Transcript Proportionality – regulate the banks, keep off the backs

Proportionality – regulate the banks,
keep off the backs of clinical researchers
Charles Warlow, Edinburgh
Centre for Socio-legal studies, Oxford
March 2009
Alder Hey retained organs scandal
Bristol Heart Scandal
These were nothing
whatsoever to do with
research approved by a
Research Ethics Committee
– and nor are eRecords
Harold Shipman
Types of clinical research – ie research
on/with patients (and their tissues)
• Invasive - from biopsy to catheterising arteries to taking a
blood sample – consent unarguable (almost)
• Non-invasive – from interviewing, to questionnaire, to
medical records – consent perhaps not always necessary
• Interventional – randomised and non-randomised
therapeutic interventions ie drugs (eg Northwick Park),
surgery, physiotherapy, systems of care (eg stroke units) etc
- consent surprisingly variable for non-randomised studies
The risks of harm are very different, but so too is the potential
to affect larger or smaller numbers of patients – so get things
into proportion
Increasing research regulation
Statutory regulation
UK Data Protection Act (1998)
UK Human Rights Act (1998)
•
Health
and Social Care Act (2001) (England and Wales)
•
Adults with Incapacity (Scotland) Act (2000)
European Clinical Trials Directive (2001)
Human Tissue Act (2004) (England and Wales)
Mental Incapacity Act (2005) (England and Wales)
Human Tissue Act (2006) (Scotland)
•
Guidance from professional bodies
General Medical Council
Confidentiality & security advisory group for Scotland (CSAG)
World Medical Association
Medical Research Council
British Medical Association
Department of Health
Royal College(s) of Physicians etc etc etc
Wasting researchers’ time, but this may
if recorded and published change the
system
Research ethics committee practice
in Scotland: a story from 1998
• Observational population-based study
of incidence and prognosis of
intracranial vascular malformations
• Multicentre Research Ethics
Committee (MREC) approval July
1998
• Then to the Local Research Ethics
Committees (LRECs) of 15 health
boards
LREC receipt to meeting:
standard 2 weeks
Median delay = 28 days
Application to LREC approval
Median delay = 39 days
Each LREC required
• one copy of the protocol
• a variable number of copies of:
–
–
–
–
MREC application form
Local investigator form & CV
MREC correspondence
Consent form & info. sheet
23 pages
8 pages
6 pages
7 pages
_______
44 pages
A4 pages used
5789 A4 pages, weighing
26.9 kg
….. and all for three trivial
modifications, one not
within the local committee’s
jurisdiction
literally weighing…
A new era: Central Office for Research
Ethics Committees (COREC) in 2000
COREC established by (English) Department of Health
(UK liaison) in 2000
– distributes decision-making to any resaerch ethics
committee (REC)
– uniform on-line application form, albeit lengthy
– extended jurisdiction of one REC decision
– focus on process of REC review
• implement, develop, maintain, standardise & oversee
process; training; appeals; information
• European Clinical Trials Directive (2001)
• Good clinical practice (GCP) for all types of research, not
just trials
Another new era: National Research
Ethics Service (NRES) 2007 –
The process of ethics approval is improving
• emphasis on national (UK) and service (with advice)
• aims for consistency, between and within RECs
• time lines (measurable but ?relevance – what about quality?)
• not meant to review the science
But still no transparency such as release of minutes, or research
into the process itself (variation in decision making?), or
quality
Adults with Incapacity
(Scotland) Act 2000
No surgical, medical, nursing, dental or psychological research shall be
carried out on any adult who is incapable in relation to a decision about
participation in the research unless—
(1) research of a similar nature cannot be carried out on an adult who is capable
in relation to such a decision; and the circumstances mentioned in subsection
(2) are satisfied.
(2)The circumstances referred to in subsection (1) are that—
(a) the purpose of the research is to obtain knowledge of—
the causes, diagnosis, treatment or care of the adult’s incapacity; or the
effect of any treatment or care given during his incapacity to the adult
which relates to that incapacity; and
(b) the conditions mentioned in subsection (3) are fulfilled.
