NIH

 
This week, reflect on what you learned from the NIH materials about protecting the rights of human research participants. 

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1

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. Nuremberg trials

    B. Syphilis Study at Tuskegee
    C. Jewish Chronic Disease Hospital Study
    D. 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. It was written by the National Commission for the Protection of Human Subjects.
    B. It articulated ethical principles that formed the basis for the HHS Human Subjects Regulations.
    C. Belmont is another word for individual autonomy and respect.
    D. 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. Evaluation
    B. Research Development
    C. Testing
    D. All of the above

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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. They are a neonate.
    B. They are incarcerated or involuntarily confined.
    C. They are unconscious.
    D. 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. That women have completed the first trimester.
    B. That the study be conducted first in men.
    C. Permission of the father.
    D. Consideration of risks and potential benefits for the fetus and the pregnant woman.

    10. The three fundamental principles of Informed consent are:

    A. Voluntariness, Equipoise, Respect
    B. Voluntariness, Comprehension, Disclosure
    C. Benefits, Comprehension, Privacy
    D. 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. Keeping data in a password-protected database
    B. Storing images in a secured cabinet
    C. Coding data or specimens and keeping the key to the code in a separate, locked drawer
    D. 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

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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

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  • Answer Key
  • Codes and Regulations

    1. b) Syphilis Study at Tuskegee
    2. a) True
    3. b) It articulated ethical principles that formed the basis for the HHS Human Subjects Regulations
    4. b) False
    5. d) All of the above
    6. 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. d) All of the above
    8. c) Provide assent, unless the IRB determines that they are too young
    9. d) Consideration of risks and potential benefits for the fetus and the pregnant woman
    10. b) Voluntariness, Comprehension, Disclosure
    11. b) False
    12. a) True

    Beneficence

    13. d) All of the above are ways to maintain confidentiality
    14. b) False
    15. a) Scientific uncertainty that one study intervention is superior to another
    16. b) False
    17. b) False

    Justice

    18. d) In addition to the cultural norm, individual informed consent is required
    19. d) All of the above
    20. d) B or C
    21. b) False

      Codes and Regulations: Section Quiz
      1. Identify the most influential event that led to the HHS Policy for Protection of Human Research Subjects:
      2. An institutionally designated authority, other than the investigator, should determine that proposed studies are exempt from regulatory requirements.
      3. The Belmont Report is significant because:
      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.
      5. A “systematic investigation designed to develop or contribute to generalizable knowledge” may include:
      6. An “autonomous person” is someone who:
      Respect for Persons: Section Quiz
      7. Why might an individual have diminished autonomy?
      8. In order to participate in research, children must:
      9. For research involving pregnant women, participation requires:
      10. The three fundamental principles of Informed consent are:
      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.
      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.
      Beneficence: Section Quiz
      13. What is an appropriate method for maintaining confidentiality of private information obtained from human subjects?
      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.
      15. Which of the following most accurately describes clinical equipoise?
      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.
      17. Therapeutic misconception is the tendency for investigators to mislead research participants about the research purpose, procedures or benefits.
      Justice: Section Quiz
      18. In localities where community consent is the norm,
      19. NIH has specific policies addressing:
      20. IRBs reviewing research in a different geographical location and/or cultural context have a responsibility to:
      21. It is ethical to use deceptive methods in research when the scientific goals of the project can be achieved by non-deceptive methods.
      Answer Key

    ProtectingHuman Research Participants

    NIH Of fic e

    of E xt ramural R e se a rc h

  • 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.

