How did the present pharmaceutical industry evolve?

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• How did the present pharmaceutical industry
  evolve?
• How does industry protect their discoveries?
• Whats 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?

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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

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• Started as a chemicals business, Charles Pfizer
  and Company, founded in Brooklyn by cousins
  Charles Pfizer and Charles Erhardt, in 1849.

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• They started selling an antiparasitic
  (anthelmintic, i.e. anti-worm) agent called
  santonin
• But they made more money from making citric acid,
  which is used as flavoring and preservative in
  soft drinks.

5

• The cousins kept buying land and expanded their
  chemicals plant.

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• Developed new technology to produce citric acid
  through the fermentation of glucose or sucrose

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• During WWII, Pfizer used its fermentation
  capability to manufacture penicillin

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• Due to success in production, penicillin became
  cheap and thus it was difficult to make enough
  profit to support the company
• Decided to research other antibiotic classes
• Developed more extensive research facility in
  Groton, CT.

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• 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.

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• Parke, Davis Co. originated in Detroit with the
  manufacture of chemical preparations in 1866.

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What did the pharmaceutical industry sell?
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• 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.

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Labeling and Regulation
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• As the transition from quackery to useful
  pharmaceutical products took place, there became
  a need for proper labeling of pharmaceutical
  products.

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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.

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• Attempts were made to increase regulation and to
  limit financial links between pharmaceutical
  companies and prescribing physicians, including
  by the relatively new US FDA.

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Then, Disaster Strikes (for the first time)
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The Sulfanilamide Disaster

• In 1937, S. E. Massengil Company created an
  elixir (liquid form) of the antibiotic
  sulfanilamide using diethylene glycol as solvent.

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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

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• This resulted in the deaths of more than 100
  people in the U.S.

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• The United States Federal Food, Drug, and
  Cosmetic Act (abbreviated as FFDCA, FDCA, or
  FDC) was passed by Congress in 1938
• This law gives authority to the FDA to oversee
  the safety of food, drugs, and cosmetics.

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The Industry Continues to Develop New Products
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• 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.

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Then Disaster Strikes (for the second time)
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• A new sedative/anti-nausea drug was marketed in
  the 1950s.
• The drug was used by many pregnant women to
  control morning sickness

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• It was quickly withdrawn in the 1960s when the
  active ingredient (thalidomide) was found to be
  severely teratogenic.
• But not before it had caused at least 10,000
  severe birth defects

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Product Development Continues
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• Other tranquilizers, such as Valium (diazepam),
  discovered in 1960, became best selling drugs,
  despite their propensity to cause addiction.

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• 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.

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• A number of new cancer drugs were produced in
  the 1970s

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Smaller Drug Companies are Struggling
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• 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.

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The Accelerating Pace of Technology Affects the
Pharmaceutical Industry
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• New technologies, and new regulations, were
  beginning to transform the pharmaceutical
  industry in the 1980s. These included the
  routine use of x-ray crystallography, the
  subsequent dawn of computer-assisted drug
  discovery, and the beginning of high throughput
  screening.

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Product Development Continues
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• 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.

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The Increasingly High Cost of Healthcare is
Recognized
39

• The 1980s also saw the beginning of an effort to
  hold down the cost of healthcare through Health
  Management Organizations (HMOs).

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The Drug Companies Continue to Consolidate (and
to try to improve efficiency)
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• 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 RD.

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• 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 (RD). 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
stock-market value of 110 billion (US180
billion).
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The Industry is Beginning to Be Disliked, by Some
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• 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.

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Marketing Rules Change, Allowing Pharmaceutical
Companies to Directly Market to Consumers
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• 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.

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Product Development Continues
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• The new antidepressants, the SSRIs, notably
  Fluoxetine (Prozac), rapidly became bestsellers.

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Technology Continues to Impact the Industry
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• Drug development progressed from a hit-and-miss
  approach to rational drug discovery in both
  laboratory design and natural-product surveys.
• Demand for nutritional supplements and so-called
  alternative medicines created new opportunities
  and increased competition in the industry.

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Disasters Continue
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• In 1999, with FDA approval, Merck put a new
  pain-reliever on the market to treat pain due to
  osteoarthritis.
• This drug is a selective inhibitor of COX-2.

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• Merck withdrew the product in 2004, after it was
  associated with increased risk of heart attack
  and stroke associated with long time use.

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• The accusation that Merck may have had clinical
  data predicting this potential problem, and
  ignored it, opened the company to numerous
  lawsuits and engendered further dislike of the
  industry.

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• 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.

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• 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.

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• 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.

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Industry revenues

• 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.

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Top Pharmaceutical Companies (sales)
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Like few other industries, the pharmaceutical
industry is driven and supported by research and
discoveries
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How does the pharmaceutical industry protect its
discoveries?
63
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.

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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

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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.

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• 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)

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Naming of Drugs
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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.

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• 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.

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• 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

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• 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.

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• 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.

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• A listing of appropriate drug stem names can be
  found in the National Library of Medicines Drug
  Portal
• The stems refer to the mechanism of action of the
  drug (not the disease condition)
• Link

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• 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.

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• Link
• Link

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The Pharmaceutical Industry Needs to Continue to
Discover New Drugs to Survive(how to discover
drugs?)
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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.

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Lipinskis 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)

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Can the pharmaceutical industry continue to
invent new cures?
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How many useful biological targets are there that
would recognize a drug?
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How many drug targets are there?
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With respect to drugs, targets, and classes of
drugs, where are we today?
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What classes are important?
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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/Produ
  ctRegulation/SulfanilamideDisaster/default.htm
• Hopkins Andrew L Groom Colin R The druggable
  genome. Nature reviews. Drug discovery
  (2002), 1(9), 727-30.

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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.

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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 Lipinskis 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 Lipinskis Rules?