In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Selection of inappropriate outcomes can compromise the utility of a trial. However, the process of selecting the most suitable outcomes to include can be complex. Our aim was to systematically review studies that address the process of selecting outcomes or outcome domains to measure in clinical trials in children.
Methods and Findings
We searched Cochrane databases (no date restrictions) in December 2006; and MEDLINE (1950 to 2006), CINAHL (1982 to 2006), and SCOPUS (1966 to 2006) in January 2007 for studies of the selection of outcomes for use in clinical trials in children. We also asked a group of experts in paediatric clinical research to refer us to any other relevant studies. From these articles we extracted data on the clinical condition of interest, description of the method used to select outcomes, the people involved in the selection process, the outcomes selected, and limitations of the method as defined by the authors. The literature search identified 8,889 potentially relevant abstracts. Of these, 70 were retrieved, and 25 were included in the review. These studies described the work of 13 collaborations representing various paediatric specialties including critical care, gastroenterology, haematology, psychiatry, neurology, respiratory paediatrics, rheumatology, neonatal medicine, and dentistry. Two groups utilised the Delphi technique, one used the nominal group technique, and one used both methods to reach a consensus about which outcomes should be measured in clinical trials. Other groups used semistructured discussion, and one group used a questionnaire-based survey. The collaborations involved clinical experts, research experts, and industry representatives. Three groups involved parents of children affected by the particular condition.
Very few studies address the appropriate choice of outcomes for clinical research with children, and in most paediatric specialties no research has been undertaken. Among the studies we did assess, very few involved parents or children in selecting outcomes that should be measured, and none directly involved children. Research should be undertaken to identify the best way to involve parents and children in assessing which outcomes should be measured in clinical trials.
Ian Sinha and colleagues show, in a systematic review of published studies, that there are very few studies that address the appropriate choice of outcomes for clinical research with children.
When adult patients are given a drug for a disease by their doctors, they can be sure that its benefits and harms will have been carefully studied in clinical trials. Clinical researchers will have asked how well the drug does when compared to other drugs by giving groups of patients the various treatments and determining several “outcomes.” These are measurements carefully chosen in advance by clinical experts that ensure that trials provide as much information as possible about how effectively a drug deals with a specific disease and whether it has any other effects on patients' health and daily life. The situation is very different, however, for pediatric (child) patients. About three-quarters of the drugs given to children are “off-label”—they have not been specifically tested in children. The assumption used to be that children are just small people who can safely take drugs tested in adults provided the dose is scaled down. However, it is now known that children's bodies handle many drugs differently from adult bodies and that a safe dose for an adult can sometimes kill a child even after scaling down for body size. Consequently, regulatory bodies in the US, Europe, and elsewhere now require clinical trials to be done in children and drugs for pediatric use to be specifically licensed.
Why Was This Study Done?
Because children are not small adults, the methodology used to design trials involving children needs to be adapted from that used to design trials in adult patients. In particular, the process of selecting the outcomes to include in pediatric trials needs to take into account the differences between adults and children. For example, because children's brains are still developing, it may be important to include outcome measures that will detect any effect that drugs have on intellectual development. In this study, therefore, the researchers undertook a systematic review of the medical literature to discover how much is known about the best way to select outcomes in clinical trials in children.
What Did the Researchers Do and Find?
The researchers used a predefined search strategy to identify all the studies published since 1950 that examined the selection of outcomes in clinical trials in children. They also asked experts in pediatric clinical research for details of relevant studies. Only 25 studies, which covered several pediatric specialties and were published by 13 collaborative groups, met the strict eligibility criteria laid down by the researchers for their systematic review. Several approaches previously used to choose outcomes in clinical trials in adults were used in these studies to select outcomes. Two groups used the “Delphi” technique, in which opinions are sought from individuals, collated, and fed back to the individuals to generate discussion and a final, consensus agreement. One group used the “nominal group technique,” which involves the use of structured face-to-face discussions to develop a solution to a problem followed by a vote. Another group used both methods. The remaining groups (except one that used a questionnaire) used semistructured discussion meetings or workshops to decide on outcomes. Although most of the groups included clinical experts, people doing research on the specific clinical condition under investigation, and industry representatives, only three groups asked parents about which outcomes should be included in the trials, and none asked children directly.
What Do These Findings Mean?
These findings indicate that very few studies have addressed the selection of appropriate outcomes for clinical research in children. Indeed, in many pediatric specialties no research has been done on this important topic. Importantly, some of the studies included in this systematic review clearly show that it is inappropriate to use the outcomes used in adult clinical trials in pediatric populations. Overall, although the studies identified in this review provide some useful information on the selection of outcomes in clinical trials in children, further research is urgently needed to ensure that this process is made easier and more uniform. In particular, much more research must be done to determine the best way to involve children and their parents in the selection of outcomes.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050096.
A related PLoSMedicine Perspective article is available
The European Medicines Agency provides information about the regulation of medicines for children in Europe
The US Food and Drug Administration Office of Pediatric Therapeutics provides similar information for the US
The UK Medicines and Healthcare products Regulatory Agency also provides information on why medicines need to be tested in children
The UK Medicines for Children Research Network aims to facilitate the conduct of clinical trials of medicines for children
The James Lind Alliance has been established in the UK to increase patient involvement in medical research issues such as outcome selection in clinical trials