Transcript Document

Experiments with Static Electricity in the Nursery:
Ethical Complexities in Pediatric Research
Benjamin S. Wilfond MD
Seattle Children’s Hospital
Treuman Katz Center for Pediatric Bioethics
Center for Clinical and Translational Research
University of Washington
Division of Bioethics, Department of Pediatrics
Center for Genomics and Healthcare Equality, Department of Bioethics and Humanities
Regulatory Support and Bioethics Core, Institute of Translational Health Sciences
When are randomized controlled trials
appropriate in pediatrics?
• Placebo controlled trials of controller medications for
asthma?
NHLBI asthma guideline adherence in clinical
asthma trials including children (n = 70)
Coffey, M. J. et al. Pediatrics 2004;113:87-94
When are randomized controlled trials
appropriate in pediatrics?
• Placebo controlled trials of controller medications for
asthma?
• RCT of newborn screening for cystic fibrosis?
Impact of cystic fibrosis newborn screening on height and
weight in a trial involving 650,000 randomized children
Farrell, P. M. et al. Pediatrics 2001;107:1-13
When are randomized controlled trials
appropriate for surgical interventions?
• Video-assisted thoracoscopic surgery and fibrinolytics for
empyema?
Comparison of urokinase and video-assisted thoracoscopic
surgery for treatment of childhood empyema
Am J Respir Crit Care Med. 2006 Jul 15;174(2):221-7
When are randomized controlled trials
appropriate for surgical interventions
• Video-assisted thorascopic surgery and fibrinolytics for
empyema
• Arthroscopic surgery vs placebo surgery for
osteoarthritis
A controlled trial of arthroscopic surgery for
osteoarthritis of the knee
N Engl J Med. 2002 Jul 11;347(2):81-8.
What is special about pediatric research?
• Historically both “understudied” and “overstudied”
• Children may be vulnerable to
• Not understand the risks and benefits of research
• Not be able to object to enrollment
• Children may enroll in research
• Not in their interest
• Against their wishes
• “Protecting” children in 45 CFR 46
•
•
•
•
Limiting risks
Parental Permission
Adolescent consent
Child Assent
Limiting pediatric research based on risks and
benefits (45 CFR 46.404-407)
Minimal risk
Minor increase
over minimal risk
Risk is justified
by the benefits
Prospect of
direct benefit
404
Risk/benefit is as
favorable as
alternatives
405
Commensurate
experiences
No prospect of
direct benefit
Vital knowledge about
subjects disorder
404
406
Greater than minor
increase over
minimal risk
Risk is justified
by the benefits
Risk/benefit is as
favorable as
alternatives
405
Address serious
problem affecting
children
407
What is Minimal Risk?
•
The US regulations define minimal risk as:
“Probability and magnitude of harm or discomfort anticipated in
the research are not greater in and of themselves than those
ordinarily encountered in daily life or during the performance
of routine physical or psychological examinations or tests”
45CFR 46.102(i)
Use of minimal risk as criterion for:
• IRB review (expedited)
• Waiver of consent
• Waiver of documentation of consent
• Prohibition of some research
Survey of IRB Chairs (N=188)
Minimal Risk
Minor increase
More than a Minor
increase
Blood draw
82%
17%
1%
Sexual activity survey
45%
30%
25%
Allergy skin testing
23%
43 %
27 %
PK Study
1/100,000 chance of
death
8%
30%
59%
LP
6%
24%
70%
Drug tested safe in 500
adults
5%
23%
65%
Shah S, et al. JAMA 2004 291:476-482
Risks of Research Procedures
Per million
events
(Wendler and Emanuel 2005)
Nausea
Syncope
Surgery
Deaths
Drawing Blood
375
0
0
Allergy Skin
Testing
1625
0
0
< 500
0
Research
Apheresis
Basketball
Car Ride
10,000
160
0.4
Charitable Participation Standard as a normative
interpretation of minimal risk (Wendler and Emanuel 2005)
• Children are exposed to risk for the benefit of parents, siblings, and
neighbors
• Children are exposed to risk for their own psychological benefit in doing
charity
• Habitat for Humanity,
• Shoveling snow for a neighbor
• Research is like this type of charity
• Minimal risk standard should expose children to the same risks that would
be permitted for charitable activities
8 Ethical Benchmarks of Research
1.
