Pediatr Drugs 2007; 9 (4): 215-218 1174-5878/07/0004-0215/$44.95/0
UPDATE FROM THE ALLIANCE
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Challenges in International Pediatric Pharmacology A Milestone Meeting in Shanghai Stuart MacLeod,1,2,3 Robert Peterson,1,2 Yi Wang,4 Zhiping Li,4 Yonghao Gui4,5 and Jane Schaller1,3,6 1 2 3 4 5 6
University of British Columbia, Vancouver, British Columbia, Canada Child & Family Research Institute, Vancouver, British Columbia, Canada Centre for International Child Health, Vancouver, British Columbia, Canada Fudan University Children’s Hospital, Shanghai, China Chinese Paediatric Society, Shanghai, China International Paediatric Association, Vancouver, British Columbia, Canada
There has been a rapid growth in the awareness of the importance of issues surrounding the choice of optimal drug therapy for children in recent years as the proportion of children internationally has grown. In many parts of the developing world, children now make up more than 50% of the population and, according to United Nations Children’s Fund (UNICEF) figures, there are now close to 3 billion children aged 0–18 years worldwide.[1] It is generally recognized that drug therapy for children is often instituted without an adequate scientific foundation.[2-4] Many drugs commonly used in pediatrics have not been adequately studied in an infant, child, or adolescent population, and new therapies are regularly introduced without a requirement for study in these target groups. The international scientific establishment engaged in the study of basic, clinical, and population pharmacology in children is extremely limited. Furthermore, most recognized centers of excellence in pediatric pharmacology are located in high-income countries where the pediatric population proportion is low. There is an urgent public health need for the transfer of knowledge from pediatric pharmacology research units in developed countries to centers of populations in low- and middle-income countries. There is a parallel need for enhanced research capacity in Asia, Africa, and Latin America where most of the world’s children reside. The Millennium Development Goals (MDGs) for the years 1990–2015 give substance to a number of pediatric pharmacology issues.[5] For example, MDG 4 calls for a two-thirds reduction in child mortality and much of the effort needed will center on improved approaches to therapeutics for infectious diseases (diarrhea, pneumonia, malaria, HIV/AIDS) and improved immunization. MDG 5 calls for improvements in maternal health, including a reduction in maternal mortality, which is essential to better child survival and health. Again, many of the issues to be addressed are
related to optimal drug therapy. MDG 6 specifically addresses the challenges of reducing mortality from HIV/AIDS, malaria, and tuberculosis. Finally, MDG 8 calls for assurance of availability and access to appropriate essential therapies at a country level. This array of challenges led to the planning of an international satellite symposium on challenges in pediatric pharmacology, which was held in Shanghai, China in July 2006 preceding the International Union of Basic and Clinical Pharmacology (IUPHAR) 15th World Congress of Pharmacology in Beijing, China. Delegates from 15 countries attended the symposium. As detailed in the discussion that follows, the results of that meeting represent a milestone in international efforts to improve pediatric therapeutics in several dimensions. 1. Background The Shanghai meeting was the latest in a series of active international discussions aimed at creating an integrated, multidisciplinary, inter-professional effort to mobilize both applied and theoretical pharmacology research in support of improved drug therapy for children. As the problems have been amplified over the last 15 years, meetings have been held in Halifax, Canada (International Pediatric Association [IPA], WHO),[6] London, UK, and Bellagio, Italy[7] with the support of the Rockefeller Foundation, and in Liege, Belgium[8] with the support of the European Society for Developmental and Pediatric Pharmacology, working together with the National Institute for Child Health and Human Development (NICHD). The NICHD has, since 1995, sponsored a network of Pediatric Pharmacology Research Units[9] that represents one of the major assets available internationally for studying better medicines for children. In 2006 there was an acceleration of discussion, with international meetings in Baltimore, USA in March and
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Stockholm, Sweden in June culminating in the symposium in Shanghai. In all of these meetings it was apparent that there is a growing sense of urgency and purpose. The timing is opportune for the creation of an international alliance of pediatricians, pharmacologists, pharmacists, and health policy specialists interested in childhood therapy and committed to pursuing better outcomes in hospital and community settings. The urgency of this task is especially underscored by conditions in low-income countries where there is a disproportionately high burden of disease and a relatively limited research capacity. This dissociation of scientific capacity and disease burden is particularly evident with respect to parasitic, bacterial, and viral diseases.[10,11] 2. Shanghai Symposium The four major themes featured at the symposium are outlined in this section. 2.1 Optimal Therapeutics for Children: What are the Immediate Challenges?
