A quarter century of progress in paediatric clinical pharmacology: A personal view

Children make up 28% of our population but represent 100% of our future. Dr Chok Wan Chan, International Paediatric Association

Although it is clear that the need of children for evidence‐based drug therapy is of critical importance, the world has been slow to embrace paediatric clinical pharmacology as an essential science for optimal child health. The importance of clinical pharmacology as a bridging discipline between basic science knowledge in pharmacology and toxicology and effective clinical practice was described by the World Health Organization 45 years ago 1 and has more recently been highlighted in a number of publications 2, 3, 4, 5.

Commentators have focused primarily on the expected contributions of clinical pharmacology as a core discipline in adult internal medicine and its subspecialties, but the even greater potential importance in paediatrics has generally been ignored. The above quote from Dr Chan, past president of the International Paediatric Association, delivered as part of a plenary address at the Second Oriental Congress of Paediatrics in Shanghai (October 2013) underscores the folly in continuing to disregard the imperative for a science‐based approach to paediatric therapeutics.

In 1968 Shirkey highlighted the plight of ‘therapeutic orphans’ 6. The term quickly became popular but has, in some ways, contributed to continuing uncertainty about the central mission of paediatric clinical pharmacology. Not all observers are clear as to whether the orphans are children themselves, inadequately studied therapies, or even the diseases that have been deprived of treatment with fully evaluated and appropriately labelled medications.

Despite obstacles, the discipline of paediatric clinical pharmacology has evolved over the past quarter century in parallel to, but frequently lagging behind, the course of adult clinical pharmacology. From a beginning focus on bridging from pharmacology/toxicology knowledge to better drug therapy emphasis has shifted to better understanding of biological mechanisms of disease that determine therapeutic choice and, more recently, to what may be called translational therapeutics centred on the understanding of individualized genetics, genomics and epigenetic factors that may determine a drug’s action in a particular child patient 7. Paediatric clinical pharmacologists are increasingly confronted by the need to expand the relevant basic knowledge of pharmacology and toxicology in order to enable a move beyond treatment with small molecule chemical entities to comfort with a broader therapeutic armamentarium that includes more complex biological products.

At the beginning of the modern era of paediatric clinical pharmacology the shortfalls in evidence‐based therapy were most dramatically apparent for newborns, infants and young children. Patients in this age group have been particularly deprived of evidence‐based treatment and off label therapies have for too long remained the rule rather than the exception 8, 9, 10. Furthermore, rare, genetically determined conditions commonly presenting in childhood have usually been treated empirically leaving such patients without the benefit of targeted and fully evaluated treatments 11.

In the 1990s the therapeutic environment in paediatrics was characterized by questions more than answers 12, 13, 14. Potential solutions presented by the emerging discipline of paediatric clinical pharmacology had only begun to differentiate themselves from the earlier traditions in adult medicine. The ensuing years have seen extraordinary progress.

At least some of the potential for impact of paediatric clinical pharmacology is evident from the Copenhagen consensus conferences held in 2008 and 2012 convening leading experts including Nobel prize winners in economics and posing the question of what would be the most cost effective initiatives worldwide in health, wellness and survival. Both consensus conferences led to agreement on a list of essential initiatives that perhaps, not surprisingly, has a disproportionate focus on measures to improve child health. While many of the recommended actions, such as provision of micronutrients, zinc and iron, or improvement in worldwide availability of vitamin A fall into the arena of preventive therapies, a pressing need was also flagged for drugs that may be used to manage sources of life threatening illness for children in tropical and low income settings, such as malaria, helminthic diseases and HIV/AIDS.

Clinical pharmacology has always taken its most important foundations from the basic sciences of biochemistry, pharmacology and toxicology and important progress in the 1980s derived from the rapidly increasing understanding of biochemical mechanisms determining the absorption, distribution, metabolism and excretion of drug products. The ontogeny of mechanisms for drug distribution and response in children were well delineated during this period, with particular emphasis on clinically significant variations in biotransformation 15. Breakthroughs in descriptions of pharmacokinetic behaviour in low birth weight, very low birth weight and normal infants set the stage for a cascade of new information made understandable by a strengthening description of the genomic determinants of drug oxidative and conjugating enzymes 16, 17.

