Regulatory Landscape and Financial Analysis of Big Pharma Innovation

The Status of the Regulatory and Economic Landscape for Innovation in Big Pharma:
Commentary and Financial Analysis
SC 48100
Spring 2007
Dr. Rudolph Navari
University of Notre Dame
--------------------------
Lindsay Meyer
lmeyer2@nd.edu
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TABLE OF CONTENTS Page
I. Framework
a. Executive Summary/Abstract 3
b. Introduction 3-5
c. Brief History of the FDA 5-6
d. Discovery and Development Process
i. Preclinical Trials 6-7
ii. Clinical Trials 7-8
iii. The NDA & Review Process 8-9
e. Appraisal of the Current System 9-10
II. Key Players in the Branded Pharmaceutical Industry 10
a. Pfizer 10-12
b. Merck 12-14
c. Abbott 14-15
d. Wyeth 15-17
e. Bristol-Myers 17-18
III. Competitors
a. Specialist Biotech firms 18-19
b. Mid-cap 19-20
c. Generic 20
IV. Financial Background
a. Trends in R&D Spending 20-22
b. Relative Strength of each Pipeline 22-23
c. Clinical Applications 23
d. Economic Ramifications 23-25
Sources Used 26-28
Appendix
1 New Drug Development Process 29
2 R&D Spending of Selected Firms Matrix 30
3 3 Year Spending Trends 31
4 2004-05 Percentage Change Graph 32
2005-06 Percentage Change Graph 33
Overlay 34
5 Financial Statements 35-39
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EXECUTIVE SUMMARY (ABSTRACT)
The purpose of engaging this topic is to: examine the current regulatory environment for
new drugs, gain an understanding of breakthrough innovation in pharmaceuticals, evaluate the
efforts of key players, and make projections about the future of this industry. As therapeutics
has evolved away from their theistic origins, natural products, synthetic chemistry, and
biopharmaceuticals have emerged. Yet many difficulties remain for this specialized industry.
The approval process for a new drug can take upwards of eight years and cost $800 million.
The progression from test tube to commercial distribution includes preclinical trials followed by
three phases of clinical (human) trials, marked by ongoing dialogue between the Food and Drug
Administration (“FDA”). Five of largest American pharmaceutical companies have intensified
their efforts in Research and Development (“R&D”) in recent years. But in a space marked with
competition from generic manufacturers and maturing biotech companies, understanding the
dynamics of this highly scrutinized market requires an awareness of the political and economic
climate these key players face. Where this industry is headed is much less clear than where it
is coming from. Careful analysis is one lens through which to examine all of these intricate
elements and is the focus of this research paper.
INTRODUCTION
So long as humans have existed, there has been disease. This trend is written
throughout history as humans began to congregate in settlements some 5000 years ago.1
The
Ebers papyrus is among the earliest records of diseases and subsequent remedies dating back
to 1550BC.2
At this time in history, the prevailing mindset was that gods inflicted illness as a
punishment for wrongdoing. Therefore, medicines were aimed to ameliorate relationships with
the gods and improve human conditions.
1
Rang 3
2
Rang 3
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Fast forward several thousand years and we take note of the departure from the theistic
basis of medicine. A series of advances in the late 19th
century spurred the creation of an
“industry.” Three factors fostered progress. First, basic scientific innovation helped medicine
evolve in the empirical sense. Second, synthetic organic chemistry and the development of a
chemical industry in Europe aided growth. Third, the rise of entrepreneurship sparked medical
supplies trade in America.3
In aggregate, these essential ingredients have pushed us towards
today’s landscape. More importantly, our contemporary taxonomic system focused on chemical
structure arose during this period.
There are three main sources of drugs. Natural products include antibiotics, atropine,
digoxin, ephedrine, insulin, opium alkaloids, and vaccines. Synthetic chemistry gave rise to
antiepileptics, antihypertensives, bronchodilators, diuretics, and local anesthetics. Synthetic
chemistry has accounted for the majority of new drugs since 1950.4
Finally, biopharmaceuticals
– human insulin, growth hormone, interferon and the like have emerged from recombinant DNA
technology.
Though this continuum has evolved significantly, the challenges faced in modern
medicinal treatments are increasingly complex. The current state of regulatory affairs aims to
protect the health of American citizens. But a plethora of existing literature suggests that the
bureaucratic red tape encountered with the FDA and exorbitant costs discourages new drug
development. Merrill Goozner’s 2004 work, The $800 Million Pill, attempts to expose some of
the major shortcomings surrounding the current regulatory system. His startling conclusion is
that the big pharmaceutical companies are economies of scale, well-suited for their work… but
profiting handsomely while medical infrastructure crumbles in the wake of ever-increasing costs.
So what measures will be required for a dramatic overhaul of the system? Based on the
lengthy evolution towards status quo, it is unlikely that sweeping changes are in store anytime
3
Rang 4
4
Rang 9
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soon. Our best resource is knowledge. With an understanding of the “system” and the key
players in it, we become better equipped to navigate through the red tape to determine how
effectively the big companies are operating, particularly with respect to research and
development.
BRIEF HISTORY OF THE FDA
Many people would be surprised to learn that $0.25 of each consumer $1.00 spent is
tied to the FDA. Not only is this agency responsible for drugs, therapeutics and medical
devices, but it also patrols most food products, animal feed, and cosmetics.5
The 1906 passage
of the Federal Food and Drugs Act served as the official catalyst for the creation of the Bureau
of Chemistry. In July 1930, the name became as it is at present and in 1953, the Agency was
transferred from the Department of Agriculture to the Department of Health, Education and
Welfare. It was eventually transferred to its current home, the Department of Health and Human
Services upon the Department’s creation in 1980.
The political climate has been an influential factor in the FDA’s decisions in recent years.
Congress has passed laws which extend the patent term of drugs to compensate for the time
incurred in the review and approval process. They have also instituted specific procedures for
reimbursement to the FDA for review of drugs, helping to hasten the evaluation process.6
Congressional investigations coupled with external and internal committee reports have
probed into the agency's mission through much of the past century. Interestingly, many issues
which have which have polarized the American population come to light. These issues have
included sodium benzoate, sulfur dioxide, and other food preservatives during the Wiley era;
Banbar in the 1930s; aminotriazole-tainted cranberries in the 1950s; vitamins in the 1970s; and
5
Swann
6
Swann
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breast implants in the 1990s.7
Despite much attention being drawn to these and other high
visibility cases, they are just a small fraction of the agency's efforts, but remain key contributors
to 20th century U.S. history.
DISCOVERY AND DEVELOPMENT PROCESS – PRECLINICAL TRIALS
Long before drugs land in the hands of consumers, numerous phases of tests (see
Appendix 1) are performed to ensure that only the safest and most effective compounds make it
to market. Current estimates suggest that a period of eight and a half years is required to test a
new drug.8
Even before clinical trials may commence on potential new drugs, sponsors –
generally pharmaceutical companies, must submit data that demonstrates the new compound is
safe to for use in small clinical studies. This requirement can be fulfilled by compiling existing
non-clinical data from past in vitro lab studies on the compound or by compiling data from
previous clinical tests of the compound in another country, characteristically similar to the US.
Another option is to launch new preclinical studies to provide evidence supporting the safety of
administering the compound to humans.9
During preclinical development, the FDA likes to
obtain a pharmacologic profile of the drug, toxicity results in two species of animals, and short-
term toxicity studies ranging from 2 weeks to 3 months.
Before clinical studies commence, there must be compelling evidence which
demonstrates the biological activity of the compound to be examined. An apt corollary is having
data which demonstrates the safety of the drug for human testing. Preclinical meetings are
conducted to open the communication lines about testing phases, data requirements, and
unresolved scientific issues.
Animal studies are generally punctuated and minimized to insure humane care. In
general, one rodent and one non-rodent species are tested to determine if there are differences
7
Swann
8
Center - Development
9
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in how species react to the drug. Specific metrics obtained from animal studies include blood
absorption, toxicity, metabolites, and excretion.10
The initial phase of animal testing usually
lasts between two weeks and three months, with longer term testing continuing for several more
years. Animal testing often continues after human testing has commenced, to determine if there
are long-term birth defects associated with use. Animal testing forms the basis for clinical trials.
If early successes are demonstrated on animal subjects, the next course of study is with
humans.
CLINICAL TRIALS
Phase 1 clinical studies include the introduction of a new drug into humans. These
