Protecting Human Subjects in Research

David Borasky, CIP

Office of International Research Ethics

Family Health International

People

Protecting People in Research: An Overview

• Ethical Principles

• Historical Perspectives

• Guidelines and Regulations

• Informed Consent

• IRBs

• Current Issues

• Case Studies

Regulatory Definitions

Research means a systematic investigation, including research development, testing and evaluation,designed to develop or contribute to generalizable knowledge.

Regulatory Definitions

Human subject means a living individual about whom an investigator conducting research obtains:

(1) data through intervention or interaction with the individual; or

(2) identifiable private information.

Basic Ethical Principles

“The expression ‘basic ethical principles’ refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions. Three basic principles, among those generally accepted in our cultural tradition, are particularly relevant to the ethics of research involving human subjects: the principles of respect of persons, beneficence and justice.”

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

Respect for Persons

Two ethical convictions:

• individuals should be treated as autonomous agents

• persons with diminished autonomy are entitled to protection

Two separate moral requirements:

• requirement to acknowledge autonomy

• requirement to protect those with diminished autonomy

Beneficence

Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being.

Two general rules:

• Do not harm

• Maximize possible benefits and minimize possible harms

Justice

“Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of ‘fairness in distribution’ or ‘what is deserved.’ An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly.”

Research Ethics in the 20th Century

• How did we arrive at this point?

• Human nature being what it is….

• Informs public perception and promotes discussion of issues

Cuba, 1900

Yellow Fever studies conducted by US Army Major Walter Reed

• Exposed people to mosquito bites• Successfully determined method of transmission• Coercive stipends offered to people who

volunteered in the research

Germany, 1900

City code (Berlin) regulating human research

• Protections for vulnerable populations• Informed consent• Description of risks

Germany, 1931

Reich Circular

•More restrictive than the Berlin Code•Animal testing required•Additional protections for vulnerable pops.•Special training in the conduct of research

Germany, WWII

As part of the German war effort, Nazi doctors performed numerous medical experiments on concentration camp prisoners.

High Altitude Tests

Hypothermia Experiments

Potable Seawater Experiments

The Doctors Trial, Nuremburg

Human Radiation Experiments

• Driven by the Cold War

• Exposed people to radiation through a variety of methods to evaluate the effect of exposure to radiation on humans

• Discovery of scandal led to ACHRE

Willowbrook State School,1956-1963

• Studies of Hepatitis A virus on institutionalized children

• Deliberate infection

• Beds only available to those who signed their children up as research subjects

Obedience to AuthorityYale University, 1960’s

• Staged experiments that required deceiving people who volunteered in the study

• Participants told to shock students who gave wrong answers

• Participants not aware that the “students” were confederates of the study team

“I observed a mature and initially poised businessman enter the lab smiling and confident. Within 20 min he was reduced to a twitching stuttering wreck… rapidly approaching a point of nervous collapse. He pulled on his earlobe, twisted his hands, and at one point pushed his fist into his forehead and muttered: ‘Oh, God, let’s stop it.’”

Stanley Milgram, 1963

Jewish Chronic Disease Hospital, 1963

• Elderly debilitated patients injected with live cancer cells to study immunologic response

• Patients not informed– investigators did not want to frighten unnecessarily

– a priori hypothesis that cells would be rejected

NEJM, 274:1354-60, June 16, 1966

The San Antonio Contraceptive Study

• Mostly poor Mexican-American women

• Randomized, placebo-controlled, double blinded crossover design clinical trial

• No mention of placebo

• 10 pregnancies while on placebo

“Untreated Syphilis in the Male Negro”Macon County AL, 1932-1972

• Sponsored by the USPHS (now CDC)

• 400 subjects with latent syphilis

• 200 controls

• No treatment

• Burial stipend of $50

“Bad” Blood

Spinal Tap “Treatment”

Lessons for future long-range studies:

“Incentives for maximum cooperation of the patients must be kept in mind. What appears to be a real incentive to an outsider's way of thinking may have little appeal for the patient. In our case, free hot meals meant more to the men than $50 worth of free medical examination.”

“The value of rapport and sympathy between patient and physician, and between patient and nurse… never can be overestimated. Material incentives can merely supplement and support a basic feeling of good will. A kind word is often worth a carton full of free medicines. A single home visit is worth more than a dozen letters on impressive stationery.”

From “Twenty Years of Followup Experience in a Long-Range Medical Study,” Rivers et al, Public Health Reports, 69:391-5, 1953

The Story Breaks - 1972

Philadelphia Enquirer, 1972

HIV/AIDS Research

• 076 – Placebo controlled MTCT trial • If it’s not ethical in Philadelphia why is it

ethical in Uganda?• Is local standard of care enough in research

setting?– Angell / Lurie say no

Gene Therapy Trials

• Jesse Gelsinger

• Problems with informed consent

• Conflict of interest

• Who is liable when things go wrong?

Johns Hopkins University

• Ellen Roche dies in challenge study using hexamethonium

• Employees as participants in research

• New standards for IRB review?

