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DAVID TAYLOR
ABSTRACT
The pharmaceutical industry has a number of unusual characteristics,
both in its structure and in the nature of its business operations, which
are little known outside the industry but which materially affect the
process of bringing new pharmaceuticals to the patient. The develop-
ment of a new pharmaceutical is very time consuming, extremely costly
and high risk, with very little chance of a successful outcome. The
process of research and development is described, together with all its
challenges, including environmental ones. The commercial realities
and constraints of the business, together with its current problems, are
discussed, followed by an exploration of some of the likely future
commercial and technical developments in the business, including the
development of a greener pharmacy.
1 Introduction
The pharmaceutical industry has a number of unusual characteristics that
make it very different from what people normally think of as industry. It
is also an industry replete with contradictions; for example, despite the
undisputed fact that for over a century the industry has made a major
contribution to human wellbeing and the reduction of ill health and
suffering, it is still regularly identified by the public in opinion surveys as
one of the least trusted industries, often being compared unfavourably to the
1
2 David Taylor
The science of pharmacology developed slowly during the next century and
Oswald Schmiedeberg (1838–1921) is now generally recognised as the
founder of modern pharmacology.14 In 1872 he became professor of
pharmacology at the University of Strassburg in Austria where he studied the
pharmacology of chloroform and chloral hydrate and in 1878 published the
classic text, Outline of Pharmacology.
Coincidentally, modern organic chemistry also began to emerge at around
the same time as pharmacology. Before the 19th century, chemists had
generally believed that compounds obtained from living organisms were
endowed with a ‘‘vital force’’ that distinguished them from inorganic
compounds. However, in 1828 Friedrich Wöhler produced the organic
chemical urea, a constituent of urine, from the entirely inorganic com-
pound, ammonium cyanate. Although Wöhler was always cautious about
claiming that he had disproved the theory of vital force, this event has often
been thought of as the starting point of organic chemistry.15 These two
scientific developments in pharmacology and organic chemistry led,
amongst other developments, to the foundation of the pharmaceutical
industry in the last decade of the 19th century.
The modern pharmaceutical industry can trace its origin to two main
sources: companies such as Merck, Eli Lilly and Roche that had previously
supplied natural products such as morphine, quinine and strychnine,
moved into large-scale production of drugs in the middle of the 19th
century, whilst newly established dyestuff and chemical companies, such as
Bayer, ICI, Pfizer & Sandoz, established research labs and discovered medical
applications for their products. Nevertheless, growth was relatively modest
and at the start of the 1930s most medicines were still sold without a
prescription. Almost half of them were compounded locally by pharmacists
and in many cases physicians themselves dispensed medicines directly to
their patients.
However, a number of major advances were made in the early part of the
20th century. Salicylic acid, a natural constituent of willow bark, had been
recorded by Hippocrates as having analgesic properties. In 1897, scientists at
Bayer demonstrated that a chemically modified version of salicylic acid had
much improved efficacy and the product, aspirin, is still in widespread use
today.16 In the 1920s and 1930s both penicillin and insulin were identified
and manufactured, albeit at a modest scale. The Second World War provided
a major stimulus to the developing industry, with requirements for the large-
scale manufacture of analgesics and antibiotics and increasing demands
from governments to undertake research to identify treatments for a wide
range of conditions. After the war, the implementation of state healthcare
systems in Europe, such as the UK’s National Health Service (NHS),17 created
a much more stable market, both for the prescription of drugs and, much
more importantly, their reimbursement. This produced a major incentive for
further commercial investment in research, development and manufacture.
This greater role for the state was paralleled on both sides of the Atlantic,
with increasing government regulation of medicine production.
4 David Taylor
The post-war period from the 1950s to the 1990s saw major advances in
drug development with the introduction of new antibiotics, new analgesics,
such as acetaminophen and ibuprofen, and complete new classes of
pharmaceuticals such as oral contraceptives, ß-blockers, ACE inhibitors,
benzodiazepines and a wide range of novel anti-cancer medicines.
The thalidomide scandal of 196118 triggered a complete reassessment
of state controls on the industry. New regulations now demanded proof of
efficacy, purity and safety, with the latter leading to a massive increase in the
requirements and costs of research and development, particularly in the
clinical testing of new drugs.19 As the barriers to entry in drug production
were raised, a great deal of consolidation occurred in the industry. Likewise,
the processes of globalisation, which had begun before the war, increased.
