The Ethics of
Research
Medical Ethics Year 2
Medical Research vs. Medical
Treatment
• Medical treatment is aimed at the welfare of
particular identifiable patients; the doctor’s clear
obligation is to the patient.
• Human biomedical research seeks to improve
the health and well being of patients as a whole,
so the obligation to the patient remains but is in
conflict with other obligations and incentives.
Medical Ethics Year 2
Medical Research
• Substantial rewards
• Career promotion - ‘Publish or perish’
• Proven investigation skills
• Salary increases
• Financial incentives from pharmaceutical companies,
e.g. renewed research funding
• Respect from colleagues
Medical Ethics Year 2
Medical Research
• Unfortunately these competing interests have at
times put research participants’ welfare at risk.
Medical Ethics Year 2
Medical Research
• Medical research by its nature subjects human
participants to risky and sometimes invasive
procedures for the sake of others.
• Why not research on animals, human cells,
computer modeling?
• The response of complex human organisms to
biomedical intervention requires specific
research.
Medical Ethics Year 2
Why Research Ethics?
•
• Medical research on humans raises difficult and
important ethical and legal questions.
• The field of research ethics is devoted to the
systematic analysis of these questions to ensure
that 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.
Medical Ethics Year 2
Historical Background
• Consent
• The assumption that informed consent is a prerequisite to research on human subjects has not
always been recognised.
Medical Ethics Year 2
Historical Background
• Monstrous Nazi Medical trials by German and
Japanese doctors on unconsenting subjects, in
utter disregard of their rights and interests.
• Experiments involving hypothermia (icy water
immersion), twin studies, typhus vaccination
experiments, etc.
Medical Ethics Year 2
Historical Background
• Subsequent to the trials and conviction of many
of the medical perpetrators at Nuremburg, the
Nuremburg Code (1947) was set up.
Medical Ethics Year 2
Nuremberg Code (1947)
•
•
The judgment by the war crimes tribunal at
Nuremberg laid down 10 standards to which
physicians must conform when carrying out
experiments on human subjects.
1. ‘The voluntary consent of the human subject
is absolutely essential…’
Medical Ethics Year 2
Nuremberg Code (1947)
•
1. ‘The voluntary consent of the human subject
is absolutely essential…The duty and
responsibility for ascertaining the quality of the
consent rests upon each individual who
initiates, directs, or engages in the
experiment…’
Medical Ethics Year 2
Nuremberg Code (1947)
2. ‘…fruitful results for the good of society,
unprocurable by other methods or means…
3. …so designed and based on (prior) knowledge
…that the anticipated results justify the
performance of the experiment.
4. …so conducted to avoid all unnecessary
physical and mental suffering and injury.
Medical Ethics Year 2
Nuremberg Code (1947)
5. No experiment…(if) there is…reason to believe
that death or disabling injury will
occur…except…where the experimental
physicians also serve as subjects.
6. The degree of risk…should never exceed
…the humanitarian importance of the problem
to be solved…
7. Proper preparations…and adequate facilities…
Medical Ethics Year 2
Nuremberg Code (1947)
8. …conducted only by scientifically qualified
persons. The highest degree of skill and
care…
9. During the course of the experiment the
human subject should be at liberty to bring the
experiment to an end…
10. …the scientist in charge must be prepared to
terminate the experiment at any stage, if he
has cause to believe…
Medical Ethics Year 2
Declaration of Helsinki (1964)
• World Medical Association (WMA)
• To address medical research enrolling patients
as subjects.
• Probably the most influential document
governing research worldwide
• Amended 2008
Medical Ethics Year 2
Declaration of Helsinki (1964)
•
Added 3 important points to Nuremberg Code
1. Distinction between therapeutic research (aims to
benefit patients) and non-therapeutic research (aims to
generate scientific knowledge)
2. An institutional mechanism should be in place to
ensure that the main ethical principles were followed.
3. Provision of proxy consent by family members when
subjects could not consent themselves.
