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Ethics in Clinical Research

This document discusses ethics in clinical research. It outlines the goals of clinical research as generating useful knowledge about human health while minimizing risks to participants. The document then discusses key ethical requirements like informed consent, minimizing risks and exploitation of subjects, and ensuring their rights and welfare are respected. It provides a brief history of clinical research ethics through figures like Herophilos, Avicenna, Jenner, and Walter Reed. Finally, it discusses major codes and guidelines that guide ethical clinical research like the Nuremberg Code, Declaration of Helsinki, Belmont Report, and ICH/GCP guidelines.
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0% found this document useful (0 votes)
542 views74 pages

Ethics in Clinical Research

This document discusses ethics in clinical research. It outlines the goals of clinical research as generating useful knowledge about human health while minimizing risks to participants. The document then discusses key ethical requirements like informed consent, minimizing risks and exploitation of subjects, and ensuring their rights and welfare are respected. It provides a brief history of clinical research ethics through figures like Herophilos, Avicenna, Jenner, and Walter Reed. Finally, it discusses major codes and guidelines that guide ethical clinical research like the Nuremberg Code, Declaration of Helsinki, Belmont Report, and ICH/GCP guidelines.
Copyright
© Attribution Non-Commercial (BY-NC)
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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Ethics in Clinical Research

23/08/2010
Goals of Clinical Research
• New therapies
• Improving outcomes
• Reducing toxicities/side effects
Moral problem in clinical research

• The goal of clinical research is


generation of useful knowledge about
human health and illness
• Benefit to participants is not the purpose
of research (although it does occur)
• People are the means to developing
useful knowledge; and are thus at risk
of exploitation
Ethics of Clinical Research

• Ethical requirements in clinical research


aim to:

– minimize the possibility of exploitation;

– ensure that the rights and welfare of subjects


are respected while they contribute to the
generation of knowledge.
History of Clinical Research
• Herophilos (335-280 BC)
• Avicenna (980-1037)
• Edward Jenner (1749-1823)
• Walter Reed (1851-1902)
Herophilos (335-280 BC)
• Began to use scientific inquiry in medicine.
• -used dissection
• -recognized brain as center of nervous system
• -described difference between arteries and
veins
• -described changes in the pulse with disease
Avicenna (980-1037)
Introduced experimentation into medicine and the idea of a clinical trial.
The Canon of Medicine
1. The drug must be free from any extraneous accidental quality.
2. It must be used on a simple, not a composite, disease.
3. The drug must be tested with two contrary types of diseases, because
sometimes a drug cures one disease by Its essential qualities and
another by its accidental ones.
4. The time of action must be observed, so that essence and accident
are not confused.
5. The effect of the drug must be seen to occur constantly or in many
cases, for if this did not happen, it was an accidental effect.
6. The experimentation must be done with the human body, for testing
a drug on a lion or a horse might not prove anything about its effect
on man.
Edward Jenner (1749-1823)
• Smallpox
• In late 1700’s about 20% of
people died of smallpox.
Observation
• Milkmaids didn’t get
smallpox.
• They got cowpox.
Experiment
• Jenner innoculated 17 people
with the pus from cowpox
blisters.
Clinical trials as of 1800
• Make an observation and develop a
hypothesis.
• Try your idea on a person.
Walter Reed (1851-1902)
• Army Doctor, born in Virginia.
• Experiments on Yellow Fever in
Cuba
• Reed thought patients involved in
medical experiments should
consent to their participation
• This was the first informed
consent.
• Informed consent document (in
Spanish) for Antonio Benigno,
November 26, 1900.
Reed’s informed consent
• Each volunteer explicitly consented to
participate, and balanced the certainty
of contracting yellow fever in the
general population against the risks of
developing an experimental case,
followed by expert and timely medical
care.
• The volunteers agreed to remain at
Camp Lazear for the duration of the
experiments, and as a reward for
participation would receive $100 "in
American gold," with an additional
hundred-dollar supplement for
contracting yellow fever.
Codes and Guidelines
• Nuremberg Code (1949)

