12/03/2014
1
Madarina Julia
Medical and Health Research Ethics Committee
(MHREC)
Faculty of Medicine UGM
Fakultas Kedokteran Universitas Gadjah Mada
Introduction to Ethics Introduction to Ethics Introduction to Ethics Introduction to Ethics
in Clinical Researchin Clinical Researchin Clinical Researchin Clinical Research
• Ethics in health research is a fairly new
knowledge…
• IT BEGAN WITH…
12/03/2014
2
SCANDAL and TRAGEDY
in the history of MEDICAL RESEARCH
• NAZI doctors (WWII)
• Tuskegee Syphilis Study (1932-1972)
• Willowbrook hepatitis studies (1950s)
• Jewish Chronic Disease Hospital (1960s)
• San Antonio Contraception Study (1970s)
• The Thalidomide experience
• John Hopkins Study
• etc.
“GREAT INVENTIONS” in history
eg…
•James Lind: Vitamin C
•Edward Jenner: cowpox vaccine
However… long … long ago…
12/03/2014
3
James Lind and the cure of scurvy:
an experimental approach
• On the 20th of May, 1747, I took twelve patients
in the scurvy, on board the Salisbury at sea.
…Two others has each one orange and lemon
every other day…
Edward Jenner
and the history of smallpox and vaccination
On May 14, 1796, using matter from cowpox lesions, he
inoculated an 8-year-old boy, James Phipps. Subsequently, the
boy developed mild fever and discomfort in the axillae. Nine
days after the procedure he felt cold and had lost his
appetite, but on the next day he was much better…
12/03/2014
4
SCANDAL and TRAGEDY
in the history of MEDICAL RESEARCH
19391939--1945: W1945: World orld WWarar IIII
• Experimentation to
Holocaust Victims
• No consent
• Subjects not killed by
experiments would be
killed and dissected
• 1947: Doctor’s trial at
Nuremberg
� 1947: the Nuremberg Code
12/03/2014
5
1932193219321932----1972: Tuskegee Syphilis Study1972: Tuskegee Syphilis Study1972: Tuskegee Syphilis Study1972: Tuskegee Syphilis Study
• US Public Health Service funded
study to evaluate the natural
history of untreated syphilis
• 399 uneducated black men with
syphilis
• Thought they were receiving
beneficial medical care:
– lumbar puncture and pink
tablets
No medicine is offered when it
becomes available…
1950195019501950’’’’s: Willowbrook Hepatitis s: Willowbrook Hepatitis s: Willowbrook Hepatitis s: Willowbrook Hepatitis
StudiesStudiesStudiesStudies
• Parents promised admission to school in exchange for
"vaccinations”
– School was for children with mental disabilities
• Healthy children intentionally given hepatitis C virus
– Monitored to see effects of gamma globulin
They will get it anyway…
12/03/2014
6
1963: Jewish Chronic Disease Hospital1963: Jewish Chronic Disease Hospital1963: Jewish Chronic Disease Hospital1963: Jewish Chronic Disease Hospital
• 22 elderly chronically ill patients were injected with live
cancer cells
• Purpose was to "discover the secret of how healthy
bodies fight the invasion of malignant cells“
• Cover-up by hospital administration
– New York State medical licensing board placed
researcher on probation for one year
They will die anyway…
San Antonio Contraception StudySan Antonio Contraception Study
• 1970’s Evaluate the effectiveness
of female birth control pills.
• Indigent patients with no other
place to go for advice or
medication but the clinic.
• Randomized: active
contraceptive and placebo.
• Women not informed.
• Results: High number of
unplanned pregnancies in
placebo group.
12/03/2014
7
The Thalidomide Experience
• Thalidomide was approved in Europe as a sedative drug in
the late 1950s. Safety in pregnant women has not been
established.
• It caused 10,000 - 20,000 birth defects
1999: Death in Gene Therapy Trial
• 18-year-old James Gelsinger died during a gene-therapy study to treat enzyme disorders (Boston)
• Issues:
– Conflict of interest
• Researcher James Wilson held a 30-percent equity stake in the company that owned the rights to license the drug that Wilson was testing.
