Designing Ethical Research

Nur Azid Mahardinata*

* PhD Student on Bioethics
University of Amsterdam The Netherlands
* Secretary of the Center for Bioethics and Medical Humanities,
School of Medicine UGM
* Member of the IRB - School of Medicine - UGM

Learning Objectives:

Understand about research and the argumentation of what makes

research ethical
Understand the importance of International and National Ethical
Guidelines
Able to explain and relate the 8 ethical requirements in health
related research with their current research project

What is Research?
Research by definition is:
an activity designed to test an hypothesis, permit conclusions to be
drawn, and thereby to develop or contribute to generalizable
knowledge (expressed for example in theories, principles, and
statements of relationships)
Generalizable knowledge has two components:
1. The finding is valid
2. Disseminated
Should be differentiated with:
Innovative clinical care
Case series analysis
Quality improvement procedure
Public health practice
News reporting and public opinion polls

Health Related Research

The goal of health related research is to improve human wellbeing
Human involvement is inevitable in the thorough process of health
related research. Unfortunately, the person who benefit from the
research generally are not those who suffer its risks
How can the rights of individual persons be reconciled with the
demands of the scientific enterprise?

Why do we need ethics in health

related research?
I. Historical justification
II. Ethical justification

I. Historical Justification
1)
1)
2)
3)
4)
5)

Nazi War Crimes (1939 1945)

The Tuskegee Syphilis Study
The Jewish Chronic Disease Hospital Study
Willow brook Hepatitis
Johns Hopkins study
Etc.

Nazi War Crimes

Nuremberg Test
The use of concentration camp
prisoners for several clinical
trials, i.e.:
High-altitude (low-pressure)
experiments
Freezing experiments
Malaria experiments
Incendiary bomb experiments
Sulfanilamide experiments

Nazi War Crimes

The horrors of the proceeding and

many other "experiments," were
exposed during and after World War
II.
Those who conducted these
experiments were tried separately
from other Nazi war criminals because
of their professional status as
physicians and the atrocious nature of
their crimes.
1947: Doctors trial at Nuremberg
23 physicians & admin
16 found guilty, 7 sentenced to
death

1947: the Nuremberg Code

1932-1972: Tuskegee Syphilis Study

Effects of Untreated Syphilis
in the Negro Male
Funded by US Public Health
Service
399 black men with syphilis +
200 black men as control
Treatment for bad blood
local term to mean a variety of
illnesses
Lumbar puncture and pink
tablets

1997: Apology to 8 survivors

1963: Jewish Chronic Disease

Hospital
22 elderly patients 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

1963-1966: Willow brook Hepatitis

Studies
Parents promised admission
to school in exchange for
"vaccinations
School was for children with
mental disabilities

Healthy children intentionally

given hepatitis virus
Monitored to see effects of
gamma globulin

Johns Hopkins Study

12

II. Ethical Justificationn

Clinical research develops generalizable knowledge that improves
health or increases understanding
People who participate in clinical research are a means to
securing that generalizable knowledge
As means, these people can be exploited, that is be used as a
means for the benefits of others
Ethical requirements for clinical research are meant to minimize
the possibility of exploitation

Medical research with human is justifiable because it seeks

knowledge that not only is of theoretical interest but also will
benefit many people and society as a whole. The question is
whether such a laudable collective goal can be pursued with full
protection of the rights and dignity of individuals.

So.What Makes Research Ethical?

Informed consent
IRB reviews
Informed consent and IRB reviews
Not violate religious dogmas: Quran, Holy Bible, The Ten
Commandments, etc.
Compliance with International Ethical Guidelines, such as
Nuremberg, Helsinki, and Belmont
All of the above??

Key Ethical Questions in Research

With Human Participants
Are the risks to research participants excessive in light of the
potential benefits?
Have the participants given informed and voluntary consent to
participate in the research?
Are the burdens of the research distributed fairly, and will people
have equitable access to the benefits of the research?

What Ethical Principles Should Guide

Human Participants Research?
1. Respect for persons
To give weight to autonomous person considered opinions and
choices. There are two main issues:
1. Informed consent
2. Persons with impaired decision making capacity

2. Beneficence
Protects the participants well-being (benefit-risk analysis)
3. Justice
The benefits and burdens of research be fairly distributed

Respect for Persons Informed Consent

Information researchers must provide for participants:
The fact that the study involves research, and the purpose of the
research
Research procedures, risks and discomforts, benefits, and
alternatives. Experimental procedures must be identified as such
How confidentiality will be maintained
The fact that participation is voluntary and maybe discontinued at any
time
Whom to contact with questions about the study or the rights of
participants
If the research involves more than minimal risk, what treatment and
compensation are available if injury occurs