    Archived Content: Last maintained 9/26/2018

    http://www.nih.gov/

    http://www.nih.gov/

    http://grants.nih.gov/grants/guide/notice-files/not-od-00-039.html

    http://grants.nih.gov/grants/guide/notice-files/not-od-00-039.html

    http://www.hhs.gov/

    http://www.hhs.gov/

    http://www.nih.gov/

    http://grants.nih.gov/grants/guide/notice-files/not-od-00-039.html

    http://grants.nih.gov/grants/guide/notice-files/not-od-00-039.html

    http://www.hhs.gov/

    http://www.hhs.gov/

    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.

    http://www.hhs.gov/

  • 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

    http://www.hhs.gov/ohrp/archive/nurcode.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/archive/nurcode.html

    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-for-
    medical-research-involving-human-subjects/ for more information.

    https://www.atomicheritage.org/history/human-radiation-experiments

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    https://www.atomicheritage.org/history/human-radiation-experiments

    https://www.atomicheritage.org/history/human-radiation-experiments

    https://www.atomicheritage.org/history/human-radiation-experiments

    https://www.atomicheritage.org/history/human-radiation-experiments

    https://www.atomicheritage.org/history/human-radiation-experiments

    https://www.atomicheritage.org/history/human-radiation-experiments

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    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.

    http://www.apa.org/ethics/index.aspx

    http://www.un.org/Overview/rights.html

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    http://www.apa.org/ethics/index.aspx

    http://www.apa.org/ethics/index.aspx

    http://www.apa.org/ethics/index.aspx

    http://www.un.org/Overview/rights.html

    http://www.un.org/Overview/rights.html

    http://www.un.org/Overview/rights.html

    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.

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects

    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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    https://www.gpo.gov/fdsys/pkg/CFR-1999-title21-vol1/xml/CFR-1999-title21-vol1-part50.xml

    http://www.fda.gov/

    front page

    http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    https://www.gpo.gov/fdsys/pkg/CFR-1999-title21-vol1/xml/CFR-1999-title21-vol1-part50.xml

    https://www.gpo.gov/fdsys/pkg/CFR-1999-title21-vol1/xml/CFR-1999-title21-vol1-part50.xml

    https://www.gpo.gov/fdsys/pkg/CFR-1999-title21-vol1/xml/CFR-1999-title21-vol1-part50.xml

    http://www.fda.gov/

    http://www.fda.gov/

    http://www.fda.gov/

    front page

    front page

    front page

    http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html

    http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html

    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

    https://ehss.energy.gov/ohre/roadmap/index.html

    http://privacyruleandresearch.nih.gov/

    http://www.hhs.gov/ocr/privacy/

    http://www.hhs.gov/ohrp/humansubjects/commonrule/index.html

    https://ehss.energy.gov/ohre/roadmap/index.html

    https://ehss.energy.gov/ohre/roadmap/index.html

    https://ehss.energy.gov/ohre/roadmap/index.html

    http://privacyruleandresearch.nih.gov/

    http://privacyruleandresearch.nih.gov/

    http://www.hhs.gov/ocr/privacy/

    http://www.hhs.gov/ocr/privacy/

    http://www.hhs.gov/ocr/privacy/

    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.

    http://grants.nih.gov/grants/policy/coi/index.htm

    http://grants.nih.gov/grants/policy/coi/index.htm

    http://grants.nih.gov/grants/compliance/42_CFR_50_Subpart_F.htm

    http://www.hhs.gov/ohrp/

    http://www.hhs.gov/ohrp/sachrp

    http://grants.nih.gov/grants/policy/coi/index.htm

    http://grants.nih.gov/grants/compliance/42_CFR_50_Subpart_F.htm

    http://grants.nih.gov/grants/compliance/42_CFR_50_Subpart_F.htm

    http://grants.nih.gov/grants/compliance/42_CFR_50_Subpart_F.htm

    http://www.hhs.gov/ohrp/

    http://www.hhs.gov/ohrp/

    http://www.hhs.gov/ohrp/

    http://www.hhs.gov/ohrp/sachrp

    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:

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/sachrp

    http://www.hhs.gov/ohrp/sachrp

    http://www.hhs.gov/ohrp/sachrp

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html

    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

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparta

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparte

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparta

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparta

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparte

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subparta

    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.”