(3) The conditions are—
- the research is likely to produce real and direct benefit to the adult;
- the adult does not indicate unwillingness to participate in the research;
- the research has been approved by the Ethics Committee;
- the research entails no foreseeable risk, or only a minimal foreseeable
risk, to the adult;
- the research imposes no discomfort, or only minimal discomfort, on the
adult; and
- consent has been obtained from any guardian or welfare attorney who
has power to consent to the adult’s participation in research or, where
there is no such guardian or welfare attorney, from the adult’s nearest relative.
Why it may be misleading to use the
results of a trial in mild strokes to inform
the treatment of severe strokes
100 severe strokes: 60 die reduced by 10% to 54 by treatment
100 mild strokes: 30 die reduced by 10% to 27 by treatment –
same relative risk reduction which is a reasonable expectation,
but very different absolute risk reduction
But, treatment causes 2 fatal cerebral haemorrhages/100
treated irrespective of initial stroke severity
Therefore, for severe strokes:
Treatment avoids 4 deaths/100 treated (60 – 54 + 2):
…..number-needed-to-treat to avoid one death = 25
but for mild strokes only 1 (30 – 27 + 2):
…..number-needed-to-treat = 100
Amendment December 2006 of Adults with Incapacity (Scotland) Act, 2000
Where the research consists of a clinical trial of a medicinal product, the
research may be carried out b) without the consent of any guardian or welfare
attorney, or the adult's nearest relative, if it has not been practicable to contact
any such person before the decision to enter the adult as a subject of the
clinical trial is made, and consent has been obtained from a person, other than
a person connected with the conduct of the clinical trial, who is (A) the doctor primarily responsible for the medical treatment provided to that
adult, or (B) a person nominated by the relevant health care provider.
(c) without the consent of any guardian or welfare attorney, or the adult's
nearest relative, if treatment is being, or is about to be, provided for an adult
who is incapable in relation to a decision about participation in the research as
a matter of urgency;
(ii) having regard to the nature of the clinical trial and of the particular
circumstances of the case it is necessary to take action for the purposes of the
clinical trial as a matter of urgency;
(iii) it has not been reasonably practicable to obtain the consent of any such
person;
(iv) it has not been reasonably practicable to obtain the consent of any of the
persons mentioned in paragraph (b) (A) or (B); and
(v) the action to be taken is carried out in accordance with a procedure
approved by the Ethics Committee
“Where the research consists of a clinical trial
of a medicinal product………..”
So where does that leave a clinical trial of out of hospital
defibrillation for cardiac arrest, or a study of a blood
biomarker for status epilepticus vs pseudo-status, for
example?
Consent for observational studies – in
particular medical records
Non-intrusive observational studies
(research, audit, service planning, public
health monitoring, drug safety etc)
• Identifiable (non-anonymised) data are often required
– for record linkage
– to identify individuals during follow-up
– to sort out diagnoses (eg epilepsy, migraine, even stroke)
– to avoid double counting
– to avoid consent bias
– for control patients
– for indirect follow up via GPs, hospital discharges, deaths
• Ideally consent should be obtained from patients for use of their
identifiable data but this may be impractical or impossible
(dead, demented, anxious, unaware of diagnosis, too many etc)
• Data Protection Act is a problem but its over-interpretation even
more so (GMC, Section 60 Health & Social Care Act, England)
The underlying tension between patient
confidentiality and the public health
Confidentiality
individualism
autonomy
rights-based
citizenship
risk of disclosure
Disclosure
collectivism
social responsibility
benefits of data
sharing
The key test is surely proportionality,
but this requires judgement – not the application
of rigid rules by bureaucrats
The Data Protection Act,1998 third
schedule
Any use of identifiable data relating to the “physical or
mental health or condition of a living individual requires his
or her informed consent”……..
but there is a qualification: or that the “processing is
necessary for medical purposes” (which most have
assumed to include medical research)
“The [Data Protection Act 1998] itself does not
necessarily require consent for the use of health
information in medical research. The key is to ensure
that people know what is happening with their
information. The [Information Commissioner] takes the
same view as that expressed by Mr Havers – namely,
that researchers could be bolder. The statute sets out
broad principles for handling personal information. It is
not about absolutes.”
