Ethical consideration in clinical trials

1. Ethics of Clinical Trials
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Dr. Ssuna Bashir
Clinical Epidemiology and Biostatistics
MBCh.B (MUST) Msc. (MAK)
Fellowship in Mixed methods Research (MAK)
Email: sbn144@gmail.com Mob. +256775655562

2. Learning objectives
• Historical perspective
• IRB and informed consent
• Planning and design
• Conduct
• Reporting
• Statistical ethics
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3. Historical Perspective
• 1947 Nuremburg Code
• 1948 UN Universal Declaration of Human Rights
• 1964 Declaration of Helsinki
• 1979 Belmont Report
• 1997 CIOMS International Ethical Guidelines for Biomedical
Research (Updated 2002)
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4. Nuremburg Code
• Voluntary consent of the human subject is essential.
• The anticipated results must have a basis in biological knowledge and animal
experimentation such that the experiment has potential for yielding fruitful
results for the good of society.
• The procedures should avoid unnecessary physical and mental suffering and
injury.
• The degree of risk for the patient should not exceed the humanitarian
importance of the problem to be solved.
• The study must be conducted by qualified scientists, with a high degree of skill
and care throughout the experiment.
• The investigator has an obligation to terminate the experiment if injury,
disability or death of the subject seems likely.
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5. 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
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6. Belmont Report
• Principal of Respect: individuals should be treated as autonomous agents,
and second, that persons with diminished autonomy are entitled to
protection
• Principal of 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.
• Principle of Justice: An injustice occurs when some benefit to which a
person is entitled is denied without good reason or when some burden is
imposed unduly. There are several widely accepted formulations of just
ways to distribute burdens and benefits. Each formulation mentions some
relevant property on the basis of which burdens and benefits should be
distributed.
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7. CIOMS
• Benefits and risks to subjects
• Vulnerable populations
• Research in populations with limited resources
• Strengthening capacity for ethical and scientific review
• Ethical obligation of sponsors to provide health care
• Choice of controls
• Equitable distribution of burdens and benefits
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8. Institutional Review Board
• The risks to the study participants are minimized and reasonable in
relation to the anticipated benefits.
• The selection of study participants is equitable.
• Informed consent is obtained and appropriately documented for each
participant.
• There are adequate provisions for monitoring data collected to ensure
the safety of the study participants
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9. Institutional Review Board
• The privacy of the participants and the confidentiality of the data are
protected
• Investigators must submit a research protocol, and study data
collection tools to IRB for approval prior to the conduct of the study.
• The IRB also requires the investigator to provide the following:
• Progress reports on an annual basis
• Reports of any serious adverse events in the human subjects when
they occur
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10. Informed Consent
• The principle of respect for persons implies that each study
participant will be made aware of potential risks, benefits and costs
prior to participating in a clinical study.
The informed consent must describe explicitly the following
information:
• The research nature of the study
• The reasonable foreseeable risks and discomfort
• The potential benefits and alternatives
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11. Informed Consent
• Procedures for maintaining privacy
• Treatment for injuries incurred
• Individuals to contact for questions
• The voluntary nature of the study and the possibility of withdrawal at
any time
• Not entering the study does not lead to loss of benefits
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12. Planning and design
Research question
• The question addressed by a clinical trial should be important enough
to justify possible adverse effects of the treatment that will be
administered. Studies that pose unimportant questions are unethical
as well, even if they pose minimal risk. What marketing question
would have enough benefit to justify risks to subjects? What about
situations where there is an approved and available therapy?
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13. Research question…
• The study question also involves the choice the study population.
Which population can answer the question? Does the potential
benefit outweigh the risk to these study subjects? Is the selection
just?
• Ethical considerations of respect for persons, beneficience and justice
imply three requirements for the conduct of research, namely,
informed consent, disclosure of the risks and benefits, and the
appropriate selection of research subjects. Applying ethical principles
also requires optimal study design, a balance of risk and benefit for
study participants, consideration of patient privacy, impartial
oversight of consent procedures.
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14. Study Sites:
• The choice of the study population is also related to the place(s) the
trial will be conducted. There is greater generalizability and
potentially faster enrollment if a trial is conducted in multiple and
varied geographic locales. The concept of justice should be applied
• Is the location selected due to prevalent disease and relevance of the
results ? Or for sponsor conveniences such as lower cost and fewer
administrative and regulatory burderns? Is the standard of care in this
country less than optimal care and thus event rates higher? Will the
treatment be available in this locale once the trial is complete?
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15. Randomization
• Some physicians and patients feel that it is inappropriate to base a
patient's treatment on chance, as is done in a randomized clinical
trial.
• Randomization is justified when there is relative ignorance
(collectively) about the best treatment. The situation in which there is
genuine uncertainty as to the best available therapy is
called equipoise. (Piantadosi 2005)
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16. Randomization…
• Blinding helps control for bias. Physicians with strong convictions
about a certain treatment or intervention could bias the clinical trial
in a different direction, especially if they are not “blinded” to
treatment/intervention assignment.
