Lecture Thirteen: Science, Ethics, and the (Pharmaceutical) Industry

The Age of High Science in American Medicine

Golden Ages

1. The golden age of public health: 1880-1920
2. The golden age of surgery: c. 1880-
3. The golden age of medical practice: 1900-1960
4. The golden age of scientific (pharmaceutical) medicine: 1935-?

Cures

1. 1888: Rabies vaccine
2. 1891: Diptheria antitoxin, concept of stimulating immune system
3. 1907: Salvarsan, 606, concept of toxic receptors
4. 1921: Insulin, addition of normal bodily substances
5. 1935: Sulphanilimide
6. 1941: Penicillin
7. 1944: Streptomycin [5-7 are antibacterial agents]
8. 1948: Corticosteroids

The Emergence of Clinical "Science"

1. The Paris hospitals, early 19th century
   • PCA Louis and the numerical method, 1830s-1840s
     1. Hospital as an experimental site
     2. Verlarge (tractable) patient populations
     3. Bleeding does not improve pneumonia
2. Karl Pearson (1857-1936)
   • Mathematics of correlation and regression
3. Raymond Pearl (1879-1940)
   • Application of Pearsonian statistics in medicine, 1940s

The Pharmaceutical Industry

1. Pharmacopeias: lists of recognized medicaments (and modes of preparation); problems of strength
   • 11th century Arabia
   • 1618: London Royal College of Physicians
   • 1820: U.S. Pharmacopeia
   • 1888: National Formulary
   • 1906, 1938: Accepted as legal standards
2. Proprietaries: Hamlin's Wizard Oil
   • "Rheumatism, toothache, deafness, burns, bites of dog, quinsy, diphtheria, gastralgia, cholera morbus, bleeding gums, ... and just about everything else?"
3. Ethicals: laudanum

Lydia Pinkham

Regulation of the Pharmaceutical Industry: Part One

1. Federal Pure Food and Drugs Act, 1906 (The Wiley Act), Section 8, Mislabeling in the case of drugs
   • First. If it be an imitation of or offered for sale under the name of another article.
   • Second. If the contents of the package as originally put up shall have been removed, in whole or in part, and other contents shall have been placed in such package, or if the package fail to bear a statement on the label of the quantity or proportion of any alcohol, morphine, opium, cocaine, heroin, alpha, or beta eucaine, chloroform, cannabis indica, chloral hydrate, or acetanilide, or any derivative or preparation of any such substances contained therein.
2. Problems: Pinkham's vegetable tonic (20% alcohol)
3. A 1912 Amendment allows action against "false and fraudulent" claims

Empirical Age of Pharmacology to mid-1950s

1. Lots of new compounds; interest in families of compounds
2. Assumption of structural molecular specificity
3. Little knowledge of how drugs work
4. Drug testing in the 1930s
   • Safety, but new uses and combinations
5. Rasmussen's classes
   • Freelancers: established clinical scientists
   • Efficient: wannabe clinical scientists; practitioners with access to patients
   • Friendly experts: the insidious "general consultant"

Regulation of the Pharmaceutical Industry: Part Two

1. 1937: Sulfanilamide incident
2. Elixir Sulfanilamide: sulfanilamide + diethylene glycol + raspberry flavoring
3. 100 deaths
4. Defense:
   • "We have been supplying a legitimate professional demand and not once could have foreseen the unlooked-for results.  I do not feel that there was any responsibility on our part"
5. Fined, under 1906 Act for mislabeling
   • Elixir = alcohol

Regulation of the Pharmaceutical Industry: Part Three

1. Leads to passage of Foods, Drugs, and Cosmetic Act, 1938; establishes the Food and Drug Administration (FDA)
   • Amendments, 1940s to 1951:
     1. Lead to prescription-only drugs after 1951
     2. Requirements for pre-approval testing
2. Medical advertising
   • After 1951, to gatekeeper physcians
   • After 1980s, to public
     1. Back to consumer medicine

It's My Body: Why Not Let Me Choose?

1. Problem of drugs; diagnostic techniques
   • Efficacy, 1962, enforced after 1970
   • False positives and negatives
   • Rise (or tolerance)-benefit ratio
   • Presumption of universal human
2. State interests in citizenry vs. therapeutic liberty
   • Ecological interests; veterinary antibiotic use
3. Inability to choose
   • Over-the-counter (OTC) vs. prescription

Controlled Trials (and Epidemiology)

1. Diagnostic accuracy - Disease + patient + stage
   • Problematic before serology: large numbers mask
2. Meaningful control
   • Complicated conceptually in epidemiology and ethically in treatment trials
3. Elimination of bias - ideally double-blind
   • Presumes biomedical model of cure
4. Agreed measures of success
   • Requires standardized modes of measurement
5. Meaningful long-term follow-up
   • Requires enormous commitment of social workers, statisticians: even necessary?

The Concept of Clinical Trials

1. Arrowsmith's trials of plague antidote: St. Hubert
   • Gottlieb's instruction: follow the Protocol
   • Sondelius' capitulation: follow Gottlieb
   • Arrowsmith's capitulation: save lives, scrifice science
2. Reception of Arrowsmith: science is a hard but noble master

Federal Funding of Medical Research: Part One

1. Pre-WWII
   • Rockefeller Foundation
     1. Rockefeller Institute, New York; A De Witt Tubbs / Simon Flexner
     2. Carnegie Foundation; Flexner Report

Federal Funding of Medical Research: Part Two

1. 1930: NIH; 1938: Bethesda
2. 1937: National cancer institute - grants to outside researchers
3. 1941: Committee on Medical Research: mass production of malaria, artificial quinine, leads to CDC in 1946
4. 1950: NSF - peer review grants
5. Overall federal expenditure on medical research:
   • 1941: c. 3 million
   • 1951: 76 million
6. 1948: National Heart Institute; 1949: NIMH (374,000 to 42.6 million by 1962)
   • Child development, juvenile delinquincy, television violence, suicide prevention, alcoholism
7. 1968: Separation of Surgeon General's Office

27 Institutes: How Many Do You Know?

Federal Funding of Medical Research: Part Three

1. 1938: usphs total = 2.8 million
2. 1945: 180,000 for research alone
3. 1947: 4 million for research alone
4. 1950: 46 million for NIH alone
5. 1955: 81 million for NIH alone
6. 1960: 400 million for NIH alone
7. No similar funding for increasing medical education

The Politics of Public Medicine: Medical Advocacy

1. 1937: National Foundation for Infantile Paralysis; March of Dimes
   • Salk vaccine, 1952: an upper-class disease
2. 1948-1949: American Cancer Society; Mary Lasker