Protecting Human Subjects in Research:

1
Protecting Human Subjects in Research Ethical
and Historical Perspectives Presented by Office
of Research Compliance Georgia Institute of
Technology Barbara S. Henry, MPA,
CIP Director Melanie J. Clark, BA,
CIP Compliance Administrator
2
Significant Events

Nuremberg Code 1947 U.S.
Scandals Henry Beecher "Ethics and Clinical
Research" Public Health Service Policy
Adopting IRBs Declaration of Helsinki
Stanford Prisoner Study (1971) PHS
Tuskegee Study Revealed (1972) National
Research Act 45 CFR 46
Belmont Report (1979)
PHS Syphilis Study, formerly Tuskegee Study
1930 1940 1950 1960 1970 1980
3
Nazi War Crimes - WWII
Victims of Dr. Josef Mengele's medical
experiments at Auschwitz-Birkenau. Poland, 1944.

• Nazi physician Carl Clauberg (l)
• performed medical experiments on prisoners in
  Block 10 of the Auschwitz camp.
• Poland, between 1941 and 1944

4
Nuremberg Trials Led to the Enduring Nuremberg
Code

5
Nuremberg Code - 1947

• Voluntary consent
• Anticipate scientific benefits
• Benefits must outweigh risks
• Animal experiments first
• Avoid suffering
• No intentional death or disability
• Do no harm
• Subject may withdraw at any time
• Investigators must be qualified
• Investigation will stop if harm occurs

6
Mid 20th Century Scandals

• Willowbrook State School, Staten Island, New
  York, 1950s
• Children at this institution for the retarded
  were fed
  extracts of stools from individuals
  infected with the
  hepatitis virus.
• Justification by Willowbrooks Research
  Director, Dr. Saul Krugman, was that children in
  the crowded facility would likely contract
  hepatitis anyway.
• Parental permission was obtained through
  misleading them about lengthy admission process
  for non-participating children.
• Jewish Chronic Disease Hospital Cancer
  Experiments - 1960s
• Twenty two chronically ill, debilitated,
  non-cancer patients injected with live human
  cancer cells
• They were not told about the cancer cells
  because doctors (researchers) "did not wish to
  stir up any unnecessary anxieties in the
  patients" who had "phobia and ignorance" about
  cancer.
• Research funded by U.S.P.H.S. and American
  Cancer Society.
• Two years later, the American Cancer Society
  elected the principal investigator to be their
  Vice-President.

7
Obedience to Authority Studies 1960s
1961-1962 Stanley Milgram, Yale University
researcher
The Milgram Study A lesson in depravity, peer
pressure, and the power of authority
8
Henry K. Beecher, Father of IRB - 1966

• Ethics and Clinical researchNew England
  Journal of Medicine 1966
• Created the prospective, double-blind,
  placebo-controlled clinical trial (gold standard
  of clinical research)
• Published landmark article about 22 published
  medical studies presenting risk to subjects
  without their informed consent
• Beechers revelations were the impetus for
  creation of Institutional Review Board system and
  informed consent standards

9
Public Health Service Adopts IRBs - 1960

• 1964 World Medical Association adopts Helsinki
  Declaration, establishing basic ethical
  principles for human research.
• 1966 The Office for Protection from Research
  Risks (OPRR) was established in National
  Institutes of Health, and Institutional Review
  Boards were required.