Medical Ethics Year 2
Historical Background
• 2 years after the Helsinki declaration a paper in the
NEJM (1966) by Henry K. Beecher, Harvard anaesthetist
indicated that healthcare professionals in other countries
were found to have conducted research unethically on
their research subjects.
• 22 studies
• Hundreds of the patients did not know the risks of the
studies they were participating in and hundreds more
didn’t even know they were subjects of research at all.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Case 1
To improve the understanding of disease
• Melanoma tissue was transplanted from a daughter
to her volunteering and informed mother, ‘in the
hope of gaining a little better understanding of
cancer immunity and in the hope that the production
of tumor antibodies might be helpful in the treatment
of the cancer patient.’
• The daughter died the next day (her condition had
been recognised as terminal). The mother died from
metastatic melanoma 451 days post transplantation.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Case 2
Known effective medicine withheld
• Relapse rate of typhoid fever
• Chloramphenicol had been shown to be an
effective treatment (halving typhoid mortality)
• 408 charity cases with typhoid fever
• 251 given chloramphenicol (20 ( 7.97%) died)
• 157 symptomatic treatment only (36 (22.9%)
died)
• i.e. 23 patients died who should not have.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Case 3
Minimum blood flow requirements for
cerebral circulation
• To determine cerebral haemodynamic and metabolic
changes…before and during acute reductions in arterial pressure
induced by drug administration +/or postural adjustments.
• N =48 (hospitalised), age 20’s to 90’s, various B.P’s inc.
malignant hypertension / Femoral arteries and jugular veins
cannulated.
• Signs of cerebral insufficiency were confusion, non-responsive
state,
• By altering the tilt of the patient signs of confusion could be
altered in seconds from alertness to confusion,…the patient was
maintained in this state for the remainder of the experiment
• With the onset of collapse, CO and RVP decreased
sharply…since signs of cerebral insufficiency developed without
evidence of coronary insufficiency… ‘the brain may be more
sensitive to acute hypotension than the heart.’
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Case 4
Does ureteral reflux occur in the normal
bladder?
• Vesico-ureterography was performed on 20 new
born babies (<48 hrs old).
• Catheterisation and multiple X-ray exposure
while bladder filling and voiding. Multiple spot xrays taken to record presence or absence of
ureteral reflux. None was found.
• Effects of multiple X-Ray exposure long term???
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Tuskegee Syphilis Study
• 1932 - 1972
• Epidemiological Study - The Natural History of Syphilis
• Study of a cohort of African-American men with syphilis.
• The men were either not told or were misled about the
nature of their disease
• They were denied treatment and discouraged from
seeking alternative advice or treatment.
• Even when effective treatment for syphilis became
available form the 1940’s, they were not offered this.
They were followed up until 1972, when the study was
closed owing to public outcry.
Medical Ethics Year 2
Belmont Report (1979)
US National Commission for the Protection of Human
Subjects of Biomedical and Behavioral Research
•
3 guiding principles for ethical research
1. Respect for persons
2. Beneficence – favorable risk-benefit ratio.
(includes Nonmaleficence)
3. Justice – equitable distribution of the burdens
and benefits of research; must not exploit the
vulnerable nor exclude the eligible who may
benefit
Medical Ethics Year 2
Nuremberg Code (1947)
•
•
The judgment by the war crimes tribunal at
Nuremberg laid down 10 standards to which
physicians must conform when carrying out
experiments on human subjects.
1. ‘The voluntary consent of the human subject
is absolutely essential…The duty and
responsibility for ascertaining the quality of the
consent rests upon each individual who
initiates, directs, or engages in the
experiment…’
Medical Ethics Year 2
Nuremberg Code (1947)
2. ‘…fruitful results for the good of society,
unprocurable by other methods or means…
3. …so designed and based on (prior) knowledge
…that the anticipated results justify the
performance of the experiment.
4. …so conducted to avoid all unnecessary
physical and mental suffering and injury.
Medical Ethics Year 2
Nuremberg Code (1947)
5. No experiment…(if) there is…reason to believe
that death or disabling injury will
occur…except…where the experimental
physicians also serve as subjects.
