go to the following link to view 12 recorded webinars related to Human Research Protection on the U.S. Department of Health and Human Services YouTube channel:
Assignment Instructions: This week, reflect on what you learned from the NIH materials about protecting the rights of human research participants.
Discuss at least three of the following in your paper:
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Protecting Human Research Participants:
Select Quiz Questions
Codes and Regulations: Section Quiz
1. Identify the most influential event that led to the HHS Policy for Protection of Human
Research Subjects:
A.
B.
C.
D.
Nuremberg trials
Syphilis Study at Tuskegee
Jewish Chronic Disease Hospital Study
Willowbrook Study
2. An institutionally designated authority, other than the investigator, should determine
that proposed studies are exempt from regulatory requirements.
A. True
B. False
3. The Belmont Report is significant because:
A.
B.
C.
D.
It was written by the National Commission for the Protection of Human Subjects.
It articulated ethical principles that formed the basis for the HHS Human Subjects Regulations.
Belmont is another word for individual autonomy and respect.
It was a seminal document about the concept of informed consent.
4. 45 CFR 46 requires Federal Departments and Agencies to rely solely on IRBs to
evaluate risks to subjects, protection against these risks, potential benefits of the
research and the importance of the knowledge to be gained.
A. True
B. False
5. A “systematic investigation designed to develop or contribute to generalizable
knowledge” may include:
A.
B.
C.
D.
Evaluation
Research Development
Testing
All of the above
1
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6. An “autonomous person” is someone who:
A. Has reached the legal age to provide informed consent in the State.
B. Is willing to accept certain risks if the research will benefit others in the future.
C. Understands the risks and benefits of his or her participation and is able to make a voluntary
decision if adequate information is provided.
D. Meets all eligibility criteria for a study and asks the investigator if she or he may participate.
Respect for Persons: Section Quiz
7. Why might an individual have diminished autonomy?
A.
B.
C.
D.
They are a neonate.
They are incarcerated or involuntarily confined.
They are unconscious.
All of the above.
8. In order to participate in research, children must:
A. Provide written informed consent
B. Provide written permission
C. Provide assent, unless the IRB determines that they are too young
9. For research involving pregnant women, participation requires:
A.
B.
C.
D.
That women have completed the first trimester.
That the study be conducted first in men.
Permission of the father.
Consideration of risks and potential benefits for the fetus and the pregnant woman.
10. The three fundamental principles of Informed consent are:
A.
B.
C.
D.
Voluntariness, Equipoise, Respect
Voluntariness, Comprehension, Disclosure
Benefits, Comprehension, Privacy
Disclosure, Equipoise, Privacy
11. The regulations strongly suggest but do not require that the informed consent
process be delivered in a language that is understandable to the subject.
A. True
B. False
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12. If informed consent information is presented orally, it must be documented using a
short form that states that all the required elements were presented orally.
A. True
B. False
Beneficence: Section Quiz
13. What is an appropriate method for maintaining confidentiality of private information
obtained from human subjects?
A.
B.
C.
D.
Keeping data in a password-protected database
Storing images in a secured cabinet
Coding data or specimens and keeping the key to the code in a separate, locked drawer
All of the above are ways to maintain confidentiality
14. If a researcher determines that his/her study poses no more than minimal risk as
defined in 45 CFR 46, there is no need for the protocol to have IRB review and
approval.
A. True
B. False
15. Which of the following most accurately describes clinical equipoise?
A. Scientific uncertainty that one study intervention is superior to another
B. A reasonable balance of risks and benefits to research subjects
C. When the probability and magnitude of harm or discomfort is not greater than those ordinarily
encountered in daily life or during the performance of routine physical or psychological exams
D. A double blind controlled trial
16. Because the expedited IRB review process is generally used for certain types of
minimal risk research, it is less stringent than review by the full IRB.
A. True
B. False
17. Therapeutic misconception is the tendency for investigators to mislead research
participants about the research purpose, procedures or benefits.
A. True
B. False
3
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Justice: Section Quiz
18. In localities where community consent is the norm,
A. A family member’s consent for another individual may be sufficient, as long as community
consent is given
B. Federal regulations preclude the conduct of PHS-funded research
C. Community consent to participate in the research study is sufficient and no IRB approval is
required
D. In addition to the cultural norm, individual informed consent is required
19. NIH has specific policies addressing:
A. Inclusion of children in research
B. Inclusion of women and minorities in research
C. Treatment for research subjects in HIV/AIDS antiretroviral studies following completing of trials
in developing countries
D. All of the above
20. IRBs reviewing research in a different geographical location and/or cultural context
have a responsibility to:
A. Obtain knowledge of the local context by talking to those who have traveled to the region
B. Defer to an IRB that is in the situated within the local research context
C. Ask specialists with direct knowledge of the local research context to participate in IRB
discussions
D. B or C
E. A or C
21. It is ethical to use deceptive methods in research when the scientific goals of the
project can be achieved by non-deceptive methods.
A. True
B. False
4
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Answer Key
Codes and Regulations
1.
2.
3.
4.
5.
6.
b) Syphilis Study at Tuskegee
a) True
b) It articulated ethical principles that formed the basis for the HHS Human Subjects Regulations
b) False
d) All of the above
c) Understands the risks and benefits of his or her participation and is able to make a voluntary
decision if adequate information is provided
Respect for Persons
7.
8.
9.
10.
11.
12.
d) All of the above
c) Provide assent, unless the IRB determines that they are too young
d) Consideration of risks and potential benefits for the fetus and the pregnant woman
b) Voluntariness, Comprehension, Disclosure
b) False
a) True
Beneficence
13.
14.
15.
16.
17.
d) All of the above are ways to maintain confidentiality
b) False
a) Scientific uncertainty that one study intervention is superior to another
b) False
b) False
Justice
18.
19.
20.
21.
d) In addition to the cultural norm, individual informed consent is required
d) All of the above
d) B or C
b) False
5
Protecting Human Research Participants
NIH Office of Extramural Research
Introduction
Research with human subjects can occasionally result in a dilemma for investigators. When the
goals of the research are designed to make major contributions to a field, such as improving the
understanding of a disease process or determining the efficacy of an intervention, investigators
may perceive the outcomes of their studies to be more important than providing protections
for individual participants in the research.
Although it is understandable to focus on goals, our society values the rights and welfare of
individuals. It is not considered ethical behavior to use individuals solely as means to an end.
The importance of demonstrating respect for research participants is reflected in the principles
used to define ethical research and the regulations, policies, and guidance that describe the
implementation of those principles.
Who?
This course is intended for use by individuals involved in the design and/or conduct of National
Institutes of Health (NIH) funded human subjects research.
What?
This course is designed to prepare investigators involved in the design and/or conduct of
research involving human subjects to understand their obligations to protect the rights and
welfare of subjects in research. The course material presents basic concepts, principles, and
issues related to the protection of research participants.
Why?
As a part of NIH’s commitment to the protection of human subjects and its response to Federal
mandates for increased emphasis on protection for human subjects in research, the NIH Office
of Extramural Research released a policy on Required Education in the Protection of Human
Research Participants in June 2000. This course is specifically designed for extramural
investigators and is one (of many) possibilities for meeting the policy requirement.
Because this course is intended to allow investigators to fulfill the Required Education in the
Protection of Human Research Subjects, it assumes that the investigators’ research will be
funded by NIH and is therefore subject to all U.S. Department of Health and Human Services
(HHS) regulatory and NIH policy requirements.
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The information presented is neither prescriptive nor exhaustive and does not replace or
supersede local, state, or Federal regulations applicable to human research or any institutional
policies regarding the protection of human subjects.
Course Objectives
Upon completion of this course, you should be able to:
•
•
•
•
•
•
•
•
•
Describe the history and importance of human subjects protections
Identify research activities that involve human subjects
Discover the risks a research project might pose to participants
Understand how to minimize the risks posed by a research project
Describe additional protections needed for vulnerable populations
Understand additional issues that should be considered for international research
Describe appropriate procedures for recruiting research participants and obtaining
informed consent
Identify the different committees that monitor human subjects protections
Understand the importance of study design in the protection of research participants
The first module examines significant historical events that have contributed to the way we
view the protections for participants in clinical research today.
History
What This Module Covers:
Before discussing the current system for the protection of human subjects in research, it is
important to review some of the significant historical events that have influenced current
ethical guidelines and HHS regulations.
This module covers the following topics:
•
•
•
•
Goals and Principles of Human Subjects Protection
Nazi Medical War Crimes
Syphilis Study at Tuskegee
Timeline of Important Historical Events
Goals and Principles of Human Subjects Protection
Human subjects are essential to the conduct of research intended to improve human health. As
such, the relationship between investigators and human subjects is critical and should be based
on honesty, trust, respect.
Historical Events
Nazi Medical War Crimes (1939-1945)
Although not the first example of harmful research on unwilling human subjects, the
experiments conducted by Nazi physicians during World War II were unprecedented in their
scope and the degree of harm and suffering to which human beings were subjected.
“Medical experiments” were performed on thousands of concentration camp prisoners and
included deadly studies and tortures such as injecting people with gasoline and live viruses,
immersing people in ice water, and forcing people to ingest poisons.
In December 1946, the War Crimes Tribunal at Nuremberg indicted 20 physicians and 3
administrators for their willing participation in the systematic torture, mutilation, and killing of
prisoners in experiments. The Nuremberg Military Tribunals found that the defendants had:
•
•
Corrupted the ethics of the medical and scientific professions
Repeatedly and deliberately violated the rights of the subjects
The actions of these defendants were condemned as crimes against humanity. Sixteen of the
twenty-three physicians/administrators were found guilty and imprisoned, and seven were
sentenced to death.
