ABOUT THE AUTHOR
Benjamin Zycher is a senior fellow at Manhattan
Institute’s Center for Medical Progress and a member
of the advisory board of the quarterly journal Regulation
and the advisory councils of Consumer Alert and USA for
Innovation. During the first two years of the Reagan Administration,
Dr. Zycher was a senior staff economist at the President’s
Council of Economic Advisers. He is also a former senior
economist at the RAND Corporation, a former vice president
for research at the Milken Institute, and a former member
of the Board of Directors of the Western Economic Association
International. He holds a Ph.D. in Economics from the University
of California Los Angeles (1979) and a master’s degree
in Public Policy from the University of California Berkeley
(1974).
Dr. Zycher’s research focuses on the economic and
political effects of regulation, government spending, taxation,
and counterterrorism public expenditures. He has done considerable
work on health-care policy and the economics
of the pharmaceutical sector and on energy and environmental
policy. He is the author of “Defense Economics”
and
“OPEC” in The Concise Encyclopedia of Economics
(2008).
Joseph A. Dimasi is Director of Economic Analysis
at the Tufts Center for the Study of Drug Development, an
independent non-profit multidisciplinary research organization
affiliated with Tufts University, where he has been since
1987. Prior to joining the Tufts Center for the Study of
Drug Development, Dr. DiMasi was a member of the Department
of Economics at the College of the Holy Cross. Dr. DiMasi
received his Ph.D. in Economics from Boston College (1984)
and a B.A. in both Mathematics and Economics from the University
of Massachusetts at Boston (1975).
Dr. DiMasi has served on the editorial boards of the Drug
Information Journal, the Journal of Research in Pharmaceutical
Economics, and the Journal of Pharmaceutical Finance, Economics
& Policy. He has testified before the U.S. Congress
in hearings leading up to the FDA Modernization Act of 1997
and reauthorization of the Prescription Drug User Fee Act.
Dr. DiMasi’s research interests include the R&D
cost of new drug development, clinical success and phase
attrition rates, development and regulatory approval times,
the role that pharmacoeconomic evaluations have played in
the R&D process, pricing and profitability in the pharmaceutical
industry, innovation incentives for pharmaceutical R&D,
and changes in the structure and performance of the pharmaceutical
and biotechnology industries.
Christopher-Paul Milne is currently Associate Director
of the Tufts Center for the Study of Drug Development (Tufts
CSDD) and a Visiting Fellow at the Innogen Center, University
of Edinburgh, Scotland. Formerly a practicing veterinarian
in New Jersey and Maryland, Dr. Milne later attended Johns
Hopkins University where he earned a master’s degree
in public health with a concentration in epidemiology and
health statistics. For six years, he worked as a researcher,
Manager of the Public Response Program, and Emergency Response
Coordinator for the New Jersey Department of Health. Dr.
Milne is a graduate of the Franklin Pierce Law Center (1998)
and is currently a licensed attorney.
Dr. Milne joined the Tufts Center for the Study of Drug
Development (Tufts CSDD) in 1998 as a Senior Research Fellow
in order to address legal and regulatory issues that affect
the research and development of new drugs and biologicals.
Dr. Milne has served on the Editorial Board of the Drug
Information Journal and is currently the co-Track Chair
for R&D Strategies for the Drug Information Association
2008 Annual Meeting.
I. Introduction and Central Findings
Rising health-care spending on pharmaceuticals developed
and marketed by pharmaceutical companies has drawn increased
scrutiny to industry’s role in the drug innovation
process. Critics allege that companies “free-ride”
on public investments in scientific research, without making
major scientific contributions themselves.
Specifically, a recent argument that has grown in prominence
can be summarized as follows: most of the important scientific
advances that yield new and improved medicines do not result
from private-sector research, but instead are the fruits
of research efforts financed or conducted by public agencies,
the National Institutes of Health (NIH) foremost among them.
The central focus of this study is an examination of that
argument. We apply the scholarly literature on drugs and
drug classes deemed important clinically, combined with
data on the most prescribed medicines in 2007, to construct
a list of thirty-seven important drug classes (a group of
drugs used to treat a given medical condition in similar
ways), among which thirty-two are discussed in the scientific
literature in sufficient detail to allow us to develop summary
case histories. We explore also the development histories
of three specific drugs that have figured prominently in
the public discussion of the role of the private sector
in drug development. In short, this study examines thirty-five
drugs and drug classes in the context of private-sector
contributions to the advance of pharmaceutical science.
We find that, for the discovery and/or development of all
or virtually all of the thirty-two drug classes discussed
in Section III, the scientific contributions of the private
sector were crucial; and the same is true for three drugs—Taxol,
Epogen, and Gleevec—that have received widespread attention,
as discussed in Section IV. All or almost all the drugs
discussed below would not have been developed—or, at
best, would have been delayed significantly—in the
absence of private-sector scientific discoveries.
We
can separate the pharmaceutical research and development
process, crudely, into three categories: the basic science
of discovering biologic targets; the applied science of
discovering compounds useful for exploiting those biologic
targets; and the science of discovering compounds with improved
characteristics in terms of clinical practice, manufacturing
protocols, and the like. Table 1 presents summary data derived
from our thirty-five case histories in terms of the respective
private research efforts and each of the three categories;
the numbers are for the drugs and drug classes in our overall
sample of thirty-five for which private-sector research
was responsible for some substantial contribution in the
respective categories, as indicated in the published literature.
Among our thirty-five summary case histories for drugs
and drug classes, the private sector contributed at least
seven significant scientific advances in basic science,
at least thirty-four in applied science, and at least twenty-eight
in terms of improved clinical performance of compounds,
manufacturing processes, and the like.[1]
This study does not dispute the importance of publicly
funded research. Both NIH-sponsored and private-sector research
are crucial for the advance of pharmaceutical science and
the development of new and improved medicines. Research
conducted at universities and government laboratories, often
funded by the NIH or other government agencies, has been
an indispensable component of the advance of pharmaceutical
science and the development of new medicines. In general,
the research conducted or sponsored by the NIH is concentrated
in the basic science of disease biology, biochemistry, and
disease processes, a major goal of which is the identification
of biologic targets that in theory might prove vulnerable
to “attack” by drugs yet to be developed.
Often, such work takes decades, cannot be patented, and
yields discoveries long in advance of the subsequent scientific
and clinical work leading to development of drugs; indeed,
it is often difficult to trace the development of a given
drug back to a specific set of NIH research grants.[2]
At the same time, the scientific contributions of the private
sector have not been negligible, or limited to a mechanical
sorting process through thousands of chemical compounds
to find the ones useful for exploiting the research findings
funded by the NIH, combined with the implementation of subsequent
clinical trials.[3] Instead, the scientific
contributions of the private sector also have been crucial,
but have been weighted heavily toward the applied science
of discovering ways to exploit the findings of basic science
in pursuit of treatments and cures for adverse medical conditions.
This scientific work can be characterized as the discovery,
synthesis, testing, and (often complex) manufacturing of
candidate compounds intended to exploit the targets in order
to cure or mitigate the adverse effects of medical conditions.
Accordingly, NIH and private research efforts are concentrated
in distinct but highly complementary dimensions of the overall
research and development process for pharmaceuticals.
Given the interdependence of public and private research
efforts, why has this question—the allocation of the
credit for the advance of pharmaceutical science—increased
in prominence? Pharmaceuticals are costly to develop and
often are expensive for buyers. U.S. spending on prescription
medicines has been increasing, as a result of some combination
of rising prices, increasing use (in part due to an aging
population), and perhaps a shift toward more costly (and
effective) medicines.[4] In 2007, over
20 percent of that total spending on drugs was paid out-of-pocket
by consumers, while the role of government programs as purchasers
of drugs has grown to almost 35 percent of the total.[5]
The visibility of prices and total costs for pharmaceuticals
has yielded political pressures and criticism, as the private
and public purchasers of drugs have focused more attention
upon public policies affecting the cost and availability
of prescription drugs.[6] These political
pressures are reflected as well in changing perceptions
of the pharmaceutical industry both by the public and by
observers and commentators; among the latter there has developed
a view on the part of some that, to summarize crudely, the
prices demanded by drug producers often are greater than
the (medical) value of the drugs, or are greater than the
contribution by those producers to that value. Part of this
argument is the “me-too” premise, to wit, that
drug producers invest (or waste) substantial resources in
the development of drugs that are little better than ones
already on the market.[7]
The focus of this study, as noted above, is on the second
part of the argument: that the private sector is responsible
for few (if any) important pharmaceutical innovations. Instead,
all or most of the important scientific “breakthroughs”
leading to the development of new and improved medicines
are purported to result from research sponsored or conducted
by government agencies, the National Institutes of Health
foremost among them; the private-sector pharmaceutical industry
supposedly adds little scientifically. Marcia Angell, a
physician and former acting editor in chief of the New England
Journal of Medicine, argues that “learning about the
disease or condition is usually the beginning of the ‘research’
part of R&D, and it can take a very long time—sometimes
decades. There is no question that this is the most creative,
and the least certain, part of the R&D process. Contrary
to industry propaganda, it is almost always carried out
at universities or government research labs, either in this
country or abroad. In the United States, most of it is supported
by the National Institutes of Health.”[8]
Angell goes on to argue that once the given disease is
understood, along with the biological paths available to
treat it, the private sector then begins its work by synthesizing
a molecule that will exploit the disease process in useful
ways, and then by conducting expensive clinical trials,
which Angell characterizes as “the least creative part
of the process.”[9]
Why is the record of private-sector scientific contributions
to the development of new medicines important? If the centrality
of pharmaceutical research funded by the NIH is the reality—if
private-sector research and development investments do not
yield important scientific advances—then policy questions
surrounding drug prices (federal negotiation of prices for
Medicare Part D; importation of price-controlled medicines
from abroad; FDA regulation of the industry) might be easier
to resolve.
