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ADVOCACY

April 2003, Volume 8, Number 4

Better drug therapy for children: Time for action

Michael J Rieder MD PhD FRCPC

Although the past century has seen the most remarkable advances in medical management in history, the benefits of the therapeutic revolution have not been equally shared (1). As child health care workers appreciate, and as noted elsewhere in this issue of Paediatrics & Child Health, there is no evidence-based support for the efficacy, optimal dosing and safety of the majority of drugs commonly used in children. Academic paediatrics has let therapeutics for children evolve by default, driven by inferences from adult medicine and emotional rather than evidence-based prescribing practice. Given the increasing number and complexity of new therapies entering clinical practice, this usual state of affairs is clearly unacceptable for now and certainly for the future.

Why Don’t We Do Drug Research in Children? Urban Myths in Drug Research in Paediatrics

The significant gap between the intensity of therapeutics research in adults and children has been appreciated for some time (2,3). The factors that led to drug research in children lagging behind that in adults are multiple and can be summarized as follows. Drug research in children is difficult. There are technical difficulties in obtaining samples of blood and other biological fluids, notably in sufficient number and quantity for pharmacokinetic studies. The usual end-points used in adult studies frequently cannot be used for studies involving children, so often a surrogate end-point is needed. This can potentially make the study more difficult and surrogate end-points must be justified and validated. Children are unlikely to tolerate the degree of invasive monitoring often used in early-phase adult studies. As well, there are many fewer paediatric subspecialists than in the adult medicine world and thus it may be difficult for a single centre to conduct drug research in children in a timely manner.

Some of these factors are inherent in the research establishment. Researchers have been uneasy with ethical issues involved in the conduct of drug research in children. Finally, there is the perception that drug use in children is infrequent and confined to a relatively small number of drug classes, primarily antimicrobials (4). Thus, there has been the perception by funding agencies and industry that therapeutic issues in children are relatively minor and that there is little economic pressure to pursue this drug research. As well, drug regulatory agencies have not required studies in children for new molecular entities unless the agent in question was intended for use primarily in children.

Slaying the Dragon: Dealing with Urban Myths in Drug Research

into Paediatrics

As detailed above, the reasons for not conducting drug research in children are many and, to be fair, some were valid in their day. However, it is the purpose of this advocacy piece to note that many of these reasons are either no longer valid or, in some cases, never were valid.

Is drug research in children difficult? Yes it is. However, recent advances in paediatric clinical pharmacology, many of which have occurred in Canada, have made drug research in children much easier than it would have been a decade ago. Measurement of drugs or drug metabolites in saliva, use of sparse sampling techniques and population pharmacokinetics, permit pharmacokinetic studies using smaller specimen volumes and many fewer samples than has been the case previously (5-7). As well, the use of topical anesthetic creams and indwelling catheters have permitted investigators to obtain blood samples from children in a much less painful fashion than in the past.

As well, the methodology of clinical research in paediatrics has improved considerably. A generation of methodologists have left us with a legacy of numerous validated, reliable and accurate measurement tools for outcomes as variable as pain in a preterm neonate in the neonatal intensive care unit to the palatability of oral antibiotics among children being treated for otitis media in the general ambulatory care clinic (8,9). Although much work remains to be done, there are many more tools in the armamentarium of the paediatric researcher than was the case as recently as a decade ago. Similarly, the methodology of clinical trials has also adapted to paediatric needs. Although the randomized double-blind clinical trial remains the gold standard, there are a number of alternate strategies for conducting research in children, notably critically ill children can be used for situations when a conventional clinical trial design would be unsuitable (10).

As noted, there are relatively few paediatric subspecialists compared with the larger number of investigators in adult sub-specialties. However, researchers have increasingly appreciated the importance of working in a collaborative nature through networks, and over the past decade a number of paediatric networks have developed, both in Canada and elsewhere. The success of the Neonatal Network and the Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC), to name two of a number of Canadian networks, in conducting multicentre trials to study common and important problems in children are examples of how investigators in different centres can work together to improve child health through research (11).

As well, serious disease remains a major problem for children in the developing world. One of the challenges that we face as a global community is the ‘North-South’ imbalance, the disparity in resources and prospects between the developed and developing world. The provision of optimal drug therapy in the developing world is a major challenge, notably because serious disease remains a common problem for those children who make up the majority of the world’s children, that being those in the developing world.

The ethical issues involved in conducting research in children are real and not easy to deal with. We have found that investigators in Canada believe that ethical issues are the main barriers to conducting drug research in children (12). The field remains plastic, with key issues and problems changing on a regular basis. As noted elsewhere in this issue, there is an urgent need for Health Canada, the Canadian Institutes of Health Research and the National Council on Ethics in Human Research to work with investigators, universities and the Canadian Paediatric Society to review and revise the TriCouncil guidelines to provide Canadian investigators with clear guidelines on the ethical conduct of drug research in children. A promising development is that there are a number of scholars and clinicians with interest and expertise in biomedical ethics, and this area is now attracting interest from a number of key stakeholders.