• Although most often individual subjects are randomized to treatment,
in some situations, the unit of randomization is a larger entity, such as
a hospital or community. How would individuals consent to such
research?
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17. Control Group
• Assigning patients to a placebo treatment, however, is not always
ethical. Placebo control is untenable when the disease is life-
threatening and an effective therapy is available. In such a case the use
of standard accepted therapy as an active control treatment is valid.
• Should the new intervention be compared with the best known
therapy or with placebo? Will a placebo control result in significant
harm to subjects? What if there is no accepted optimal therapy? What
if the optimal therapy is very costly or not available in some
locations? The selection of the control group has many ethical
considerations.
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18. Conduct
Recruitment
• Although it is vital to enroll enough subjects to answer the study
questions adequately, recruitment must also follow ethical norms.
Coercion should be avoided. For this reason, any financial
compensation for the subject's time and travel will reflect actual
expenses or small amounts that would not entice a person to enroll in
the study for financial gain.
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19. Conduct…
Early Termination for other than scientific or safety reasons:
• Related to planning, studies should only be conducted if resources are
adequate to complete the study. Early termination for reasons other
than science or safety reflect a lack of ethical concern. Subjects
agreed to participate so an important question could be answered.
There should be an answer.
Data Integrity:
• Data falsification must not be tolerated in any manner. Central
statistical monitoring and other procedures may help detect potential
fraud.
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20. Monitoring
• During the course of a comparative trial, evidence may become
available that one treatment is superior as a result of periodic interim
analyses. Interim statistical analyses may be incorporated into the
study design to provide periodic investigations of treatment
superiority prior to study completion.
• Should patients receiving an inferior treatment continue in this
manner? If there is evidence that a particular type of patient is
unlikely to respond to therapy, should entrance criteria be modified?
Is the adverse experience profile markedly worse for one therapy?
Investigators are required to report such circumstances to their IRB.
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21. Monitoring…
• Most multi-center clinical trials involve an independent board of
scientists to monitor the trial results and render decisions as to
whether the trial should continue or be modified in some
manner. Safety monitoring is required. These committees have
various names, such as Data and Safety Monitoring Board, External
Advisory Committee, etc.
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22. Reporting
Reporting:
• Investigators should report trial results completely and in a timely manner.
Registration of trials on clinicaltrials.gov and publishing associated results
online can reduce publication bias, the bias resulting from journals favoring
studies with significant results. Publish or find mechanisms to disseminate
results effectively.
Authorship:
• 'Ghost authorship' occurs when people writing a paper are not fully disclosed
(i.e. draft written by contract writer) or when authors are included who did
not actually participate in the research project (for example, an influential
name). Journals combat such deception by asking authors to specify the
contribution of each person listed as an author.
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23. Statistical ethics
In terms of data collection in clinical trials, statisticians should do the
following:
• Collect only the data needed for the purposes of the inquiry
• Inform each participant about the nature and sponsorship of the project
and intended uses of the data
• Establish the intentions and ability of the sponsor to protect confidentiality
• Inform participants of the strengths and limitations of confidentiality
protections
• Process the data collected according to the intentions and remove
participant-identifying information
• Ensure that confidentiality is maintained when data are transferred to
other persons or organizations
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24. Statistical ethics…
In terms of dealing with sponsors/clients, statisticians should do the
following:
• Clarify their qualifications to undertake the inquiry
• Reveal any factors that may conflict with impartiality
• Accept no contingency fee arrangements
• Apply statistical methods without regard for a desirable outcome
• Outline alternate statistical methods along with the chosen methods
• Maintain confidentiality with regard to other sponsors/clients
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25. Summary.
• Risk-benefit balance.
• Informed consent process.
• Vulnerable participants.
• Privacy and confidentiality.
• Data safety monitoring.
• Participant recruitment procedures.
• Qualification of investigators.
• Conflict of interest.
• Clinical trial insurance and indemnity.
• Essential clinical trial documents.
• Clinical trial registration.
• Dissemination of trial results.
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26. PrEP Trial
• PrEP trial in community X: examining the safety and efficacy of
tenofovir as PrEP
• Conducted in collaboration with X health administration and the
Ministry of Health
• Is enrolling 2,400 HIV-negative intravenous drug users (IDUs) – male
and female – at 17 drug treatment clinics in community X
• Participants are recruited at the drug treatment clinics, at community
outreach sites, and through a peer referral program.
• No clean needles or needle exchange being provided to participants
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27. Discussion
1. Which ethical principles are potentially being violated in the PrEP
trial?
2. Should the researchers be expected to provide needle exchange
when such programs are not available in Wakiso?
3. How could the trial have been designed to be more ethical?
4. What impact do you think these ethical concerns have
on the validity of the trial results?
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