Historical Events
The Nuremburg Code
In the August 1947 verdict, the judges included a section called Permissible Medical
Experiments. This section became known as the Nuremberg Code and was the first
international code of research ethics.
This set of directives established the basic principles that must be observed in order to satisfy
moral, ethical, and legal concepts in the conduct of human subject research. The Code has been
the model for many professional and governmental codes since the 1950s and has, in effect,
served as the first international standard for the conduct of research.
The Code Provides Ten Directives for Human Experimentation
Historical Events
The Syphilis Study at Tuskegee
Arguably the most notorious example in the United States of the violation of the rights and
welfare of human subjects was the long-term study of black males conducted by the United
States Public Health Service in Tuskegee, Alabama. This study of the natural history of
untreated syphilis was initiated in the 1930s and continued until 1972.
The Syphilis Study at Tuskegee involved approximately 600 African-American men: about 400
with syphilis (cases) and about 200 without syphilis (controls). These men were recruited
without informed consent and, in fact, were led to believe that some of the procedures done in
the interest of research (e.g., spinal taps) were actually “special free treatment.”
By 1936, it was apparent that many more infected men than controls had developed
complications, and 10 years later, reports indicated that the death rate among those with
syphilis was about twice as high as it was among the controls. In the 1940s, penicillin was found
to be effective in the treatment of syphilis. The Syphilis Study at Tuskegee continued, however,
and the men were neither informed about nor treated with the antibiotic.
Historical Events
Outcomes of the Syphilis Study at Tuskegee
The first accounts of this study appeared in the national press in 1972. The resulting public
outrage led to the appointment of an ad hoc advisory panel by the Department of Health,
Education and Welfare (which later was split into the Department of Education and the
Department of Health and Human Services [HHS]) to review the study and develop
recommendations to ensure that such experiments would never again be conducted.
Outcomes included:
1. National Research Act of 1974
2. Basic HHS Policy for Protection of Human Research Subjects
3. National Commission for the Protection of Human Subjects of Biomedical and
Behavioral Research
Timeline of Events
Click on the desired date or event to read more about that historical moment in the modern
history of human experimentation.
1932-1972: Syphilis Study at Tuskegee
More information may be found in:
Brandt, AM. 1978. Racism and Research: The Case of the Tuskegee Syphilis Study. Hastings
Center Report 8(6): 21-29, and in
Jones, JH. 1993. Bad Blood: Tuskegee Syphilis Experiment. Rev. ed. New York: Free Press
1939-1945: Nazi Medical War Crimes
More information may be found in: Annas, GJ, and Grodin, MA. 1992. The Nazi Doctors and the
Nuremburg Code, Human Rights in Human Experimentation. New York: Oxford University Press.
1944-1974: Cold War Human Radiation Experiments
The U.S. Government conducted more than 400 experiments to determine the effects of
exposure to ionizing radiation on human health or to calibrate instruments designed to detect
radiation. Most studies involved minimal risks and most of those involving greater than minimal
risks included appropriate informed consent.
There were, however, cases where human subjects suffered physical injuries as a result of
participating in studies that offered no prospect of direct benefit, or from interventions that
were considered controversial at the time that were presented as standard practice.
See https://www.atomicheritage.org/history/human-radiation-experiments for more
information.
1946: Nuremberg Doctors’ Trial
The individuals who conducted Nazi experiments during WWII were tried separately from other
war criminals because of their professional status as physicians and the horrendous and unique
nature of their crimes. They were found guilty of “crimes against humanity.”
See https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-formedical-research-involving-human-subjects/ for more information.
1947: Nuremberg Code & APA
Nuremberg Code
During the trial at Nuremberg, the judges codified fundamental ethical principles for the
conduct of research. The Nuremberg Code set forth ten conditions to be met before research
could be deemed ethically permissible. The Nuremberg Code became the first international
standard for the conduct of research and introduced the modern era of protection for human
research subjects.
American Psychological Association
The American Psychological Association began to develop a code of Ethical Standards that
included issues in human subjects research.
See http://www.apa.org/ethics/index.aspx for more information.
1948: United Nations adopted Universal Declaration of Human Rights
The United Nations adopted The Universal Declaration of Human Rights, which was inspired by
atrocities committed during World War II and states the conviction that human rights needed
to be preserved at the international level.
See http://www.un.org/Overview/rights.html for more information.
1953: First U.S. Federal Policy for Protection of Human Subjects
The first U.S. Federal policy for the protection of human subjects was put into place for
research conducted at the Clinical Center, NIH. This policy provided a mechanism for
prospective review of proposed research by individuals having no direct involvement or
intellectual investment in the research. This system is the model for the current IRB system.
1963: Jewish Chronic Disease Hospital Study
Studies were undertaken at the Jewish Chronic Disease Hospital in New York to develop
information about the human immune system’s response to cancer. Live cancer cells were
injected into chronically ill and debilitated patients who were told they were receiving a skin
test. The investigators were eventually prosecuted and found guilty of fraud, deceit, and
unprofessional conduct.
1963-1966: Willowbrook Study
Studies were carried out at the Willowbrook State School for “mentally defective persons,” to
gain an understanding of the transmission of infectious hepatitis and, subsequently, to test the
effects of gamma globulin in preventing or ameliorating the disease.
Residents of Willowbrook, all of whom were children, were deliberately infected with hepatitis,
by ingesting the stools of infected persons or receiving injections of more-purified virus
preparations. The investigators maintained that hepatitis infection was inevitable for this
population; however, critics asserted that the consent process was unethical because coercive
tactics were employed as only children whose parents gave permission to participate in the
studies were admitted to Willowbrook.
1964: Declaration of Helsinki
The World Medical Association drafted the first international agreement recommending ethical
standards for clinical research.
The most recent version of the Declaration of Helsinki, in addition to translations of the
Declaration into languages other than English, can be found on the WMA Web site.
Like the Nuremberg Code, the Declaration makes informed consent a central requirement for
ethical research. The Declaration does, however, allow for surrogate consent when the
research subject is incompetent, physically or mentally incapable of giving consent, or a minor.
The Declaration, which has undergone multiple revisions, also states that research with these
groups should be conducted only when the research is necessary to promote the health of the
population represented and when this research cannot be performed on legally competent
persons.
1966: Henry Beecher’s Publication
Henry Beecher published an article in the New England Journal of Medicine describing 22 cases
of human subjects research that involved ethical violations. Beecher argued against increasing
regulations and in favor of responsible investigators. His perspective has been cited as
influencing Federal policy to outline general requirements for informed consent and to
delegate specific standards to local review processes.
1974: Federal Protections for Human Subject
After the Syphilis Study at Tuskegee was exposed, the Senate Committee on Labor and Human
Resources held hearings on this study and other alleged health care abuses. The outcomes of
these hearings were:
The enactment of the National Research Act of 1974 requiring the Department of Health,
Education, and Welfare to codify its policy for the protection of human subjects into
regulations; and
The formation of the National Commission for the Protections of Human Subjects of Biomedical
and Behavioral Research, which drafted the Belmont Report.
1979: The Belmont Report
The National Commission for the Protection of Human Subjects of Biomedical and Behavioral
Research issued Ethical Principles and Guidelines for the Protection of Human Subjects of
Research. This is the cornerstone document of ethical principles and HHS regulations for the
protection of research subjects based on respect for persons, beneficence, and justice.
See http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html for more information.
1980: Publication of the FDA Regulations
FDA established regulations for clinical research: Code of Federal Regulations, Title 21, Part 50.
The FDA regulates research involving products regulated by the FDA, including research and
marketing permits for drugs, biological products, and medical devices for human use, etc.,
whether or not HHS funds are used. If HHS funds are used in FDA-regulated research, the
research must be compliant with both HHS and FDA regulations. More information about the
FDA regulations and FDA-specific requirements can be found at http://www.fda.gov/.
1981: HHS & FDA Revise Regulations
In 1981, with the Belmont Report as foundational background, HHS and the Food and Drug
Administration revised, and made as compatible as possible under their respective statutory
authorities, their existing human subjects regulations.
1982: CIOMS Guidelines
The Council for the International Organization of Medical Sciences (CIOMS) published the
International Ethics Guidelines for Biomedical Research Involving Human Subjects (CIOMS
Guidelines). These guidelines are designed to assist investigators from technologically advanced
countries to conduct ethical research involving human subjects in resource-poor countries.
These 15 guidelines addressed issues including informed consent, standards for external
review, recruitment of subjects, and more. For further information about CIOMS and the
Guidelines, refer to http://www.cioms.ch/
1991: Publication of the Common Rule
The Federal Policy for the Protection of Human Subjects or the “Common Rule” was published
in 1991 and codified in separate regulations by 15 Federal departments and agencies
See: http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html for more information.
