MEDICAL RESEARCHWMA – SEYCHELLES BASIC CONCEPTS IN ETHICS SEMINAR, 10TH & 11TH JULY 2015 (July 2015)

Professor A Dhai Immediate Past-President SAMA

Director: Steve Biko Centre for BioethicsHoD Bioethics Discipline

Faculty of Health Sciences University of the Witwatersrand, Johannesburg

South African Unit of the UNESCO International Network in Bioethics

1. Concepts2. Research Ethics: The need3. International Instruments4. Vulnerability5. Benchmarks

Outline

“The benefits of biomedical progress are obvious, clear and powerful. The hazards are much less well appreciated.”

Leon Kass

What are the objectives of Ethics?

● How we ought to act in a given situation

● Providing strong reasons for doing so

involves a critical reflection of morality with its intent to safeguard human dignity and to promote justice, equality, truth, and trust.

Introduction

About means of ensuring vulnerable people are protected from exploitation and other forms of harms

Evolving language : passive subject → active participant

Research Ethics

• Autonomy• Beneficence• Non-maleficence• Justice

Prima facie – not absolute; overridden by weightier concerns

- lack hierarchical order rendering ranking arbitrary

Principle-based Ethics

• Distinct entities

• Ethics constrained by law

• Law: minimal standard

• Quasi legal status of guidance documents

Ethics & Law

• Determine whether issue at hand is ethical one• Check facts of the case• Check for constraints on actions• Check which ethical values are involved • Consult authoritative sources• Consider alternative solutions in light of values and

principles they uphold & their likely consequences• Discuss proposed solutions with those whom it will effect• Make decision – act on it with sensitivity to others

affected• Evaluate decision – be prepared to act differently in

future

Analysis Process

(WMA – MEDICAL ETHICS MANUAL: WMA website)

• Regulatory

• Ethical

Research Ethics - Components

• Historical

• Ethical

Research Ethics – the Need

CAN THE DEMANDS AND GOALS OF SCIENCE AND BIOMEDICAL RESEARCH BE PURSUED WITH FULL PROTECTIONS OF THE RIGHTS AND DIGNITY OF THE RESEARCH PARTICIPANT AND COMMUNITY?

HEALTH RESEARCH - CHALLENGES

SUCCESSES NOT WITHOUT COST

SOME REALITIES

“In the workroom next to the dissecting room, fourteen Gypsy twins were waiting and crying bitterly. Dr Mengele didn’t say a word to us, and prepared a 10cc and a 5cc syringe. From a box he took Evipal and from another box he took chloroform, and put these on the operating table. After that the first twin was brought in … a 14 year old girl. Dr Mengele ordered me to undress the child and put her head on the dissecting table. Then he injected the Evipal into her right arm intravenously. After the child had fallen asleep, he felt for the left ventricle of the heart and injected 10cc of chloroform … . After 1 little twitch the child was dead … in this manner all 14 were killed.”

POSNER’S TESTIMONY

Mengele then removed the eyes from the dead twins and shipped them off to Berlin for further study.

Japanese Experiments: Unit 731 “Germ doctors” cut up a live Chinese girl … .

Ethics in research was:

“ ... born in scandal and reared in protectionism”.

Levine C. Has AIDS Changed the Ethics of Human Subjects Research?” Law, Medicine and Health Care. (1998); 16: 163-73.

• Concerns date back to at least the end of the nineteenth century.

• Individuals and groups being exploited and harmed, concept of vulnerability emerged.

• In parallel, concerns over their participation grew in prominence in national and international policy and guideline documents.

• Tensions between scientific progress and societal interests on and individual rights and interests

• Dilemma - goal of health research which is to improve human well-being.

“... born in scandal ...”

• Even very early experiments with humans had positive outcomes:

• 1700’s James Lind, and scurvy studies

• 25 years later, Edward Jenner’s smallpox vaccine.

