REGULATIONS and GUIDANCES
HISTORICAL PERSPECTIVE
There are 2 major milestones that occurred in the development of laws and guidelines that govern the
conduct of clinical trials internationally.
The Nuremburg Code (1947): This code was a result of discovery of human experimentation during
World War II and the Nuremburg trials which followed. The code contains 10 points which define
necessary components of medical experimentation using human subjects, including voluntary consent
of subjects, investigations of scientific merit, avoidance of unnecessary harm to subjects, experiments
conducted by qualified people, and the right of subjects to withdraw from the experiment. The Code
includes 10 elements which should be considered when designing and executing an experiment:
 Voluntary consent of the human subject.
 Designed to produce fruitful results.
 Designed and based on animal studies and knowledge of the natural history of disease or
problem under study so anticipated results justify the experiment.
 Conducted to avoid unnecessary harm and suffering.
 No experiment is conducted that is expected to result in death or disabling injury.
 Degree of risk should never exceed the problem’s humanitarian importance.
 Proper preparations should be made to protect the subject against injury, disability or death.
 Experiment should be conducted by scientifically qualified persons.
 The human subject should be able to bring the experiment to an end.
 The scientist must be able to terminate the experiment if there is reason to believe continuing
will result in injury, disability or death.
Declaration of Helsinki (1964): Issued by the World Medical Association (WMA) , the Declaration of
Helsinki is a statement of ethical principles to guide physicians and other participants in medical
research involving human subjects, including medical research on identifiable human material or
identifiable data forms , and form the basis for human research ethics internationally. All physicians are
morally bound to follow the principles. The declaration is based on the Nuremburg Code and added
that the interest of the subject should always be given a higher priority than the interests of society and
that every subject in clinical research should get the best known treatment. Its core principles are
respect for the individual, the individual’s right to self-determination, and the right of the individual to
make informed decisions. This document is modified every few years, most recently in 2013.
UNITED STATES
There are laws that govern the conduct of clinical research in the United States. The Legislative Branch
of the federal government is responsible for U. S. laws. Congress creates laws and passes bills. The
President then signs those bills into law. Federal laws are published in the United States Code (USC) and
are legally binding.
Federal regulations are issued by the Executive Branch (i.e., agencies such as Department of Health and
Human Services). They explain how the agency intends to carry out a law. Federal regulations are
created through a process known as rulemaking and published in the Code of Federal Regulations (CFR).
If an agency needs to add, revise, or delete a regulation, they publish a proposed rule in the Federal
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Register and ask for public comment. After review of the feedback, changes are made, and the final rule
is published in the Federal Register with dates that the regulation becomes effective and enforceable.
All regulations are legally binding.
Guidances are issued by the various agencies, published in the Federal Register, and provide more
information or guidance on how a particular regulation is implemented. Gudiances are not legally
binding.
Belmont Report: A series of highly publicized abuses in research led to the enactment of the 1974
National Research Act (Public Law 93-348), which created the National Commission for the Protection of
Human Subjects of Biomedical and Behavioral Research. One of the charges to the National Commission
was to identify the basic ethical principles and guidelines for the conduct of biomedical and behavioral
research involving human subjects. In 1978, the Commission published “Ethical Principles and Guidelines
for the Protection of Human Subjects of Research,” also known as the Belmont Report. The report
identifies three principles for the ethical conduct of research involving human subjects:
1. respect for persons
2. beneficence, and
3. justice.
Research conducted or supported by the Department of Health and Human Services (HHS)
(This includes all NCI sponsored or funded clinical research)
The Office for Human Research Protections (OHRP) provides leadership in the protection of the
rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Basic
regulations governing the protection of human subjects in research supported or conducted by the
Department of Health and Human Services were first published at 45 CFR Part 46 in 1974. The current
version of the regulations includes five subparts:
 Subpart A (issued in 1974, revised in 1981 and 1991 and technical amendments in 2005): Basic
set of protections for all human subjects of research conducted or supported by HHS.
 Subpart B (issued in1975 with most recent revised in 2001): Provides additional protections for
pregnant women, human fetuses, and neonates involved in research.
 Subpart C (issued in 1978): Provides additional protections pertaining to biomedical and
behavioral research involving prisoners as subjects.
 Subpart D (issued in 1983): Provides additional protections for children involved as subjects in
research.
 Subpart E (issued in 2009): Registration of institutional review boards (IRBs).
OHRP Guidances are found at: http://www.hhs.gov/ohrp/policy/index.html
Federal Policy for the Protection of Human Research Subjects
In 1991, the “Federal Policy for the Protection of Human Research Subjects,” informally known as
the “Common Rule” was issued by 15 federal departments and agencies. The Common Rule was based
on the HHS 45 CFR Part 46 Subpart A, and includes identical language in the separate regulations of
those departments and agencies. Three departments and agencies have not issued the Common Rule
but apply all parts of 45 CFR Part 46:
 Central Intelligence Agency,
 Social Security Administration, and
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 Department of Homeland Security.
