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The History of Drug Therapy in America

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Title: The History of Drug Therapy in America


1
The History of Drug Therapy in America
  • Source The 800 Million Pill The Truth behind
    the Cost of New Drugs

2
Early Beginnings
  • Roosevelt was re-elected
  • in 1936 but his personal
  • Life was challenged with
  • The fever of his son,
  • FDR Jr. who had Tonsillitis
  • The infection seeped
  • Into the blood which in
  • Those days, fatal.

3
George Tobey Jr. White House Physician
  • Tobey administered a German drug called,
    Protosil, which was a derivative of a chemical
    dye cure used in the treatment of bacterial
    infections.
  • FDR Jr. recovered and the New York Times
    proclaimed this event as the new era of Wonder
    Drugs

4
Wonder Drug Era
  • Prontosil ushered in an era of drug therapy and
    Drug Marketing
  • Prior to this, Depression-era Pharmaceuticals
    were a sprinkling of small firms peddling a
    handful of cures (1930 symposium listed only
    seven diseases they could affect)

5
The Bayer Corporation
  • 1932 German Gerhard Domagk in Elberfeld,
    Germany (developed one of the first drugs for the
    treatment of Syphilis), treated a cured white
    mice from streptococcus with a red dye
    derivative.

6
  • The agent which was
  • Responsible for the cure
  • Was not the dye but
  • A chemical called,
  • Sulphanilamide which
  • Was activated once the original medication was
    metabolized

7
  • Hitler called the drug, quackery and forced
    Domagk, in 1939, to refuse the Nobel Prize for
    chemistry

8
Enter the Era of Sulfa Drugs
  • Many countries began developing their own version
    of the sulfa drugthese were called me-too
    medications.
  • In 1937, a small Tennessee Corporation called
    Massengill started making a liquid form for
    Southerners and children, b/c they believe these
    folks liked it that way

9
Me-Too
  • Sulfa did not dissolve in water or alcohol, the
    company suspended it in diethylene glycol, an
    industrial solvent used to make antifreeze.
  • No on thought to test the product before putting
    it on the market..100 people died (mostly
    children). The President did not take any
    responsibility and the chief chemist committed
    suicide.

10
Me-too
  • The 1906 Pure Food and Drug Act was subsequently
    altered (originally designed for the prevention
    of selling contaminated food).
  • For the first time, the newly created FDA made
    drug companies prove their products were safe for
    human consumption.

11
  • Result was the Drug Companies peddling their
    wares to the Doctors.
  • With all this competition, the price of sulfa
    drugs plunged

12
For Example
  • The first miracle antibiotics which came along
    following WW II had been massed produced by the
    government (penicillin for wartime efforts) were
    licensed to five firms who engaged in fierce
    competition and from 1945 to 1950 the price of
    penicillin fell from 3,955 to 282 a pound

13
Next Generation of Antibiotics
  • Late 1940, Selman Waksman of Rutgers U. developed
    streptomycin which was the first effective
    treatment for tuberculosis.
  • Earned a Nobel Prize and was Americas most
    celebrated research scientist in the late 1940s

14
Jonas Salk
  • Developed the first polio vaccine in the
    mid-1950s and refused to patent the vaccine

15
.But Selman.
  • Patented the streptomycin and licensed it to the
    Merck Research Laboratories
  • THIS WAS A WATERSHED EVENT IN THE EVOLUTION OF
    THE DRUG INDUSTRY FOR THE FIRST TIME THE PATENT
    AND TRADEMARK OFFICE (PTO) GAVE A 17 YEAR
    EXCLUSIVITY MONOPOLY TO A PRODUCT IN ITS RAW
    STATE HAD BEEN PART OF NATURE..

16
BACKLASH
  • Merck was worried about the publics response to
    generating massive profits so Merck returned the
    license for streptomycin to the nonprofit Rutgers
    Research Foundation and the drug was sold broadly
    and genericallyit fell to rock bottom prices
    like the penicillin story.