The most recent decade has brought a wave of therapeutic improvements based on expanded knowledge of anomalous gene expression in several devastating childhood conditions, including cystic fibrosis 18, mucopolysaccharidosis 19, 20 and lysosomal storage diseases, such as Pompe’s disease 21, among others. These conditions are almost certainly forerunners of a coming era in personalized treatment and will be joined increasingly by treatments in paediatric oncology selected on the basis of tumour cell genomics 22. Internationally, the genetics research community has set ambitious targets for the definition of the genetic determinants of an increasing proportion of the 7–8000 candidate rare disorders. It is anticipated that, by 2020, diagnostic tools for most conditions will be available and individualized therapies for 200 disorders will have been developed and studied 23, 24.

The tailoring of personalized treatments to the genetic and epigenetic characteristics and genomics of a particular child will eventually go far beyond application exclusively in rare genetic disorders. Stephen Spielberg, one of America’s leading paediatric clinical pharmacologists, recently described ‘the dawn of personalized paediatric therapeutics', drawing particularly in his remarks on the potential for improved treatment of neurodevelopmental and major depressive disorders, conditions clearly influenced by both genetics and the environment 7.

In a period of such rapid therapeutic evolution there are abundant opportunities for paediatric clinical pharmacologists willing to work closely with colleagues from other relevant disciplines to move beyond a traditional role of providing drug information and therapeutic guidance. The development of multidisciplinary research teams and in some cases dedicated networks will be of paramount importance as will be the pioneering of innovative clinical trial designs and sampling methods 5, 25. Progress will be required with alternative, adaptive and pragmatic trial designs and with techniques appropriate to paediatric investigation, including sparse sampling, population pharmacokinetics and non‐invasive/micro sampling.

Methodological innovation

The essence of paediatric clinical pharmacology is to be found in its ability to develop unique methods for the study of innovative treatments in children. In many cases the approach required will depend on the introduction of novel techniques for study of highly vulnerable neonates or children in the early stages of debilitating disease 26. As a tangible step forward, the past 5 years has seen the emergence of an international network of investigators committed to the development and promulgation of standards for clinical investigation in children, the StaR Child Health network 27. StaR Child Health is characterized as ‘a group of methodologists, clinicians and policy makers who seek to enhance the quality, ethics and reliability of paediatric clinical research by promoting the use of evidence‐based standards for guidance for clinical studies with children’.

The key objectives described for StaR Child Health include the following:

• raising awareness of the crucial importance of research design, conduct and reporting of clinical research;

• assisting in the development, dissemination and implementation of evidence‐based standards for clinical research for children;

• becoming a global centre providing resources and supporting training related to the design, conduct and reporting of clinical research in children;

• conducting empirical research on design, conduct and reporting of clinical research.

To date, participants in StaR Child Health have held three international meetings and have published an initial set of six research standards in 2012 28. The critical work of the StaR Child Health network will continue to provide new tools for use by paediatric clinical pharmacologists in the Herculean task of amassing evidence to support the labelling of therapies for children of various ages and development across a range of illness burdens.

In order for the discipline of paediatric clinical pharmacology to maintain the pace of recent development there will be a continuing need for enhancement of informatics skills including the fine tuning of procedures for data management, data sharing and transfer, data storage and biobanking. The use of both research and administrative data for modelling and in silico simulations will be important especially in the study of relatively rare childhood conditions where populations accessible for participation in clinical investigations may be sparse or widely scattered. Continued work is also required to define the proper role of data safety monitoring boards in risk management for paediatric clinical trials.

Evolution of the paediatric therapeutic policy environment

The past 25 years have seen a dramatic shift internationally toward emphasis on the role to be played by paediatric clinical pharmacology, clinical pharmacy and clinical toxicology 29, 30, 31, 32, 33. It is clear that practitioners as well as policy makers worldwide are no longer prepared to accept therapeutic choices made on the basis of intuition or conventional wisdom. Decision making in paediatric therapeutics has now joined the mainstream of evidence‐based medicine 10.

