Download Randomised Controlled trials 3

RCT 3
Ethical Issues in Clinical Research
Applicability of RCT methods to all
new health interventions
Notes from Page 223 handbook
Powerpoint slides on HaDPoP Website
Study Designs in Epidemiology
Observational Studies
Prevalence surveys
Experiments
Randomised Controlled Trials
Analytical studies
Cohort Studies
Case Control studies
Learning Outcomes
Demonstrate an understanding of the ethical issues
inherent in experimental research on human
subjects
Be able to discuss the historical and contemporary
efforts to overcome the ethical problems related
to the use of experimental study designs in
clinical practice
Recognise the wide applicability of RCT methods in
areas other than the testing of new drugs.
Be able to describe how a new drug and a new
medical or surgical technique should be evaluated
using RCT methods
Expertise in the Medical School
• Jane Hutton - written extensively on
ethical aspects of clinical trials,
informed consent in clinical research
• Jenny Kurinczuk - member of the
Leicestershire Research Ethics
Committee
All patients should have
treatments which are
properly tested
• Collective ethic
• Not logical because there would be no
opportunity to test new interventions
• Many treatments in current use have not
been properly evaluated
It is the individual ethic
that patients in clinical trials
should come to no harm
with which we are mainly
concerned today
The problems with Randomised
controlled trials include:• Treatment choice is dictated by
chance
• We don’t know how well the new
treatment works - are we placing
the patients at risk?
• The answer will be of benefit to
future not current patients
Patients are being used by
researchers to test out
whether the intervention is
any good – research subjects
are used as a means not an end
in themselves
Two groups of Ethical issues
ONE
Research should be scientifically sound
conducted to the highest standard and
research findings should be made
accessible
TWO
Patients used as research subjects should
be treated with respect and dignity as
human beings
Research should be sound
Robust study design
– Control biases
– Make sure the trial is big enough: if sample
size is too small error factors will be big –
you may miss a real difference
Very important to involve statisticians early
Research findings should be accessible:
• Non-publication of important findings
– Drug companies burying results
• Publication of results in a misleading way
– Statistical as opposed to clinical significance
• Non-publication of negative results
– ‘Publication bias’
– This may cause work to be repeated unnecessarily
Research should be conducted to the highest
standard
Treating patients with respect and
dignity important considerations…..
• Clinical equipoise
• Address patient centred issues
• Approval by Research Ethics Committee
• Full informed consent
• Complete freedom to refuse to take
part incurring no penalties
Research Ethics Committee
Application form …..
• Investigators; sponsors; payments
• Aims and benefits of project & scientific
background in layman’s terms
– Is it asking an important question?
• Study design including size and power
– Will the question be answered?
– Are the procedures acceptable?
• Selection, recruitment & payment of subjects
• Copies of consent form & information sheets
for subjects
Research Ethics Committee
considers …..
• Details of drugs/devices/investigations
• Potential hazards/side effects & possibility
of discomfort or distress
• Ethical considerations
• Information to GP & hospital consultant
• Will patients be compensated if harm caused?
• Arrangements for data protection/storage
– confidentiality is protected but data not discarded
Treating patients with respect and
dignity important PROBLEMS…..
