Human Research History and Regulations

• Identify the history events that lead to the
development of principles, regulations,
and guidance to conduct human research
• Briefly describe these regulations and
• Define the term “Good Clinical Practice”
and how is applies to clinical research
Human Research Protection Program
Historical Perspective
ICH Guidelines 1996
Common Rule 1991
Consolidated HHS/FDA Regulations 1981
Belmont Report 1979
1972 The Syphilis Study (Expose’)
Declaration of Helsinki 1964
Amendments to the Food
Drug and Cosmetic Act 1962
Nuremberg Code 1947
Human Radiation Experiments
1942 The Nazi Experiments
The Syphilis Study begins
Nuremberg Code
The trial verdict adopted ten points constituted the
"Nuremberg Code".
Legal force of the document was not established
and it was not incorporated directly into either
the American or German law, the Nuremberg
Code and the related Declaration of Helsinki are
the basis for the Code of Federal Regulations
governing federally-funded research in the
United States
Nuremberg Code – 10 points
The voluntary consent of the human subject is absolutely essential. This means that the person involved should have legal capacity
to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of
force, fraud, deceit, duress
The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of
The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history
of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
No experiment should be conducted where there is a prior reason to believe that death or disabling injury will occur; except,
perhaps, in those experiments where the experimental physicians also serve as subjects.
The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved
by the experiment.
Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote
possibilities of injury, disability, or death.
The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be
required through all stages of the experiment of those who conduct or engage in the experiment.
During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached
the physical or mental state where continuation of the experiment seems to him to be impossible.
During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has
probable cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation
of the experiment is likely to result in injury, disability, or death to the experimental subject.
Declaration of Helsinki
The fundamental principle is respect for the
individual , their right to self determination and
the right to make informed decisions.
Belmont Report
Basic Ethical Principles:
• Respect for persons
– (informed consent process)
• Beneficence – do no harm
– (maximum benefit/minimized risk)
• Justice- well considered procedures administered
– (fairness of the selection of subjects)
Common Rule
• In 1981, DHHS and FDA issued regulations based on the Belmont Report.
– DHHS issued Code of Federal Regulations (CFR) Title 45 (public welfare), Part 46
(protection of human subjects).
– The FDA issued CFR Title 21 (food and drugs), Parts 50 (protection of human subjects) and
56 (Institutional Review Boards)
• In 1991, the core DHHS regulations were formally adopted = "Common
The main elements of the Common Rule include :
– requirements for assuring compliance by research institutions
– requirements for researchers obtaining and documenting informed consent
– requirements for IRB membership, function, operations, review of research, and record
– additional protections for certain vulnerable research subjects-- pregnant women, prisoners,
and children
Good Clinical Practice (GCP)
• Good Clinical Practice offers protection for human subjects in clinical
trials. There is no one source of guidance for GCP. They are embodied
within laws, regulations and guidance such as:
The Belmont Principles
IRB and Consent Regulations
Guidelines on the obligations of investigators, sponsors and monitors
Code of Federal Regulations retaining to drugs and devices
Form FDA 1572
ICH Guidelines
Official guidance documents
International Conference on
Harmonization (ICH)
• ICH guidance was published as a worldwide
guideline for GCP in an effort to standardize for
clinical trials
Importance of GCP and ICH
• Following GCPs ensures the accuracy and reliability of data
generated in the course of a clinical trial.
• Compliance with GCPs during clinical trials will ensure that:
– The rights and safety of human subjects are not
– Appropriately and adequately trained staff manage the study.
– The study is carefully documented.
– Protocol is strictly adhered to.
Standard Operating Procedures for any
Clinical Trial
• GCPs are recognized as the standard operating procedures for a
clinical trial
• GCPs, therefore, encompass all aspects of a clinical trial
including (but not limited to:
– Obtaining informed consent
– Documenting accurate case histories
– Maintaining completed “paper trails” for all study documents
– Reporting adverse events
– Proper record storage and retention