Canadian directions for enhancing drug discovery and investigation in children: A brighter future

The development of safe and specific drug therapy has been one of the major medical milestones of the 20th century. However, in the search for novel drug therapy, children have long been considered to be an afterthought (ie, the recipients of medications that have previously been shown to be of benefit to adults and that are given to children because of the lack of any other proven treatment). The term ‘therapeutic orphans’ has commonly been applied to paediatric patients because infants and children have been excluded from approved indications for the majority of drugs (1). Fortunately, the recent introduction of legislative change in the United States offers the promise of an increased opportunity for drug trials and pharmacological investigations involving this often forgotten population (2).

With the above in mind, members of the Canadian Paediatric Society, Therapeutic Products Program of Health Canada and the Pharmaceutical Manufacturers Association of Canada met with representatives from government, the United States-based Federal Drug Administration (FDA), industry and academia at a workshop entitled “Drug Investigation in Children – Canadian Directions”, which was held March 22 to 23, 1999 in Ottawa to discuss the current state and future of drug investigation in Canada. Further to that encouraging beginning, several prominent paediatric investigators began planning to form a Canadian Paediatric Clinical Pharmacology Network to explore research possibilities and make drug research involving children a priority in Canada.

In the process of pharmaceutical drug development, children have, for various reasons, been excluded from the benefit of many therapeutic advances. About 80% of drugs approved by the FDA during the past 30 years have been approved with a labelling disclaimer regarding use by children (3). The conditional approvals include many drugs that are routinely used in clinical practice to care for children. Despite determined advocacy by professional groups, such as the American Academy of Pediatrics and the Canadian Paediatric Society, the number of conditional approvals has been relatively unchanged for the past three decades. In addition to the lack of commercial incentives for testing new drugs in children, there are methodological challenges to conducting research in this age group. Appropriate formulations for easy administration to children may not be available, and laboratory monitoring may be complicated by the small volume of samples that can be obtained, particularly from infants and younger children. Ethical and consent issues may be of concern, although increased direction in this area is provided by guidelines published by the American Academy of Pediatrics (4).

Thus, physicians who care for children have been left with an armamentarium of drugs that are marketed for adults, with precautionary disclaimers stating that safety and efficacy in children have not been established. In addition, there is often a lack of age-related dosing guidelines for newer drug entities. Good medical practice dictates that standards of care are followed, which in paediatrics often involves the use of empirical therapy because inadequate information is available for drugs in this age group. With the recent emphasis on evidence-based medicine, such off-label prescribing presents the physician with a major therapeutic dilemma in which ‘best evidence’ may not exist and in which clinical guidelines call for the use of therapy in the absence of regulatory approval.

This situation is aggravated by the proven potential for significant differences between adults and children, especially infants. It comes as no surprise to paediatricians that children are not little adults; developmental changes are associated with significant pharmacokinetic and pharmacodynamic variations, some of which have been associated with major adverse outcomes. For example, a child’s renal drug excretion at birth is approximately one-third that of adults; thus, drugs, such as aminoglycosides, that are eliminated mostly by this route, require dose adjustment to avoid toxicity in children. Similarly, the failure to appreciate that there is maturation in the activity of drug metabolizing enzymes led to the neonatal tragedy known as the ‘gray baby syndrome’. Diseases that are not seen in adults, such as Kawasaki disease and juvenile rheumatoid arthritis, are commonly treated in children. As well, the latent and delayed effects of medication must be considered. Extrapolating the medical community’s knowledge about drug therapies in the adult population to the paediatric patient may, therefore, not always be in the best interest of the child.

A previous attempt to improve drug prescribing information in children was less than successful. The Child Health Initiative: Inadequate Labelling of Drug Products for Use in Children, which was part of the Brighter Future for Canadian Children campaign, was a joint effort of the Drug Therapy and Hazardous Substances Committee of the Canadian Paediatric Society, the Canadian Pharmaceutical Association and Health Canada from 1992 to 1995. The goal of this project was to revise the product monographs of prescription drugs in the Compendium of Pharmaceuticals and Specialties (5) to reflect more accurately the available paediatric research, and incorporate updated information to coincide more closely with current clinical practice (6). The project was able to collect a large amount of data on drug use in infants and children. Unfortunately, in the vast majority of cases, the data were neither collected nor reported in a fashion that facilitated regulatory changes. As well, the project did not involve pharmaceutical partners early enough in the process, and the stimulus for change was diffused.

However, recent legislative changes introduced by the FDA led to increased optimism, and incentives for paediatric drug trials and research involving children. The FDA 1994 Rule (Pediatric Labeling Rule) mandated that all drugs, both old and new, should have paediatric dosing and safety information on their labels if a drug had the potential for use in paediatric patients (7). However, because compliance with this rule was voluntary, its effectiveness was arguable. In many cases, the available data were insufficient to result in a useful labelling change. Fortunately, in 1997, the Food and Drug Administration Modernization Act was passed. This act provides for a six-month patent extension for manufacturers who sponsor paediatric studies, investing in the development of paediatric safety and dosage guidelines for drugs identified by the FDA as needing such information (2). The hope is that the extra six months of market exclusivity will provide a financial incentive to industry to offset the economic imbalance of a limited market versus development costs. The adoption of the 1998 Final Pediatric Rule, a regulation that requires manufacturers to conduct paediatric studies for certain new and marketed drugs, and biological products, is another step forward (7).

The potential benefits from the anticipated increase in the number of paediatric studies include collection of better information about the efficacy and safety of prescription drugs in children. It is expected that more drugs will be labelled for use in children, and dosing guidelines appropriate for children will be available. A likely by-product will be formulations that are practical for use in this age group.

One of the priorities for paediatric investigators in Canada should be to take advantage of this window of opportunity to conduct paediatric drug studies in this country. Experts in drug research involving children have already taken the first steps to form the Canadian Paediatric Clinical Pharmacology Network. Experience in the United States with the Pediatric Pharmacology Research Unit Network, which is supported by the National Institute of Child Health and Human Development, suggests that such collaborative efforts are most likely to be successful (8). Canada is fortunate that, despite the previous problems with drug investigations, the country has a number of productive and accomplished paediatric clinical pharmacologists, and the recent developments in enhanced federal research funding bode well for the development of the Canadian Paediatric Clinical Pharmacology Network. The future does, truly, look brighter as the vision of evidence-based medicine in paediatrics moves closer to reality in the 21st century.