• Clinical equipoise – some say impossible
• Approval by research ethics committee – not
universally obtained
• Full informed consent – difficulties in
children/unconscious patients. Some say impossible
anyway
• Complete freedom to refuse to take part
incurring no penalties -Some new treatments are
only accessible in trials
• Interfering with trust in the doctorpatient relationship
Ongoing debate in many areas:
• The lack of inclusion of children and
elderly in RCTs affecting licensing of
drugs
• The standard to which full informed
consent can be achieved
• The lack of availability of treatment
except as part of an RCT
• Placebo controlled trials – new drug
compared with placebo not standard
treatment
Be able to discuss the
historical and contemporary
efforts to overcome the
ethical problems related to
the use of experimental
study designs in clinical
practice
(Historical and current
aspects of research ethics)
Hippocratic Oath (page 232)
• Around 470 BC
• Some of its principles held sacred by
doctors to this day:
– Treat the sick to best of ability
– Preserve patient privacy
– Teach the secrets of medicine to the next
generation
• Modern version states:
– I will neither treat any patient nor carry out
any research on any human being without the
valid informed consent of the subject or the
appropriate legal protector thereof………
Nuremburg Code 1947
• Following the atrocities in Nazi
concentration camps
• Basis for ethical conduct of human
experimentation
• Internationally agreed
• 10 standards
• ???means of enforcement
Declaration of Helsinki
• Recommendations guiding physicians in
biomedical research involving human
subjects
• Adopted by World Medical Assembly
1964 and amended several times since
• Supposed to extend and clarify the
Nuremburg code but has caused some
controversy
Initiatives to disseminate
Knowledge of RCTs
• Consort Statement (CONsolidated
Standards of Reporting Trials 1996 &
2001)
• Checklist of essential items and a flow
diagram to be used in reporting trials
• Used by several eminent journals now
Initiatives to disseminate
Knowledge of RCTs
• Register of ongoing Controlled Trials
• Major international searchable database of
ongoing RCTs in all areas of healthcare
• Active involvement of major drug company
GlaxoSmithKlein
• BUT NOT COMPREHENSIVE
• Current Controlled Trials Website:
[email protected]
Research Governance for
Health & Social Care
Department of Health 2001
Summarises key responsibilities
• Researchers
• Research ethics committees
• Sponsor
• Employing organisation
• Care organisation
Research Governance for Health & Social Care
Department of Health 2001 - Responsibilities
Principle investigator and other researchers
Develop proposals which are ethical
Seek ethics approval
Conduct research according to agreed protocol
and legal requirements e.g. about consent
Ensure welfare of participants
Feed back results to participants
(Last 2 = ensuring respect and dignity)
Research Governance for Health & Social Care
Department of Health 2001 - Responsibilities
Research ethics committee
 Proposed research is ethical
 Respects dignity, rights, safety and well-being of
participants
Sponsor
 Scientific quality
 Research ethics committee approval obtained
 Arrangements for management and monitoring
Research Governance for Health & Social Care
Department of Health 2001 - Responsibilities
Employing organisation
 Promoting a quality research culture
 Ensuring researchers understand and discharge
responsibilities
 Ensuring proper management and monitoring
Care organisation/professional
 Ensure research on patients in their care meets
standards set down in the research governance
framework
 Ensure ethics approval was obtained
 Retain responsibility for care
Research Governance for Health & Social Care
Department of Health 2001
For the first time this document
suggests patients have a
responsibility to consider whether or
not they should become involved in
clinical trials and contribute to
medical progress
Clinical Ethics Committees
• Discussion of ethical issues arising in
clinical practice NOT RESEARCH
e.g. do not resuscitate orders
living wills
euthanasia
rationing
operating on Jehovah’s witnesses
consent to treatment in children
Recognise the wide
applicability of RCT methods
in areas other than the
testing of new drugs.
Same steps all new
technologies?