After all, if certain public policies can be predicted
to yield less pharmaceutical research and development investment
by the private sector but not a significant adverse effect
in the development of new and improved medicines, the case
against such policies might be weakened considerably.[10]
At the same time, a shift of a major component of the overall
research and development process for drugs to the NIH from
the private sector might engender a new set of problems
and shortcomings, a topic beyond the scope of this study.[11]
A substantial literature exists on the contributions of
government-funded (NIH) research to drug development.[12]
Accordingly, we strive here to examine the general argument
that the private sector contributes little to the advance
of pharmaceutical science, with the few, if any, important
“breakthroughs” instead contributed largely or
solely by conducting (or funding) clinical trials.
Before turning to the case studies used to examine that
issue, we offer in Section II a summary of the process and
cost of drug development as useful background information.
Section III presents thirty-two summary case histories as
a systematic examination of the scientific role of the private
sector in drug development. Section IV offers more detail
on the past scientific processes yielding Taxol, Epogen,
and Gleevec, three drugs that have received considerable
attention in the literature and that have led some to conclude
that private-sector scientific contributions to drug development
have been relatively unimportant. Section V presents some
conclusions and policy implications.
II. The Process and Cost of Drug Development
For new drugs, the process of discovery, development, and
regulatory approval from the Food and Drug Administration
for commercial distribution is lengthy, risky, and very
costly.[13] For a pharmaceutical company
to be able to repeat this process, it must be reasonably
confident that the revenues that its drugs generate during
their commercial life can exceed the cost of marketing and
developing them. Below, we describe the process by which
new drugs are developed and indicate the amount of resources
that must be devoted to it.
The Drug Discovery and Development Process
New drug development is usually a sequential process. Basic
biomedical research can yield scientific knowledge of the
biochemistry of a disease process, which can then be used
to identify biological targets that molecules might affect
in such a way as to modify the disease or condition being
studied. Following the vision articulated by Vannevar Bush
in the 1940s[14] for an efficient division
of resources between basic research and applied research
and development, much basic biomedical research is conducted
in academic institutions and nonprofit institutes and is
funded to a substantial degree by the public sector, while
the bulk of applied research and development is funded by
the private sector. The complementary nature of this division
of labor and support has proved to be highly effective.[15]
Knowledge and resource feedback loops connecting the public
and private sectors have been found to enhance the productivity
of the system as a whole.[16]
Once basic research has identified targets for which drugs
might be effective, compounds are isolated, synthesized,
or bioengineered and then screened to identify the most
promising or “lead” drug candidates. These are
designated for further investigation. The process by which
lead compounds are identified is predominantly conducted
in the private sector and involves an extensive and complex
set of scientific activities such as combinatorial chemistry,
structure-activity relationship analysis, and bioinformatics.
Often, lead compounds are then modified in a process called
“lead optimization” to enhance activity or reduce
toxicity.
After a drug candidate has been marked for development,
it undergoes testing in vitro and/or in animals to test
for activity against the targeted disease or condition as
well as for serious side effects. This process may take
several years. Additional research and testing will be conducted
to assess the drug’s purity, stability, and shelf life
and to ensure that the compound can be produced on a commercial
scale. These activities are generally conducted by or funded
by industry.
If the compound remains a viable candidate after preclinical
testing, a manufacturer interested in pursuing clinical
(human) testing will detail data and findings on the drug
in an application, called an Investigational New Drug (IND)
application, which it submits to the FDA. For drugs developed
in the United States, initial human testing may have been
conducted anywhere in the world.
For drugs that proceed to regulatory marketing approval,
clinical testing is generally conducted in three successive
phases. Although Phase I studies may be conducted with patients
who have the targeted disease or condition, usually they
are conducted with healthy volunteers. Information on pharmacokinetics
(how the body absorbs, distributes, metabolizes, and excretes
the drug) and a safe dosing range is obtained from Phase
I studies. A limited number of patients with the targeted
disease or condition are tested in Phase II studies, which
provide the initial (“proof of concept”) evidence
of efficacy, information on side effects, and data to help
determine optimal dosing. Phase III studies are large-scale
trials designed to establish firmly the efficacy of the
compound and to provide further data on side effects, including
those that occur infrequently. If a drug proceeds successfully
through all three phases of development, the drug’s
sponsor will compile all the information that it has gathered
on the drug in a very lengthy application for regulatory
marketing approval. The regulatory authority will decide
whether the drug product has a sufficiently high benefit/risk
ratio and chemistry and manufacturing standards to justify
marketing approval.
Trends in Drug-Development Metrics
The drug-development and regulatory-approval process outlined
above is both lengthy (on average, 10 to 15 years)[17]
and costly (hundreds of millions of dollars in direct costs,
including the costs of failures, and at least as much in
indirect costs).[18] For every compound
that is approved for marketing, many thousands may be screened
and hundreds may enter preclinical development; of those
that make it to clinical testing, only approximately one
in five will ever get approved.[19]
The trend in pharmaceutical research and development costs
has been relentlessly upward for decades. The total costs
of pre-approval industrial research and development per
approved new drug, including both the costs of researching
drugs that failed to make it to approval and the time (“opportunity”)
costs of drug development (expenditures must be made years
before any returns can be earned), have shown a fairly consistent
compound annual growth rate of over 7 percent above general
price inflation for nearly forty years.[20]
Of particular note is the high growth rate of clinical period
costs in the last decade or so (a compound annual growth
rate of over 11 percent above general price inflation).[21]
These results are consistent with other data on the growth
in drug-development, particularly clinical, costs.[22]
To help ensure that these increases do not stifle innovation
in this crucial area, technological advances in drug-discovery
methods are needed, as well as improved preclinical identification
of promising compounds, clinical trial designs that yield
better information, faster development of the most promising
drugs, earlier termination of research and trials of drugs
that are unlikely to succeed, and the regulatory adjustments
necessary to support these initiatives. Collaborative efforts
among industry scientists, academics, government regulators,
and government scientists, such as those envisioned by the
FDA’s Critical Path Initiative,[23]
have the potential to bridge gaps in the translation of
upstream research into downstream development. If realized,
the result should be an increase in the number of useful
new therapies and an increase in the speed with which they
reach patients.[24]
III. Summary Case Histories for Thirty-Two Drug Classes
The existing literature suggests that the general assertion
of NIH/government centrality in pharmaceutical innovation—and
the near-irrelevance of the private sector in terms of important
contributions to pharmaceutical science—is problematic
at a minimum.[25] In this section,
we summarize the available case-history literature for thirty-two
drug classes to see if a dominant pattern can be discerned
in terms of a consistent presence or an absence of private-sector
contributions to pharmaceutical science. Again, the importance
of government-funded research in terms of pharmaceutical
development generally, and the science of disease processes
and the like in particular, is not in dispute; instead,
our goal is an examination of the premise that all or most
of the “big breakthroughs” come from NIH, that
is, that the private sector contributes little more than
funding for clinical trials rather than important scientific
advances.
We adopt here a summary case-history approach, using lists
of important drugs and drug classes offered by the literature.
