competition exists
for survival in a changing environment, and lack of
diversity could doom a species or lineage to extinc-
tion. Within a drug class, products with varying fea-
tures compete for patients. Over time, the emergence
of new disease targets and refined patient subgroups
* Major innovations are generally defined here as the first agents with a particular clinical action (e.g., antihypertensives) orpharmacological action (e.g., beta-blockers) or the first with the same clinical effect as existing agents but with a differentmechanism of pharmacological action (e.g., diuretics vs. beta-blockers). Incremental innovations are subsequent (follow-on)modifications in molecular structure or dosage formulation having a similar, but not identical, pharmacological action (e.g.,beta-1 selective beta-blockers vs. nonselective beta-blockers) or a different absorption, metabolism, or excretion profile (e.g.,sustained action), as well as new clinical uses or indications for existing agents.
10 The Value of Incremental Pharmaceutical Innovation for Older Americans
expands the role of some agents, while other agents
are disadvantaged by newly discovered adverse
effects. Thus, those products that are best fit for their
environment dominate the marketplace; others may
become extinct; and still others maintain positions in
niche markets.
In addition, new uses for medicines can be discovered
as a result of extensive clinical experience, often many
years after introduction of the drug into medical prac-
tice. For example, the beta-blockers, which were ini-
tially used mainly to treat hypertension and other car-
diovascular conditions, now also play a valuable role
in treating glaucoma and promoting survival after
heart attacks. These new uses became apparent from
clinical observations made after the introduction of
the initial three beta-blockers, as well as from the
development of newer beta-blockers.17
In the period from 1996 to 1999, the FDA approved
an average of more than 100 new indications annual-
ly for existing drugs.18 Table 1 provides examples of
these important new applications, many of which
involve diseases of the elderly.
Incremental Improvements andIndividualized Treatment of theElderlyThe availability of multiple, similar agents in a drug
class is of particular value to the elderly. Elderly indi-
viduals are a diverse population requiring pharma-
ceutical care that is individually tailored to each
patient. Variation in response to medications is com-
mon among the elderly, resulting in part from wide
differences in numbers and patterns of coexisting
conditions, organ function, frailty, cognitive ability,
and capacity to perform activities of daily living.
Compared with younger patients, the elderly are
more likely to experience atypical, enhanced, or
adverse drug effects.19
Figure 1. New Drugs in Existing Classes Tend to be Priced at a Discount
+10
0
-10
-20
-30
-40
-50
-60% D
iffe
ren
ce in
Pri
ce
AC
MACB
STAC ST
SSNS
PP SN CB SSPP AR AR AR CX
AR CP CP
Price lower than average of class
Price higher than average of class
AC = ACE InhibitorAR = Angiotensin II Receptor BlockerCB = Calcium Channel BlockerCX = COX-2 InhibitorMA = Macrolide AntibioticNS = Non-sedating AntihistaminePP = Proton Pump InhibitorST = StatinSN = Serotonin Reuptake InhibitorSS = Selective Serotonin Reuptake InhibitorCP = Third-generation Cephalosporin
Adapted from DiMasi, 2000
Table 1. New Uses of Drugs for Conditions Common in the Elderly
Drug or drug class Original use Later uses
Benzodiazepines Anxiety Epilepsy, panic disorder
Naltrexone Opiate dependence Alcohol dependence
Antipsychotics Schizophrenia Dementia
Carbamazepine Epilepsy Trigeminal neuralgia
Phenytoin Epilepsy Cardiac arrhythmia
Antidepressants Depression Chronic pain; obsessive-compulsive, panic, andposttraumatic stress disorders; smoking cessation
Clonidine Hypertension Chronic pain
Calcium blockers Hypertension Arrhythmias, prevention of vascular headacheand cerebral hemorrhage
Alpha-blockers Hypertension Benign prostatic hyperplasia
Captopril Hypertension Congestive heart failure
Beta-blockers Hypertension Congestive heart failure
t-PA Heart attack Stroke
Anticoagulants Venous thrombosis, Embolism associated with atrial fibrillation pulmonary embolism
Omeprazole Acid suppression for Gastroesophageal reflux disease and eradicationpeptic ulcer healing of peptic ulcer disease associated with H. pylori
Methotrexate Cancer Psoriasis, lupus
Interferon Viral disease Multiple sclerosis, various cancers
Acyclovir Genital herpes Shingles
Hydroxychloroquine Malaria Autoimmune diseases
The Value of Incremental Pharmaceutical Innovation for Older Americans 11
12 The Value of Incremental Pharmaceutical Innovation for Older Americans
Many studies have demonstrated that age-related
physiological changes affect the outcomes of drug
therapy.20 Individual physical and medical differ-
ences increase as people age; the younger-old are the
most homogenous, while the physiological integrity
of the oldest-old varies considerably.21 With so much
variation, multiple drug options are necessary for
safe, effective, and individualized therapy, especially
for our fastest growing elderly population—the old-
est-old, age 86+ years. Therapeutic options within
classes of medications offer the elderly needed choices
among similar agents with somewhat different phar-
macological properties and side effect profiles. Even
choices of dosage form (tablets, capsules, liquids) can
benefit certain elderly patients, such as those with
stroke or Parkinson’s disease, who may have difficul-
ty chewing, swallowing, and measuring or pouring
liquids.22
Table 2 lists some recent advances in drug therapy
resulting from molecular modification of existing
drugs and new dosage forms for diseases common in
the elderly.