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.120

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    http://edocket.access.gpo.gov/2006/E6-10511.htm

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.120

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    http://edocket.access.gpo.gov/2006/E6-10511.htm

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    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

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.108

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.109

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/policy/hsdc95-02.html

    http://www.hhs.gov/ohrp/policy/hsdc95-02.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.108

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.108

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.109

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/policy/hsdc95-02.html

    http://www.hhs.gov/ohrp/policy/hsdc95-02.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.101

    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)).

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    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)

    http://www.redcross.org/en/eligibility

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.redcross.org/en/eligibility

    http://www.redcross.org/en/eligibility

    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)

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    images/04_Respect/consent_document_1

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    • 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.

    images/04_Respect/consent_document_2

    images/04_Respect/consent_document_2

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    https://archive.hhs.gov/ohrp/espanol/45cfr46.htm#46.116

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    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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

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    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

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    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.408

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

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    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.408

    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

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.304

    http://www.hhs.gov/ohrp/policy/prisoner.html

    http://www.hhs.gov/ohrp/policy/prisoner.html

    http://www.hhs.gov/ohrp/policy/prisoner.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartc

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    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

    http://www.hhs.gov/ohrp/policy/hsdc97-01.html

    http://www.hhs.gov/ohrp/policy/hsdc97-01.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartb

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    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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.102

    https://humansubjects.nih.gov/coc/index

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    https://humansubjects.nih.gov/coc/index

    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 co-
    workers.

    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, research-

    related 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

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

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    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    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

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.107

    • 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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

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    http://www.hhs.gov/ohrp/policy/expedited98.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.117

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.117

    http://www.hhs.gov/ohrp/policy/expedited98.html

    http://www.hhs.gov/ohrp/policy/expedited98.html

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.110

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.111

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    http://grants2.nih.gov/grants/policy/hs/faqs_aps_dsm.htm

    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.

    http://grants2.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

    http://grants2.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

    https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Headache-Hope-Through-Research

    https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Headache-Hope-Through-Research

    http://grants2.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm

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    https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Headache-Hope-Through-Research

    https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Headache-Hope-Through-Research

    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 on-

    going 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 …

    http://grants.nih.gov/grants/guide/notice-files/not98-024.html

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    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.

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.402

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    http://grants2.nih.gov/grants/funding/children/children.htm

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.402

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#subpartd

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-010.html

    http://grants2.nih.gov/grants/funding/children/children.htm

    http://grants2.nih.gov/grants/funding/children/children.htm

    http://grants2.nih.gov/grants/funding/children/children.htm

    Experimental behavioral intervention to reduce bullying in elementary school class rooms
    An elementary school-based intervention would include whole schools or whole grades of
    children who, with parental permission, would participate in the research.

    Justice and the Use of Placebos

    The use of placebos in clinical research is relevant to all the issues addressed in this course. It
    raises issues related to justice, respect for persons, and beneficence. All three principles
    address a researcher’s duty not to exploit or deceive research participants and to treat them
    fairly.

    Risks associated with the use of placebos in research are:

    • Deception: Misleading research participants about the research purpose or procedures.

    • Therapeutic misconception: 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.”

    The principle of Justice requires that when placebos are used, prospective research participants
    must be treated fairly. Unless justifications for a waiver are approved, the informed consent
    process must disclose sufficient information to ensure that potential research participants:

    • Understand what placebos are

    • Understand the likelihood that they will receive a placebo

    • Are able to provide their fully informed consent that they are willing to receive a
    placebo

    Justifying the Use of Placebos

    Examples of justifications for the use of placebos include:

    1. When there are no approved, effective treatments for the condition, or
    2. If there is disagreement about whether standard treatment is better than placebo, or
    3. When the additional risk posed by the use of placebo is minor and withholding the

    current standard therapy would not lead to serious or permanent harm, or
    4. If the study is anticipated to result in widespread or major benefits and the receipt of

    placebo by individuals poses minimal risk

    Incomplete Disclosure and Deception

    Incomplete disclosure and deception may be useful for some research goals, but researchers
    may use them only after thorough consideration of:

