Science, Ethics
and the
Pharmaceutical Industry
The Age of High science in
American Medicine
1935-
Golden ages
• The golden age of public health 1880-1920
• The golden age of surgery, c. 1880 • The golden age of medical practice 19001960
• The golden age of scientific
(pharmaceutical) medicine 1935-?
U.S. Leading Causes of Death - 1900
Diphtheria
40.3
Senility
50.2
Cancer and other malignant tumors
64
All accidents
72.3
Nephritis (all forms)
88.6
Deaths per 100,000 population
Intracranial lesions of vascular origin
106.9
Diseases of the heart
137.4
Diarrhea, enteritis, and ulceration of the
intestines
142.7
Tuberculosis (all forms)
194.4
Pneumonia (all forms) and influenza
202.2
0
50
100
Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention
150
200
250
U.S. Leading Causes of Death - 1974
Bronchitis, emphysema, and asthma
12.6
Certain causes of mortality in early infancy
13.5
Arteriosclerosis
15.1
Cirrhosis of liver
15.6
Diabetes mellitus
17.5
Deaths per 100,000 population
Influenza and pneumonia
25.7
Accidents
49
Cerebrovascular diseases
97.2
Malignant neoplasms, including neoplasms
of lymphatic and hematopoietic tissues
169
Diseases of heart
346
0
50
100
Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention
150
200
250
300
350
400
U.S. Leading Causes of Death - 1992
Homicide and legal intervention
10.5
Human immunodeficiency virus infection
11.7
Suicide
12.2
Diabetes mellitus
19.4
Pneumonia and influenza
30.9
Deaths per 100,000 population
Accidents and adverse effects
35.4
Chronic obstructive pulmonary diseases
and allied conditions
35.9
Cerebrovascular diseases
56.9
Malignant neoplasms, including neoplasms
of lymphatic and hematopoietic tissues
204.1
Diseases of heart
285.9
0
50
100
Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention
150
200
250
300
350
Cures
• Rabies vaccine, 1888
• Diphtheria antitoxin, 1891: concept of stimulating
immune system
• Salvarsan, 1907 – 606: concept of toxic receptors
• Insulin, 1921, addition of normal bodily
substances
• Sulphanilimide, 1935, penicillin, 1941,
streptomycin, 1944: antibacterial agents
• Corticosteroids, 1948
The emergence of clinical
“SCIENCE”
• The Paris Hospitals, early 19th century
• PCA Louis and the numerical method, 1830s1840s
This image is © Wellcome Images, available
under a Creative Commons License.
– Hospital as an experimental site
– Very large (tractable) patient populations
– Bleeding does not improve pneumonia
• Karl Pearson (1857-1936)
– Mathematics of correlation and regression
http://commons.wikimedia.org/wiki/File:Karl_Pearson.jpg
• Raymond Pearl (1879-1940)
– Application of Pearsonian statistics in
medicine, 1940s
http://en.wikipedia.org/wiki/Raymond_Pearl
The pharmaceutical industry
• 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
• www.usp.org
• Proprietaries: Hamlin’s Wizard oil
• "Rheumatism, toothache, deafness, burns,
bites of dog, quinsy, diphtheria, gastralgia,
cholera morbus, bleeding gums,... and just
about everything else!"
• Ethicals: laudanum
Image courtesy of the National Library of Medicine,
National Institutes of Health.
Lydia Pinkham
http://commons.wikimedia.org/wiki/File:Lydia_Pinkham.png
http://en.wikipedia.org/wiki/File:LydiaPinkham-VegetableCompound.gif
Regulation of the pharmaceutical
industry
• 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.
• Problems: Pinkham’s vegetable tonic (20% alcohol)
• Amendment 1912 allows action against “false and fraudulent” claims
– Http://www.fda.gov/opacom/laws/wileyact.htm
Empirical age of pharmacology (to
mid 1950s)
•
•
•
•
Lots of new compounds; interest in families of compounds
Assumption of structural molecular specificity
Little knowledge of HOW drugs work
Drug testing in the 1930s
– Safety, but new uses and combinations
• Rasmussen’s classes
– Free-lancers: established clinical scientists
– Efficient: wannabe clinical scientists: practitioners with access to
patients
– Friendly experts: the insidious “general consultant”
Regulation of the pharmaceutical
industry/2
• 1937 Sulfanilamide incident:
• Elixir Sulfanilamide: sulfanilamide +
diethylene glycol + raspberry flavoring
• 100 deaths:
• 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.“
• Fined, under 1906 act for mislabeling
(elixir = alcohol)[
Photo courtesy of U.S. Food and Drug Administration.
