Principle Of Ethic in Research

1. Madarina Julia
Medical and Health Research Ethics Committee
(MHREC)
Faculty of Medicine UGM
Fakultas Kedokteran Universitas Gadjah Mada
Introduction to Ethics
in Clinical Research

2. • Ethics in health research is a fairly new
knowledge…
• IT BEGAN WITH…

3. SCANDAL and TRAGEDY
inthe 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.

4. “GREAT INVENTIONS” in history
eg…
•James Lind: Vitamin C
•Edward Jenner: cowpox vaccine
However… long … long ago…

5. James Lindandthecureofscurvy:
anexperimental 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…

6. Edward Jenner
andthe history ofsmallpox andvaccination
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…

7. SCANDAL and TRAGEDY
in the history of MEDICAL RESEARCH

8. 1939-1945: World War II
• 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

9. 1932-1972: 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…

10. 1950’s: Willowbrook Hepatitis
Studies
• 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…

11. 1963: 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…

12. San 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.

13. 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

14. 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

15. Johns Hopkins Study (2001)
15

16. 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

17. 17
Milestones in the Development of
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. 18
… Milestones in Research Ethics
Development
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

19. 19
Good 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. 20
Public
Perception

21. 21
THE BELMONT REPORT
NationalCommissionfortheProtectionofHumanSubjectsof
BiomedicalandBehavioralResearch

22. RespectforPersons
• 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.)

23. 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

24. Autonomy
“Everyindividual hastherighttoautonomy andself-
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

25. Informed
Consent
Independent
Ethical Review
“TheTwinPillarsofProtection ofRightsandwelfareof
humansubjects”

26. 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 Informed Consent
-- before and during the study --

27. Consent “Process” not a “one 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

28. 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!

29. Common 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

30. The truth, the whole truth and
nothing but the truth

31. Beneficence
an 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”

32. Beneficence ...
The ethical obligation to:
• To maximize benefits
• To minimize harms
– Benefit /risk ratio
favourable
– Sound Research design
–Competent Investigators

33. … 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

34. • 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
Justice

35. • 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 justice

36. 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 justice

37. 37
What Makes Clinical Research Ethical?
(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. 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?
(Emanuel, Wendler & Grady, 2000) …

39. 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?
(Emanuel, Wendler & Grady, 2000) …

40. 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?
(Emanuel, Wendler & Grady, 2000)

41. References
• 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. 42
“Rather fall with honor than succeed
with fraud”
Sophocles,
one of the most influential writers of Ancient Greece.

43. Assessment yang dilakukan oleh
reviewer anggota komisi etik

44. 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)

45. 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)?

46. 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

47. 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?

48. 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

49. 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?

50. Mohon sistemassessmentdiatas
dipelajari, untukmemudahkan
komunikasi dengan Komisi Etik
terima kasih…