Fuchs and Sox created a list of thirty major medical innovations
by searching through twenty-five years of the Journal of
the American Medical Association and the New England Journal
of Medicine.[26] Of those thirty innovations,
fifteen were drugs or drug classes.[27]
Cockburn and Henderson constructed a list of twenty-one
drugs “identified by two leading experts as ‘having
had the most impact upon therapeutic practice’ between
1965 and 1992.”[28] Another list
of “drugs that were ‘blockbusters’ in 1993
(in terms of sales)” is provided by Gelijns et al.,
but it largely duplicates the Fuchs-Sox and Cockburn-Henderson
lists.[29] Those lists are useful for
the work reported here because they were constructed independently;
but they are a bit dated. In order to capture the relevant
histories of newer drugs, we include in the construction
of Table 2 the twenty-five brand-name drugs most prescribed
in the U.S. in 2007, as reported by Verispan VONA.[30]
Table 2 presents a list of thirty-seven drug classes and
respective drugs merged from the Fuchs-Sox, Cockburn-Henderson,
and Verispan VONA compilations.[31]
The discussion that follows offers a summary of the respective
case histories available in the literature for the drug
classes.[32]
1. Angiotensin Converting Enzyme (ACE) Inhibitors.[33]
Captopril was the first ACE inhibitor proven effective when
taken orally. It was approved by the FDA in 1981 for use
in patients responding poorly to other therapies, with severe
hypertension, and for patients on multidrug regimens. Additional
clinical experience showed that use of the drug at lower
doses yielded continued effectiveness with minimal side
effects, particularly for patients suffering from congestive
heart failure, coronary insufficiency, diabetes, and asthma.
Scientific study conducted by John Vane at the Royal College
of Surgeons of England in the 1960s showed that an extract
of the venom of the Brazilian arrowhead viper acted as an
ACE inhibitor. Miguel Ondetti and others at Squibb then
isolated several peptides from the venom in the early 1970s;
one was teprotide (already isolated by Vane), which then
was synthesized and tested extensively in animals by the
Squibb scientists. It proved to be an effective hypertensive
agent when administered intravenously but ineffective when
administered orally. The Squibb researchers then tested
about 2,000 nonpeptides without success in the search for
an ACE inhibitor effective with oral administration. A paper
by Byers and Wolfenden of the University of North Carolina,
supported by NIH research grants, yielded scientific findings
that led the Squibb researchers to synthesize additional
binding compounds for ACE.[34] Sneader
notes: “The resulting compound … was still not
potent enough to be considered as a candidate compound for
clinical investigations and it required considerable effort
and ingenuity to enhance its potency.”[35]
The Squibb researchers then experimented with a number
of molecular approaches until discovering that replacement
of the carboxyl molecule group with a thiol group, yielding
“a one-thousand-fold increase in inhibitory activity
for captopril. This was the first nonpeptide ACE inhibitor
suitable for introduction into the clinic.”[36]
In sum, private-sector research at a minimum yielded a chemical
compound with sufficient potency to make it an effective
candidate for clinical use.
2. Angiotensin II Antagonists.[37]
Losartan, approved originally by the FDA in 1995, has been
shown in extensive clinical trials to be as effective as
the ACE inhibitors as antihypertensives but without the
dry cough caused by the latter. In 1982, Yoshiyasu Furukawa,
Shoji Kishimoto, and Kohei Nishikawa of Takeda Chemical
Industries reported that they had developed a chemical derivative
of imidazole-5-acetic acid that inhibited the hypertensive
effect of angiotensin II.[38] Building
upon that scientific advance, DuPont Merck began a research
program that yielded its own imidazole derivative, which
was called losartin. Merck scientists synthesized losartin
in 1991, after which extensive clinical studies were conducted,
followed by FDA approval in 1995. Scientists at Ciba-Geigy
subsequently developed valsartin, which is not metabolized
in the liver and therefore less likely to interact with
certain other drugs, and it is not contraindicated in the
case of patients with liver disease. Accordingly, private-sector
research at a minimum yielded compounds reducing the adverse
side effects of existing therapies.
3. Calcium Channel Blockers.[39] Nifedipine
was first approved by the FDA in 1981. There is some dispute
between German and Belgian researchers over the sources
of the initial discoveries that drugs could induce calcium
withdrawal from cells, thus relaxing smooth muscle cells
in the walls of blood vessels; but it is clear that a substantial
part of that work was conducted by Albrecht Fleckenstein
at the University of Freiburg.[40]
In any event, scientists at Bayer reported in 1970 on the
antihypertensive effects of a group of compounds called
dihydropyridines;[41] Bayer then proceeded
to synthesize and screen more than 2,000 variations of the
compounds. Nifedipine was chosen as the compound for further
investigation—in tests on animals, it was shown to
be particularly effective—and clinical work confirmed
both its antihypertensive effects and the fact that the
drug acted as a calcium channel blocker. Maxwell and Eckhardt
report that the development of all first-generation calcium
channel blockers resulted from research in the private sector.[42]
This research led to the discovery of a compound that exploited
the advance in basic science identifying a useful biological
target.
4. Beta Blockers.[43]
Propranolol, approved by the FDA in 1967, was the first
beta blocker to be marketed successfully; the more technical
term for beta blockers is “beta-adrenoceptor antagonists.”
Pathbreaking scientific work on adrenoceptors was conducted
by Raymond P. Ahlquist of the University of Georgia in the
late 1940s, when he determined that they could be separated
into alpha and beta families.[44] The
first beta-adrenoceptor antagonist (or beta blocker) was
discovered by scientists at Lilly Laboratories in 1957;
those findings were confirmed subsequently by other researchers
at Emory University. Several years of work then followed
at Imperial Chemical Industries (ICI, subsequently part
of AstraZeneca), led by James W. Black, who in 1988 was
one of three awarded the Nobel Prize in Physiology or Medicine.
Black presented the initial pharmacological findings for
the first beta blocker, pronethalol, in 1962, which proved
to have some adverse toxicity effects. Other scientists
at ICI then synthesized propranolol and demonstrated its
antihypertensive effect in 1964.[45]
Indications for propranolol have increased—for angina
pectoris, arrhythmias, myocardial infarction, glaucoma,
and migraine—and the pharmaceutical sector over time
has developed a series of improved beta blockers offering
various therapeutic advantages over propranolol.[46]
This history of the development of beta blockers is consistent
with the dominant development path for drugs: a basic scientific
advance was followed by private research that discovered
compounds that exploit the basic scientific knowledge and
that yield improved drugs with broader applications and
the like.
5. Platelet Aggregation Inhibitors.[47]
Dipyridamole received FDA approval in 1961, and earlier
was a component of a group of homopurine compounds for which
the Karl Thomae Company was granted a British patent in
1959. It was initially used as a coronary dilator; publicly
funded research at the Medical Research Council discovered
that it had a significant effect in inhibiting the formation
of platelet clumps (thrombi). Further advances in the development
of platelet aggregation inhibitors have focused on specific
conditions: ticlopidine (Roche Pharmaceuticals) for prevention
of thrombotic stroke; dipyridamole (Boehringer Ingelheim)
for prevention of thrombosis after cardiac valve replacement;
clopidogrel (Sanofi-Aventis) as a substitute for ticlopidine
with fewer side effects; and abciximab (Centocor/Eli Lilly)
for use after angioplasty. At a minimum, therefore, private
work improved the degree to which clinical practice was
able to exploit the initial scientific discovery in terms
of specific medical conditions; that is, it developed compounds
able to attack more specialized biological targets associated
with specific medical conditions or needs.
6. Statins.[48] Beginning
with the ongoing Framingham Heart Study, which has been
conducted by the National Heart, Lung, and Blood Institute
of the NIH since 1948, the causal relationship between elevated
cholesterol levels and cardiovascular disease has become
widely recognized. In 1976, Akira Endo and other researchers
at the Sankyo Company and at Beecham Research Laboratories
independently isolated mevastatin from fungi, after having
screened more than 8,000 microbial extracts. Further research
by Endo and colleagues showed that mevastatin reduced cholesterol
levels in the liver;[49] subsequently,
Endo and researchers at Merck separately isolated lovastatin
from a different fungus. Lovastatin was shown to be more
potent than mevastatin and was the first HMG-CoA reductase
inhibitor approved by the FDA, in 1987, for the reduction
of plasma cholesterol. Further research by private-sector
laboratories has yielded additional statin drugs more potent
and/or with fewer side effects than lovastatin: pravastatin,
simvastatin, atorvastatin, and others, the newer of which
have been synthesized in laboratories rather than isolated
from natural materials. Private-sector research, in short,
developed compounds exploiting new knowledge of a specific
disease process, and developed improvements in terms of
potency and side effects.