The choice of dosage form can be particularly impor-
tant for older individuals. Elderly persons residing in
long-term care facilities, who are often extremely frail
and predisposed to adverse drug effects, may benefit
from dosage forms that use advanced technology.23
Controlled-release formulations, for example, confer
great advantage because they have a long duration of
action and are taken only once or twice daily. The sim-
plified regimen saves nursing time, improves general
compliance, and allows greater independence.24 In addi-
tion, the steady-state drug levels achieved by these for-
mulations reduce side effects while maintaining efficacy.
The constant drug levels provided by controlled-
release dosage forms is of particular importance for
long-term care residents with Parkinson’s disease.25
Continuous release of levodopa is essential for opti-
mal symptom control, and this goal is best attained
through the use of a controlled-release formulation.26
Additional advantages include fewer unpredictable
lapses in efficacy, avoidance of the need for progres-
sively shorter dosing intervals to maintain efficacy,
reduced risk of orthostatic hypotension, and
improved ability to engage in activities of daily living
and social interaction.27 Thus, the use of a controlled-
release product is believed to represent “a major step
in treating Parkinson’s disease in the frail elderly.”28
Multiple agents provide pharmacological variability
and choice in treating major diseases of the elderly.
The benefits of pharmacodiversity are amply illus-
trated by examples from the following important dis-
eases and conditions: cardiovascular disease, stroke
and other clotting disorders, arthritis, osteoporosis,
urinary incontinence, diabetes, cancer, and chronic
obstructive pulmonary disease.
Cardiovascular ConditionsCardiovascular disease is extremely common in older
individuals and represents the leading cause of death
in this population.29 One type of cardiovascular dis-
ease, hypertension, is the second most common med-
ical condition in older adults, with a prevalence of
74% among persons 75 years or older.30
Hypertension is a major risk factor for cardiovascular
diseases associated with high mortality rates. For
example, hypertension is present in 75% of persons
with congestive heart failure and in 79% of those
who have had a stroke.31
The many beta-blockers developed by pharmaceuti-
cal companies to treat hypertension and a variety of
other cardiovascular conditions illustrate the advan-
tages of a fully developed class of drugs. These agents
differ in potency, effects on the nervous system,
pharmacokinetic properties (which determine appro-
priateness for patients with impaired kidney or liver
function), potential for interaction with other drugs,
efficacy in specific racial groups, complexity of the
dosage regimen, adverse effect profiles, and other fea-
tures. This array of differences enables customized
prescribing according to the patient’s specific needs.
Another advantage is that undesirable side effects in
an individual patient can be avoided by switching to
another agent in the class.
Table 2. Recent Incremental Improvements for Diseases of the Elderly*
Condition Drug Advantage
Alzheimer’s Disease Rivastigmine 1 Similar efficacy but different side-effect profile Galantamine 1 provides choice
Arthritis Meloxicam 1 Once-daily nonsteroidal anti- inflammatory
Asthma Fluticasone/salmeterol 2 Combination inhaler contains steroid + long-actingbronchodilator
Fluticasone 2 User-friendly formulation of inhaled corticosteroids
Blood clots Bivalirudin 1 Anticoagulant for use in angioplasty
Depression Fluoxetine 2 Once-weekly capsule improves patient compliance
Diabetes Glyburide/metformin 2 Two-drug product combines enhanced insulin production with enhanced insulin effect
Metformin 2 Once-daily tablet improves compliance
Glaucoma Unoprostone 1 Ophthalmic prostaglandin for second-line therapy
Levobetaxolol 2 Single-isomer beta-blocker with improved efficacy
Heartburn Esomeprazole 1 Single-isomer proton pump inhibitor with improved action
Calcium/magnesium/ Combination of drugs with complementary effectsfamotidine 2
Osteoporosis Alendronate 2 Once-weekly tablet improves patient complianceNorethindrone/estradiol 2 Combination for prevention of postmenopausal
osteoporosis
Prostate cancer Triptorelin 1 Long-acting formulation for palliative treatment
Leuprolide 2 Implantable dosage form
*Approved by FDA in 2000 and early 2001.