10
Stanford Prisoner Study 1971 http//www.prison
exp.org/
11
PHS Syphilis StudyDisclosed 1972
1932, Public Health Service study, in
collaboration with the Tuskegee Institute in
Macon County, Alabama, undertook a study of
untreated syphilis in hopes of justifying
treatment programs for blacks. 600 black men
(399 with syphilis, 201 without) were told they
had "bad blood," a local term used to describe
syphilis, anemia, and fatigue. Penicillin,
treatment of choice, was discovered in 1940s but
was withheld. In exchange for taking part in the
study, the men received free medical exams, free
meals, and burial insurance. Although
originally projected to last 6 months, the study
actually went on for 40 years.
12
PHS Syphilis Study
To entice their continued participation, PHS
doctors sent them a letter titled, Last
Chance for Special Free Treatment. The men
submitted to painful and dangerous spinal
taps. The fact that autopsies would eventually
be required was also concealed. The Surgeon
General of the United States participated in
enticing the men to remain in the experiment,
sending them certificates of appreciation after
25 years in the study. By end of study in
1970s, 28 men were dead of syphilis, 100 were
dead of related complications, 40 of their wives
were infected, and 19 of their children were
born with congenital syphilis.
13
PHS Syphilis Study

• Sometimes, with the best of intentions,
  scientists and public officials and others
  involved in working for the benefit of us all,
  forget that people are people. They concentrate
  so totally on plans and programs, experiments,
  statistics on abstractions that people become
  objects, symbols on paper, figures in a
  mathematical formula or impersonal subjects in
  a scientific study.
• Atlanta Constitution, July 27, 1972

14
National Research Act - 1974

• Upgraded Office for Protection from Research
  Risks policies to REGULATION
• Established a National Commission for Protection
  of Human Subjects of Biomedical and Behavioral
  Research
• Identify basic ethical principles
• Develop guidelines to assure research is carried
  out according to those principles
• Required institutions receiving HEW (PHS) funding
  for human research to establish Institutional
  Review Boards
• 1975 HHS promulgates Title 45 of Federal
  Regulations, Protection of Human Subjects
• 1976 Held the now famous conference at
  Smithsonians Belmont Conference Center

15
The Belmont Report

• Ethical Principles and Guidelines for the
  Protection of Human Subjects of Research
• Respect for Persons
• Individual autonomy
• Protection of individuals with reduced autonomy
• Beneficence
• Maximize benefits and minimize harms
• Justice
• Equitable distribution of research costs and
  benefits
• The National Commission for the Protection of
  Human Subjects of Biomedical and Behavioral
  Research
• April 18, 1979

16
Significant Events
Common Rule 1991 Nicole Wan dies at
Rochester 1996 President Clinton apologizes
to PHS Syphilis study survivors Jesse
Gelsinger dies at U Penn OPRR shuts down LA
VA Medical, Duke, U Ill, U Colo, U Penn
OPRR shuts down VCU, UAB, U Okla
OPRR reorganized as
OHRP, moved to Cabinet level and
Director replaced, June 2000 Ellen
Roche dies at Johns Hopkins OHRP suspends JH
federally funded research Secretary's
Advisory Committee on Human Research
Protections replaces National Human
Research Protections Advisory
Committee
1990 1996 1997 1999 2000 2001 2002
17
Common Rule - 1991

• The Common Rule (Federal Policy) has been adopted
  by these federal agencies
• 7 CFR Part 1c Department of Agriculture
• 10 CFR Part 745 Department of Energy
• 14 CFR Part 1230 National Aeronautics and Space
  Administration
• 15 CFR Part 27 Department of Commerce
• 16 CFR Part 1028 Consumer Product Safety
  Commission
• 22 CFR Part 225 International Development
  Cooperation Agency, Agency for International
  Development
• 24 CFR Part 60 Department of Housing and Urban
  Development
• 28 CFR Part 46 Department of Justice
• 32 CFR Part 219 Department of Defense
• 34 CFR Part 97 Department of Education
• 38 CFR Part 16 Department of Veterans Affairs
• 40 CFR Part 26 Environmental Protection Agency
• 45 CFR Part 690 National Science Foundation
• 49 CFR Part 11 Department of Transportation

18
Nicole Wan Rochester University - 1996
19
President Clinton Apologizes - 1997

"The United States government did something that
was wrongdeeply, profoundly, morally wrong. It
was an outrage to our commitment to integrity
and equality for all our citizens... clearly
racist. President Bill Clinton apologizes to
study survivors, May 16, 1997
20
Jesse Gelsinger U Penn - 1999