• Drugs are subject to specific
government regulations – licensing via
Committee on Safety of Medicines
(UK)
• Other interventions e.g. screening
programme; new operation;
rehabilitation programme – no legal
requirements
We don’t want therapeutically
useless procedures
Benefits of random allocation are
UNIVERSAL
Whatever the intervention, well-designed and
implemented RCTs give the best evidence
that differences ARE NOT due to
confounding
NOT too difficult
IS very important
we should be doing it
The importance of timing
• New treatments deemed too experimental
– unethical to use in RCT
• Suddenly widely accepted – unfair to
deprive half the patients by random
allocation to control treatment
• Do not miss the window of opportunity
• All new treatments should undergo rigorous
evaluation
• ECMO page 229
(Extracorporeal Membrane Oxygenation)
NHS Health Technology Assessment
Programme
• Commissions research and reviews of
Health Technologies
(prevention; rehab; vaccines; pharmaceuticals;
devices; medical and surgical procedures)
• Reports to NICE
(National Institute for
Clinical Excellence) about effectiveness and costeffectiveness of Health Care interventions
• NICE appraises the reports and
issues guidance to the NHS
NHS Health Technology Assessment
Programme – cycle of work
Asks for suggestions of technologies
which need assessing
Determines a list of priorities for the
year
Asks for proposals from University or
NHS departments willing to evaluate
the prioritised technologies
Chooses and funds the best proposals
NHS Health Technology Assessment
Programme
The Website
– lists completed technology assessments
• free download
– Lists activity (reviews/research) in progress
– Every year lists areas for submission of research
proposals – competitive process
Problems
– Many new technologies – limited resource –
prioritisation process
– Delays in assessment
– Delays in issuing guidance
– Argument about guidance issued
– Drug companies have the most money
Be able to describe how a
new drug and a new medical
or surgical technique should
be evaluated using RCT
methods
New drug
• Initial work on animals & cell cultures
• Phase 1 – initial testing on humans
Actions/metabolism/major side-effects (few dozen)
• Phase 2 – controlled experiments
Effectiveness and common side-effects (<1000)
• Phase 3 – clinical trials
comparison with standard treatments
(thousands)
• Phase 4 – post licensing after release
monitoring and new uses
New drug
• Licensing depend on results of phase
3 clinical trials
• No option with new drugs
• This work is often supported by
money from drug companies
• The shape of an RCT testing drug A
against drug B has been described
Screening Programme
• Does Screening for Colorectal cancer
improve survival?
• Plan A – biased study:
Offer screening to a population – measure
mortality from colorectal cancer in
screened versus non-screened individuals
Very likely that more health conscious people
present for screening
Screening Programme
• Does Screening for Colorectal cancer
improve survival?
• Plan B - RCT:
People in the target age range randomly
allocated to receive an invitation for
screening or not
Measure mortality from colorectal cancer in
those offered screening and compare with
those not offered screening
Also measure side-effects of screening
Screening Programme
• Does Screening for Colorectal cancer
improve survival?
• Three high quality RCTs of screening
for colorectal cancer have been
performed.
• Results show that mortality can be
reduced by 15%
• But further evaluation is needed…..
Screening Programme
• Should we set up a screening programme?
• National Screening Committee considers
• Evidence for benefit
• Quality of screening in non-research setting
versus that in trial
• Costs
• Acceptability
• There are 2 pilots underway to answer
these questions
RCT Operation
• The UK small aneurysm trial
• Lancet 1998 1649-54
• Early elective surgery prevents
rupture of abdominal aortic
aneurysms but operative mortality is
5-6%
• Risk of rupture for aneurysms smaller
than 5cm seems low
RCT Operation
• The UK small aneurysm trial
Question: Does prophylactic open surgery
decrease long-term mortality risk for small
aneurysms?
Method:
1090 patients aged 60-76 years with
symptomless aaas 4.0-5.5 cm diameter
Randomly assigned to elective open surgery OR
ultrasound surveillance
Follow-up for 4.5 years
Primary end-point = death
RCT Operation
The UK small aneurysm trial - results
Overall hazard ratio for all-cause mortality in
the early surgery group compared with the
surveillance group was 0.94 (confidence
interval 0.75-1.17 p=0.56).
Mortality did not differ between groups at 2, 4
or 6 years
Conclusion: Ultrasonographic surveillance for
small aaa is safe, and early surgery does not
provide a long-term survival advantage. Our
results do not support a policy of open
surgical repair for abdominal aortic aneurysm
4.0-5.5cm diameter
RCT Operation
• The UK small aneurysm trial
Problems in clinical research
• Conflict between the way Universities are
assessed and NHS priorities
• Political aspects in the NHS - who decides
the research priorities
• Pharmaceutical bias where drugs are
assessed more than other technologies
catch 22 situation cos once assessed there
is pressure to introduce them into practice
so other technologies lag even further
The Future
• Better understanding of the need to
evaluate all Health Care interventions
in the best possible way probably by
RCTs
• Better participation and
understanding and therefore
empowerment of patients