investigations are closely monitored and routinely rely on twenty to eighty healthy volunteer
subjects. The goal of this phase is to determine metabolic and pharmacologic actions of the
drug in humans. Any side effects associated with varying the dose are also studied. Being the
first step, the most emphasis is put on obtaining “sufficient information about the drug’s
pharmacokinetics and pharmacological effects” before moving forward with Phase 2 studies.
One possible outcome from Phase 1 is truncating the study due to safety reasons or failure to
disclose risks. It is significant to note that although CDER may offer advice in areas to the
sponsors, it may be disregarded so long as it does not pertain to patient safety. The more
hopeful of outcomes however, is approval to progress to Phase 2.
Phase 2 includes preliminary controlled clinical studies to gather data about the
effectiveness of a drug for a specific indication in patients with the disease or condition.11
This
step helps determine what side effects and risks are associated with the drug in the short term.
During this phase, tests are more tightly controlled tests are performed on several hundred
people. At the conclusion of Phase 2 testing, another series of meetings occur to determine
10
11
Schacter 104
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eligibility for advancing to Phase 3. An agreement between the Agency and sponsor is drafted
to help outline the objectives and plan for particular studies. This process is meant to assist in
avoiding excessive expenditures by clarifying expectations. Optimal productivity is achieved at
this meeting when the sponsor submits protocols for Phase 3 studies, in advance of the end of
Phase 2 meeting.
Assuming that the sponsor has been granted license to proceed, Phase 3 includes
larger scale controlled and uncontrolled trials on several hundred to several thousand subjects.
The intent of this phase is to gain clarity around the benefit-risk relationship of the drug.12
An
adequate basis for extrapolating results to general populations is established and provides
information pursuant to physician labeling.
Similar to Phase 1, clinical holds can be imposed during Phase 2 or 3 if the study is
deemed unsafe. Additionally, deficient protocols and the failure to meet stated objects can also
be grounds for a dismissal. Though many factors come into play, diplomacy is exercised by
taking great care not to make such determinations in isolation, but in reference to current
scientific knowledge, and experiences with the design of clinical trials or similar drugs under
investigation.13
THE NDA AND APPROVAL PROCESS
Following the three phases of clinical trials, a pre-NDA meeting is held to discuss the
application. Information communicated by the sponsor at this meeting includes a summary of
the clinical studies and the proposed format for organizing and presenting the data.14
This
meeting also serves to help the review committee become acquainted with the information to be
submitted. Subsequent meetings may occur in the 90 days after the submission of the
application to resolve issues originally uncovered.
12
Schacter 147
13
14
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The Center for Drug Evaluation and Research (“CDER”) is responsible for ensuring that
drugs are safe and effective.15
With a staff of 1,800 physicians, statisticians, pharmacists, and
chemists, this arm of the FDA does not test drugs but rather reviews each New Drug Application
(“NDA”). Pharmaceutical companies or the groups seeking to market the new drug must test it
and provide evidence regarding its safety and efficacy.
Beyond the CDER, Institutional Review Boards (“IRB's”) are utilized to ensure the rights
and welfare of those participating in clinical trials. The role of these boards is to make certain
that participants are fully informed and have given written consent before trials are initiated.16
IRB’s are monitored by the FDA with the sole purpose of protecting the welfare of participants in
medical research. They are generally composed of five or more experts and lay people with
diverse backgrounds, helping to ensure competence in professional conduct and practice.
APPRAISAL OF THE CURRENT SYSTEM
It is difficult to fathom just how costly the introduction of a new drug can be. It’s all
money… and big companies seem to have an endless supply of it. America benefits
significantly from having centralized policy-making in Congress, and a regulatory arm to protect
our health. It goes without doubt that there are flaws in the system and bipartisan discord is to
be expected. But deference to the government is in order for taking up these issues. For the
vast majority of the American public – uneducated in medicine or pharmacology, our lives
depend on the responsible decision making of those fit for the job.
The American system is one of the most sophisticated in the world. The lengthy process
of clinical trials converges to alphabet soup with NDA reviews by the CDER and IRB monitoring
but taking the long view demonstrates the necessity of maintaining bureaucratic elements.
Without the red tape, we would be a nation at risk. Further, a more thoughtful analysis also
15
Center - Application
16
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reveals that we would be a world at risk without the FDA. Developing and stabile countries alike
depend on the United States to be a model for establishing and maintaining high standards for
human health.
KEY PLAYERS IN THE BRANDED PHARMACEUTICAL INDUSTRY
A comprehensive analysis of Research and Development (“R&D”) spending was
conducted for five large pharmaceutical companies: Pfizer, Merck, Abbott, Wyeth, and Bristol-
Myers. To make projections and draw conclusions from any raw data, it is essential that we
begin by broadly summarizing the state of each company’s research initiatives, including unique
opportunities as well as challenges and threats. This probe will allow for a better-informed
critique of capital allocations.
PFIZER
Beginning with the highest-revenue generating company, Pfizer is entering a new
generation with Jeff Kindler at the helms as Chief Executive and Chairman of the Board.
Kindler has outlined 5 “immediate priorities” which include: (1) Maximizing revenues in both the
short and long term, (2) Establishing a lower and more flexible cost basis, (3) Creating smaller,
more accountable operating units that will enhance innovation and draw on the advantages of
scale and resources, (4) Actively and more meaningfully engage with customers, patients,
physicians, and other collaborators to provide them with greater value, and (5) Making Pfizer a
great place to work.”17
Pfizer’s 2006 Annual Report boldly states, “Pfizer has considerable
strengths – talented, experienced and dedicated people, outstanding medicines, a promising
pipeline, strong financial resources, and unmatched scale.”18
17
Strong 5
18
Strong 4
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This fanfare leaves something to be desired by way of research initiatives, but much of
the pomp and circumstance around meeting financial goals as delineated in the Annual Report
can be reduced to pleasing shareholders – the target audience. That said, Pfizer has
championed several recent additions to their portfolio of medicines including Lyrica for
neuropathic pain, Chantix for smoking cessation, and Sutent for cancer. Inhaled insulin under
the brand-name Exubera was released in 2006 as was Eraxis, an antifungal drug. In total,
Pfizer’s top nine medications grossed around $1 billion in 2006. Lipitor, the world’s best selling
drug, is Pfizer’s one true cash cow, and revenues from this drug were up 6%, year-over-year
between 2005 and 2006. Despite favorable research credits in over 100 clinical studies, this 6%
jump represents moderation from the previous year-over-year percentage change of +12%.
This pattern of exponential decay can feasibly be extrapolated as Lipitor’s exclusivity dwindles
and competition from other more cost-effective statin drugs cut into cash flows.
Loss of patent-protection of two important
drugs – Zithromax and Zoloft, was another hard hit
for the company in 2006. Both Zithromax
(azithromycin), and Zoloft (sertraline) are now
marketed and sold by generic drug makers. In
addition, closure of five research facilities does not
bode well for the future of research and development
at Pfizer. The lofty goal of “tripling the Phase III R&D
pipeline by the end of 2009, and then introducing four
new internally developed products each year
beginning in 2011”19
seems to require a substantial
commitment to research and cooperation with the
Figure 1 Pfizer’s Nine
Therapeutic Areas
19
Strong 7
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FDA. On the offensive, Pfizer claims that its current pipeline is the strongest in the firm’s history
and that its organizational structure, known as the “Therapeutic Area Model” is a sustainable
competitive advantage. This model reduces to nine Therapeutic Areas –
Cardiovascular/Metabolic/Endocrine, Oncology, Neuroscience, Infectious Disease, Pain,
Inflammation, Ophthalmology, Allergy/Respiratory, and Genitourinary – all representing unmet
medical needs (see Figure 1).20
As of January 2007, Pfizer’s pipeline included 131 compounds in Phase I trials, 37 in
Phase II trials, 5 in Phase III trials, and 4 in Registration. They also had 72 product-line
extensions, accounting for 249 total programs.21
Their leadership in tyrosine kinase inhibition
and DNA-based vaccines is promising in the treatment and prevention of disease. So is Pfizer
truly “working for a healthier world” as suggested by the company slogan? Status quo, all signs
point to yes.
MERCK
Merck has been the rock in a hard place since it voluntarily removed Vioxx from the
market in 2004. An appraisal of Merck’s 2006 Annual Report demonstrates their continued
commitment to the “Plan to Win,” an initiative unveiled by Chief Executive and Chairman Dick
