Ethics

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Ethics in Medical Research
3
Ethics in Medical Research

• History
• Informed Consent
• Medical Procedures in Researches
• Research on Excess Blood samples and Tissues
• Clinical Trial
• Research on Vulnerable Groups
• Confidentiality

4
History
From NIH Human Participant Protections
Education for Research Teams
5
History
From NIH Human Participant Protections
Education for Research Teams
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The Nuremberg Trials

• Their crimes included experiments involving
• High altitude/low pressure
• Freezing
• Malaria
• Sea water
• Mustard gas
• Twin tests
• Sterilization
• The Nazi regime exploited human beings by forcing
  them to participate in research without consent.
• The mortality rate of these war time research
  studies was typically 25 - 30.
• The Nuremberg Trials were heard from 12/46 to
  8/47

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History
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The Nuremberg code 1948

• Should include voluntary participation
• Subjects should give consent
• Benefits must outweigh risks

9
Declaration of Helsinki 1964

• Research with humans should be based on
  laboratory and animal experimentation
• Research protocols should be reviewed by an
  independent committee
• Informed consent is necessary
• Research should be conducted by
  medically/scientifically qualified individuals
• Risks should not exceed benefits

10

• In New Zealand, women were denied standard
  treatment for cervical cancer. They were never
  asked to give their properly informed voluntary
  consent to participate in the experiment. Many of
  these women died when timely treatment almost
  certainly could have saved their lives.

11

• Prisoners in the USA, in a series of studies,
  were subjected to malaria, typhoid, and cholera,
  and it has been asked why anyone would volunteer
  to accept such a risk.

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The Thalidomide Study

• Thalidomide was approved as a sedative in Europe
  in the late 1950s.
• The FDA never approved the drug, but samples were
  sent to US doctors.
• By 1961 thalidomide was shown to be very harmful
  to the fetus, interfering with the normal
  development of arms and legs.

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The Thalidomide Study

• These events lead to the passage of the Drug
  Amendments of 1962 to the Food, Drug and Cosmetic
  Act.
• This was the first US statues that required
  subjects be informed of a drugs experimental
  nature and to consent before starting the
  research study.

14
Henry K. Beechers Article(1966)

• Beecher was a very prominent member of the
  medical establishment and he was professor of
  anesthesiology at Harvard Medical School.
• Beechers 22 examples included withholding
  antibiotics from men with rheumatic fever,
  purposely infecting institutionalized children
  with hepatitis (Willowbrook), injecting live
  cancer cells into nursing home patients (Jewish
  Chronic Disease Hospital).
• The Beecher article was significant in that it
  showed that abuses and exploitations of humans in
  research continued despite codes of ethics.

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• The Henry K. Beecher Prize in Medical Ethics
  Since 1998, the Beecher Prize has been awarded by
  the Division of Medical Ethics to the HMS student
  who submits the most original and compelling
  essay on a topic in medical ethics. The 1,000
  prize was created in the name of one of the most
  important figures in the history of medical
  ethics as a way of fostering the development of
  students with strong interests in medical ethics.
• The Harvard Medical School Student Journal of
  Ethics Begun in 1996, the student-written and
  edited Journal annually publishes the work of HMS
  students on issues in contemporary bioethics.
  Recent issues have focused on such topics as The
  Present and Future State of Ethical Issues in
  Reproductive Medicine and Genetics in Medicine
  Today and Tomorrow. The Division of Medical
  Ethics provides oversight and financial support.

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Tuskegee Study of Syphilis(1932-1972)

• 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
• Told they were being treated for bad blood
• Medical research staff lied to patients

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Tuskegee Syphilis Study
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Tuskegee Study of Syphilis
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Research Ethics Guidelines

• The Nuremberg Code(1947)
• The Declaration Of Helsinki 7 declarations (1964
  2004)
• CIOMS/WHO International Ethical Guidelines For
  Biomedical Research Involving Human
  Subjects(1993-2004)
• ICH/GCP-International Conference on
  Harmonization- Good Clinical Practice(1996)

20
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21
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22
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  ?????????? ???? ????? ? ????? ???????? (1378)
• ????? ?????26???? ????? ???????? ???? (1379

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Bioethics Principles

• ???? ??? ????? ???? ???????? ?? ?????????????
  ??????
• ?????? ?? ??? ? ???????? autonomy
• ??????? beneficience
• ??? ???????? non-maleficience
• ????? justice

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Autonomy

• Individuals should be treated as autonomous
  agents (capable of self-determination)
• Persons with diminished autonomy deserve
  protection
• Application Informed consent and
  confidentiality

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Beneficence / non-maleficience