Practical issues were examined, including the rational use of antibiotics for the treatment of community-acquired, lower respiratory tract infections (Dr Daiming Wang) and the benefits of applying pediatric clinical pharmacology research to improved therapeutic practices in pediatric neurology (Dr Li Wang). The need for methodologic innovation was addressed by speakers from Canada and France (Dr Bob Peterson and Dr Gerard Pons) and the efforts of international organizations to improve pediatric therapy were addressed from the perspective of the WHO/UNICEF (Dr Noel Cranswick), the NICHD (Dr Anne Zajicek), the IUPHAR (Dr Kalle Hoppu), and the IPA (Dr Jane Schaller). These presentations established the existence of a sound foundation for action and emphasized the knowledge gap that exists between the present state of scientific preparedness and the reality of therapy for children in many parts of the world. 2.2 Challenges in Safe Medication Practice
An important knowledge gap exists between our understanding of human genomics and its application to the achievement of better therapeutic outcomes and minimized adverse drug reactions. A cutting edge presentation by Dr Evelyne Jacqz-Aigrain from France examined the opportunities for improved therapeutic success in the treatment of acute lymphoblastic leukemia, while Dr Bruce Carleton from Canada examined the parallel problem of minimizing drug risk in children through the development and application of genomic biomarkers. An international panel discussed issues related to natural health products, off-label prescribing, use of drugs during lactation, use of antidepressant therapy during pregnancy, issues of drug quality, © 2007 Adis Data Information BV. All rights reserved.
and measures that may be taken to assure optimal therapy in critical care settings. 2.3 Therapeutic Choices for Optimal Outcome in Critically Ill Neonates and Children
Keynote presentations included a review by Dr Robert Poole from Stanford University, USA of total parenteral nutrition, emphasizing measures to make this high-risk therapy safe for infants and children. Dr Bo Sun of Fudan University, China discussed the Chinese experience with clinical trials for testing new drugs and therapies in neonatal and intensive care units. Dr Alvin Zipursky from the University of Toronto, Canada provided a report on a symposium held at the Pediatric Academic Societies meeting in San Francisco, USA (May 2006) concerning neonatal infectious diseases in developing countries. A subsequent panel discussion included presentations on antimicrobial use in five Chinese pediatric hospitals and problems with the management of childhood infectious diseases in Kenya, South Africa, and Singapore. The issues of vertical transmission of hepatitis B in China and the management of infantile influenza infection in Japan were also discussed. 2.4 The Future of Drug Therapy for Neonates, Infants, and Children
A plenary discussion by Dr Yizhun Zhu on drugs in pediatrics, the potential and future, provided a foundation for this theme. An important future challenge was presented by Dr Jean-Paul Collet of Canada. Dr Collet discussed the methodologic issues inherent in the evaluation of traditional Chinese medicines. A subsequent panel discussion included presentations on a more integrated approach to the delivery of better medicines for children and on the future promotion of individualized therapy for children. Other visions of the future were presented in respect to neonatology, drug safety, drug quality in a developing country setting, and antenatal drug risk. 3. International Alliance for Better Medicines for Children At the conclusion of the symposium, a colloquium of pediatricians, pharmacologists, and pharmacists was held. This session featured a review of issues identified in the Shanghai symposium and in preceding meetings in 2006. The international pediatric community and pediatric pharmacologists and pharmacists have not traditionally worked closely together until these events of 2006, which have resulted in the formation of the International Alliance for Better Medicines for Children. The Alliance will focus on defining which medicines are essential for children at country and regional levels, appropriate formulations for children, drug regulatory mechanisms, adequate Pediatr Drugs 2007; 9 (4)
Challenges in International Pediatric Pharmacology
clinical trials to assure safety, and, ultimately, assurance that suitable medicines for children will actually be available for all children at country levels throughout the world. These goals are closely allied with the Millenium Development Goals, which set a standard of reduction of child mortality by two thirds by the year 2015. The Alliance is committed to working as closely as possible with both WHO and UNICEF and other international agencies. The representatives of 15 countries which formed the International Alliance for Better Medicines for Children agreed on the following statement as an accurate reflection of their commitment to improving access to safe and reliable medicines for children worldwide.