Clark in the 2005 Annual Report. Situated amongst glitz and glamour about generating
shareholder value and developing flexible cost structures is plenty of useful information about
the progress the company is making on the R&D front. Five new products were launched in
2006. Gardasil, the cervical cancer vaccine has been hailed by TIME Magazine as one of
2006’s Inventions of the Year. With an estimated 50% of women becoming infected with human
papillomavirus during their lifetime and some 240,000 of them dying annually from cervical
cancer, the market for this drug is obviously large. This vaccine received public attention earlier
20
Strong 13
21
Strong 22
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this year as Texas governor, Rick Perry issued an executive order mandating that the vaccine
be administered to all girls entering the sixth grade in the state as of September 2008.22
Texas
was not the lone state to make such moves. By February 2007, some 20 other states had
explored similar legislation. But on April 25, 2007, the Texas legislature overruled Perry’s
executive order, thereby forbidding mandatory vaccination until at least 2011. The conflict of
interest? Perry’s Chief of Staff is on Merck’s Texas lobbying team. Merck contributed $6000 to
Perry’s election campaign. Public drama aside, the vaccine has quickly been catapulted into
the national spotlight and offers protection from 70% of HPV-related cervical cancer cases.
Also on the vaccine front was the 2006 introduction of Zostavax, aimed at preventing
shingles and Rotateq, which offers immunity to the rotateq virus. Additional product launches
included Januvia, a treatment for Type 2 diabetes, and Zolinza, a treatment for cutaneous T-cell
lymphoma. In 2007, the company plans to file three NDA’s with the FDA for drugs like
raltegravir,, a promising first-in-class treatment for HIV infection; gaboxadol, a novel compound
to treat insomnia; and a compound that combines Merck’s own extended-release niacin with
laropiprant. This last compound, also known as MK-0524A, is expected to further help patients
manage cholesterol by decreasing LDL cholesterol, increasing HDL cholesterol and lowering
triglycerides.23
As of February 2007, Merck had 29 compounds in Phase I Clinical trials, 20 compounds
in Phase II trials, and 5 in Phase III. Three drugs were under review, Emend, Janumet, and
Arcoxia. Despite success in 2006 with five product approvals, Merck is off to a dismal start to
2007 with the rejection of Arcoxia on April 28, 2007. A letter to the company stated that they
“would need to provide additional data in support of the benefit-to-risk profile for the proposed
doses of Arcoxia in order to gain approval.”24
22
Carreyrou
23
Five 2
24
Dooren
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The resilience of Merck in locating strategic opportunities in the osteoarthritis market in
the wake of the Vioxx catastrophe, demonstrates their resolve to rise above setbacks. As the
Vioxx lawsuits continue, Merck’s track record is now a respectable ten wins and five losses.25
Armed with skilled defense attorneys and cash flows from new drugs, the Vioxx legal battles
seem less of an impediment to their growth. It is possible that Merck will come to define the first
decade of the 21st
century as one of their best, rather than one of their worst.
Figure 2 Abbott’s Key
Business Areas
ABBOTT
Abbott Chief Executive and
Chairman Miles White had a busy but
productive 2006, overseeing the
acquisitions of both the former Guidant’s
vascular business and Kos
Pharmaceuticals. As a leader in the
broader healthcare market, Abbott
differs slightly from its purebred
pharmaceutical competitors. The company operates in three key business areas (see Figure 2)
including medical products, nutritional products, and pharmaceuticals. This diversified array of
products helps to normalize cash flows, with the potential of one business unit to act as a hedge
against another’s underperformance. This model, while not unheard of for companies in the
healthcare industry, has also contributed to firm-wide growth in revenues.
Humira is Abbott’s flagship biologic for the treatment of autoimmune disorders in which a
human protein, tumor necrosis factor (TNF), plays a role in disease progression. Humira is a
fully human monoclonal antibody that blocks TNF, reducing inflammation.26
The drug, a long-
25
Tesoriero
26
2006 Annual 35
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term growth driver, is now being reviewed for it’s usefulness in treating Crohn’s disease. The
Humira pen, a one-touch, easy-to-grasp device that offers patients an easier way to self-
administer Humira was also recently launched. Abbott continues to study other indications for
which Humira could be effective including psoriasis, juvenile RA and ulcerative colitis. They
also expect to submit a new drug application for psoriasis in 2007.
Abbott’s pipeline is markedly weaker than that of Pfizer or Merck. It is also far less
publicized and required some digging around to find. A February 2007 presentation used at the
Merrill Lynch Healthcare Conference highlights early state programs in oncology, neuroscience,
and infectious disease. The Phase III trials of their psoriasis drug, are right on track and a NDA
will be filled for a controlled-release Vicodin in 2007, at the conclusion of Phase III testing.27
Opportunities in the statin market also exist and a compound which combines TriCor and
Crestor is also in Phase III testing. Simcor, a fruit of the Kos acquisition, is viewed as a “next
generation Niaspan”28
and also in late-stage clinical testing.
Despite over-reliance on Humira, Abbott is well-positioned in the short-term with many
effective compounds in Phase III clinical trials. However, they will need to continue working on
new projects to ensure that their consistent stream of new drugs continues to flow from pipeline
to patient.
WYETH
Wyeth had an excellent 2006, posting $1 billion in revenues each for six different
products. The company also made great strides in biotechnology, becoming the fourth largest
company in this more specialized field.29
Four NDA’s were filed and in January 2007, a
serotonin-norepinephrine reuptake inhibitor called Pristiq was approved. Wyeth currently
remains exclusivity rights for Effexor and Effexor XR, the world’s leading antidepressant
27
Freyman - Merrill
28
Freyman - Cowen
29
Leading 1
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franchise.30
Prevnar, another Wyeth product is the world’s best selling vaccine with some 42
million doses manufactured in 2006.31
Despite recent press questioning the risk-benefit profile
of hormone therapy in women, the company’s Premarin sales were up 21% in the US last year.
It’s apparent that the company is experiencing “good times” and easily meeting its goal
of submitting two NDA’s each year. In the past six years, 75 new drug therapies have been
placed into development, with the majority having the potential to become first-or-best in class
therapies.32
The Wyeth pipeline can be isolated into six core areas: Women’s Health and Bone,
Vaccines and Infectious Disease, Neuroscience, Inflammatory Disease,
Oncology/Immunology/Hemophilia, and Gastrointestinal/Metabolic. Many compounds are being
reviewed for efficacy under multiple indications and research efforts eclipse small molecules,
biologics, and vaccines.33
Robert Essner, Chief Executive and Chairman, has a pet project of his own. His special
focus is working to combat Alzheimer’s disease. He recently articulated the scope of the
problem by saying, “I know of no disease in our country where more patients are waiting with so
much need and so little hope. It does not have to be so.”34
With 4.5 million sufferers, Essner
has passionately taken up the issue, engaging politicians and clinicians alike to encourage
additional research and accelerated and informed drug reviews.35
Seeking a sustainable competitive advantage of its own, Wyeth recently implemented its
Learn and Confirm paradigm for drug development. This system is a two-phase approach to
streamlining the traditional multiple phases of development. The effort places additional
emphasis on high-performing teams, quick and efficient decision making and improved clinical
trial designs.36
By partnering with a worldwide logistics provider, the company is also able to
30
Leading 2
31
Leading 2
32
Leading 7
33
Leading 4
34
Leading 27
35
Leading 5
36
Leading 4
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accelerate the shipment of clinical trial materials. This approach to re-engineering the
development process will help Wyeth remain a formidable competitor for years to come.
BRISTOL-MYERS
Bristol-Myers was the only company to outwardly proclaim 2006 as a year of transition.
With the departure of Peter Dolan as Chief Executive, James Cornelius assumed the interim
position and was named permanent CEO on April 26, 2007.37
Their Annual Report began by
immediately addressing the concerns regarding Plavix and patent infringement by Apotex.
Making no effort to disguise the issues, Chairman James Robinson wrote, “Clearly, our Plavix
business – and the company’s financial strength and reputation – were seriously damaged by
this turn of events. It was a major setback that we sincerely regret.”38
Despite the problems with
Plavix, Bristol-Myers successfully launched four new products. Orencia treats rheumatoid
arthritis, Sprycel is a promising alternative for leukemia patients resistant to Gleevac, and Atripla
is a once-per day formulation of AIDS drug Sustiva.39
Licensing agreements with Somerset
Pharmaceuticals have also led the company to introduce EMSAM, a transdermal patch to help
combat depression in adults. Figure 3 Bristol-Myers’ pipeline
In the wake of setbacks
with Plavix, the company has been
aggressively pursuing the so
called pipeline within a product.
By expanding the range of
diseases which Erbitux and Abilify
are available to treat and
37
Lublin
38
Together 2
39
Together 2
Page 17 of 39