Collaborative Partnership
2.
Social Value
3.
Scientific Validity
4.
Fair Subject Selection
5.
Favorable Risk-Benefit Ratio
6.
Independent Review
7.
Informed Consent
8.
Respect for Human Subjects
Emanuel et al. (2000) JAMA; (2004) J Infect Dis
Justifications of placebos
• Scientific validity
• Social value
• Risks and benefits
• Each arm compared to standard approach
• Minimizing risks
• Inclusion criteria
• Study duration
• monitoring
Goals are different and constrained by
ethical obligations
Benefit to
patient and
family
Clinical Care
Promote
scientific
knowledge
Research
Joffe and Miller. Hastings Center Report 2008
Elements of Informed Consent
• Decisional Capacity
• Ability to understand options
• Comprehension
• Context dependent
• Ability to understand
consequences of actions
• Ability to relate consequences
to set of personal values
• Voluntariness
• Persuasion
• Coercion
• Disclosure
• Reasonable practitioner
• Reasonable patient
• Particular patient
Approaching informed consent
• Content
• Inverse relationship between
disclosure and comprehension
• Context
• Communication style
• Communication setting
• Family’s life circumstance and
situation
• Clinical
• Cultural
Consent/Assent/Permission
• Parental Permission
• Not the same as consent
• More limited scope and authority than consent
• Adolescent Consent
• In addition to parental permission
• In place of parental permission in some contexts
• Child Assent
• Not necessary in all research
• Not “mini-consent”
• Obtaining assent vs respecting “dissent”
• Limited disclosure and volunatiness
Assent for a blood draw?
• Can the parents tell his child she should do it?
• What if the child does not understand what the blood will
be used for?
• What if the child does not know she has a disease?
• What if the child says she doesn’t want it?
• What if the researchers pays $20
• What if the parents gives his child $20
• What should happened when the child is older: can the
research continue?
Research Bioethics Consultations
Providing a forum for discussion and analysis of ethical
issues in clinical and translational research
The Institute of Translational Health Sciences provides a wide range of range of resources to promote translational research. ITHS offers Research Bioethics
Consultations as a resource to researchers, trainees, research staff, IRBs, research participants and their families and communities.
Bioethics consults are advisory in nature, providing an opportunity for in-depth conversation and analysis of ethical issues in clinical and translational research,
and can be requested for urgent issues related to a particular research participant. Any recommendations provided are supplemental to the authority and
oversight of other groups involved in reviewing the research, like an IRB or
DSMB.
EXAMPLES OF CONSULT QUESTIONS
Consultation discussions can take place by telephone or in-person. If
requested, the consultant can provide a written report of the considerations
and recommendations.
Community Engagement
• How can I establish sustainable relationships with communities?
• How should I negotiate disagreements with community stakeholders?
• How should I share the research data with the community?
Consultation details may be discussed amongst the bioethics consultants,
but these will not be discussed with others involved in the issue without
the requestor’s permission.
Study Development
• Should I provide incentives for participation?
• What if informed consent isn't practical for my study?
• When is a placebo-control ethically appropriate?
To ensure a balanced understanding of the facts or to facilitate
reconciliation of a conflict, the consultant is available talk to others involved
in the issue if desired by the requestor.
Study Implementation
• What should I do if a participant doesn't have the capacity for consent?
• Can I withdraw a participant against his/her wishes?
• What must I do if my participants need medical care or other help?
Study Analysis
• Should I tell participants about their research findings?
• What if a participant requests their data be withdrawn?
• Who should be an author on the publication of my study?
In some cases, full consideration of the issue may warrant additional
consultation in another area. The consultant may recommend referral to
legal counsel, ombudsperson, psychiatry, human resources, etc.
There is generally no charge for research bioethics consultations. ITHS
membership is not required for individuals or groups requesting
consultations.
To request a consultation or to find out more:
Call (206) 987-2000
Ask for the Research Bioethicist on-call
Conclusions
• The ethical principles for research are not the same as
for clinical care
• Randomized controlled trials can be justified based on
scientific need/social value and risk/benefit
• In pediatric research
• Limit exposure to risks
• Attention to parental permission
• The goal of assent is engage with children in a developmentally
appropriate manner: not “mini” assent
• Don’t hang babies from ceilings (without a net)