Ethical Issues in Clinical Research

(FMC, Dec. 22, 2016)

Ghaiath Hussein, MBBS, MHSc. (Bioethics), Doctoral Researcher (UK)

Assistant Professor of Bioethics

Outline ■Research in context: the Knowledge

Management Cycle (KMC)■historical background on research

ethics■What makes research ethical?■Definition and examples of scientific

misconduct■How to make your research ethical

and avoid scientific misconduct?

Where are we in R&D?

Source: http://www.worldmapper.org/display.php?selected=165

Where are we in R&D?Expenditure on R&D as % of GDP (2013):[1]

– Arab world: 0.5% – China (2%), – EU (2.3%), – USA (2.8%), – Israel (4%)

Number of researchers (per 1,000,000 population) [2]

■ Morocco : 864 ■ Argentina: 1,236■ Malaysia: 1,643■ Slovenia: 4,255■ Israel: 6,494

Published scientific papers (1996 -2013):[3]

Egypt (42nd): 104,784 Brazil: 529,841Israel: 247,561 India: 868,719Turkey: 348,836 USA: 7,846,972

What is Research? “Research” is defined as an undertaking intended

to extend knowledge through a disciplined inquiry or systematic investigation.

Systematic methodological scientific approach for basic facts around a certain problem in order to find solutions based on these facts.

Research on Humans:The systematic undertaking of activities that involve

the collection of human personal data, measurements, and/or biological samples for purposes that are not related to clinical management of a health condition

Research in Context...the KMC

Generation

Dissemination

SynthesisUtilization

Assessment

Policy makers

Research

Statistics

Clinicians

Knowledge Management Cycle

Publ

icatio

ns

Conf

eren

ces

Semin

ars

Cochrane

EMBaseKnowledge

Brokers

M & E

Better Research is Better Health

“Good” research: Good Science & Good Ethics

“Good” Evidence: near-top to hierarchy of Evidence

Evidence-Based Healthcare: Better practice that is based on best evidence

Better health status

Here Comes

RECs!

What Makes Good Research?

Good Science

Good Ethics

•Problem selection•SMART objectives•Proper methodology•Proper analysis

•Fair subject selection•Favorable Risk-Benefit Ratio•Independent Review•Informed Consent

Criteria of “Good” Science Research

■Systematic: The research developed, implemented and reported in a systematic manner.

■Methodological: Adopt & use skillfully the research methods, materials, approaches in order to ensure reliability of the results & findings.

■Scientific: The research should be scientifically sound through utilizing scientific approaches, tools and techniques.

Criteria for Good Ethics: What Makes Research Ethical?

1. Social or Scientific Value2. Scientific Validity3. Fair Subject Selection4. Favorable Risk-Benefit Ratio5. Independent Review6. Informed Consent7. Respect for the potential and enrolled

subjects

What’s Research Ethics? It is the field of ethics that systematically analyze

the ethical (and legal?) questions raised by research involving human subjects.

Its main focus is to ensure that the study participants are protected and, ultimately,

that clinical research is conducted in a way that serves the needs of such participants and of society as a whole.

It works when and only when it is applied before theresearch is conducted

HISTORICAL BACKGROUND

BORN IN SCANDAL… THE EVOLUTION OF RESEARCH ETHICS

History of Research EthicsPre-World War II: Research standards left up to the

discretion of the individual researcher

18th and 19th Centuries ■James Lind “scurvy study in sailors - Salisbury■Edward Jenner cowpox vaccine test■1897 Giuseppe Sanarelli yellow fever test

1900 Walter Reed established several [first ever] “safeguards”

■ Self-experimentation■ Only adults would be enrolled in research■ Written informed consent■ Reimbursement (inducement)

World War II: Nazi Doctors’ ExperimentationExperiments conducted on inmates of Nazi concentration camps1945-1949:Trials in Nuremberg, Germany– physicians convicted of crimes against humanity

The Nuremberg Code (1947) The first provision of the code requires that “the

voluntary informed consent of the human subject is absolutely essential.” The code provides other details implied by such a requirement:

■Voluntary consent absolutely essential (restricting research with infants, children, developmentally challenged, etc.)

■Freedom from coercion■Comprehension of the risks and benefits

involved■Experiment to be conducted by highest qualified

persons■ Risk/Benefit Analysis essential to ethics review■ Scientific Soundness is important to ethics

reviewThe code on the web:

http://ohsr.od.nih.gov/nuremberg.php3

The Declaration of Helsinki (DOH)

The World Medical Association created the Declaration of Helsinki in 1964 and amended regularly since 1975

The main issues emphasized were: “The well-being of the subject should take precedence

over the interests of science and society”Respect for Persons – people are not a means to an

end; researchers have duty to protect life, health, privacy and dignity of research participants

Consent should be in writingStandard of care must be best available, even for

control group Greater access to benefit Use caution if participant is in dependent relationship

with researcher Limited use of placebo

More than 400 African- American men with latent syphilis were followed for

the natural course of the disease rather than receiving treatment.

