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.
3.
4.
‘…fruitful results for the good of society, unprocurable
by other methods or means…
…so designed and based on (prior) knowledge …that
the anticipated results justify the performance of the
experiment.
…so conducted to avoid all unnecessary physical and
mental suffering and injury.
Medical Ethics Year 2
Nuremberg Code (1947)
No experiment…(if) there is…reason to believe that
death or disabling injury will occur…except…where
the experimental physicians also serve as subjects.
5.
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.
9.
10.
…conducted only by scientifically qualified persons. The
highest degree of skill and care…
During the course of the experiment the human subject
should be at liberty to bring the experiment to an
end…
…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.
2.
3.
Distinction between therapeutic research (aims to
benefit patients) and non-therapeutic research (aims
to generate scientific knowledge)
An institutional mechanism should be in place to
ensure that the main ethical principles were followed.
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 x-rays
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
Respect for persons
Beneficence – favorable risk-benefit ratio. (includes
Nonmaleficence)
Justice – equitable distribution of the burdens and
benefits of research; must not exploit the vulnerable nor
exclude the eligible who may benefit
1.
2.
3.
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.
3.
4.
‘…fruitful results for the good of society, unprocurable
by other methods or means…
…so designed and based on (prior) knowledge …that
the anticipated results justify the performance of the
experiment.
…so conducted to avoid all unnecessary physical and
mental suffering and injury.
Medical Ethics Year 2
Nuremberg Code (1947)
No experiment…(if) there is…reason to believe that
death or disabling injury will occur…except…where
the experimental physicians also serve as subjects.
5.
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.
2.
3.
Distinction between therapeutic research (aims to
benefit patients) and non-therapeutic research (aims
to generate scientific knowledge)
An institutional mechanism should be in place to
ensure that the main ethical principles were followed.
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-in-themselves.’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 side-effects
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
Prospective
2. Randomised
3. Placebo controlled
Blinded / Double blinded
1.
4.
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 researcher- subject?
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.
Capacity to understand
(placebo, randomisation, etc.)
All hazards are made clear
If unknown this too must be made clear
1Beecher,
‘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
1.
2.
Careful study design and execution
such that
The research question is answered reliably and
efficiently
Sufficient numbers are enrolled to make the
results meaningful
3. Compliance must be ensured.
Medical Ethics Year 2
Case
1
5
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
1
5
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
1
6
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
1
6
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
Medical Ethics Year 2