EDITORIAL
Children: Are We Doing Enough? S Ito1 Use of medicines in children is often off-label or off-evidence because essential information is lacking. Over the last two decades, consistent efforts have been made to render the regulatory framework more amenable to the needs of the pediatric population. Methodological progress is also evident. However, the consistent effort must be sustained. If we are to have drugs of better efficacy and safety for children, those responsible for child care will have to assume this responsibility for developing active programs of clinical pharmacology and drug testing in infants and children. The alternative is to accept the status of “ Therapeutic Orphans” for their patients. Shirkey, H. Editorial comment: Therapeutic orphans. Pediatrics 104, 583–584 (1999)
RESCUING THERAPEUTIC ORPHANS
When Dr Shirkey, who was trained both in pediatrics and pharmacy, coined a term “Therapeutic or pharmaceutical orphans” for children more than half a century ago in 1963,1 he was not probably anticipating any meaningful change to this problem in the foreseeable future. Three decades after his remark, the regulatory and drug research environment for children finally started changing. Two years before his editorial comments cited above, the Food and Drug Administration Modernization Act of 1997 (FDAMA) came into effect. In 2002, the Best Pharmaceuticals for Children Act (BPCA) was authorized, which eventually became a permanent law 10
years later in 2012, along with the Pediatric Research Equity Act (PREA). Under BPCA, pharmaceutical companies may receive a 6-month extension on patent exclusivity if they conduct FDA-requested pediatric studies of the drug in question. On the other hand, PREA mandates companies to conduct pediatric drug studies in their drug development programs under certain conditions. These changes in the US drug regulatory framework for pediatric patients were followed by similar initiatives in other developed countries, including the European Union (EU), which enacted the Paediatric Regulation in 2007. For the 5-year period between September 2007 and November 2013, 469 pediatric studies were completed under BPCA and PREA, and 526 labeling changes were made by August 2014.2 Similarly, in the EU under the Paediatric Regulation of 2007 more than 300 changes were made in medicine’s product information (i.e., labeling). Over the last decade, the so-called orphaning clause in drug labeling that excludes children from therapeutic indications is clearly decreasing, but off-label use of medicines is still prevalent in children.
1
Division of Clinical Pharmacology and Toxicology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Correspondence: S Ito ([email protected]) doi:10.1002/cpt.167
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VOLUME 98 NUMBER 3 | SEPTEMBER 2015 | www.wileyonlinelibrary/cpt
EDITORIAL
On the verge of expiry of BPCA and PREA in 2012, the Institute of Medicine (IOM) published the FDA-commissioned report “Safe and Effective Medicines for Children: Pediatrics Studies Conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.”3 In this 2012 report, the IOM committee concluded that BPCA, PREA, and related policies helped create better information on the efficacy, safety, and appropriate medicine prescribing for children. This is likely to be one of the factors for the US Congress to enact BPCA and PREA as permanent laws. However, the report also argued that some areas require closer attention. One of such “needs improvement” domains was the neonatal population. NEONATES
In this issue, the Review article by Allegaert and van den Anker provides an overview on the challenging aspects of neonatal prescribing and drug development.4 There is no doubt that drug studies in neonates are more difficult than in other age groups. One of the reasons is the rapidly developing pharmacokinetic (PK) and pharmacodynamic (PD) parameters. In other words, the age category of neonates consists of multiple age subgroups, which demand enormous sample sizes in dose-finding PK studies. The neonatal population is the final frontier of therapeutic orphans, but we cannot afford to allow them to continue being the final frontier of therapeutic orphans. This is a question of societal priority we all must answer in full. PEDIATRIC PHARMACOMETRICS
If done properly, a pharmacometrics approach with modeling and simulation is a powerful method that can compensate for a lack of observed data points (to some extent). This is particularly important in the pediatric population, which poses substantial challenges in a conventional PK CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 3 | SEPTEMBER 2015
study design of intense time-defined sampling in individual patients. In their Stateof-the-Art article,5 Vinks et al. describe essentials of pediatric pharmacometrics. One of the points they articulate is the importance of accessible pediatric population PK/PD models. If these data in the drug development processes become transparent and easily accessible to the community, the benefits for our children will be tremendous. As our “Systems Approach” theme issue illustrated,6 communal innovation based on shared data seems most appropriate in the pediatric population. TUBERCULOSIS IN CHILDREN
Infection continues to be a significant problem in global health settings. As Schaaf et al. elegantly articulate,7 tuberculosis remains a threat to our children. The authors further indicate lack of PK/PD data for optimal dosing schedules. We may have become too lenient to allow blind use of these drugs, most of which are old drugs with a relatively long history of use. Moreover, tuberculosis is not just the problem in the developing countries. In the era of immunomodulating biologics, pediatric tuberculosis may become the next major infection even in the developed countries, but our therapeutic infrastructure requires intense overhaul. FUTURE
Roughly half of drug use in children is offlabel, and the number is much higher in the advanced care settings and the neonatal population. Although “off-label” and “offevidence” are not necessarily the same thing, “off-label” use of medicines is often based on no or little evidence, associated with more safety issues. We have been making a steady progress over the last decades, but it is time for us to ask ourselves if our effort is sufficient. CONFLICT OF INTEREST The author declares no conflicts of interest. 223
EDITORIAL
C 2015 ASCPT V
1. Shirkey, H. Editorial comment: Therapeutic orphans. Pediatrics. 104, 583–584 (1999). 2. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/ DevelopmentResources/ucm190622.htm 3. Institute of Medicine: Committee on pediatric studies under BPCA and PREA. Safe and effective medicines for children: pediatrics studies conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.