David Smith, Deputy Information Commissioner
Lothian Health Board: Information
for Clinical Audit
We may record some of your personal health information in
databases used by doctors and others for clinical audit.
This is one way in which we maintain high-quality care; we
will check a group of similar cases to your own against
agreed standards to see where improvements can be
made. Some of these audits are done over groups of
hospitals, over Scotland or even the whole UK. In these
cases we make every effort to use anonymous information.
We are obliged to act on refusal to participate if possible.
ie ‘opt out’
Lothian Health Board: Information
for Research
We may use some of your personal health information in
research. This is when healthcare staff use information
from their patients to help them find the causes of disease
and the effects of treatment and for planning new
treatments. If the research involves you personally you
will be contacted and asked for your consent.
ie ‘opt in’
Law versus guidance
• Data Protection Act
– personal data can be processed without consent
(exemptions for some forms of medical research)
• NHS Code of Practice: Confidentiality (2003)
– “…do not use/disclose identifiable data, unless
originally understood by confider, or + permission”
• GMC Confidentiality… (April 2004)
– doctors should, “…seek patients’ express consent to
disclosure of information, where identifiable data is
needed for any purpose other than the provision of
care or for clinical audit…”
The future does not look promising…
“My board is quite clear: you can’t look at patients’
records and look at confidential clinical information
without consent”
Harry Clayton, Chairman of the National Information
Governance Board, 2009
A slightly odd view considering he was
once CEO of the Alzheimer Disease Society!
"The problem about the Data Protection Act is that it is almost
incomprehensible. It is very difficult to understand. The precise
limits of it are problematic. There are constant difficulties about
what information you are allowed to share between
departments for instance. I just think it needs to be looked at
again at some stage to make it more simple"
Lord Falconer (The Constitutional Affairs Secretary),
reported in the Guardian, October 18th 2004
My own personal losses if unobtrusive health
record data collection is prohibited, or subject
to consent in every case
• The broken leg story
• The cancerous colon story
• The gall bladder story
The emphasis throughout its history has been the empirical
study of different areas of law with a view to understanding
its place and role in society. Good empirical research, we
believe, is based on well-developed theoretical ideas and
traditions, and may lead to their adjustment and deepening.
Unique opportunity in the Scottish
Intracranial Malformation Study (SIVMS)
to study the effects of consent bias
• prospective, population-based cohort study of all IVMs
presenting in adults in Scotland from 1999, with complete
prospective follow up
• we could not obtain consent from everyone (dead,
consultant/GP refusal, no response to letter)
• yet at first we had Multicentre Research Ethics Committee
approval to collect baseline and follow-up data on the whole
cohort via GP and hospital records (Record Linkage available in
Scotland)
• analysis of patients with brain AVMs enrolled 1999-2002
(n=187)
GP/consultant
approval sought to
approach patient
n=187
SIVMS
Patient approached
Patient not approached
n=131
n=56
Proxy non-consent
Consented
Refused
No-response
n=111
n=0
n=20
Implicit nonconsent
CONSENTERS
NON-CONSENTERS
Questionnaire
Medical records & GP questionnaires
Type of presentation
Initial presentation
Consenters
n
%
Non-consenters
n
%
Haemorrhage
Epilepsy
Focal deficit
Incidental
46
37
7
21
45
12
1
18
41
33
6
20
Fisher’s exact test = 11.3, p = 0.009
59
16
1
24
Dependence at presentation
Rankin
0-2 (not dependent)
3 (dependent/dead)
Consenters
n
%
77
34
Chi-square = 13.8, p = 0.0002