17
Antibiotics
  • The government took a hands-off approach after
    that and no other licenses were distributed to
    other companies and so the antibiotic development
    field became controlled by few companies and the
    new antibiotic prices skyrocketed.

18
The Antibiotic Cartel Investigations
  • Federal Trade Commission was concerned
  • About lack of competition among Drug Companies
  • In the 1950s, Drug Companies were discovering
    class after class of new medicines including
    antidepressants, antacids, anti-inflammatories,
    antihistamines, and new drugs to control blood
    pressure

19
CopyCats
  • Whenever a new drug was found, other firms
    introduced copycat versions of the original
    molecule within a very short time.
  • These copycats or me-too drugs would enter the
    market place at the same or within a few
    percentage points of the innovators price

20
Enter Senator Estes Kefauver of Tennessee
  • A Yale-trained lawyer who was a fast-tracker
    because of this hearings on the Mob and gambling
  • Held a series of hearings from 1960-62 evaluating
    the price fixing of the Drug Companies
  • What came of the hearings is that the companies
    had to prove the drugs were not only safe, but
    effective

21
1935-1960s First Great Era of Drug Discovery
  • The era of Molecular Modification
  • Produced by late 60s more than 200 sulfa drugs
    more that 270 antibiotics 130 antihistimines and
    100 major tranquillizers
  • THE KEY NEW DRUGS OFFER THE PHYSICIAN AND
    PATIENT NO SIGNIFICANT CLINICAL ADVANTAGES BUT
    ARE DIFFERENT ENOUGH TO WIN A PATENT AND THEN BE
    MARKETED USUALLY AT THE IDENTICAL PRICE OF THE
    PARENT PRODUCT OR EVEN A HIGHER PRICE.

22
1970S-1980SERA OF CELLULAR INTERACTIONS
  • A Second wave of drug innovation
  • Drawing upon the governments involvement in
    disease after WW II (NIH), researcher promised
    cures for chronic conditions that had become the
    leading causes of deathheart disease, cancer,
    diabetes and dementia

23
New Drugs included
  • 1. Angiotensin Converting Enzymes (ACE for Blood
    Pressure)
  • 2. Statins for lowering cholesterol
  • 3. Anti-depressants
  • 4. Antacids
  • 5. Antihistimines
  • 6. Calcium Channel Blockers
  • 7. Erectile Dysfunction Drugs

24
By the 1990s
  • Leading pharmaceutical companies were basically
    producing comparable products
  • Market was divvyed up but their was no
    competition on prices
  • Result Drug prices, like health care generally,
    were soaring at double-digit prices
  • Came under public scrutiny me-too practices
    were being called into question

25
Pharmaceutical Rationale
  • Not copycat or me-too drugs but rather these
    drugs had fewer side-effects than their
    predecessors
  • No such thing as one-size fits all drug
  • Each patient is unique and may respond to the
    same drug differently. What works for one person
    does not necessarily work for another. Physicians
    and patients benefit from a variety of medicines
    available to treat each ailment.

26
Clinton Administration (1993-4) was not impressed
  • Of the 127 new drugs approved between 1989-1993,
    David Kessler of the FDA only a few offered a
    clear clinical advantage over existing therapies.

27
For Patients and Providers???
  • This can lead to misleading promotions, conflicts
    of interest, increased costs for health care and
    inappropriate prescribing.

28
Example Stomach Acid Wars of the 1990s
  • Chronic condition went far beyond non
    prescriptive acid neutralizers that can be
    purchased anywhere in in almost every form
    imaginable, from crunchy tablets to chalky liquids

29
Stomach Wars
  • Stomach ulcers
  • Reflux disease
  • Erosive Esophgitis

30
Stomach Wars
  • Originally, used HISTAMINES.
  • In 1937 Diphehydramine or BENADRYL was
    discovered. (Which also provided the chemical
    basis for the wildly popular antidepressant,
    FLUOXETINE or PROZAC)