Continued after penicillin available 40 wives infected, 19

children born with congenital

syphilis

TUSKEGEE SYPHILIS STUDY,ALABAMA ( 1932 – 1972 )

The Belmont Report (1979) 1972: the public became aware of the

Tuskegee study 1974: the National Commission for the

Protection of Human Subjects of Biomedical and Behavioral Research was established.

1978: the commission submitted its report titled, The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research.

Those principles respect for persons, beneficence and justice are accepted as the 3 fundamental principles for the ethical conduct of research involving human participants.

Year Benchmark2013 WMA updates DOH (Brazil)2010 TCPS updated2008 WMA updates DOH (Seoul)2004 WMA updates DOH (Tokyo)2002 WMA updates DOH (Washington) CIOMS Guidelines updated2000 WMA updates DOH (Edinburgh)1998 Tri-Council Policy Statement (TCPS)published in Canada1996 WMA updates DOH (South Africa)1993 CIOMS guidelines for biomedical research involving human subjects1991 US CFR title 45, Part 46 issued CIOMS Guidelines for Epidemiological studies1989 WMA updates DOH (Hong Kong)1983 WMA updates DOH (Venice)1981 US Common rule updated1979 The Belmont Report1975 WMA updates DOH (Tokyo)1966 Dr. Beecher’s Article “Ethics and Clinical Research”1964 World Medical Association (WMA) published the Declaration of Helsinki (DOH)1947 The Nuremberg Code1900 Walter Reed’s ‘consent’ for yellow fever experimentsPre-1900 Edward Jenner smallpox vaccines

Is it over?... Torvan trial in Kano, NigeriaKano Trovan clinical trials in 1996, on pediatric age group, during the worst ever meningococcal meningitis.

Lack of proper Governmental authorization and informed consent during the studies publicized in 2000, by Washington Post.

Court trial and release of investigation panel reports

stalled in Nigeria.Suit for 5.8 billion USD moved to the USA

and report leaked there too.Settlement out of court being discussed.

EXAMPLES OF ETHICAL ISSUES

IN RESEARCH

Some ethical issues in research

Before

•Benefit/harm analysis•Vulnerability (Risk-Vulnerability Matrix)

•Fair selection of participation•Conflict of Interests (COI)

During

•Informed Consent

•Privacy and confidentiality•Risk to researchers•Risk to participants

After

• Sharing results

• Sharing benefits

• Integrity & publication ethics

Core ethical principles/issues in research(Source: WHO Training manual: Ethics in research, surveillance and patient care in epidemics, emergencies and disasters, WHO (2014))Ethical principle/issue

Definition1 Examples of guidelines

Respect for people’s autonomy

The duty to respect people’s ability to make decisions on issues related to their health and their body, if they are competent to make such decisions; and the duty to protect individuals with impaired or diminished autonomy

CIOMS, General principlesTCPS, article 1.1Belmont Report 

Core ethical principles/issues in research(Source: WHO Training manual: Ethics in research, surveillance and patient care in epidemics, emergencies and disasters, WHO (2014))Ethical principle/issue

Definition1 Examples of guidelines

Beneficence The moral duty to pursue actions that promote the well-being of others and the ethical obligation to maximize benefit and to minimize harm

CIOMS, Belmont Report,  

Non-maleficence

The moral duty not to cause harm to others through interventions

CIOMS, DOH (articles 16–18)

Justice Primarily distributive justice, which requires equitable distribution of benefits and burdens, i.e. distribution such that no segment of the population is unduly burdened by the harms of research or denied the benefits of the knowledge generated from it

CIOMS (guidelines 10 and 12)DOH (articles 16–18)TCPS (article 1.1 and Chapter 4)  

Core ethical principles/issues in research(Source: WHO Training manual: Ethics in research, surveillance and patient care in epidemics, emergencies and disasters, WHO (2014))Ethical principle/issue

Definition1 Examples of guidelines

Vulnerability A status in which some people may struggle to protect their interests or be at greater risk of being exploited. This situation is usually linked to specific physical, financial, educational or social circumstances. Groups considered as vulnerable vary by guideline, but children, mentally retarded and handicapped people, prisoners, refugees, terminally ill patients and women are often cited as the prime vulnerable groups.

CIOMS ( guidelines 13–16), DOH (articles 19 & 20)Common rule, subparts B, C and D TCPS (Chapter 9) 

Privacy The right or expectation not to be interfered with or to be free from surveillance or, more generally, a moral right to be left alone. In practical terms, privacy is for instance concerned with the setting in which a person’s health-related information is acquired.