7. Fibrates.[50] Thorp
and Waring, researchers at ICI, reported in 1962 that clofibrate
reduced cholesterol levels in laboratory animals.[51]
A subsequent large clinical study (of 5,000 patients) funded
by the World Health Organization showed that mortality from
noncardiovascular diseases was higher in the group given
clofibrate than the group given a placebo; at the same time,
clofibrate reduced the incidence of nonfatal coronaries
in patients with no previous history of heart disease. Accordingly,
use of the drug was restricted by the FDA to patients for
whom hyperlipidemia did not respond to changes in diet and
to patients with very high triglyceride levels. In response,
Parke-Davis screened more than 8,000 related compounds for
lipid-lowering effects in laboratory animals; gemfibrozil
was found effective in that research. It was synthesized
in 1968 and approved by the FDA (brand name Lopid) in 1981.
In a five-year clinical study, gemfibrozil reduced the rate
of serious coronary events but not the total mortality rate,
compared with a placebo group.[52]
In sum, private research discovered a compound that exploited
existing knowledge about a disease process, and synthesized
numerous follow-on compounds in an effort to improve the
clinical usefulness of the drugs.
8. Cholesterol Absorption Inhibitors.[53]
The absorption of cholesterol from the intestine requires
an enzyme; scientists at Schering-Plough initiated a research
program in the early 1990s to identify compounds that would
block the enzyme and thus inhibit absorption of cholesterol.[54]
This effort led to the development of ezetimibe, which received
FDA approval in 2002, and was subsequently marketed as Zetia.
Although the Schering-Plough research was directed at ACAT
inhibitors, “the actual mechanism by which this compound
inhibits absorption of
cholesterol is not yet fully understood.”[55]
The development of ezetimibe reflects the common pattern
of pharmaceutical science: private research developed a
compound designed to exploit a target identified by earlier
basic science.
9. H2 Blockers.[56]
Before the development of H2 blockers, treatment of peptic
ulcers was limited to the intensive use of antacids, various
drugs (anticholinergics) with unpleasant side effects, or
surgery. Pharmaceutical scientists recognized that histamine
induces the secretion of gastric acids, but none of the
available antihistamines blocked that effect. In 1964, James
W. Black, Robin Gannellin, and colleagues at Smith Kline
& French hypothesized that more than one histamine receptor
existed; this led to the synthesis of more than 700 compounds
over eight years. Burimamide was the first of them found
to be a blocker specific for gastric acids. However, it
was not absorbed well orally; in 1973, Black discovered
metiamide, which was proven active orally but which had
serious side effects in some patients. Further work enabled
Black and his associates in 1975 to discover cimetidine,
which received FDA approval in 1977, and was marketed as
Tagamet by Smith Kline & French (which, through a series
of mergers, became GlaxoSmithKline in 2000). The clinical
and financial success of cimetidine led to the development
of a number of other H2 blockers, among them ranitidine,
developed by GlaxoSmithKline and approved by the FDA in
1984. Marketed as Zantac, it is more specific than cimetidine
as an antagonist for H2 receptors and has fewer side effects.
Private-sector research developed a compound that exploited
the basic science of histamines, with further research aimed
at the discovery of follow-on compounds with improved clinical
properties.
10. Proton Pump Inhibitors.[57]
The discovery of the histamine H2 blockers induced a search
for alternative drugs that might inhibit the secretion of
gastric acids without blocking the histamine receptor. Cimetidine
required multiple doses per day and yielded undesirable
fluctuations in gastric acid levels; in addition, it did
not treat gastro-esophageal reflux disease (GERD) or some
other related conditions well. In 1968, George Sachs and
colleagues at Smith Kline & French began work that discovered
the proton pump that forces acid across the protective gastric
mucosa. Collaboration at scientific conferences and the
like yielded a search begun in the 1970s at Astra Pharmaceuticals
(formerly AB Hässle) for drugs that might improve upon
the performance of the H2 blockers. Earlier compounds[58]
proved overly toxic or afflicted with other problems, but
continued work resulted in the discovery of omeprazole in
1978. It was approved by the FDA in 1989, marketed as Prilosec.
Omeprazole displayed significant variability across patients
in terms of acid secretion and other effects, and a significant
proportion of patients require higher or multiple doses.
Accordingly, in 1987, Astra began a research program intended
to find a proton pump inhibitor that increased bioavailability
by reducing liver involvement. Several hundred compounds
were synthesized and screened over five years, after which
esomeprazole was demonstrated in clinical trials to be superior
to omeprazole for some patients.[59]
It was approved by the FDA in 2001 and marketed as Nexium.
Private-sector research in this case discovered a central
disease process previously unknown, and developed compounds
designed to exploit that target and to improve clinical
performance.
11. Selective Serotonin Reuptake Inhibitors.[60]
The search for drugs with which to treat depression began
in the late 1950s, leading to the investigation and development
of early monoamine oxidase inhibitors, particularly iproniazid,
a drug that had been developed earlier by Hoffmann–La
Roche for the treatment of tuberculosis. It and several
successor drugs exhibited nontrivial degrees of liver toxicity
and other adverse side effects, inducing a search for improved
alternatives. Scientists at J. R. Geigy Ltd. began to conduct
clinical trials with several of its potential antipsychotic
drugs, leading to further research on the effects of imipramine,
an uptake inhibitor for norepinephrine and serotonin. The
discovery of imipramine, combined with earlier work at the
NIH by Julius Axelrod on the identification of neurotransmitters
(for which Axelrod won the Nobel Prize in Physiology or
Medicine in 1970), led to the development of a class of
drugs called the tricyclic antidepressants; some were specific
inhibitors of norepinephrine, and others for serotonin,
while others blocked the uptake of dopamine. These drugs
had several common side effects, among them cardiac toxicity
and dry mouth. The continued search for safer and more effective
antidepressants led in 1972 to the discovery of fluoxetine
by researchers at Lilly Laboratories; it is a drug much
more selective for serotonin than for norepinephrine.[61]
Marketed as Prozac, it received FDA approval late in 1987.
This private research effort, building upon earlier breakthroughs
in basic science, developed compounds designed to exploit
targets suggested by brain chemistry, and then developed
newer drugs with improved effectiveness and reduced side
effects.
12. Serotonin Norepinephrine Reuptake Inhibitors.[62]
Duloxetine was synthesized in 1988 by part of the Lilly
research team that had discovered fluoxetine. Unlike the
latter, highly selective for serotonin, the researchers
reported that “LY227942 has the pharmacological profile
of an antidepressant drug and is useful to study the pharmacological
responses of concerted enhancement of serotonergic and norepinephrine
neurotransmission.”[63] This development
of duloxetine advanced the search for drugs effective at
exploiting biologic targets in the brain.
13. Bronchodilators.[64]
Isoproterenol was discovered in 1940 at Boehringer Ingelheim,
and for years was the treatment of choice for acute asthma
attacks because it induced a strong bronchodilator effect
without the hypertensive effects of earlier drugs. Its effects
are of short duration, however, and it acts as a potent
heart stimulant; accordingly, research proceeded to find
a similar drug (beta2-adrenoceptor agonist) that would not
stimulate the heart. Albuterol (also called salbutamol)
was discovered in 1967 at Allen and Hanbury (now part of
GlaxoSmithKline). Another such drug with greater selectivity
for the beta2-adrenoceptor is terbutaline, developed at
Astra Pharmaceuticals. Note that the crucial distinction
of the different effects of alpha- and beta-adrenoceptors
was discovered by Raymond Ahlquist of the School of Medicine
at the University of Georgia, a breakthrough in the basic
science that made the discovery of the newer drugs possible.[65]
Maxwell and Eckhardt note that when inhaled, “the more
selective [beta2] agonists are virtually devoid of the side
effects related to vasoconstriction and/or cardiac stimulation
that are evident with epinephrine and isoproterenol.”
They note as well that of the four major scientific advances
leading to the discovery of albuterol, one was made at a
university, one by a government agency, and two by the private
sector.[66] The advance in basic science
achieved by Ahlquist led the private sector to search for
compounds improving upon the clinical performance offered
by existing therapies.
14. Inhaled Corticosteroids.[67]
The usefulness of cortisone for the treatment of arthritis
led in the late 1940s and early 1950s to the synthesis of
several anti-inflammatory corticosteroids, which quickly
were recognized as useful for the treatment of asthma. However,
heavy use yielded a number of serious side effects; accordingly,
interest grew in the development of inhaled versions of
the drug class. Early efforts exhibited substantial variability
in terms of effectiveness and difficulty in terms of preserving
the useful local (respiratory) effects while reducing the
adverse systemic side effects. Further work led to the synthesis
of beclomethasone by Glaxo, with a patent issued in 1966.