Other departments and agencies have adopted one or more of the other HHS subparts and some have
their own additional human subject protection regulations. Click on the link for a complete listing of the
agencies that follow the Common Rule.
Research regulated by the Food and Drug Administration (FDA)
The Food and Drug Administration (FDA) is an HHS agency that regulates clinical investigations of
products under its jurisdiction, such as drugs, biological products, and medical devices. FDA regulations
are published in title 21 of the CFR. FDA’s human subject protection regulations include:
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21 CFR Part 11: Electronic Record/Electronic Signatures
21 CFR Part 50: Protection of Human Subjects, specially informed consent
o Subpart D: Provides additional protections for children
21 CFR Part 54: Financial Disclosure clinical Investigators
21 CFR Part 56: Institutional Review Boards
21 CFR Part 312: Investigational New Drug Application
21 CFR Part 314: Applications for FDA Approval to Market a New Drug
21 CFR Part 601: Biologics Licensing
21 CFR Part 812: Investigational Device Exemptions
FDA Information Sheets of Interest to the CTN
General Information Sheets
 Charging for Investigational Products - Information Sheet
 Cooperative Research - Information Sheet
 Exception from Informed Consent Requirements for Emergency Research
 Informed Consent, A Guide to - Information Sheet
 Institutional Review Boards Frequently Asked Questions - Information Sheet
 Non-local IRB Review - Information Sheet
 "Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices Information Sheet
 Payment to Research Subjects - Information Sheet
 Recruiting Study Subjects - Information Sheet
 Screening Tests Prior to Study Enrollment - Information Sheet
 Sponsor - Investigator - IRB Interrelationship - Information Sheet
Drugs and Biologics
 Emergency Use of an Investigational Drug or Biologic - Information Sheet
 Evaluation of Gender Differences in Clinical Investigations - Information Sheet
 Statement of Investigator (Form FDA 1572) - Frequently Asked Questions – Information Sheet
 Treatment Use of Investigational Drugs - Information Sheet
 Waiver of IRB Requirements for Drug and Biological Product Studies - Information Sheet
Devices
 Medical Devices, Frequently Asked Questions About - Information Sheet
 Significant Risk and Nonsignificant Risk Medical Device Studies - Information Sheet
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FDA Operations
 FDA Inspections of Clinical Investigators - Information Sheet
 FDA Institutional Review Board Inspections - Information Sheet
FDA Guidances of interest to the CTN
General Guidances
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21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations, Process for Handling
Referrals to FDA Under
Clinical Holds, Submitting and Reviewing Complete Responses to
Data Monitoring Committees for Clinical Trial Sponsors, The Establishment and Operation of
Clinical Trial
Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials
Exception from Informed Consent Requirements for Emergency Research
Financial Disclosure by Clinical Investigators
Financial Relationships and Interests in Research Involving Human Subjects
Investigator Responsibilities — Protecting the Rights, Safety, and Welfare of Study Subjects
Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling
Claims
ICH Guidances adopted by the FDA
IRB and Informed Consent
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Adverse Event Reporting to IRBs - Improving Human Subject Protection
Centralized IRB Review Process in Multicenter Clinical Trials, Using a Central IRB
HIPAA Authorizations Under FDA Regulations, IRB Review of Stand-Alone
Informed Consent Elements, 21 CFR 50.25(c), Questions and Answers
IRB Continuing Review After Clinical Investigation Approval
IRB Registration, Frequently Asked Questions
IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research
Sites, and the Determination of Whether an IND/IDE is Needed
Drugs and Biologics
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Exploratory IND Studies
IND Exemptions for Studies of Lawfully Marketed Drug or Biological Products for the Treatment
of Cancer
Safety Reporting Requirements for INDs (Investigational New Drug Applications) and BA/BE
(Bioavailability/Bioequivalence) Studies
Electronic Data
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Computerized Systems Used in Clinical Trials
Electronic Records; Electronic Signatures - Part 11, Scope and Application
THE INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR
REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE (ICH)
ICH is a coalition of regulatory authorities and representatives from the pharmaceutical industry
whose goal is cooperation among the groups in Japan, Europe and the U. S. (FDA represents the U. S.) to
protect the rights and welfare of the clinical subjects. They have establish global standards for the
conduct of clinical research - a consolidated guideline that sets minimal standards for clinical trials (CT)
to ensure the quality and integrity of the data and identifies and defines responsibilities of key
personnel/groups involved in clinical trials.
The guidelines are divided into 4 major categories of standards are:
• Quality guidelines
– chemical and pharmaceutical Quality Assurance
• Safety guidelines
– in vitro and in vivo pre-clinical studies
• Efficacy guidelines
– clinical studies in human subject
– E2: data management
– E6: Good Clinical Practice (GCP) Guidelines
• Multidisciplinary guidelines
– cross-cutting topics that do not fit into one of the above categories
Adoption and implementation of ICH GCP guidelines vary between the founding countries:
 EU implemented the ICH GCP guideline as a legal directive in 1996
 Japan translated the document and legally enacted its version in 1997
 U.S. FDA adopted the E6 guideline as a guidance document.
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