TCPS (Chapter 5), DOH (article 24) 

Core ethical principles/issues in research(Source: WHO Training manual: Ethics in research, surveillance and patient care in epidemics, emergencies and disasters, WHO (2014))Ethical principle/issue

Definition1 Examples of guidelines

Confidentiality The principle that ensures that identifiable information is kept out of reach of others. All identifiable information about individuals, whether recorded (written, computerized, visual, audio) or simply held in the memory of health professionals, is subject to the duty of confidentiality.

CIOMS (Guideline 18), TCPS (Chapter 5)

Research ethics review

A process by which a group of experts in research, ethics and other disciplines decides whether a research protocol fulfils the ethical standards of research before being undertaken

CIOMS, Guidelines 2 and 20; Common Rule, subpart A, (articles 46.107, 46.108 and 46.109); DOH (article 23); TCPS (Chapter 6)

INFORMED CONSENT

What is IC?■A process whereby potential research

participants decide whether they want to participate in the proposed study after receiving information about it.

■Decisions must be made free from coercion, by a competent person who can understand the information given and appreciate the associated risks.

■The information given to the participant should be in a language and format suitable to the participant’s ability to comprehend it.

Components of IC:1. "Disclosure" refers to the provision of

relevant information by the clinician and its comprehension by the patient. This refers to the process during which physicians provide information about the proposed research to the participant

2. "Capacity" refers to the patient's ability to understand the relevant information and to appreciate those consequences of his or her decision that might reasonably be foreseen.

3. "Voluntariness" refers to the patient's right to come to a decision freely, without force, coercion or manipulation.

Eight Required Elements[45 CFR 46.116(a) & 21 CFR 50.25]

1. Statement that study in research and information on purposes / duration / procedures / experimental procedures

2. Reasonably foreseeable risks or discomforts3. Reasonably expected benefits4. Alternative procedures5. How confidentiality will be maintained6. Information on compensation for injuries (unless

minimal risk)7. Contact persons for information on research,

injury, subject’s rights8. Voluntary participation, no penalty or loss of

benefits for refusal or withdrawal

Six Additional Elements1. Statement that there may be risks

which are unforeseeable2. Under what circumstances

investigator could terminate subject’s participation

3. Additional costs to subjects4. Consequences of subject’s

withdrawal from research5. Statement that will be told of new

findings6. Approximate number of subjects in

study

Waiver of Informed ConsentConditions to waiver IC:

Poses no more than Minimal risk Waiver or alteration will not adversely

affect the rights and welfare of the subjects

Research could not practicably be carried out without the waiver or alteration

Does not involve a therapeutic intervention

Subjects will be provided with additional pertinent information

All of the above must apply

Documentation of Informed Consent Written consent document

Language understandable to the subject or the subject’s Legally Authorized Representative (LAR), or

Signed by subject or subject’s LAR

Copy SHALL be given to subject Opportunity to read before

signing

Principles for Providing Information to Participant:

Make it clear; avoid jargonUse language appropriate to the

participant’s level of understanding in a language of their fluency

Invite questions from the patient and check for understanding

Summarize the imparted information

Provide contact information (and other resources)

2. Capacity:Refers to the presence of a group/set of

functional abilities a person needs to possess in order to make a specific decisions

(Griso and Applebaum, 1998). These include: To UNDERSTAND the relevant

information To APPRECIATE the relatively

foreseeable consequences of the various available options available.

3. Voluntariness:■Refers to a participant’s right to

make participation decisions free of any undue influence.

Influences include:■Physical restraint or sedation■Coercion involves the use of

explicit or implicit threat to ensure that the treatment is accepted

■Manipulation involves the deliberate distortion or omission of information in an attempt to induce the subject’s participation

Practical Challenges to a "Fully Informed Consent"■Diagnostic uncertainty■Complexity of medical information■Linguistic and cultural differences■Overworked health personnel■Paternalistic approach in doctor-patient

relationship in developing countries, including KSA.

CONFLICTS OF INTEREST (COI)

Conflicts of interests

What is an interest?

• An interest may be defined as a commitment, goal, or value held by an individual or an institution.

• Examples include a research project to be completed, gaining status through promotion or recognition, and protecting the environment.

What is COI?• Conflicts of interest are “situations in which

financial or other personal considerations may compromise, or have the appearance of compromising, an investigator’s judgement in conducting or reporting research.” AAMC, 1990

• COI exists when two or more contradictory interests relate to an activity by an individual or an institution.

• “A conflict of interest in research exists when the individual has interests in the outcome of the research that may lead to a personal advantage and that might therefore, in actuality or appearance compromise the integrity of the research.”