Respect for Persons Informed Consent

Some problems with informed consent:
Participants often do not understand the purpose of the
research
Participants commonly misunderstand essential features of the
research design
IRSs emphasize consent forms rather than consent
discussions

Respect for Persons Informed Consent

Effort to improving participants comprehension:
Spend more time talking with participants
Questions and feedback
Use multicomponent interventions
Simplify consent forms
Design the consent process from the participants point of view
Use simple language that laypeople can understand
Disclose serious but rare risks of the research procedures
Explain how the research procedures differ from standard medical
care
Do not overstate benefits to participants
Invite questions
Use consent form templates provided by the local IRB

Respect for Persons Informed Consent

How do we assessed the adequacy of informed consent:
Direct question
Questionnaire
Participants in RCT should understand the following crucial items:
Research is different from clinical care
The effectiveness of the research intervention is unknown
The research intervention has risks
The intervention are determined by chance and not by what a
physician believes is best for the individual participant

Respect for Persons Informed Consent

Vulnerability of research participants can be caused by:
Power differences
Cognitive or communicative impairments
Social and economic disadvantages
Alternatives to enhancing voluntariness of research participants:
Reduce the influence of more powerful persons
Frame information about payment to minimize undue influence
Check whether decisions are voluntary
Monitor refusal rates

Respect for Persons Impaired Decision

Making Capacity
Component of decision making capacity:
Understand pertinent information
Appreciate the relevance to his situation
Use reasoning to make a decision
Make and communicate a choice
When researchers enrolled persons who are lacking on their
decision making capacity, two questions should be addressed:
Who should make decisions for such persons?
What standards should be used in making decision?

Respect for Persons Impaired Decision

Making Capacity
The typical order of preference surrogate decision maker:
1. A guardian or conservator appointed by the courts
2. A proxy appointed by the person when still competent
3. The persons spouse or domestic partner
4. Adult children
5. Other close relatives

Beneficence
Maximize possible benefits and minimize possible harms
A. Favorable Benefit and Risk Ratio
B. Sound Research design
C. Competent Investigators

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
Types of benefit:
Direct benefit
Collateral benefits
Hope and other psychosocial rewards
Payments

Justice
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

Individual justice
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

Social justice
Equity requires ...
Subjects should be drawn from the qualifying population in the
general geographic area of the trial without regarding the race,
ethnicity, economic status, or gender unless there is sound
scientific reason to do the otherwise

Hints for Justice

Justice
1. to each person an equal share,
2. to each person according to individual need,
3. to each person according to individual effort,
4. to each person according to societal contribution, and
5. to each person according to merit

International Ethical Guidelines

1947
1948
1964
1979
1982
1991

Nuremberg Code
Declaration of Human Rights
Declaration of Helsinki
Belmont Report
CIOMS
Common Rule

Nuremberg Code (1947)

1.
2.
3.

Voluntary consent of the human subjects is absolutely essential

The experiment should yield fruitful results
Experiment based on results of animal experimentation or natural
history to justify the experiment
4. Experiment should avoid all unnecessary physical/mental
suffering/injury
5. No experiment where reason to believe that death/injury will occur
6. The degree of risk should never exceed the importance of the problem
to be solved
7. Proper preparations/facilities to protect the subject
8. Experiment conducted only by science/qualified
9. Subject should be at liberty to end experiment
10. The scientist must terminate an experiment where there is probable
cause to believe that injury, disability, or death will result

United Nations General Assembly

(1948)

The Declaration of Human Rights

Declaration of Helsinki 1965

(World Medical Association)
1. Scientific merits pre clinical basis and scientific literature
2. Protocol referred to independent committee for consideration
3. Done by qualified persons
4. Predictable risks proportional to benefits
5. Respect for rights of subjects
6. Accuracy of publication
7. Full information to subjects
8. Address dependent relationship with doctor
9. Consent from legal guardian
10. Ethical consideration section in the protocol

Belmont Report (1979)

Differentiate research and practice
"practice" refers to interventions that are designed solely to
enhance the well-being of an individual patient or client and that
have a reasonable expectation of success
The three principles derived from Belmont Report are:
1. Respect for person
2. Beneficence
3. Justice

CIOMS
1982 Council of International Organizations of Medical
Sciences (CIOMS )
The International Ethical Guidelines for Biomedical Research
Involving Human Subjects I (1982) II (1993) III (2002)
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

Good Clinical Practice

1995 World Health Organization (WHO)
Guidelines for Good Clinical Practice for Trials on Pharmaceutical
Products International Conference on Harmonization of Technical
Requirement for Registration of Pharmaceutical for Human Use
menjadi
Good Clinical Practice (ICH-GCP)