introducing hepatitis-B drug Baraclude into Asia where the disease runs rampant, have all
helped to bolster the company’s financial health.
So what’s inside the Bristol-Myers bag of tricks? There are six compounds in Stage III
clinical trials (see “Life Cycle Management” in Figure 3) three of which are oncologic agents – a
historically strong area for the company. 40
However, it is evident that as the company
continues to struggle on a financial basis... a problem which has unfortunate consequences for
R&D efforts. Collaborations to co-develop were highlighted, enabling the company to “share
costs and risks.”41
SPECIALIST BIOTECH FIRMS
While the pure-play pharmaceutical companies continue making strides, the likes of
Amgen and Genentech have risen to an equally powerful status. In 2002, one third of all
research projects in clinical trials involved biopharmaceuticals.42
Making use of the “low
hanging fruit of the biotechnology revolution,” Amgen was the first to package a recombinant-
engineered version of erythropoietin, the enzyme produced in the kidney which signals bone
marrow to manufacture red blood cells.43
Yet recent problems with these drugs have arisen for
Amgen, and mandates from the FDA to include the “black-box warning” about using the lowest
possible dose44
have led many speculators to believe that the company is experiencing growing
pains.
Amgen has continually typified success. An investment of $100 in 1980 was worth $1.5
million at the height of the tech boom in 2001.45
The company landed applause from Forbes –
as the Company of the Year in 2004. But as Marilyn Chase of the Wall Street Journal writes,
“Amgen has arrived as a big pharmaceutical company – and now confronts some of the same
40
Together 3
41
Together 3
42
Lednicer 325
43
Goozner 2
44
Harper
45
Goozner 2
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problems as Pfizer Inc. or Merck & Co. Among them: heavy reliance on a few blockbusters, an
uncertain pipeline of new drugs despite heavy research spending, questions about safety and
marketing and, recently, the prospect of competition from generics makers.”46
While it certainly is not fair to frame the mega-cap pharmaceutical titans as failures, the
article helps to illustrate an important point. The press has all but reduced big pharma as
robber-barons of the 21st
century; gouging consumers, and contributing to the major
shortcomings of the United States healthcare system. Assuming this to be true, the rise of
biotech firms into companies which become characteristically similar to the biggest names in
pharmaceuticals, while exciting, is alarming in it’s own regard.
MID-CAP FIRMS
Also worth mentioning are the Sepracor’s of the world… high-potential drug makers with
specialized niches. For Sepracor, there is dominance in the insomnia market with Lunesta and
the asthma/COPD markets with Xopenex. But with just four products47
in its pipeline, it can’t
reasonably expect to rise to blue chip status without large capital injections or strategic
acquisitions. In the middle of 2006, there was speculation that Pfizer was contemplating making
a stab at Sepracor, but the rumors never materialized. Sepracor continues to gain brand
recognition and market share with Lunesta – whose revenues skyrocketed 31% between 2005
and 2006.48
For Sepracor and other firms in this mid-market genre, a suitable exit strategy is sale to
a larger company with the resources to help market and distribute the drug on a global basis.
However, it’s worth mentioning that valuable scientific innovation is fostered at smaller
pharmaceutical companies. They play an important role in focused and specialized drug
development, likely benefiting society more broadly than most people recognize by taking a
46
Chase
47
Products
48
Gaining
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disciplined and careful approach to drug development. Other companies that fit this archetype
include Gilead Sciences, Invitrogen Corp., and MedImmune.
GENERIC COMPETITORS
Each year, an average of 22 drugs loses patent protection.49
Commercial sales of
branded drugs generally fall to half their peak by six years after patent expiration and approach
zero at twenty years from expiration.50
The major advantage to being in the generic drug
industry is that the initial investment in research and development is forgone completely
because the technology has already been brought to market. To retain a competitive edge,
many drug makers have shifted their efforts into evaluating existing drugs feasibility for
treatment of other conditions than currently approved and marketed for. Successfully
demonstrating that a compound is capable of treating other conditions is grounds for extension
of exclusivity rights for the sponsoring organization.
For most consumers, the availability of generic drugs helps to diffuse high healthcare
costs. Consequently, generic drug manufacturers have gained prominence and popularity with
the public. This competitive pressure has steered many pharmaceutical companies towards
pioneering studies to examine the efficacy of existing products at treating other diseases. This
is all in hopes of retaining patent exclusivity in the shadow of heightened generic competition.
Unfortunately, by and large this practice is futile. It is an irresponsible use of shareholder
dollars, and a negative externality of the free-market system.
TRENDS IN R&D SPENDING
In an industry where 70% of profits are generated by 20% of the drugs marketed, there
is a huge incentive to discover the next blockbuster drug – one which generates more than $1
49
Lednicer 322
50
Scacter 203
Page 20 of 39