1 New molecular entity, not first in class; 2 New dosage form of existing molecular entity.
The Value of Incremental Pharmaceutical Innovation for Older Americans 13
14 The Value of Incremental Pharmaceutical Innovation for Older Americans
Several generations of beta-blockers have appeared
over the last few decades. Compared with the first-
generation agents, second-generation beta-blockers
are less likely to produce constriction of blood vessels
throughout the body. Thus, they may benefit patients
with mild to moderate heart failure when used in
combination with angiotensin-converting enzyme
(ACE) inhibitors. Third-generation beta-blockers may
have even better myocardial protective properties.
The third-generation beta-blocker carvedilol has a
wide spectrum of pharmacological effects and has
recently been found effective in patients with severe
heart failure. Although carvedilol slows heart rate, it
improves left ventricular function, allowing the heart
to pump more blood. Carvedilol had previously been
found effective in patients with mild to moderate
heart failure, but it was considered ineffective in
more severe cases because it decreases heart rate and
contractility. However, patients with severe heart fail-
ure who were treated with carvedilol, along with
other therapy for this condition (diuretics, ACE
inhibitors, digitalis), had a 35% lower mortality risk
compared with patients treated with conventional
therapy only.32 This should be of great importance
since an estimated 750,000 to 1 million mostly older
Americans suffer from severe heart failure, which is
the single most frequent reason for hospitalization
among older adults.33 The drug could save an esti-
mated 50,000 lives a year among these patients.
Calcium channel blockers, which block the influx of
calcium into muscle cells, have rapidly gained impor-
tance in the treatment of hypertension, angina, car-
diac dysrhythmias, heart failure, cardiomyopathy,
stroke, and other cardiovascular conditions. However,
since the relative strength of their effects varies among
the calcium blocker agents, specific agents can be dif-
ferentially effective in a given condition. Physicians
can choose the most appropriate agent for an individ-
ual patient.
More than a dozen calcium channel blockers with a
wide range of chemical structures are now available
in the United States. Agents in the largest group, the
dihydropyridines, have different sites and modes of
action on calcium entry into smooth and cardiac
muscle cells. Second-generation dihydropyridines
have more selective actions than first-generation
agents. For example, nicardipine targets vascular
muscle rather than cardiac muscle, which results in
greater dilation of heart and peripheral blood ves-
sels but less depression of the heart’s ability to con-
tract. This difference may be of particular advantage
for hypertensive patients who also have congestive
heart failure.34 Second-generation agents with no
depressant effect on the heart also may provide car-
dioprotection that is not demonstrable with the
first-generation drugs.35 Some second-generation
agents have a slow onset of action and a long half-
life, allowing for once-daily administration.36
Various calcium channel blockers also differ in
their ability to enter the brain and in their effective-
ness in dilating blood vessels of the brain. Those
that enter the brain dilate cerebral blood vessels
and protect against brain ischemia. They improve
survival and neurological outcome after acute
ischemic stroke and are also useful in treating com-
plications of brain hemorrhage.37
Advanced dosage forms and delivery systems for
existing cardiovascular agents can provide consider-
able therapeutic advantage, especially for elderly
patients with cardiovascular disease. Controlled-
release dosage forms often impart improved efficacy,
safety, or compliance benefits. In the management of
hypertension, once-daily dosing that provides 24-
hour coverage protects against the risk of sudden
death, heart attack, and stroke caused by the abrupt
rise in blood pressure after one arises from overnight
sleep.38
Heart Attack, Stroke, and Other ClottingDisordersHeart attack treatment was revolutionized in 1987
with the introduction of tissue plasminogen activator
(t-PA), a naturally occurring protein manufactured
using the techniques of recombinant biotechnology.
t-PA works by stimulating the body’s own clot-dis-
solving mechanism. Although t-PA is frequently a
lifesaver, time is of the essence in preventing damage
to the heart and t-PA administration can require up
to 90 minutes. An improved, second-generation clot-
buster called tenecteplase was introduced in 2000,
which can be administered in a single 5-second injec-
tion. This incremental innovation represents alter-
ation in only six amino acids at four sites in the t-PA
molecule.
In addition to its original use in heart attacks, t-PA is
now also used in stroke patients to dissolve blood
clots in the brain, restore blood flow, and thereby
limit permanent brain damage. Approved in 1996 for
stroke, t-PA therapy now represents an important
advance in the treatment of stroke, which is the lead-
ing cause of disability in seniors and the third leading
case of death.