• Two general complementary rules
• Do not harm
• Maximize possible benefits and minimize possible
  harms
• Application Risk/Benefit assessment

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Justice

• Fairness in the distribution of the benefits and
  burdens of research (distributive justice)
• Application
• Fair procedures and outcomes in the selection of
  subjects
• Protection of vulnerable subjects

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Beneficence / non-maleficience

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Informed consent

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Informed Consent

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31
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32
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33
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34
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35
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36
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37
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CRITERIA FOR CONDUCTING STUDIES WITH EXCEPTION
FROM INFORMED CONSENT

• Subjects are in life-threatening situation
• Available treatments are unproven and/or
  unsatisfactory
• Participation in study holds prospect of direct
  benefit to patients
• Study could not feasibly be conducted without
  exception from informed consent requirement

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Confidentiality

• A researcher may be entrusted with private
  information so
• Field notes, tapes, questionnaires etc. must be
  stored in a safe place
• Data should only be used for the purpose agreed
  with the participant and not shared with others
  unless that has been agreed
• You should be ready to destroy material if the
  participant decides to withdraw participation or
  retract what they have told you.

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Anonymity

• The researcher has the responsibility of keeping
  the identity of participants private so that they
  will not be personally identifiable in any
  outputs UNLESS there is a specific reason why
  they should be identified or they specifically
  request their identity to be given.
• The researcher should explain when anonymity may
  not be maintained (when someone can be identified
  by the position they hold, for example).

42
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43
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44
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Ethics in clinical Trial
47
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Phase Participants Participants Research questions
Phase Number Characteristics Research questions
I 20-80 Usually young, healthy, male volunteers Tolerability Pharmacokinetics Pharmacodynamics
II 100-300 Patients rather than volunteers Effectiveness Dosage, Safety
III 1,000-3,000 Approximate real-life patient population Compare to placebo, current treatments Effects of compound on targets, side-effects
48
?????? ????????? ?????? (?????)
Phase Research questions
IIIb Marketing cost/value Compares with market leader Further data on safety and efficacy
IV New formulations Identify best patients Safety assessment
49
Good Clinical Practice (GCP)

• A standard for clinical studies which encompasses
  the design, conduct, monitoring, termination,
  audit, analyses, reporting and documentation of
  the studies and which ensures that the studies
  are scientifically and ethically sound and that
  the clinical properties of the treatment under
  investigation are properly documented.

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Protocol

• A document that describes the objective(s),
  design, methodology, statistical considerations,
  and organization of a trial. The protocol usually
  also gives the background and rationale for the
  study, but these could be provided in other
  protocol referenced documents.

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Protocol

• Backgrounds
• Objective
• Population and sampling
• Data collection
• Statistical analysis
• Legal and ethical considerations
• Quality
• Resources and requirements
• Early termination

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Protocol

• Enroll appropriate subjects
• Try to meet recruitment goals
• Follow randomization and blinding procedures
• Treatment administration per protocol
• Measurement of study outcomes
• Maintain audit trail (paper/electronic)
• Complete/process/file all study reports
• Appropriate post-study follow-up for participants
• Participate in dissemination of results

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54
??????? (?????)

• Declaration of Helsinki (prior to 2000)
• In any medical study, every patient--including
  those of the control group, if any--should be
  assured of the best proven diagnostic and
  therapeutic method. This does not exclude the
  use of inert placebo in studies where no proven
  diagnostic or therapeutic method exists (emphasis
  added).

55
??????? (?????)

• Declaration of 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, and
  therapeutic method exists (emphasis added).

56
??????? (?????)

• Declaration of Helsinki (October 2002 statement)
• ... 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
  prophylactic, diagnostic or therapeutic method,
  or - Where a prophylactic, diagnostic or
  therapeutic 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.

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??????? (?????)

• When Placebo Controls May be Used
• There is no standard treatment
• Standard treatment has been shown to be no better
  than placebo
• Evidence causes doubt about therapeutic advantage
  of standard therapy

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??????? (?????)

• When Placebo Controls May be Used
• In a population of patients who are refractory to
  standard treatment and for whom there is no
  standard second-line treatment
• Testing add-on treatment to standard therapy when
  all subjects in the trial receive all treatments
  that would normally be prescribed

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??????? (?????)

