Designing Ethical Research Lecture

8/10/2019 Designing Ethical Research Lecture

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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 makesresearch 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 well-

being

• 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) Nazi War Crimes (1939 – 1945)

1) The Tuskegee Syphilis Study

2) The Jewish Chronic Disease Hospital Study3) Willow brook Hepatitis

4) Johns Hopkins study

5) 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 separatelyfrom other Nazi war criminals because

of their professional status as

physicians and the atrocious nature of

their crimes.

• 1947: Doctor ‘s 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 withmental 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 ameans 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: Qur‘an, 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 peoplehave equitable access to the benefits of the research?



What Ethical Principles Should Guide

Human Participants Research?

1. Respect for persons

2. Beneficence

3. Justice

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

Protects the participants well-being (benefit-risk analysis)

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




• 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




• 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 medicalcare

– Do not overstate benefits to participants

– Invite questions

– Use consent form templates provided by the local IRB




• 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




• 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 person‘s 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 Nuremberg Code

• 1948 Declaration of Human Rights

• 1964 Declaration of Helsinki

• 1979 Belmont Report

• 1982 CIOMS

• 1991 Common Rule



Nuremberg Code (1947)

1. Voluntary consent of the human subjects is absolutely essential

2. The experiment should yield ―fruitful‖ results

3. Experiment based on results of animal experimentation or natural

history to justify the experiment

4. Experiment should avoid all unnecessary physical/mentalsuffering/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 subject8. 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 Coun ci l o f Internat ional Organizat ion s 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

menjadiGood 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 danPengembangan Kesehatan

Pasal 8

Penelitian dan pengembangan kesehatan terhadap manusia hanya dapat

dilakukan atas dasar persetu juan ter tu l is dar i manusia yang bersangku tan

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. Community partnership

2. Social Value

3. Scientific Validity

4. Fair subject selection

5. Favorable risk-benefit ratio

6. Independent review

7. Informed consent

8. 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 thehealth 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 study—not vulnerability or

privilege—should 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 enhanced—but consider only benefits fromresearch not benefits from added health services or

payment.

3. If potential benefits to the individual outweigh risks to the

individual then proceed4. 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 consent—such as children and mentally

impaired—must 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

G l N i f h b



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.

Designing Ethical Research Lecture

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