This resulted in new drug development being dominated by a small number
of very large multi-national companies and the beginning of the era of the
‘‘blockbuster’’ drug.
In 1977, Tagamet, an ulcer medication, became the first ever blockbuster
pharmaceutical, earning its manufacturers, GSK, more than US$ 1 billion
a year and its creators the Nobel Prize. This was followed by a succession
of products, each seemingly more successful than its predecessors. Prozac,
the first selective serotonin re-uptake inhibitor (SSRI) was launched by
Eli Lilly in 1987 and omeprazole, the first proton pump inhibitor (PPI),
was introduced by Astra in 1989. Atorvastatin, marketed as Lipitor in 1996,
became the world’s best-selling drug of all time, with more than
US$ 125 billion in sales over approximately 15 years.
This was probably the golden age for the industry, with research
producing an apparently endless stream of increasingly successful and
profitable products; since then, the industry has been beset by a series of
major problems, many of which have yet to be solved.
In fact, the only common factor which unites pharmaceuticals is their use;
substances that we identify as pharmaceuticals are simply those substances
that we use as human (or animal) medicines. This means that, in principle,
any substance might be identified, at some point, as a pharmaceutical.
Not surprisingly therefore, many pharmaceuticals are also used for
non-pharmaceutical purposes. For example, the vasodilation properties of
nitroglycerine were only discovered by William Murrell20 after its invention
by Alfred Nobel as the active constituent of dynamite. Similarly, the dis-
coverers of warfarin ((R,S)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-
one) at the University of Wisconsin in 194821 would be amazed that at the
beginning of the 21st century this rat poison is still the most frequently
prescribed anticoagulant in the world. This is not just a historical oddity.
The most recent example is dimethylfumarate, which has widely been used
as a mould inhibitor. It is interesting to note that a year after the European
Union applied the new REACH regulation to impose severe restrictions on
its use as a mould inhibitor,22 dimethylfumarate under its trade name,
Tecfidera, was granted a pharmaceutical marketing authorisation in 2013 for
use against multiple sclerosis.23 In other words, the global inventory of
chemical substances can be divided into two groups: pharmaceuticals and
those substances for which no pharmaceutical use has yet been identified,
e.g. before 2013 dimethylfumarate was not a pharmaceutical, however, after
2013 it was.
Many commentators seem to believe that pharmaceuticals should be
subjected to different regulatory treatment because they are ‘‘designed to be
biologically active’’,24 with the implication that this criterion is sufficient
to differentiate pharmaceuticals from other substances. However, this is
incorrect, being derived from a misunderstanding about pharmaceutical
development and it wrongly implies that pharmaceuticals are uniquely
biologically active by design. It would be more appropriate to say that
pharmaceuticals are selected from the many substances that produce a
specific effect in animals, including humans, based on their overall safety.
The majority of pharmaceuticals are initially discovered using high-
throughput screening techniques capable of screening 4100 000 com-
pounds day1, applied to chemical ‘‘libraries’’ containing several million
compounds.25 The vast majority of chemicals are known to exhibit some
biological activity, so the screening assay is designed to identify only those
substances that exhibit the specific biological activity of interest. It is not
unusual for this initial screening step to generate several hundred potential
leads which then need to be refined down to 1 or 2 candidates for further
investigation. All these initial potential leads exhibit the relevant biological
activity but this may be accompanied by other less-welcome toxicological
properties which must be ruthlessly screened out of the selected set during
the refining period. Thus the final candidate(s) will have the desired bio-
logical activity, but few or no undesirable properties; the purpose of the
refining process is to eliminate those compounds with worse toxicological
profiles, many of which may already exist in the environment.
6 David Taylor
for new drugs.49,50 The majority of the candidate drugs never make it to the
market place because, during development, the drug is found not to work or
to have serious side effects that mean it can never be used in patients.
However, a small number of new pharmaceuticals do enter the market each
year and the patent system ensures that for a limited period of time the
innovating company retains exclusive rights to sell the pharmaceutical.