■ NAS, Integrity in Scientific Research

What comprises COI?• Stock ownership• Paid employment Board membership • Patent applications (pending or actual) • Research grants (from whatever source) • Travel grants and honoraria for speaking or

participation at meetings• Gifts Membership of lobbying organizations• Relationship with the National Research

Ethics Review Committee, or with possible reviewers of the paper

• Relationship with organizations and funding bodies Membership of a government advisory board

Levels of COI1- Researchers• The REC should assess the likelihood

that the researcher’s judgment may be influenced, or appear to be influenced, by private or personal interests (TCPS, 2000)

2- Conflicts of Interest by REC Members• It is of the highest importance that

members of the REC avoid real or apparent conflicts of interest .

• E.g.: their research are reviewed by their REC or when they have been in direct academic conflict or collaboration with the researcher whose proposal is under review.

Levels of COI3- Institutional Conflicts of Interest• Situations may arise where the parent

organization has a strong interest in seeing a project approved before all ethical questions are resolved.

• The REC must act independently from the parent organization.

• Institutions must respect the autonomy of the REC and ensure that the REC has the appropriate financial and administrative independence to fulfill its primary duties.

Is it always bad?COIs may result in:

1. Loss of objectivity 2. Reordering of priorities

towards applied research 3. Degradation of the nature of

science as a collegial enterprise

4. Exploitation of trainees 5. Transfer of time and interest

to commercial ventures

Practical Steps to resolve COI

• Disclosure / transparency • Stringent analysis of COI, • Review of contracts between

funders and researchers• Close external monitoring• Blinding of study, when possible• Restrict review of colleague’s

work• Peer review of manuscripts

What is Ethical Review?■ It is a process by which research proposals

are reviewed for their compliance and accordance with the national/international ethical principles & guidelines for research involving human subjects.

All research involving living human subjects by collecting identifiable information or materials including:

Research with human remains, cadavers, tissues, biological fluids, embryos and fetuses.

Interviews, surveys and questionnaires. Secondary data analysis of data from living

human subjects.

RESEARCH MISCONDUCT

(FFP)

Research Misconduct (FFP) Research misconduct is defined as fabrication, falsification, or plagiarism in proposing, performing, or reviewing research, or in reporting research results.– Fabrication is making up data or results and

recording or reporting them.– Falsification is manipulating research materials,

equipment, or processes, or changing or omitting data or results.

– Plagiarism is the appropriation of another person’s ideas, processes, results, or words without giving appropriate credit.

– Research misconduct does not include honest error or differences of opinion.

– Research misconduct includes the destruction of, absence of, or accused person's failure to provide research records accurately documenting the questioned research. 

Office of Research Integrity (ORI)’s Definition of Plagiarism

■… plagiarism to include both the theft or misappropriation of intellectual property (IP) and the substantial unattributed textual copying of another's work. It does not include authorship or credit disputes.

■… the unattributed verbatim or nearly verbatim copying of sentences and paragraphs which materially mislead the ordinary reader regarding the contributions of the author.

■The theft or misappropriation of intellectual property (IP) includes the unauthorized use of ideas or unique methods obtained by a privileged communication, such as a grant or manuscript review.

Forms of misconduct■Falsification

التزوير■Obfuscationالتضلي

ل■Fabricationالتلفيق■Plagiarism سرقة

فكرية■Self-plagiarism■Ghost writing

الشبحية الكتابة

■Bare assertions دليل بال التأكيد

■ Improper authorship

■Misappropriationاختالس

■Bibliometric inflation

■Violation of ethical standards

Source: http://en.wikipedia.org/wiki/Scientific_misconduct

How to maintain research ethics and avoid scientific misconduct?Before

conduct of research

• Develop clear research plan (who will do what when and how)

• Submit protocol to ethical review

• Prepare (communicate) well with your research community

• Agree on authorship

During conduct of research

• Follow the approved protocol

• Gain consent• Involve the

community• Protect

yourself, your team, & your participants

• Regularly check your data

After research

• Share your study report(s) with

• Return ‘something’ back to the researched community

• Publish following publication ethics

• Use Reference Management Software

References

1. World Bank’s interactive website: http://data.worldbank.org/indicator/GB.XPD.RSDV.GD.ZS

2. World Bank website: http://data.worldbank.org/indicator/SP.POP.SCIE.RD.P6?order=wbapi_data_value_2011+wbapi_data_value&sort=desc

3. SCImago. (2007). SJR — SCImago Journal & Country Rank. Retrieved December 09, 2014, from http://www.scimagojr.com

4. Training manual: Ethics in research, surveillance and patient care in epidemics, emergencies and disasters. Geneva, Switzerland: World Health Organization; 2014.

This presentation and more material can be found online:

http://www.slideshare.net/ghaiathhttps://www.youtube.com/ghaiathme

• You may also contact me on my email: ghaiathme@gmail.com