11

The Ethics of Conducting Clinical Trials

in the Midst of an Epidemic:

Lessons from Arrowsmith and the Neel-Yanomami Expedition

Harry Perlstadt, PhD MPHProgram in Bioethics, Humanities, and SocietyDept of Sociology, Michigan State University

11th World Congress on Public Health

Rio de Janeiro, BrazilAugust 24, 2006

22

Current “Epidemic” Clinical Trials National Institute of

Allergy and Infectious Diseases (NIAID)

HIV-AIDSTo discover which vaccine might most successfully

protect people from the HIV virus (preventive vaccine) or

from becoming ill after they acquire the HIV virus (therapeutic vaccine)

H5N1 Avian FluTo investigate safety and ability of vaccine that could generate an immune response and be administered under the skin

33

Two Case Studies

Arrowsmith by Sinclair Lewis, published in 1925. Declined Pulitzer Prize First American to win Nobel Prize in Literature

Biogeneticist/ Physician James V. Neel conducted a series of expeditions among the Yanomami– an Amazonian people— to study

How genetic variation arises and How village life effects its dispersion.

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Ethical Issues

Scientific intent to test efficacy in clinical trial during an epidemic [basic research] versus Humanitarian intent of treatment and inoculation during an epidemic [practice]

Naturally occurring phenomena versus Investigator controlled treatment/ intervention Respect for community includes informed consent and involvement of indigenous peoples/ groups

55

Framework for Research in Developing Countries

Science 298 (13 Dec 2002)

Benefits to Participants during the ResearchImprovements to health and health careCollateral health services unnecessary for research studyPublic health measuresEmployment and economic activity

66

Framework for Research in Developing Countries

Science 298 (13 Dec 2002)

Collaborative PartnershipCommunity involvement at all stagesFree, un-coerced decision making by

population bearing the burdens of the research

TransparencyCentral publicly accessible repository of

benefits agreements (case law standards)

Process of community consultation

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Background to Writing Arrowsmith

Third Bubonic Pandemic 1894-1908 China, India, Egypt, South Africa, Hawaii, San Francisco, Australia, Russia, Peru, Brazil

Alexandre Yersin isolates bacterium (yersinia pestis) Shibasaburo Kitasato identifies plague bacillus 1894

Bombay experiments to test if plague entered body via alimentary canal or surface cuts, skin abrasions.

Paul Louis Simond identifies it as a rat diseasetransferred by a blood sucking flea 1898

Felix d’Herelle discovers viral parasite that kills bacteria 1917

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Background to Writing ArrowsmithSinclair Lewis –mother was daughter of a physician, she died of TB when he was 6; father a country doctor; brother a surgeon

Consulted with Paul de KruifBacteriologist Univ of Michigan, Ph.D. 1916 WWI in France Sanitary Corps investigates gas

gangreneU of M lab of Frederick Novy works on streptococci Rockefeller Inst 1920 mechanism of respiratory

infectionFired by Simon Flexner for writing:

Nowhere in the medicine that was practiced in the 1920s could one detect a scientific approach to disease prevention and treatment; it was all a mélange of religious ritual, more or less accurate folk-lore, and commercial cunning.

Wrote The Microbe Hunters (1926) now a classic

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Characters from De Kruif’s Life

Whole dissertations have been written about who’s who in the novel’s dramatis personae

McGurk Institute is a thinly veiled Rockefeller Institute Dr. Max Gottlieb is a hybrid of Frederick Novy and Jacques Loeb Leora is modeled after Rhea, de Kruif’s second wife Martin Arrowsmith is a cleaned-up,

heroic version of de Kruif

Although I personally favor Arrowsmith as a combination of Lewis’s father and brother

And de Kruif serving as the model for Gustaf Sondelius a one man army against disease

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Plague on St Hubert Caribbean Island

Dr. Stokes, the parish medical officer, asks McGurk Institute to help prevent spread of plague.

Arrowsmith discovers a phage that kills bacteria but is beaten to publication by Felix d’Herelle (the real life researcher at the Pasteur Institute)

Dr. Gottlieb asks Arrowsmith to go to the island and conduct an experiment (clinical trial) with the phage in order to deduce its real value.

Dr. Sondelius argues that the phage should be givento all, but Arrowsmith wants to give it to half, so that he may monitor and evaluate it.

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Doing the Clinical Trial

Arrowsmith faces opposition to running his experiment, so he presents his case to a group consisting of the island’sSurgeon General, Governor, Board of Health, and members of the House of Assembly

Turned down, Arrowsmith goes and inoculates a small village, but village must be evacuated and burned to be disinfected.

Other islanders despise Arrowsmith - call him names and throw stones because he is withholding their salvation.