Early Gains of Health Research

• Abuses in the field were starting to surface: • 1890’s, anti-vivesectionists ---> laws to protect children -

institutionalised children subjected to vaccine experiments• 1897, Guiseppe Sanarelli, Italian bacteriologist injected

yellow fever organism into subjects• 1900’s first attempt to test polio vaccine stifled. • Beginning of 1900’s, research rules imposed by Prussian

State and US Congress contemplating prohibition of medical experiments for particular groups such as pregnant women

• Early 1900 Walter Reed set up Yellow Fever Board

Birth of Protectionism

• Early 1900 Walter Reed commissioned to identify cause of yellow fever in Cuba.

• Developed ethical guidelines - safeguards for research to be overseen by US Army’s Yellow Fever Board.

• Forerunner to REC / IRB • Guidelines included:

– self experimentation by Board members – written contracts clearly explaining risks for locals who were not Board

members – payment in gold for locals volunteers– $100 compensation if became ill with yellow fever– enrolment to be restricted to adults >24 years– children excluded – all journal publications to use “with his full consent”.

Early Self-Regulation

• Helped legitimise health research in aftermath of emerging scandals - researchers inoculated against regulation by legendary status of self-experimentation. – Dr Jesse Lezear died after subjecting himself to mosquito bites and helped

confirm hypothesis of disease spread. – Reed’s untimely death a few years later - error by a colleague - mistakenly

believed because volunteer subject while on Board– Werner Forssmann -1930 - cardiac catheterisation on himself - Nobel

Prize in Physiology or Medicine in 1956– JBS Haldane subjected himself to various gases in decompression

chamber experiments to find out how best welfare of sailors in submarines could be protected

• Illusion - medical researchers of such exceptionally moral character - elevated to the status of martyrs.

Martyr Myth of Medical Researchers

• New science of anthropology

• Used by Europeans as means to study non-European peoples.

• Studies and experimentation on slaves, the poor, those considered as uncivilized, less than human.

• Even colonial and imperial rule often justified by anthropological research

– Described native peoples of Africa, the Americas and Asia as being of inferior intelligence and ability and hence in need of paternalistic rule by European powers or immigrants.

– Race category being used to base findings.

“... born in scandal ...” : Contributions from Anthropology

• Lethal human experimentation during WW11, - Unit 731 - covert biological and chemical warfare research and development unit of the Imperial Japanese Army - in Northeast China. – some of the most notorious war crimes >12000 men, women and children died– 70% Chinese – 30% Russian.

• Scientists from Unit 731 -prominent careers after war, in politics, academia, business and medicine.

• Perhaps not tried because information and experience of great value for the United States biological weapons development program - alleged a deal to this effect concluded between the United States and Japan in 1948.

UNIT 731

• “High-altitude (low-pressure) experiments: Prisoners into low pressure tanks to see how long they could survive with little oxygen – those surviving - drowned; autopsies followed.

• Freezing experiments: forced to remain without clothing in freezing weather for 9 to 14 hours, / in freezing water. Rewarming then attempted.

• Malaria experiments: infected with malaria and then given variety of “anti-malarial” drugs.• Mustard gas experiments: wounded then infected with mustard gas/ forced to inhale mustard gas

then followed with experimental treatments• Sulphanilamide experiments: bacterial culture, gangrene-producing culture, wood shavings, glass

shards into inflicted wounds - treatment with sulphanilamide. Control group - NO sulphanilamide. • Typhus experiments: injected with an antityphus vaccine - then infected with typhus. Control - no

treatment; others infected with typhus simply to ensure virus remained active within the prison camps.

• Poison experiments: Poisons fed to prisoners in food - those who did not die - killed for purposes of autopsy.

• Incendiary bomb experiments: Burnt with phosphorus from English incendiary bombs for examining of wounds.

• Sterilization experiments: chemical sterilization and x-ray sterilization - conventional too costly • Anthropological studies - killed for skeleton collection of “repulsive but characteristic subhuman”

prototypes.

Some Nuremberg Atrocities

• Vulnerable - subhuman, of decreased intelligence, of no moral status and lacking human dignity.

