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 Senility Cancer and other malignant tumors All accidents Nephritis (all forms) Intracranial lesions of vascular origin Diseases of the heart Diarrhea, enteritis, and ulceration of Tuberculosis (all forms) Pneumonia (all forms) and influenza
0 50 100 150 200 40.3 50.2 64 72.3 88.6 106.9 137.4 142.7 194.4 202.2 250 Deaths per 100,000 population

Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention

U.S. Leading Causes of Death - 1974

Bronchitis, emphysema, and asthma Certain causes of mortality in early infancy Arteriosclerosis Cirrhosis of liver Diabetes mellitus Influenza and pneumonia Accidents Cerebrovascular diseases Malignant neoplasms, including neoplasms of lymphatic and hematopoietic tissues Diseases of heart
0 50 100 150 200 250 300 12.6

13.5

15.1

15.6

17.5 Deaths per 100,000 population 25.7

49

97.2

169

346

350

400

Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention

U.S. Leading Causes of Death - 1992

Homicide and legal intervention Human immunodeficiency virus infection Suicide Diabetes mellitus Pneumonia and influenza Accidents and adverse effects Chronic obstructive pulmonary diseases and allied conditions Cerebrovascular diseases Malignant neoplasms, including neoplasms of lymphatic and hematopoietic tissues Diseases of heart
0 50 100 150 200 250 10.5

11.7

12.2

19.4

30.9 Deaths per 100,000 population

35.4

35.9

56.9

204.1

285.9 300 350

Source: Leading Causes of Death, 1900-1998, Centers for Disease Control and Prevention

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, streptomy cin, 1944: antibacterial agents Corticosteroids, 1948

The emergence of clinical SCIENCE

The Paris Hospitals, early 19th century
PCA Louis and the numerical method, 1830s1840s
Hospital as an experimental site Very large (tractable) patient populations Bleeding does not improve pneumonia
This image is Wellcome Images, available under a Creative Commons License.

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: Hamlins Wizard oil

"Rheumatism, toothache, deafness, burns, bite s 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: Pinkhams 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 Free-lancers: established clinical scientists Efficient: wannabe clinical scientists: practitioners with access to patients Friendly experts: the insidious general consultant

Rasmussens classes

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

Its 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

Arrowsmiths trials of plague antidote: St. Hubert Gottliebs instruction: follow the Protocol Sondelius capitulation: follow Gottlieb Arrowsmiths 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 Generals 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.

Credits
Slide 8
Pierre Charles Alexandre Louis 1787-1872. ccby-nc-sa. Accessed from http://images.wellcome.ac.uk/ on August 9, 2010. Photo of Karl Pearson. In the public domain. Accessed from http://commons.wikimedia.org/wiki/File:Karl_Pearson.jpg on August 9, 2010. Photo of Raymond Pearl. In the public domain. Accessed from http://en.wikipedia.org/wiki/File:Raymond_Pearl_o.jpg on August 9, 2010. Hamlin's Wizard Oil. In the public domain. Accessed from http://www.nlm.nih.gov/ on August 9, 2010. Lydia E. Pinkhams Herb Medicine. In the public domain. Accessed from http://commons.wikimedia.org/wiki/File:Lydia_Pinkham.png on August 9, 2010. Lydia E. Pinkhams Vegetable Compound. In the public domain. Accessed from http://en.wikipedia.org/wiki/File:LydiaPinkham-VegetableCompound.gif on August 9, 2010. Bottle of Sulfanilamide. In the public domain. Accessed from http://www.fda.gov/default.htm on August 9, 2010. NIH Org Chart 1949. In the public domain. Accessed from http://www.history.nih.gov/exhibits/history/docs/page_07a.html on August 9, 2010. B&W photo of Mary Lasker. In the public domain. Accessed from http://profiles.nlm.nih.gov/TL/B/B/D/C/_/tlbbdc.jpg on August 9, 2010.

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