1993-1994: Revelation of Human Radiation Experiments
President Clinton established the Advisory Committee on Human Radiation Experiments to
investigate human radiation experiments during the period 1944 to 1974; examine cases in
which radiation was intentionally released into the environment for research purposes; identify
ethical and scientific standards for evaluating these events; and deliver recommendations to
the Human Radiation Interagency Working Group. The Committee recommended government
apologies and financial compensation in cases where:
Efforts were made by the government to keep information secret from these individuals, their
families or the public to avoid embarrassment or potential legal liability, and where this secrecy
had the effect of denying individuals the opportunity to pursue potential grievances
There was no prospect of direct medical benefit to the subjects, or interventions considered
controversial at the time were presented as standard practice, and physical injury attributable
to the experiment resulted
See https://ehss.energy.gov/ohre/roadmap/index.html for more information
1995: Establishment of The National Bioethics Advisory Commission
The National Bioethics Advisory Commission (NBAC) was established to promote the protection
of the rights and welfare of human subjects in research, identify bioethical issues arising from
research on human biology and behavior, and make recommendations to governmental
entities regarding their application. The NBAC term ended in 2001.
1996: Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule
In response to a congressional mandate in the Health Insurance Portability and Accountability
Act of 1996 (HIPAA), the U.S. Department of Health and Human Services (HHS) issued the
regulations Standards for Privacy of Individually Identifiable Health Information. For most
covered entities, compliance with these regulations, known as the “Privacy Rule”, was required
as of April 14, 2003.
The Privacy Rule was enacted in response to public concerns over potential abuses of the
privacy of health information. Implementation and oversight of the Privacy Rule are the
responsibility of the HHS Office for Civil Rights. Additional information about how the Privacy
Rule impacts research can be found at http://privacyruleandresearch.nih.gov and at
http://www.hhs.gov/ocr/privacy/
1999: The Death of Jesse Gelsinger
On September 17, 1999, 18 year-old Jesse Gelsinger became the first subject in a gene transfer
clinical trial to die from a reaction to a recombinant viral vector. Jesse suffered from a
deficiency of ornithine-transcarbamylase (OTC), a necessary enzyme, and enrolled in a Phase I
dose-escalation trial at the University of Pennsylvania. The clinical trial involved the injection of
an adenoviral vector containing the gene. Jesse died after receiving the injection.
Subsequent investigations found that the Principal Investigator was an inventor for the
technology used in the trial and held equity in the start-up company to which the technology
was licensed. This case brought significant attention to the issue of financial conflicts of interest
in research. Additional information about financial conflict of interest can be found on the NIH
Conflict of Interest (COI) Page. The HHS regulations governing conflicts of
interest,”Responsibility of Applicants for Promoting Objectivity in Research for Which PHS
Funding is Sought”, can be found at 42 CFR 50, Subpart F.
2000: The Office of Human Research Protections
The Office of Human Research Protections (OHRP) was elevated to the level of the U.S.
Department of Health and Human Services, replacing the NIH Office for Protection from
Research Risks (OPRR). The OHRP provides leadership for all 17 Federal agencies that carry out
research involving humans under the Common Rule regulations. The Office has regulatory
authority for the protection of human subjects in research and policies and procedures for
Institutional Review Boards.
To learn more about OHRP, visit http://www.hhs.gov/ohrp/
2004: The Secretary’s Advisory Committee on Human Research Protections
The Secretary’s Advisory Committee on Human Research Protections (SACHRP) was established
to provide expert advice and recommendations to the Secretary of Health and Human Services
and the Assistant Secretary for Health on issues and topics pertaining to or associated with the
protection of human research subjects. See http://www.hhs.gov/ohrp/sachrp.
Course Regulations
What This Module Covers:
•
•
The Belmont Report – Ethical Principles and Guidelines for the Protection of Human
Subjects of Research
HHS Regulations for the Protection of Human Subjects, 45 CFR 46
The Objectives For This Module Are:
•
•
To identify the three principles of ethical human subjects research identified in the
Belmont Report
To comprehend the current HHS regulations, including:
o Risks associated with participation in research and appropriate protections
against risks
o Vulnerable populations that need specific protections
o Situations in which research involving humans is exempt from regulatory
requirements
The Belmont Report
Following the public outrage over the Syphilis Study at Tuskegee, Congress established the
National Commission for the Protection of Human Subjects of Biomedical and Behavioral
Research in 1974. The National Commission was charged with:
1. Identifying the ethical principles to guide all research involving human subjects
2. Developing guidelines for the conduct of ethical research involving human subjects
In 1979, the National Commission drafted The Belmont Report – Ethical Principles and
Guidelines for the Protection of Human Subjects of Research.
The Belmont Report identified three principles essential to the ethical conduct of research with
humans:
1. Respect for persons
2. Beneficence
3. Justice
These three basic principles serve as the foundation of the current HHS regulations and
guidelines for the ethical conduct of human subjects research supported by HHS.
Respect for Persons
“To respect autonomy is to give weight to the autonomous person’s considered opinions and
choices while refraining from obstructing his or her actions…” -Belmont Report
The principle of respect for persons can be broken down into two basic ideas:
1. Individuals should be treated as autonomous agents
2. Persons with diminished autonomy are entitled to additional protections
The challenges in applying the Belmont principle of respect for persons are in:
• Making sure that potential participants comprehend the risks and potential benefits of
participating in research
• Avoiding influencing potential participants’ decisions either through explicit or implied
threats (coercion) or through excessive compensation (undue influence)
Beneficence
“Persons are treated in an ethical manner not only by respecting their decisions and protecting
them from harm, but also by making efforts to secure their well-being. Such treatment falls
under the principle of beneficence. The term beneficence is often understood to cover acts of
kindness or charity that go beyond strict obligation. In this document, beneficence is
understood in a stronger sense, as an obligation” -Belmont Report
Two general rules have been articulated as complementary expressions of beneficent actions:
1. Do no harm
2. Maximize possible benefits and minimize possible harms
The challenge inherent in applying the Belmont principle of beneficence is how to determine
when potential benefits outweigh considerations of risks and vice versa.
Justice
“Just as the principle of respect for persons finds expression in the requirements for consent,
and the principle of beneficence in risk/benefit assessment, the principle of justice gives rise to
moral requirements that there be fair procedures and outcomes in the selection of research
subjects”. – Belmont Report
Justice requires that individuals and groups be treated fairly and equitably in terms of bearing
the burdens and receiving the benefits of research.
The principle of justice may arise in decisions about inclusion and exclusion criteria for
participation in research and requires investigators to question whether groups are considered
for inclusion simply because of their availability, their compromised position, or their
vulnerability — rather than for reasons directly related to the problem being studied.
The challenge of applying the Belmont principle of justice is how to decide which criteria
should be used to ensure that harms and benefits of research are equitably distributed to
individuals and populations.
Review
The Belmont Report identifies three principles essential to the ethical conduct of research with
humans.
Move word or statement under appropriate category in diagram.
page 6 review (TODO)
The HHS Regulations – Protection of Human Subjects
The ethical principles for research involving human subjects described in the Belmont Report
are codified in the Code of Federal Regulations, 45 CFR 46. The NIH follows all Subparts of the
HHS regulations:
Subpart A – Basic HHS Policy for Protection of Human Research Subjects
Subpart B – Additional Protections for Pregnant Women, Human Fetuses and Neonates
Involved in Research
Subpart C – Additional Protections Pertaining to Biomedical and Behavioral Research Involving
Prisoners as Subjects
Subpart D – Additional Protections for Children Involved as Subjects in Research
Subpart E – Registration of Institutional Review Boards
Subpart A – Basic HHS Policy for Protection of Human Research Subjects
Subpart A, also called “The Common Rule”, describes the required protections for all human
subjects.
Subpart A defines a human subject as “a living individual about whom an
investigator…conducting research obtains:
1. Data through intervention or interaction with the individual, or
2. Identifiable private information.”
Subpart A defines research as “a systematic investigation…designed to develop or contribute to
generalizable knowledge.”
This definition includes:
• Research development
• Testing
• Evaluation
Case Study: Human Heart Study
An investigator will be using human hearts in order to study factors leading to heart failure.
One group of normal, control hearts will be obtained from cadavers. A set of diseased hearts
will be obtained from individuals who are to receive a heart transplant.
Does this study involve human subjects?
What Do You Think?
a) Yes, this study involves human subjects
b) No, this study does not involve human subjects
Additional Protections
The Belmont principle of respect for persons states, in part, that individuals with diminished
autonomy may need additional protections. Subparts B, C, and D describe additional
protections for some of the populations that are considered particularly vulnerable:
Subpart B
Additional Protections for Pregnant Women, Human Fetuses and Neonates Involved in
Research
Subpart C
Additional Protections Pertaining to Biomedical and Behavioral Research Involving Prisoners as
Subjects
Subpart D
Additional Protections for Children Involved as Subjects in Research
Vulnerable Populations
Subparts B, C and D define the specific categories of research in which pregnant women,
human fetuses and neonates, prisoners, or children respectively may be involved. The subparts
describe additional requirements for informed consent, and may specify additional
responsibilities for the Institutional Review Board (IRB) when reviewing research involving these
populations, and list the requirements for research that need additional levels of review and
approval
Other vulnerable populations include, but are not limited to, mentally disabled persons and
economically and/or educationally disadvantaged persons. While the regulations do not specify
what additional protections are necessary for these groups, the HHS regulations (45 CFR
46.111) do require that investigators include additional safeguards in the study to protect the
rights and welfare of these individuals “when some or all of the subjects are likely to be
vulnerable to coercion or undue influence.”
Case Study: Fetal Imaging
Read the study description below and determine if Subparts B, C or D of HHS Regulations
require additional protections for the study’s participants:
A study proposes to test a novel fetal imaging technology designed to enhance image quality
and allow physicians to assess more accurately prenatal health. This technology has been
tested both on pregnant mammals and non-pregnant women with no adverse effects. Pregnant
women will be recruited at their regularly scheduled prenatal check-ups and those who consent
to participate will receive the experimental scan.
