Lecture 2

History and Ethical codes

Research ethics scandals

• Here are few famous and less-well-known examples of research ethics ‘scandals’ which led to the establishment of the present system of independent ethics committees reviewing research.

• History of research ethics is often assumed to have begun with the scandals that took place in Nazi Germany, both unethical research and ethical regulation of research preceded those events.

1972 Syphilis Study Exposed

1966 The Beecher Article (NEJM)

1932 The Syphilis Study Begins

Trigger Events

1947

1962

1964

1979

1981

1991

Nuremberg Code

Kefauver-Harris Amendments Food, Drug and Cosmetic Act

Declaration of Helsinki

Belmont Report

Consolidated HHS/FDA Regulations

Common Rule

The Nazi Experiments

US Human Radiation Experiments

The Thalomide Tragedy

Milgram Study

20th Century Research Ethics Milestones

‘Back to the Future’

• Edward Jenner’s smallpox vaccine, England, 1796– involved injecting an eight-year-old child with pus from a cowpox

infection and then deliberately exposing the child to smallpox to establish their acquired immunity. While a great step forward in the fight against smallpox, the exposure to risk this involved for the child would be unlikely to be condoned today.

• The Neisser case, Prussia, 1898– Albert Neisser conducted clinical trials on serum therapy in

patients with syphilis. This was done by injecting serum from patients with syphilis into those who were admitted for other reasons, without either informing them of the experiment or seeking informed consent. When, subsequently, some of these patients contracted syphilis Neisser concluded that the vaccination had failed.

– This was followed in 1931 by the German minister of the interior issuing

– Guidelines for New Therapy and Human Experimentation, which further emphasised the necessity of considering the risks involved in research, and seeking informed consent, in particular for non-therapeutic research.

• The Little Albert experiment, United States, 1920– It aimed to demonstrate the phenomenon of human conditioning by

conditioning an 11-month old infant to fear rats by associating them with fear inducing circumstances such as a loud noise. The research was conducted without the knowledge or consent of Albert’s parents.

• Medical experimentation in Nazi Germany, 1939-45– Experiments carried out on concentration camp prisoners included

involuntary sterilisation, subjection to radiation, freezing to induce hypothermia, infection of research subjects with malaria and tuberculosis (TB), and many other unethical experiments, conducted without the consent of the research subjects, and often leading predictably to extreme pain, mutilation and death.

– These experiments led to the development of the Nuremberg Code in 1947, largely as a legal document to codify what was unethical about the Nazi research, but also as a code for future research. It also strongly influenced the development of the World Medical Association’s Declaration of Helsinki in 1964, a code of ethics developed by physicians to self-regulate the conduct of medical experimentation.

• Thalidomide use – Thalidomide was used in the 1950s to combat unpleasant

symptoms associated with pregnancy. At the time it was being used it was not usually disclosed to patients that the drug was investigational and still in the testing phase of the regulatory process. After women in Europe, Canada, and the U.S. were treated with the drug it was discovered that the drug had teratogenic effects, causing severe deformities in the fetus. Thalidomide was soon banned worldwide. Unfortunately, approximately 12,000 babies were born with severe deformities due to thalidomide.

• Tuskegee syphilis study, United States, 1932-72• This was a clinical study carried out between 1932 and 1972 in Tuskegee, Alabama,

by the US Public Health Service. About 400 mostly illiterate African-Americans with syphilis were recruited into the study as well as two hundred healthy controls. The aim of the study was to observe the natural progression of the disease when left untreated, and in particular to compare the progression of the disease in African-Americans with the results of an earlier retrospective study of the disease in Europeans.

• Patients were unaware and were disguised with “special free treatments”. • study subjects were blocked from receiving effective treatment and prevented from

getting in the armed forces. At the end of the study only 74 subjects remained alive, 40 of their wives had been infected and 19 children had been born with syphilis, some of which might have been prevented if these men had been given treatment.

• The aftermath of Tuskegee led to the formalisation of ethics review in America, and was also influential on the 1975 revision of the Declaration of Helsinki which introduced the requirement for the independent review of all research.

• This and the other well-known research ethics scandals listed above are clearly ethically troublesome, but it is important to realise that these high-profile cases form only a minority of cases of unethical research.

Codes of Ethics and legal constraints• Ethical codes and guidelines are a means of establishing and articulating

the values of a particular institution or society, and the obligations that it expects people engaged in certain practices to abide by.

• Some prominent examples of codes and laws which bear on researchers’ conduct are listed below:– The Nuremberg Code. – The World Medical Association’s Declaration of Helsinki. – The Council for International Organizations of Medical Sciences’

(CIOMS) International Ethical Guidelines for Biomedical Research Involving Human Subjects.

