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How did the present pharmaceutical industry evolve?
How does industry protect their discoveries?
What’s in a name? How are drugs named?
How does the pharmaceutical industry decide which
diseases and/or biological mechanisms to target?
• How many drug targets are there and how does one
pick a good drug target?
History of the Pharmaceutical Industry
• Most of today's major pharmaceutical companies were
founded in the mid to late 19th centuries.
• They often evolved from pharmacies, who desired to produce
their own medications in bulk.
• Usually the products involved alkaloids, particularly including
quinine
• John K. Smith founded a pharmaceutical company in
1841
• He brought in his bookeeper, Mahlon Kline a few
years later
• Finally, he merged his company with the perfume
factory of Harry B. French to form Smith, Kline, and
French.
• Parke, Davis & Co. originated in Detroit
with the manufacture of chemical
preparations in 1866.
• Key discoveries of the 1920s and 1930s,
such as insulin and penicillin, became
mass-manufactured and distributed
(penicillin in WW II). Switzerlnd, Germany
and Italy had particularly strong industries,
with the UK and US following suit.
Old versus New Drug Labels
• Legislation was enacted to test and approve drugs and to
require appropriate labeling.
• Prescription and nonprescription drugs became legally
distinguished from one another as the pharmaceutical
industry matured.
• Attempts were made to increase regulation and to limit
financial links between pharmaceutical companies and
prescribing physicians, including by the relatively new US
FDA.
The Sulfanilamide Disaster
• In 1937, S. E. Massengil Company created an
elixir (liquid form) of the antibiotic
sulfanilamide using diethylene glycol as
solvent.
Ethylene Glycol
Diethylene Glycol
• Diethylene glycol is a great solvent, but
extremely toxic.
• Unfortunately, at the time, there were no
legal requirement to test the toxicity of the
formulation
• This resulted in the deaths of more than
100 people in the U.S.
• The United States Federal Food, Drug, and
Cosmetic Act (abbreviated as FFDCA,
FDCA, or FD&C) was passed by Congress
in 1938
• This law gives authority to the FDA to
oversee the safety of food, drugs, and
cosmetics.
• Numerous new drugs were developed during the 1950s
and mass-produced and marketed through the 1960s.
• This included the first oral contraceptive, The Pill,
Cortisone, blood-pressure drugs and other heart
medications. MAO Inhibitors, chlorpromazine (Thorazine),
Haldol (Haloperidol) and the tranquilizers ushered in the
age of psychiatric medication.
• The thalidomide tragedy of the 1960s resulted in many
pregnant women being prescribed a new tranquilizer that
resulted in severe birth defects.
• This resulted in increased calls for more regulation of the
pharmaceutical industry.
• Other tranquilizers, such as Valium
(diazepam), discovered in 1960, became best
selling drugs, despite their propensity to
cause addiction.
• In 1964, the World Medical Association issued its
Declaration of Helsinki, which set standards for
clinical research and demanded that subjects be
given informed consent before enrolling in an
experiment. Pharmaceutical companies became
required to prove efficacy in clinical trials before
marketing drugs.
• A number of new cancer drugs
were produced in the 1970s
• By the mid-1980s, small biotechnology firms were
struggling for survival, which led to the formation of
mutually beneficial partnerships with large
pharmaceutical companies and a host of corporate
buyouts of the smaller firms.
• Pharmaceutical manufacturing became concentrated,
with a few large companies holding a dominant position
throughout the world and with a few companies
producing medicines within each country.
• New technologies, and new regulations, were
beginning to transform the pharmaceutical industry
in the 1980s. These included the routine use of xray crystallography, the subsequent dawn of
computer-assisted drug discovery, and the
beginning of high throughput screening.
• The search for new drugs to combat the rapidly spreading
(and fatal) retroviral disease HIV were a feature of
pharmaceutical industry research in the 1980s and
1990s.
• The 1980s also saw the beginning of an effort to hold down the
cost of healthcare through Health Management Organizations
(HMOs).
• A new business atmosphere became institutionalized
in the 1990s, characterized by mergers and
takeovers, and by a dramatic increase in the use of
contract research organizations for clinical
development and even for basic R&D.
• In addition to the bad name that the
pharmaceutical industry was beginning to acquire
due to the high cost of healthcare and
prescription medication tragedies, animal rights
advocates began to confront the industry due to
their use of animals in the initial evaluation of new
products.
• Glaxo Wellcome + SmithKline Beecham
= GlaxoSmithKline
Merger of Glaxo Wellcome and SmithKline Beecham creates
pharmaceutical giant
Alison Abbott, MUNICH, Munich
JONNY EGGITT/FT
Garnier: to head Glaxo SmithKline.
The merger of the British pharmaceutical companies Glaxo Wellcome and SmithKline Beecham,
which comes into effect this summer, creates a giant which could rank number one in the world
in terms of spending on research and development (R&D). It will boast a portfolio of 30 new
drugs and 19 vaccines in clinical trial.
Glaxo Wellcome is currently the fifth-largest pharmaceutical company in the world in terms of
turnover and SmithKline Beecham is ranked twelfth. The new company will have a stockmarket value of £110 billion (US$180 billion).
• Marketing changed dramatically in the 1990s, partly because
of a new consumerism.
• The Internet made possible the direct purchase of medicines
by drug consumers and of raw materials by drug producers,
transforming the nature of business.
• In the US, Direct-to-consumer advertising proliferated on
radio and TV because of new FDA regulations in 1997 that
liberalized requirements for the presentation of risks.