    • Whether the scientific goals of the research can be achieved by methods that do not
    involve incomplete disclosure or deception

    • Whether participants would consider the information withheld during the informed
    consent process important to their decision to participate in the study

    • Whether it is possible to inform participants that they will only learn about all the goals
    of the research after the research study is over

    Waiver of Informed Consent

    Incomplete disclosure and deception present challenges to justice because prospective
    participants’ “informed consent” will not be fully informed. HHS regulations (45 CFR 46.116(d))
    allow informed consent to be waived only if:

    • Participation in the research involves no more than minimal risk

    • The waiver must not adversely affect the rights and welfare of research participants

    • Incomplete disclosure or deception must be essential to the ability to carry out the
    research

    • Whenever appropriate, research participants will be given additional pertinent
    information after they have participated in such a study (debriefing)

    To Debrief or Not to Debrief

    Debriefing of research participants after the study involves an explanation of the deception or
    incomplete disclosure of research goals to participants as well as a complete disclosure of the
    true goals of the research. Debriefing is generally considered to be appropriate, but must
    depend on whether the disclosure will result in harm.

    Debriefing is appropriate when it will benefit the research participant’s welfare by:

    • “… correct[ing] misperceptions, or

    • reduc[ing] pain, stress, or anxiety concerning the [research participant’s] self-perception
    or performance …“

    Fairness in International Research

    When HHS-supported research takes place outside of the United States questions about fair
    treatment and fair standards may arise. This may be especially true of research conducted in
    countries where:

    • Resources may be scarce and/or

    • Other vulnerabilities may be pronounced
    A few of the many issues that demand careful consideration with respect to justice, as well as
    beneficence and respect for persons, include:

    • How can research conducted in resource-poor setting avoid exploiting participants?

    • What is owed to participants in clinical research and to the population of the host
    country after studies are complete?

    • In addition to following the HHS regulations, what standards and assurances to protect
    research participants should investigators and non-US institutions use when conducting
    research abroad?

    • How can regional or cultural differences be negotiated?

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html#46.116

    http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm

    http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm

    http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm

    • For settings where cultural values impact informed consent, how should processes be
    altered?

    Sustaining Benefits Locally

    Investigators should think about how benefits to individual research participants and the local
    population may be sustained after the study is complete.

    When planning a study, researchers and sponsors may:

    • “… make reasonable, good faith efforts before the initiation of a trial to secure, at its
    conclusion, continued access for all participants to needed experimental interventions
    that have proven effective for the participants …”

    • Consider how any effective treatment emerging from the research could be provided to
    the rest of the population

    Sustaining Benefits for Participants with HIV/AIDS in NIH-Supported Clinical Trials of
    Antiretroviral Agents

    The NIH values continued treatment for research participants in HIV/AIDS antiretroviral studies.

    “For antiretroviral treatment trials conducted in developing countries, the NIH expects
    investigators/contractors to address the provision of antiretroviral treatment to trial
    participants after their completion of the trial. The NIH recommends investigators/contractors
    work with host countries’ authorities and other stakeholders to identify available sources of
    antiretroviral treatment.”

    Information is found in the NIH Guidance for Addressing the Provision of Antiretroviral
    Treatment for Trial Participants Following their Completion of NIH-Funded HIV Antiretroviral
    Treatment Trials in Developing Countries.

    Standards and Assurances for International Research

    The HHS Office for Human Research Protections (OHRP) has set the expectation that the HHS
    regulations, as well as any additional institutional and local standards, will be followed in all
    research conducted or supported by HHS.

    Investigators:
    If you plan to engage in NIH-funded research in non-U.S. settings you must comply with the
    protections and standards set out in the HHS regulations Subpart A. Researchers may go
    beyond HHS regulations, however, to meet the ethical, legal, and social standards for the local
    setting.