[12] We, concerned pediatricians, clinical pharmacologists and pharmacists of the world, representing the International Pediatric Association and the International Union of Pharmacology and its Children’s Committee, call urgent attention to: • the convention on the Rights of the Child, which states the right of every child to the highest attainable standard of health; • and the MDGs, which include calls for a two-thirds reduction in child mortality (MDG 4), improving maternal and newborn health (MDG 5), combating HIV/AIDS, malaria, and other diseases including tuberculosis (MDG 6); and availability of essential medicines (MDG 8). We duly note that access to safe and reliable medicines for children worldwide and the rational use of such medicines are essential to attainment of child health and achievement of the MDGs. We are gravely concerned that major impediments to achieving access to and rational use of better medicines for children worldwide exist in 2006, particularly in the developing world. These include the present realities that: • many children, and especially those of the developing world, do not have access to safe and effective medicines in formulations that address children’s health needs; • evidence-based treatment guidelines for major childhood diseases are not universally available; • a clear definition of medicines essential for the care of children does not exist; • drugs are often used inappropriately in children, with insufficient attention to the unique physiologic needs and developmental stages of childhood; • pediatricians, other child health providers, and clinical pharmacologists and pharmacists are too often inadequately trained in the appropriate use of medicines in children, and there is a critical shortage of pediatric pharmacologists and pharmacists, particularly in the developing world; research focused on medicines for children is inadequately • emphasized and supported; • many medicines potentially useful to children are not tested in children, leading to wide off-label use of adult-tested drugs in © 2007 Adis Data Information BV. All rights reserved.
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children, and global principles to guide ethical, safe, and valid clinical trials of drugs in children are ignored or do not exist; • regulatory capacities to support access to medicines through acquisition, distribution, and monitoring mechanisms and to collect and respond to reports of adverse drug reactions in children are inadequate and hamper the availability and safety of medicines for children at a country level, particularly in the developing world; • efforts to address the many issues of better medicines for children have been fragmented and uncoordinated, and there is no identifiable global partnership of concerned and informed stakeholders to advocate for and work together to achieve the reality of better medicines for children in countries throughout the world. We therefore resolve that through an international alliance we will address these impediments through: • bringing the combined strengths, knowledge, and expertise of our professions together to advocate and work for the reality of access to safe and effective medicines for all children at country levels worldwide; • responding to the need for evidence-based clinical treatment guidelines pertinent to the important causes of newborn and child mortality and morbidity worldwide, with due attention to regional and country needs; • defining a global essential medicines list for children based on a definition of the specific health needs of children in countries and regions throughout the world; • building human resources through educational programs and enhanced teaching and training programs in the safe and appropriate use of drugs in children for pediatricians, general physicians, health workers at all levels, and clinical pharmacologists and pharmacists; promoting the training of more pediatric pharmacologists and pharmacists, particularly in the developing world; and developing educational materials to support the rational use of medicines for professionals, caregivers, governments, and consumers; • promoting basic, clinical, and operational research important to safe and effective therapies for children, including safety evaluations, production of stable formulations for children, pharmacokinetics/pharmacodynamics, epidemiologic studies, and basic aspects of host responsiveness and toxicity; • defining global standards for the testing of drugs in children and for the conduct of ethical and safe pediatric clinical trials, with attention to the infrastructure necessary for the conduct of such trials, and the issues of benefit to participating sites and participants; • supporting the development of a national regulatory capacity for market authorization, acquisition, and distribution of drugs, counterfeit surveillance, and clinical trial authorization, with particular attention to medicines for children; Pediatr Drugs 2007; 9 (4)
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working together as professionals, and promoting working relations with other stakeholders, including civil society and its organizations, governments, the WHO, the UNICEF, industry, and donor organizations.
the creation of an Alliance to support the regulatory, research, and educational initiatives required if we are to achieve optimal pharmacotherapy for children. As the Alliance progresses we plan to present regular progress reports in Pediatric Drugs and we are grateful to the editor and publishers for providing this opportunity.