31
First to do studies on Histaminesgtgt
  • James Black of Smith, Kline and French
  • He had developed the first drugs that could block
    adrenalines effect on the heart by identifying
    two receptors (alpha and beta) that bound to
    adrenaline (heart only has one receptor the
    beta)
  • His team developed the first beta-blocker,
    PROPRANOLOL (A MAJOR BREAKTHROUGH IN BP AND HEART
    DISEASE)

32
Black applied same concept to the stomach..
  • Some 700 drugs later, Black found the drug that
    blocked the Histamine receptorTAGAMET
    (Cimetidene)
  • Others jumped on the bandwagon with Glaxo
    producing Ranitidine or ZANTAC
  • (similar but of course had fewer side
    effects)..became the best selling drug in the
    world.

33
While Black concentrated on the acid blocking
others took a different approach
  • Others concentrated on the actual engines in the
    stomach cells that produced the acidGeorge
    Sachslooked at the Acid Pump as the
    target..developed the drug OMEPRAZOLE or PRILOSEC

34
  • By the 1990s, Antacid sales in the U.S. were
    over 7 Billion (Merck 1)
  • The proton-pump inhibitor, PRILOSEC, became the
    best-selling medicine in the world (By 2000, it
    had U.S. Sales of 5 Billion)
  • TAP Pharmaceuticals me-too proton pump drug,
    PREVACID - 3 Billion

35
Along came Barry Marshall of the Royal Perth
Hospital of Australia
  • Marshall isolated a bacterimm
  • Called Helicobacter Pylori

36
Marshall
  • His approach to stomach ulcers, gastritis and
    stomach cancer was this bacteria, which infects
    one half of the worlds population

37
Marshall
  • No Drug Company would champion a solution that
    could be handled with short, cheap course of
    generic antibiotics when they were making
    millions treating chronic recurrences with
    expensive prescription antacids.

38
What was the Response??
  • Instead of pursuing this potential cure for
    ulcers, companies like ASTRA the producers of
    PRILOSEC came up with OPERATION SHARK FIN
  • An effort to fund a drug to replace PRILOSEC
    after it came off patent and became generically
    available.
  • They tried Drug combinations and oral suspensions
    but they came up with a molecule that was in
    essence, HALF OF PRILOSECand called it NEXIUM

39
This allowed them to extend the Patent
  • It is a quirk of the chemistry of organic
    molecules
  • Most organic molecules come in two shapes because
    their carbon atoms arrange themselves in six
    sided rings.

40
  • The side chains of atoms that make the molecule
    unique can attach themselves to either side of
    the symmetrical rings

41
  • The result is a mixture of two versions of the
    molecule, each with the same chemical formula,
    but different in that they are mirror images of
    each other much like a persons left and right
    hands.
  • Each version is called an ENANTIOMER or ISOMER

42
  • Sometimes only one ISOMER is active against
    disease. The other is inactive or causes unwanted
    side effects.
  • Drug Companies separated the two sides
  • (Nobel Prize for Chemistry in 2001 Sharpless,
    Noyori, Knowles

43
  • This new process succeeded in rescuing some drugs
    that had been shelved due to side effects
  • TERFENADINE OR SELDANE (Merrell Dow, later
    Aventis)
  • (non-sedating anti-histimine originally caused
    heart palpitationsIt is known today as ALLEGRA

44
Operation Shark Fin
  • Nexium was nothing
  • more than Pilosecs
  • Isomers. Getting rid of half the drug would
    provide no beneficial effects for the patient.
    Yet the FDA approved it because one-half the old
    entity was a new entity.

45
Nexium and Prilosec (contd)
  • The Astra Corporation still needed more evidence
    to support the new drug. They funded four studies
    on erosive esophagitis. The slower metabolizing
    Nexium healed 90 after eight weeks while the
    Prilosec healed 87 after the same time span. Two
    of the studies showed no difference and were
    never release to the public.