6. The degree of risk…should never exceed
…the humanitarian importance of the problem
to be solved…
7. Proper preparations…and adequate facilities…
Medical Ethics Year 2
Declaration of Helsinki (1964)
•
Added 3 important points to Nuremberg Code
1. Distinction between therapeutic research (aims to
benefit patients) and non-therapeutic research (aims to
generate scientific knowledge)
2. An institutional mechanism should be in place to
ensure that the main ethical principles were followed.
3. Provision of proxy consent by family members when
subjects could not consent themselves.
Medical Ethics Year 2
CIOMS (2002)
• Council for International Organisations of
Medical Sciences CIOMS
• Addresses definition of what is medical research
Medical Ethics Year 2
Ethics Review Committee /
Board
• Common commitment of ensuring the protection of the
rights and welfare of the research subjects.
• Proposals involving research on human subjects should
be submitted to the ‘local’ ethics review committee or
board of the institution or hospital for consideration and
approval.
• Ethical issues must permeate research and must guide
research design, i.e. in the first stages of planning.
• Increasingly theses boards and committees are being
consulted in the planning stages of research.
Medical Ethics Year 2
• A Research Experiment is either Ethical
from the beginning or not. It does not
become so after the event!
• ‘Ends Do Not Justify Means’
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Doctors have a duty to protect their patients from
harm, but medical research exposes them to risk
of harm, then it seems a doctor has a duty to
discourage them from participating in research.
• However this conflicts with the doctor’s duty as a
researcher to promote science and the health of
future patients.
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• ‘When may a society, actively or by
acquiescence, expose some of its
members to harm in order to seek benefits
for them, for others, or for society as a
whole?’
• (Jay Katz, 1993)
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Kant’s second formulation of the categorical
imperative, in human biomedical research
• ‘ researchers have a duty to treat these subjects
not only as means, but also as ends-inthemselves.’1
1Glannon,
Biomedical Ethics(2005), OUP
Medical Ethics Year 2
Trials
• Randomised clinical trials are a standard form of
medical research.
• Efficacy of certain treatments,
• e.g.
• Is Treatment A better than Placebo?
• Is Treatment A better than Treatment B?
Medical Ethics Year 2
4 Phase Trials
• Prior animal trials
• Phase I non-therapeutic drug trial
• Toxicity studies – i.e. the highest dose human can
tolerate.
• Usually healthy volunteers (except Phase 1 trials of
cancer drugs where patients have already exhausted all
other treatments and have a life span of a few months
only).
• Altruistic volunteers or monetary compensation seeking?
• Desperate patients with false hopes?
Medical Ethics Year 2
4 Phase Trials
• Phase II non-therapeutic trial
• Optimal dosing regime
• Testing for experimental conditions for Phase III
to allow definitive result
• Specify end-points (e.g.5 yr SR)
• Note: Phase I & II non-therapeutic hence
researchers main moral obligation is to protect
from harm (risk of serious side-effects)
Medical Ethics Year 2
4 Phase Trials
• Phase III therapeutic trial
• Largest number of patients
• May be therapeutic in nature
• Is the treatment effective and what are the sideeffects
Medical Ethics Year 2
4 Phase Trials
• Phase IV therapeutic trial
• Post approval (by e.g. FDA) and marketing
• Monitor side-effects and gather additional
information, e.g. broader usage.
• Note: Phase III & IV therapeutic hence
researchers main moral obligation is to ensure
appropriate risk-benefit ratio
Medical Ethics Year 2
4 Phase Trials
•
Gold Standard Trial
1. Prospective
2. Randomised
3. Placebo controlled
4. Blinded / Double blinded
Medical Ethics Year 2
Equipoise
• Randomised clinical trials are a standard form of
medical research.
• Patients are randomly assigned to one of the
arms of the trial.
Medical Ethics Year 2
Equipoise
• Widely accepted that randomised clinical trials,
to be morally sound, require equipoise, that is
uncertainty as to the merits of each arm of the
trial.
• Treatment A vs. Placebo?