Treatment of stroke with t-PA is cost effective. A
study by the National Institute for Neurological
Diseases and Stroke found that hospital length of stay
was shorter for patients treated with t-PA and that
more treated than untreated patients were discharged
to home rather than to institutional care. Hospital
costs for treated patients increased by $1700 per
patient, but rehabilitation and nursing home costs
were reduced by $6200, for a net savings of $4500.
In addition to this decline in costs, quality of life also
improved.39
Another type of clotting disorder, deep venous
thrombosis (DVT), is associated with more than
600,000 hospitalizations annually in the United
States and results in more than 200,000 deaths
caused by pulmonary embolism.40 Pulmonary
embolism is the second most common cause of unex-
pected death in the United States and is a major
killer among hospitalized patients. The immediate
result of a blood clot that lodges in the pulmonary
artery is partial or complete obstruction of blood flow
to the lung. Certain kinds of surgery common in the
elderly, such as hip fracture repair or joint replace-
ment, are particularly likely to cause clots.
Patients with acute DVT have traditionally been hos-
pitalized and treated with a continuous infusion of
heparin for 5 to 10 days, followed by oral anticoagu-
lation therapy on an outpatient basis. But the wide
variability in anticoagulant response among patients
treated with heparin requires frequent monitoring
and dosage adjustments to keep anticoagulation in
the therapeutic range.
The low-molecular-weight (LMW) heparins, intro-
duced in the 1990s, are smaller pieces of the heparin
molecule and represent a major therapeutic and eco-
nomic advance over unfractionated heparin in the
treatment and prevention of coagulation disorders.
They can be administered once daily by subcuta-
neous injection without subsequent monitoring or
dose adjustment. A major use of the LMW heparins
is for treatment and prevention of DVT after surgery.
Compared with unfractionated heparin, LMW
heparins have greater bioavailability, and their use is
associated with little interpatient and intrapatient
variability.41 However, the different LMW heparins
each have different relative effects on clotting factors.
For this reason, LMW heparins are unique and not
necessarily therapeutically interchangeable, although
their general pharmacological and clinical characteris-
tics are similar.42
The LMW heparins are at least as safe and effective as
unfractionated heparin in the treatment of DVT and
are associated with less bleeding and fewer episodes
of heparin-induced thrombocytopenia.43 Their longer
half-life and more predictable anticoagulant effects
enable subcutaneous administration without labora-
tory monitoring. Thus, the use of LMW heparins can
shift the management of DVT to the ambulatory set-
ting. This shift allows substantial cost savings by pre-
venting or shortening hospitalization and increases
patient comfort and satisfaction with health care.44
Treatment of DVT with LMW heparin was found to
be more cost-effective than therapy with unfraction-
ated heparin because the hospital stay was 60% to
70% shorter without an increase in the cost of home
The Value of Incremental Pharmaceutical Innovation for Older Americans 15
16 The Value of Incremental Pharmaceutical Innovation for Older Americans
health care.45 Furthermore, social functioning and
physical activity were better in the group receiving
LMW heparin.46
Economic appraisals of DVT therapy with LMW
heparins compared with unfractionated heparin have
shown a 20% reduction in disease management costs
attributable to decreased length of hospital stay and
an average cost savings of over $900 per patient.47
Elimination of even a single hospital day by use of
LMW heparin would likely yield a savings, based on
a drug cost of less than $200 per day. The average
cost of treating a patient with uncomplicated DVT
was reduced by $5000 to $8000 when LMW heparin
was used instead of unfractionated heparin therapy.48
The properties of these agents also enable their use in
nursing home settings, with consequent cost savings
due to reduced need for hospitalization.49
ArthritisArthritis affects over 49% of older Americans and is
the leading cause of disability among persons aged
65 years or older.50 Nonsteroidal anti-inflammatory
drugs (NSAIDs) often provide relief from arthritis
pain and inflammation. Although the NSAIDs all
have similar effectiveness and side effect profiles, they
differ in their effects on individual patients. It is diffi-
cult to predict a patient’s response to a particular
agent, and tolerance and clinical response to a given
NSAID vary widely among patients. Studies of pre-
scribing patterns indicate that physicians utilize the
full range of available agents; and regardless of which
NSAID is used initially, a second or third agent must
often be tried before finding one that produces an
optimal effect, with an acceptable level of side
effects.51
The main side effect of these agents is gastric distress,
and increasing evidence linking NSAID use to peptic
ulcer disease and gastrointestinal hemorrhage in the
elderly is cause for concern. Gastropathy caused by
NSAIDs is recognized as the most frequent serious
complication from a drug therapy.52
Thus, there is a great need for improved agents in
this mature class. In 1999, the vitality of the NSAID
class re-emerged with the introduction of the first
cyclooxegenase-2 (COX-2) specific inhibitors, which
appear to cause fewer gastrointestinal side effects
compared with conventional, nonselective NSAIDs.
