PHRP Website Protecting Human Research Participants

http://phrp.nihtraining.com/

……………………………………………………………………… 111Glossary

……………………………………………………………………… iOverview

…………………………………………………….. 1Introduction

…………………………………………………….. 3History

………………………………………… 16Codes and Regulations

………………………………………… 37Respect for Persons

…………………………………………………… 62Beneficence

…………………………………………………….. 88Justice

……………………………………………………. 109Conclusion

Protecting Human Research Participants NIH Office of Extramural Research

Developed: 3/1/2008

Updated: 2/4/2011

Protecting Human Research Participants NIH Office of Extramural Research

© 2008 Office of Extramural Research, National Institutes of Health Overview – i –

Overview The following information describes how to use this PDF to complete the online version of this course

and receive a certificate of completion.

Internet Access Requirements

The PDF version of the NIH Office of Extramural Research Protecting Human Research

Participants (http://phrp.nihtraining.com) is intended to allow registrants to review most course

content in hard copy or off-line (without internet access). It is important to note that:

• You must have internet access to complete the quizzes and receive your certificate of completion.

• You need to have internet access if you wish to view the hyperlinked documents referenced throughout the PDF.

Tracking Your Completion and Testing Your Knowledge

Your progress through this course is tracked electronically and is recorded when you COMPLETE a

section. Because you are not reading the materials on the website, once you finish reading a PDF

section you should return to the online tutorial in order to “complete” each section. You may quickly

click through each screen of the course section. This will allow the tutorialʼs electronic tracking to

record your progress. If you must leave the online course prior to completion, it is advised that you

first complete the section in which you are working. Completion  of  a  section  is  registered  when  a  

checkmark  appears  to  the  left  of  the  section  title  on  the  Main  Menu screen.

Additionally, there are four quizzes that must be taken online. They are found at the end of the

following course sections:

• Codes and Regulations,

• Respect for Persons,

• Beneficence, and

• Justice.

After submitting a quiz, it is scored. Once  you  have  completed  the  quiz  with  a  satisfactory  score,  a  

green  check  mark  will  appear  to  the  right  of  the  quiz score  on  the  Main  Menu screen. If you answer

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less than the required number of questions correctly, the section must be reviewed and the quiz

retaken until a satisfactory score has been attained. You may retake the quiz only after clicking

through each screen of the online section.

Remember: your progress is only recorded when, on the Main Menu screen, you see a check mark:

1. To the left of each of the 7 sections AND

2. To the right of each of the 4 quizzes

If you do not see check marks after completing a section or a quiz, please submit a ticket through the

online Technical Support Form (http://esupport.nihtraining.com/index.php).

Exiting and Re–entering the Online Program

You can exit and re-enter the program at any time. Log in with the same email address and password,

and the program will remember which sections you have completed. Because the course is being

tracked, book marking and returning to a screen will not work for purposes of tracking your completion.

You MUST go through the log in process in order for your progress to be tracked.

Certificate of Completion

Once you have successfully completed the course, including the quizzes, a link will appear in the Main

Menu allowing access to your certificate of completion.

To access your certificate, log in to the course and select the “Get Certificate” link from the Main

Menu. If you do not remember your password, use the “Forgot your password” link on the

Registration/Login screen.

This certificate may be accessed and printed at any time.

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Resources

• Primary source documents: Within each section are links to primary source documents. These links are blue and italicized. When connected to the internet and clicked on, a new window will open with the source document content. Please note that the security settings on your computer may generate a warning message asking you to confirm if the link you are trying to connect to is a trusted site. All links within this document have been verified.

• Glossary Terms: Within each section terms found in the glossary are identified with red, italicized text. The glossary should be referenced for each of these terms, as the term definitions are pertinent to fully understand the topics.

• Glossary: There is a glossary section located at the end of this document.

• Citations: Citations are indicated within the text by a number appearing as a superscript next to the content. The corresponding citation information can be found within the left margin of the corresponding page in this document.