A further patent was issued for the inhaled version of the
drug in 1989.[68] Maxwell and Eckhardt
attribute to the private sector two of the three major scientific
advances crucial for the development of the drug, with the
third attributed to a hospital study. Again, the private
research yielded compounds with improved properties in terms
of clinical practice.
15. Nonsteroidal Anti-Inflammatory Drugs.[69]
Analgesics are drugs that reduce pain, while antipyretics
reduce fever and anti-inflammatory drugs reduce the inflammation
caused by arthritis or other conditions. Aspirin (acetylsalicylic
acid) has all three properties; it was invented by a chemist
at Bayer in the late 1890s. The most common side effects
of aspirin are gastrointestinal irritation, often manifesting
itself as bleeding in the intestinal tract, and a reduction
of blood-clotting activity. Research continued at various
centers, leading to the synthesis of paracetamol (or acetaminophen)
at Bayer; it does not produce gastrointestinal bleeding
but is less effective than aspirin in terms of its anti-inflammatory
effect. Merck developed indomethacin (Indocin), effective
in terms of the treatment of arthritis but, again, causing
significant gastrointestinal side effects. Merck developed
sulindac in the early 1960s, a drug with milder gastrointestinal
effects. In addition to that central problem with aspirin
and the earlier NSAIDs, it became clear during the 1950s
that the long-term use of corticosteroids for treatment
of arthritis causes serious medical problems. After synthesizing
and testing about 600 compounds, researchers at Boots Pharmaceuticals
developed ibuprofen in 1964, with fewer gastrointestinal
effects than aspirin and without the problems caused by
the corticosteroids. Subsequently, other firms introduced
such other NSAIDs as naproxen, ketoprofen, and fenoprofen,
which generally are more potent than ibuprofen, have beneficial
effects that are more long-lasting, and take effect more
gradually. In sum, again, private research yielded a series
of compounds with improved clinical properties and reduced
side effects.
16. Cox-2 Inhibitors.[70]
It was not until the 1970s that the therapeutic action of
aspirin and other NSAIDs was identified: it inhibits prostaglandin
production by the cyclooxygenase (Cox) enzyme, an effect
that yields both the therapeutic and adverse side effects
of the NSAIDs. In the late 1980s, two scientific teams—one
from Brigham Young University and Harvard University, the
other from UCLA—identified a new gene that codes for
a second form of the Cox enzyme. This discovery of that
second form engendered a renewed search for anti-inflammatory
drugs. The basic hypothesis was that inhibition of the (older)
Cox-1 might be the cause of the familiar adverse side effects,
while inhibition of the newly discovered Cox-2 might yield
the desired anti-inflammatory effect. In 1990, researchers
at the Dupont Company developed a drug called DuP697 and
presented evidence that its benign gastric effects indeed
were due to the different inhibition of the Cox enzymes.
Researchers from Taisho Pharmaceutical reported the same
effect with a different drug, called NS398. These findings
induced rapid innovation: G. D. Searle developed celecoxib
after screening more than 2,500 compounds, and Merck developed
rofecoxib, which was withdrawn from the market in 2004.[71]
This private research effort represents the classic pattern:
a discovery of compounds exploiting the targets identified
by more basic research conducted at the university level.
17. Long-Acting Opioids.[72]
Oxycodone was synthesized in 1916 by scientists at the University
of Frankfurt; an alternative method for synthesizing the
drug subsequently was developed at Knoll Pharmaceuticals.
More recently, research has been aimed at development of
powerful analgesics less addictive than morphine and other
available opioids. The FDA approved Oxycontin (Purdue Pharmaceuticals)
in 1995; it is a controlled-release variant of oxycodone.
Private research in this case produced a drug with improved
characteristics for clinical practice.
18. Fluoroquinolone Antibiotics.[73]
The development of fluoroquinolone antibiotics began in
1946 when scientists at the Sterling-Winthrop Research Institute
synthesized a new form of chloroquine, a by-product of which
was found to be effective against certain bacteria. Further
work by scientists at Sterling in the early 1960s led to
the discovery of nalidixic acid, which was followed by Warner-Lambert’s
oxolinic acid and by several discoveries in the 1970s and
1980s, particularly by private pharmaceutical firms in Japan.
Ciprofloxacin was discovered by Bayer, and approved by the
FDA in 1987; it is far more potent than nalidixic acid,
and after testing against 20,000 different bacteria strains,
it is shown to be effective (in varying degrees) against
over 98 percent of them. Several additional such antibiotics
were synthesized and approved over the following years,
among them norfloxacin, levofloxacin, and gemifloxacin.
This process of private-sector research, synthesis, testing,
and approval has yielded a succession of antibiotics increasingly
potent, with fewer side effects, more narrowly targeted,
and effective against strains of bacteria developing resistance
to older drugs.
19. Third-Generation Cephalosporins.[74]
Cephalosporins first were discovered by Giuseppe Brotzu
in Sardinia and by researchers at Oxford in the late 1940s
and early 1950s; but they proved not to be clinically useful.
However, the Oxford researchers did develop cephalosporin
C, and a research team at Ciba subsequently developed a
process for producing it on a large scale. Cephalosporin
C shared some characteristics with various penicillins,
so a number of researchers sought methods with which to
transform penicillins into cephalosporins in order to treat
a broader range of conditions. The effort at Lilly was successful
and led to the discovery in 1962 of cephalothin, the first
clinically useful cephalosporin. Further work at Lilly and
Bristol-Myers developed newer versions of these drugs with
effectiveness against an even broader range of conditions,
and with improved absorption properties.[75]
Second-generation cephalosporins were developed in the 1970s
and were effective against a wider spectrum of bacteria—in
particular, against organisms resistant to penicillins.
Among the first was cefoxitin, developed at Merck and patented
in 1971; but it is not effective when taken orally. Lilly
then developed cefaclor (Ceclor), effective orally, and
approved by the FDA in 1979. Another advance was Glaxo’s
cefuroxime (Ceftin), which has improved absorption characteristics
from the digestive tract. The first third-generation cephalosporin
to be marketed in the U.S. was cefotaxime (Claforan), developed
by Hoechst-Roussel and approved by the FDA in 1981. It offers
a broader range of antibacterial activity with a longer
therapeutic effect. Another is cefprozil (Cefzil), approved
by the FDA in 1991; it is effective when administered orally.
Another example is ceftriaxone (Rocephin), developed by
Hoffmann–La Roche and approved by the FDA in 1984.
It is effective for substantially longer periods of time,
so that some conditions can be resolved with a single dose.
As in the case of the fluoroquinolone antibiotics, private-sector
research has led to the discovery, development, and introduction
of a succession of drugs with improved potency, improved
clinical properties, and, again, effective against strains
of bacteria developing resistance to older drugs
20. Imidazole and Triazole Antifungals.[76]
The incidence (by population proportion) of fungal diseases
has grown over the last several decades—perhaps in
substantial part, as reported, in response to the expanding
array of drugs useful in treating them—and fungal diseases
are now recognized as common complications of cancer chemotherapy
and AIDS. After some early successes with the use of imidazoles
as anesthetics, researchers at Janssen developed miconazole
and determined it to be an antifungal effective against
a wide range of infections. However, it was not absorbed
well from the digestive system and so could not be administered
orally; further research at Janssen resulted in the development
of ketoconazole in 1976, the first broad-spectrum imidazole
suitable for oral administration. It was approved by the
FDA in 1981. Further work at the drug companies was aimed
at increasing the oral effectiveness and reducing the side
effects of the antifungals; Pfizer researchers tested hundreds
of analogues to ketoconazole, eventually synthesizing fluconazole
(Diflucan), which received FDA approval in 1990. It is about
100 times as potent as ketoconazole, with better effectiveness
when administered orally. It also can be administered once
daily.
21. Antivirals (Herpes Simplex/Zoster).[77]
The synthesis of acyclovir was a milestone in the development
of antiviral drugs; it proved not to be toxic even at concentrations
more than 100 times those required for antiviral effect,
and it is effective against a range of herpes-like viruses.[78]
It was approved by the FDA in 1985 and marketed as Zovirax
by GlaxoSmithKline. Work in the late 1940s at Burroughs
Wellcome, Sloan Kettering, and Indiana University demonstrated
that certain purine compounds inhibited some viruses in
the laboratory. Side effects in animal tests led Burroughs
to abandon the search for antiviral compounds for many years.