Second-generation COX-2 agents are in development;
these may offer more rapid onset of action, pro-
longed effectiveness, and once-daily dosing.
OsteoporosisOsteoporosis leads to 1.5 million fractures per year—
mostly in the hip, spine and wrist—and costs $10
billion annually, according to the National
Osteoporosis Foundation. It threatens 25 million
Americans, mostly older women. One in three
women past age 50 will suffer a vertebral fracture,
according to the Foundation.53 Fractures are the
most common cause of hospitalizations among
women age 75 years or older.54
Hormone replacement therapy (HRT) is the standard
prevention for the decline in bone mass at
menopause. HRT is now available in many natural
and synthetic forms. In addition, several nonhor-
mone therapies have recently become available to
strengthen bone and provide alternate choices for
individualized treatment.
Estrogen is available in several pharmacologic formu-
lations. Conjugated estrogen, a mixture of natural
estrogens derived from the urine of pregnant mares,
is the most commonly prescribed estrogen therapy.
Estradiol, the most potent estrogen, is available as
tablets, skin patches, a vaginal ring, by injection, and
as a pellet inserted under the skin twice a year. A
vaginal tablet has been developed for estropipate,
which is a version of estrone (a weaker form of estro-
gen). Very small (nickel-sized), water-resistant patch-
es are also available.55
To avoid the risk of endometrial cancer, estrogen is
generally prescribed along with a progestin or prog-
esterone; this is known as combined hormone
replacement therapy. Progestins include medrox-
yprogesterone, norethindrone acetate synthesized
from male hormones, and norgestrel. Oral dosage
forms that combine both estrogen and progestins are
available. Progestins may sometimes be prescribed
alone for hot flashes and other acute menopausal
symptoms. When combined with estrogen, a recently
introduced natural form of finely ground
(micronized) progesterone derived from wild yams
can protect against heart disease. Natural proges-
terone has fewer side effects than progestins, but a
shorter duration of action; and increasing the dose
can cause drowsiness. A natural progesterone cream,
which is administered vaginally, may prove to be
effective in combination with an estradiol patch. It
blocks the processes that can lead to uterine cancer
and has few side effects.56
Women who cannot or will not take HRT have other
treatment options to prevent bone loss, often avail-
able in user-friendly formulations. One choice is cal-
citonin, a hormone that regulates calcium levels in
the blood and inhibits bone loss. Treatment with cal-
citonin became much easier with the introduction of
a nasal spray in 1996. This drug is a potent, synthetic
version of calcitonin and has been shown to slow and
reverse bone loss. Before the nasal spray was avail-
able, calcitonin had to be injected every day or two,
because the drug is quickly destroyed in the
stomach.57
The bisphosphonates represent a second nonhormon-
al treatment for osteoporosis. These agents can
increase bone mass as much as 8 percent and reduce
fractures as much as 30 to 40 percent. But taking
these medications properly can be a challenge.
Because the bisphosphonates irritate and can damage
the esophagus, they must be taken upon awaking
and at least a half hour before eating, with a full glass
of water; and the person should remain upright for a
half hour after taking it.58 The recent introduction of
once-weekly formulations should greatly facilitate
compliance with these medications.
Urinary IncontinenceThe inability to control urination affects 17 million
Americans,59 more than the number of people with
Alzheimer’s disease and osteoporosis combined.60 It
is a significant cause of disability and dependence
among the elderly. Urinary incontinence is often the
primary cause of institutionalization of the elderly
due to the burden of care.61 Between 15% and 30%
of elderly suffer some form of incontinence62; in the
frail elderly the rate may be over 50%.63 Managing
urinary incontinence cost American society about
$26 billion in 1995.64
Oxybutynin, which acts through blockade of mus-
carinic acetylcholine receptors in the bladder, has
been the mainstay of therapy for several decades. Its
utility is limited, however, by its significant side
effects, including dry mouth (the most common side
effect), constipation, blurred vision, and confusion
and drowsiness, especially in the elderly. These side
effects, which appear in more than 50% of patients,
lead to frequent termination of therapy; in one study
only 18% of patients remained on therapy after one
year.65
A once-daily, controlled-release formulation of oxy-
butynin, introduced in 1999, represents a substantial
improvement over immediate-release oxybutynin,
because it is equally effective but has an improved
side effect profile.66 This dose delivery system main-
tains consistent release of medication over 24 hours,
thereby averting the peaks seen with immediate-
release oxybutynin. This flat concentration profile
may be responsible for the less severe dry mouth
reported with once-daily oxybutynin compared with
the immediate-release product (25% vs. 46%).67 In
addition, absorption of the once-daily product
appears to occur mostly in the large intestine, rather
than in the stomach, which limits the formation of
metabolites that may be responsible for the side
effects.68
Tolterodine, a newer agent in the same family as oxy-
butynin and having a similar mechanism of action, is
as effective as immediate-release oxybutynin but has
The Value of Incremental Pharmaceutical Innovation for Older Americans 17
18 The Value of Incremental Pharmaceutical Innovation for Older Americans
an improved side effect profile. In one study, 60% of
patients remained on tolterodine therapy for one
year.69 Despite its higher cost, long-term therapy with
tolterodine was found to be more cost-effective than
immediate-release oxybutynin because of its ability to
reduce the need for incontinence protection supplies.