4. Update on Recent Events Acknowledgments Since the July 2006 Declaration (see section 3), discussion has taken place among the potential partner organizations, and the membership roster for the Alliance is currently taking shape. On 25 March 2007, a number of the partners came together in conjunction with the annual meeting of the American Society for Clinical Pharmacology and Therapeutics in Anaheim, CA, USA and a plan of action was agreed that will lead to formalization of the Alliance and identification of its priority activities before 31 December 2007. A foundation steering committee met by teleconference on 25 July 2007, with broad international representation and participation by pediatricians, clinical pharmacologists and pharmacists. As it becomes more formally established, the Alliance will welcome participation from all groups interested in better medicines for children. IPA and IUPHAR presented formal statements supporting a resolution on better medicines for children at both the WHO Executive Board (January 2007) and the World Health Assembly (May 2007). This resolution was subsequently considered and passed by the World Health Assembly on May 23, 2007 (WHA 60.20), mandating that WHO and Member States now act on the issues of better medicines for children.[13] Following the passage of the WHA 60.20 the executive board passed a resolution establishing a subcommittee of the Expert Committee on the Selection and Use of Essential Medicine.[14] This subcommittee is to prepare a list of essential medicines for children; to determine the suitability criteria for dosage forms of medicines for children, with particular attention to conditions in developing countries; to review the feasibility of manufacturing appropriate formulations of priority medicines for which no dosage form for children currently exists; and to identify the clinical research gaps regarding safety and efficacy of essential medicines for children (EB121.R2). The subcommittee held its first meeting on 9–13 July 2007. In summary, an eventful 12 months has passed since the milestone meeting in Shanghai. Substantial progress has been made in
© 2007 Adis Data Information BV. All rights reserved.
No sources of funding were used to assist in the preparation of this report. The authors have no conflicts of interest relevant to the content of the report.
References 1. UNICEF. State of the world’s children report 2007 [online]. Available from URL: http://www.unicef.org/publications/index_36587.html [Accessed 2007 Jul 22] 2. Gazarian M, Kelly M, McPhee JR, et al. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust 2006; 185: 544-8 3. American Academy of Pediatrics Committee on Drugs. Uses of drugs not described in the package insert (off-label uses). Pediatrics 2002; 110: 181-3 4. MacLeod SM. Better paediatric drug labeling: noble quest or quixotic fantasy? Balli`ere’s Clin Paediatr Intern Pract Res 1998; 6: 471-81 5. United Nations. Millennium development goals [online]. Available from URL: http://www.un.org/millenniumgoals [Accessed 2007 Jul 22] 6. Rieder MJ, Koren G, MacLeod SM. Pediatric clinical pharmacology and the health of the world’s children. Dev Pharmacol Ther 1990; 14: 201-4 7. MacLeod SM. Clinical pharmacology and optimal therapeutics in developing countries. J Clin Epidemiol 1991; 44 Suppl.: 89S-93S 8. Beggs SA, Cranswick NF, Reed MD. Improving drug use for children in the developing world. Arch Dis Child 2005; 90: 1091-3 9. National Institute of Child Health and Human Development. Pediatric Pharmacology Research Unit (PPRU) Network [online]. Available from URL: http:// www.nichd.nih.gov/research/supported/ppru1.cfm [Accessed 2007 Jul 22] 10. Prologue: drugs and vaccines around the world. Health Aff 2006; 25: 312 11. Ridley DB, Grabowski HG, Moe JL. Developing drugs for developing countries. Health Aff 2006; 25: 313-24 12. Pediatric Pharmacy Advocacy Group. Alliance for Better Medicines for Children declaration [online]. Available from URL: http://www.ppag.org/en/art/?.348 [Accessed 2007 Jul 22] 13. WHO. 60th World Health Assembly Resolution WHA 60.20: better medicines for children: 23 May 2007 [online]. Available from URL: http://www.who.int/gb/ ebwha/pdf_files/WHA60/A60_R20-en.pdf [Accessed 2007 Jul 22] 14. WHO. Expert Committee on the Selection and Use of Essential Medicines: establishment of a subcommittee: 24 May 2007 [online]. Available from URL: http://www.who.int/gb/ebwha/pdf_files/EB121/B121_R2-en.pdf [Accessed 2007 Jul 22]
Correspondence: Dr Stuart MacLeod, K4-104 Ambulatory Care Building, Child & Family Research Institute, 4480 Oak Street, Vancouver, V6H 3V4, Canada. E-mail:
[email protected]
Pediatr Drugs 2007; 9 (4)