However, other researchers pursued the use of purines as
antivirals, with some success; such new findings led Burroughs
almost twenty years later to resume this work, which led
to the synthesis in the mid-1970s of acyclovir, a drug that
proved highly active against the herpes simplex virus (HSV)
and others. The Burroughs team included Gertrude B. Elion
and George H. Hitchings, both of whom shared the Nobel Prize
in Physiology or Medicine (with James W. Black) in 1988,
in part for the synthesis of acyclovir. In sum, private-sector
research led to the discovery of a compound that exploited
previous research findings and that displayed sharply lower
toxicity in clinical practice.
22. HIV Antiretrovirals/Nucleoside Reverse Transcriptase
Inhibitors (NRTIs).[79] Enfuvirtide
was the first drug to inhibit the entry of HIV-1 virus into
host (CD4) cells. It was approved by the FDA in 2003, and
marketed by Roche as Fuzeon. Highly active antiretroviral
therapy (HAART) has combined several classes of drugs in
“cocktails” tailored for individual patients and
their respective strains of HIV virus. Such therapy, however,
eventually fails for the majority of patients, particularly
because of increasing drug resistance.
Accordingly, there is a continuing need for new antiretrovirals
effective against HIV strains resistant to existing therapies.
Enfuvirtide is such a drug, developed in a partnership between
researchers at Duke University who formed a pharmaceutical
company called Trimeris, and scientists at Roche Laboratories.
It inhibits HIV-1 but not (the less virulent) HIV-2. Matthews
et al. note[80] that “it is by
far the most complex antiretroviral ever manufactured at
such a large scale.” The enfuvirtide molecule is large
(in the context of small-molecule drugs), and thus the manufacturing
process in highly complex, involving 106 steps.[81]
(A typical manufacturing process for small-molecule drugs
involves eight to twelve steps.) This highly complex large-scale
manufacturing process itself can be viewed as a significant
scientific achievement, as was the previous effort to develop
drugs effective against strains of HIV exhibiting resistance
to older therapies.
AZT (zidovudine) was first synthesized in 1964 at the Michigan
Cancer Foundation (under an NIH grant) as a potential drug
for leukemia. In the mid-1970s, German scientists reported
that AZT inhibited a retrovirus, but little interest ensued
because retroviruses were unknown in humans. But in 1983,
scientists in France isolated HIV and determined that it
is a retrovirus. Scientists at Burroughs Wellcome then began
programs to search for drugs that would attack retroviruses;
AZT was one of fourteen chosen for screening, and laboratory
results obtained in late 1984 were highly encouraging. Samples
of AZT were then sent to the National Cancer Institute for
further testing; the scientists there concluded quickly
that it was highly effective. The NCI findings were replicated
at Duke University; subsequently, clinical trials were conducted,
and AZT received FDA approval in 1987. It is marketed by
GlaxoSmithKline as Retrovir. In the context of AZT, the
historical record makes it clear that private research used
prior scientific findings to find a compound effective against
a particular retrovirus.[82]
23. Hypoglycemic Agents and Thiazolidinediones.[83]
In 1947, researchers at the U.S. Vitamin Corporation synthesized
metformin, a drug introduced in Europe in 1957 to treat
diabetes. Because of side effects, it was not marketed in
the U.S. (as Glucophage, Bristol Myers Squibb) until its
approval by the FDA in 1995. In 1975, researchers at Takeda
Laboratories synthesized a number of compounds in the search
for agents with hypoglycemic effects. A candidate compound
(AL-321) was chosen, a large number of analogues were developed,
and pioglitazone was discovered and approved by the FDA
as Actos in 1999. Researchers at SmithKlineBeecham enhanced
the potency of pioglitazone, and rosiglitazone was the result.
It, too, received FDA approval in 1999, and is marketed
as Avandia. Both drugs reduce blood-sugar levels by lowering
resistance to insulin in patients with type-2 diabetes.
In short: private-sector research efforts yielded the initial
and improved compounds of a drug used widely.
24. Selective Estrogen Receptor Modulators.[84]
Approved by the FDA in 1977, tamoxifen for many years has
been the frontline treatment for estrogen-positive receptor
breast cancer. Professor Charles Huggins of the University
of Chicago conducted the earliest studies on the use of
sex hormones for cancer therapy. Further work was done in
the 1940s at the University of Edinburgh and at ICI, which
received a British patent in 1944 for an artificial estrogen.
Tamoxifen was synthesized in 1962 by scientists at ICI,
who discovered that one of its components acted as a blocker
for estrogen receptors. It was patented in 1964, and shown
to be efficacious in a large clinical trial in Manchester
in 1971. Private-sector work appears to have been central
throughout the process of discovering biologic targets and
drugs designed to exploit them.
25. Chemotherapy Agents.[85]
In 1964, scientists at Michigan State University discovered
that electric current transmitted by platinum electrodes
interfered with the division of bacteria cells. Alternative
compounds containing platinum were tested, and a number
were found to block cell division.[86]
The findings were reported in 1969, and cisplatin, a chemical
containing platinum, was subjected to successful clinical
tests. Further work on alternative platinum compounds and
on kidney toxicity attendant upon administration of cisplatin
was conducted in England, at Bristol Myers, and at the National
Cancer Institute. Cisplatin was approved by the FDA in 1978
and marketed by Bristol Myers as Platinol. Private research
thus contributed to the discovery of a compound exploiting
an earlier advance in basic biologic science.
26. 5-HT3 Blockers.[87]
Work by scientists at the University of Edinburgh in the
1950s centered on some nerve/serotonin interactions and
distinguished between different serotonin receptors.[88]
One of these later was renamed the 5-HT3 receptor; one important
problem caused by chemotherapy is nausea caused when cells
in the gastrointestinal tract release 5-HT. Further work
by scientists at Glaxo identified receptor blockers, and
then synthesized a number for testing. One, named ondansetron,
was found active when taken orally and was approved for
antinausea therapy by the FDA in 1991. It is marketed as
Zofran by GlaxoSmithKline. This is another example of the
recurrent theme: private research yielding compounds exploiting
the targets identified by basic research.
27. PDE5 Blockers.[89]
The search for asthma treatments led to a discovery in the
early 1960s that a particular enzyme (a peptide) had the
effect of relaxing involuntary muscles.[90]
Further work discovered several variants of that enzyme,
as well as the fact that PDE5 in kidney tissue inhibits
the effect of the peptide. Accordingly, research at Pfizer
in the mid-1980s focused on the development of an antagonist
to PDE5, which might have the effect of using kidney function
to reduce blood pressure by increasing the excretion of
sodium and water. The Pfizer team focused on zaprinast,
a compound that had been developed at Rhône Poulenc
but that had gone unmarketed. They created a number of chemical
variations of zaprinast, and after the synthesis of more
than 1,600 compounds, sildenafil was discovered as an inhibitor
of PDE5 with 100 times the potency of zaprinast. Clinical
trials were discouraging when the drug was tested on patients
with coronary heart disease, but “one of several side
effects was only revealed when participants in a trial of
sildenafil on 30 men in the Welsh town of Merthyr Tydfil
in 1992 were questioned about their reluctance to return
unused tablets when the trial was stopped.”[91]
Sildenafil reverses erectile dysfunction and has advantages
over earlier treatments in terms of safety and effectiveness
when taken orally. It was approved by the FDA in 1998, and
marketed by Pfizer as Viagra. In this case, private research
efforts in the development of a compound for one purpose
yielded beneficial effects in a very different clinical
function.
28. Nonsedating Antihistamines.[92]
Several synthetic antihistamines were developed in the late
1940s, but their major side effect was sedation. Researchers
at American Schering in 1951 synthesized chlorpheniramine
(Chlor-Trimeton), which caused less sedation than the antihistamines
available earlier. Researchers at the Richardson-Merrell
Company in 1973 developed terfenadine as a potential tranquilizer;
it performed poorly in that function, but was then tested
and found to be a nonsedating antihistamine. However, it
had toxic cardiac effects when taken with some other medicines,
and was withdrawn from the market. Subsequent efforts at
Schering-Plough to develop antihistamines with anti-ulcer
properties led to the discovery of loratadine, which received
FDA approval in 1993, and was marketed by Schering-Plough
as Claritin. Other successful compounds are cetirizine (Zyrtec),
approved by the FDA in 1995, and fexofenadine (Allegra),
approved by the FDA in 1996. In short, private research
yielded a series of improved compounds.