WHO Guidelines for Ethics Committee

2000 World Health Organization (WHO)
Operational Guideline for Ethics Committee that Review
Biomedical Research

National Guidelines
2001 Badan Pengawas Obat dan Makanan (BPOM)
Cara Uji Klinik yang Baik (CUKB) Telah ditetapkan untuk
dilaksanakan di Indonesia dengan Keputusan Kepala BPOM RI
Nomor 02002/SK/KBPOM
1995 PP RI No 39 tahun 1995 tentang Penelitian dan
Pengembangan Kesehatan
Pasal 8
Penelitian dan pengembangan kesehatan terhadap manusia hanya dapat
dilakukan atas dasar persetujuan tertulis dari manusia yang bersangkutan
Pasal 20
Barang siapa dengan sengaja menyelenggarakan penelitian dan
pengembangan kesehatan tanpa persetujuan tertulis sebagaimana
dimaksud dalam Pasal 8, dipidana dengan paling banyak Rp. 10.000.000,(sepuluh juta rupiah)

 Keputusan Menteri Kesehatan R.I. Nomor

1333/Menkes/SK/X/2002 tentang Persetujuan Penelitian
Kesehatan terhadap Manusia
Disamping denda tersebut dapat dikenakan sanksi administratif
Komisi Nasional Etik Penelitian Kesehatan (KNEPK)
Dibentuk dengan Kepmenkes No. 1334/Menkes/SK/X/2002
Pedoman Nasional Etik Penelitian Kesehatan (2005)
Telah ditetapkan berlakunya dengan Kepmenkes RI No.1031/
Menkes/SK/ VII/2005

Ethical aspects in health related research

1.
2.
3.
4.
5.
6.
7.
8.

Community partnership
Social Value
Scientific Validity
Fair subject selection
Favorable risk-benefit ratio
Independent review
Informed consent
Respect for human subjects

1. Community Partnership
To be ethical clinical research must involve the community in
which it occurs.
This requires:
community participation in planning, conducting and
overseeing research, and integrating research results into the
health system.
avoidance of supplanting existing health care services and the
sharing rewards with the community.

2. Social Value
To be ethical clinical research must lead to improvements in
health or advancement in generalizable knowledge
Valueless research includes non-generalizable studies, me too
studies, and non-disseminated research

3. Scientific Validity
Research must be conducted in a methodologically rigorous
manner that is practically feasible
Invalid research includes underpowered studies, studies with
biased endpoints, instruments, or statistical tests, and studies that
cannot enroll sufficient subjects.

4. Fair Subject Selection

The scientific objectives of the studynot vulnerability or
privilegeshould guide inclusion criteria and targeted populations
Convenient groups should not be selected. Groups cannot be
excluded without scientific reasons. However, higher risk is a
reason to exclude certain groups

5. Favorable Risk-Benefit Ratio

Clinical research must be conducted in a manner consistent with
the standards of clinical practice
4 Steps Evaluation
1. Risks identified and minimized
2. Potential benefits enhancedbut consider only benefits from
research not benefits from added health services or
payment.
3. If potential benefits to the individual outweigh risks to the
individual then proceed
4. If risks outweigh benefits to the individual, then evaluate
risks against social benefit of knowledge gained.

6. Independent Review
Because investigators have multiple legitimate interests, they
have potential conflicts of interest. Independent review of the
research minimizes these conflicts.
Independent review also assures society it will not benefit from
abuse of subjects

7. Informed Consent
Informed consent ensures individuals decide whether they enroll
in research and whether research fits with their own values,
interests, and goals.
For those who cannot consentsuch as children and mentally
impairedmust be sure research fits with their interests
Informed consent consists in 3 elements
1. Disclosure of information to the subject
2. Understanding by the subject
3. Voluntariness of the decision

Informed consent..cont

There are 8 elements that should be included in each informed

consent form:
1) Purpose and duration of participation
2) Risks
3) Alternatives
4) Benefits
5) Confidentiality of records
6) Compensation for injuries
7) Person to contact for answers to questions
8) Voluntariness and right to withdraw

8. Respect for Human Subjects

The ethical requirements of research do not end with a signed
consent document. Also include:
1. Protecting confidentiality
2. Permitting withdrawal
3. Providing new information
4. Monitoring welfare
5. Informing them of what was learned from the research

General Notions of the above

8 requirements
All 8 requirements are necessary and essential to make clinical
research ethical
Independent review and informed consent are procedural
requirements to ensure certain values are achieved. Other
procedures may achieve these values. In some circumstances,
independent review and informed consent can be waived
No simple formula for resolving conflicts
Adjust design to meet the requirements. This is sometimes
termed balancing or weighing or specifying the principles
The important point is to be clear about what is being done and
give reasons why

THANK YOU

Refferences
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.