The overall cost to successfully treat a patient with
tolterodine was $3937 versus $9022 with immediate-
release oxybutynin.70
An extended release, once-daily form of tolterodine is
now available. It reduces the number of incontinence
episodes and improves tolerability compared with
immediate-release tolterodine,71 and the new dosage
form is likely to improve patient compliance.
Another approach to management of urinary inconti-
nence is to introduce agents directly into the bladder.
This enables instillation of high concentrations of
drug at the target organ, thereby avoiding systemic
side effects. Instillation of capsaicin, a substance P
antagonist that desensitizes nerve pathways involved
with bladder contractions, has been effective in some
types of urinary incontinence,72 but it produces sig-
nificant irritation and burning. Resiniferatoxin, a
newly developed analog of capsaicin, has 1000-fold
increased potency and causes almost no irritation. A
single administration of this agent can significantly
increase bladder capacity and reduce frequency of
incontinence incidents.73
A new once-monthly delivery system for long-term
administration of oxybutynin or other drugs directly
into the bladder is in development. A reservoir that
can be easily inserted into the bladder is filled with
the desired drug, and a pump releases a precise
quantity of the drug into the bladder over the course
of a month.74
Diabetes Diabetes affects 18.4% of Americans aged 65 or
older.75 Type 2 (non—insulin-dependent) diabetes is
the most common form. It affects older Americans
most often because of increased longevity, obesity,
and lack of exercise. Uncontrolled diabetes frequently
causes heart disease, severe kidney and nerve dam-
age, blindness, and the need for amputations.
Increasing recognition that tight control of blood glu-
cose significantly reduces the vascular complications
of diabetes76 has led to more aggressive treatment of
patients. New oral agents and insulin analogs devel-
oped in the mid-1990s have contributed substantially
to our ability to tighten control of glucose levels by
targeting insulin resistance and insulin secretory
defects as well as by targeting both fasting and post-
prandial blood glucose levels with minimal risk for
hypoglycemia. These new agents now provide the
options necessary for achieving tight control and also
allow individualized treatment.
The sulfonylurea agents, which stimulate the beta cells
of the pancreas to release more insulin, are a mainstay
in the management of diabetes. These agents differ
widely in potency, duration of action, range of avail-
able dosages, metabolism, side effects, convenience,
and potential for interaction with other drugs. This
variety of characteristics enables the matching of an
agent to an elderly patient’s nutritional status and
dietary habits, age, concomitant medications, and
other medical conditions.77 For example, potent,
long-acting sulfonylurea agents should not be pre-
scribed for elderly patients with poor or irregular
dietary habits; and elderly patients with severe renal
insufficiency should not be treated with those sulfony-
lurea agents that may accumulate in the body.
The availability of alternate sulfonylurea agents can
be beneficial in cases where the effectiveness of a
given sulfonylurea has decreased over time.
Switching to another sulfonylurea can help these
patients regain control of blood glucose and may
avoid the need for insulin therapy.78
Many people with diabetes are challenged with the
requirement of managing doses of multiple drugs sev-
eral times a day. Some of the sulfonylurea agents are
effective in single daily doses and may be associated
with improved medication compliance. Similarly, a
sustained-release, once-daily formulation of met-
formin, an agent that enhances the effect of insulin, is
available. A combination product containing met-
formin and a sulfonylurea agent reduces the number
of pills and may facilitate patient compliance.
The insulin molecule has been manipulated exten-
sively to produce a range of insulin products that
vary in their time of onset and duration of action.
Intensive treatment regimens often utilize several
types of insulin, injected at different times of the day.