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://www.hhs.gov/ohrp/international/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://grants.nih.gov/grants/policy/antiretroviral/

    http://www.hhs.gov/ohrp/international/

    http://www.hhs.gov/ohrp/international/

    Institutions:
    Non-U.S institutions engaged in HHS-conducted or -supported human subjects research must
    obtain an international (non-U.S.) Federalwide Assurance (FWA) from OHRP.

    IRB Review for Research in International Settings

    Institutions have a profound responsibility to ensure that all IRBs designated under Federalwide
    Assurance possess sufficient knowledge of the local research context to satisfy the
    requirements for human subjects protections regardless of the IRB’s geographic location
    relative to the institution and the research.

    Knowledge of the local context may be provided by:

    • Specialists with personal, direct knowledge of the local research context who participate
    in IRB discussions and provide insight on achieving protections for research participants

    • An IRB situated within the local research context

    Local Cultural Norms and Informed Consent

    In unfamiliar settings, investigators should:

    • Become familiar with local cultural norms and

    • Seek guidance from community advisors and the IRB

    Investigators should incorporate cultural norms into the research process whenever possible
    and appropriate. Examples of cultural norms include community consent and informed consent
    from family representatives:

    • If community consent is the cultural norm, it may be appropriate to obtain community
    consent in advance of obtaining informed consent from individuals. Community consent
    cannot replace the informed consent from individuals.

    • If cultural norms require permission from a family member before an individual may
    enroll in research, it may be appropriate to obtain permission from the family member
    in addition to informed consent from the prospective research participant.

    Justice: Summary

    Justice requires:

    • Fair procedures and outcomes in the selection of research participants, and

    • Distribution of benefits and burdens among the populations participating in research.

    Individual justice requires that:

    • Benefits of participation in research are offered to a diverse eligible population, and

    • Risks of participation in research are shared by a diverse population

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    http://www.hhs.gov/ohrp/assurances/assurances/index.html

    Social justice requires that consideration is given to classes of subjects that ought, and ought
    not, to participate in research. Considerations are based on:

    • The ability of members of that class to bear burdens and

    • The appropriateness of placing further burdens on already burdened persons.

    This section also examines:

    • Inclusion of women, minorities and children

    • Placebos

    • Incomplete disclosure and deception

    • Debriefing participants after the study

    • International research

    • Research in resource-poor countries

    This section also discusses the NIH guidelines regarding continued treatment for research
    participants in HIV/AIDS antiretroviral studies.

  • Conclusion
  • This course is designed to provide a minimum level of knowledge that an individual should have
    before designing a protocol for research involving human subjects.

    There are numerous additional sources of training on this topic. Some are provided through:

    • The NLM Bioethics Information Resources and through

    • The HHS Office of Research Integrity RCR Resources — Human Subjects

    Further Training

    You may wish to consult NIH staff and resources about research participant protections, such
    as:

    • Scientific Review Officers

    • Program Directors

    • Specialized offices within the NIH Institutes/Centers

    • The NIH Office of Extramural Research Human Subjects Web site

    • NIH Grants Info: grantsinfo@nih.gov

    You may also have access to resources at your institution or at nearby institutions, such as:

    • IRBs

    • IRB Administrators

    • Experienced clinical investigators

    • Hospital Ethics Committees

    • Former research participants

    • Advocacy groups

    • Communities of potential participants

    • Professional Societies

    Staying Current

    The material in this course will be updated periodically to reflect current issues.

    Institutions and investigators that are using this Web-based training to meet the NIH
    requirement for Required Education in the Protection of Human Research Participants should
    check back at least once a year to be sure that your knowledge reflects the most current
    thinking on the various topics.

