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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…

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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…

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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…

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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

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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…

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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.

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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

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Johns Hopkins Study (2001)Johns Hopkins Study (2001)Johns Hopkins Study (2001)Johns Hopkins Study (2001)

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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

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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

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… 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

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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

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Public Public

PerceptionPerception

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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.)

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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

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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 --------

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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!

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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

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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

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… 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

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• 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

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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

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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) …

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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) …

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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)

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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.

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“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.

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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)

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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

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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

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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…