Onset times range from 15 minutes to 4 hours; peak
effect times range from 1 to 24 hours.79 Premixed
preparations of insulins with different onset and
duration times offer added convenience, improved
compliance, greater dosage accuracy, and reduced
risk of hypoglycemia. These mixtures are especially
useful for elderly or physically impaired patients who
have difficulty preparing an insulin injection from
two vials.
The development of this array of insulin products
began with the advent of longer-acting insulins.
Human insulin, prepared by recombinant DNA tech-
nology, became commercially available by 1980 and
has made immunological responses to impurities
rare. In the 1990s, rapid-acting, short-duration
insulin analogs became available. Technical improve-
ments in insulin delivery have led to continuous sub-
cutaneous insulin infusion and convenient pen-type,
multiple-dose injection devices. Pulmonary, nasal,
and oral administration methods are in various stages
of development.
The upcoming insulin nasal sprays will be a plus for
individuals who are squeamish about injections, and
they will reduce infections and injection site prob-
lems, including accidental needle sticks. They will
negate the need for needles and syringes, which add
costs and create disposal concerns.
Despite the many choices and combinations of avail-
able therapy, most patients with diabetes still do not
achieve sustained normal blood sugar levels and are
prone to hypoglycemia and other serious conditions.
Multiple daily doses of insulin, however finely tuned,
do not mimic normal insulin physiology; and current
oral therapies are not suited for some groups of
patients. Thus, despite the large number of available
medications, more agents in these drug classes are
needed. For example, synthetic insulin analogs with
a greater affinity for the liver may provide better
metabolic control. Such agents are in development.80
CancerEighty-five percent of cancers occur in persons over
the age of 50. Clinical advantages of new dosage
forms and therapies for cancers common in the elder-
ly are described below. In addition to these specific
innovations, a major general shift from intravenous to
newer forms of oral chemotherapy is beginning to
occur. This is likely to be associated with substantial
cost savings consequent to reduced need for hospital
services and other costs associated with intravenous
treatment. For example, hospital time was reduced by
two-thirds and costly medication side effects more
than halved when colorectal cancer patients were
treated with the oral agent capecitabine compared
with intravenous therapy.81
Breast cancer is the most common cause of cancer
death in women over 65 years of age.82 Agents that
block estrogen receptors or reduce estrogen synthesis
have been used as palliative treatments for breast can-
cer in postmenopausal women. Since the late 1970s,
tamoxifen has been the standard first-line treatment
because it was shown to be as effective as other treat-
ments used at the time but caused fewer side effects.83
Additional innovation is needed for breast cancer
therapy, however, because resistance develops to
tamoxifen, and disease recurrence or progression dur-
ing tamoxifen therapy is common. Despite being well
tolerated, tamoxifen is associated with an increased
risk of endometrial cancer with long-term use.84
The aromatase inhibitor drugs, which block estrogen
synthesis, have been used in breast cancer treatment
since the early 1980s. However, these drugs also
have shortcomings: they have either weak action or
The Value of Incremental Pharmaceutical Innovation for Older Americans 19
20 The Value of Incremental Pharmaceutical Innovation for Older Americans
nonspecific effects and are frequently associated with
substantial toxicity.85 Recently, several new-genera-
tion aromatase inhibitors have been developed that
are far more specific and more powerful in their
mechanism of action than their predecessors.
Two new-generation aromatase inhibitors, letrozole
and anastrozole, rival tamoxifen in their clinical ben-
efit and toxicity profile in postmenopausal patients
with breast cancer.86 They appear to have a particu-
larly low incidence of gastrointestinal side effects and
may cause fewer blood clots and vaginal bleeding
episodes than tamoxifen.87 These agents have now
been approved by the FDA as first-line therapy for
breast cancers in postmenopausal women.
Evidence is emerging for an important new use in
breast cancer for raloxifene, a drug used for prevention
and treatment of osteoporosis, another condition com-
mon in elderly women. A large-scale, multicenter study
found that raloxifene reduced the risk of invasive breast
cancer by 72% in postmenopausal women who took
this drug for 4 years.88
The incidence of brain cancer is rising, especially
among the elderly, and these tumors are a leading
cause of cancer death. Brain cancers are difficult to
manage because they often elude traditional
chemotherapy and recur rapidly after treatment.
However, new drug delivery systems now allow
chemotherapy drugs to be delivered directly to the
brain at constant rates over days, months, or even
years.