When the patent expires anyone is free to manufacture and sell what is now
termed a ‘‘generic pharmaceutical’’. The majority of pharmaceuticals, i.e. all
those that are out of patent, are therefore manufactured and sold by the
generic pharmaceutical companies. Generic pharmaceutical companies
never have an unsuccessful product, whereas the research pharmaceutical
companies rarely have a successful one. This has a major effect on the profile
of the business, the way in which companies are structured and the way in
which they operate.
Generic pharmaceutical companies are low-cost, low-margin and low-risk
businesses. The products that they choose to manufacture and sell have
already been shown to be valuable and commercially successful in the
market place. Generic companies do not need to incur any research and
development costs, although some of the larger companies do undertake
process-orientated R&D in order to introduce more efficient, and lower cost,
manufacturing. Although manufacturing in the industry is highly regulated,
product volumes are small and manufacturing costs are relatively low.
Marketing costs are also very low since the products are already well
established in the marketplace and the demand is well understood. In many
ways, generic pharmaceutical companies are in commodity markets where
competitive differentiation is based on cost of goods and profitability is
determined by market share.
The research pharmaceutical companies operate under a completely
different business model. It is these innovative companies that bring the
new pharmaceuticals to the market. This is very expensive, time consuming,
and involves extremely high risks. Research and development in the
pharmaceutical industry is very expensive, but it is the development activity
that dominates the costs, particularly in the clinical trials which follow the
pre-clinical development.
Research into ill health and disease can sometimes identify targets where
chemical intervention could generate positive outcomes. High-throughput
screening and other techniques can then be used to identify possible sub-
stances that might be suitable candidate drugs. The most likely candidate(s)
then move from research into development. This not only involves the major
issues of determining whether the candidate drug works satisfactorily
(efficacy) but also whether it causes any significant side effects (safety). It
is also necessary to investigate whether the active substance can be
delivered to the patient satisfactorily, i.e. can the substance be turned into a
useable drug?
The success rate though this development phase is extremely low: o1% of
candidate drugs eventually end up in the pharmacy. This rate is continuing
10 David Taylor
manufacture trial batches of the substances (the active ingredients) for use
in the subsequent clinical trials and eventually for full-scale manufacture.
In parallel, work will begin on the potential ‘‘druggability’’56 of these
substances, i.e. can the active ingredient be converted into a form that could
be taken by a patient such that the substance can interact with the target.
This is by no means a straightforward task. The ideal pharmaceutical from
the perspective of the patient is a tablet taken once a day. Any departure from
this ideal has an adverse impact on adherence, i.e. the likelihood that the
patent will actually adhere to the treatment regime. However, if, for example,
you need the pharmaceutical to be absorbed in the intestine, you have to
ensure that it is able to pass though the highly acidic conditions in the
stomach without being degraded, which can be a challenging problem.57
At the end of all this activity it is possible that a candidate drug, and
potentially a reserve candidate, will have emerged. The reserve candidate is
usually the second best candidate to emerge at this point and is the one that
can be taken forward rapidly to replace the lead candidate should any
unexpected problems arise during the clinical trials.
than 1 in 100 people will not have been identified previously.64 In addition,
the higher level of statistical power in the Phase 3 trial may also demonstrate
that the drug has, in fact, little if any efficacy.65 In fact, frequently the drug
doesn’t work or works much less effectively than originally predicted or only
works on a sub-set of the population. This information is itself immensely
valuable in furthering our knowledge and without this detailed empirical
evidence pharmacology would revert to merely anecdotal observation which,
in turn, would ensure that future developments in pharmacology would be
delayed.
Failures of drug candidates at this late stage in the process are, of course,
bad news for the business; by this point a very large amount of money, time
and research effort will have been invested, all of which will have been to no
avail. The impact on the morale of the research team should also not be
forgotten; it is not unusual for a medicinal chemist, for example, to have
spent his/her whole career in the industry and to have never worked on a
successful product. As a consequence, the industry has devoted considerable
efforts in the last few decades to address this problem of late-stage at-
trition.66 The result is that more and more promising drug candidates are
terminated early in the process, at the first sign of any potential problem,
which history tells us may have led to the unnecessary elimination of many
potentially successful drugs. For example, neither aspirin nor penicillin
would have made it to the market under today’s industry drug-development
regimes.
