Columbia University IRB

IRB 101

July 14, 2005

George Gasparis, Executive Director, CU IRB

Asst. V.P. and Sr. Asst. Dean for Research Ethics

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Objectives

Today’s session will provide information on:

• History and Trends in Human Research Ethics and Regulations

• Introduction to Relevant Regulations

• Introduction to Operation of the CUMC IRB

• Understanding of IRB Review Criteria

• Submitting to the IRB Successfully

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Well Known Major Cases Involving Unethical Research

Nazi Experimentation in

Concentration Camps

World War II

1939-44

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THE NUREMBERG CODE

Became the first widely recognized ethical code of conduct for human research

First Tenet - The voluntary consent of the human subject is absolutely essential.

[from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, October 1946–April 1949. Washington, D.C.: U.S. G.P.O, 1949–1953.]

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Nuremberg Code and Voluntary Consent (Continued)

The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

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Not Well Publicized Ethical Tragedies

Chemical and Biological warfare experimentation in Asia – 1920s

-Documented by Dr. Sheldon Harris’ book: “Ethics of Biological Warfare Research”

-The Big Three: Ishii Shiro, Katano Masaji, and Wakamatsu Ywiro conducted biological warfare (bw) and chemical warfare (cw) research on thousands of subjects in China, Indonesia, New Guinea, and the Philippines (and possibly Korea).

-Ishii used a minimum of 10-12,000 subjects in Northern Mantsuria

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Not Well Publicized Ethical Tragedies (cont’d)

Chemical and Biological warfare experimentation in Asia – 1920s

-Research was done on slaves, prisoners, and citizens in dozens of chemical factories; Units 731 (headed by Ishii Shuro; and the

largest unit), Unit 100, and Unit 555 were the most famous.

-Research was also done on frostbite (by freezing subjects), gangrene, decompression (exploding subjects), cholera, dysentery, and virtually every known pathogen.

-About 250,000 people were killed in China alone.

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Not Well Publicized Ethical Tragedies (cont’d)

Chemical and Biological warfare experimentation in Asia – 1920s

-Subjects were referred to as “monkeys” or “marutas” (“logs”).

-American POWs were not tested at major centers, but were tested, including surgical excision of livers while alive.

-Every Japanese officer above Major and every Minister of Office, and the Imperial family knew of the experiments.

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Declaration of Helsinki, 1964

A more developed research code of conduct expanding to address clinical research

-Developed by the World Medical Assembly

Has undergone 8 revisions; the most recent in October 2000

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SUCH CONDUCT COULD NOT OCCUR IN THE U.S.,

RIGHT?

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Well Known Major Cases Involving Unethical Research in the U.S.

• Tuskegee Syphilis Study 1932-1972

• U.S. Radiation Experiments 1940s

• Willowbrook Study, NY 1956-1972

• Milgram Study, 1961

• Jewish Chronic Disease Hospital, 1963

• U.S. Army LSD studies/National Airport, 1963-4

• Stanford Prison Study, 1971

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Not Well Publicized Ethical Tragedies

Dr. Albert Kligman’s research at the Holmesburg prison – 1951 - 1970’s

-Documented by Dr. Allen Hornblum’s book: “Acres of Skin”

-Conducted chemotherapy, psychotropic drugs, and burn studies in Ohio

-Came to the prison in 1951 to study athlete’s foot; earlier he performed ringworm studies on retarded children.

-Total of 1,200-1,400 patients; 70-80% were in studies.

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Not Well Publicized Ethical Tragedies (cont’d)

Dr. Kligman’s research at the Holmesburg prison – 1951 - 1970’s

-One Example:-Dow Chemical sponsored study of diazanon

-he was paid $10,000/pt.

-increased dose 480x and left patients untreated

-no adverse events reported

-Other Examples:-Tested benzylates, atropine, and other psychotropic drugs

and chemical warfare agents

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Not Well Publicized Ethical Tragedies (cont’d)

Dr. Kligman’s research at the Holmesburg prison – 1951 - 1970’s

-In 25 years of studies, he only received a handful of lawsuits.

-Subjects were given waivers to sign (not consent); if subjects accepted a payment, they would waive rights to suit the investigator, University of Pennsylvania, or jail.

-At the time, Pennsylvania only had a 2 year statute of limitations from time one knew or should have known.

