Refining the Declaration of Helsinki’s additional protections for research in children

A N N A W E S T R A , M A , M D , P H D
J U L I A N A C H I L D R E N ’ S H O S P I T A L , T H E H A G U E /
D E P . O F M E D I C A L E T H I C S , E R A S M U S M C , R O T T E R D A M
1 1 T H W O R L D C O N G R E S S O F B I O E T H I C S
W M A S A T E L L I T E M E E T I N G :
T H E F U T U R E O F T H E D E C L A R A T I O N O F H E L S I N K I
R O T T E R D A M , J U N E 2 6 T H , 2 0 1 2
Refining the Declaration of
Helsinki’s additional protections
for research in children
a.e.westra@lumc.nl
1
Anna E. Westra
Helsinki’s Paragraph 27
 For a potential research subject who is incompetent,
the physician must seek informed consent from the
legally authorized representative.
 These individuals must not be included in a research
study that has no likelihood of benefit for them
unless it is intended to promote the health of the
population represented by the potential subject, the
research cannot instead be performed with
competent persons, and the research entails only
minimal risk and minimal burden.
a.e.westra@lumc.nl
2
Anna E. Westra
Presentation
I will argue
1. Why I endorse the focus on protection of this group
of subjects, as well as the central role of the
requirement of minimal risk and burden
2.That Paragraph 27 however is not very subtle,
and how the two issues that deserve most attention
could be dealt with
3.Why now, time has come for refinement
a.e.westra@lumc.nl
3
Anna E. Westra
a.e.westra@lumc.nl
Anna E. Westra 4
Presentation
I will argue
1. Why I endorse the focus on protection of this group
of subjects, as well as the central role of the
requirement of minimal risk and burden
2.That paragraph 27 however is not very subtle,
and how the two issues that deserve most attention
could be dealt with
3.Why now, time has come for refinement
a.e.westra@lumc.nl
5
Anna E. Westra
Background: the ethical dilemma
• Research with children is necessary to improve
prevention and medical care for children as a group
• Not all necessary data can be provided by studies that
are likely to benefit the subjects themselves
• Risks and burdens that are not compensated for by
potential benefits are faced purely for research reasons:
the so called ‘net’ research risks and burdens
• Children cannot consent to facing these risks/burdens
a.e.westra@lumc.nl
6
Anna E. Westra
Ways of dealing with this dilemma
a.e.westra@lumc.nl
Anna E. Westra
7
Focus on the importance of the research
1. No additional protective measures at all
2. Only some basic additional safeguards: benefit for the group;
not possible with competent adults; risks and burdens as low as
possible (European CTD)
Focus on protection: such research only acceptable if
1. No risks or burdens at all
2. Minimal risk and burden (Helsinki; European Convention)
3. Subjects that are healthy: Minimal risk and burden;
Subjects with the disease: A minor increase over minimal (US)
Helsinki’s choice seems best
a.e.westra@lumc.nl
Anna E. Westra
8
 Focus on protection seems valid:
 Proxy consent does not have the same moral value as informed
consent (altruism seems to be rather personal)
 Risk of using children merely as a means
 Minimal risk and burden requirement seems valid:
 No risk and burden at all, is not necessary1
 No valid grounds for allowing a minor increase over minimal
risk for all subjects with the disease under study2
1.Wendler D. The ethics of pediatric research, 2010; 2.Westra AE et al. Regulating ‘‘Higher Risk, No Direct Benefit’’ Studies
with Children: Challenging the US Federal Regulations. In: Schildmann J et al, eds. Human Medical Research, 2012
Presentation
I will argue
1. Why I endorse the focus on protection of this group
of subjects, as well as the central role of the
requirement of minimal risk and burden
2.That paragraph 27 however is not very subtle,
and how the two issues that deserve most attention
could be dealt with
3.Why now, time has come for refinement
a.e.westra@lumc.nl
9
Anna E. Westra
Paragraph 27: not very subtle
a.e.westra@lumc.nl
Anna E. Westra
10
 Issue 1:
When distinguishing between studies with and
without potential benefit, the ‘net’ research risks and
burdens often cannot accurately be identified
 Issue 2:
Not all children need the same level of protection
Research in children versus in adults
 More complex ethical review process:
The net research risks and burdens should be minimal
 More need to identify the net research risks and burdens
 More complex study designs:
 More often combined with medical care
 More often a mixture of components
 More difficult to identify the net risks and burdens