Do Subparts B, C or D require that participants in this study receive additional protections?
What Do You Think?
a) Yes, additional protections for participants in this study are required under Subparts B, C
or D
b) No, additional protections for participants in this study are not required under Subparts
B, C or D
Case Study: Observational Study of Challenges Returning to Work
Read the study description below and determine if Subparts B, C or D of HHS Regulations
require additional protections for the study”s participants:
A study proposes to observe the challenges for former prisoners returning to office jobs.
Researchers will recruit individuals who have spent over ten years in prison, have completed
their sentences, and are now interviewing for office jobs.
Do Subparts B, C or D require that participants in this study receive additional protections?
What Do You Think?
a) Yes, additional protections for participants in this study are required under Subparts B, C
or D
b) No, additional protections for participants in this study are not required under Subparts
B, C or D
Case Study: Treatment and Prevention Research in Adolescents
Read the study description below and determine if Subparts B, C or D of HHS Regulations
require additional protections for the study”s participants:
A study proposes to examine the effectiveness of a medical treatment and prevention program
for adolescents in a location where the legal age for consent to such treatment is 12. The
adolescents involved range from ages 12 to 17.
Do Subparts B, C or D require that participants in this study receive additional protections?
What Do You Think?
a) Yes, additional protections for participants in this study are required under Subparts B, C
or D.
b) No, additional protections for participants in this study are not required under Subparts
B, C or D.
Requirements for Federal Support of Human Subjects Research
The HHS regulations (45 CFR 46.120) require that Federal Departments and Agencies that
conduct or support human subjects research must evaluate all applications for research using
the following criteria:
•
•
•
•
Risks to the subjects
Adequacy of protection against these risks
Potential benefits of the research to the subjects and others
Importance of the knowledge gained or to be gained
Equivalent Protections for International Research
When research covered by the HHS regulations takes place in countries other than the United
States, the HHS regulations (45 CFR 46.101(h)) allow a department or agency head to approve
the substitution of alternative polices, codes, or regulations to protect human subjects in lieu of
the requirements of 45 CFR 46 as long as the alternatives afford protections that are at least
equivalent to those provided in 45 CFR 46.
In a Federal Register Notice on July 7, 2006, HHS clarified that the requirements of the HHS
regulations (45 CFR 46) must be satisfied for all HHS-conducted or -supported research covered
by the Federalwide Assurance, regardless of whether the research is conducted domestically or
internationally. As of the publication of that Notice, HHS had not deemed any other procedural
standards equivalent to 45 CFR 46.
Engagement in Human Subjects Research
Each institution that is engaged in NIH-funded human subjects research must:
•
•
Obtain or hold a current Federalwide Assurance (FWA), assuring that an institution will
comply with HHS regulatory requirements for the protection of human subjects (this is
obtained from the HHS Office for Human Subjects Protections (OHRP)); and
Certify to NIH that grant applications and contract proposals describing research
involving human subjects has been reviewed and approved by an Institutional Review
Board (IRB) designated in the FWA, and will be subject to continuing review by an IRB.
IRBs are committees that consist of 5 or more members with varying expertise and diversity
that are responsible for reviewing and approving human subjects research activities on behalf
of institutions.
The Common Rule specifies:
• IRB membership (45 CFR 46.107)
• IRB functions & operations (45 CFR 46.108)
• IRB review of research (45 CFR 46.109 and 45 CFR 46.110)
• Criteria for IRB approval of research (45 CFR 46.111)
And more!
The roles and responsibilities of IRBs are discussed extensively in the module on Beneficence.
Exemptions
The HHS regulations describe categories of human subjects research that may be exempt from
requirements described in the HHS regulations including IRB oversight.
Studies proposing only research that falls under one or more of the exempt categories of
research do not require IRB review and approval, but the HHS Office for Human Research
Protections (OHRP) has stated that: “Institutions should have a clear policy in place on who
shall determine what research is exempt under 46.101(b)” and that investigators should not be
able to determine whether or not their own research is exempt. This authority should rest with
the IRB or other entity designated by the institution.
The exemptions can be found at 45 CFR 46.101(b).
Codes and Regulations: Summary
This module examined:
• The three basic ethical principles described in the Belmont Report
• The subsequent codification of these principles in 45 CFR 46 of the Code of Federal
Regulations
The Belmont Report summarizes the three basic ethical principles of clinical research as:
1. Respect for persons
a. Individuals should be treated as autonomous agents
b. Persons with diminished autonomy are entitled to additional protections
2. Beneficence
a. Do no harm
b. Maximize possible benefits and minimize possible harms
3. Justice
a. Requires that individuals and groups be treated fairly and equitably in terms of
bearing the burdens and receiving the benefits of research
45 CFR 46 codifies these basic principles:
•
•
•
•
Subpart A describes the required protections for all Federally conducted or supported
human subjects research
Subpart B covers additional protections for pregnant women, human fetuses and
neonates
Subpart C outlines additional protections pertaining to biomedical and behavioral
research involving prisoners as subjects
Subpart D provides for additional protections for children
Additionally, the regulations discuss methods of determining whether research is exempt from
the regulations.
Respect for Persons
What This Module Covers:
•
•
•
•
•
•
•
•
The informed consent process
Requirements for documentation of informed consent
Waivers of informed consent
Diminished autonomy and legally authorized representatives
Participation of pregnant women in research
Assent from children and permission from parents
Obtaining informed consent from prisoners
Community consent
The Objectives For This Module Are:
•
•
To outline the requirements for informed consent
To state when waivers of informed consent and legally authorized representatives are
appropriate
Respect for Persons
Quote from the Belmont Report — To respect autonomy is to give weight to the autonomous
persons considered opinions and choices while refraining from obstructing his or her actions…
The principle of respect for persons can be broken down into two basic ideas:
1. Individuals should be treated as autonomous agents
2. Persons with diminished autonomy are entitled to additional protections
Informed Consent
The Belmont principle of respect for persons is primarily applied by requiring that all human
subjects research participants provide voluntary informed consent to participate in research.
The three fundamental aspects of informed consent are:
1. Voluntariness
2. Comprehension
3. Disclosure
Informed Consent
The HHS regulations (45 CFR 46.116) require that investigators obtain legally effective informed
consent from prospective participants in a way that allows them to consider whether or not to
participate and that minimizes the possibility for coercion or undue influence.
Potential participants must understand that enrolling in the research is voluntary and that they
may withdraw from the study at any time without penalty or loss of benefits (45 CFR 46.116(a)).
In order for participation in research to be voluntary, the potential for coercion and undue
influence must be minimized.
Case Study: Sleeping Sickness Study on Campus
An investigator, who is a professor at a large university, is developing a grant application for
submission to the NIH to study sleeping sickness (trypanosomiasis). This study will investigate
surface antigen expression in trypanosomes, the parasite that causes sleeping sickness, in order
to develop a vaccine. These parasites grow in human blood and lymph.
The study will require fresh human blood daily for several months, and thus will require
research participants. A research assistant will maintain a schedule of research participants to
ensure that the study performs one collection per day and that blood collections are in
accordance with American Red Cross Blood Donation Eligibility Guidelines, i.e., healthy, weigh
at least 110 pounds, and have not donated a pint (570 ml.) of whole blood in the last 8 weeks
(56 days). Participants will be compensated.
It is now time to make a decision about recruitment of the research participants.
Case Study: Sleeping Sickness Study on Campus
Based on the number of students and employees in her classes and lab, the researcher feels
confident that she will have enough participants needed for the proposed research if she simply
recruits among them. But she knows that some colleagues advertise their studies through
postings on campus. The investigator is faced with two possible options for recruiting normal,
healthy research participants:
Recruit the students in her upper level classes and the technicians from her lab, and give $5
compensation to participants per blood draw, or
Recruit from the general university population (students, faculty and staff) by posting fliers
around campus, and give $5 compensation to participants per blood draw
The investigator discusses the grant application and proposed research procedures with you.
You think that the compensation plan is appropriate and that $5 would not be an undue
influence for either population to participate.
From which population would you advise the researcher to recruit?
What Do You Think?
a) Recruit the students in her upper-level classes and the technicians from her lab to
participate in the study
b) Post fliers around campus to recruit participants from the campus population (students,
faculty and staff)
Informed Consent
Informed consent should be understood as an on-going process rather than a level of legal
protection for an institution. It is not intended to be a one-time act of having a participant sign
a form.
Informed consent is designed to inform research subjects about the purpose, risks, potential
benefits and alternatives to the research that allows people to make a decision about whether
or not to participate based on their own goals and values. This exchange of such information
should occur at enrollment and throughout the study.
Informed Consent
Investigators are responsible for providing information during the informed consent process in
a manner that is understandable to the potential participants. Investigators should not enroll
anyone in a study unless the investigator is confident that the individual comprehends all
information disclosed and agrees to procedures described during the informed consent
process.
Investigators can use methods in addition to a consent form to enhance individuals’
comprehension. Some examples include:
•
Oral presentations that provide potential participants with the opportunity to discuss
the information and ask questions
• Providing additional educational materials, such as brochures, about research in general
and/or the specific procedures that will be used in the study
• Video presentations that familiarize potential participants with the procedures that will
be used in the study
The informed consent process must be delivered in “… language that is understandable to the
subject …” (45 CFR 46.116). This may mean adjusting the reading levels of documents provided
or translating documents and presentations into the language with which participants are most
comfortable.
