The plight of paediatric drug therapy

The pursuit of better drug therapy for children and youth is a public health issue of worldwide concern. Health care practitioners treating children have long appreciated the limitations of research data supporting optimal therapy for their patients. It is a lamentable fact, true even in 2011, that most drugs used in paediatrics have not been adequately studied, although the level of relevant research has recently increased dramatically.

International attention became focused on this issue as early as 1968, when Dr Harry Shirkey coined the term ‘therapeutic orphans’ to describe the situation of infants, toddlers and children who, in his view, were being deprived of access to properly validated modern drug therapy (1). Clearly, there are some exceptions to this alarming broad view: adequate studies have been conducted in some drug categories including antibiotics, respiratory therapies, anti seizure treatments, analgesics and vitamins. It is also true that considerable emphasis has sometimes been placed on the study of drugs intended for use in conditions relatively prevalent in childhood including, among others, infections, attention-deficit disorder, autism, asthma and seizures.

Canada has been a leader in paediatric therapeutics since a ground-breaking research program started at McGill University (Montreal, Quebec) in the 1970s, which focused on neonatology, drug safety, and the development of drug biotransformation capacity in utero and in infancy. In the 1980s, the University of Toronto (Toronto, Ontario) devoted substantial resources to the fostering of paediatric clinical pharmacology at The Hospital for Sick Children (Toronto), resulting in a world-leading program with important research findings in toxicology, pharmacogenetics, anti-infective therapy, anesthesia, analgesia, oncology, respirology, neonatology and obstetrical pharmacology. In spite of Canada’s international leadership in such therapeutic areas, there has been only limited success in changing the national drug regulatory environment and in securing adequate labelling for most products used in paediatrics.

Drug evaluation and regulation evolved steadily throughout the past century as a more sophisticated process of drug discovery resulted in an ever-increasing number of therapeutic entities with potential for use in younger patients. An influence of equal importance has been the recognition of unanticipated toxicities affecting children, in particular, sulfanilamide in the 1930s, chloramphenicol in the 1950s and thalidomide in 1960 (2–4). In 1962, the drug regulatory framework in the United States was overhauled by the amendments to the Food, Drug and Cosmetic Act. In spite of such progress, relatively little parallel attention was paid to drug therapy for children (5–10). Until the early 1990s, paediatric prescribers were usually left without adequate product labelling, but this situation has begun to change through efforts made in the United States and Europe to better serve children through regulatory and policy reform (11,12).

Recent data in the United States suggest that most drugs likely to be commonly used in paediatric practice are now receiving appropriate research attention before licensure (13). In 2007, the European community introduced legislation requiring companies filing for licensure of new products to submit a paediatric investigation plan if there was any likelihood of use in children (14). These legislative initiatives are beginning to bear fruit in the form of appropriate product labelling of new products for therapeutic use in infants, toddlers, children and youth, although some would argue that recent progress is still insufficient to the enormity of gaps in evidence-based paediatric treatment.

Because of earlier inadequacies in drug evaluation and the lack of a legislative structure to encourage drug investigation in the paediatric population, many older therapies continue to be used without being acceptably studied. This knowledge gap is likely to remain challenging for government decision makers and practitioners as well as for children and families.

BETTER MEDICINES FOR CHILDREN: AN INTERNATIONAL PRIORITY

While the lack of adequate drug labelling information in paediatrics has created anxiety for prescribers in North America and Europe, in the rest of the world, the issue is even more critical. There are now more than two billion children in low- and middle-income countries, and in large population centres such as India and China. In these countries, childhood morbidity and mortality is much more common than in Canada, and drug therapy is often the most cost-effective intervention. Optimal treatment remains almost unachievable in many regions for common causes of mortality such as neonatal sepsis, childhood respiratory infections, diarrhea, malaria and HIV/AIDS.

In 2007, the World Health Assembly (WHA) recognized the urgency of the gap in evidence of childhood prescribing support, and passed WHA resolution 60.20, calling for better medicines for children (15). Since that time, an essential medicines list for children has been introduced (16), and a good start has been made in improving standardized treatment guidelines for resource-poor settings. The work undertaken by the WHO includes an emphasis on the development of new formulations appropriate for use in remote areas sometimes subject to extremes of climate (17). The WHO program has also worked with Standards for Research in Child Health (StaR Child Health) to emphasize the importance of improved clinical trial methods to address the needs of such children (18,19).

CHANGING PERCEPTIONS

Within the fields of child health care, paediatric pharmacology and paediatric pharmacy, there has been a shift in focus over the past 25 years toward essential drug research ‘for’ children as distinguished from studies that are simply conducted ‘on’ paediatric subjects (13,20,21). This shifting paradigm recognizes collective responsibility for activities that will help to build a comprehensive database concerning the safety and efficacy of drugs used in newborns, infants, toddlers, children and youth, recognizing that physiological development assures that each of these groups will be unique with respect to absorption, distribution, metabolism and excretion of therapeutic drugs (22). Furthermore, it is becoming increasingly evident that age-related differences extend, in some cases, to an alteration in both beneficial and toxic drug effects.