• Treatment A vs. Treatment B?
Medical Ethics Year 2
Equipoise
•
Equipoise is uncertainty in the expert medical
community, not in the researcher.
•
(Benjamin Freedman, ‘Equipoise and the Ethics of Clinical Research’
NEJM, 1987).
•
The traditional role of the doctor is incompatible with
this. The doctor's duty is first and foremost to each
individual patient. Doctors cannot act for the public
good and for the good of each patient.
•
(Samuel Hellman, ‘The Patient and the Public Good', Nature
Medicine(1985)).
Medical Ethics Year 2
Randomisation
•
Similar concerns for the doctor,
• however again if there is a genuine
uncertainty about the efficacy of a certain
treatment, then a randomised controlled
trial is the best way to yield objectively
valid results.
Medical Ethics Year 2
Randomisation
•
Treating the patient as a means for the sake of
generating scientific knowledge
• But also
• Treating the patient as an end by obtaining
consent to participate in the trial and ensuring
the potential risks are commensurate with the
potential benefits.
• Physician-Researcher dual role is thus fulfilled
Medical Ethics Year 2
Randomisation
• Early Breast Cancer
• Lumpectomy vs. Mastectomy
• Uncertainty allows valid entry of patient into
clinical trial comparing the two surgical
approaches.
• Thus the surgeon is treating her patients as
means in deriving valid scientific data but also
as ends in offering each patient a 50% chance
of receiving the best treatment, as yet
unknown.
Medical Ethics Year 2
Placebo
•
•
Placebo-controlled trials are scientifically
more robust than active-controlled trials.
• Shorter duration
However sick patients in the placebo arm
of the trial are not receiving any
treatment for the duration of the trial,
hence exposed to greater risks.
Medical Ethics Year 2
Placebo
•
Declaration of Helsinki 2000 revision – new
treatments must be tested against ‘best
available’ treatments unless there is no proven
treatment exists.
•
This approach is supported by deontological
and consequentialist arguments, in considering
the best interests of the sick patient, although
scientifically it may not be the most sound
approach.
Medical Ethics Year 2
Placebo
•
Placebo controlled trials for surgical
procedures have clear ethical difficulties
Medical Ethics Year 2
Placebo
• 1999
• Parkinson’s fetal cell implant trial
• Patients in the intervention group
- General anaesthetic
- Burr holes penetrating the inner cortex of the
brain
- Fetal tissue implanted
- Low dose immunosuppressive drug x 6/12
Medical Ethics Year 2
Placebo
• 1999
• Parkinson’s fetal cell implant trial
• Patients in the control group
- General anaesthetic
- Burr holes not penetrating the cortex of the
brain
- No fetal tissue implanted
- Low dose immunosuppressive drug x 6/12
Medical Ethics Year 2
Placebo
•
Did the significant risks in this study to
both groups outweigh the potential
benefits to them or to future patients?
• Does this contravene the duty of care of
the doctor not to enroll their patient in
this type of study?
• Is the ‘sham’ surgery unethical in its
deliberate deceit of the patient by the
surgeon?
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Doctors have a duty to protect their patients from
harm, but medical research exposes them to risk
of harm, then it seems a doctor has a duty to
discourage them from participating in research.
• However this conflicts with the doctor’s duty as a
researcher to promote science and the health of
future patients.
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Doctor-researcher must strike a delicate balance
between the two obligations to patients-subjects.
• Particularly difficult with non-therapeutic
research, where the patient derives no benefit.
• The benefit is for future patients.
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Deontological approach - respect the patient’s
right not to be harmed.
• Consequentialist approach – more weight to the
scientific knowledge to be gained by the
research participation.
Medical Ethics Year 2
Dual role of Clinician and
Researcher
• Fiduciary nature of the doctor-patient
relationship - is it the same for the researchersubject?
• Do not harm
• Respect and promote autonomous decision
making
Medical Ethics Year 2
Research Ethics Committees
• Must act to ensure five conditions are adhered to
in any research protocol before them.
