We did a comprehensive search of scientific reports including the databases MEDLINE (January, 1966–June, 2003) and Embase (January, 1980–June, 2003) using the terms children and clinical trials, with translation of relevant articles in non-English language articles. We also undertook hand-searching of reference lists of relevant studies, reviews, and proceedings of scientific meetings, and a search using the Google search engine which identified some important issues about clinical trials in
ReviewClinical trials in children
Section snippets
The importance of clinical trials in children
Clinical trials in children have resulted in significant improvements in their health care. A well-known example is childhood acute lymphoblastic leukaemia, in which the 5-year survival improved from 25% to more than 70% as a result of multicentre trials.1 Unfortunately, since there are few paediatric trials,2 the list of improvements in child health resulting from clinical trials is not long and is restricted to some childhood diseases, heavily clustering around cancer. Consequently, many
Benefits of trial participation
Participants in randomised controlled trials (RCTs) derive many benefits, including access to new treatments that might not be routinely available. The Declaration of Helsinki requires that treatment offered to the control group should be the current best standard treatment, and that those allocated to the experimental group receive a treatment proposed to be as good as or better than standard treatments.7 Hence, a well-designed RCT could arguably offer a patient the optimum treatment approach.8
Risks of trial participation
Along with benefits, there are also potential risks and inconveniences for trial participation. Potential risks specific to children, that are not usually of concern when considering studies in adults, include discomfort, inconvenience, pain, fear, separation from parents or familiar surroundings, effects on growing or developing organs, and size or volume of biological samples.15 Pragmatic clinical trials, which do not impose a burden of treatment, testing, and monitoring greater than routine
Public policy
The importance of clinical trials in children23, 24 is increasingly recognised by major research groups and professional bodies worldwide such as the National Institutes of Health (NIH)25 and American Academy of Pediatrics (AAP) in the USA,15 the Medical Research Council (MRC)19 and Royal College of Paediatrics and Child Health (RCPCH)21 in the UK, the European Agency for the Evaluation of Medicinal Products (EMEA),26 European Commission,27 and European Federation of Pharmaceutical Idustries
The ethics of consent for children
There is a tension between the need to safeguard the health of an individual child and the obligation of society to facilitate research that will result in improved outcomes for children in the future.38, 39 When considering trial participation, parents and paediatricians are usually more concerned about the risks and benefits for the individual child than any societal benefit.22, 40 The Nuremberg Code, formulated in 1947 in response to the inhumane experimentation in Nazi camps,41 is the basis
Institutional review boards/independent ethics committees
Central to ensuring the protection of child subjects is the careful ethical review of research protocols at many levels by researchers, funding and scientific bodies, and research ethics committees.21 The institutional review board (IRB) or independent ethics committee (IEC) are charged with the responsibility of ensuring that the associated research risks are reasonable in relation to the potential benefits and knowledge to be gained.49, 50
A review of the IRB system in the USA shows that IRBs
Clinical trials versus clinical practice
The public perception of clinical trials as experiments, in which people are treated as human guinea pigs has led to a misleading distinction being made between clinical practice and clinical research.8, 54 It often seems more acceptable (to doctors, parents, and IRBs, because of their self-limited frame of reference) to use untested medications on children as “routine clinical care” rather than enrol eligible children in a relevant clinical trial, in which the effects of interventions can be
Why are so few children involved in trials?
Given the smaller pool of patients available for trials in children, the higher fixed and marginal costs are a major disincentive for the pharmaceutical industry to fund trials in children, particularly when the market size at the end of an expensive research and development programme is often small. The most common excuses for failure to do paediatric studies are the high cost of the studies compared with the size of the potential market, the difficulty of finding enough patients to
Doctor factors
Parents and paediatricians acknowledge the important influence that paediatricians have on a parent's decision regarding trial participation.22, 40, 69 When recruiting adults to clinical trials, the reluctance of the primary treating doctor to enrol patients is a major reason for poor recruitment rates.70, 71, 72 This is thought to stem from their perceived conflict between their roles as caregiver and scientist.54, 73 Other common barriers include forgetfulness or lack of awareness of trials
Parent factors
In paediatric trials, parental consent is required for children's participation. The balance of perceived benefits and barriers or risks of participation, and the importance of the study influences parents' willingness to participate.22, 88, 89 Perceived benefits for parents include the opportunity to access new treatments, better care being given to their child, gaining greater access to health-care professionals and health information, meeting others in similar circumstances, gaining hope
Child factors
The child's health status modifies the risk-benefit balance for parents. Although many paediatricians think parents will be less willing to participate in trials if their child's illness is severe,40, 87 the reverse has been found to be true.14 Parental consent for trials is higher during a child's acute illness. For example, recruitment rates were higher for admitted inpatients or children recruited from the emergency room compared with those identified through outpatient records.69 Similarly
Trial factors
There is poor awareness and understanding of paediatric RCTs by parents.40, 69, 97, 98, 99 The rationale for the random allocation of treatment and the use of placebo is generally poorly understood by adult doctors,72 paediatricians,40 adult patients,100 and parents.22, 98 Because of this confusion, the presence of a placebo group is often a barrier to trial participation,101 and is viewed by some to be unethical for life-threatening illnesses.22, 40 Although they are less common, many parents
Participation in paediatric oncology trials
The participation of children with cancer in clinical trials has become increasingly common since the 1970s, and is arguably responsible for the large increases in cancer survival observed since then. Highly significant increases in 5-year survival rates for common childhood cancers were noted in a population-based series of more than 15 000 childhood cancer cases registered in Great Britain from 1971 to 1985 (eg, from 37% to 70% for acute lymphoblastic leukaemia, from 22% to 70% for
The future for paediatric trials
Better education of the medical community and the public is needed about the rationale and benefits of trials and the potential dangers of using health-care interventions that have not been appropriately studied. Negatively biased media coverage about clinical trials involving children needs to be balanced with public-awareness campaigns with positive stories about the societal benefits of RCTs, highlighting the possible harm from unpredicted adverse events because of a lack of paediatric
Search strategy and selection criteria
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