billion in annual sales. Between 1982 and 1998, US-based companies’ spending on R&D
efforts jumped from $5 billion to $40 billion.51
At present, approximately 15-20% of total sales
are reinvested into R&D, a percentage higher than any other industry. Of this spending, a full
third is committed to discovery, two-fifths to preclinical and clinical development, and the
balance to regulatory and miscellaneous expenses.52
Surprisingly, there has been a movement
away from cardiovascular disease, even as rates continue to spiral upwards. The priority
spending areas have been in treatments for metabolic disorders and cancer.
For the past three years, Merck has been the most aggressive spender (see Appendix 2)
among the comp group studied. Merck pumped a record-setting 21.6% of total revenue into
R&D in 2006. Abbott has been somewhat of the anomaly, allocating a smaller percentage
(≤10%) annually. However, Abbott operates three business segments and R&D efforts on the
pharmaceutical front are only one third of their overall investment in research. It is impossible to
position the spending trends of the studied firms on a spectrum. Individual circumstances and
preferences fluctuate each year, such that no singular company is likely to retain the top
position for a longer time horizon.
R&D spending in 2006 was higher than that of 2004 for all companies studied (see
Appendix 3). Three companies, Merck, Wyeth, and Bristol-Myers spent a greater percentage
each year. Two companies, Pfizer and Abbott decreased spending between 2004 and 2005,
then increased spending between 2005 and 2006 – to a higher margin then that of the decrease
subsequently spending a greater percentage in 2006 than 2004.*
Another useful method for displaying these spending habits is to examine year-over-year
percentage changes of the raw amount spent by each firm (see Appendix 4). Between 2004
and 2005, both Pfizer and Merck spent less overall dollars on R&D, despite spending as a
51
Lednicer 312
51
Lednicer 312
*The liability in using percentage of total revenue as a basis for benchmarking spending is that total revenue also
fluctuates. Therefore, our analysis becomes skewed as revenue rises and falls. But on an absolute basis, comparisons
are no more effective because of differences in size between firms. Ratios, while not free from error, are the most effective
tool in comparative financial analysis.
Page 21 of 39

