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The Value of Incremental Pharmaceutical Innovation for Older Americans by Albert Wertheimer, PhD, MBA Director, Center for Pharmaceutical Health Services Research, Temple University School of Pharmacy Thomas W. O’Connor, Jr., PharmD, MBA Director, Continuing Professional Education, Temple University School of Pharmacy Richard Levy, PhD Vice President, Scientific Affairs, National Pharmaceutical Council © 2001 Temple University
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The Value of Incremental Pharmaceutical Innovation for Older Americans

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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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Page 1: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

Page 2: The Value of Incremental Pharmaceutical Innovation for Older Americans

..

Page 3: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

Page 4: The Value of Incremental Pharmaceutical Innovation for Older Americans

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.

Page 5: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

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..

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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

Page 8: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

Page 9: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

Page 10: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

Page 11: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

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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

Page 13: The Value of Incremental Pharmaceutical Innovation for Older Americans

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.

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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

Page 15: The Value of Incremental Pharmaceutical Innovation for Older Americans

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

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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.

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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

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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.

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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

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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

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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

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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

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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

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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

Page 25: The Value of Incremental Pharmaceutical Innovation for Older Americans

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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..

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Temple UniversityCenter for Pharmaceutical Health Services Research

Philadelphia, PA 19140( 2 1 5 ) 707 – 7 787

www.temple.edu/tuhs