Risks

1
Risks Benefits in Research Special Reference
to Pediatric Research

• Nahed Moustafa, MD
• Professor Head of Forensic Med. Clinical
  Toxicology Department, Suez Canal University
• Certified Trainer of Research Ethics, Maryland
  University, USA

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Agenda

• Introduction
• Historical examples of risky pediatric clinical
  research
• Favorable risk- benefit ratio
• Risks Components, Types, Grades, Minimization
• Benefits
• Minimization of risks in pediatric research.

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Introduction

• Research Ethics Committee (REC) is charged with
  mandate of protecting the rights and welfare of
  research subjects
• REC spend
• - much time reviewing
• the informed consent
• - little time analyzing
• the risks potential benefits

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Introduction-2

• Because of childrens increased vulnerability,
  guidelines
• requires the permission of a parent or legal
  guardian
• strictly limits the research to which children
  may be exposed

5
Some Historical Examples

• Willowbrook State Hospital for the Mentally
  Retarded (1950s 1960s)
• Institutionalized children were purposefully
  infected with hepatitis virus to study the
  natural history and epidemiology of the disease
  in children

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Favorable Risk-Benefit Ratio

• Potential benefits are enhanced
• Risks are identified and minimized
• The potential benefits to individual subjects
  society are proportionate to or outweigh the
  risks

Justification Beneficence, Nonmaleficence, Non-ex
ploitation
Risk
Benefit
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Risks To Whom?
To Society
To Subject
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Risks Components

• Magnitude of harm
• Death
• Slight discomfort
• Probability of harm
• - 1/ 1,000,000
• - 1/ 10

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Types of Risks
Physical
Social
Economic
Psychological
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Types of Risks-2

• Physical subjects may suffer bodily harm
• minor or serious
• temporary or permanent
• immediate or delayed
• Psychological
• Survey research
• Genetic testing
• Social
• breach of confidentiality
• Stigma
• Discrimination
• Economic
• Travel to clinic

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Levels of risks
Minimal
Above minimal
Too risky
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Levels of risks-2

• Minimal risk The probability 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

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Levels of risks-2

• Minimal Risk
• Regulations do not index it to a particular
  pediatric population
• Institute of Medicine Recommendations -- Minimal
  Risk
• Normal experiences of average, healthy, normal
  children (absolute standard)

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Levels of risks-3

• Minimal risk is used as
• 1-sorting mechanism directing the attention of
  REC to studies posing greater risks
• 2- threshold limiting the amount of
  non-therapeutic risk to which vulnerable
  research subjects may be exposed

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Levels of risks-4

• Minimal risk may be age dependent
• (blood draw may be minimal risk for an adult but
  not for a young child!!!)
• Remember
• The risks need not be physical in order to be
  greater than minimal risk
• e.g., privacy confidentiality risks push the
  study into greater than minimal risk

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Levels of risks-5

• Minimal Risk
• Seems to raise more questions than it answers!

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Mimimization of Risk

• Proper research design
• Inclusion/exclusion criteria
• exclude high risk/vulnerable subjects
• Strict withdrawal criteria
• Alternation in study design
• Emergency medication
• Availability of resources
• (well equipped research center)
• Confidentiality protections
• Safety monitoring
• Qualified personnel
• Compensation provisions

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Benefit to whom?
To Research Subject
To Society
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Benefits to Research Subjects

• Direct Benefit
• arising from the intervention being studied
• information that can influence care
• Collateral Benefit
• Also called indirect benefit
• access to medical care not available for economic
  reasons
• Inspirational
• Altruism
• Aspirational
• benefit to society (arises from the results of
  the study)

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Benefits to Research Subjects-2

• Payments or incentives benefits???
• Should not be considered as benefits in the
  calculation of risk/benefit ratio
• REASON Any level of research risk could be
  offset by such gains if they were significant
  enough

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We have to avoid
Undue-inducement
coercion
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Benefits to Research Subjects-2

• No benefits from the research
• Phase I trials that are testing maximum tolerated
  dose
• Non-therapeutic research procedures
• e.g., Mechanism of disease

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Benefits to Society

• Specific new, effective intervention
• Post-trial availability
• Knowledge which sometimes in the future may lead
  to effective interventions

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Risk Judgments in vulnerable populations

• Persons incapable of giving informed consent
• Patients with psychiatric illnesses
• Patients with dementia
• Patients with acute critical illnesses
• Children

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Minimization of risks in pediatric research

• REC that regularly reviews pediatric research
  should include one or more individuals who are
  knowledgeable in pediatric ethical, clinical and
  psychological issues

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Minimization of risks in pediatric research-2

• REC should consider the risks from the childs
  perspective not simply focus on physical and
  economic risks.
• For example the research area should be child
  friendly i.e. has a space for parents to remain
  with the child

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Minimization of risks in pediatric research-3

• REC should approve the research design that
  minimizes the risks, e.g.,
• A protocol that can not answer the research
  question should not be approved
• A sample size that exceeds the number of children
  necessary to answer the research question expose
  additional children to unnecessary risks, should
  not be approved

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Minimization of risks in pediatric research-4

• 3- A pediatric trial requires different efficacy
  endpoints based on considerations of age
  development of the subjects
• 4- A pediatric trial may need to evaluate any
  adverse impact on
• physical cognitive
• growth development

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Minimization of risks in pediatric research-5

• Minimizing discomfort distress
• Skillful persons
• Play equipments
• Food appropriate for age
• A familiar environment in which he usually has
  his care hospital or clinic
• Minimizing the blood volume withdrawn through the
  use of sensitive assays
• Use indwelling catheter rather than repeated
  veni-puncture for blood sampling

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RiskBenefit Determination Vulnerable Subjects
Protocol
Non-Therapeutic Procedures
Therapeutic Procedures
Risks Identified Risks Minimized
Risks Identified Risks Minimized Test of
Clinical Equipoise
Risks Reasonable to Knowledge to be Gained
Risks Reasonable to Benefits
Maximum Risk Threshold No More Than Minor
Increase gt Minimal Risk
Acceptable Only If For Both Therapeutic/
Non-Therapeutic Procedures
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• The previous slide quoted from
• Weijer, C. (2000) The ethical analysis of risk.
  Journal of Law, Medicine and Ethics, 28 344-361

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Remember

• Trust
• can take years to build and a moment to break

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Thank you
nmoustafa2004_at_yahoo.com