    We welcome your feedback and suggestions on the material covered in this course.

    http://www.nlm.nih.gov/bsd/bioethics.html

    https://ori.hhs.gov/human-subject-research-0

    https://humansubjects.nih.gov/

    mailto:grantsinfo@nih.gov

    mailto:http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html

    http://www.nlm.nih.gov/bsd/bioethics.html

    http://www.nlm.nih.gov/bsd/bioethics.html

    https://ori.hhs.gov/human-subject-research-0

    https://ori.hhs.gov/human-subject-research-0

    https://ori.hhs.gov/human-subject-research-0

    https://ori.hhs.gov/human-subject-research-0

    https://ori.hhs.gov/human-subject-research-0

    https://humansubjects.nih.gov/

    https://humansubjects.nih.gov/

    https://humansubjects.nih.gov/

    https://humansubjects.nih.gov/

    mailto:grantsinfo@nih.gov

    mailto:grantsinfo@nih.gov

    mailto:grantsinfo@nih.gov

    mailto:http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html

    mailto:http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html

      Introduction
      Who?
      What?
      Why?
      Course Objectives
      History
      What This Module Covers:
      Goals and Principles of Human Subjects Protection
      Historical Events
      Historical Events
      Historical Events
      Historical Events
      Timeline of Events
      1932-1972: Syphilis Study at Tuskegee
      1939-1945: Nazi Medical War Crimes
      1944-1974: Cold War Human Radiation Experiments
      1946: Nuremberg Doctors’ Trial
      1947: Nuremberg Code & APA
      Nuremberg Code
      American Psychological Association
      1948: United Nations adopted Universal Declaration of Human Rights
      1953: First U.S. Federal Policy for Protection of Human Subjects
      1963: Jewish Chronic Disease Hospital Study
      1963-1966: Willowbrook Study
      1964: Declaration of Helsinki
      1966: Henry Beecher’s Publication
      1974: Federal Protections for Human Subject
      1979: The Belmont Report
      1980: Publication of the FDA Regulations
      1981: HHS & FDA Revise Regulations
      1982: CIOMS Guidelines
      1991: Publication of the Common Rule
      1993-1994: Revelation of Human Radiation Experiments
      1995: Establishment of The National Bioethics Advisory Commission
      1996: Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule
      1999: The Death of Jesse Gelsinger
      2000: The Office of Human Research Protections
      2004: The Secretary’s Advisory Committee on Human Research Protections