People are frequently surprised that drug development takes such a long
time. Approximately 10 years is likely to elapse between the news media
articles that ‘‘scientists have discovered a cure for X’’ and patients actually
receiving the medication, even if the development is successful. The reason
is that it actually takes this amount of time and the extensive clinical trial
procedures involved to discover if the treatment will actually work. However,
this raises ethical issues, particularly with life-threatening diseases where
patients and their doctors are desperate to try any new treatment as soon as
possible. This becomes a challenge when it seems clear from early trial data
that the drug may have significant beneficial outcomes, but by the time a
marketing authorisation is approved many potential patients will be dead.
Consequently a number of regulatory programmes67 now exist to provide
‘‘expanded access’’ or ‘‘compassionate access’’ to patients with serious or
life-threatening conditions who do not meet the enrolment criteria for the
clinical trial in progress when it is clear that patients may benefit from the
treatment, that the therapy can be given safely outside the clinical trial
setting, that no other alternative therapy is available, and the drug developer
agrees to provide access to the drug. These programmes are, however,
carefully managed so that the body of clinical trial data itself is not
compromised. However, there is increasing demand for wider and more
rapid access to unproven therapies where the need is severe.68
A successful conclusion of the phase 3 trials enables the innovating
company to assemble all the relevant data on the candidate drug for
The Pharmaceutical Industry and the Future of Drug Development 15
4 Commercial Realities
4.1 Problems with Patents
A successful pharmaceutical, once approved by medicines regulators such as
the FDA in the United States and the EMA in the European Community, can
then be sold. The innovating company will have already patented the drug
and thus has exclusive rights to sell the product until the patent expires.
However, although patents in developed countries are usually granted for
20 years, the window of sales exclusivity will be significantly less, in most
cases no more than 10 years. This is because the innovating company
needs to patent the drug well before its first launch in order to protect its
intellectual property. During this short period, of ten years or less, the
innovating company has to recoup all the R&D costs of both the drug(s)
being sold and of all the other drugs that failed during development,
together with the manufacturing and marketing costs. The instant that the
patent expires, generic competition will lead to a dramatic reduction in price
and major loss of market share.
The Pharmaceutical Industry and the Future of Drug Development 17
Table 1 Example of ‘‘pay for delay’’ mechanism.
Annual Profit/1000 Scrips
Patent Status Cost Price Scrip Price Patent Holder Generic Company
In patent $1 $10 $9000 $0
Expired $2 $1000 $1000
Patent holder pays generic company $2000/ $7000 $2000
1000 prescriptions to delay manufacture
and sale
Since patent life is one of the key determinants of the income that can be
generated from a product it is not surprising that research companies try to
extend patent life as much as possible.76 This ‘‘patent evergreening’’48 can
sometimes be done simply by patenting the manufacturing process or the
drug formulation or, in some cases, the drug delivery system, all of which
can be implemented much closer to the launch date. Generic companies, on
the other hand, endeavour to have patents set aside or to find ingenious
ways to get around the patents.
There has also been an increase in recent years in ‘‘pay for delay’’ agree-
ments between patent holders and generic manufacturers. Table 1 shows an
example of how these work. If the patent holder pays the generic company
not to manufacture then both the patent holder and the generic company
benefit, but the price remains higher after patent expiry than it would have
done. However, the legality of these deals is under question.77
It is not only the inevitable loss of market share from generic companies
that the innovating company must be concerned about. Once a candidate
drug is patented, many years before product launch, the concept and
principle on which the drug is based will become public knowledge. All
research pharmaceutical companies are keenly aware that everyone else is
keeping a close watch on their patents. Companies can be expected to begin
investigating interesting patents for areas of research in which they already
have major interests and it is, therefore, quite common for several drugs
with the same or similar modes of action to be simultaneously under
development in different companies, each one being carefully designed to
avoid infringing existing patents. Indeed, one of these follow-on drugs might
make it into the market first, which could have serious consequences for the
original innovator’s sales.
These drugs are often given the derogatory term ‘‘me-toos’’ and frequently
dismissed as being unnecessary and wasteful products of competition.
However, these drugs, which may only show incremental improvements on
the original, are nonetheless important to patients. It is frequently found
that a patient who cannot tolerate or fails to respond to one drug may benefit
from one of the ‘‘me-toos’’.78
This short and increasingly diminished patent life available after
pharmaceutical launch has consequences throughout the business. This has
been recognised by legislators and a number of mechanisms have been
introduced to provide extensions to marketing exclusivity in order to
18 David Taylor
companies to consider. For example, imagine the response that you would
get from a finance minister presented with the value proposition in the case
study above for the development of a single drug!
