Clinical Trials in ChildrenEthical and practical issues

goes hand in hand

Ansgar BergProfessor / Clinical Research Physician

Pediatric Clinical Research Unit

Haukeland University Hospital

Bergen, Norway

Putting children first –Communicating the Need for Pediatric

Studies

We want children to benefit from the dramatic

and accelerating rate of progress in medical

care that is fueled by scientific research.

Putting children first -Communicating the Need for Special

Protection

At the same time, we do

not want to place any

children at risk of being

harmed by participating in

such research, even though

their very involvement may

be essential to improving

the overall medical care of

children.

Access versus Protection

The concern is how best to balance these potentially conflicting objectives

Pediatric research in the 21st century

• The barriers to inclusion of children in research studies have drawbacks:

– Medical treatment of children is often based upon extrapolating data from adults

– Scientifically evaluated treatments are less available to children

– Delayed access to new treatments = loss of lives

• The goal today is to encourage pediatric research and reflects a shift in focus from protection to access

o Change from protecting children against clinical

research to protecting children through clinical research

Medicines for ChildrenEU Paediatric regulation

• In force in all Member States since 2007

– Combination of carrot and stick (incentive vs. threat)

• Incentive: patent extension

• Threat: no validation of submission without agreed PIP

• New key institution: EU Paediatric Committee (PDCO), composed by representatives from each member state

– Coordinated by EMA

• Paediatric Investigation Plan (PIP) for patented drugs for new indications and for new drugs at the end of human PK

6

Important issues related to children participation in clinical

research

• Fundamental ethical principles

– Informed consent

– Risk and harm

• Scientific complexity

Informed Consent

Children as Vulnerable Subjects

• Vulnerable research participants are persons who are relatively or absolutely incapable of protecting their own interest.

• Most children do not have the capacity to provide their own consent and someone else than the child has to make the decision about participation in research.

• Children are therefore more vulnerable than competent adults and need special protection

How does the researcher obtain ”informed consent” in children

• Informed consent in pediatrics = Parentalpermission + voluntary assent from the child

Parents Investigator

Child

Which Children Can Assent?

• An assent is simplified, single page version of the main consent that explains what is going to take place to the child if s/he agrees to take part

• Most guidelines require the positive agreement (”assent”) of children who are capable of providing it.– However the guidelines do not specify which children

are capable of assent.

– In Norway regulations state that this determination should take into account the ”age, maturity and psychological state of the child”

Current Data

• The existing data suggest children are able to make their own research decisions by the age 12-15.

• The ethical committee recommends all children from 12 years of age to provide a separate assent.

– Every effort should be made to understand and respect differences of opinion between the child and his/her legal representative

Practical aspects – informed consent

Problem

• Participation based on psychosocial reasons

– Parents that protect the child

• Strong advocates

• Many questions

• Special needs

Solution

• Focus on medical issues

– Unethical not to learn the benefits of this and future children

– Children have the right to best therapy

• Agree and inform

• Give answers

• Good compliance

Practical aspects – informed consent

Problem

• Informed consent in emergency trials

– Entering children in trials without prior informed consent

Solution

• Retrospective informed consent

– from the parents should be obtained as soon as possible according national law

Assessment of Risk and Harm to Children

Categories of Risk

• Not greater than minimal risk research

• Greater than minimal risk - prospect of direct benefit to subjects

• Greater than minimal risk - no prospect of direct benefit to subjects

Minimal Risk

• ”that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinary encountered in daily life or during the performance of routine physical or psychological examinations or tests”

Risk assessment in children

Risk assessment varies with age

• Physical (invasiveness, potential harm and

reversibility of adverse effects and reactions).

• Physiological (pain, distress and fear)

• Social (interference with daily living)

Probability, magnitude and duration

• Accumulation of research in the same population (over-studied population)

Risk minimizing measures

• Adequate pediatric expertise required

– Regulatory authorities (Ethical Committee)

– Industry (quality of scientific questions and research design)

– Physicians and trial site (minimize risk, distress and discomfort).

Risk minimizing measures

• Pain, distress, and fear minimization

• Assessment of and monitoring the level of risk

• Assays in relation to age/bodyweight –blood sampling

– Neonates: Per trail, blood loss should not exceed 3 % of the total blood volume (80 ml/kg BW) and should not exceed 1% at any single time

Scientific complexity

21

The number of patients is small

22

22 2

20% of the EU-population, i.e. c.100 million are less

than 18 years old, incl. heterogeneous subgroups.

preterm's neonates infants children adolescents

< 36th gest. wk 0 - 27 d 1 – 23 mo 2 – 11 yr 12 – <18

yr

Different pharmacokinetics and different presentation / pathophysiology of similar disease make age- and development related research important

Problems (and solutions?)

• Adult diseases with different presentation

– Learn form adults – DO NOT COPY

• Non-adult diseases

– Subspecialize paediatrics

• Rare diseases

– Centralize and/or collaborate – other trial design

• Dynamic patients

– Adjust therapy by age/BSA

• Developmental/growth aspects and toxicity

– Long term follow up studies!23

Pediatric control groups

Problem

Use of placebo is

often needed for

scientific reasons

Use of placebo in

children is more

restricted (unable to

provide consent)

Solutions?

• Placebo use is notalways equivalent to absence of treatment

• Set up appropriaterescue treatmentand escapeprocedures

24

Healthy children / ”volunteer” studies

Problem

In principle healthy

children should not

be enrolled as

healthy volunteers

Solution

• Some studies have to be performed in healthy children(vaccine trials).

• If so: wheneverpossible the older age group should be considered for inclusion before theyounger ones

25

Children in research – advantages?

• Normal organ function (> 2 year)

• Few competitive diseases

• Compliance

• Paediatric doctor and nurses are flexible individuals which is an important success factor in clinical trails

26

Conclusions

• Research with children are not only morally acceptable but morally obligatory.

• A robust system for protecting human research participants in general is a necessary foundation for protecting child research subjects in particular.

• Well-designed and well-executed clinical research involving children is essential to improve the health of future children, and future adults.

Conclusions• Effective implementation of policies to protect

child participants in research requires appropriate expertise in child health at all stages in the design, review, and conduct of such research.

• The way forward will be a constructive dialog among the key stakeholders to ensure that risk and harm are minimized in research with children! Only by this means we can continue to improve worldwide child healthcare

28