For example, a polymer matrix is used to deliver the
cancer drug carmustine directly to the brain after sur-
gery for recurrent glioblastoma. Wafers impregnated
with this potent drug are placed in the remaining
cavity after removal of the tumor. The agent diffuses
into the brain tissue over the course of about a
month, killing the remaining malignant cells while
minimizing systemic adverse reactions. The polymer
does not need to be removed since it eventually
degrades.89
Prostate cancer affects approximately one in eight,
mostly older, American men and is the second lead-
ing cause of cancer death for men in the United
States. Testosterone suppression therapy is an impor-
tant long-term palliative treatment for the advanced
stages of this disease. A new, long-duration testos-
terone suppression therapy for the palliative treat-
ment of advanced prostate cancer was introduced in
2000. The product is implanted under the skin
under the upper arm to deliver continuous treatment
for an entire year. Previous testosterone suppression
treatments involved intramuscular depot injections
that must be repeated every few months.
Chronic Obstructive Pulmonary Disease(COPD) COPD includes emphysema and chronic bronchitis—
diseases that are characterized by obstruction of air-
flow. Approximately 16.4 million Americans suffer
from COPD, which is the fourth leading cause of
death, claiming 100,360 American lives in 1996. The
annual cost is about $32 billion, including health
care expenditures of $21 billion and indirect costs of
$11 billion.90 The prevalence of COPD among older
adults is 17%. COPD is the second most frequent
cause of hospitalization in women between 65 and
74 years of age.91
Pharmacological treatment of COPD should be indi-
vidualized to maximize benefit and minimize side
effects of the medications.92 Bronchodilators agents,
including anticholinergics such as ipatroprium and
beta-agonists, which dilate the airways, are the main-
stay of treatment. These drugs are used in inhaled,
metered-dose formulations and differ in potency,
selectivity of action in the lung, duration of action,
and side effects. Anticholinergic and beta-agonist
agents can be combined effectively in COPD
patients93 and combination products containing an
agent from both classes are available.
The shorter-acting agents (e.g., albuterol) are often
used for exercise-induced bronchoconstriction and
acute flare-ups. Salmeterol or formoterol are often
used for long-acting treatment. Formoterol acts
immediately, whereas the onset of salmeterol’s effect
is delayed. Long-acting formulations may be useful
when administered at bedtime to patients who report
nocturnal symptoms.94 An anticholinergic agent with
extended action of up to 36 hours is in development.
Albuterol is now being manufactured in its purer,
single-isomer form: levalbuterol. This agent contains
only the isomer responsible for the bronchodilating
effect of albuterol. The discarded isomer has no ther-
apeutic effect, interferes with the overall efficacy of
the drug, and may cause detrimental airway hyperac-
tivity. Levalbuterol appears to be more potent than
albuterol and requires a lower dose to achieve its
therapeutic effect. Consequently, fewer beta-agonist
side effects are experienced, which is especially
important for elderly patients with cardiovascular,
thyroid, and other conditions that are aggravated by
beta-agonist actions.95
Policy ImplicationsThe examples above underscore the importance of
pharmaceutical innovation, as well as ensuring
patient access and choice among alternative drug
treatments. The adequacy of drug benefit programs
for the elderly and other chronic care patients
depends on the extent to which they cover the range
of drug therapies necessary for appropriate care.
Policies that foster the availability of unique, incre-
mental pharmaceutical innovations along with break-
through drug discoveries can have important implica-
tions for treatment outcomes and patients’ quality of
life, as well as ongoing research investment in new,
more effective medicines.
Such policies increase diversity and variability within
drug classes and thereby enable differentiated, indi-
vidualized therapy. The availability of a wide range of
choices is especially important for elderly patients,
who have the greatest need for individualized care
and are at greatest risk for compromised outcomes if
choices are overly circumscribed.
Incremental innovation within existing drug classes is
a major source of differentiated therapy. This source
will soon be complemented by important selective
therapies based on our rapidly growing understand-
ing of the molecular and genetic basis of disease.
Dozens of biotechnology firms are now conducting
R&D focused primarily on applying new scientific
knowledge and technology to diagnosing and treating
major diseases of the elderly, and their products will
further broaden the range of therapeutic options.96
The convergence of these two sources of individual-
ized treatment may result in unanticipated synergies
and major advances in preventing, treating, and per-
haps even curing many of the costly, life-threatening,
disabling chronic diseases and conditions that afflict
older Americans.
Policy makers need to grapple with the short-term
risks and benefits associated with current drug bene-
fit reform proposals, intellectual property protection,
and related issues. These policy decisions can have
long-term consequences for the availability of both
breakthrough and incremental pharmaceutical inno-
vations. This paper has focused on a major risk that
is generally not considered — the potential inhibition
of a substantial, underappreciated, but ultimately
vital component of advances in pharmaceutical tech-
nology — incremental innovation.
The Value of Incremental Pharmaceutical Innovation for Older Americans 21
..
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www.temple.edu/tuhs