Regulatory imperatives, economic incentives, new methods and technology and the chance to make a difference in the health of children worldwide provide compelling reasons to pursue global drug studies in children.
The Rationale for Conducting Clinical Trials in Children
At first glance there would seem to be little reason to conduct clinical trials among children; after all, children are mostly healthy and rarely need medication; if they do need medication, these are usually antibiotics. In reality, these myths are far from the truth with respect to actual drug use among children (Rieder et al. 2003). Although majority of the children in the developed world are healthy, medication use is in fact common; a recent study demonstrated that, on average, children in Canada receive 3.9 prescriptions per year, and that these prescriptions were drawn from more than 1,400 different therapeutic entities (Khaled et al. 2003). The average is somewhat misleading, in that 60% of children received two or less prescriptions per year, while 26% of children accounted for 72% of drug use (Khaled et al. 2003). Thus, for roughly a quarter of Canadian children, drug use is common and involves a wide range of treatments. Similar patterns appear to apply to other developed nations, while in the developing world the need for therapy for problems uncommon in developed countries is even more acute (Beggs et al. 2005). The majority of medications do not have efficacy, dosing or safety data for use in children, and the problem of “off-label” drug use among children is endemic (Cuzzolin et al. 2006).
This has been a problem for child health care providers for some time, but recent initiatives in the United States and the European Union have provided an impetus for the industry to reconsider plans with respect to clinical trials among children (Benjamin et al. 2006, Watson 2006). This has been coupled, in the United States, with a regulatory imperative to conduct drug studies when drugs are being approved with a high likelihood of being used in children. Thus, there are clear moral, scientific, regulatory and economic reasons to consider conducting drug studies among children.
Why Global Trials?
If we accept the premise that clinical trials need to be conducted among children, why would we want to do so on a global basis? There are several pressing reasons for this. First, although drug use among children overall is common, the experience of any given centre may be more limited, and thus ensuring that adequate number of children are enrolled may require involving multiple centres in different countries, the best example of this being the highly successful international collaborations in clinical investigation in paediatric oncology. As well, expertise in conducting clinical research in children is scant, and planning for a clinical trial needs to consider making use of centres – often in different countries – that have this expertise.
Second, there is the issue of testing drugs in the populations that they will be used in. Currently, most drug research for children is conducted in Caucasian and Afro-American children. However, the majority of children in the world are not Caucasian or Afro-American. This is notably an issue in Asia, in that there are well-described polymorphisms in drug clearance that are particularly germane to Asian children (Chowbay et al. 2005). The importance of children for Asia’s future – with respect to negative population growth in countries such as Japan and the need for a stable and expanding workforce in countries such as China – highlight the need for clinical trials in children, and the need for these to be multi-centred and multi-national.
Challenges in Global Clinical Trials Involving Children
Conducting clinical trials in children is a challenging enterprise at the best of times, more so when the trial is to be conducted in different countries (Matsui et al. 2003). Issues include considerations such as recruiting and study design strategies, suitable formulations and end-points.
The choice of study centres and recruiting strategies are key decisions early in the study that can make or break a clinical trial. Expertise in drug research in children is, as noted, somewhat scarce, and experience has shown that successful research programs in children’s drug research need to have expert staff and a child and family-friendly research environment. When considering centres, track record is an important consideration. These decisions may need to be implemented with a certain degree of tact, notably in countries where this expertise may not be in what is considered the national centre for paediatrics. Recruitment strategies need to be realistic, and a frank appraisal of the centre’s potential for recruitment and track record are essential components of planning for a successful clinical trial.
Study design needs to take this into account. Study designs that work well for research in adults often flounder when applied to children, notably if the study design calls for frequent blood sampling, especially in infants. Alternate study designs – including the use of scant sampling regimens and modeling strategies – may be needed to produce a study design that is feasible to execute and attractive to parents and children (Reed 1999, Johnson 2005). As part of study design, the choice of a suitable end-point is an important and often neglected decision. End-points, which are well suited for adult trials, may not be germane or even feasible in trials in children (Zhang & Schmidt 2001, Curley & Zimmerman 2005). Failure to address this issue early in trial design may result in a study that does not have the power to provide a definitive answer, exposing children to trial-related risks without addressing the question under study. This also offers the ability to be innovative, examples being the development of scoring systems to evaluate pain in pre-verbal children and facial hedonic scales to evaluate palatability (Angelilli et al. 2000, Lynn & Dawson 2003, Holsti et al. 2006). Selection and validation of appropriate end-points is also an area where international collaboration can be essential in the successful conduct of a clinical trial. Fortunately, there is an expanding pool of expertise available in this area as well as a wide range of new technologies germane to clinical research in children.