– Data safety monitoring
– Informed consent
12/03/2014
8
Johns Hopkins Study (2001)Johns Hopkins Study (2001)Johns Hopkins Study (2001)Johns Hopkins Study (2001)
15
ALL research involving human subjects:
Systematic investigation on living
individual(s) – contribute to
generalizable knowledge
- data obtained through
intervention or interaction
with the individual
- identifiable private
information
12/03/2014
9
17
Milestones in the Development of Milestones in the Development of Milestones in the Development of Milestones in the Development of Milestones in the Development of Milestones in the Development of Milestones in the Development of Milestones in the Development of
Research Ethics Research Ethics Research Ethics Research Ethics Research Ethics Research Ethics Research Ethics Research Ethics ……………………
1946 Nuremberg Trial of doctors responsible for the
Nazi experiments
1947 Nuremberg Code outlining ethical principles
required for research
1948 United Nations adoption of Universal
Declaration of Human Rights
1964 Declaration of Helsinki international agreement
on recommendations
18
… Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics … Milestones in Research Ethics
DevelopmentDevelopmentDevelopmentDevelopmentDevelopmentDevelopmentDevelopmentDevelopment
1979 Belmont Report promoting three principles for
research
1982 Council for the International Organization of
Medical Sciences (CIOMS) publication of the
International Ethics Guidelines for Biomedical
Research Involving Human Subjects (2008/2009)
1993 WHO International Ethical Guidelines for
Biomedical Research Involving Human Subjects.
1996 ICH/GCP-International Conference on
Harmonization- Good Clinical Practice
12/03/2014
10
19
Good Clinical Practice (GCP) 1996Good Clinical Practice (GCP) 1996
• An international ethical and scientific quality
standard for designing, conducting, recording and
reporting trials that involve the participation of
human subjects.
• Ensures protection of participants and credibility
of data
20
Public Public
PerceptionPerception
12/03/2014
11
21
THE BELMONT REPORTTHE BELMONT REPORTNational Commission for the Protection of Human Subjects of National Commission for the Protection of Human Subjects of
Biomedical and Behavioral ResearchBiomedical and Behavioral Research
Respect for Persons
• Treat individuals as autonomous agents
(Autonomy)
• Protect persons with diminished autonomy
(vulnerable subjects: persons who are likely to
have compromised autonomy related to decisions
about research participation: patients, children,
debilitated people, prisoners, etc.)
12/03/2014
12
Precautions
• Children
• Mentally Challenged
• Institutionalized Individuals
• Subordinates/ Staff/ employee
• Students
• Prisoners
• Pregnant/ Lactating women
• Disease/condition
• Poor
• Military
• Tribals
• Uneducated
• Ethnic minorities/refugees
• Homeless/frail and old
• Not to include unless the study demands special groups
• Informed consent from the legal guardians
• Informed consent from the individuals wherever possible
• No inducement of guardians
• Assent from minors
• Respect their right to refuse participation
Autonomy“Every individual has the right to autonomy and
self-determination”
• Voluntary consent to participate in research
• Informed consent to participate in research
• Protection of privacy and confidentiality
• The right to withdraw from research participation without
penalty
12/03/2014
13
Informed
Consent
Independent
Ethical Review
““The Twin Pillars of Protection of Rights and welfare of The Twin Pillars of Protection of Rights and welfare of
human subjectshuman subjects””
Good Clinical Practice Training
• Disclosure - Provision of adequate information
• Comprehension – understand and seek
clarification
• Capacity/Competence
• Assent, Proxy consent/ substitute judgement
• Decision making
• Voluntariness, free from coercion
Core Elements of Valid Core Elements of Valid Core Elements of Valid Core Elements of Valid Informed Consent Informed Consent Informed Consent Informed Consent
-------- beforebeforebeforebefore and and and and duringduringduringduring the the the the studystudystudystudy --------
12/03/2014
14
Consent Consent Consent Consent Consent Consent Consent Consent ““ProcessProcessProcessProcessProcessProcessProcessProcess”” not a not a not a not a not a not a not a not a ““one time eventone time eventone time eventone time eventone time eventone time eventone time eventone time event””
New Risk information Loss or gain of
Initial consent subject capacity Study extension End of study
Recruitment
process
Extended
Follow-up
Consent form
Change in research
(procedures, visits)
Change in drug status
ONGOING DISCUSSION/ INTERACTION DURING STUDY VISITS
Contents - informed consent
• Trial involves research
• Purpose of trial
• Trial treatments and the
probability for random assignment
• Trial procedures to be followed
• Participant’s responsibilities
• Aspects of trial that are
experimental
• Foreseeable risks, pain or
discomfort
• Potential benefits
• Alternatives
• Compensation arrangements
ICH GCP 4.8.10
• Payments / reimbursements
• Free to refuse / withdraw
• Monitors and auditors will be
granted access to medical
records
• Confidentiality arrangements
• Results
• Organising and funding the
research
• 24 hour contact details
• Expected duration
• Approx numbers of participants
• Version numbers and dates!