percentage of total revenue remaining flat. Between 2005 and 2006, all five companies spent
higher amounts, with Pfizer still lagging and Merck jumping 24.3%. The other mover and shaker
during this period was Abbott who made a swing of its own, from a modest 7.3% increase to a
23.8% increase. An overlay of these percentage changes is provided in Appendix 4 and
illustrates the magnitude of these oscillations.
While this data is telling, it only represents a snapshot of the bigger picture, because of
the condensed time horizon. Three years is hardly representative of anything, especially given
that the broader economic conditions during these years went relatively unchanged. Still, the
nagging question remains. Does being the most aggressive financier of research efforts always
yield the highest payoffs?
RELATIVE STRENGTH OF PIPELINE
An appraisal of each company’s pipeline is one method for determining the fruits of
research investments but is far from perfect. With five glossy Annual Reports each claiming to
have the “best” or “strongest” pipeline, finding fact from fiction is a task of its own.
Quantitatively, Pfizer’s 249 said programs far exceed that of any of its closest competitors. In
this numbers game where so many compounds will fail at each subsequent level of testing,
having more compounds to start with is a true advantage. Yet the benefits of being big will not
pay off for several more years. Just because Pfizer’s pipeline is the most well endowed today,
does not mean that it is the leader in the field today. Investments in R&D serve as a bellwether
for current financial health, but are also one of the strongest predictors of future franchise
success.
Pfizer’s market capitalization gives it a special advantage. On an efficiency basis, the
likes of Merck and Abbott are doing just as well given their size and scale. At a certain
threshold, the law of diminishing marginal returns will also become a factor, reducing the yield
on subsequent inputs. With fixed parameters (employees, laboratory space, and capital)
Page 22 of 39

pharmaceutical companies are only capable of set levels of R&D activity. Therefore, making
prudent decisions and managing multiple projects is critical.
PROBABLE CLINICAL APPLICATIONS
Domestically there will surely be a heightened emphasis on individualized medicine
going forward. As biopharmaceuticals establishes a firm place within healthcare, technology will
likely reflect the demand for it. This is notable because the framework established to ensure the
quality, safety, and efficacy or conventional synthetic drugs is not entirely appropriate for
biopharmaceutical products.53
Preventative medicine also continues to gain popularity and with
the rise of this trend has come increased interest in vaccines. Particularly for developing
nations, such products will deliver immunity from simple diseases, furthering the prospects for
global industrial development.
New medicines will be necessary to combat problems like obesity which have continued
rising to an epidemic proportion. As diagnostic capabilities improve, so will the ability of drug
companies to treat these conditions. We may still be years away from the magic bullet for
cancer or AIDS, but the effort continues on the research front. To our advantage, as the
amount of research data compounds almost exponentially, new treatments can be developed
more efficiently.
BROADER ECONOMIC RAMIFICATIONS
Having vigorously explored the landscape for pharmaceutical innovation, it is clear that
markets provide some tremendous advantages. A fair and just evaluation of the industry
requires much deference to the progress which has been made on multiple fronts – from the
regulatory end to the clinical front. Taking a more disciplined view requires one to become an
advocate of a particular party. Framing this analysis from different perspectives leads to vastly
53
Lednicer 290
Page 23 of 39

different conclusions. Assuming the role of policy-maker is completely different from the role of
a patient, a clinical research director, or even a top executive at a major pharmaceutical
company. But policy-makers, clinical research directors and even top executives have all been
a patient requiring treatment for an illness or injury at one time or another. From this
perspective, we can all laud the innovative breakthroughs which have helped to drastically
improve the quality of life.
Still, challenges remain. A recent showdown between the Thai government and Abbott
Laboratories underscores the conflicts that remain for pharmaceutical companies hoping to
profit by introducing drugs in developing countries. The government, striving to act in the best
interest of its citizens informed Abbott that the patent on their costly Kaletra AIDS medicine
would be broken. This would allow Thailand to produce or import cheaper versions of the drug.
Abbott fought back by announcing in March 2007 that they would halt the introduction of new
drugs in Thailand. This brought a surge of unrest by activists and a crescendo of bad publicity.
By April 24, 2007, Abbott had reversed its decision saying that it would introduce Kaletra in
Thailand, if the government respects its patent. Perhaps Thailand is a poor example of the
friction between government and drug companies due to its recent coup. Some pharmaceutical
executives question the actions of government in the wake of this takeover, suggesting that the
government is only trying to win the favor of citizens.54
Who wins in this mess? Most people would concede that the dynamics of the current
system are not accommodative to patients. But is it the blue chip behemoths themselves that
live lavishly off of their one-hit wonders? The business cycle suggests that continued growth is
not always possible and that in time, even the best-positioned of companies will experience a
downturn. Competition will always remain a powerful contingent as well but generic alternatives
generally do not often become an option until many years after a new drug is introduced.
Protecting the interests and investments of the major drug manufacturers remains important.
54
Hookway
Page 24 of 39