• 18-year old volunteer in U Penns gene therapy
  study of partial omithine transcarbamylase
  deficiency (OTC), which interferes with livers
  ability to metabolize ammonia.
• Jesse died at U Penn Hospital after being
  injected with genetically altered adenovirus.
• U Penn researchers had financial conflict of
  interest.

http//www.sskrplaw.com/gene/jessieintent.html
21
Universities, Hospitals Shut Down

• Mar 1999 West Los Angeles Veterans
  Administration Medical Center
• May 1999 Duke University Medical Center
• Aug 1999 University of Illinois
• Sep 1999 University of Colorado
• Sep 1999 University of Pennsylvania
• Jan 2000 Virginia Commonwealth University
• Jan 2000 University of Alabama at Birmingham
• Jun 2000 University of Oklahoma Tulsa
• Jun 2001 Johns Hopkins Medical University

22
Twins Study VA Commonwealth - 2000

• Dad opened college-aged daughters mail and found
  VCU survey from ongoing twin study.
• Family members would have become research
  subjects without giving consent.
• 1000 VCU studies with human subjects were shut
  down by Office for Human Research Protections
  (OHRP).
• Living individuals become research subjects when
  investigators obtain private, identifiable
  information about them.

23
OPRR Replaced by OHRP

• DHHS Press Release, June 6, 2000
• Edward Greg Koski, Ph.D., M.D., will serve as
  the first director of the Office for Human
  Research Protections (OHRP), a new office at the
  Department of Health and Human Services to lead
  efforts for protecting human subjects in
  biomedical and behavioral research, HHS announced
  today.
• As recommended last year by the Advisory
  Committee to the Director of NIH, the new office
  will be located at the HHS department level, in
  the office of the Assistant Secretary for Health.
  It replaces the Office for Protection from
  Research Risks (OPRR), which was part of the
  National Institutes of Health (NIH) and had
  authority over NIH-funded research. 

24
Ellen Roche Johns Hopkins - 2001

• Healthy lab technician volunteered for asthma
  study of hexamethonium bromide.
• Respiratory effects of hexamethonium bromide were
  not known to investigator prior to study.
• Previous participant had respiratory problems,
  solution was changed without IRB being informed.
• Johns Hopkins forced to halt 300 million in
  medical research
• Ellen Roche died. Compensation for her
  participation 365. Johns Hopkins settled out
  of court with her family.

25
Fred Hutchinson Cancer Research Center 2001

• Patients died in two failed clinical trials at
  the center.
• The Center and its doctors had a financial
  interest in the trials.

26
Office of Research Compliance505 Tenth Street,
NWResearch Administration Building

• Melanie Clark, Compliance Administrator
• Melanie.clark_at_osp.gatech.edu
• 404-894-6942
• Barbara Henry, Director, Research Compliance
• Barbara.henry_at_osp.gatech.edu
• 404-894-6949
• Phil Sparling, IRB Chair
• Phil.sparling_at_ap.gatech.edu
• 404-894-3402

27
The IRB Process at Georgia Tech

• Presentation
• Part II

28
What is an IRB?

• Independent panel conducts review of proposed
  research, to protect the rights and welfare of
  participants
• At least 5 members, both genders
• Diversity and appropriate expertise
• Varied professions
• Scientists
• Non-scientists
• At least one unaffiliated member
• Sensitive to community attitudes
• Knowledge of vulnerable populations
• Ad hoc consultants

29
What is research?

• Research As defined by 45 CFR 46, "a systematic
  investigation, including research development,
  testing and evaluation, designed to develop or
  contribute to generalizable knowledge"

30
What is a Human Subject?

• Is a living individual about whom an investigator
  obtains either
• Data through intervention or interaction with the
  individual or
• Identifiable private information

31
What you need to submit!

• IRB application
• IRBWISE
• Project description
• Consent/Assent/Parental Permission
• All recruitment flyers scripts
• Human Subjects Training Certificate
• Questionnaire, surveys or interview guides