12/03/2014
15
Common BarriersCommon BarriersCommon BarriersCommon Barriers
• Randomisation
• Technical language
Ok, what part of antiaromatase neoadjuvant therapy for adenocarcinoma of the sigmoid colon demonstrating the EGFR receptor mutation don’t you understand?
Awareness of randomisation can confound results
The truth, the whole truth and The truth, the whole truth and The truth, the whole truth and The truth, the whole truth and
nothing but the truthnothing but the truthnothing but the truthnothing but the truth
12/03/2014
16
Beneficencean obligation to secure the well being
of the research subjects
• DO NO HARM
• Maximize possible benefit and minimize
potential risk
“Do unto others as you would have them do unto you”
Beneficence ...Beneficence ...
The ethical obligation to:
• To maximize benefits
• To minimize harms
– Benefit /risk ratio
favourable
– Sound Research design
– Competent Investigators
12/03/2014
17
… Beneficence… Beneficence
� Well-being of the subject takes precedence over
interests of science and society
� The physician in medical research [must] protect
life, health, privacy, and dignity of the subject
• To treat each person according to what is morally
right and proper
• Equitable distribution of both burdens and
benefits of the research
– Fair subject selection
– Research be responsive to the health needs of
population studied
– Product developed made reasonably available
JusticeJustice
12/03/2014
18
• Selection of subjects
requires that reserachers
exhibit fairness
• Not offer potential benefit
only to some patients who
are in favor or select only
‘undesirable’ persons for
risky research
Individual justiceIndividual justice
Equity requires ...
• Subjects should be drawn from the qualifying
population in the general geographic area of
the trial without regard race, ethnicity,
economic status, or gender unless there is
sound scientific reason to do otherwise
Social justiceSocial justice
12/03/2014
19
37
What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical? What Makes Clinical Research Ethical?
(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …
1. Adds value
enhancement of health or knowledge must be
derived from the research; positive contribution to
knowledge about health and well being
2. Scientific merit and validity
Use of accepted scientific principles and methods,
including statistical techniques, to produce reliable
and valid data
38
3. Independent review
Review of the design of the research trial, its proposed subject population, and risk-benefit ratio by individuals unaffiliated with the research
4. Favorable risk-benefit ratio
Minimization of risks; enhancement of potential
benefits; risk to the subject are proportionate to
the benefits to the subject and society
What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?
(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …
12/03/2014
20
39
5. Informed consent
Provision of information to subjects so that the individual understands this information and can make a voluntary decision whether to enroll and continue to participate
6. Fair subject selection
Selection of subjects so that stigmatized and
vulnerable individuals are not targeted for risky
research and the rich and socially powerful not
favored for potentially beneficial research
What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?What Makes Clinical Research Ethical?
(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …(Emanuel, Wendler & Grady, 2000) …
40
7. Respect for potential and enrolled subjects
Respect for subjects by …
a. Permitting withdrawal from the research
b. Protecting privacy through confidentiality
c. Informing subjects of newly discovered risks or benefits
d. Informing subjects of results of clinical research
e. Maintaining welfare of subjects
… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?… What Makes Clinical Research Ethical?
