Research,Human Subject Protection

&Institutional Review Board (IRB)

Jed Delmore, MD

Please pass the Red Bull!

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History of Human Subjects Protection

• Nuremberg Code (1947)

• Unethical Research in the U.S.

• Declaration of Helsinki (1964)• Revised - ’75,’83,’89,’96,’00,’02,’04,’08

• National Research Act (1974)• Resulted in The Belmont Report

• Regulations

• Modern Day Problems

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Nuremberg

During the Nuremberg War Crimes Trials:

23 German doctors were charged with crimes against humanity for

“performing medical experiments upon concentration camp inmates and other living human subjects, without their consent, in the course of which experiments the defendants committed the murders, brutalities, cruelties, tortures, atrocities, and other inhuman acts.”

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Nuremberg

As part of the verdict, the Court enumerated some rules for "Permissible Medical Experiments", now known as the “Nuremberg Code”. These

rules include:

-voluntary consent

- experiment yielded results for good of society

- benefits outweigh risks

-ability of the subject to terminate participation

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Nuremberg Code (1947)

Creation of the Nuremberg Code (1947)

Although it did not carry the force of law, the Nuremberg Code was the first international document which advocated voluntary participation and informed consent.

10 principles includes: informed consent and absence of coercion; properly formulated scientific experimentation; and beneficencetowards experiment participants.

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SUCH CONDUCT COULD NOT OCCUR IN THE U.S.

Trust me I’m a doctor.

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

• Willowbrook (1956 -1965)

• Jewish Chronic Disease (1963)

• USPHS Syphilis Study (aka Tuskegee Study) (1932-72)

• And More modern day problems….

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The Willowbrook Hepatitis Study

• New York (1963-1966)• Conducted on mentally retarded,

institutionalized children• Involved systematically infecting the children

with hepatitis• Parents were coerced into consenting

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Jewish Chronic Disease Hospital

• New York (1963)• Cancer Experiments• Injection of live cancer cells• Hospitalized elderly patients• Indigent subjects were injected with live

cancer cells without their knowledge or consent

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US Public Health Services

“Study of Untreated Syphilis in the Negro Male”

American medical research project conducted by the U.S. Public Health Service from 1932 to 1972

Tuskegee syphilis study examined the natural course of untreated syphilis in black American men when there was no effective treatment

subjects all poor sharecroppers - unknowing participants subjects not told that they had syphilis - nor offered effective treatment once it came available

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Declaration of Helsinki (1964)

At the conclusion of the Nuremberg Trials it was decided that as biomedical research efforts expanded, there was an international need for a more specific code of ethics to review research.

This specific code was formulated in 1964 and called the Declaration of Helsinki.

Declaration of Helsinki

Recommendations Guiding Medical Doctors in Biomedical Research Involving Human Subjects

Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964

Revised by the World Medical Assembly in Tokyo, Japan in 1975, in Venice, Italy in 1983,

and in Hong Kong in 1989 and the 48th General Assembly, Somerset West, Republic of

South Africa, October 1996, 52nd General Assembly, Edinburgh, Scotland in 2000, Note

clarification on paragraph 29 added by WMA, Washington 2002, Note clarification on

paragraph 30 added by WMA, Tokyo 2004, 2008 Cairo/Sao Paulo.

“Concern for the interests of the subject must always

prevail over the interests of science and society.”

Declaration of Helsinki

In cases of incompetence informed consent should be obtained from

legal guardian or responsible relative

Some risks justified by potential therapeutic or diagnostic value to the

patient

US Government Regulation

After problems in US Medical Research were highlighted, the US government decided to look into government regulation of human experimentation and develop

ethical guidelines for such research.

US Government Response to Research Abuses

1973 Kennedy Hearings “Quality of Health Care – Human Experimentation”

1974 National Research Act

Established the “National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research”

Required IRBs at institutions receiving federal support for human subjects research

National Research Act (1974)

• Established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (i.e., “The National Commission”)

• Initially met over a four-day period in 1976

• Met at the Smithsonian Institute's Belmont Conference Center (thus “The Belmont Report”)

• Monthly deliberations over the next four years

• Resulted in The Belmont Report

Respect for Persons

informed consent ,

respect for privacy

Beneficence(nonmalficence)

first do no harm,

good research design,

competent investigators,

favorable risk/benefit analysis:

maximize benefits,

minimize risks.

Justice

equitable selection of subjects

appropriate inclusion and

exclusion criteria.

What is an IRB?An Institutional Review Board (IRB) is a group of people

formally designated (by feds and Institution) to review and monitor research involving human subjects.

Direct arm of the federal government when it comes to protection of human subjects

The Federal Government and the IRB

DHHS

FDA NIHOffice of Human

Research Protection

21 CFR 50 & 56 45 CFR 46

Institutional Review Board

What is the purpose of an IRB?

The purpose of the IRB is to protect the rights and welfare of individuals who are participating as subjectsin research (THIS IS IT, #1, Numero Uno)

The IRB has authority to approve, disapprove, and require modifications to research projects involving human subjects

IRB Membership

• Scientific members

• Ethicist

• Non-scientific community members

• Representatives of at risk populations as needed

• Consultant of needed

• All serve a purpose, especially the non-scientific members

New study comes to the IRB. Now what? (The short version.)

• Are human subjects involved?

• Is it research?

• What is the level of risk to the subject?

• Is Consent required and are the risks outlined in the consent document in an understandable way?

• Is extra surveillance required?

• HIPAA compliance.

Research is defined as a systematic

investigation, including research

development, testing and evaluation,

designed to develop or contribute to

generalizable knowledge.

Is the Proposed Project Research?

Are Human Subjects involved ?

Human subject means a living individual about whom an investigator (whether professional or student) conducting research obtains

(1) Data through intervention or interaction with the individual, or

(2) Identifiable private information – also sometimes called Private Health Information or PHI (use of PHI also invokes HIPAA privacy rules)

HeLa Cells & Henrietta Lacks??

Surely we don’t need that supervision these days? (OHRP Non-compliance Letters.)

• 2000 University of Oklahoma, Tulsa• Melanoma vaccine trial with multiple violations including

design, safety, risks, recruitment and consent.

• 2001 University of Pennsylvania• Subjects exposed to inhalation of different acetone

concentrations to assess irritation thresholds. Consent was inadequate and misleading

• 1999 University of Pennsylvania• Jessie Gelsinger dies 4 days after injection with an adenvovirus

vector carrying a corrected gene for OTC (ornithine transcarbamylase) for which he was deficient. He exceed exclusion criteria, previous side effects and deaths in monkeys were not disclosed, and PI and University ownership in company not disclosed.

Surely we don’t need that supervision these days? (OHRP Non-compliance Letters.)

• 2010 SUPPORT –(Surfactant,Positive Pressure and Pulse Oximetry Randomized Trial) Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network• Neonates > 24 weeks and less than 27-6 weeks were

randomized to two oxygen saturation ranges.

• More deaths were seen in the lower saturation range.

• Questions regarding the Informed Consent and risks of low oxygen saturation not being addressed were raised by consumer protection groups ( Public Citizen) and OHRP.

• Questions regarding interference/input from NIH officials to HHS/OHRP supervision were raised and addressed.

Surely we don’t need that supervision these days? (OHRP Non-compliance Letters.)

Surely we don’t need that supervision these days? (OHRP Non-compliance Letters.)

Surely we don’t need that supervision these days? (OHRP Non-compliance Letters.)