Ethics & Medical Research

Kedah Research Day

Dato Dr. Ong Loke Meng
28/11/2013
 Why research ethics?
The purpose of Research subjects are
research is to develop the means to securing
generalizable such knowledge;
knowledge to improve respect for their
health, and is safety, dignity and
therefore valuable to autonomy is
society necessary
“The primary ethical struggle in clinical research is that a
few individuals are asked to accept burden or risk as
research subjects in order to benefit others and
society…... ethical concerns arise because of the
potential for exploitation and/or abuse of these
human research subjects.” Christine Grady in “Principles and
Practice of Clinical Research ”
 Outline
• History of ethics
• Principles of ethics
• Open discussion
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Tuskegee syphilis experiment
• natural history of syphilis
• 399 with AA men with latent syphilis & 201
controls were recruited
• diagnostic spinal was offered as free Rx
• placebo was given without knowledge despite
availability of penicillin in 1947
• patients prevented from getting Rx
• 1972 the press highlighted the study
 Tuskegee syphilis study
• 28 men died of syphilis
– 100 died related complications
– 40 of their wives become infected
– 19 children had congenital syphilis
• study terminated after congressional hearing
& advisory committee review
• US government paid US$ 9 million in
compensation
• presidential apology in 1997
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Nazi experiments
• Eugenics & creating a super Aryan race
• As many as 30 experiments were conducted
by Nazi doctors on concentration camp
prisoners
 Nazi experiments
• High altitude • Seawater
• Freezing • Phosgene
• Sulfanilamide • Bone, muscle, and joint
• Twins transplantation
• Poison • Sterilization
• Tuberculosis • Artificial insemination

http://www.pbs.org/wgbh/nova/holocaust/experiside.html
Nazi physician
• Karl Brandt, Hitler's
personal physician and
Major General Reich
Commissioner for
Health and Sanitation
• found guilty of war
crimes at the "Doctors
Trial" was executed
 Nazi experiments
• High altitude
– saving pilots ejected at high altitude
– placed inmates in low pressure chamber to
simulate high altitude and monitored physiological
response until death
• Freezing
– saving pilots from freezing ocean or Russian front
– placed inmates in freezing vats in pilot suits or
naked up to 4-5 hours, monitored response until
LOC then resuscitation
 Nazi experiments
• Limb amputation
– Amputated & attempt
transplantation
• Seawater
– forced to drink salt water
• Twins
– secrets of multiple birth
– collected living data from
twins & injected
chloroform into heart
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Nuremberg Doctors’ Trial
• 23 German physicians tried
• 15 found guilty
• 7 hanged
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Nuremberg code
• 10 articles
• Article 1: ““The voluntary consent of the
human subject is absolutely essential.”
• Article 9: “Subjects have the right to withdraw
at any time”
• Articles (2-8, 10): Scientific value; Favorable
risk/benefit ratio; Suffering by subjects be
avoided
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Helsinki Declaration
• Ethics of conducting medical research
• Adopted at in June 1964 at WMA General
Assembly
• 2013 revision (draft)
 General principles (2013)
• The health of my patient will be my first
consideration
• duty of the physician to safeguard health,
well-being and rights of patients in medical
research
• Medical progress must include studies
involving humans
 General principles (2013)
• Primary purpose of research to understand,
prevent, diagnose, treat. Even best proven Rx
must be evaluated continually
• ethical standards to ensure respect, protect
health & rights
• can never take precedence over the rights and
interests of individual research subjects
 General principles (2013)
• protect the life, health, dignity, integrity, right
to self determination, privacy & confidentiality
• ethical, legal and regulatory norms
• minimises harm to the environment
• appropriate ethics & scientific training &
qualifications
• underrepresented groups provided
appropriate access to research
 General principles (2013)
• combine medical research with medical care
should justify its value & participation will not
adversely affect health
• ensure appropriate compensation and
treatment for injury
Milestones in history of research ethics
• 1932-72 − Tuskegee syphilis experiment
• 1939-45 − Nazi experiments
• 1946 − Nuremberg Trial of doctors
• 1947 − Nuremberg Code
• 1964 − Declaration of Helsinki
• 1979 − Belmont Report
 Basic Ethical Principles
1. Respect for Persons
2. Beneficence
3. Justice
 1. Respect for persons
• Individuals should be treated as autonomous
agents
– able to deliberate their own goals
– respecting their choice
• Protect those with diminished autonomy
– immature or those incapacitated needs extra
protection
– extent of protection depends on risk of harm &
likelihood of benefit
 1. Respect for persons
• Voluntary participation
• Adequate information
 2. Beneficence
ensure well being of individuals
• Non-maleficence (Do no harm)
• Maximise possible benefits & minimise
possible harm
 3. Justice
• Fair distribution of benefits and burden of
research
• Avoid exploitation
• To each person an equal share, according to
individual need, according to individual effort,
according to societal contribution, according
to merit
Role of the independent ethics committee

IRB / IEC

GCP

Investigator Sponsor
 Vulnerable groups
• Minors
• Those incapable of giving consent
• Emergency situations
• Those with incurable diseases
• Persons in nursing homes
• Unemployed or impoverished persons, ethnic
minority groups, homeless persons, nomads,
refugees
ICH GCP 1996, Malaysian GCP 3rd ed, 2011
 Vulnerable groups
• Members of a group with a hierarchical
structure
– medical, pharmacy, dental and nursing students,
subordinate hospital and laboratory personnel,
employees of the pharmaceutical industry,
members of the armed forces, and persons kept in
detention

ICH GCP 1996, Malaysian GCP 3rd ed, 2011

 Scientific validity
• All research should be specified in a detailed
protocol
– provide justification
– plan of the study
– assessment of the potential benefits and risks of
the study
– mitigation of potential risks
 Case study
• Plan to recruit healthy Malaysians volunteers
for phase 1 study in UK
• Screening will be done in Malaysia
• Expenses will be covered plus £100/day
• Would local approval be necessary?
• Would you approve the study?
 Ethical concerns
• Justification for using Malaysian population
• Possible exploitation
• Possible inducement, coercion
• Liability of the local institution approving the
study
 Case study
• In the early 1990's, AZT was shown to reduce
perinatal vertical transmission of HIV (076
protocol)
• In a new study investigate if shorter less
intensive treatment was effective vs placebo
in resource poor setting (Africa & Thailand)
• Funded by NIAID, NIH, WHO, CDC
• Would you approve this study?
 Ethical concerns
• Use of placebo control
• Vulnerable population
• Research in resource-limited communities
• Truly informed consent
 What does ethics guidance say?
Individuals in the control arm must receive:
 “An established effective intervention” (CIOMS)
 “The best current prophylactic, diagnostic and therapeutic
method” (Declaration of Helsinki, 2008)
 Ideal: “best proven therapy;” Minimum: “highest level of care
attainable in light of … the circumstances listed" (UNAIDS
vaccine guidance)
 Ideal: “best proven;” Minimum: “the best intervention
available for the disease as part of the national health system”
(Nuffield Council)
 “Highest achievable” standard should be the goal (Benatar &
Singer, BMJ, 2000)
When is placebo as a comparator ethical ?

• Reason to use a placebo is scientifically sound and

• Ethically acceptable as a comparator if:
– no proven intervention exists
– mild condition, and surveillance in place
– use causes no increased harm
– duration of placebo use is minimised
– escape/reserve treatment available
– valid informed consent obtained from volunteers
– ethical review committee agrees
 Summary
• medical progress will require research in
humans
• respect, beneficence & justice are the basic
principles of ethics
• research scientific & ethical standards to
protect research participants
Thank you for your attention