A History of Human Research Protections and

Institutional Review Boards

Roger L. Bertholf, Ph.D.Associate Professor of

PathologyChair, University of Florida

IRB-03

The Nuremberg TrialsThe Nuremberg Trials

• The International Military Tribunal (1945)

• The Doctors Trial (1946)• The Nuremberg Code (August,

1947)

• The International Military Tribunal (1945)

• The Doctors Trial (1946)• The Nuremberg Code (August,

1947)

The Nuremberg CodeThe Nuremberg Code• Established necessity of

informed consent• Introduced concept of

beneficence• Introduced the notion of

proportionality between risk and benefit

• Established necessity of informed consent

• Introduced concept of beneficence

• Introduced the notion of proportionality between risk and benefit

The Declaration of Helsinki

The Declaration of Helsinki

• Adopted by the World Medical Association in 1964

• Provided guidelines for the conduct of human subjects research– Institutional Review Boards– “generally accepted scientific principles”– Distinction between clinical and basic

research– Placebo controversy

• Adopted by the World Medical Association in 1964

• Provided guidelines for the conduct of human subjects research– Institutional Review Boards– “generally accepted scientific principles”– Distinction between clinical and basic

research– Placebo controversy

The Tuskegee Syphilis Study

The Tuskegee Syphilis Study

• PHS initiated syphilis treatment program in 1928

• Discovered 35 – 40% infection rate in Macon County, AL

• Revised study to observation only• Enlisted help of the Tuskegee

Institute• Terminated in 1972

• PHS initiated syphilis treatment program in 1928

• Discovered 35 – 40% infection rate in Macon County, AL

• Revised study to observation only• Enlisted help of the Tuskegee

Institute• Terminated in 1972

The Belmont ReportThe Belmont Report• Drafted by the National Commission for

the Protection of Human Subjects in Biomedical and Behavioral Research

• Final version adopted in 1979• Three sections:

– Clinical practice vs. research– Three guiding principles of ethical research– Application of the three principles

• Drafted by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research

• Final version adopted in 1979• Three sections:

– Clinical practice vs. research– Three guiding principles of ethical research– Application of the three principles

Clinical practice vs. research

Clinical practice vs. research

• What is the purpose of the activity?

• Are results generalizable?• Example

• What is the purpose of the activity?

• Are results generalizable?• Example

Three Guiding Principles of Ethical Research

Three Guiding Principles of Ethical Research

• Respect for Individuals• Beneficence• Justice

• Respect for Individuals• Beneficence• Justice

Respect for IndividualsRespect for Individuals• Individuals act as autonomous

agents• Individuals act as autonomous

agents

An autonomous person is an individual capable of deliberation about personal goals and of acting under the direction of such deliberation. To respect autonomy is to give weight to autonomous persons’ considered opinions and choices while refraining from obstructing their actions unless they are clearly detrimental to others. To show lack of respect for an autonomous agent is to repudiate that person’s considered judgments, to deny an individual the freedom to act on those considered judgments, or to withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.

Respect for IndividualsRespect for Individuals• Individuals act as autonomous

agents• Individuals who are not capable of

acting as autonomous agents are entitled to special protections– Minors– Mentally incapacitated persons– Prisoners

• Individuals act as autonomous agents

• Individuals who are not capable of acting as autonomous agents are entitled to special protections– Minors– Mentally incapacitated persons– Prisoners

BeneficenceBeneficence• Guided by two basic principles:

– Do no harm– Maximize benefits and minimize

potential harms

• Risks should be in proportion to potential benefits

• Research design should ensure valid results

• Guided by two basic principles:– Do no harm– Maximize benefits and minimize

potential harms

• Risks should be in proportion to potential benefits

• Research design should ensure valid results

JusticeJustice• Benefits and risks of human research

should be fairly distributed• How do you select human research

subjects?– Societal allocation of burdens and

benefits– Equality, need, contribution, effort, merit

• Social vs. individual justice

• Benefits and risks of human research should be fairly distributed

• How do you select human research subjects?– Societal allocation of burdens and

benefits– Equality, need, contribution, effort, merit

• Social vs. individual justice

The Informed ConsentThe Informed Consent• Complete disclosure of all procedures,

any foreseeable risks, and any reasonably anticipated benefits

• Informed consent can be waived only if:– The risks are no greater than minimal– The research cannot be practically

conducted if consent is required– Subjects are debriefed, when appropriate

• Complete disclosure of all procedures, any foreseeable risks, and any reasonably anticipated benefits