• Declaration Of Helsinki (1964)

• The Belmont Report (1979)

• CIOMS/WHO International Guidelines (1993, 2002)

• ICH/GCP-International Conference on
Harmonization- Good Clinical Practice (1996)
Nuremberg Code
• Informed consent required for experiments.
• Experiments must be scientifically necessary
and conducted by qualified personnel.
• Human trials should be preceded by animal
studies and surveys of a disease's natural
history.
• Benefit to science must be weighed against
risks and suffering of experimental subjects.
Declaration of Helsinki
• A policy statement made by the World
Medical Association in 1964, The declaration
of Helsinki, forms the basis for ethical research
on human subjects.
Declaration of Helsinki
• Clinical research should be based on animal and laboratory
experiments.
• Clinical research should be conducted and supervised only by
qualified medical workers.
• Clinical research should be preceded by a careful assessment of
risks and benefits to the patient.
• Human beings should be fully informed and must freely consent to
the research.
• Responsibility for the human subject must always rest with a
medically qualified person, and never with the subject.
• Results of experiments that do not comply with ethical guidelines
should not be accepted for publication.
• Special care must be taken with informed consent of minors.
• Also mentions consideration of the welfare of animal subjects and
the environment.
Declaration of Helsinki
• Respect for the individual
• Right to self determination
• Right to make informed decisions (informed
consent)
• Needs of subject always comes before needs
of society
Belmont Report
• Principle of Respect: recognizes the autonomy
of humans and requires clear informed
consent.
• Principle of Beneficence: Research must be
shown to be beneficial.
• Principle of Justice: The benefits to some must
be balanced against the risks to subjects.
Ethical framework: 7 principles
• Valuable scientific question
• Valid scientific methodology
• Fair subject selection
• Favorable risk-benefit evaluation
• Independent review
• Informed consent
• Respect for enrolled subjects
Emanuel E, Wendler D, Grady C. What makes clinical research ethical? Journal of the American
Medical Association 2000; 283(20):2701-11
Essential Elements of Ethical Research

Valuable Scientific Question

A socially, clinically, or scientifically useful


research question that will generate useful
new knowledge about human health
Essential Elements of Ethical Research

Valid Scientific Methodology

Study design, methodology, statistical power,


and feasible strategy that will yield valid, reliable,
generalizable, and interpretable data.
Essential Elements of Ethical
Research

Fair Subject Selection

Selection of subjects for reasons of


science, related to the purpose of the study,
not because they are readily available,
vulnerable, or otherwise easily exploited, or
are favored.
Selection of subjects
• Consistent with scientific goals:
– Select subjects to minimize risks and
maximize benefits
– Do not exclude subjects without a good
reason of science, vulnerability, or
susceptibility to risk or burden.
– Consider distribution of burdens and benefits
of research
Vulnerability
• There is an order of preference in selecting
subjects, for instance, adults before children
(Belmont Report)

• Exclude vulnerable subjects unless their


participation is needed for scientific reasons
(CIOMS)
Essential Elements of Ethical Research

Balance of Risks and Benefits

• Minimize risks to subjects


• Maximize benefits to individual subjects and to
society
• Benefits should be proportional to or outweigh
risks.
Risks in research
• Defining risks
– Probability and magnitude
– Types of risk
– Uncertainty

• Minimizing risks
Benefits in research
• Defining benefits
– Direct versus secondary benefits

• Maximizing benefits

• Balancing risks and benefits


Benefits and Risks in Research
Interests other than those of the subject
may on some occasions be sufficient by
themselves to justify the risks involved in
the research, so long as the subjects’
rights have been protected.