A consideration especially germane to clinical trials in children is determining an appropriate formulation. Medication-naïve children below the age of 5 are typically unable to take conventional tablets or capsules, and thus alternate formulations such as liquids or aerosols may be necessary. When using a liquid medication, considerations include dosing frequency, stability and storage requirements. Palatability is an important consideration in formulation design, and in an international trial the formulation should be designed with consideration of culturally based preferences in flavour.
The importance of ethical considerations in international clinical trials involving children cannot be overstated. It is critical to adhere to a high ethical standard, and to avoid the appearance (and fact) of coercion. This is complicated by the different practices with respect to research in different regions. As an example, a trial that involved healthy child volunteers could be considered in the United States and China, might be considered in Canada and would not be possible in most European countries. The area of ethical conduct of research in children is constantly changing, and in cases of uncertainty dialogue with experts in the area of paediatric ethics would be prudent.
There are many challenges in conducting international paediatric drug studies. However, regulatory imperatives, economic incentives, new methods and technology and the chance to make a difference in the health of children worldwide provide compelling reasons to pursue global drug studies in children.
Angelilli ML, Toscani M, Matsui DM, Rieder MJ: Palatability of oral antibiotics among children in an urban primary care center. Arch Pediatr Adolesc Med 2000;154:267-70
Beggs SA, Cranswick NE, Reed MD: Improving drug use for children in the developing world. Arch Dis Child 2005; 90: 1091-3
Benjamin DK Jr, Smith PB, Murphy MD, Roberts R, Mathis L, Avant D, Califf RM, Li JS: Peer-reviewed publications of clinical trials completed for pediatric exclusivity. JAMA 2006; 296: 1266-73
Chowbay B, Zhou S, Lee EJ: An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore.
Drug Metab Rev 2005;37:327-78
Curley MA, Zimmerman JJ: Alternative outcome measures for pediatric clinical sepsis trials. Pediatr Crit Care Med 2005;6(3 Suppl):S150-6
Cuzzolin L, Atezi A, Fanos V: Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety. Expert Opin Drug Saf 2006; 5: 703-18
Holsti L, Grunau RE, Whifield MF, Oberlander TF, Lindh V: Behavioral Responses to Pain Are Heightened After Clustered Care in Preterm Infants Born Between 30 and 32 Weeks Gestational Age. Clin J Pain 2006;22:757-764
Jayaraman S, Rieder MJ, Matsui DM: Compliance assessment in drug trials: has there been improvement in two decades? Can J Clin Pharmacol 2005;12(3):e251-3
Johnson TN: Modelling approaches to dose estimation in children. Br J Clin Pharmacol 2005; 59:663-9
Khaled LA, Ahmad F, Brogan T, Fearnley J, Graham J, MacLeod S, McCormick J: Paediatric drug use: An overview. Paed Child Health 2003; 8: 13A-17A
Lyon F, Dawson D: Oucher or CHEOPS for pain assessment in children. Emerg Med J 2003 Sep;20:470
Matsui D, Kwan C, Steer E, Rieder MJ: The trials and tribulations of doing drug research in children. Can Med Assoc J 2003; 169: 1033-4
Reed MD: Optimal Sampling Theory: An Overview of Its Application to Pharmacokinetic Studies in Infants and Children. Pediatr 1999; 104: 627-32
Rieder MJ, Matsui D, MacLeod S: Myths and challenges – Drug utilization by Canadian children. Paed Child Health 2003; 8: 7A-8A
Watson R: EU offers incentives to firms to produce medicines for children. BMJ 2006; 332: 1352
Zhang B, Schmidt B: Do we measure the right end points? A systematic review of primary outcomes in recent neonatal randomized clinical trials. J Pediatr 2001;138:76-80