(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)(Emanuel, Wendler & Grady, 2000)
12/03/2014
21
ReferencesReferences
• World Medical Association, "Declaration of Helsinki"
(1964, rev. 2000)
• Handbook for Good Clinical Research Practice (WHO)
• The National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research, “The
Belmont Report”(1979)
• Ezekiel Emanuel, David Wendler, and Christine Grady.
2000. What Makes Clinical Research Ethical? JAMA
283(20): 2701-11.
42
“Rather fall with honor than succeed Rather fall with honor than succeed Rather fall with honor than succeed Rather fall with honor than succeed
with fraudwith fraudwith fraudwith fraud”
Sophocles,
one of the most influential writers of Ancient Greece.
12/03/2014
22
Assessment yang dilakukan oleh
reviewer anggota komisi etik
Item yang ditelaah oleh reviewer...
1. Kejelasan tujuan penelitian
2. Apakah melibatkan subjek manusia? Atau hewan coba (termasuk informasi/ bagian dari manusia: catatan medik, registry, jenazah, jaringan tersimpan, dll.)
3. Kejelasan metodologi (prospektif atau retrospektif, data sekunder, cara pengambilan sampel, cara intervensi, cara alokasi random, dll.)
4. Kecukupan informasi dan data pada latar belakang (untuk menjawab pertanyaan mengapa penelitian perlu dilakukan)
12/03/2014
23
Item yang ditelaah oleh reviewer...
5. Penilaian risiko dan manfaat (risk and benefit ratio): DO NO HARM
6. Kejelasan kriteria inklusi
7. Kejelasan kriteria eksklusi
8. Kriteria pemberhentian kerterlibatan subjek (withdrawal criteria)
9. Keterlibatan vulnerable subject
10.Apakah keterlibatan subjek sukarela? Apakah ada tekanan (secara halus atau kasar)? Inducement (iming-iming)?
Item yang ditelaah oleh reviewer...
11.Apakah besar sampel mencukupi? Atau terlalu
banyak?
12.Apakah ada kelompok kontrol atau placebo?
13.Kualifikasi dan pengalaman peneliti (dibuktikan
dengan CV yang berisi riwayat pendidikan dan
track record penelitian dan publikasi)
14.Pernyataan conflict of interest (bila perlu)
15.Fasilitas dan infrastruktur tempat penelitian
12/03/2014
24
Item yang ditelaah oleh reviewer...
16.Apakah perlu ijin/konsultasi dengan
masyarakat? Bila penelitian berisiko berdampak
pada masyarakat/ institusi sekitar.
17.Keterlibatan peneliti lokal
18.Apakah ada kontribusi pengembangan
kemampuan penelitian dan terapi di Indonesia?
19.Apakah ada keuntungan untuk masyarakat?
20.Apakah ada penelitian serupa dan bagaimana
hasilnya?
Item yang ditelaah oleh reviewer...
21.Apakah spesimen dikirim ke luar negeri?
22.Apakah prosedur untuk mendapat informed
consent memadai/ sudah benar?
23.Bagaimana isi informed consent? Apakah jelas
dan mudah dipahami?
24.Kejelasan bahasa dari informed consent:
menggunakan bahasa yang akan mudah
dipahami oleh subyek penelitian (awam)
25.Apakah ada contact person? Peneliti, dokter
penanggung jawab dan komisi etik
12/03/2014
25
Item yang ditelaah oleh reviewer...
26.Bagaimana kerahasiaan identitas dan
informasi dijamin peneliti?
27.Apakah ada bujukan atau iming-iming
(inducement)?
28.Apakah dukungan medis/psikososial
mencukupi?
29.Apakah disediakan sarana untuk menangani
kejadian yang tidak diinginkan akibat
intervensi?
30.Apakah disediakan kompensasi yang layak?
Mohon sistem assessment di atas
dipelajari, untuk memudahkan
komunikasi dengan Komisi Etik
terima kasih…
Top Related