Finally allowed to do experiment in another parish, finds plague attacked unphaged people more than injected

After Leora dies of plague, he inoculates anyone who wants it. Plague slackens due to phage and/or rat extermination.

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Time out for Ethics

Ethical Issues Arrowsmith

Scientific intent to test efficacy

++

Humanitarian intent to treat +

Informed consent of communities

+?

Natural occurrence +

Controlled experiment +

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The Yanomami

Hunters, fishers, and farmers who live in the Amazon rain forest on the border of Brazil and Venezuela.

They live in 300 villages spread over a territory about the size of Portugal. The remoteness of the region allowed them to develop in almost complete isolation from the outside world.

With a population of 22,000, the Yanomami are the largest indigenous group in South America that still lives mainly in a traditional manner.

Since the discovery of gold in the 1970s, thousands of miners have streamed into Yanomami territory, decimating native populations with diseases such as measles, influenza and TB.

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Research Goals

Atomic Energy Commission (funder): Genetic mutation due to radiation

Neel (researcher/ investigator): Genetically inherited differences between Yanomami individuals/ villages, --

the differential reproductive rate of headmen.

Yanomami told goal was to look inside their blood to find infectious diseases, implying that the research would yield immediate health benefits to them.

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Main Activities

Samples of Yanomami blood, feces, urine, sputum were studied for various traits related to health -- presence of intestinal parasites or hepatitis B.

Reported on Yanomami health needs to government Published health-related findings in international journals.

Medical treatment was provided by the expedition in 1968, 1969, 1970Sent medications to missionaries working among the Yanomami for several years.

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A Noteworthy Discovery and a Plan

CDC found antibody titers of Yanomami blood from 1966 expedition revealed vulnerability to measles. Neel meets with CDC in Atlanta

Neel plans a prophylactic vaccination campaign Targets Yanomami communities most likely to face early exposure to new epidemic diseases (Oct, 1967)

Selected (donated) Edmonston B because it gave a longer immunity than the Schwarz

vaccine, and, when administered with gamma globulin, did not have more serious side effects.

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Against Disease, the Strongest Fence

Neel learns of measles in Brazil (Nov 28) in Venezuela (Dec 11) Gets 2000 vaccine doses, sends 1000 to missionaries working among the Yanomami in Brazil (Jan 11)

His "all Orinoco" plan included controlling movement in/ through the five primary ports of entry, liberal use of penicillin, vaccination and gamma globulin when practical (Feb 16)Neel provided penicillin and terramycin not only to those affected in the villages he visited, but also to those who would be able to bring it to persons affected elsewhere.

No evidence suggests he attempted to discourage anyone from providing treatment, and he spent much of his own time administering vaccines and antibiotics.

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Research Within a Humanitarian Effort

Naturally occurring phenomena (rather than investigator controlled treatments) provided research opportunities.

During epidemic/ vaccination campaign Neel made research observations of the course of the disease in victims and observed vaccination reactions.

Compared reactions in people who were vaccinated with and without immunoglobulin, because Roche vaccinated without immunoglobulin prior to Neel's arrival

Observations also allowed exploring theory about high mortality from measles among Native Americans

1919

Debate over the Measles Epidemic

Darkness in El Dorado by Patrick Tierney claimed:

A measles vaccine known to be virulent in genetically isolated populations was given to the Yanomami as part of a project designed by Neel, allegedly inspired by eugenics theories.

An epidemic rapidly ensued and the research team allegedly was advised not to provide any medical assistance to the sick and dying Yanomami, and resulted in at least 30 deaths if not many more.

Similarity with the infamous Tuskegee experiment.

American Society of Human Genetics Found these allegations to be gross

mispresentations and basically false Am. J. Hum. Genet., 70:1-10, 2002

:

2020

The Yanomami Claims

To receive compensation for biological samples allegedly collected by scientists without the Yanomami people's informed consent.

“The whites said: ‘I’m going to give you a machete… when you come to give blood… I’ll give you fishing hooks.’ That’s why people went to give them blood.”

To have these samples, some still in U.S. laboratories, returned for burial.

“Whatever is of the dead must be destroyed… Our custom is that when the Yanomami die, we destroy everything. To keep it in a freezer is not a good thing. We thought it was destroyed.”

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Time out for Ethics

Ethical Issues Neel / Measles

Scientific intent to test efficacy

0

Humanitarian intent to treat ++

Informed consent of communities

?

Natural occurrence +

Controlled experiment 0

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Time out for Ethics

Framework for Research Neel Sample Collection

Improve Health and Health Care

+

Collateral Health Services +

Public Health Measures ++

Community Involvement all stages

0

Free, un-coerced decision making

0

Respect for Community 0