The History of Drug
Therapy in America
Source: The $800 Million Pill: The
Truth behind the Cost of New
Drugs
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”.

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

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)

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.
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


Hitler called the drug,
“quackery” and forced
Domagk, in 1939, to
refuse the Nobel Prize
for chemistry
Enter the Era of Sulfa Drugs
Many countries began
developing their own
version of the sulfa
drug…these 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

“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.

“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.

Result was the Drug
Companies peddling
their wares to the
Doctors.
 With all this
competition, the price
of sulfa drugs plunged

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
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 America’s most
celebrated research
scientist in the late 1940’s
Jonas Salk

Developed the first
polio vaccine in the
mid-1950’s and
refused to patent the
vaccine
….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……..

BACKLASH

Merck was worried about
the public’s 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 generically…it fell to
rock bottom prices like the
penicillin story.
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.
The Antibiotic Cartel Investigations
Federal Trade Commission was concerned
About lack of competition among Drug
Companies…
*In the 1950’s, Drug Companies were
discovering class after class of new
medicines including antidepressants,
antacids, anti-inflammatories,
antihistamines, and new drugs to control
blood pressure

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
innovator’s price

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

1935-1960’s
First Great Era of Drug
Discovery



The era of Molecular Modification
Produced by late 60’s 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.
1970’S-1980’S
ERA 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
death…heart disease, cancer,
diabetes and dementia

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

By the 1990’s
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

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.”

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.
For Patients and Providers???

This can lead to misleading
promotions, conflicts of interest,
increased costs for health care and
inappropriate prescribing.
Example: Stomach Acid Wars
of the 1990’s

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
Stomach Wars
Stomach ulcers
 Reflux disease
 Erosive Esophgitis

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)

First to do studies on
Histamines>>
James Black of Smith, Kline and French
 He had developed the first drugs that could
block adrenaline’s 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)
Black applied same concept to the
stomach…..
Some 700 drugs later, Black found the drug that
blocked the Histamine receptor…TAGAMET
(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.


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
acid…George
Sachs…looked at the
Acid Pump as the
target..developed the
drug OMEPRAZOLE
or PRILOSEC
By the 1990’s, 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 Pharmaceutical’s “me-too” proton
pump drug, PREVACID - $3 Billion

Along came Barry Marshall of the
Royal Perth Hospital of Australia
Marshall isolated a bacterimm
Called Helicobacter Pylori

Marshall

His approach to stomach ulcers, gastritis and
stomach cancer was this bacteria, which infects
one half of the world’s population
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.
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 PRILOSEC…and
called it NEXIUM

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.


The side chains of atoms that make the
molecule unique can attach themselves to
either side of the symmetrical rings
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 person’s
left and right hands.
 Each version is called
an ENANTIOMER or
ISOMER

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

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 palpitations…It is known
today as ALLEGRA…

Operation Shark Fin
Nexium was nothing
more than Pilosec’s
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.

Nexium and Prilosec (cont’d)

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.
Prilosec and Nexium (cont’d)

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!
The 1990’s 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.

Claritin
Schering-Plough’s CLARITIN, an antiallergy medication was a nonsedating
alternative to an earlier generation of
antihistamines.
 By late 1990’s generated over $2 Billion
annually

Claritin was on the verge of making
even more money. Why?

1997 legislation legalized direct to
consumer advertising
Claritin (cont’d)
Consumers were encouraged
to ask their physician for a
month’s 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

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.
With other anti-histamines being
suspect, CLARITIN moved to #1
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.
Searle’s CELEBREX and Merke’s
VIOXX
2001..Parmacia came up with
BEXTRA
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

Aspirin, Naproxen or Ibuprofen are Nonsteroidal Anti-inflammatory (NSAID’s)
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 “Superaspirins”.


The medical selling
point of COX-2
inhibitors was that it
would avoid the
development of
stomach ulcers. They
marketed a campaign
against NSAID’s
COX-2 Drugs netted $3.5 Billion
annually.
Two Question Emerged…
A. Were the
traditional NSAID’s
really as dangerous
as a growing volume
of medical reports
claimed?
 And did the Cox-2
inhibitors solve the
problem?

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.
Problems with COX-2

Vioxx was developing
heart problems and
did not have the
same Cardiovascular
benefits as the
NSAID’s!
Celebrex had Problems..

Its studies were
replicated and the
findings were “junk
science”.
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






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.