46
Prilosec and Nexium (contd)
  • In 2001, Nexium hit the market with detailers
    pushing the drug with a massive television
    campaign. The company (now Astra Zeneca) used its
    lawyers to block the generic drug from the
    marketplace while convincing the FDA to allow
    Prilosec onto the over-the-counter (OTC) market
    thus frustrating the generic manufacturers and
    giving Nexium free rein as the prescription
    antacid!

47
The 1990s Practice
  • Billions of dollars poured into research to
    develop alternatives to drugs that were
    approaching the end of their patent terms.
  • In most cases the alternatives were little
    changed from the originals.
  • The better the original the more the possibility
    of generating a copycat version with renewed
    patent life.

48
Claritin
  • Schering-Ploughs CLARITIN, an anti-allergy
    medication was a nonsedating alternative to an
    earlier generation of antihistamines.
  • By late 1990s generated over 2 Billion annually

49
Claritin was on the verge of making even more
money. Why?
  • 1997 legislation legalized direct to consumer
    advertising

50
Claritin (contd)
  • Consumers were encouraged to ask their physician
    for a months supply for 80.00 despite the fact
    that it worked only slightly better than the
    placebo.
  • It is such a low dose with only 43-46 of
    Claritin users gaining relief as compared to the
    sugar pill

51
Claritin/Carcinogen
  • CLARITIN or LORATADINE had to prolong its
    introduction until 1993 until the results were
    in..BUT..
  • Those on SELDANE and HISMANAL (other non-sedating
    antihistamines) began turning up in emergency
    wards complaining of chest pain from other
    interactions.

52
With other anti-histamines being suspect,
CLARITIN moved to 1
53
The old Tactic was reused
  • Just before CLARITIN was to lose its patent, the
    drug was redesigned as DESLORATADINE, thus
    keeping the patent and CLARITIN was put OTC
    again frustrating the generic protagonists.

54
Searles CELEBREX and Merkes VIOXX
55
2001..Parmacia came up with BEXTRA
56
History - Cox-2 Inhibitors
  • Philip Needleman, of the Washington University
    Schools of Medicine in St. Louis believed there
    must be a specific enzyme that caused
    inflammation and pain around the arthritic joints
    and traumatic injuries.
  • It was well known that the enzyme called
    cyclo-oxygenase or COX for short, triggered the
    production of prostaglandins which in turn caused
    swelling

57
  • Aspirin, Naproxen or Ibuprofen are Non-steroidal
    Anti-inflammatory (NSAIDs) drugs which reduce
    the pain by blocking the action of COX and
    limiting the production of prostaglandins.
  • Needleman believed there were two types of COX
    and developed the Super-aspirins.

58
  • The medical selling point of COX-2 inhibitors was
    that it would avoid the development of stomach
    ulcers. They marketed a campaign against NSAIDs

59
COX-2 Drugs netted 3.5 Billion annually.
60
Two Question Emerged
  • A. Were the traditional NSAIDs really as
    dangerous as a growing volume of medical reports
    claimed?
  • And did the Cox-2 inhibitors solve the problem?

61
After Face Testing the validity of the
extrapolation studies
  • The claims were greatly overestimated with less
    than 2 of all NSAID users suffering G-I
    problems.

62
Problems with COX-2
  • Vioxx was developing heart problems and did not
    have the same Cardiovascular benefits as the
    NSAIDs!

63
Celebrex had Problems..
  • Its studies were replicated and the findings were
    junk science.

64
What do we learn from all this?
  • By 2004, there were 52 drugs with more than 1
    Billion in sales of which 42 were slated to lose
    their patient protection by 2007.
  • Instead of looking for generics or new drugs the
    emphasis is new and improved
  • 71.4 of Drug Companies Budget or 15.7 Billion
    spent on direct consumer ads

65
  • Drug Prices will remain high
  • Generics will be limited
  • We must rely on alternative approaches to taking
    drugs
  • Drug Company claims are biased (We can rely upon
    their information as much as we can depend upon a
    beer company to teach us about alcoholism)
  • Important drugs do not need promotion but
    me-too drugs do.
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