Without the incentive to produce, scientific innovation might stall, leaving patients behind. For
this reason, there is still careful work to be done. Who will ultimately be responsible is not
strictly black and white but to fully address the US healthcare crisis, pharmaceutical reform of
some scale will be absolutely essential.
Page 25 of 39

SOURCES USED
2006 Annual Report. Abbott Laboratories.
<http://www.abbott.com/global/url/content/en_US/70.10.20:20/general_content/General_
Content_00125.htm>.
Center for Drug Evaluation and Research. “Drug Approval Application Process.” 2006. US
Food and Drug Administration. 11 Apr. 2007
<http://www.fda.gov/cder/regulatory/applications/default.htm>.
Center for Drug Evaluation and Research. “The New Drug Development Process.” 21 Feb.
2007 <http://www.fda.gov/cder/handbook/>.
Dooren, Jennifer Corbett. “U.S. Regulator Rejects Merck Drug.” Wall Street Journal. 28 Apr.
2007 < http://online.wsj.com/article/SB117768083169584816-
search.html?KEYWORDS=merck+arcoxia&COLLECTION=wsjie/6month>.
Carreyrou, John and Rubenstein, Sarah. “Merck Ends Lobbying for Cervical Cancer Vaccine.”
Wall Street Journal. 2 Feb. 2007
<http://online.wsj.com/article/SB117200727319814015-
search.html?KEYWORDS=texas+gardasil&COLLECTION=wsjie/6month>.
Chase, Marilyn. “Amgen’s Star Fades Amid Safety Questions.” Wall Street Journal. 10 Apr.
2007. <http://online.wsj.com/article/SB117616926211164674-
search.html?KEYWORDS=amgen&COLLECTION=wsjie/6month>.
“Five Patients, Five Lives, Five Breakthroughs.” 2006 Annual Report. Merck & Co.
<http://phx.corporate-ir.net/phoenix.zhtml?c=73184&p=irol-reportsannual>.
Freyman, Thomas. “Cowen Healthcare Conference.” Presentation. 14 Mar. 2007
<http://library.corporate-ir.net/library/94/940/94004/items/235754/cowen0307.pdf>.
Freyman, Thomas. “Merrill Lynch Healthcare Conference.” Presentation. 7 Feb. 2007
<http://library.corporate-ir.net/library/94/940/94004/items/230382/ML0207071.pdf>.
Page 26 of 39

Gaining Momentum.” 2006 Annual Report. Sepracor Inc. < http://phx.corporate-
ir.net/phoenix.zhtml?c=90106&p=irol-reports>.
Goozner, Merrill. The $800 Million Pill: The Truth Behind the Cost of New Drugs. Los Angeles:
University of California Press, 2004.
Harper, Sean and Kamin, Marc. “Important Drug Warning and New Prescribing Information.”
2007. Amgen. 28 Mar. 2007
<http://wwwext.amgen.com/pdfs/misc/healthcare_professionals_letter.pdf>.
Hookway, James and Zamiska, Nicholas. “Thai Showdown Spotlights Threat to Drug Patients.”
Wall Street Journal. 24 Apr. 2007
<http://online.wsj.com/article/SB117735181629579246-
search.html?KEYWORDS=thailand+abbott&COLLECTION=wsjie/6month>.
“Leading the Way to a Healthier World.” 2006 Annual Report. Wyeth. <http://phx.corporate-
ir.net/phoenix.zhtml?c=78193&p=irol-reportsannual>.
Lednicer, Daniel. New Drug Discovery and Development. Hoboken: John Wiley & Sons, Inc.,
2007.
Lublin, Joann and Rubenstein, Sarah. “Bristol will name Cornelius CEO.” Wall Street Journal.
26 Apr. 2007 < http://online.wsj.com/article/SB117751174939782051-
search.html?KEYWORDS=bristol+myers&COLLECTION=wsjie/6month>.
“Products and Pipeline.” 2006. Sepracor. 28 Mar. 2007
<http://www.sepracor.com/products/index.html>.
Rang, H P. Drug Discovery and Development: Technology in Transition. Edinburgh: Elsevier,
2006.
Schacter, Bernice. The New Medicines: How Drugs are Created, Approved, Marketed, and
Sold. Westport: Praeger Publishers, 2006.
“Strong Medicine – Our Prescription for Change.” 2006 Annual Report. Pfizer, Inc.
<http://www.pfizer.com/pfizer/are/investors_reports/index.jsp>.
Page 27 of 39

Swann, John P. “History of the FDA.” US Food and Drug Administration. 20 Mar. 2007
<http://www.fda.gov/oc/history/historyoffda/default.htm>.
Tesoriero, Heather. “Vioxx Federal Trial – Three’s a Charm?” Law Blog. 2007. Wall Street
Journal. 24 Apr. 2007. <http://blogs.wsj.com/law/?mod=home_law_left&paged=2>.
“Together We Can Prevail.” 2006 Annual Report. Bristol-Myers Squibb.
<http://investor.bms.com/phoenix.zhtml?c=106664&p=irol-reportsannual>.
Page 28 of 39

APPENDIX 1 – NEW DRUG DEVELOPMENT PROCESS55
55
http://www.fda.gov/cder/handbook/develop.htm
Page 29 of 39

APPENDIX 2 – R&D SPENDING OF SELECTED FIRMS
R&D Spending of Selected Pharmaceutical Firms, 2004 – 2006
(Percentage of Total Revenue)
2004 2005 2006
17.5%
14.6%
14.2%
12.9%
8.6%
17.5%
14.7%
14.5%
14.3%
8.2%
21.1%
17.1%
15.7%
15.3%
10.0%
Page 30 of 39

APPENDIX 3 – THREE YEAR SPENDING TRENDS
3 Year Spending Trends
14.6%
17.5%
8.6%
14.2%
12.9%
14.5%
17.5%
8.2%
14.7%
14.3%
15.7%
21.1%
10.0%
15.3%
17.1%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
Pfizer Merck Abbott Wyeth Bristol-Myers
PFE MRK ABT WYE BMY
Firm and Ticker
SpendingasaPercentageofTotalRevenue
2004 2005 2006
Page 31 of 39