Is History Doomed to Repeat Itself?

Previous transgressions in the conduct of research have led to the development of guidelines, regulations and codes.

Some of these documents were created in response a specific incident. Others symbolize a desire to better. All require that people in research be treated ethically.

The Nuremberg Code

• Voluntary consent / ability to stop

• Build on previous knowledge

• Avoid unnecessary risks

• Benefit to society

• Qualified investigators

• Justification of risks

The Declaration of Helsinki

• Consent in writing

• Independently reviewed

• Protocol must be followed

• Caution if investigators are treating their patients

• Best proven diagnostic and therapeutic methods*

The Belmont Report

• Established the National Commission

• Response to Tuskegee

• Identified three basic ethical principles– Respect for Persons– Beneficence– Justice

US Regulations

• Reflect principles of Belmont

• 45 CFR 46 (1981)– Special protections for pregnant women,

prisoners, and children

• The Common Rule (1991)

• FDA Regulations

Council for International Organizations of Medical Sciences

• Response to rise of international research

• Benefits for all participants

• PI has duties in informed consent process

• Participant has right to compensation for injury

International Conference on Harmonization

• Result of a collaboration of public and private organizations in the US, Europe, and Japan– limited acceptance in developing world

• Designed to standardize the drug development and approval process

• Sets standards for protocol development• Includes sponsor responsibilities

National Bioethics Advisory Commission

• Issued report on international research in 2001– responsibilities of sponsor – benefits for host countries– use of placebo must be justified– consent issues (alternatives to US standard)

• Commission now dissolved

Helsinki (2000)

“The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods. This does not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, diagnostic or therapeutic method exists.”

Paragraph 29 WMA Declaration of Helsinki October 2000 revision

Clarification

“We say almost explicitly … that if there is treatment, then you cannot give a sugar pill to the control group.”

Delon Human, Secretary General, World Medical Association October 7, 2000

Clarification (reprise)

“A placebo-controlled trial may be ethically acceptable, even if proven therapy is available, under the following circumstances:

- Where for compelling and scientifically sound methodological reasons its use is necessary to determine the efficacy or safety of a…method; or

- Where a…method is being investigated for a minor condition and the patients who receive placebo will not be subject to any additional risk of serious or irreversible harm.”

World Medical Association Council

Informed Consent

What is informed consent?

• document

• process

• legal protection

• for whom?

Early consent form used by Maj. Walter Reed for Yellow Fever Studies

(26 Nov. 1900)

An informed consent document is…

• a form through which people are offered the opportunity to participate in research

• a tangible symbol that can be of great importance to people who volunteer

• a legal document that protects institutions

• as important or unimportant as the research staff makes it

The informed consent process is…

• a dialogue between the prospective participant and members of the research team

• a process that does not necessarily end when a person enrolls in a study

• the embodiment of Respect for Persons• often overshadowed by the perceived importance of

the document

What is an IRB?

Protocol Regs,

codes,

policy,

ethics.

What is an IRB?

– 5 member minimum– Sufficiently qualified– Diversity of members– Scientist & Non-scientist member(s)– Un-affiliated member(s)– No members in conflict

WHO, DHHS, FDA, and ICH

What the IRB Reviews

• Risks are minimized (Beneficence)

– Consistent with sound research design– When possible, using procedures that are

already being performed

What the IRB Reviews (cont’d)

• Risk vs Benefit (Beneficence)

– Only consider Rs and Bs that result from the research

– Long range risks should not be considered

What the IRB Reviews (cont’d)

• Equitable Selection of Subjects (Justice)

– The purpose of the research– Research setting– Vulnerable populations

What the IRB Reviews (cont’d)

• Informed Consent (Respect for Persons)

– Properly sought– Properly documented

What the IRB Reviews (cont’d)

• When Appropriate

– Data monitoring– Privacy and confidentiality– Vulnerable population protections

Don’t forget!

• Continuing review required at least annually– Status of the project– Problems?– New information in the literature?

Wait, there’s more!

• Also subject to IRB review and approval– Changes to the protocol– Changes to informed consent documents– Advertisements/recruiting materials– Serious Adverse Events

On the Horizon

• New science = new problems

• More internal / external oversight

• Financial conflict of interest

• Revised Standards?

New Science, New Problems

Cloning, stem cell research, gene

therapy, increased international research, etc.

More Supervision

• Institutions expanding their role as research monitor

• OHRP, FDA adding to their rosters of compliance auditors– attention shifting to int’l research

• IRB / institutional accreditations

Financial Conflict of Interest

• Research is becoming increasingly privatized

• PI’s may own the intervention they are studying

• Do people have a right to know?

Revised Standards

• US Congress to consider legislation in ‘02

• CIOMS revision in ’02

• Helsinki under pressure to reconsider

• Two new national committees

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Summary

• Research with people– is subject to ethical principles– is governed by regulations– must be approved by an IRB– has entered a new regulatory environment