Case Study: Sleeping Sickness Study on Campus
Now that your colleague studying sleeping sickness has decided on the method of recruitment
for the study participants, she must write an informed consent document for the participants to
sign.
The researcher has prepared two different draft consent documents and must select one to
submit to her IRB for review.
Read the two consent documents and then choose the document that best informs the
potential participants about the study in which they will enroll:
•
Consent Document 1 (PDF)
• Consent Document 2 (PDF)
Which of these two consent documents would you choose to use?
What Do You Think?
a) Choose Consent Document 1
b) Choose Consent Document 2
Waivers of Informed Consent
The HHS regulations (45 CFR 46.116(c)) allow institutional review boards (IRBs) to waive or alter
some or all of the required elements of informed consent if all of the following conditions are
met:
1. “The research or demonstration project is to be conducted by or subject to the approval
of state or local government officials and is designed to study, evaluate, or otherwise
examine: (i) public benefit or service programs; (ii) procedures for obtaining benefits or
services under those programs; (iii) possible changes in or alternatives to those
programs or procedures; (iv) possible changes in methods or levels of payments for
benefits or services under those programs, and
2. The research could not practicably be carried out without the waiver or alteration”.
Waivers of Informed Consent
The HHS regulations (45 CFR 46.116(d)) also allow IRBs to waive or alter some or all of the
required elements of informed consent if all of the following conditions are met:
1. “The research involves no more than minimal risk to the subjects
2. The waiver or alteration will not adversely affect the rights and welfare of the subjects
3. The research could not practicably be carried out without the waiver or alteration
4. Whenever appropriate, the subjects will be provided with additional pertinent
information after participation”
Practicability and Waivers of Informed Consent
Decisions about waivers of informed consent often concern the issue of practicability. Although
practicability is not defined in the HHS regulations, it is not sufficient for an investigator to
argue simply that seeking consent would be time-consuming or incur additional cost.
In some situations, a waiver of informed consent may be appropriate for a medical record
review or for using existing data or specimens that can be linked to identifiable individuals.
Specific decisions regarding practicability are made by the IRB.
Case Study: New Analyses of Existing Data
An investigator has collected identifiable data from participants in a research study. He has
completed the analyses that were originally proposed and described in the NIH grant
application, the protocol approved by the IRB, and the informed consent document approved
by the IRB. The informed consent document made no mention of using the data in additional
research but gives permission for the investigator to re-contact the participants.
Now, based on new hypotheses, the investigator plans to conduct new analyses to fulfill
purposes different from those described in the informed consent document, the NIH grant
application and the IRB-approved protocol. He knows that he needs to obtain approval for the
new research from his IRB and his NIH Program Official.
Does the investigator need to obtain new informed consent from the participants?
What Do You Think?
a) Yes, the investigator does need to obtain new informed consent
b) No, the investigator does not need to obtain new informed consent
Requirements for Documentation of Informed Consent
The HHS regulations require that informed consent be documented using a written form that
either contains all of the required elements (45 CFR 46.116(a)) or a short form that states that
all of the required elements have been presented orally. This form must be signed by either the
participant or the participant’s legally authorized representative (45 CFR 46.117).
The HHS regulations (45 CFR 46.117(c)) allow IRB’s to waive the requirement for documented
informed consent if they find that either:
1. “The only record linking the participant to the research would be the [informed] consent
document and the principal risk to the participants would be the potential harm
resulting from a breach of confidentiality. Each subject will be asked whether the
subject wants documentation linking the subject with the research, and the subject’s
wishes will govern, or
2. The research presents no more than minimal risk to the participants and involves no
procedures for which written consent is normally required outside of the research
context.”
Diminished Autonomy
An individual’s autonomy can be affected by several factors including age, cognitive
impairment, illness, and treatments. An individual’s capacity to consent to a particular study
should be assessed based on:
1. The individual’s level of capacity, and
2. The complexity and risks of the study, i.e., the capacity needed for an individual to be
able to understand the study well enough to consent to participate
Decisional Capacity and Legally Authorized Representatives
The Belmont principle of respect for persons states that investigators need to make special
provisions when including individuals in research who have diminished the capacity for making
decisions in their own best interests.
The HHS regulations, therefore, require that legally authorized representatives provide
voluntary informed consent for individuals with the diminished capacity to participate in
research (45 CFR 46.116).
While the HHS regulations allow for legally authorized representatives to make substituted
decisions for individuals who need assistance, investigators should obtain consent from the
participants to the extent possible. Because some individuals may be only temporarily or
intermittently incapacitated (e.g., due to injury or medications), investigators should attempt to
approach these individuals at a time when they do have the capacity to consent to research. If a
participant regains the capacity to consent to research after the research has begun,
investigators should obtain the participant’s informed consent before continuing his or her
participation in the study.
Participation of Pregnant Women in Research
Because research involving pregnant woman may affect the woman, the fetus, or both the
woman and the fetus, additional issues must be considered for studies of pregnant women.
The HHS regulations require:
• Preclinical studies be completed prior to the involvement of pregnant women
• A consideration of risks and potential benefits for the fetus and pregnant woman
The HHS regulations prohibit:
• Inducements of any kind to terminate a pregnancy
• Investigators from taking part in decisions about terminating a pregnancy
• Investigators from determining the viability of a neonate
Investigators, IRBs, and funding agencies must comply with requirements described in Subpart
B of the HHS regulations.
Children’s Participation in Research
Children may not have full capacity to make decisions in their own best interests; and
therefore:
Children are considered a vulnerable population, and
Children are unable to provide “legally effective informed consent” as required by the HHS
regulations at 45 CFR 46.116
Because children cannot provide informed consent, children provide assent to participate in
research, to the extent that they are able, and parents/guardians give permission for a child to
participate in research.
The additional regulatory requirements of assent and permission for research involving children
(45 CFR 46.408) are intended to make sure that investigators respect the decisions of both
children and their parents. Parental permission must be obtained for research involving
children “in accordance with and to the extent that consent is required by 45 CFR 46.116.”
Assent and Permission for Children’s Participation in Research
The ages, maturity and psychological states of the children involved in the research should be
taken into account when determining whether children have the capacity to assent. This
determination is made by the IRB. The IRB may require that investigators conduct an individual
assessment of each child’s ability to assent or may make a general determination for all
children involved in the study.
The content and language of the assent process should be appropriate to the age and
education/developmental stage of the children providing assent. It may be necessary to have
multiple assent documents or assent processes if the children to be enrolled in the research are
of different ages or at different stages of development.
Case Study: Lack of Assent from a Child
A child has a rare genetic disorder. No treatment is currently available. You have designed a
longitudinal study that will examine the progression of the disorder. The study will involve
standard physical and psychological examinations, including drawing 10ml of blood 4 times per
year.
After enrollment, at which time the parents provided permission for the child to participate in
the study and the child provided assent, he panics and screams that he doesn’t want to
participate and wants to go home when he sees the nurse holding a needle for the blood draw.
The parents are present and want the child to participate.
Do you need to withdraw this child from your study because he has withdrawn his assent?
What Do You Think?
This is not an easy question because it does not have a clear “yes” or “no” answer. Various
issues to consider are explored on the next page.
Case Study: Lack of Assent from a Child
A number of issues should be considered to assist with decision-making. First, investigators
need to identify the institutional resources available to help decide the appropriate action, e.g.
the IRB, the Ethics Committee, a research participant’s advocate, the patient’s personal
physician. Second, the investigators and others involved in the deliberations should consider
issues such as:
TODO: Respect-page-21
Obtaining Informed Consent from Prisoners
Research involving prisoners requires approval by an IRB whose membership is specifically
constituted to address the concerns of this vulnerable population per 45 CFR 46.304. If the
research is conducted or supported by HHS, it must also be approved by the Secretary of HHS
through the Office for Human Research Protections (OHRP). This approval signifies that “the
proposed research falls within the categories of research permissible under 45 CFR
46.306(a)(2)”.
The HHS regulations (45 CFR 46, Subpart C) require additional protections for prisoners who are
involved as participants in research because they may “be under constraints because of their
incarceration which could affect their ability to make a truly voluntary and uncoerced decision
whether or not to participate as subjects in research”.
The requirements specific to informed consent for prisoners are:
1. “Any possible advantages accruing to the prisoner through his or her participation in the
research, when compared to the general living conditions, medical care, quality of food,
amenities and opportunity for earnings in the prison are not of such a magnitude that
his or her ability to weigh the risks of the research against the value of such advantages
in the limited choice environment of the prison is impaired”
2. “Adequate assurance exists that parole boards will not take into account a prisoner’s
participation in the research in making decisions regarding parole, and each prisoner is
clearly informed in advance that participation in the research will have no effect on his
or her parole”
Community Consultation
In some cultures, it is not appropriate to obtain informed consent solely from the individual
participants, because the individual’s interests may be considered to be intimately entwined
with their community’s interests. The appropriate way to attain community consent may vary
widely but is often achieved through meetings with large groups of community representatives
or community leaders.
It is also appropriate to consult a community before conducting research when the research
involves risk to discrete, identifiable populations. For example, members of a community may
feel stigmatized if a number of members of that community participate in research that may
reveal unpopular or dangerous traits.
