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

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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.

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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

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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)

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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.

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• 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

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

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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

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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.

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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.

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

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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

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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

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Jonas Salk

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

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.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..

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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.

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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.

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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

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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

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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

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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.

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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

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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

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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

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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.

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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.

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For Patients and Providers???

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

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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

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Stomach Wars

• Stomach ulcers
• Reflux disease
• Erosive Esophgitis

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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)

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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)

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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.

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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

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• 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

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Along came Barry Marshall of the Royal Perth
Hospital of Australia

• Marshall isolated a bacterimm
• Called Helicobacter Pylori

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Marshall

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

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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.

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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

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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.

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

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• 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

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• 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

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• 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

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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.

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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.

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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!

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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.

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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

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Claritin was on the verge of making even more
money. Why?

• 1997 legislation legalized direct to consumer
  advertising

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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

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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.

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With other anti-histamines being suspect,
CLARITIN moved to 1
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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.

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Searles CELEBREX and Merkes VIOXX
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2001..Parmacia came up with BEXTRA
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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

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• 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.

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

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COX-2 Drugs netted 3.5 Billion annually.
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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?

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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.

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Problems with COX-2

• Vioxx was developing heart problems and did not
  have the same Cardiovascular benefits as the
  NSAIDs!

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Celebrex had Problems..

• Its studies were replicated and the findings were
  junk science.

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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

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• 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.