Ethics in Clinical Research
Ethics in Clinical Research
23/08/2010
Goals of Clinical Research
• New therapies
• Improving outcomes
• Reducing toxicities/side effects
Moral problem in clinical research
• 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
• Minimizing risks
Benefits in research
• Defining benefits
– Direct versus secondary benefits
• Maximizing benefits
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
• Understanding
• Authorization
Essential Elements of Ethical Research
• 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:
• 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
•Approve
vote
Discussed at Convened •Provisionally Memo to PI
Meeting Approve
•Not Approve
IRB Jurisdiction
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
Benefit
Toxicity
Phase III Trials: Ethical Considerations
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