Emergency Research
One example of a situation in which community consent is required is emergency research in
life-threatening situations where obtaining informed consent is not feasible. In order for
investigators to obtain a waiver of informed consent for emergency research, investigators
must obtain consent from the communities in which the research will be conducted in addition
to a number of other requirements. These requirements are described in Informed Consent
Requirements in Emergency Research.
Investigators should note that this emergency waiver of informed consent does not apply to
research that falls under Subpart B (pregnant women, human fetuses and neonates) or Subpart
C (prisoners) of the HHS regulations.
Respect for Persons: Summary
During the informed consent process, the principle of respect for persons is applied by
requiring that all human subjects provide voluntary informed consent to participate in the
research.
Practical application of this principle means that potential study participants must:
•
•
•
Give their consent freely and voluntarily
Have the decisional capacity to understand the information presented to them
Be provided complete information about the study in order to make an informed
decision
This module has examined:
• Information that should be included during the informed consent process
• The types of situations that can be considered for waiver of informed consent
• The appropriate involvement of legally authorized representatives for consent
• Obtaining consent from vulnerable populations, e.g. pregnant women, prisoners and
children.
• The need to undertake community consultation when the individual’s interests are
intimately entwined with their community’s interests
Beneficence
What This Module Covers:
•
•
•
•
Risks and benefits
Privacy and Confidentiality
Institutional Review Boards (IRBs)
Data and Safety Monitoring
The Objectives For This Module Are:
•
•
•
•
•
To understand what aspects of research may constitute a benefit to research
participants
To identify possible risks to be considered in evaluating research
To discuss methods to protect privacy of individuals and confidentiality of data
To define the role of an IRB to ensure the rights and welfare of human subjects and
To outline requirements for Data and Safety Monitoring for clinical trials
Quote from the Belmont Report: ‘Persons are treated in an ethical manner not only by
respecting their decisions and protecting them from harm, but also by making efforts to secure
their well-being. Such treatment falls under the principle of beneficence. The term beneficence
is often understood to cover acts of kindness or charity that go beyond strict obligation. In this
document, beneficence is understood in a stronger sense, as an obligation.’
Two general rules have been articulated as complementary expressions of beneficent actions:
• Do no harm
• Maximize possible benefits and minimize possible harms
Investigators and members of their institutions are obliged to give forethought to the
maximization of benefits and the reduction of risk that might occur from the research
investigation.
Risk
Risk is the “probability that a certain harm will occur.”
All research involves some level of risk. We often think of risks in terms of physical harms that
may occur as a result of participation in research protocols, but harms may also result from
aspects of participation other than from research procedures. For example, harms may result
from simply agreeing to be a participant in research, or they may result from disclosure of
findings from a research study.
Most risks encountered by participants in research fall into the following categories:
Physical
Physical risks may include pain, injury, and impairment of a sense such as touch or sight. These
risks may be brief or extended, temporary or permanent, occur during participation in the
research or arise after.
Psychological
Psychological risks can include anxiety, sadness, regret and emotional distress, among others.
Psychological risks exist in many different types of research in addition to behavioral studies.
Social
Social risks exist whenever there is the possibility that participating in research or the revelation
of data collected by investigators in the course of the research, if disclosed to individuals or
entities outside of the research, could negatively impact others’ perceptions of the participant.
Social risks can range from jeopardizing the individual’s reputation and social standing, to
placing the individual at-risk of political or social reprisals.
Legal
Legal risks include the exposure of activities of a research subject “that could reasonably place
the subjects at risk of criminal or civil liability.”
Economic
Economic risks may exist if knowledge of one’s participation in research, for example, could
make it difficult for a research participant to retain a job or to find a job, or if insurance
premiums increase or loss of insurance is a result of the disclosure of research data.
Minimal Risk
Recall that the principle of beneficence involves maximizing possible benefits and minimizing
possible harms to research participants. All research involves some degree of risk; however,
some research is considered to be of minimal risk.
Minimal risk is defined in the Common Rule to be “that the probability and magnitude of harm
or discomfort anticipated in the research are not greater in and of themselves than those
ordinarily encountered in daily life or during the performance of routine physical or
psychological examinations or tests.” (45 CFR 46.102(i))
Types of Risk
Because research involves risks, investigators, Institutional Review Boards (IRBs), and other
members of the research team must take responsibility for protecting participants against the
risks of participating in research. Protections vary according to the kind of risk:
Physical
In many situations, physical risks in research can be minimized by carefully and skillfully
following protocols, by having trained individuals conduct research procedures, through careful
monitoring of research participants’ health status, by recruiting appropriate populations, and
by providing clinical care when needed.
Psychological
Possible ways to protect against psychological risks include reminding participants of their right
to withdraw from research or limit their participation if they become uncomfortable, providing
counseling or psychological support for participants who experience distress, or thoroughly
debriefing research participants after research sessions are completed.
Social
Often, minimizing social risks to participants involves protecting confidential data, including not
only the data collected, but the fact of participation in the research project itself.
Legal
Protections against legal risks often involve protecting the confidentiality of research data. For
non-NIH funded studies conducted in the United States, investigators can apply for Certificates
of Confidentiality (CoC), which are intended to prevent investigators from being forced to
disclose data that can be linked to identifiable research participants in legal proceedings. NIH
funded research automatically have the CoC protections.
Economic
Protecting confidentiality of data is one method for protecting against economic risks, such as
those to employability and insurability. Investigators may elect to keep research data separate
from medical records in order to prevent employers and insurance companies from obtaining
information that could put the participants at risk.
Examples of Risk and Appropriate Protections
Risk Category: Physical
Risk Example: Fatigue
Protection Example: Supervision by physical trainer for signs or measures of fatigue beyond
those defined as acceptable in the research protocol.
Risk Category: Social
Risk Example: Stigma
Protection Example: investigators do not disclose identifiable data to research participants coworkers.
Risk Category: Psychological
Risk Example: Anxiety
Protection Example: Friend or spouse can stay with participant during study procedures
Risk Category: Legal
Risk Example: Disclosure of illegal drug use
Protection Example: Investigators increase protections for individual research participant’s data
from legal subpoena by obtaining a Certificate of Confidentiality.
Risk Category: Economic
Risk Example: Loss of job or advancement
Protection Example: Investigators do not disclose information data to research participant’s
employer.
Designing Research: Anticipated Benefits Greater than Potential Harms
In general, the goal of research is to benefit society by contributing to generalizable knowledge
about diseases, disorders, public health concerns, etc. Participation in research may:
• Benefit individual participants or communities
• Neither benefit nor harm individual participants or communities
• Pose risks to individual participants
The HHS regulations apply specifically to individual participants in research and require that:
• Risks are minimized
• Unavoidable risks are justified as necessary for sound scientific design
•
Research studies are anticipated to make progress toward important, generalizable
knowledge
Regulatory Requirement for Explaining Benefits and Risks
After minimizing risks to the extent possible, the HHS regulation requires that investigators
consider:
1. Protections against risks: Where appropriate, investigators must describe procedures
for minimizing potential risks, including risks to confidentiality, plans for ensuring any
necessary medical or professional intervention, plans for data and safety monitoring for
clinical trials, etc.
2. Potential benefits to individual participants: The proposed research has a favorable
ratio of potential benefit to risk. This balancing act is often called a risk-benefit analysis
3. Importance of the knowledge to be gained: Investigators reasonably anticipate that the
research will contribute to generalizable knowledge. This generalizable knowledge is
considered a benefit to others, and risks to research participants must be reasonable in
relation to the importance of the knowledge that reasonably may be expected to result
Compensation for Research Participation
Some types of research involve a significant commitment from research participants in terms of
time or effort, and investigators may wish to provide compensation.
Institutions should consider establishing standards for fair and appropriate compensation.
During the informed consent process, investigators should explain to potential research
participants:
1. If there will be compensation for their participation in the research
2. Appropriate expectations for receiving full, partial, or no compensation if research
participants complete the study or withdraw prior to its completion
3. That compensation is meant to reimburse research participants for their time, researchrelated inconveniences and/or research-related discomforts
Compensation is not a benefit of the research.
Avoiding Undue Inducement
While the use of inducements to participate in research is considered appropriate under many
circumstances, sometimes inducements can be unduly influential and inappropriate. These are
referred to as undue inducements. As discussed in the Respect for Persons section, the level
and kind of compensation must take into consideration the vulnerabilities of the research
population to minimize the possibility of undue inducement.
“Undue inducements are troublesome because:
1. offers that are too attractive may blind prospective subjects to the risks or impair their
ability to exercise proper judgment; and
2. they may prompt subjects to lie or conceal information that, if known, would disqualify
them from enrolling — or continuing — as participants in a research project.”
Careful consideration of compensation is not only critical for beneficence, but may be critical
for sound research. Considerations should include, but are not limited to, issues like
participants’ “medical, employment, and educational status, and their financial, emotional, and
community resources.”
Avoiding the Therapeutic Misconception
Some research studies include examinations, diagnostic tests, and/or interactions with
healthcare providers in addition to experimental interventions. These aspects of a research
protocol may benefit participants by helping them to better understand a disease or condition,
and may help in the participants’ medical decision-making. While it is often appropriate to
include treatment procedures in the conduct of research studies, there is a risk that research
participants may misunderstand the benefits of research if they think that potential benefits of
participation in research are certain. This is called the therapeutic misconception. Therapeutic
misconception is the tendency for research participants to:
“… downplay or ignore the risks posed to their own well-being by participation … [due to] the
participants’ deeply held and nearly unshakeable conviction that every aspect of their
participation in research has been designed for their own individual benefit”.