The Belmont Report


Essential Elements of Ethical Research

Independent Review
Minimize conflict of interest
Public Accountability
Independent review of clinical research
ensures the public that investigator biases
have not distorted the approach, that ethical
requirements have been fulfilled, and that
subjects will not be exploited.
Criteria for IRB Review
• Risks … are minimized.
• Risks are justified by anticipated benefits,
if any, to the subjects or the importance of
the knowledge to be gained
• Subjects will be selected and treated fairly
• Informed consent is adequate
Essential Elements of Ethical Research

Informed Consent
Respect for Persons

Voluntary agreement to participate, based


on understanding the objectives, risks,
benefits, and alternatives of the research.
Informed Consent
• The voluntary consent of the human
subject is absolutely essential.
Nuremberg Code
• For all biomedical research involving
human subjects, the investigator must
obtain the informed consent of the
prospective subject…or authorized
representative. CIOMS guidelines
Informed Consent
• “To the degree subjects are capable, they
should be given the opportunity to choose
what shall or shall not happen to them”.
The Belmont Report

• Extra protections for those with limited


capacity to consent
Informed consent
• Disclosure of information

• Understanding

• Voluntary decision making

• Authorization
Essential Elements of Ethical Research

Respect for Enrolled Subjects


Beneficence and Respect for Persons

• Right to withdraw.
• Confidentiality of subject data.
• Informing subjects of new information and of
study results.
• Monitoring subject welfare.
Respect for enrolled subjects
• During the course of the experiment the human
subject should be at liberty to bring the
experiment to an end… Nuremberg Code
• …Every precaution should be taken to respect
the privacy of the subject ,the confidentiality of
the subject’s information, and to minimize the
impact of the study on … physical and mental
integrity and on the personality of the subject.
Helsinki 2000
7 principles
• Valuable scientific question
• Valid scientific methodology
• Fair subject selection
• Favorable risk-benefit evaluation
• Independent review
• Informed consent
• Respect for enrolled subjects
Investigator Conflicts of Interest
• Professional gain: publications/promotion
• Financial gain
– Patient finder’s fee to collaborators
– Recruitment bonuses
– Affiliation with/funding from sponsor for future
studies, consultant relationships
• Other incentives (e.g., travel, presentations)
• Per patient payment system presents conflicts of
interest inherent in capitalist society
Potential Consequences of Investigator
Conflicts of Interest
Attempting to increase study enrollment
• Coercing subjects to enroll and discouraging
withdrawal, treatment alternatives
• Enrolling fictitious or ineligible patients
Bias trial toward positive results
• Failure to report adverse events
• Failure to comply with protocol regimens
• Alteration of outcome data
• Data fabrication
Ethical Safeguards Against
Financial Conflicts of Interest
• Full disclosure (institution, collaborators,
journal editors, FDA)
– Disclosure not meant to prevent investigators
from participating in research
– Disclosure statements also apply to study staff,
spouses, and dependent children
• Restrictions (decisions, presentations)
• Regulatory/legal action for failure to
comply
Sponsor Conflicts of Interests
Pressure investigator to withhold negative
results or to “spin” positive results
• Unreasonable control of data analyses
• Discrediting investigator’s research (through
word-of-mouth, publications, presentations)
• Threat of loss of contractual work
• Threat of legal action
Unethical Sponsor Behavior:

• Randomized clinical trial of isradipine vs


hydrochlorothiazide in 883 hypertensives
• No difference for 1º endpoint (carotid
intramedial thickness)
• Isradipine caused increase in CV events
• Sponsor not prepared for negative results
• Interfered with publication process
Institutional Review Boards (IRBs)
• Primary institutional responsibility for protection of
human research subjects (PI responsible for study
conduct)
• Human research may be conducted only after IRB
review and approval
• Types of IRBs
– LOCAL (covered for Human Research at academic
institutions)
– INDEPENDENT (national) Preferred by most
pharmaceutical industry sponsors; may be used by any
non-academic independent site
IRB Membership
• >5 members, both men and women
• Diversity of backgrounds
• Sensitive to community attitudes
• Expertise and experience (ad hoc experts added as
needed)
• >1 scientist
• Nonaffiliated member from the local community
• Members must avoid conflict of interest
• >1 non-scientist must be present for all votes
IRB Membership
>1 member with specific expertise about vulnerable
subjects:
Children
Pregnant women
Prisoners
Students
Handicapped
Mentally disabled
Chair of the IRB
Respected individual
Fair and impartial
Oblivious to pressure from PIs and administration
IRB Jurisdiction
• Research or Therapy?
– Research is a systematic investigation designed to
contribute to generalizable knowledge
• Human subjects or not?
– Human subjects are living individuals about whom
an investigator obtains data through intervention
or interaction or obtains identifiable private
information
Ethical Principles in Human Research:
What the IRB Seeks*
Respect for Persons:
• Written Informed Consent
Beneficence:
• Risk vs. Benefit Decisions
Justice:
• Subject Selection
• Recruitment
• Inclusion/Exclusion Criteria
*Source: The Belmont Report, April 18, 1979
see http://ohsr.od.nih.gov
IRB Review
• Well-designed research proposal
• Plan for proper execution of proposal
• Avoids unnecessary risk to subjects
• Protects investigators and institution
• Minimizes risk to subjects (consider risk vs. benefit)
• Equitable subject selection
• Informed consent obtained
• Safety monitoring
• Confidentiality of data
Categories of Human Research

• Exempt
• Expeditable
• Full Board Review
Exempt research
• Educational testing
• Surveys without individual’s identification
• Use of existing data, documents, or records
with no identifiers or links to subjects
• Only the IRB can decide a project is exempt!
Expedited Review
• One experienced IRB member
• Reported to full IRB
• Study with minimal risk of harm, and…
1. Drugs or devices - no IND
2. Blood - healthy adults; others
3. Hair, nails, teeth, excreta, secretions
4. Noninvasive clinical procedures
5. Data, documents, records
6. Voice, video, image recordings
7. Behavior or characteristics
IRB Procedures
Full Board Review
Protocol
Rev. Fm. +
Protocol +
Dept Office of
Consent PI
Form Chair Research

All IRB Written 3 IRB


Members Comments Members

•Approve
vote
Discussed at Convened •Provisionally Memo to PI
Meeting Approve
•Not Approve
IRB Jurisdiction

• Institutional Officials may disapprove


IRB-approved research
• Institutional Officials may not approve
research disapproved by IRB
IRB Review and Approval
• Up to one year approval (IRB may shorten
duration)
• Progress report - renewal one year
• ANY change in protocol or consent form must
be communicated to IRB
• Minor changes may be expedited
Informed Consent
• Provided to subject, or legally authorized
representative (spouse, next of kin)
• Minors-parental consent (one or both) and
assent of child, unless child emancipated
• Explanation in lay language
• Questions answered
• Copy of form given to subject
• A process, not a form with a signature!
Informed Consent:
Mandatory Elements
• Research • Confidentiality
• Purpose • Compensation,
• Description treatment for injury
• Procedures • Contact for questions
• Risks • Contact for research
• Benefits subject’s rights
• Alternatives • Right to refuse or
withdraw
When May IRB Waive
Consent Process?
• Minimal risk
• Rights and welfare not adversely affected
• Not practical without waiver (but must
provide information after participation)
– Amiodarone for resuscitation
• Procedure does not require written consent
outside of research
Examples of Research Requiring IRB
Approval

• Clinic chart review when any identifier


recorded
• Clinical trial of investigational new drug
• Venous blood sample from volunteer
• Patient data with identifiers obtained from
colleagues
Examples of Research not Requiring
IRB Approval
• Use of autopsy material
• Case report
• Chart review - no identifiers recorded (IRB
declares exempt)
• Monitoring of clinic operations for quality
control
Clinician vs. Scientist
• The clinician is concerned with acting in the
best interests of the individual patient
medically.
• The clinical scientist is concerned with
answering questions and testing hypotheses,
and such scientific information will benefit
humanity in general.
Clinical Equipoise
• A state of general uncertainty on the part of the
clinical investigator regarding the therapeutic
merits of each arm in a trial.
• Equipoise is an ethically necessary condition in all
cases of clinical research.
• If equipoise is disturbed during the course of the
trial, the trial may need to be terminated, and all
subjects previously enrolled offered the superior
treatment.