29. Immunosuppressants.[93]
The first drug acting as an immunosuppressant was mercaptopurine
(Purinethol), discovered as an anti-leukemia drug by researchers
at Wellcome in 1952. Several years later, scientists at
Tufts University and the Harvard Medical School tested a
number of existing drugs for immunosuppressive effect; mercaptopurine
was found to be the most effective. The Wellcome researchers
subsequently screened a number of compounds related to mercaptopurine,
and chose azathioprine (Imuran) for further research. It
received FDA approval in 1959. In 1972, researchers at Sandoz
discovered the immunosuppressive effect of cyclosporine;
its effectiveness was demonstrated in 1978 in patients undergoing
bone-marrow transplants, and it received FDA approval in
1983. Cyclosporine (Sandimmune) yielded a significant advance
over the earlier immunosuppressants, in that it acts selectively
against tissue rejection, with much less adverse effect
on the immune response to infection. Scientists from Fujisawa
Pharmaceutical Corporation in 1984 isolated a new immunosuppressant
called tacrolimus, which proved effective for patients with
liver transplants; it was approved by the FDA in 1994. In
1997, the FDA approved daclizumab (Zenapax) from Hoffmann–La
Roche; it is the first drug that blocks only the immune
cells attacking a transplanted organ. Accordingly, the early
work was pursued by both private and public researchers,
but the evolution of improved drugs with fewer side effects
and more specific targeting was the result of private-sector
research.
30. 5-Alpha Reductase Inhibitors.[94]
5-alpha reductase is an enzyme that converts testosterone
into a more potent form called dihydrotestosterone. Individuals
who have a 5-alpha reductase deficiency tend to display
underdevelopment of the prostate gland. Accordingly, scientists
at Merck hypothesized that inhibitors of 5-alpha reductase
might yield benefits for men suffering not from prostate
underdevelopment but from benign prostate enlargement. A
screening program for such inhibitors led to the discovery
of finasteride (Proscar) in 1985, approved by the FDA in
1992.[95] This is another case in which
private research discovered a way to exploit a biologic
target.
31. Triptans (Selective 5-HT1 Agonists).[96]
The first drug to treat migraine headaches was ergotamine,
discovered by researchers at Sandoz in 1945. Sandoz researchers
discovered methysergide as well in the 1950s; but it can
have serious side effects with long-term use. However, its
effectiveness in the treatment of migraines aroused interest
in compounds with similar characteristics; this led to the
discovery at Glaxo of sumatriptan, a drug highly selective
as a vasoconstrictor of the carotid arteries (which are
stretched by increased blood flow during a migraine attack)
through a leveling effect on serotonin in the brain. Sumatriptan
was approved by the FDA in 1992 and marketed as Imitrex
by GlaxoSmithKline. Several other triptans have been developed
and introduced, in efforts to find drugs faster-acting,
longer-acting, with greater availability through oral administration,
and with fewer side effects. Examples are zolmitriptan (Zomig),
naratriptan (Amerge), and frovatriptan (Frova). Again, private
research developed a series of compounds exploiting an adverse
biologic process and exhibiting improved clinical performance.
32. Interferons.[97]
Interferons are proteins produced by the immune system in
response to the presence of tumors and such foreign agents
as viruses. Three distinct interferons have been discovered,
designated as alpha, beta, and gamma, with variations within
each of the three types. Most pharmaceuticals are “small-molecule”
chemicals; proteins are “large-molecule” compounds
already produced by living organisms. Accordingly, while
small-molecule drugs are produced with chemical processes,
large-molecule proteins are produced by living cells. Interferons
were discovered by researchers at the National Institute
for Medical Research in London and found to increase resistance
to a number of viral infections.[98]
A method of purifying interferon was developed by scientists
at the NIH in the 1970s,[99] but production
on a scale sufficient for clinical usefulness required genetic
engineering (“cloning”), a process developed for
the interferons by researchers at Biogen, Genentech, and
Roche. The private researchers succeeded in recombining
two different interferon genes into new, hybrid interferons,
the “first time that proteins had been engineered in
this way, resulting in a new kind of biosynthetic interferons
with unique biological properties.”[100]
There is no dispute that this private discovery represented
a major scientific advance.
Table 3 reorganizes the discussion of our thirty-two drug
classes by decade of the respective initial research breakthroughs,
and then lists the sources of the three kinds of scientific
advances (if revealed by the literature), delineated as
basic science, applied science, and improvements in clinical
application, manufacturing, and the other later stages of
preparing a drug for use.
Among our thirty-two summary case histories for drug classes,
the private sector contributed at least seven significant
scientific advances in basic science, at least thirty-one
in applied science, and at least twenty-five in terms of
improved clinical performance of compounds, manufacturing
processes, and the other later stages of preparing a drug
for use.[101]
These summary case histories suggest strongly that the
purely scientific contributions of the private sector to
drug development have not been negligible. Instead, we find
that for all or virtually all thirty-five drugs (or drug
classes) discussed in this study, the scientific contributions
of the private sector were crucial to their discovery or
development. The dominant pattern emerging from the case
histories is the delineation of a biological target from
basic research on disease processes and biological science,
often—but not always—conducted at universities
or other institutions likely to have received government
funding.[102] That investigation of
biological targets—enzymes, receptors, and so on—is
followed by scientific advances in the discovery, development,
synthesis, and screening of inhibitors and other compounds
that might prove reactive with the biological targets. Those
compounds then must be optimized in terms of their targeting
properties, toxicities must be analyzed and research conducted
to mitigate them, and large-scale production processes must
be invented or adapted.
These findings are consistent with other surveys available
in the literature. Maxwell and Eckhardt find that for the
development of the thirty-two innovative drugs examined,
75 percent had crucial scientific contributions from the
pharmaceutical industry; for government and universities,
the respective figures are 9 percent and 53 percent. For
38 percent of the drugs, crucial scientific contributions
came solely from the industry; for 22 percent, they came
from nonindustrial sources.[103] Cockburn
and Henderson found that of nineteen “key enabling
discoveries” in their list of twenty-one drugs, publicly
funded research was responsible for fourteen, while private
research was responsible for the synthesis of the compound
in sixteen of eighteen cases.[104]
The Joint Economic Committee found that “public funding
of research was instrumental in the development of 15 of
the 21 drugs”; but, as noted above, only ten of the
fifteen are not duplicated in their list.[105]
The NIH study found that of all forty-seven FDA-approved
drugs meeting a $500 million annual sales threshold in 1999,
“it was determined that NIH has Government use or ownership
rights to patented technologies used in the development
of four of those drugs.”[106]
The GAO found that “in 2001 the government had licensing
rights in only 6 brand name drugs associated with the top
100 pharmaceuticals that VA procured and in 4 brand name
drugs associated with the top 100 pharmaceuticals that DoD
dispensed.”[107]
IV. Summary Case Histories for Taxol, Epogen, and Gleevec
Of the many criticisms directed at the pharmaceutical industry
over the last few years, one of the most damning is that
the industry produces few, if any, of the scientific breakthroughs
responsible for the medicines it sells. Angell, for example,
argues that “publicly funded medical research—not
the industry itself—is by far the major source of innovative
drugs.”[108]
Angell illustrates her argument by citing Taxol, Epogen,
and Gleevec as examples “of the many important drugs
not discovered by big pharma” and by presenting brief
case histories of their development.[109]
As shown below, Angell’s discussion of these three
drugs[110] is incomplete at best, yielding
a narrative not supported by fuller accounts of how these
compounds evolved from interesting ideas into breakthrough
medicines.
Taxol
Angell’s account of the development of Taxol can be
summarized as follows.[111] Paclitaxel
(the active ingredient in Taxol) was derived from the bark
of the Pacific yew tree in the 1960s. In 1991, Bristol-Myers
Squibb (BMS) signed a cooperative research and development
agreement (CRADA) with the National Cancer Institute (NCI),
a part of the NIH. The main contribution of BMS was providing
the NCI with seventeen kilograms of paclitaxel, which the
firm obtained from a chemical company. The Pacific yew was
in short supply, a problem for BMS solved in 1994 by NIH-funded
scientists at Florida State University, who devised a method
of synthesizing paclitaxel and who promptly licensed it
to BMS. The company spent very little on research and development
before getting initial approval to treat cancer of the ovary
with the drug, but has undoubtedly spent substantial sums
since then on testing it on other cancers. All the research
on Taxol, which Angell calls “the bestselling cancer
drug in history,”[112] was conducted
at, or supported by, the NCI over thirty years, at a cost
to taxpayers of $183 million. Angell sums up her Taxol account
by asserting that “it was virtually given as a gift
to a large drug company for marketing, commercial exploitation,
and further development. The public pays again when it buys
Taxol at the exorbitant price Bristol-Myers Squibb charges
for a drug it neither discovered nor developed.” [113]
That version of the extensive and complicated history of
the discovery and development of Taxol omits a series of
important events and thus minimizes and misrepresents the
interdependence of and interplay between the public and
for-profit sectors, which eventually made this drug one
of the first breakthrough treatments for cancer.
