CLINICAL DRUG DEVELOPMENT PERSPECTIVES

ON THE ETHICS OF HUMAN EXPERIMENTATION

Edmund J.D. Lee

Pharmacology Department

National University of Singapore

• Historical Perspectives of drug

development

• Impact on Clinical Trial Ethics

CLINICAL DRUG DEVELOPMENT PERSPECTIVES

ON THE ETHICS OF HUMAN EXPERIMENTATION

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

• 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 Thalidomide Tragedy

…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 self-

determination 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

• 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 Thalidomide Tragedy

• 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 Declaration of Helsinki of the

World Medical Association, Finland 1964

• 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

The Belmont Report 1978

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

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.

In Singapore....

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

Good Clinical Practice – definition (EC)

0

50

100

150

200

250

1976 1982 1987 1990

Direct Cost Indirect Cost

New Drug Development Increasing costs

$54 M

$87 M

$125 M

$231 M

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