Regulation of the pharmaceutical
industry/3
• Leads to passage of Foods, Drugs, and
Cosmetic Act, 1938, est. FDA
– Amendments, 1940s, to 1951:
• lead to prescription-only drugs after 1951
• Requirements for pre-approval testing
• Medical Advertising
– After 1951, to gatekeeper physicians
– After 1980s, to public
• Back to consumer medicine
It’s my body: why not let me
choose?
• Problem of drugs; diagnostic techniques
–
–
–
–
Efficacy, 1962, enforced after 1970
False positives and negatives
Risk (or tolerance)-benefit ratio
Presumption of universal human
• State interests in citizenry vs therapeutic
liberty
– Ecological interests – veterinary antibiotic use
• Inability to choose
– OTC vs prescription
Controlled trials (and epidemiology)
• 1. Diagnostic accuracy
– Disease + patient + stage
• 2. Meaningful control
• 3. Elimination of bias
ideally double blind
• 4. agreed measures of
success
• 5. Meaningful long-term
follow-up
• Problematic before
serology: large numbers
mask
• Complicated conceptually
in epidemiology and
ethically in treatment trials
• Presumes biomedical
model of cure
• Requires standardized
modes of measurement
• Requires enormous
commitment of social
workers, statisticians:
Even necessary?
The concept of clinical trials
• Arrowsmith’s trials of plague antidote: St. Hubert
– Gottlieb’s instruction: follow the Protocol
– Sondelius’ capitulation: follow Gottlieb
– Arrowsmith’s capitulation: save lives, sacrifice
science
• The Reception of Arrowsmith: science is a hard but
noble master
Federal funding of medical
research
• Pre WWII
– Rockefeller Foundation
• Rockefeller Institute, New York
– A De Witt Tubbs/Simon Flexner
• Carnegie Foundation
– Flexner Report
– U.S. Public Health Service Hygienic Institute
• Joseph Kinyoun
• Goldberger, pellagra, 1935
• Theobald Smith, Rocky Mountain Spotted Fever
Federal funding/ 1930 NIH (Bethesda,
1938) 2
• 1937 National Cancer Institute — grants to outside researchers
• 1941 Committee on Medical Research : mass production of malaria, artificial
quinine, leads to CDC 1946
• 1950 NSF: peer review grants
• overall fed expenditure on medical research
–
–
1941 c. 3 million
1951 76 million
• National heart institute, 1948, NIMH 1949 (374K to 42.6 mil by 1962),
• Child development, juvenile delinquincy, television violence, suicide prevention,
alcoholism
•
Separation of Surgeon General’s office 1968
– http://www.hhs.gov/ophs/
Image courtesy of Office of NIH History, National Institutes of Health.
27 Institutes: How many do you
know?
•
•
•
•
•
•
•
•
•
•
•
•
•
NCI
NEI
NHLBI
NHGRI
NIA
NIAAA
NIAID
NIAMS
NIBIB
NICHD
NIDCD
NIDCR
NIDDK
•
•
•
•
•
•
•
•
•
•
•
•
•
•
NIDA
NIEHS
NIGMS
NIMH
NINDS
NINR
NLM
CIT
CSR
FIC
NCCAM
NCMHD
NCRR
CC
http://www.nih.gov/icd/index.html
Federal funding/3
1938 usphs total = 2.8 m
• 1945 180,000 for research alone
• 1947 4 million for research alone
• 1950 46 m for NIH alone
• 1955 81 m “
• 1960 400 m “
• no similar funding for increasing medical
education.
The politics of public medicine:
medical advocacy
• National Foundation
for Infantile Paralysis,
1937 — march of
dimes
• Salk vaccine, 1952: an
upper class disease
• American Cancer
Society, (Mary
Lasker)1948-49
Mary Lasker in front of
one of her paintings
Photo courtesy of the National Library of Medicine,
National Institutes of Health.