• Nuremberg Trial defence :– Allies also engaged in medical experiments in servicing war effort. – type of medical experimentation in Nuremberg commonplace even before the war. – no legal restrictions on such experiments.

• Prosecution’s attempts at demonstrating clear international rules governing medical experimentation wavered– Judges attempted to create their own set of rules - two medical advisors to the

judges, Drs Andrew Ivy and Leo Alexander tasked

• Drafted ten point memorandum “Permissible Medical Experimentation” Nuremberg Code

Nuremberg Trial

• Code’s key contribution: – to merge Hippocratic ethics and human rights into one – Principles 2-8 and 10 - physician-researchers protect the best interests of their subjects. – Principles 1 and 9 subjects can protect themselves as well. – Principle 9 gives subject as much authority as physician-researcher to end participation before its

conclusion.

• Influence of Code on international documents substantially significant - Universal Declaration of Human Rights adopted in 1948 makes claims closely associated with the Code.

– Preamble -“disregard and contempt of human rights that have resulted in barbarous acts which have outraged the conscience of mankind.”

– Article 5 “No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment.”

– Article 27 “Everyone has the right freely ... to share in scientific advancement and its benefits.”

• Code and Declaration– interpreted as establishing basis for underpinning principles of free and informed consent and

avoiding harms and exploitation in scientific experiments with human participants.

Nuremberg Code: Positive Impact

• For many years - researchers - “business as usual” – did not recognise - good reasons for concerns and protecting participants.

– Nazi transgressions attributed to abnormalities associated with totalitarian regime with unquestionable brutality

– notion - researchers working in democratic states would not succumb to

atrocities and exploitation of vulnerable in research

– Code not applicable in civilized democracies - document necessary to strain barbarians.

– evidence in fifties - vulnerable individuals and populations being exploited and harmed in research in democracies like the US, despite Code’s safeguards.

Nuremberg Code : Impact on Research Community

• Genuine and deep concern by some– First International Congress of Neuropathology (1952) - Pope Pius X11 - “The Moral Limits of

Medical Methods of Research and Treatment”• highlighted relatively recent lessons from Nuremberg Trial • firmly endorsed requirement on necessity to obtain informed consent • Pope - Nuremberg trials taught that “... man should not exist for the use of society; on the contrary,

the community exists for the good of man.”

• Concerns on the power of medical researchers possibly cause of gradual disappearance of “human experiment” - replacement with more reassuring “research”.

• Henry Beecher’s landmark article in NEJM (1966) -“Ethics and Clinical Research”– 22 cases of research by leading researchers violating basic ethical standards – Studies published in highly acclaimed and reputable reviewed journals

• World Medical Association (WMA), perturbed by ongoing mistreatment of research participants and restrictive nature of the Code re informed consent from those that lacked capacity, began discussions on the ethics of research in the mid fifties.

Post Code Concerns

• WMA established in London in 1946 , & launched at 1st General Assembly in Paris in 1947.

• Focussed on crimes committed in doctor-patient relationship in WW11 Germany

• Declaration of Geneva (1948), & International Code of Medical Ethics (1949), - guidance documents for physicians specifically in clinical care context - resounding presence in Declaration of Helsinki (DoH) : use in the introduction of the DoH through all its revisions.

• Physician-researchers bound by : “The health of my patient will be my first consideration” (Declaration of Geneva) and “A physician shall act in the patient’s best interest when providing medical care.” (International Code of Medical Ethics).

• 1964 DoH - adopted after a twelve year debate:– 1st formal declaration by WMA for physicians doing research – served for 1st time to distinguish biomedical researchers as specific class of physicians

1964 : Birth of Declaration of Helsinki

• Seven revisions and two clarifications• 1975, 1983, 1989, 1996, 2000, 2008, 2013.

• Widely regarded as cornerstone document of human research ethics

• Not legally binding but draws authority from:• Degree in which it has been codified in or influenced legislation

• 2013: – more readable structure, – revised paragraphs on vulnerable groups, research ethics committees,

post study provisions – introduction of compensation for research related injuries – specific reference to biobanks.

