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 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

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 America’s most celebrated research scientist in the late 1940’s

14. Jonas Salk • Developed the first polio vaccine in the mid-1950’s 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 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.

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 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

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 innovator’s 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. 1935-1960’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.

22. 1970’S-1980’SERA 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

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 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

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 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

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 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)

32. 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.

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 acid…George Sachs…looked at the Acid Pump as the target..developed the drug OMEPRAZOLE or PRILOSEC

34. 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

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 world’s 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 PRILOSEC…and 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 person’s 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 palpitations…It is known today as ALLEGRA…

44. 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.

45. 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.

46. 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!

47. 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.

48. Claritin • Schering-Plough’s CLARITIN, an anti-allergy medication was a nonsedating alternative to an earlier generation of antihistamines. • By late 1990’s 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 (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