32
Applying Ethics to the RegulationsThe Belmont
Report

• Respect for persons
• Informed Consent
• Privacy and confidentiality
• Beneficence
• Study design
• Maximize benefits and minimize harms
• Justice
• Subject selection
• Vulnerable populations

33
Criteria that the IRB Uses to Evaluate Protocols
for Approval

• Risks are minimized
• Acceptable riskbenefit ratio
• Equitable selection of subjects
• Informed consent process
• Privacy and confidentiality
• Additional safeguards for vulnerable populations

34
Three Ways to Minimize Risk

• Alternatives
• Other procedures that are less risky
• Precautions
• Procedures to decrease the likelihood that harms
  occur
• Safeguards
• Procedures to deal w/harms if they occur

35
Categories of Research

• Exempt
• Expedited
• Full

36
Level of Risk and Review Category

• Full Committee
• _____________________________________
• Minimal Risk
• Expedited
• Exempt
• Risk

37
Exempt Research

• The determination must be made by the IRB after
  an application is filed by the investigator
• Categories are found in 45CFR46.101(b)

38
Expedited Research

• Presents no more than minimal risk to human
  subjects and
• Involves ONLY procedures listed in one or more of
  the categories authorized by 45CFR46.110 and
  21CFR56.110

39
Full Board

• More than minimal risk
• Procedures not included in the authorized
  categories

40
How long will it take?

• Exempt
• w/in 1-2 weeks of receipt date
• Expedited
• w/in 2 weeks of receipt date
• Full
• Meetings are every third Friday of the month and
  applications are due by the 1st of the month

41
Renewals

• Approval periods are granted on the basis of
  degree of risk of a protocol but cannot be
  greater than 1 year.
• Renewal application
• On IRBWISE go to the approved protocol screen
• Progress report
• All forms must be re-reviewed

42
Anything Else?

• All Amendments must be submitted to IRB for
  review and approval prior to commencement.
• Any change to the protocol or consent form
• All Adverse Events must be submitted for IRB
  review even if they are not study related.

43
Principal Investigators RESPONSIBILITIES

• Obtain approval prior to start of research
• Inform IRB of
• Adverse events
• Changes in protocol
• Violations
• Continuing review request
• Obtain consent prior to enrolling subjects

44
Informed Consent is a PROCESS not a piece of
paper
45
46.116 General requirements for informed consent

• Statement that it is research
• Purpose procedures
• Health and financial risk
• Compensation/costs
• Confidentiality
• In case of injury
• Subjects rights
• 8th grade reading level

46
WAIVERS

• Parental permission
• Documentation of consent
• Consent

47
Waiver of Parental Permission or Consent

• the research involves no more than minimal risk
  to the subjects
• the waiver or alteration will not adversely
  affect the rights and welfare of the subjects
• the research could not practicably be carried out
  without the waiver or alteration and
• whenever appropriate, the subjects will be
  provided with additional pertinent information
  after participation.

48
Waiver of Documentation of Consent

• That the only record linking the subject and the
  research would be the consent document and the
  principal risk would be 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
• That the research presents no more than minimal
  risk of harm to subjects and involves no
  procedures for which written consent is normally
  required outside of the research context  

49
Bottom Line

• The ability to conduct research using human
  subjects is a privilege granted to us by society
  for the advancement of knowledge and the
  bettering of the human condition.

50
Important Info
http//www.compliance.gatech.edu/IRB

• IRBWISE information
• Human Subjects Training
• FAQ
• Policies and Procedures
• Consent Templates

51
Office of Research Compliance505 Tenth Street,
NWResearch Administration Building

• Melanie Clark, Compliance Administrator
• Melanie.clark_at_osp.gatech.edu
• 404-894-6942
• Barbara Henry, Director, Research Compliance
• Barbara.henry_at_osp.gatech.edu
• 404-894-6949
• Phil Sparling, IRB Chair
• Phil.sparling_at_ap.gatech.edu
• 404-894-3402