Helsinki Evolution

• Preamble (1-2)• General Principles (3-15)• Risks, Burdens and Benefits (16-18)• Vulnerable Groups and Individuals (19-20)• Scientific Requirements and Research Protocols (21-22)• Research Ethics Committees (23)• Privacy and Confidentiality (24)• Informed Consent (25-32)• Use of Placebo (33)• Post-Trial Provisions (34)• Research Registration and Publication and Dissemination of Results (35-36)• Unproven Interventions in Clinical Practice (37)

Declaration of Helsinki 2013 : Principles and Paragraphs

• Nuremberg Code – 1947

• Universal Declaration of Human Rights – 1948: “No one shall be subject to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his free consent to medical or scientific experimentation”

• Declaration of Helsinki – 1964 (updated x 7)

• Council of International Organisation of Medical Scientists (CIOMS)- 1993 ; 2002 (currently undergoing revisions)

• International Conference on Harmonisation (ICH) Good Clinical Practice Guidelines – (1995 ; 2002)

• Singapore Statement on Research Integrity - 2010

Some Pertinent International Instruments & Guidelines

• Bill of Rights of the Constitution of South Africa

• National Health Act (No.61 of 2003)

• Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa – 2006 (2ed)

• Ethics in Health Research: Principles, Structures & Processes – 2004 (undergoing revisions)

• Ethical and Legal Guidelines for Biotechnology Research in SA (DST) - 2006

• Health Professions Council of South Africa Ethical Guidelines

South African Instruments & Guidelines

• “Vulnerability is an inability or decreased ability of a research participant to sufficiently safeguard her/his own needs and interests resulting in her/him being at an increased likelihood of being identifiably wronged in varying degrees if special safeguards to protect her/him are not invoked by the Research Ethics Committee”

Dhai A. A study of vulnerability in clinical research. PHD theses

VULNERABILITY

• Will any participant be used in the research as a means to an ends she/he may not endorse?

• Will all the research participants in this study be able to safeguard their own needs and interests?

• If no, is there an increased likelihood of any of them being identifiably wronged as a result of their participation in the study?

• Is there an increased likelihood of any participant being identifiably wronged to a greater degree than other participants?

• Have the identifiable wrongs been recognised? • Have special safeguards been developed to protect those

participants in need of such safeguards?

Vulnerability Assessment Scale

Dhai A. A study of vulnerability in clinical research. PHD theses

Cluster of Wrongs Examples

Physical Wrongs Medical physical risks outweighing benefits, non-medical physical wrongs, e.g., pain, discomfort

Consent Wrongs

Exploitation because of, e.g., :

Lack of capacity (e.g., extremes of age, mental disorders, anxiety, emergency)

Understanding barriers (e.g., language, low levels of literacy)

Diminished freedom or voluntariness (e.g., manipulation, coercion)

Social WrongsConfidentiality breach / inappropriate dissemination of results of research (e.g., stigmatisation, stereotyping, discrimination, physical / gender-based violence, job loss, legal sanction)

Psychological Wrongs Anxiety, stress, emotional suffering (e.g., could be triggered by research tool, e.g., sensitive questions in interview schedule)

Justice Wrongs no post study access to proven intervention, inequitable standards of care usually with international research, no provision for compensation for research-related injuries.

IDENTIFIABLE WRONGS: Clusters and Examples

Dhai A. A study of vulnerability in clinical research. PHD theses

• Consultation and meaningful collaboration

• Worthiness

• Justifiable and Defensible Study Design, Methodology & Processes

• + Benefit / Risk ratio

• Respect for persons

• Avoidance / Ethical Management of Conflicts of Interest

Some Benchmarks

“The benefits of biomedical progress are obvious, clear and powerful. The hazards are much less well appreciated.” - Leon Kass

“It is hoped that by the end of this presentation the hazards are much better appreciated.”- Ames Dhai

• www.sajbl.org.za

South African Journal of Bioethics and Law (SAJBL)

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