• Case Studies: Throughout the course, Case Studies are presented to illustrate the topics being discussed. Each case study will pose a hypothetical question with the answer provided on the following page. To receive the maximum benefit from the case study exercise, attempt to answer the question based on your knowledge of the topic before viewing the next page.

Questions

For questions related to the online course, please consult the “FAQ Page” which is accessible online

from the Main Menu screen of the course.

Protecting Human Research Participants NIH Office of Extramural Research

© 2008 Office of Extramural Research, National Institutes of Health Introduction – 1 –

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) (http://www.nih.gov/) – 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 NIHʼs 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 (http://grants.nih.gov/grants/guide/notice-files/not-od-

00-039.html) in June 2000. This course is specifically designed for

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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 investigatorsʼ

research will be funded by NIH and is therefore subject to all U.S. Department of

Health and Human Services (HHS) (http://www.hhs.gov/) regulatory and NIH policy

requirements.

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.

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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, and respect.

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Historical Events

Nazi Medical War Crimes (1939–1945)

This photograph documented the results of a medical experiment that included skin burns caused by doctors at the Ravensbrueck concentration camp in 1943. It was entered into evidence at the Doctors Trial at Nuremberg.

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:

Photo source: Photo Archive, United States Holocaust Memorial Museum, courtesy of National Archives and Records Administration, College Park; used with permission.

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• 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.

The Nuremburg Code

View from above of the defendants dock during a session of the Medical Case (Doctors) Trial in Nuremberg, which ran from December 9, 1946 to July 19, 1947.

In the August 1947 verdict, the judges included a section called Permissible Medical

Experiments. This section became known as the Nuremberg Code

(http://ohsr.od.nih.gov/guidelines/nuremberg.html) 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.

Photo source: Photo Archive, United States Holocaust Memorial Museum, courtesy of Hedwig Wachenheimer Epstein; used with permission.

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The Code provides ten Directives for Human Experimentation

1. Voluntary consent of the human subject is absolutely essential

2. The experiment must yield generalizable knowledge that could not be obtained in any other way and is not random and unnecessary in nature

3. Animal experimentation should precede human experimentation

4. All unnecessary physical and mental suffering and injury should be avoided

5. No experiment should be conducted if there is reason to believe that death or disabling injury will occur

6. The degree of risk to subjects should never exceed the humanitarian importance of the problem

7. Risks to the subjects should be minimized through proper preparations

8. Experiments should only be conducted by scientifically qualified investigators

9. Subjects should always be at liberty to withdraw from experiments

10. Investigators must be ready to end the experiment at any stage if there is cause to believe that continuing the experiment is likely to result in injury, disability or death to the subject

The Syphilis Study at Tuskegee

An unidentified subject of the Tuskegee Syphilis Study provides a blood sample to study investigators in the early 1950s.

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

Photo source: Records of the Centers for Disease Control and Prevention.

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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.

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/humansubjects/guidance/45cfr46.html)

3. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

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Timeline of Events in the History of Human Research Participants Protections

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 http://www.hss.energy.gov/healthsafety/ohre/ 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

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horrendous and unique nature of their crimes. They were found guilty of “crimes

against humanity.”

1947 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.

See http://www.hhs.gov/ohrp/archive/nurcode.html for more information.

1947 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

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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 systemʼs response to cancer. Live

cancer cells were injected into chronically ill and debilitated patients who were told

they were receiving a skin test. The investigators were eventually prosecuted and

found guilty of fraud, deceit, and unprofessional conduct.

1963-1966 Willowbrook Study

Studies were carried out at the Willowbrook State School for “mentally defective

persons,” to gain an understanding of the transmission of infectious hepatitis and,

subsequently, to test the effects of gamma globulin in preventing or ameliorating the

disease.

Residents of Willowbrook, all of whom were children, were deliberately infected with

hepatitis, by ingesting the stools of infected persons or receiving injectio