Freedman, B: Equipoise and the ethics of clinical research. NEJM 1987; 317:141-5.
Can Equipoise Ever Be Achieved?
• The clinical community is split regarding preferred
treatment. Some clinicians favor A and others favor
B.
• Each side recognizes that the opposing side, which
is recognized as responsible and competent, has
evidence to support its position.
• There exists an honest, professional disagreement
among expert clinicians about the preferred
treatment.
• A clinical trial is instituted with the aim of resolving
this dispute.
The Ethics of Randomized Clinical Trials
• Reflect the classic conflict between rights-based
moral theory and utilitarianism.
• Rights-based theory would suggest that human
beings are bearers of dignity, and should never
be used as objects, or means to an end, but
rather ends in themselves.
• Utilitarian theory defines what is right as that
which produces the greatest good for the
greatest number--social utility.
• The morally correct act is that which produces
the greatest pleasure and the least pain overall.
The Ethics of Randomized Clinical Trials

• Utilitarian theory denies the ethical


obligation of the physician to see the
interests of the individual patient as primary
and compelling.
• The randomized clinical trial is utilitarian in
that it asks physicians to sacrifice the
interests of their particular patients for the
sake of the study, and ultimately for the
benefit of society.
Phase I Trials: Ethical Considerations

Benefit

Toxicity
Phase III Trials: Ethical Considerations

• Investigational therapy vs. standard of care


presents huge conflicts
• Demands a state of equipoise to be an ethical
study.
Research Ethics
Unethical medical research – World War II
There were many unethical clinical research trials during the
World War II.
One example: An Office of Scientific Research and
Development was established in the US to combat diseases
such as dysentery, influenza and malaria, diseases that
commonly affect soldiers.
One of the research teams created a potential vaccine for
dysentery. To test it the researchers used orphans and
mentally retarded individuals in institutions. The orphans
developed high fevers, thus proving that the vaccine did
not work.
Another research team gave psychotic patients with malaria.
Unethical Study
Tuskegee Study of Syphilis
• Federally-funded study of natural history of
syphilis (TSS)
• In 1932, no effective treatment
• 412 infected, indigent blacks enrolled
(vulnerable population)
• 1951-penicillin standard treatment; TSS
subjects excluded from penicillin
• 1972/74-public disclosure; hearings;
financial settlement
Unethical Treatment of Human
Subject-Gene Transfer Trial
• Jesse Gelsinger, an 18 yr. old with
mild ornithine transcarbamylase
deficiency
• Symptoms controlled with drugs
and diet
• Gene-therapy study to
determine safety, not efficacy;
consent incomplete
• Injection of virus vector that had
killed animals
• Parents inadequately advised
about risks
• PI conflict of interest
• 4 days after therapy, patient
brain-dead 17 Sep 99
Hexamethonium challenge study
• Normal volunteers inhaled
hexamethonium as pulmonary
vasodilator; large literature on
toxicity (in older publications)
• Volunteer #1 with “flu” not
reported to IRB
• Shortly thereafter, volunteer
#3, 24 years old died of
respiratory failure 2 June 2001

Ellen Roche
Volunteer #3
Investigator Fraud:
Dr. Robert Fiddes
• Conducted >200 studies for 47 sponsors at Southern
California Research Institute
• Used false study subjects, laboratory results, urine
samples, medical records, radiographs!
• Passed all audits, but turned in by “whistle blowing”
former employee
• Sentenced to 15 months in prison, fined $800,000,
lost medical license (1997)
• FDA debars Dr. Fiddes and 3 nurse coordinators from
all clinical research activities (2002)
Ethics and Clinical Research:
Conclusions & Suggestions
• Learn more about clinical trials
– Take a training course
– Review Belmont Report, Declaration of Helsinki,
other consensus documents
• When planning a clinical study consult early
with a statistician
• Get to know your IRB or ethics committee

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