The role of research

Research into the causes of childhood illness underpins much of what we see as standard practice today. However, many of our daily clinical decisions are based on little or no evidence. Children are not small adults, but individuals with specific and ever changing developmental and physiological needs. Despite this, paediatricians are often obliged to extrapolate from adult trials and to prescribe drugs for which there is little clinical trial data from children. Challenges facing the development of research for young people are listed in Box 37.1.

How, then, can child-specific clinical research be driven and what does it offer to the health of young people? Paediatricians involved in caring for children with rare, complex or life-threatening disorders are constantly looking to understand that disease in more detail, to identify high-risk patients and to develop innovative management strategies. For example, molecular characterization of malignant diseases has opened the door to the application of targeted therapies in place of non-selective cytotoxic chemotherapies. Cellular and genetic manipulation of donated stem cells will reduce the risk of rejection or graft-versus-host disease in recipients. Delivery of the wild type CFTR gene will reconstitute normal function, preventing the destructive lung disease seen in cystic fibrosis. However, the majority of child health research seeks to provide evidence relevant to the clinical management of children with more common diseases, forming the evidence base from which we develop our practice, and is the domain of all paediatricians (Box 37.2). Whether as chief investigator, recruiting patients or as someone committed to improving local practice, understanding the principles and practice of clinical research is a key component of paediatrics. All paediatricians have a responsibility to improve children’s healthcare and research is an essential part of this process.

Medical research is conducted across a number of different settings. Different components flow, in two directions, with clinical problems and observations being investigated at a fundamental level and improved fundamental knowledge being applied to the patient setting. The resultant interplay of ideas, questions, solutions and new questions (Fig. 37.1) is what defines the process of medical research. Whilst the boundaries can merge, broadly the style of research being conducted allows these different settings to be considered separately.

Clinical research seeks to take potential diagnostic, monitoring or therapeutic strategies, identified by basic and translational research, into a representative clinical setting. It asks the question, ‘Does this treatment improve the health and well-being of real patients?’ Addressing this question will normally be performed in steps, or phases, with different aims at each phase (Table 37.1). Phase I and II (early phase) trials recruiting small numbers of patients and focusing on determining the safety and appropriate dosing/schedule of a new intervention, may be combined so that patients are initially recruited to a phase I element followed by progression to a phase II element. This is increasingly common in trials of new therapies designed specifically for rare patient or disease/molecular subgroups.

Increasingly, experimental medicine (see Fig. 37.1, and see Personalized medicine, below) seeks to use human trials to generate pre-clinical data. For example, a clinical trial with a primary aim of investigating the effect of a new cytotoxic anti-cancer drug can also be used to assess the pharmacokinetics/pharma­codynamics of that drug and the effect on similar, potentially cross-reactive pathways in normal tissue. These studies cannot be performed in vitro or in healthy human volunteers due to the potential toxicity.

The origins of all clinical trials should be an identifiable clinical need. This is one of the key contributions to be made by translational researchers. The process of identifying a need, investigating potential solutions and then validating them is key to framing the clinical research question (Fig. 37.2). Whilst basic scientists may follow lines of investigation which appear interesting in the hope of further defining fundamental elements of biology, a greater expectation must be placed on the question underpinning a clinical trial. Asking a child and their family to consent to novel intervention or additional investigations can only be ethically justified if the benefit outweighs the risk. There must therefore be a reasonable expectation of patient benefit, identified as a clinical need. It may not, for example, be justified to randomize children between two established therapies with an equivalent, well-documented success rate, simply to demonstrate equivalence in a formal setting. If, however, there was a rationale for one treatment being more effective or less toxic than the other, then this would need to be investigated in a randomized clinical trial. The research question becomes:

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