APPENDIX 4A – PERCENTAGE CHANGE 2004 – 05
Change in R&D Spending: 2004-05
-3.1%
-4.0%
7.3%
11.7%
9.8%
-6.0%
-4.0%
-2.0%
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
PFE MRK ABT WYE BMY
Firm and Ticker
Year-over-YearPercentageChange
Page 32 of 39

APPENDIX 4B – PERCENTAGE CHANGE 2005 – 06
Change in R&D Spending: 2005-06
2.1%
24.3%
23.8%
13.1%
11.7%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
PFE MRK ABT WYE BMY
Firm and Ticker
PercentageChange
Page 33 of 39

APPENDIX 4C – PERCENTAGE CHANGE OVERLAY
Change in R&D Spending
-3.1%
-4.0%
7.3%
11.7%
9.8%
2.1%
24.3% 23.8%
13.1%
11.7%
-10.0%
-5.0%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
PFE MRK ABT WYE BMY
Firm and Ticker
PercentageChange
2004-05 2005-06
Page 34 of 39

APPENDIX 5A
Pfizer Inc.
Statement of Profit & Loss56
Calendar Years 2004 - 06
PERIOD ENDING 31-Dec-06 31-Dec-05 31-Dec-04
Total Revenue 48,371,000 51,298,000 52,516,000
Cost of Revenue 7,640,000 8,525,000 7,541,000
Gross Profit 40,731,000 42,773,000 44,975,000
Operating Expenses
Research Development 7,599,000 7,442,000 7,684,000
Selling General and Administrative 15,589,000 16,997,000 16,903,000
Non Recurring 2,158,000 3,044,000 2,264,000
Others 3,261,000 3,409,000 3,364,000
Total Operating Expenses 28,607,000 30,892,000 30,215,000
Operating Income
or Loss 12,124,000 11,881,000 14,760,000
Income from Continuing Operations
Total Other Income/Expenses Net 1,392,000 124,000 -406,000
Earnings Before Interest And Taxes 13,516,000 12,005,000 14,354,000
Interest Expense 488,000 471,000 347,000
Income Before Tax 13,028,000 11,534,000 14,007,000
Income Tax Expense 1,992,000 3,424,000 2,665,000
Minority Interest -12,000 -16,000 -10,000
Net Income From Continuing Ops 11,024,000 8,094,000 11,332,000
Non-recurring Events
Discontinued Operations 8,313,000 16,000 29,000
Extraordinary Items - - -
Effect Of Accounting Changes - -25,000 -
Other Items - - -
Net Income 19,337,000 8,085,000 11,361,000
Preferred Stock And
Other Adjustments - - -
Net Income
Applicable To
Common Shares $19,337,000 $8,085,000 $11,361,000
56
Data from CaptialIQ
Page 35 of 39

APPENDIX 5B
Merck & Co.
Total Revenue 22,636,000 22,011,900 22,938,600
Cost of Revenue 6,001,100 5,149,600 4,959,800
Gross Profit 16,634,900 16,862,300 17,978,800
Operating Expenses
Non Recurring 142,300 322,200 -
Others - - -
Total Operating Expenses - - -
Operating Income
or Loss 3,544,300 5,536,600 6,622,300
Total Other Income/Expenses Net 878,300 2,334,600 1,352,200
Interest Expense 375,100 385,500 -
Income Tax Expense 1,787,600 2,732,600 2,161,100
Minority Interest -120,500 -121,800 -
Discontinued Operations - - -
Effect Of Accounting Changes - - -
Other Items - - -
Net Income 4,433,800 4,631,300 5,813,400
Preferred Stock
And Other
Adjustments - - -
Net Income
Applicable To
Common Shares $4,433,800 $4,631,300 $5,813,400
57
Data from CaptialIQ
Page 36 of 39

APPENDIX 5C
Abbott Laboratories
Total Revenue 22,476,322 22,337,808 19,680,016
Cost of Revenue 9,815,147 10,641,111 8,884,157
Gross Profit 12,661,175 11,696,697 10,795,859
Operating Expenses
Non Recurring 2,014,000 17,131 279,006
Others - - -
Operating
Income or Loss 2,042,219 4,362,268 3,898,320
Total Other Income/Expenses Net 174,512 499,007 376,367
Income Tax Expense 559,615 1,247,855 949,764
Minority Interest - - -
Discontinued Operations - - 60,015
Other Items - - -
Net Income 1,716,755 3,372,065 3,235,851
Preferred Stock
And Other
Adjustments - - -
Net Income
Applicable To
Common Shares $1,716,755 $3,372,065 $3,235,851
58
Data from CaptialIQ
Page 37 of 39

APPENDIX 5D
Wyeth
Calendar Years 2004 – 06
Total Revenue 20,350,655 18,755,790 17,358,028
Cost of Revenue 5,587,851 5,431,200 4,947,269
Gross Profit 14,762,804 13,324,590 12,410,759
Operating Expenses
Non Recurring - - 4,500,000
Others - - -
Operating Income
or Loss 5,151,768 4,457,494 -349,642
Earnings Before Interest And Taxes 5,928,751 5,137,423 -19,542
Income Before Tax 5,429,904 4,780,589 -129,847
Income Tax Expense 1,233,198 1,124,291 -1,363,844
Minority Interest - - -
Discontinued Operations - - -
Other Items - - -
Net Income 4,196,706 3,656,298 1,233,997
Preferred Stock And
Net Income
Applicable To
Common Shares $4,196,706 $3,656,298 $1,233,997
59
Data from CaptialIQ
Page 38 of 39

APPENDIX 5E
Bristol-Myers Squibb60
Statement of Profit & Loss
Total Revenue 17,914,000 19,207,000 19,380,000
Cost of Revenue 5,956,000 5,928,000 5,989,000
Gross Profit 11,958,000 13,279,000 13,391,000
Operating Expenses
Non Recurring 161,000 -268,000 267,000
Others - - -
Operating Income or
Loss 2,460,000 4,182,000 4,197,000
Interest Expense 498,000 - -
Income Tax Expense 610,000 932,000 1,519,000
Minority Interest -440,000 -592,000 -521,000
Discontinued Operations - 8,000 10,000
Other Items - - -
Net Income 1,585,000 3,000,000 2,388,000
Preferred Stock And
Net Income
Applicable To
Common Shares $1,585,000 $3,000,000 $2,388,000
60
Data from CaptialIQ
Page 39 of 39

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