During the past quarter century of important evolution the most dramatic policy advances designed to better serve the needs of the paediatric population have been made in the United States, beginning with passage of the FDA Modernization Act in 1997 34 and, more recently in the European Union, beginning in 2007 35. In both jurisdictions policy changes that were introduced to encourage evidence‐based therapeutic decision making for children have been accompanied by initiatives aimed at the development of infrastructure needed to support better clinical investigation of drug therapies. In the United States this began with the support of Paediatric Pharmacology Research Units (PPRU) by the National Institute of Child Health and Human Development (NICHD) 36 and in Europe relevant initiatives have been supported under recent Framework programmes since 2007 37, 38. Parallel efforts by the European Medicines Agency have been made to improve the clinical trial regulatory environment in child health. An important element has been the creation of a network of paediatric research programmes (Enpr‐EMA) 39 and the spawning of four new clinical research networks in diabetes, gastroenterology, cardiology and intensive care. The most notable subsequent progress in American infrastructure development has been the creation of the Pediatric Trials Network by the NICHD in 2010 40.

These developments in America and Europe have been matched since 2007 by action undertaken by the World Health Organization. The World Health Assembly in 2007 passed a Better Medicines for Children proposal (WHA resolution 60.20) 41. Since that time, an essential medicines list for children has been introduced and is now in its fourth edition. Paediatric clinical pharmacologists from a variety of settings have also joined forces in leading an international effort to apply clinical pharmacology expertise to the development of standard treatment guidelines.

Knowledge transfer, education and training

Paediatric pharmacology at its core is a teaching discipline and as the validated information base in paediatric therapeutics in child health has grown, the work of knowledge mobilization has been enhanced. Some of this effort is still channelled through paper‐based materials 42, 43, 44. However, increasingly, electronic dissemination of treatment recommendations is becoming the primary means for conveying clinical pharmacology analyses aimed at improving child health outcomes.

Without question, there is a significant human resource shortfall in paediatric clinical pharmacology. There is no accurate estimate of the numbers of clinician scientists trained in the discipline available for service in both developed and developing countries, but a realistic estimate would be that there are fewer than 1000 fully trained professionals in medicine and related health disciplines prepared to contribute to the important research and knowledge mobilization work required to reduce childhood morbidity and mortality through improved evidence‐based drug therapy. Efforts are currently underway to develop an asset map to describe available human resources for all relevant aspects of clinical investigation training and knowledge transfer. This will be the starting point for what should become a consistent, continuing effort to maintain a current and freely available listing of individuals with diverse skills committed to the pursuit of better drug therapy for children of all ages 45.

Substantial progress has been made in the development of regulated national training programmes for paediatricians pursuing careers as clinical pharmacology specialists in Europe and North America. Further opportunities exist for subspecialty trainees interested in gaining expertise in therapeutic evaluation. Continued investment of fiscal and human resources in expanded training is imperative.

A major opportunity is also open to paediatric pharmacists, especially those with clinical training. Such individuals are more numerous than medical child health specialists with clinical pharmacology training and they are well positioned to contribute to the development and dissemination of evidence‐based treatment guidelines.

Importance of networks

The evolving influence of paediatric clinical pharmacology in recent decades has benefited greatly from the development of strong translational research networks. This trend began most importantly with the creation of PPRUs in the United States with NICHD funding in the 1990s 36. More recently, these units have been supplanted by a comprehensive paediatric clinical trials network led by Duke University 40. This network is focused on the study of off‐patent medicines but nonetheless provides an outstanding model of what may be achieved with appropriate infrastructure support to enable the necessary investigation of innovative therapies for children and youth. Another early example of networking that has paid major dividends for improved paediatric therapy is the Children’s Oncology Group (COG) which spans North American centres for paediatric oncology 46. The COG has played an exceptional role in validating new treatments and treatment protocols for childhood cancer.

Increasingly, other national and regional networks have emerged, bringing together a range of investigators, often over a wide geographic distribution and overcoming some of the logistical challenges of paediatric clinical investigation. Two important pan‐European initiatives are the creation of Enpr‐EMA as described earlier 39 and the more recent support through Europe’s Framework Program 7 of the Global Research in Paediatrics (GRIP) programme that has also attracted international partners from North America and Japan 47. A number of national networks are also gaining momentum in Canada, France, Germany, the Netherlands and the United Kingdom. The Children’s Research Network established in the United Kingdom has been extremely well funded and particularly successful 48. UK investigators have made notable contributions to paediatric clinical pharmacology through their description of the clinical trials toolkit/route map which offers clear indication of standards that must be met in order to achieve evidence‐based paediatric therapy 49.