• The new antidepressants, the SSRIs,
notably Fluoxetine (Prozac), rapidly
became bestsellers.
• Drug development progressed from a hit-andmiss approach to rational drug discovery in both
laboratory design and natural-product surveys.
• Demand for nutritional supplements and socalled alternative medicines created new
opportunities and increased competition in the
industry.
• Controversies emerged around adverse
effects, notably regarding Vioxx in the US,
and marketing tactics.
• Pharmaceutical companies became
increasingly accused of disease mongering
or over-medicalizing personal or social
problems.
• There are now more than 200 major pharmaceutical
companies, jointly said to be more profitable than
almost any other industry, and employing more
political lobbyists than any other industry.
• Advances in biotechnology and the human genome
project promise ever more sophisticated, and
possibly more individualized, medications.
• The cost of bringing a new drug to market,
beginning with the initial research, and
continuing through clinical trials, has been
estimated as high as $800 million, per drug.
Industry revenues
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For the first time ever, in 2006, global spending on prescription drugs
topped $600 billion, even as growth slowed somewhat in Europe and
North America.
Sales of prescription medicines worldwide rose 7 percent to $602
billion, according to IMS health, a pharmaceutical information and
consulting company.
The United States still accounts for most, with $252 billion in annual
sales. Sales there grew 5.7 percent.
Top Pharmaceutical Companies (sales)
How does the pharmaceutical
industry protect its discoveries?
Patents
• Under current law, a patent protects the
new invention for a period of twenty years
from the earliest date of filing.
• To be patented, the invention must
demonstrate novelty
• One category under which most drug
discoveries are filed is a new composition of
matter.
Patent Protection by Country
• U.S. patents are handled by the US Patent and
Trademark Organization (USPTO).
• The USPTO tries to make it easy for an
individual inventor to file and maintain a patent.
• LINK
European Patents
• European Patents are handled through the
European Patent Organization (EPO).
• The costs of filing and maintaining a patent
in the various European countries can be
quite substantial.
• Once the patent term of a drug is expired, other
companies can produce and market the drug.
• This extra competition will reduce the price
• However, these companies must use the
generic name for the drug (not the brand name,
see below)
Naming of drugs
•A marketed drug has three names: a chemical name, a
generic name, and a brand name.
•A chemical name is given when a new chemical entity
(NCE) is developed.
• The chemical name is a scientific name based on the
compound's chemical structure (e.g., 6-thioguanine) and
is almost never used to identify the drug in a clinical or
marketing situation.
• Often, the name is long and difficult to pronounce, and,
since it has numbers, the number in the name might
become confused with the numbers in the prescription.
• The generic name (or non-proprietary name) is
granted by the USAN Council and is commonly
used to identify a drug during its useful clinical
lifetime.
• Link
• The generic name does not belong to the
company that discovers the drug (or owns
the patent). Once the patent lifetime is
expired, any company may market the
drug under the generic name.
• The generic name must be screened to
assure that it does not resemble any other
generic or brand name.
• The generic name must also be
appropriate for the class of drug.
• A listing of appropriate drug stem names
can be found in the National Library of
Medicine’s Drug Portal
• The stems refer to the mechanism of action
of the drug (not the disease condition)
• Link
• The company that patents the drug creates the
brand name (trademark). This name identifies the
drug during the 17 years that the company has
exclusive rights to make, sell, and use it under
patent law.
Link
Link
What does a drug
look like?
• If you are looking for drugs, you may be
advised to know what they look like.
• Christopher Lipinski, while working for
Pfizer in the 1990s, looked at thousands of
drugs and drug candidates and came up
with some generalizations.
Lipinski’s Rules of Five
An orally active drug should have the following:
•No More than five hydrogen bond donors
•No more than ten hydrogen bond acceptors
•A molecular weight under 500 Da
•An octanol-water partition coefficient (logP) less than 5
(where P = ratio of solubility in octanol / solubility in water)
How many useful biological
targets are there that would
recognize a drug?
How many drug
targets are there?
What classes are important?
Assigned Reading
• Gundersen L The complex process of naming drugs.
Annals of internal medicine (1998), 129(8), 677-8.
• http://www.medscape.com/viewarticle/469843
• (you will need to create a free medscape account,
and to click on the box at lower right to see all 4
sections)
• http://www.fda.gov/AboutFDA/WhatWeDo/History/Pro
ductRegulation/SulfanilamideDisaster/default.htm
• Hopkins Andrew L; Groom Colin R The druggable
genome. Nature reviews. Drug discovery (2002),
1(9), 727-30.
Assigned Reading (graduate
students only)
• Lipinski, C. A.; Lombardo, F.; Dominy, B.
W.; Feeney, P. J. Experimental and
computational approaches to estimate
solubility and permeability in drug discovery
and development settings. Advanced Drug
Delivery Reviews (2001) 46: 3-26.
Homework
• For each of the top ten pharmaceutical companies (slide
33), find their top selling drug, draw its structure, and
explain what indication (disease) the drug is intended to
treat.
• What does USAN stand for? What does the USAN council
do?
• Approximately how many generic and trademark (brand)
names are currently in use in the US?
• What are Lipinski’s Rules?
• Graduate students only: What specific changes occurring
in the assay procedure prompted Chris Lipinski to come up
with his rules. Explain.
• Graduate students only: What chemical principles are
underlying Lipinski’s Rules?