      Course Regulations
      What This Module Covers:
      The Objectives For This Module Are:
      The Belmont Report
      Respect for Persons
      Beneficence
      Justice
      Review
      The HHS Regulations – Protection of Human Subjects
      Subpart A – Basic HHS Policy for Protection of Human Research Subjects
      Case Study: Human Heart Study
      Does this study involve human subjects?
      Additional Protections
      Vulnerable Populations
      Case Study: Fetal Imaging
      Do Subparts B, C or D require that participants in this study receive additional protections?
      Case Study: Observational Study of Challenges Returning to Work
      Do Subparts B, C or D require that participants in this study receive additional protections?
      Case Study: Treatment and Prevention Research in Adolescents
      Do Subparts B, C or D require that participants in this study receive additional protections?
      Requirements for Federal Support of Human Subjects Research
      Equivalent Protections for International Research
      Engagement in Human Subjects Research
      Exemptions
      Codes and Regulations: Summary
      Respect for Persons
      What This Module Covers:
      The Objectives For This Module Are:
      Respect for Persons
      Informed Consent
      Informed Consent
      Case Study: Sleeping Sickness Study on Campus
      Case Study: Sleeping Sickness Study on Campus
      From which population would you advise the researcher to recruit?
      Informed Consent
      Informed Consent
      Case Study: Sleeping Sickness Study on Campus
      Which of these two consent documents would you choose to use?
      Waivers of Informed Consent
      Waivers of Informed Consent
      Practicability and Waivers of Informed Consent
      Case Study: New Analyses of Existing Data
      Does the investigator need to obtain new informed consent from the participants?
      Requirements for Documentation of Informed Consent
      Diminished Autonomy
      Decisional Capacity and Legally Authorized Representatives
      Participation of Pregnant Women in Research
      Children’s Participation in Research
      Assent and Permission for Children’s Participation in Research
      Case Study: Lack of Assent from a Child
      Do you need to withdraw this child from your study because he has withdrawn his assent?
      Case Study: Lack of Assent from a Child
      Obtaining Informed Consent from Prisoners
      Community Consultation
      Emergency Research
      Respect for Persons: Summary
      Beneficence
      What This Module Covers:
      The Objectives For This Module Are:
      Risk
      Physical
      Psychological
      Social
      Legal
      Economic
      Minimal Risk
      Types of Risk
      Physical
      Psychological
      Social
      Legal
      Economic
      Examples of Risk and Appropriate Protections
      Designing Research: Anticipated Benefits Greater than Potential Harms
      Regulatory Requirement for Explaining Benefits and Risks
      Compensation for Research Participation
      Avoiding Undue Inducement
      Avoiding the Therapeutic Misconception
      Assessing Risks and Potential Benefits
      Equipoise and Importance of Knowledge to be Gained
      Case Study: Equipoise in Research Involving Autistic Children
      Privacy and Confidentiality
      Case Study: Confidentiality in Clinical Research
      Confidentiality
      Coded Private Information and Human Subjects Research
      Case Study: Research with Anonymized Data
      Institutional Review Boards
      IRB Membership
      Working with the IRB
      Criteria for IRB Approval of Research (45 CFR 46.111)
      Expedited IRB Review
      Data and Safety Monitoring
      Data and Safety Monitoring Boards
      Case Study: Reducing Exposure to Mercury
      Beneficence: Summary
      Justice
      What This Module Covers:
      The Objectives For This Module Are:
      Individual Justice and Social Justice
      More on Social Justice
      Equity vs. Equality in Human Subjects Research
      Equitable Distribution
      Challenges to Achieving an Equitable Distribution of Benefits and Burdens
      NIH Inclusion Policies: Women and Minorities
      Case Study: Migraine Intervention Trial
      Case Study: Esophageal Cancer
      Inclusion of Children in Research
      Excluding Children from Research
      Policy Exceptions
      Definition of Children: HHS Regulations and NIH Policy
      HHS regulations
      NIH Inclusion Policy
      Case Study: Selecting Populations to Include in Clinical Research
      Research on early diagnosis of senile dementia
      Clinical trial comparing approved treatments for leukemia
      Experimental behavioral intervention to reduce bullying in elementary school class rooms
      Justice and the Use of Placebos
      Justifying the Use of Placebos
      Incomplete Disclosure and Deception
      Waiver of Informed Consent
      To Debrief or Not to Debrief
      Fairness in International Research
      Sustaining Benefits Locally
      Sustaining Benefits for Participants with HIV/AIDS in NIH-Supported Clinical Trials of Antiretroviral Agents
      Standards and Assurances for International Research
      Investigators:
      Institutions:
      IRB Review for Research in International Settings
      Local Cultural Norms and Informed Consent
      Justice: Summary
      Conclusion
      Further Training
      Staying Current

    This week, reflect on what you learned from the NIH materials about protecting the rights of human research participants.

    ·

    ·
    ·

    · Describe the circumstances that influenced the need for a policy to protect human research subjects. Give examples of specific ways human research subjects can be harmed by researchers.

    · Identify three vulnerable populations and the special restrictions associated with human research among these groups. Evaluate the requirements and restrictions. Do you think they are adequate? Why or why not?

    · The Belmont Report summarizes the ethical principles and guidelines for research involving human subjects. Three core principles are identified: respect for persons, beneficence, and justice. Even though these principles are considered equal, prioritize them in order of importance to you. Explain your decisions.

    · Although you are not implementing a change project at this time, and you may not be directly involved in research as part of your professional responsibilities, explain the reasons why it is important for you to know about these rights and protections.

    3 pages only

    2 scholarly articles

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