Historical Development of International Regulations in Clinical Research
Medicines at the Beginning of the XX Century
Medicines were advertised and sold in “Medicine Shows” from town to town in the USA
They were natural products from plants, animals, or minerals, chosen on an empirical basis There was no control for safety or efficacy No pre-marketing testing was required Few drugs proved to be effective (i.e., Morphine, Digitalis, Quinine, etc.)
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.
- Public protests reached the US Congress.
Pure Food and Drug Act created the Food and Drug Administration (FDA) in 1906 Correct labeling was required for every 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 and Diethyleneglycol
Congress generated the US Food, Drug, and Cosmetic Act requiring scientific proof of safety for any drug before marketing
The Nazi Experiments During the Second World War
Thousands of Jewish people were forced to participate in inhuman experiments
Child victims of provoked burning and wounds for experimental purposes
Experimental starvation to test the symptoms of hunger
Characteristics of the Nazi Experiments
Conducted without the consent of participants Caused unnecessary pain, suffering, and death Absence of benefit for the individuals Lack of adequate scientific rationale
Low pressure experiment killing a prisoner
Induced hypothermia in a camp prisoner
The Nuremberg Trial 1947
Atrocities of the Nazi experiments became public Trial for war crimes included 23 Nazi doctors
The Nuremberg Code 1948
Established for the purpose of preventing the atrocities of the Nazi experiments from happening again Subject participation must be voluntary (Informed Consent)
Experiments must be supported by strong scientific rationale
Physical or mental suffering or damage is not acceptable (no harm) The subject has the right to stop his participation in the trial at any time
The Thalidomide Tragedy
Between 1950 and 1960 thousands of children were born with congenital malformations in Europe, Canada, and Latin America Mothers consumed 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
Contergan (Thalidomide) Hypnotic registered at WHO in 1954
Congenital malformations due to Thalidomide exposure during pregnancy
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 as 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
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)
The Code of Federal Regulations of the Food and Drug Administration of the USA 1977 Establishes the regulations for clinical research in the USA Introduces the concepts of “Good Clinical Practice” and “Data Integrity”
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: Autonomy Beneficence Justice
International Ethical Guidelines for Biomedical Research World Health Organization (WHO), Geneva 1993
Fifteen guidelines consisting of a comprehensive review of: Informed consent of subjects Selection of research subjects Confidentiality of data
Compensation for accidental injury
Procedures for the Ethical Review Committees Obligations of Sponsor and host country
Reviewed by more than 150 representatives from different countries (Ministers of Health, scientists, ethicists, philosophers, lawyers, etc.)
Recommendations for developing countries
The International Conference on
Harmonization – 1996
International guidelines in good clinical practice to provide unified standards for the European Union, Japan, and USA, to facilitate mutual acceptance of clinical data
Developed with consideration of current standards of the European Union, Japan, USA, Australia, Canada, the Nordic countries, and the World Health Organization (WHO)
The GCP section of the ICH covered the three elements below: Protection of trial participants Scientific support of the trial Data integrity
Regulations for the Use of Investigational
Drugs in Humans:
Regulations in Clinical Research
Pure Food and Drug Act FDA
1938US Food, Drug and Cosmetic Act Nuremberg Code Kefauver-Harris Amendment Declaration of Helsinki Code of Federal Regulations of the FDA – GCP Belmont Report Inception of ICH and GCPs International Ethical Guidelines for Biomedical Research International Conference on Harmonization – GCP effective
1906
1938 1947 1962 1964 1977 1978 1990 1993 1996
The Impact of International Regulations for
Clinical Research
- Improve the quality of clinical research, both ethically and scientifically, in the last 50 years Decrease the frequency of scientific misconduct -Standardize the rules and regulations of clinical research facilitating a globalization process
-Promote the development of thousands of new drugs for the treatment of human diseases increasing the expectancy and the qualify of life
Aspirin Felix Hoffman 1900
Penicillin Alexander Fleming 1941
Summary
-No regulations for pharmaceutical products until 1906
-Nazi experiments alert the scientific community about unethical research -Nuremberg Code establishes the need for informed consent in human research -Declaration of Helsinki introduces the concept of protocol approval by an independent ethics committee -FDA develops the concept of good clinical practice
- ICH provides international guidelines for global research development
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