• Informed consent can be waived only if:– The risks are no greater than minimal– The research cannot be practically

conducted if consent is required– Subjects are debriefed, when appropriate

The Informed ConsentThe Informed Consent• Proxy consent• Intentional/unintentional

coercion• Information must be presented

in a comprehensible manner

• Proxy consent• Intentional/unintentional

coercion• Information must be presented

in a comprehensible manner

Assessment of Risk/BenefitsAssessment of Risk/Benefits

• Research involving brutal or inhumane treatment is never acceptable

• Risks should be reduced to only those necessary to achieve the objective

• If there is risk of serious impairment, there must be extraordinary justification

• If vulnerable populations are used, there must be a specific reason for doing so

• Relevant risks must be included in the informed consent

• Research involving brutal or inhumane treatment is never acceptable

• Risks should be reduced to only those necessary to achieve the objective

• If there is risk of serious impairment, there must be extraordinary justification

• If vulnerable populations are used, there must be a specific reason for doing so

• Relevant risks must be included in the informed consent

Federal RegulationsFederal Regulations• 45 CFR 46

– The Common Rule (Part A)– Subparts B, C, and D

• 21 CFR 50 and 56– 50 includes rules for clinical

trials– 56 describes IRB responsibilities

• 45 CFR 46– The Common Rule (Part A)– Subparts B, C, and D

• 21 CFR 50 and 56– 50 includes rules for clinical

trials– 56 describes IRB responsibilities

The Multiple Project Assurance

The Multiple Project Assurance

• Any institution conducting federally funded (or regulated) research must provide the OHRP with a legally binding assurance that human research subjects are protected from unnecessary risk.– Single or Multiple– MPAs are usually approved for 5 years

• Any institution conducting federally funded (or regulated) research must provide the OHRP with a legally binding assurance that human research subjects are protected from unnecessary risk.– Single or Multiple– MPAs are usually approved for 5 years

The University of Florida MPA

The University of Florida MPA

• Provides for 4 IRBs: 01-04 (WIRB)

• Stipulates that all research at UF involving human subjects will be conducted in accordance with federal guidelines

• Provides for 4 IRBs: 01-04 (WIRB)

• Stipulates that all research at UF involving human subjects will be conducted in accordance with federal guidelines

Components of the UF MPA

Components of the UF MPA

• Institution is guided by the ethical principles in the The Belmont Report

• Specifies that IRBs will consider:– the risks to the subjects, – the anticipated benefits to the subjects and

others, – the importance of the knowledge that may

reasonably be expected to result, and – the informed consent process to be

employed.

• Institution is guided by the ethical principles in the The Belmont Report

• Specifies that IRBs will consider:– the risks to the subjects, – the anticipated benefits to the subjects and

others, – the importance of the knowledge that may

reasonably be expected to result, and – the informed consent process to be

employed.

Applicability of the UF MPA

Applicability of the UF MPA

• The UF MPA applies if any of the following conditions are met:

– the research is sponsored by this institution, or – the research is conducted by or under the direction

of any employee or agent of this institution in connection with his or her institutional responsibilities, or

– the research is conducted by or under the direction of any employee or agent of this institution using any property or facility of this institution, or

– the research involves the use of this institution's non-public information to identify or contact human research subjects or prospective subjects.

• The UF MPA applies if any of the following conditions are met:

– the research is sponsored by this institution, or – the research is conducted by or under the direction

of any employee or agent of this institution in connection with his or her institutional responsibilities, or

– the research is conducted by or under the direction of any employee or agent of this institution using any property or facility of this institution, or

– the research involves the use of this institution's non-public information to identify or contact human research subjects or prospective subjects.

IRB responsibilitiesIRB responsibilities• The IRB-03 is administratively responsible to

the President of this institution, who has delegated the responsibility to this institution’s Vice President for Research. (Dr. Win Phillips)

• This institution's IRBs have effective knowledge of subject populations, institutional constraints, differing legal requirements, and other factors which can foreseeably contribute to a determination of risks and benefits to subjects . . .

• The IRB-03 is administratively responsible to the President of this institution, who has delegated the responsibility to this institution’s Vice President for Research. (Dr. Win Phillips)

• This institution's IRBs have effective knowledge of subject populations, institutional constraints, differing legal requirements, and other factors which can foreseeably contribute to a determination of risks and benefits to subjects . . .

The Office for Human Research Protections

(OHRP)

The Office for Human Research Protections

(OHRP)

O H R PG re g K o ski, M D

O ffice o f the S e c re ta ry F D A2 1 C F R 50 , 56

O P R R(u n til Ju ne , 2 00 0)

N IH4 5 C FR 46

D H H S(F o rm er ly D H E W )

T o m m y T h o m p so n, S e c 'y

O H R PG re g K o ski, M D

O ffice o f the S e c re ta ry F D A2 1 C F R 50 , 56

O P R R(u n til Ju ne , 2 00 0)

N IH4 5 C FR 46

D H H S(F o rm er ly D H E W )

T o m m y T h o m p so n, S e c 'y