This then has a direct impact on research priorities. It is clear that despite
their size, pharmaceutical companies do not have sufficient resources to
work in all areas of medical need; however, because of development time-
scales and the need to spread their investment risk, they must work on
several candidate drugs simultaneously. In choosing which areas to work in,
a company must address the following question: assuming that our potential
candidate drugs in this area can be successfully marketed, will they generate
sufficient income during their patent life to cover their development costs, a
portion of the development costs of previously unsuccessful candidates and,
in addition, make an adequate return for the shareholders?
In other words, there needs to be a sufficiently large number of patients
who require the drugs and also these patients must be able to pay for them,
either directly or via insurance or taxation. It should, therefore, be no
surprise that pharmaceutical companies heavily invest in research into
chronic illnesses in the developed world, e.g. cancer, dementia, diabetes,
hypertension, etc., whilst paying scant attention to diseases that only affect
small numbers of patients.
economic. Antibiotics are used by patients for very short periods and sales
volumes are now insufficient to justify the necessary development costs. This
is exacerbated by the fact that any new antibiotic would now be prescribed
sparingly to ensure that antibiotic resistance was minimised. This problem
was identified as early as 200388 but only recently have serious attempts been
made to find a funding solution.89
The other requirement, in addition to having enough potential patients, is
‘‘ability to pay’’ or, more specifically, ‘‘ability to pay enough’’. This is a major
ethical dilemma for the pharmaceutical industry. It has two parts, one less
visible than the other. The less obvious issue is that it is a determinant of
which diseases receive attention. There may be a large number of potential
patients, but if none of them could afford to buy a newly developed drug
then such diseases are unlikely to be a research priority. The second issue
concerns access to medicines that have already been developed. Both issues
are now described as the access to medicines issue90 and every major
pharma company has a public policy relating to it, e.g. Pfizer.91
The first issue is being addressed by most of the major research
pharmaceutical companies who are now involved, often with philanthropic
partners, in altruistic drug-development programmes for diseases that
predominantly affect the developing world. For example, GSK has a major
drug development programme on malaria, jointly with the Gates
Foundation.92 None of these drug developments will be profitable; indeed,
most will cost money, leading to an overall reduction in profits, but the
major pharma companies accept that they have a social responsibility in this
area. Recently some pharmaceutical companies have begun to share their
entire libraries of chemical compounds, allowing other researchers to
look through them for promising drug candidates which the companies
themselves are unable to take into commercial development.93 This enables
charitable foundations, government agencies and academics to pursue
developments in these areas.
The second issue, ‘‘ability to pay’’, also has two components. It is primarily
a problem with pharmaceuticals that are still in patent, since the price of the
subsequent generic pharmaceuticals, which is available after patent expiry,
is much reduced. Traditionally this issue related solely to the developing
world and came to a climax in 1997 during the AIDS epidemic, where
millions of sufferers from the disease in Africa were unable to afford the
new retroviral pharmaceuticals that had been developed.94 Arguments over
the tension between international rights to patent protection and health
emergencies were eventually resolved and led to the Doha Declaration on
trade-related aspects of intellectual property rights (TRIPS Agreement) and
public health.95 In fact, many patented pharmaceuticals are now supplied to
developing countries at a fraction of the price that they are sold at in the
developed world.
However, this exacerbates the problem of parallel imports. Differential
prices for pharmaceuticals between developed and developing countries,
especially where the price difference is substantial, provide opportunities for
The Pharmaceutical Industry and the Future of Drug Development 23
A year later, in 2009, Bernard Munos said in print101 what had been
obvious to many in the industry for some time:
The fact that the ‘‘blockbuster’’ drug model doesn’t work has dramatic
consequences for the future of the industry. Profits from successful
pharmaceuticals are necessary to maintain the R&D effort, but unless new
pharmaceuticals replace successful pharmaceuticals when their patent
expires it becomes increasingly difficult to maintain the R&D. The scale of
the problem can be seen in Table 2.102
Faced with this ‘‘patent cliff’’, the industry has adopted two different
strategies: firstly, seeking to improve its record of innovation by acquisitions
of biotechnology companies, e.g. the acquisition of Medimmune by
AstraZeneca in 2007 for US$ 16 billion103 and the acquisition of Human
Genome Science by GSK in 2012 for $ 3.6 billion,104 together with a host of
other smaller ‘‘boutique’’ companies.