The issue of drug utilization by children has been a thorny one for some time, with the perception by many key stakeholders that drug use in children is not common, and when therapy is prescribed, it is primarily in the form of anti-infective agents and bronchodilators. A recent report by the Brogan Consulting Group demonstrated that this is not the case. This report, which was prepared as a result of a survey of a number of prescription plan databases from across Canada, has demonstrated that 20% of all drugs prescribed in Canada are to patients 18 years of age or younger. Moreover, and of great interest, the medications that are prescribed come from a wide range of therapeutic classes, including a number of psychoactive agents. The use of medications for therapy of children in Canada is common and includes a wide variety of drugs. Thus, the fact that 80% of the drugs in the Compendium of Pharmaceuticals and Specialties (13) do not have dosing or safety information for use in children becomes of even greater importance (3,4,14).

Finally, there is the issue of the drug approval process. The drug approval process has historically not included the need for studies of the drug in question among children unless children were the primary group for whom the drug was intended. An interesting historical note is how the current drug regulatory process evolved. Since the introduction of specific therapy in the 1930s, changes in drug regulation have been driven by therapeutic misadventures, often involving children. Before this time, drugs were regulated by ministries of industry or departments of commerce, with the primary concern being patent protection. The elixir of the sulfanilamide tragedy, in which the majority of victims were children, led to the development of drug regulatory agencies, with a mandate to ensure drug safety (1). The thalidomide tragedy, again, where the majority of victims were children, stimulated changes in drug regulation to ensure that drugs were both effective and safe (1). However, the legislative change that was hoped to ensure the safety of drugs in children had the unintended effect of significantly reducing the incentive and imperative for conducting drug studies in children.

However, this is in the process of changing. The United States Food and Drug Administration has made a number of changes in drug regulation that encourage, and in some cases mandate drug studies in children before regulatory approval of new molecular entities. Moreover, one of the principles in the International Conference on Harmonization , a set of guidelines for drug approval that the major industrialized countries have agreed to (11), is that drugs must be tested in populations in which they are likely to be used (15). Thus, given the expanding use of a wide variety of drug classes in paediatrics, there is likely to be regulatory pressure to conduct drug studies in children before drugs can be approved for the general market.

In summary, while drug research in children remains difficult, many of the more problematic issues have been dealt with over the past two decades. Given the rapidly expanding therapeutic repertoire, which increasingly will include peptide, factor and gene therapy, drug research in children will become an even more pressing issue over the next decade than it has been previously.

Finding the Middle Ground:

A Made-In-Canada Solution

This raises the question of how child health care workers in Canada can work to move forward the agenda of paediatric therapeutics. To frame possible solutions, one might look beyond our borders. In the United States, the Pediatric Pharmacology Research Unit Network, supported by the National Institute of Maternal and Child Health, is now approaching the end of its first decade (16). This initiative, which supports 13 centres across the United States, has had considerable success in providing infrastructure to support drug studies in children. The number of drug studies that have been completed and are on-going is impressive. However, there has been an emphasis on new molecular entities and certain therapeutic classes, such as cardiovascular agents, which is probably a reflection of the prolongation of patent afforded in the United States by conducting a drug study in children (17).

In Europe, a number of centres are active in attempting to establish a similar network, and are seeking support from the European Parliament.

What about Canada? There are a number of centres across Canada that are actively engaged in research in children. Canada has a small but very active core cadre of paediatric clinical pharmacologists. Should Canadian investigators lobby the Federal Government and Canadian Institutes of Health Research for major network support? How can we advocate enhanced research with the goal of better drug therapy for children?

In fact, Canadian paediatric clinical pharmacologists have already begun to work on this problem, and with support from the Institute of Child, Maternal and Youth Health have formed the first links of a Canadian Paediatric Clinical Pharmacology Network. Over the past two years, members of the six centres in the network have met and identified key challenges and are in the process of developing strategies to address them.

What is the implication of the success of the United States Pediatric Pharmacology Research Unit Network for the Canadian network? One of the key gaps is in infrastructure. This summer, the members of the network will meet to review their research inventories and to develop a list of needs. Once this is developed, the network members will work with key partners, including their home universities, hospitals and foundations as well as with industry, the CIHR and the Canadian Paediatric Society to find the necessary support, which in typical Canadian fashion is likely to be on a shared basis from many different sources. What could be the role of this network? As noted above, many of the drugs being studied elsewhere are new therapeutic agents. While very important, the fact remains that the majority of drugs used by Canadian children are in fact already marketed agents. Thus, a key role for the new network will be to review drug utilization data, determine which of the commonly used and important drugs needs more data and then to conduct the studies needed to guide practitioners in the safe and efficacious use of these drugs.

Moving Forward

In summary, drug research in children has not been conducted at a pace able to meet the expanding demand of the therapeutic arena and to allow physicians caring for children to practise evidence-based medicine. There are new developments that have great promise in providing Canadian investigators with the tools, incentive and support needed to conduct the studies needed to define optimal drug therapy in pursuit of our common goal of better health for Canadian children.

Acknowledgements: The support of the Canadian Institute of Child, Maternal and Youth Health is gratefully appreciated.

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