– The Charter of Fundamental Rights of the European Union. – The European Convention on Human Rights. – The European Union Good Clinical Practice Directive.– The Convention for the protection of Human Rights and dignity of the

human being with regard to the application of biology and medicine: Convention on Human Rights and Biomedicine (The Oviedo Convention).

– The European Union Clinical Trials Directive.

• Because of the complexity in the research experiments individual researchers may not be best placed to decide about the ethical issues a research project raises, and instead it may need a group of experts, both scientific and ethical, to make a good decision.

The Belmont Report

Response to Research Abuses

• Nazi atrocities in World War II drew attention to the lack of international standards on research with human participants and led to the formulation of the Nuremburg Code (1948).

• The thalidomide disaster led to the adoption of the "Kefauver Amendment" (1962) to the Food, Drug and Cosmetic Act, requiring drug manufacturers to prove to the FDA the safety and effectiveness of their products and physicians to obtain informed consent from potential subjects before administering investigational medications.

• The Declaration of Helsinki drafted by the world Medical Association in 1964 (most recently updated in 2000) builds on the Nuremberg Code and is the basis for Good Clinical Practices used today.

• The National Research Act (1974) passed primarily in response to the syphilis study, codified the requirement that human participants in research must be protected and set the stage for the issuance of the Belmont Report.

National Research Act (1974)

• Due to the publicity from the Syphilis Study, the National Research Act of 1974 was passed.

• The National Research Act created the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.

• The Commission charge was to identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human participants and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral

Research

• Carrying out its charge, the Commission prepared the Belmont Report in 1979.

• The Belmont Report is a statement of basic ethical principles and guidelines that provide “an analytical framework to guide the resolution of the ethical problems arising from research with human subjects.”

Boundaries between Practice and Research

• The distinction between practice and research is blurred; often because they occur together.

• The IRB must ensure that the researcher (and the participant) distinguishes practice from research in both social science and biomedical research

• Minimize the potential for therapeutic misconception – when one believes the purpose of clinical research is to treat rather then to gain knowledge

Basic Ethical Principles

• Respect for Persons– Individuals should be treated as autonomous

agents– Individuals with diminished autonomy are

entitled to protections

• Beneficence– Do not harm– Maximum possible benefits, and minimize

potential harms

• Justice– Fair distribution of burdens and benefits of

research

Respect for Persons

• Treat individuals as autonomous persons; allow individuals to choose for themselves

• Persons with limited autonomy need additional protection, even to the point of excluding them from activities that may harm them. The extent of protection should depend upon the risk of harm, and the likelihood of benefit.

• The judgment that any individual lacks autonomy should be periodically re-evaluated, and will vary across situations.

Beneficence

• The IRB should determine whether the risks to subjects are reasonable in relation to anticipated benefits

• Obligations of beneficence affect both the researcher and society – investigators are required to give forethought

on maximization of benefits and reduction of risk that may be involved in the research

society should recognize the longer term benefits and risk that may result from the improvement of knowledge, and from the development of novel medical, psychological, and social processes and procedures

Justice

• Treat people fairly

• Do not exploit those who are readily available or malleable

• Fair distribution of the risks and the benefits of research based upon the problem/issue under investigation

Applications of the General Principles

• Consideration of the three general principles in the conduct of research lead to the consideration of:

Informed Consent process

Risk/Benefits assessment

Selection of research participants

Application ofRespect for Persons

• Informed Consent Process Information - Does the consent form provide all the

information necessary for the individual to make a reasoned decision?

Comprehension - Is the consent form crafted in language understandable to the potential participant?

Voluntariness - Does the consent form and clearly indicate that participation in the research is voluntary?

What additional protections can be in place to protect those with limited autonomy?

How to determine whether one lacks the autonomy to make a reasoned decision?

Applications ofBeneficence

• Assessment of Risks and Benefits Risk refers to the probability of harm; when considering

risk, one should consider both the probability and the severity of the projected harm; while the term, benefit refers to something that promotes health, well-being, or welfare.

What are the risks of harm to the participants (consider physical, psychological, social, and economic harms)? Are the risks justified? Can they be minimized?

Can the research design be improved to minimize risk and maximize benefit?

What are the benefits (to the participant; to society)?

Applications of Justice

• Selection of Subjects Is the potential subject pool appropriate for the

research?

Is it appropriate to involve vulnerable populations (e.g., economically disadvantaged; limited intellectual capacity) in the research or are they being enrolled because it is convenient or because they are easily manipulated as a result of their situation?

Are the recruitment procedures fair and impartial?

Are the inclusion and exclusion criteria fair and appropriate?