Medical Ethics Year 2
1. Consent
•
Normally patients will not knowingly risk their
health or life for the sake of science.
•
•
1Beecher,
• Capacity to understand
(placebo, randomisation, etc.)
• All hazards are made clear
If unknown this too must be made clear
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Problems with Consent
• ‘A far more dependable safeguard than
consent is the presence of a truly responsible
investigator’
• (Beecher, 1966).
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Informed Consent
• Is this enough?
Medical Ethics Year 2
Informed Consent
• Swedish HIV study
• (prior to definitive AIDS treatments becoming
available)
• The study drug, which promises to delay the
onset of AIDS in HIV infected patients, carries
a risk of death of 1/500.
• Patients fully informed of the relevant facts and
risks.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Informed Consent
•
Is there a difference between doctors allowing
patients to make foolish or unreasonable
choices themselves, and actively putting those
choices before patients that they regard as
foolish, irrespective of how ‘informed’ those
patients are.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Informed Consent
•
•
•
Participation to please the doctor
Participation because of false hopes
Is voluntary informed consent ever present in
medical research?
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Informed Consent
• Difficulties but ‘it is absolutely essential to strive
for it for moral, sociologic and legal reasons.’1
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
2. Risk-Benefit Ratio
•
• Favourable risk-benefit ratio
The subject must not be exposed to undue risk
and the potential benefit of learning whether a
drug or surgical procedure works must be
worth any potential risk to the subjects.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
3. Equitable selection of
patients
•
Equitable selection of subjects that rules out
any exploitation and adequately represents
both sexes and all social groups.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
4. Privacy of subjects
•
Privacy and confidentiality of subjects must be
protected.
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
5. Confidentiality of data
•
•
Research data must be kept confidential
1Beecher,
‘Ethics and Clinical research’, NEJM (1966)
Medical Ethics Year 2
Scientifically sound
•
A research study must be sufficiently well
designed such that the maximum results can be
gleaned from the research, ensuring that
patients have not undergone risks and
discomfort in vain.
• Obligation to ensure that the study findings are
valid and replicable.
Medical Ethics Year 2
Scientifically sound
•
Careful study design and execution
• such that
1. The research question is answered reliably
and efficiently
2. Sufficient numbers are enrolled to make the
results meaningful
3. Compliance must be ensured.
Medical Ethics Year 2
Case 51
• Dr. X is a GP, with a special interest in COPD.
He is contacted by the coordinator of a study
evaluating a promising new treatment for COPD.
He is asked to provide names of potentially
eligible patients and will receive a fee of € 100
per name.
1Meslin,
EM, Dickens BM, Research Ethics, Chapter 25, Cambridge Textbook of Bioethics (CUP 2008)
Medical Ethics Year 2
Case 51
• Finder’s fee ethically and legally objectionable;
remuneration for time spent acceptable
• In breach of fiduciary duty and conflicted if
provide confidential medical info for personal
gain
1Meslin,
EM, Dickens BM, Research Ethics, Chapter 25, Cambridge Textbook of Bioethics (CUP 2008)
Medical Ethics Year 2
Case 61
• Dr. Y, a psychiatrist in private practice is asked
by a pharmaceutical company conducting
research on a new antipsychotic drug
• Acutely psychotic patients, No prev. hx
• Admission for 8 weeks
• No treatment for the duration for the placebo
arm
• Only treatment with the new drug for the active
arm
• Consent or proxy
1Meslin,
EM, Dickens BM, Research Ethics, Chapter 25, Cambridge Textbook of Bioethics (CUP 2008)
Medical Ethics Year 2
Case 61
• Consent alone is insufficient
• There must be a favourable balance of benefits
and harms
• Clinical equipoise
1Meslin,
EM, Dickens BM, Research Ethics, Chapter 25, Cambridge Textbook of Bioethics (CUP 2008)
Medical Ethics Year 2
Medical Research
• Widely agreed that medical research can be
conducted on autonomous persons, who have
given informed consent.
• However what about human infants and
children, the learning disabled, human embryos?
Medical Ethics Year 2