Download clinical drug development perspectives on the ethics of human

CLINICAL DRUG DEVELOPMENT PERSPECTIVES
ON THE ETHICS OF HUMAN EXPERIMENTATION
Edmund J.D. Lee
Pharmacology Department
National University of Singapore
CLINICAL DRUG DEVELOPMENT PERSPECTIVES
ON THE ETHICS OF HUMAN EXPERIMENTATION
• Historical Perspectives of drug
development
• Impact on Clinical Trial Ethics
Ethics of Human Experimentation
Our understanding is fairly recent and
makes reference to 3 documents
Nuremberg Code 1947
Declaration on Helsinki 1964
Belmont Report 1978
I will follow that system which . . . I consider for the
benefit of my patients, and abstain from whatever is
deleterious and mischievous.
From the Hippocratic oath
"Among the experiments that may be tried on man,
those that can only harm are forbidden, those that are
innocent are permissible, and those that may do good
are obligatory. It is immoral then, to make an
experiment on man when it is dangerous to him, even
though the result may be useful to others.
Claude Bernard 1813-1878
In 1721, an epidemic of smallpox hit London
and left the British Royal Family in fear. Reading
of Lady Wortley Montagu’s efforts, they wanted
to use inoculation on themselves. Doctors told
them that it was a dangerous procedure, so they
decided to try it on other people first. The test
subjects they used were condemned prisoners.
The doctors inoculated the prisoners and all of
them recovered in a couple of weeks. So
assured, the British royal family inoculated
themselves and reassured the English people
that it was safe.
Edward Jenner
Three main forms of Ethics
1. Virtue Ethics
Ethics is about the doer’s moral character
2. Deontological Ethics
Ethics is about obeying rules/obligations
3. Consequentialism/Utilitarianism
Ethics is about good outcomes
Synthesized 1832
Medical use 1869
The Creation of the Food and Drug Administration
• In 1906, Upton Sinclair published the
novel, The Jungle, describing the
unsanitary conditions used in the
processing of meat in Chicago
• Following public protests the US
Congress through the pure Food and
Drug Act, created the Food and Drug
Administration (FDA) in 1906
– Correct labeling was required for every
food and drug
– Testing for safety was not required
The US Food, Drug, and Cosmetic Act of 1938
• More than 100 people died
in the USA in 1937 after
consumption of “Strep-Elixir”
containing sulfanilamide &
diethyleneglycol
• Congress generated the
US Food, Drug, and
Cosmetic Act requiring
scientific proof of safety for
any drug before marketing
The Thalidomide Tragedy
• Between 1950 and 1960 thousands
of children were born with congenital
malformations in Europe, Canada, and
Latin America. Traced to mothers
consuming thalidomide during
pregnancy
• Pre-marketing tests in 300 individuals
didn’t alert investigators to toxic effects
• Consumers’ concerns reached
Congress in USA generating the
Kefauver-Harris amendment in 1962,
requiring strict safety and efficacy
control for new drugs
…but were the Nazi doctors really unethical?
Nuremberg Code 1947
Universal Declaration of Human Rights (UDHR) 1948
Nuremberg Code 1947
Universal Declaration of Human Rights (UDHR) 1948
Bioethicist Arthur Caplan :
“The Nuremberg Code explicitly rejects the moral argument that the
creation of benefits for many justifies the sacrifice of the few. Every
experiment, no matter how important or valuable, requires the express
voluntary consent of the individual. The right of individuals to control
their bodies trumps the interest of others in obtaining knowledge
or benefits from them.”
Physician and ethicist Jay Katz :
“if not explicitly then at least implicitly, commanded that the principle of
the advancement of science bow to a higher principle: protection of
individual inviolability. The rights of individuals to thoroughgoing selfdetermination and autonomy must come first. Scientific advances may
be impeded, perhaps even become impossible at times, but this is
a price worth paying.”
1932-1972
History of Pharmaceutical Industry
Late 19th Century
Beginnings of drug industry
e.g. chloral hydrate
Inter-war years
Insulin. Penicillin.
Post WW2
Exponential growth
The Thalidomide Tragedy
• Between 1950 and 1960 thousands
of children were born with congenital
malformations in Europe, Canada, and
Latin America. Traced to mothers
consuming thalidomide during
pregnancy
• Pre-marketing tests in 300 individuals
didn’t alert investigators to toxic effects
• Consumers’ concerns reached
Congress in USA generating the
Kefauver-Harris amendment in 1962,
requiring strict safety and efficacy
control for new drugs
The Declaration of Helsinki of the
World Medical Association, Finland 1964
• Most well known international regulation for
biomedical research
• Establishes the principles and rationale for research
in human subjects
• Introduces the concepts of:
– Protocol approval by an independent ethics committee
– Investigator to be responsible for the care of the
participating subjects
– Written informed consent
• Content has been reviewed in Tokyo, 1975; Italy,
1983; Hong Kong, 1989; South Africa, 1996; and
Edinburgh, 2000
The Declaration of Helsinki of the
World Medical Association, Finland 1964
• Medical progress is based on research which
ultimately must rest in part on experimentation
involving human subjects.
• In case of legal incompetence, informed consent
should be obtained from the legal guardian in
accordance with national legislation. Where physical
or mental incapacity makes it impossible to obtain
informed consent, or when the subject is a minor,
permission from the responsible relative replaces that
of the subject in accordance with national legislation.
The Belmont Report 1978
• National commission
appointed in 1974 by the
Congress of the USA for the
protection of human subjects
participating in clinical research
• Reviews the ethical principals
in clinical research:
1. Autonomy
2. Beneficence
3. Justice
Clinical Research Ethics
Milestone developments:
•
•
•
•
•
•
FDA established 1906
Nazi atrocities
Nuremberg Code 1947
Kefauver Harris amendment
Declaration of Helsinki 1964
Belmont Report 1979
GCP/ICH (1977 – 1996)
Industrial
Drug Development
Human Rights
In Singapore....
The present Singapore GCP Guidelines 1998 (rev 1999)
is modelled along the ICH/GCP Guideline.
All clinical trials have to conform to the Medicines
(Clinical Trials) Amended Regulations 1998 and the
Singapore GCP Guidelines 1998 (rev 1999).
Administered by the HSA.
Good Clinical Practice – definition (EC)
A standard by which clinical trials are
designed, implemented, and reported
so that there is
public assurance
that the data are credible,
and that the rights, integrity and confidentiality of
subjects are protected
New Drug Development
Increasing costs
Direct Cost
Indirect Cost
$231 M
250
200
$125 M
150
$87 M
100
$54 M
50
0
1976
1982
1987
1990
Year
http://www.forbes.com/sites/aroy/2012/04/24/how-the-fda-stifles-new-cures-part-i-the-rising-cost-of-clinical-trials/
Three main forms of Ethics
1. Virtue Ethics
Ethics is about the doer’s moral character
2. Deontological Ethics
Ethics is about following rules
3. Consequentialism/Utilitarianism
Ethics is about good outcomes
Are our ethics defined by procedural correctness?
To what extent are our ethical values shaped by the
commercial realities?
Cases of Scientific Misconduct
in the USA
• Willowbrook State School: Inoculation
of hepatitis virus in mentally retarded
children (1957)
• Jewish chronic disease hospital:
Injection of live cancer cells in terminally
ill subjects (1963)
• Tuskegee Experiment: Untreated
syphilis in African-American people from
Alabama, United States (1930–1970)
Thank you