a.e.westra@lumc.nl
11
Anna E. Westra
a.e.westra@lumc.nl
Anna Westra
12
Example study (ADHD)
1. Visits to hospital (30x)
2. Medication washout
3. Treatment with the new drug (initial 12 wks)
4. Treatment with the new drug after good response,
or placebo treatment (6 or 9 months)
5. Blood draw (6x); ECG (6x); physical examination
including pubertal staging (5x)
Buitelaar JK et al. Biological Psychiatry 2007;61:694-699
Study-level approach is inadequate
 Paragraph 27 distinguishes between studies
with/without potential benefit
 To adequately identify the net research risks/burdens,
study components require separate moral evaluation
 Procedures that are performed pure for research reasons:
 risks and burdens should be minimal
 Procedures that have potential benefits for the subjects
(i.e., those that are combined with medical care):
 risk/benefit profile should be acceptable
a.e.westra@lumc.nl
13
Anna E. Westra
Recommendation 1
a.e.westra@lumc.nl
Anna E. Westra
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 To stimulate research ethics committees to more
accurately identify those risks and burdens that the
research subjects have to undergo purely for research
reasons and that thus have to be minimal,
 by distinguishing between research procedures with
and without potential benefit instead of between
studies with and without potential benefit
Westra AE et al. The merits of procedure-level risk-benefit assessment. IRB 2011;33(5):7-13.
Paragraph 27: not very subtle
a.e.westra@lumc.nl
Anna E. Westra
15
 Issue 1:
When distinguishing between studies with and
without potential benefit, the ‘net’ research risks and
burdens often cannot accurately be identified
 Issue 2:
Not all children need the same level of protection
Not all children need equal level of protection
 With increasing age, children are increasingly capable
 of understanding the proposed study
 of making their own informed decisions
 If a child is generally capable of doing so, it can be
asked for its assent
 If a child can give assent: less need for protection
(although still extra protection as compared to adults)
Westra AE et al. Am J Bioeth. 2011;11(6):29-31. a.e.westra@lumc.nl
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Anna E. Westra
Helsinki’s Paragraph 28
• When a potential research subject who is deemed
incompetent is able to give assent to decisions
about participation in research, the physician must
seek that assent in addition to the consent of the
legally authorized representative.
• The potential subject’s dissent should be respected
a.e.westra@lumc.nl
17
Anna E. Westra
Recommendation 2
To allow for exceptions to the minimal risk and
burden requirement in cases of studies that involve
children who can give their assent to participate in
the study; and that involve at most a minor increase
over minimal risk
a.e.westra@lumc.nl
Anna E. Westra
18
Paragraph 27 with revisions (1)
 For a potential research subject who is incompetent,
the physician must seek informed consent from the
legally authorized representative.
 These individuals must not be included in research
procedures that have no likelihood of direct benefit
for them unless these procedures are essential parts
of a research study that is intended to promote the
health of the population represented by the potential
subject and that cannot instead be performed with
competent persons, and all together, these
procedures entail only minimal risk and burden.
a.e.westra@lumc.nl
19
Anna E. Westra
Paragraph 27 with revisions (2)
• The minimal risk and burden requirement does
not apply to studies involving subjects who are
able to give assent and involving at most a minor
increase over minimal risk and/or burden.
a.e.westra@lumc.nl
20
Anna E. Westra
Presentation
I will argue
1. Why I endorse the focus on protection of this group
of subjects, as well as the central role of the
requirement of minimal risk and burden
2.That paragraph 27 however is not very subtle,
and how the two issues that deserve most attention
could be dealt with
3.Why now, time has come for refinement
a.e.westra@lumc.nl
21
Anna E. Westra
Refining paragraph 27: why now?
a.e.westra@lumc.nl
Anna E. Westra
22
 Currently, many drugs prescribed for children have
not been proven safe and effective for them
 Extrapolation from adult studies: often inappropriate
 Need for trials has been increasingly recognised: US
and EU have taken stimulative measures (financially)
 These measures have made optimizing the system
that protects the subjects all the more pressing
a.e.westra@lumc.nl
Anna E. Westra
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