Investigators should discuss the risks and benefits of research as part of the informed consent
process in order to minimize the possibility of therapeutic misconception.
Assessing Risks and Potential Benefits
Assessing risks and potential benefits is inexact, but investigators need to be able to explain to
the funding agency, the IRB and the potential research participants how and why the potential
benefits of research outweigh the risks of participating in a particular study.
The principle of beneficence requires that investigators consider a number of factors including:
• Equipoise
• Protecting the privacy of research participants and the confidentiality of research data
• Establishing oversight mechanisms to protect the rights and welfare of research
participants and to determine the significance of the data
Equipoise and Importance of Knowledge to be Gained
A state of “equipoise” is required for conducting research that may pose risks to research
participants.
For a clinical trial to be in equipoise, investigators must not know that one arm of a clinical trial
provides greater efficacy over another, or there must be genuine uncertainty among
professionals about whether one treatment is superior than another.
Equipoise is essential for obtaining generalizable knowledge. If a clear and agreed-upon answer
exists, asking research participants to assume the risks of research that will provide the same
information is not acceptable; no new knowledge will be gained from the study.
Case Study: Equipoise in Research Involving Autistic Children
There are two standard treatments for autistic children who display a specific set of
characteristics. One treatment is a cognitive-behavioral intervention, and the other is a dietary
and biomedical intervention. Both treatments have equally strong clinical evidence supporting
their efficacy. A researcher proposes a comparison of the two interventions to determine which
is preferable. The children will be randomized to one of two groups: half of the children will
receive the cognitive behavioral intervention and the other half of the children will receive the
dietary and biomedical intervention.
Is this study in equipoise?
This study is in equipoise because there is insufficient data to persuade investigators or
physicians that one approach is preferable to the other for a child displaying the specific
characteristics.
Privacy and Confidentiality
Investigators are responsible for
• Protecting the privacy of individuals
• Confidentiality of data
Privacy means being “free from unsanctioned intrusion.” 8
Confidentiality means holding secret all information relating to an individual, unless the
individual gives consent permitting disclosure.
Case Study: Confidentiality in Clinical Research
After the conclusion of a clinical trial in a small rural community, an investigator is anxious to
publish findings. Understanding the NIH policies encouraging the reporting of demographic
differences in intervention effect, and concerned about protecting the confidentiality of
research participants, the investigator publishes only general demographic data such as sex,
age, state, and county.
Is this an appropriate and acceptable way to protect the confidentiality of research
participants?
The correct answer is No.
Publishing demographic information is only acceptable in situations where the population is
large enough, or the disease/condition is common enough that research participants cannot be
identified using the demographic data provided. This study was carried out in a small
community where it might be easy to identify participants.
For example, these protections were not sufficient after a hantavirus outbreak on an Indian
Reservation in the United States. The information published made the identity of one of the
individuals who died obvious to the local tribal leaders. In this case the published report not
only compromised the identity of the research participant, it also violated the cultural taboo
about not speaking of the recently deceased.
Confidentiality
The need for maintaining confidentiality of private information exists in virtually all studies in
which data are collected from or about living individuals. In most research, maintaining
confidentiality is a matter of following some established practices, for example:
• Properly disposing of data sheets and other paper records
• Limiting access to identified data; and/or
• Storing research records in locked cabinets or secured databases
It may also be appropriate for investigators to remove direct identifiers from human specimens
and data so that they may be analyzed without risk of accidental disclosure of private
information. De-identifying data can be done in several ways, including coding and
anonymizing.
Coded Private Information and Human Subjects Research
Research with coded private information or specimens involves human subjects if:
1. The private information or specimens were collected specifically for the currently
proposed research project through an interaction or intervention with living individuals;
or
2. The investigator(s) can readily ascertain the identity of the individual(s) to whom the
coded private information or specimens pertain
Research with coded private information or specimens does not involve human subjects if:
1. The private information or specimens were not collected specifically for the currently
proposed research project through an interaction or intervention with living individuals;
and
2. The investigator(s) cannot readily ascertain the identity of the individual(s) to whom the
coded private information or specimens pertain
Case Study: Research with Anonymized Data
You are an investigator proposing to use data from a colleague’s database to conduct secondary
analyses. You want to examine the behavior and attitudes in male spouses of female business
executives. Your colleague will provide coded data for your proposed studies, and you and he
enter into an agreement by which he will keep the key to the code and will have no other
involvement in the research. Therefore, your colleague is not an investigator in your research.
Does this study involve human subjects?
The correct answer is No.
The study does not involve human subjects because both criteria are met:
1. The private information or specimens were not collected specifically for the currently
proposed research project through an interaction or intervention with living individuals;
and
2. The investigator(s) cannot readily ascertain the identity of the individual(s) to whom the
coded private information or specimens pertain
The use of anonymized data means that the investigator cannot identify the individuals to
whom the data pertain, and obtaining the data from a colleague with whom the investigator is
not collaborating means that the colleague will not be able to link any research results to
identifiable individuals.
Institutional Review Boards
Institutional Review Boards (IRBs) are specialized committees required by HHS regulations that
safeguard the rights and welfare of human subjects. IRBs determine “the acceptability of
proposed research in terms of institutional commitments and regulations, applicable law, and
standards of professional conduct and practice” (45 CFR 46.107).
The major roles of IRBs in the oversight of research are:
1. Initial review and approval or disapproval of the proposed research activity
2. Ensuring that the proposed informed consent process meets all of the requirements of
45 CFR 46.116
3. Providing continuing oversight for progress reports and protocols for ongoing research
studies
IRB Membership
The HHS regulations (45 CFR 46.107) require that IRBs have at least 5 members from a variety
of backgrounds. The experience, expertise and diversity of the IRB members should allow the
IRB to provide a complete and adequate review of the research activities conducted at the
institution.
Research may involve issues about which IRB members lack specific expertise. In these
situations, IRBs should identify and invite individuals with specialized knowledge to assist in the
review of applications and protocols where the expertise is required.
This issue was raised in the Respect for Persons section when discussing the HSS regulations for
IRB membership when a study sought to enroll a vulnerable population (prisoners) in research.
Another example where specific expertise may be needed is when a protocol proposes a study
that will recruit participants presenting to a hospital Emergency Department (ED) with acute
appendicitis. If the IRB lacks expertise about protections for human subjects in emergency
situations, the IRB Chair should ask an expert, such as the head of the ED to advise the IRB on
the feasibility of the recruitment strategy.
Working with the IRB
Although IRBs and investigators have different roles in research, they have a shared
responsibility to ensure that research participant protections are appropriate.
As an investigator, you will work most effectively with IRBs if you understand the information
that the IRB needs in order to review and approve your proposed research study.
The HHS regulations provide general criteria for IRB approval of research, but the specific
information that you need to submit may vary among institutions, and may even vary among
IRBs at the same institution. You should contact the IRB or Research Administration office at
your institution for specific instructions.
Criteria for IRB Approval of Research (45 CFR 46.111)
• Risks to human subjects are minimized
• Risks to human subjects are reasonable in relation to anticipated benefits, if any, to
human subjects and the importance of the knowledge that may reasonably be expected
to result from the research
• Selection of human subjects is equitable
•
•
•
Informed consent will be sought from each prospective research participant or the
prospective research participant’s legally authorized representative in accordance with
and to the extent required by the HHS regulations (45 CFR 46.116)
Informed consent will be appropriately documented in accordance with and to the
extent required by the HHS regulations (45 CFR 46.117)
When appropriate, the research plan makes adequate provision for monitoring the data
collected to ensure the safety of the human subjects, and when appropriate there are
adequate provisions to protect the privacy of human subjects and to maintain the
confidentiality of data
Expedited IRB Review
Protocols may be reviewed either at a meeting of the full IRB or by “expedited review.”
For “certain types of research involving no more than minimal risk and for minor changes to
existing research,” an IRB may choose to use an expedited review procedure. The expedited
review may be conducted by the IRB chair or by designated experienced IRB member(s) (45 CFR
46.110).
Investigators should understand that expedited review is conducted by fewer individuals, but
is no less stringent and not necessarily faster than a full IRB review. If any individual reviewer
who conducts an expedited review is unable to approve a proposed study, the study must be
discussed by the full IRB.
Data and Safety Monitoring
Data and Safety Monitoring Plans describe protections for research participants and data
integrity, and oversight for clinical trials at a level that is commensurate with the risks of
participating in the clinical trial. That is, the method and frequency of monitoring is directly
related to the possible harms to research participants in the clinical trial.
The HHS regulations require that studies involving human subjects should have a monitoring
plan when appropriate (45 CFR 46.111).
The NIH requires that all clinical trials supported by NIH have a Data and Safety Monitoring
(DSM) plan.
Data and Safety Monitoring Boards
Appropriate protections and oversight can range from oversight by the Principal Investigator
and IRB for a single-site, minimal risk clinical trial, to oversight by a full Data and Safety
Monitoring Board (DSMB) and IRB(s) for a multi-site trial that involves greater than minimal
risk.
DSMBs are committees of experts who have no bias with respect to the research and may be
permitted to periodically view unblinded data and conduct interim analyses. Principal
Investigators must not view unblinded data while their studies are ongoing because they need
to maintain objectivity to the extent possible and to ensure integrity of the accruing data.