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Belmont Report, 1979

National Commission for the Protection of Human Subjects of

Biomedical and Behavioral Research

Basis of federal regulations regarding the protection of human subjects in research

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

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Belmont Report, 1979

Applies to Social and Behavioral Research, as well as Biomedical Research

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Belmont Report, 1979

Articulates 3 Basic Ethical Principles:

Respect For Persons – Autonomy of the Individual

Beneficence – Risk Minimization

Justice – Burdens and Benefits of Research are Equitably Distributed

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Relevant Regulations

Federal Regulations:

Department of Health and Human Services (HHS)

Food and Drug Administration (FDA, agency of HHS)

State Law:

New York State

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DEPARTMENT OFDEPARTMENT OFHEALTH & HUMAN HEALTH & HUMAN

SERVICESSERVICES

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Federal Regulations for the Protection of Subjects from Research Risks

45 CFR Part 46

1981

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45 CFR 46

Subpart A -- Basic Protections

Subpart B -- Pregnant Women, Neonates and Fetuses

Subpart C -- Prisoners

Subpart D -- Children

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45 CFR 46 – Subpart B Revised Subpart B issues on November 13, 2001

(effective date December 13, 2001)

Changes:

-introduces the term neonate; removes references to in-vitro fertilization;

-changes when paternal consent is required;

-strengthens the protection for the fetus by requiring that the parents are fully informed regarding the impact of the research on the fetus or neonate

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COMMON RULE

Federal Policy for the Protection of Human Subjects

(45 CFR 46 Subpart A)

June 18, 1991

17 Departments and Agencies

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OHRP Website

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

Check website for guidance on many different ethical and regulatory considerations.

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Other Relevant Federal Regulations

FDA Regulations:

Code of Federal Regulations

– Title 21, Parts 50, 56, 312, 812

• Applicable to research that involves testing of FDA regulated drugs, devices, biologics

• http://www.fda.gov/oc/ohrt/irbs/

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Trends from 1970s - Present

1970 to mid 80s – Protectionists era

1985 - ?

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Trends from 1970s - Present

1970 to mid 80s – Protectionists era

1985 -1995 – Inclusion era:

-HIV epidemic

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Trends from 1970s - Present

1970 to mid 80s – Protectionists era

1985 -1995 – Inclusion era:

-HIV epidemic

-NIH and FDA Guidance for Inclusion of Women and Minorities in Research

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Trends from 1970s - Present

1970 to mid 80s: Protectionists era

1985 -1995: Inclusion era:

1995 - Present: Pendulum has swung back towards protectionism

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Well Known Major Noncompliance Cases

Continued incidence of unethical research

• Gulf War, 1991

OPRR/OHRP Shutdowns of Academic Medical Centers:

•Duke University

•Rush Presbyterian

•UCLA

•Univ. of California at Irvine

•University of Oklahoma

+ others

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Even More Recently and Closer to Home

Continued incidence of unethical research/noncompliance:

– Nicole Wan, Univ. of Rochester, 1996

– Jesse Gelsinger, Univ. of Penn., 1999

– Ellen Roche, Johns Hopkins, 2001

Ethical Research, but serious noncompliance:

– Columbia University Medical Center, 2005 – Current OHRP investigation

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What are the implications of noncompliance?

1. Affects the Public Trust in our research enterprise

-affects recruitment

-affects sponsors’ decisions to bring studies to an institution

2. Affects economics of the research enterprise locally

3. Creates significantly more work to ensure regulatory compliance

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IRBManagement of Noncompliance Cases

Total case load:

• 43 open cases involving 21 investigators

Sources of noncompliance cases:• 12 studies – Federal regulatory agencies or NIH

• 18 studies – CUMC IRB

• 8 studies – CUMC employees or staff

• 5 studies – External to CUMC

• 1 study – Self-reporting

• 15 closed cases involving 12 investigators

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All Human Research at Columbia University

Governed by Ethical Principles and the Requirements of HHS and FDA Regulations and

NY State Law

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Columbia University

Each performance site needs:

A. Assurance of Compliance Approved by OHRP (not required by FDA regulations)

B. Board Approval (i.e., IRB, REB, ethics cmte.)

C. Consent Obtained from Each Subject, Unless Waived by the IRB

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Columbia University Medical Center

Federalwide Assurance (FWA)

FWA00002636

-Applies the Belmont Report and

45 CFR 46 to all of its Human Subjects

Research Regardless of Support

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New York Presbyterian Hospital

Federalwide Assurance (FWA)

FWA00002635

-Applies the Belmont Report and

45 CFR 46 to all of its Human Subjects

Research Regardless of Support

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When does Human Subjects Research Need IRB Review?

Not Human Research (No IRB Review)

Oral History Evaluation

Polling QA

Gray Area

Human ResearchHuman ResearchIRB ReviewIRB Review

EthnographyEthnography Pedagogical Res.Pedagogical Res.

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Definition of Human Subject

A Living Individual about who an investigator (whether

professional or student) conducting research obtains:

1. Data through intervention or interaction with the individual,

or

2. Identifiable private information

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Types of IRB Review

1) Determination if human subjects research

2) Exempt

3) Expedited Review

4) Full Committee Review

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Definition of Research

-A systematic investigation, including research development, testing and evaluation, designed to contribute to generalizable knowledge

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Types of IRB Review

1) Determination if human subjects research

2) Exempt

3) Expedited Review

4) Full Committee Review