The second strategy has been to drastically reduce operating costs using a
combination of direct cost savings from improved efficiency coupled with
portfolio rationalisation, increased collaboration and extensive outsourcing.
As a result, the number of jobs in the global research pharmaceutical sector
fell by ca. 300 000 from 2000 to 2010.105 Despite these actions, innovation
rates have not yet improved.
The first three of the criteria listed in the table would lead to lower
residues of active substances entering the environment; in other words,
reduction at source. The last two would lead to even lower potential impact
of the residual active material on ecosystems.
Current developments are already leading to candidate drugs with a lower
potential for environmental impact. For example, a better understanding of
drug metabolism and pharmacokinetics can result in lower doses being
administered to achieve the same therapeutic effect. Similarly, shorter dur-
ation of therapy, better targeting and improved drug delivery combined with
increased specificity all lead directly to smaller emissions from the patient to
the environment and thus lower environmental residues.
As we have seen above, the industry continues to struggle with the legacy
problems of the ‘‘blockbuster’’ approach and is also suffering from a decline
in the rate of invention. However, two technical revolutions are underway
which may improve this situation and may also reduce the overall environ-
mental impact of the industry.
The first of these is the advance of biopharmaceuticals.111 The vast
majority of our existing pharmaceuticals consist of relatively small
molecules produced by chemical synthesis. However, advances in our
understanding of genomics and proteomics, coupled with our increasing
technological capability to manufacture very large molecules, are leading to
a rapidly growing interest in the use of biological as opposed to chemical-
based therapies. The first biopharmaceutical, synthetic insulin, developed
by Genentech and marketed by Eli Lilly, was approved for sale in 1982 and by
2013 there were 300 biological pharmaceuticals that had been approved by
the US FDA with a further 5400 under development in the USA alone. In
2012, based on worldwide sales, 7 of the top 10 drugs were biopharmaceu-
ticals112 and it is estimated that this area now accounts for more than 40% of
all drugs in development.
The fastest growth is in the area of monoclonal antibodies, which are
components of the human immune system and are considered by some to
be the perfect human medicines. They have major therapeutic advantages.
Their high potency means that patient doses can be small, which sub-
sequently then requires only small-scale manufacture. They have exquisite
specificity and can be targeted to human receptor sub-types responsible for
pathology or disease; thus they have substantially less potential for side
effects. These proteins are then rapidly metabolised by the human body to
produce fragments with no mammalian biological activity, thus avoiding the
possibility of producing metabolites with undesirable pharmacological
activity. From an environmental perspective these substances appear to offer
major advantages; most of these compounds produce little if any residues of
the active substance, which is in any case much less likely to exert any
adverse impact on the ecosystem, since it is specifically designed to interact
only with a diseased human receptor. However, the full environmental
relevance of these substances is not yet clear. Biopharmaceuticals are not all
28 David Taylor
easily biodegraded, and modified natural compounds even less so. Struc-
turally related compounds such as plasmids have already been detected in
the environment and it is known that the protein structures known as prions
are very environmentally stable.113
The second therapeutic revolution also stems from our improved under-
standing of genomics, although it is still in its infancy. This is the area of
‘‘personalised medicine’’.114 It has been known for many years that most
pharmaceuticals do not work successfully in all patients. It was suspected
that this was due to the slightly different genetic make-up of individual
patients, but lack of appropriate experimental techniques meant that this
could not be further investigated. However, the recent rapid advances in
the mapping of the human genome and subsequent development of the
scientific disciplines of genomics, proteomics and metabolomics is leading
us to a better understanding of the molecular signals of many diseases. The
expectation is that molecular screens combined with clinical data will point
to more precise treatment options for each patient sub-group. This should
enable much more precise and effective prescribing to occur which will, in
turn, mean less overall drug use, since every prescribed dose will be effective
first time.
6 Conclusions
The research pharmaceutical industry remains beset with problems, for
most of which there do not appear to be obvious solutions.
Although it has exclusive rights to the sale of a new drug during its patent
life:
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