The challenge in low and middle income countries

Neglect of the importance of paediatric clinical pharmacology research aimed at the achievement of safe and effective drug treatment for children is an error with broad ramifications. In 2011, the world population passed seven billion individuals and almost 27% of this population is aged 0–14 years. In several low and middle income countries (LMIC), the child and youth population approaches 50% of the total.

Such demography presents an inviting target, particularly because of potentially avoidable morbidity and mortality prevalent in those under 5 years of age residing in LMIC 50. A good portion of the described morbidity and mortality could realistically be averted by improvements in drug therapy and the promotion of evidence‐based treatment guidelines for the most common causes of mortality. In 2012, dramatic improvements were reported in mortality statistics for both pneumonia and diarrhoea 51. In parallel, striking improvements in overall child health have been achievable as a result of pragmatic research on delivery of iron supplements in sprinkle formulations 52 and through the expanded use of zinc, including its addition to oral rehydration salts 53. Equally important breakthroughs have also occurred because of the necessity to address the global HIV/AIDS epidemic and to prevent viral transmission from mother to child at birth or during breast feeding 54, 55, 56.

Additional tasks for paediatric clinical pharmacologists particularly important in developing countries because of high birth rates, include the study of the risks associated with antenatal exposure to drugs 57 and achievement of improved understanding of the transfer of drugs from lactating mothers to their infants 58.

Last September an important report from the Brookings Institution offered grounds for cautious optimism, describing significant gains made, mostly through better preventive and therapeutic interventions, towards improving child mortality worldwide 59.

All domains of interest in paediatric clinical pharmacology, including drug discovery, drug development, therapeutic evaluation, regulatory and implementation science, as well as dissemination of therapeutic guidelines, are of accentuated importance in low resource settings 2. In an ideal world the research and clinical skills of paediatric pharmacology would also be more widely applied to the study of neglected tropical diseases 60, 61 such as leishmaniasis, trypanosomiasis and schistosomiasis, too often passed over by the usual funders of clinical research.

Future directions

Great as the progress has been in the past 25 years, extraordinary challenges remain and it is essential that those committed to paediatric clinical pharmacology help to develop the clinical and scientific human resource base that will be required for continued progress. Among the most important needs to be addressed in the next quarter century are:

• An expanding requirement for improved understanding of the genetic, epigenetic and genomic basis of diseases.

Clinical pharmacologists must contribute to the bridging between relevant basic sciences and the clinical settings that require more precise characterization of conditions, better diagnosis and access to evidence‐based treatment choice.

• Redirection of clinical pharmacology efforts with some priority to neurology and psychiatry.

The discipline should increasingly contribute its expertise to the study of mental health and to improved treatment of behavioural and cognitive conditions, including autism and attention deficit disorder.

• Response to a pressing requirement for improved clinical trial methods in order to sustain progress toward evidence‐based paediatric therapy.

New partnership models should be examined, including strengthened research networks, early engagement among research sponsors, clinicians, patients and families, and regulators to support better trial design. Randomized controlled trials are not always practicable and alternative non‐RCT designs and adaptive methods should be explored. It will be important to improve capacity for comparative effectiveness research and to integrate that with an increased reliance on genomic science.

• Effective linking of innovative trial methods to improved measurement techniques.

This will be particularly true in the area of central nervous system studies, where new quantitative tools for evaluation of neurocognitive development and better understanding of the future role of functional imaging are critically important.

• Strengthened focus on the needs of children in low and middle income countries.

It is in these jurisdictions where the greatest gains are to be made in reduced morbidity and mortality 62.

In conclusion, clinical pharmacologists are often gloomy about the state of their discipline and its ability to make a difference in the complex world of healthcare. In paediatrics, however, there are considerable grounds for optimism. The relatively small cohort of clinicians qualified in basic science, clinical investigation, policy research, knowledge mobilization and training relevant to improved child therapy are in great demand and should take justifiable pride in their contributions.

Over the past quarter century steady progress has been made building on earlier success in therapeutics research and teaching and in adult clinical pharmacology. Working with colleagues in basic science and parallel clinical disciplines paediatric clinical pharmacologists and their clinical pharmacy counterparts are now in a strong position to drive future advances in child treatment worldwide over the next quarter century.

Competing Interests

There are no competing interests to declare

MacLeod, S. M. (2016) A quarter century of progress in paediatric clinical pharmacology: A personal view. Br J Clin Pharmacol, 81: 228–234. doi: 10.1111/bcp.12776.