69
31
Non-consenters
n
%
32
44
42
58
All cause mortality
Consenters (red) and non-consenters (black)
1.1
2 outcomes
1.0
.9
.8
12 outcomes
.7
.6
Log rank=15.8 p=0.0001
.5
.4
.3
.2
.1
0.0
0
365
730
1095
Time (days)
1460
1825
Impact on an important study
finding
• All participants
– Haemorrhagic presentation of a brain AVM conferred
a higher subsequent risk of haemorrhage during
untreated follow-up
• 95 unruptured brain AVMs: 2 bleeds
• 92 ruptured brain AVMs: 8 bleeds
log rank=8.4
p=0.004
• Consenters only
– The relationship disappeared
• 59 unruptured brain AVMs: 1 bleed
• 52 ruptured brain AVMs: 2 bleeds
log rank=1.3
p=0.26
Time
firstseizure
seizure
Time
totofirst
Consenters (red) and non-consenters (black)
Consenters (red) and non-consenters (black)
1.1
1.1
1.0
1.0
.9
.9
.8
.8
.7
.7
.6
.6
.5
13 outcomes
.4
.5
42 outcomes
.3
.4
.2
.3
.2
0
.1
0.0
Non-consenters
Log rank=4.1 p=0.04
.1
0.0
365
730
1095
1460
1825
Time (days)
0
76
365
49
730
37
1095
23
Time (days)
1460
6
1825
1
Conclusions
• Consenters are systematically different from non-consenters in
unpredictable ways: this cannot be estimated in advance
• The only way to measure consent bias is by obtaining data from
non-consenters – Catch 22
• Insistence on consent from everyone will:
– be increasingly difficult and costly, waste investigator time on
REC forms and delay research, and waste time with
designing and administering consent forms
– harm some individual patients (over-consent)
– bias non-intrusive observational research
– which will then get the wrong result
– which will damage individual and public health
– and waste public money on research and practice
– less observational research will be done
What better way to waste money and damage patients?
To cut the red tape
• do not over react to the law (like many ethics committees)
• better organise and fund only necessary bureaucracy and have
it dealt with by well resourced support staff (NRES)
• greater research professionalism (governance issues)
• better involve patients (eg James Lind Alliance)
• better inform the media (double-edged sword)
• exploit +++ your own experiences as a patient
• evidence based criticism, or anecdotes, depending on the
audience
• rebadge research as audit – SIVMS was saved by SAIVMS –
Scottish Audit of Intracranial Vascular Malformations
Medical researchers are not alone………
We are swimming in a bureaucratic sludge, awash with
consultancies, incomprehensible accountancy language, overmanagement, juvenile debate on aims and strategies, pseudo
business practice and the dreaded “mission”
Gerry Mulgrew, New Communicado Theatre Company,
letter to the Scotsman on 1st June 1999
So how do I feel?
• Irritated - because of the constant trivia brought up by minor
bureaucrats, and the huge opportunity costs of keeping them
happy
• Exhausted - because of the extreme effort to get through all
the regulation from ethics to R&D to insurance issues, to
sponsorship problems, to contracts with all and sundry
• Insulted - to be told how to do clinical research by people who
have done little if any themselves
• Angry - because (over) regulation can force researchers either
to do bad research with misleading results, or to give up
research altogether (private practice can be very tempting)
• Even angrier - because my own health is being compromised
by over-regulation, as well as the health of countless others
I want to be trusted……
Despite their very occasional
failings, today I put my
trust in…
There has never in the UK been a successful prosecution
for the inappropriate use of medical records for research –
so again, get regulation in proportion to the risk of harm and
trust researchers, regulated by ethics committees and the
GMC, not to abuse confidential medical records
But we researchers do need to be
responsible, professional and
careful….The Herald, 27th October 2008
Would you trust
these people….
regulate the bankers!
Allen Stanford
Bernie Madoff
Fred the shred Goodwin