Case Study: Reducing Exposure to Mercury
An investigator proposes to work with the community organization of a population where
many of the residents are exposed to high levels of mercury through occupational exposure. A
previous study indicated that the harms resulting from exposure to a similar heavy metal
contaminant could be mitigated through the use of a behavioral intervention. The investigators
propose testing the intervention to see if mercury exposure can be reduced in this population.
The research design involves randomizing human subjects either to the experimental
behavioral intervention in addition to conventional therapy, or to conventional therapy alone.
Should the behavioral intervention be determined to be successful, participants who received
only conventional therapy will be offered the behavioral intervention after the completion of
the study. Research participants will know which intervention they receive because
conventional therapy does not include a behavioral component.
Does this study require a data and safety monitoring plan?
The correct answer is Yes.
A data and safety monitoring plan is required because the proposed study is a clinical trial.
Investigators are advised to refer to NIH Institute/Center policies and consult with NIH Program
Staff in order to determine the appropriate method for data and safety monitoring.
Beneficence: Summary
The Belmont principle of beneficence involves maximizing possible benefits and minimizing
possible harms to research participants.
Issues covered under Beneficence include:
• Protections against risks
• Definition of minimal risk
• Methods of weighing risks against anticipated benefits
• Potential benefits for the research participants
• The use of compensation for participation in research
• Equipoise and need for there to be genuine uncertainty about whether one treatment is
superior to another
•
•
•
•
•
Privacy & Confidentiality of research participants and research data
Use of coded private information to protect confidentiality
Use of an IRB to provide oversight for research involving human subjects
Situations that allow for an IRB expedited review procedure
Data and Safety monitoring for clinical trials
Justice
What This Module Covers:
•
•
•
Fair distribution of the benefits and burdens of research
Inclusion of Women, Minorities, and Children in Research
Issues to consider in international research
The Objectives For This Module Are:
•
•
To understand the concept of fair and equitable sharing of the benefits and burdens of
research
To learn about NIH policies on inclusion of women, minorities, and children in research
Quote from the Belmont Report: ‘Just as the principle of respect for persons finds expression in
the requirements for consent, and the principle of beneficence in risk/benefit assessment, the
principle of justice gives rise to moral requirements that there be fair procedures and outcomes
in the selection of research subjects.’
The definition of justice has two parts:
• Fair procedures and outcomes are used to select research participants, and
• There is a fair distribution of benefits and burdens to populations who participate in
research
Individual Justice and Social Justice
The Belmont Report distinguishes social justice and individual justice in the selection of
subjects:
Individual justice requires that investigators “should not offer potentially beneficial research
only to some patients who are in their favor or select only ‘undesirable’ persons for risky
research.”
Social justice “requires that distinction be drawn between classes of subjects that ought, and
ought not, to participate in any particular kind of research, based on the ability of members of
that class to bear burdens and on the appropriateness of placing further burdens on already
burdened persons.”
More on Social Justice
“The choice of participants in research needs to be considered carefully to ensure that groups
(e.g., welfare patients, particular racial and ethnic minorities, or persons confined to
institutions) are not selected for inclusion mainly because of easy availability, compromised
position, or manipulability.”
Selection should depend on reasons directly related to the research questions. When research
leads to the development of new treatments, procedures, or devices, justice demands both
that:
• These advancements are provided to those who can benefit from them, and
• The research should involve persons from groups who are likely to benefit from
subsequent applications of the research
Equity vs. Equality in Human Subjects Research
The meanings of equity and equality are similar, but not the same. The difference between
equity and equality has important implications for justice in research.
To treat “equitably” means to treat fairly;
To treat “equally” means to treat in exactly the same way.
Research should strive for equitable distribution of the risks and potential benefits of the
research. This means that investigators are treating the groups involved in the research fairly
and justly. It does not necessarily mean that all groups are equally represented, but that their
representation is fair and just based on the risks and potential benefits associated with the
research.
Equitable Distribution
In order to achieve an equitable distribution of the risks and potential benefits of the research,
investigators must determine the distribution of different groups (men and women, racial or
ethnic groups, adults and children, age, etc.) in the populations that:
• May be affected by the disease or condition under study, and
• That are anticipated to benefit from the knowledge gained through the research
Challenges to Achieving an Equitable Distribution of Benefits and Burdens
Investigators must ensure that the participants recruited for the research will not be unduly
burdened and that recruitment reflects the diversity of the population that may benefit from
the knowledge generated from the study.
Individuals with the advantages of wealth and education may have an unfair advantage in
terms of reaping the benefits of research because they may be able to afford new and costly
treatments more easily than individuals in resource-poor settings.
NIH Inclusion Policies: Women and Minorities
One way the justice principle is applied is through the inclusion of women and minorities as
participants in human subjects research. Because knowledge gained from clinical research may
define health policy and shape standards of care for all patients, it is important to consider
whether the intervention or therapy under scrutiny “affects women or men or members of
minority groups and their subpopulations differently.”
The NIH Policy and Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical
Research describes the Agency’s requirements for the inclusion of women and minorities in
NIH-supported biomedical and behavioral research involving human subjects.
Case Study: Migraine Intervention Trial
A researcher seeks to improve treatment for severe migraines that are partially responsive to
oral medication.
He proposes to test whether acupuncture, in addition to a sufferer’s oral medication, is more
effective treatment than oral medication alone. Because women are three times more likely to
experience migraines than men, he proposes to enroll three times as many women as men.
They will be recruited from racially and ethnically diverse communities.
Does this study design fulfill the principle of justice?
The correct answer is Yes.
The study includes women and men in proportion to the rates of severe migraines experienced
by each sex, and is designed to have racial and ethnic diversity. The study provides both sexes
and racial/ethnic communities with the opportunity for benefits from the clinical trials, and
does not unfairly burden any single group with the risks of research. Its design is fair.
Case Study: Esophageal Cancer
A group of investigators proposes to investigate genetic factors that may increase risks for
esophageal cancer. Genetic factors in esophageal cancer are not well understood and
esophageal cancer occurs in many racial and ethnic populations. The investigators propose to
collect DNA from cheek swabs and administer a risk factor questionnaire. Both cancer patients
and age-matched controls will be included.
The investigators have access to a predominantly Caucasian sample, and have no plans to
recruit participants outside of their available pool.
Is this an acceptable strategy?
The correct answer is No.
The NIH inclusion policies require that inclusion be generalizable to the population of the
United States. Acceptable inclusion of women and/or minorities depends both upon the
scientific question addressed by the study and the prevalence of the disease, disorder, or
condition in these populations.
In this case, it is scientifically appropriate to include a broad population. Failure to include
groups that would be affected by this condition could result in gaps in scientific knowledge.
Inclusion of Children in Research
NIH also applies the principle of justice through the NIH Policy and Guidelines on the Inclusion
of Children as Participants in Research Involving Human Subjects.
Silhouetted group of four different-aged children standing on a question mark.
The policy emerged from the observation that children have often received treatments that
have only been tested in adults, and that there is insufficient data on safe and effective uses for
many treatments provided to children. Although the past practice of excluding children may
have stemmed from good motives, “protecting” children in this way has resulted in:
1. Denying children the benefits of participation in research, and
2. Preventing the collection of sufficient data about the effects of agents in children
Excluding Children from Research
The NIH Policy and Guidelines on the Inclusion of Children in Research Involving Human
Subjects states that children must be included in all NIH-supported human subjects research
unless “… there are scientific and ethical reasons not to include them.”
If an investigator proposes to conduct clinical research that does not include children, the
exclusion of children must be fully justified using one or more of the exceptions described in
the Policy.
Policy Exceptions
1. The research topic to be studied is irrelevant to children …
2. There are laws or regulations barring the inclusion of children in the research …
3. The knowledge is already available for children or will be obtained from another ongoing study, and an additional study will be redundant …
4. A separate, age-specific study in children is warranted and preferable …
5. Insufficient data are available in adults to judge potential risk in children … in some
instances, the nature and seriousness of the illness may warrant [children’s]
participation based on careful risk and benefit analysis …
6. The study design is aimed at collecting additional data on pre-enrolled adult study
participants …
7. Other special cases justified by the investigator and found acceptable to the review
group and Institute Director
Definition of Children: HHS Regulations and NIH Policy
Although the HHS Regulations and the NIH Inclusion Policies apply to research involving
children, they vary in their definitions of children.
HHS regulations
HHS regulations at Subpart D “Additional Protections for Children Involved as Subjects in
Research” (45 CFR 46.402) defines children as:
‘Persons who have not attained the legal age for consent to treatments or procedures involved
in the research, under the applicable law of the jurisdiction in which the research will be
conducted.’
Thus for HHS regulatory requirements, the need for protections for “children” is defined by the
location in which the study will take place and the research procedures. Research that involves
children must follow the requirements for parental permission and child assent described in
the HHS regulations at Subpart D.
NIH Inclusion Policy
The NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving
Human Subjects defines children as:
‘Individuals under the age of 18.’
Additional information about the NIH Policy and Guidelines on the Inclusion of Children can be
found at the Policy Implementation Page.
Research conducted or supported by the NIH must follow both the HHS requirements for
protections and the NIH requirements for the inclusion of children.
Case Study: Selecting Populations to Include in Clinical Research
Research on early diagnosis of senile dementia
Senile dementia most commonly affect adults and it would not be appropriate to include
children in research for which there is no clinical relevance.
Clinical trial comparing approved treatments for leukemia
Since leukemia is a disease that can affect both children and adults, it is appropriate to include
both populations in a clinical trial of approved treatments.
Experimental behavioral intervention to reduce bul…
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