• When Placebo Controls May be Used (Controversial
  Conditions)
• Many argue that persons with conditions with a
  low risk of harm (understand as low probability
  or low magnitude of harm) may be entered into a
  placebo arm
• Many argue that placebo controls are ethical when
  resources are limited and standard treatment is
  not available

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• ???????? ???? ???????
• ??? ?????
• Fetal tissue neuroimplants for Parkinsons
• Arthroscopic knee surgery for arthritis
• Spine-fusion surgery for osteoporosis

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Vulnerable Populations
63
Cognitively Impaired
64
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65
Informed Consent Cognitively Impaired

• Persons with diagnosed cognitive impairment such
  as mental retardation, dementia, and coma, can
  participate in research.
• This type of research must specifically address
  how an individuals capacity to give informed
  consent will be determined.
• The signature of a legally authorized
  representative will be required
• Research with Cognitively Impaired subjects
  cannot be considered exempt by the IRB

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Informed Consent Cognitively Impaired

• For persons whose cognitive status is suspect,
  but there is no definitive diagnosis
• Use the Cognitive Impairment Algorithm in the
  Investigators Handbook to determine ability to
  give free informed consent
• Document the use of the algorithm

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Cognitively Impaired

• Document carefully the enrollment of persons
  whose cognitive status is not outwardly obvious
  e.g. stroke patients, psychiatric patients or
  persons with speech or language disorders
• If a person is enrolled in a study during a
  period of cognitive impairment and regains his
  ability to give consent he must be re-consented

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69
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70
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71
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72
Consent for Children

• Parental consent ( proxy)
• Child assent
• Complete consent/assent form for older children
  (age 13 to 17)
• Briefer statement for younger children (8-12)
• Very brief for young children ( 5-7)
• No assent for the very young (lt5)

73
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74
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75
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76
???? ????? (Conflict of interest)

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  ???? ????.
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• ????
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• ????? ???
• ?????? per case

77
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78
Protections for Financial Conflicts of Interest

• Disclosure
• To institution/IRB/COI committee
• To patients
• In journals
• Management
• Independent consent monitors
• Prohibitions
• Against types/amounts of financial interests

79
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80

• Acceptable Procedures in Medical Research

81
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82
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83
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84
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85
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  ????? 3 ??? ??? ???? ???

86

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87
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88
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• ??????? ????? ???? ??? ?????? ???? ????? ??
  ??????????? ????? ????
• ??????? ??? ?????? ?? ?? ???? ?????? ???? ??????
  ??? ??? (??????? ??? ????, ??? ????, ?????? ????
  ?????? ?? ???? ?? ?????? ?? ??????? ?...)

89
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• ?????? ?? ?????? ???? ????? ?????? ???? ? ??
  ???????? ????? ???? ???? ???? ?????

90

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  ???? ?? ????? ????? ??? ???? ???? ????

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92
Authorship (Central Principle)

• Authorship should include person(s) who can take
  public intellectual responsibility for the
  content.
• Responsibility
• Can defend the intellectual content, including
  data and conclusions.
• Must be willing to concede publicly any errors.
• In the case of fraud be willing to state
  publicly the nature and extent, and account for
  its occurrence.

93
Criteria for Authorship

• 1. Generate at least part of the intellectual
  content.
• A) Conception or design of the work
• B) Data analysis and interpretation
• 2. Drafting, reviewing or revising critically
  for important intellectual content.
• 3. Final approval of the version to be published.
• All three criteria must be met.

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Order of Authorship

• Alphabetical
• Significance to the Study (variable)
• First - Primary responsibility for collecting
  analyzing data, writing draft of manuscript.
• Last - Established investigator
• Middle - Order of importance to the study.

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Acknowledgements

• contributions that need acknowledging but do not
  justify authorship (advice, critical review of
  study proposal, data collection, participation in
  clinical trial)
• acknowledgements of technical help
• acknowledgements of financial and material
  support
• financial relationships that may constitute a
  conflict of interest.

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IRB (Institutional Review Board)Ethics Committee

• An IRB protects the rights, safety, and welfare
  of human research participants by
• Reviewing the full protocols for planned research
  studies to ensure that, in its judgment, the
  research meets the appropriate criteria.
• Confirming that the research plans do not expose
  participants to unreasonable risks.
• Conducting continuing review of approved research
  at intervals commensurate with the degree of risk
  of the trial, but not less than once a year, to
  ensure that human participant protections remain
  in force.
• Considering adverse events, interim findings, and
  any recent literature that may be relevant to the
  research.
• Assessing suspected or alleged protocol
  violations, complaints expressed by research
  participants, or violations of institutional
  policies.

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IRB (Institutional Review Board)Ethics Committee

• The IRB has the authority to
• Approve, disapprove, or terminate all research
  activities that fall within its local
  jurisdiction.
• Require modifications in protocols, including
  previously approved research.
• Require that information be given to participants
  when the IRB determines that this information
  would add to the protection of their rights and
  welfare.
• Require documentation of informed consent or
  allow waiver of documentation.

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Links for more Information

• http//www.wma.net
• http//www.cioms.ch
• http//www.ich.org

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