A more complete history of Taxol begins in the mid-1950s,
when the NCI, inspired by Eli Lilly’s discovery of
the cancer drugs vinblastine and vincristine, which derived
from tropical plants in Madagascar, began to screen natural
extracts from around the world for anticancer activity.
In the 1960s, the NCI entered into an agreement with the
U.S. Department of Agriculture, under which the latter was
to focus on plant-derived extracts. One of its successes
was an extract from the bark of the Pacific yew tree, taxus
brevifolia, from which paclitaxel was isolated by a biochemist
at Research Triangle Park in North Carolina, who renamed
it Taxol. Although Taxol looked very promising, major impediments
to further research soon arose. First, although the NCI
continued to commission the isolation of increasing quantities
of the extract, by the late 1960s it had accumulated only
a few grams of the pure material, not enough for more than
initial testing. Second, Taxol was only mildly active against
leukemia, the disease receiving the most attention at that
time, and probably for this reason it languished in NCI
labs for half a decade.[114]
However, in the wake of the declaration of the War on Cancer
and the enactment of the National Cancer Act in 1971, the
NIH reinvigorated its search for any promising cancer-fighting
agents. Work at the Albert Einstein College of Medicine
on microtubule formation demonstrated that Taxol had the
potential to affect cell division and thus possibly to impede
cancer growth. By 1978, Taxol showed promising in vitro
activity, and over the next few years showed indications
of activity in vivo as well. It took a number of years to
transform the compound into a drug that could be administered
and to resolve dosing issues sufficiently to proceed with
testing beyond animals. In late 1982, the NCI applied for
an Investigational New Drug permit for human trials.[115]
Before it could be determined whether Taxol would prove
effective as an anticancer agent, the practical problem
of getting enough of the compound to perform the necessary
tests became paramount. As Phase I and II trials took place
over the next few years, the NCI realized that harvesting
the necessary amount of bark would decimate Pacific yew
populations. It was estimated that 360,000 trees would have
to be destroyed annually if Taxol were used as a treatment
for ovarian cancer alone.[116] Because
of the practical and attendant financial obstacles, the
NCI decided to enter into a partnership with a pharmaceutical
company. NCI’s ulterior motive may actually have been
to shift the problems associated with developing Taxol onto
some other entity.[117]
In August 1989, the NCI published a CRADA Opportunity,
under whose terms NCI would turn over its existing supply
of Taxol as well as its research into the compound in exchange
for assistance with processing and purifying it and funding
further clinical trials. Only four companies responded,
and BMS was selected, at which point the problems associated
with harvesting noted above came to be borne by BMS. For
a number of years, scientists in France and the United States
had been interested in how best to extract useful materials
from the Taxus species without cutting the trees down. By
1989, researchers at Florida State University had developed
a semisynthetic process employing yew needles and petrochemical-derived
starting materials. Although the work had been done as a
way of advancing chemical science, not to develop a production
technique, BMS recognized it as a possible solution to the
production problem and obtained a license to the patented
process from Florida State. BMS started to manufacture the
trademark drug Taxol in Ireland from the needles of the
more plentiful European yew instead of the bark of the Pacific
yew. It was approved by the FDA at the end of 1992. BMS
ended its reliance on the Pacific yew entirely within a
few years.[118]
Within three years of signing the CRADA, BMS was engaged
in Taxol’s large-scale production, the lack of which
had hindered the development of this invaluable drug for
thirty years. BMS continued to work on the process and in
2004 received the Greener Synthetic Pathways Award from
the U.S. Environmental Protection Agency for replacing the
semisynthetic process of making Taxol with plant-cell fermentation
technology.[119] BMS spent a billion
dollars to solve the problem of production without destruction
of the yew tree inventory, and beyond that to explore and
expand the medical utility of Taxol, which remains a major
pharmaceutical, whether prescribed alone or in combination
with other drugs for the treatment of ovarian, breast, and
lung cancer as well as the AIDS-related condition of Kaposi’s
sarcoma.[120]
Epogen
Angell argues, in summary, that the history of Epogen begins
with the discovery in 1976, by Eugene Goldwasser, a researcher
working at the University of Chicago, of a hormone called
erythropoietin, which stimulates the production of red blood
cells, a shortage of which is the cause of anemia. Another
NIH-funded researcher at Columbia University invented a
technique for synthesizing biologics, that is, drugs produced
through the action of living cells rather than through chemical
synthesis. Amgen, a start-up biotechnology company at the
time, obtained a license for the technique and with it was
able to achieve large-scale commercial production of the
erythropoietin molecule. But before Amgen could reap huge
profits from erythropoietin, it had to obtain financing
by selling its rights to market Epogen in the United States
for all medical uses—mainly the treatment of various
cancers—other than treatment of kidney failure, and
for all uses in Europe. The rights were purchased by Johnson
& Johnson, which made essentially no contribution to
the original development of erythropoietin. Angell summarizes
the history of Epogen: “[T]here was ingenuity aplenty
on the part of both Amgen and J & J in exploiting commercial
opportunities, but not much of that had to do with the initial
discovery of the hormone and its role in the treatment of
anemia.”[121]
A fuller history reveals that Amgen’s role was pivotal,
not only in taking erythropoietin from a biological theory
to a pharmaceutical product but also in beginning the biotechnology
revolution. Although the biological role of erythropoietin
was discovered in the 1950s and its medical potential recognized
as early as the mid-1970s, ten years later a major problem
remained: “[T]he routine administration of erythropoietin
for the treatment of anemia in patients with renal failure
has hitherto been impossible because there is no source
from which native human erythropoietin can be extracted
in a sufficient quantity for therapeutic use.”[122]
Amgen identified the erythropoietin gene and created a recombinant
form of erythropoietin, with preliminary results reported
in 1984.[123] More work followed in
the mid-1980s. The production of a recombinant version was
reported in February 1985 by a team of researchers from
the biotechnology company Genetics Institute, from Kumamoto
University, and from Wright State University, with support
from Chugai Pharmaceuticals of Japan.[124]
In November 1985, Amgen researchers, together with Goldwasser,
who was supported by a grant from the National Heart, Lung,
and Blood Institute, were able to isolate and characterize
the erythropoietin gene from a human genomic library, and
then to produce a biologically active recombinant human
erythropoietin in Chinese hamster ovary cells.[125]
Further development occurred under the auspices of Amgen
(U.S.), Cilag (Switzerland), Kirin Brewery (Japan), and
Ortho Pharmaceutical (U.S.). The patent for the production
of recombinant erythropoietin was awarded to Kirin-Amgen.[126]
Once the production problem had been solved, the path was
cleared for human trials. From 1987 to 1989, reports were
published on the results of trials involving small numbers
of patients that were supported by Amgen, Ortho Pharmaceutical,
and the NIH.[127] The drug was approved
in Switzerland in 1988 and in the United States in 1989.[128]
In contrast to Angell’s version of events, the development
of Epogen entailed a long climb of thirty years, with crucial
contributions from both the public and corporate for-profit
sectors. There was good basic research in academia that
paved the way, but the drug would not have been developed
had a series of technical problems not been overcome by
teamwork among industry and academic researchers working
on three continents. Most telling of all is a comment by
Merrill Goozner, a frequent critic of the pharmaceutical
industry, about the development of Epogen: “Once Amgen
could make artificial Epo, the road was clear to prove it
worked in curing anemia.”[129]
Gleevec
In Angell’s summary of the development of Gleevec,
researchers at the University of Pennsylvania made the initial
enabling discovery leading to imatinib mesylate (later called
STI 571, and then branded as Gleevec) as a result of the
discovery of a new chromosome, dubbed the “Philadelphia
chromosome.” It was shown by work at many laboratories
that this chromosome carries a gene that directs the production
of an abnormal enzyme that causes white blood cells to become
cancerous. Similar types of enzymes were thought to be involved
in other cancers, so chemists in Israel and at Novartis
set about synthesizing molecules that would inhibit them.
Novartis patented several of these in 1994, but its management
had no immediate in
Scientific research efforts funded, respectively, by the
NIH and by pharmaceutical firms occupy very different—but
complementary—niches in the process of drug development.
Research conducted at government or university laboratories
(often funded by the NIH or other agencies) tends to be
concentrated in the basic science of disease biology, biochemistry,
and disease processes. A major goal of that work is the
identification of biologic targets that could prove susceptible
to future drug candidates. Basic research often yields advances
that cannot be patented and that often are made long before
the subsequent scientific and clinical work that leads to
viable new therapies.