PRESCRIPTION DRUG USE IN CANADIAN CHILDREN

In Canada, the myth that drugs are not extensively used in children was dispelled by a comprehensive survey conducted in 2001 examining prescription drug use under private insurance plans (23). The survey indicated high levels of paediatric use in several anticipated therapeutic categories including antibiotics, respiratory drugs, antiseizure medications, psychotropics, analgesics, hormones and vitamin preparations. Results emphasized the importance of continuing pharmacoepidemiological studies in children to track Canadian trends in medication use, and to tailor research activities and efforts to achieve appropriate labelling accordingly.

CANADIAN DEVELOPMENTS

In Canada, the child health community of caregivers, educators and researchers is known for its networking achievements; this has important implications for efforts to improve drug therapy for children. Through the efforts of the Canadian Association of Paediatric Health Centres (CAPHC), several Canadian organizations collaborated in 2004 to create the Canadian Child & Youth Health Coalition (24). The membership now includes 11 national organizations. Importantly, the Coalition engages the activities of the Council of Canadian Child Health Research, representing the 17 academic health science centres in Canada. The Coalition also includes the Canadian Child Health Clinician Scientist Program (25) and the Maternal, Infant, Child & Youth Research Network (26), both of which play key roles in promoting better clinical investigation of new therapies. An additional unique network, the Canadian Pharmacogenomics Network for Drug Safety (CPNDS), has grown from its beginnings at the University of British Columbia (Vancouver, British Columbia) to include 11 paediatric centres across Canada in an active surveillance network seeking adverse drug reactions that may prove preventable through the identification of genomics bio-markers that will enable subsequent tailoring of therapy to minimize toxicity (27,28). The CPNDS is also actively engaged with C17, which is a pan-Canadian network of paediatric oncology centres; together, these organizations are working to improve effectiveness and safety outcomes in paediatric oncology (29).

IS THERE CAUSE FOR CONTINUING CONCERN?

While concern about the therapeutic plight of children worldwide remains compellingly important, considerable progress has been made in the past 15 years, particularly in the United States and Europe. Unfortunately, Canada has lagged behind in these developments in spite of the fact that many leading international experts in paediatric clinical pharmacology and clinical pharmacy are employed in our academic centres. The challenge of training adequate numbers of clinician scientists and basic researchers with an interest in topics central to optimization of paediatric therapy remains problematic. There are opportunities for training across a broad scope of disciplines in several centres (eg, Montreal [Quebec], Toronto and London [Ontario], and Vancouver [British Columbia]), and programs of advanced training in selected therapeutic areas are offered in others (Halifax [Nova Scotia], Ottawa [Ontario], Winnipeg [Manitoba], and Calgary and Edmonton [Alberta]). It is disturbingly clear, nonetheless, that the numbers of trainees in disciplines relevant to paediatric drug evaluation are inadequate to meet future needs within Canada, much less internationally. In a recent survey for Health Canada, fewer than 100 qualified evaluators of paediatric therapy were found (unpublished). To proactively pursue improved drug therapy for children and youth, a strategic plan that allows for a period of catch-up in the training of highly qualified personnel is required.

In 2008, Health Canada created a Paediatric Expert Advisory Committee within the Health Products and Food Branch (30). This committee provides a focal point within the government for discussions about pressing therapeutic issues and the advancement of drug therapy for children and youth. At the present time, Health Canada, through the Office of Paediatric Initiatives, has requested that the Council of Canadian Academies prepare a comprehensive report about the situation of children in Canada with respect to appropriate scientific study and labelling of, and access to, a full range of therapeutic products.

SUGGESTED PRIORITY ACTIONS

If Canada is to capitalize on its human resource and research capacity in paediatric pharmacology, there are several actions recommended on a priority basis:

• Expand training capacity in therapeutic evaluation and in relevant areas of population health.

• Place more emphasis on patient-relevant research in paediatrics, addressing the most pressing clinical needs in Canada and internationally.

• Foster a multidisciplinary research environment in toxicology, pharmaceutical sciences, clinical pharmacology and pharmacogenetics.

• Proactively enhance knowledge mobilization and encourage improved prescribing performance based on exemplary clinical evidence.

• Commit to child-oriented regulatory science sufficient to address the needs of infants, children and youth.

CONCLUSION

There are grounds for cautious optimism. A way forward for the development of better-labelled paediatric therapies has been demonstrated by colleagues in the United States and Europe. Canada, through Health Canada and the Office of Paediatric Initiatives, is enthusiastically pursuing closer collaboration with international partners. Most importantly, it is recognized that Canada, through its excellent paediatric health centres and postsecondary child health academic programs, has unparallelled expertise available that may be applied to the challenge. Children worldwide have been in peril because of unvalidated drug therapy, but the first cautious steps toward improvement of this dire situation have been taken. It is essential that Canada now play a role in maintaining the international leadership – academically and professionally – that it has demonstrated over the past 50 years.