224
4. Allegaert, K., van den Anker, J. Neonatal drug therapy: the first frontier of therapeutics for children. Clin. Pharmacol. Ther. (this issue). 5. Vinks, A.A., Emoto, C. & Fukuda, T. Modeling and simulation in pediatric drug therapy: application of pharmacometrics to define the right dose for children. Clin. Pharmacol. Ther. 98, 298–308 (2015). 6. Ito, S. System, crowd, and communal innovation: can the monks solve the elephant?. Clin. Pharmacol. Ther. 93, 369–371 (2013). 7. Shaaf, H.S., Garcia-Prats, A.J. & Donald, P.R. Antituberculosis drugs in children. Clin. Pharmacol. Ther. 98, 252–265 (2015).
VOLUME 98 NUMBER 3 | SEPTEMBER 2015 | www.wileyonlinelibrary/cpt
Children: Are We Doing Enough? S Ito1 Use of medicines in children is often off-label or off-evidence because essential information is lacking. Over the last two decades, consistent efforts have been made to render the regulatory framework more amenable to the needs of the pediatric population. Methodological progress is also evident. However, the consistent effort must be sustained. If we are to have drugs of better efficacy and safety for children, those responsible for child care will have to assume this responsibility for developing active programs of clinical pharmacology and drug testing in infants and children. The alternative is to accept the status of “ Therapeutic Orphans” for their patients. Shirkey, H. Editorial comment: Therapeutic orphans. Pediatrics 104, 583–584 (1999)
RESCUING THERAPEUTIC ORPHANS
When Dr Shirkey, who was trained both in pediatrics and pharmacy, coined a term “Therapeutic or pharmaceutical orphans” for children more than half a century ago in 1963,1 he was not probably anticipating any meaningful change to this problem in the foreseeable future. Three decades after his remark, the regulatory and drug research environment for children finally started changing. Two years before his editorial comments cited above, the Food and Drug Administration Modernization Act of 1997 (FDAMA) came into effect. In 2002, the Best Pharmaceuticals for Children Act (BPCA) was authorized, which eventually became a permanent law 10
years later in 2012, along with the Pediatric Research Equity Act (PREA). Under BPCA, pharmaceutical companies may receive a 6-month extension on patent exclusivity if they conduct FDA-requested pediatric studies of the drug in question. On the other hand, PREA mandates companies to conduct pediatric drug studies in their drug development programs under certain conditions. These changes in the US drug regulatory framework for pediatric patients were followed by similar initiatives in other developed countries, including the European Union (EU), which enacted the Paediatric Regulation in 2007. For the 5-year period between September 2007 and November 2013, 469 pediatric studies were completed under BPCA and PREA, and 526 labeling changes were made by August 2014.2 Similarly, in the EU under the Paediatric Regulation of 2007 more than 300 changes were made in medicine’s product information (i.e., labeling). Over the last decade, the so-called orphaning clause in drug labeling that excludes children from therapeutic indications is clearly decreasing, but off-label use of medicines is still prevalent in children.
1
Division of Clinical Pharmacology and Toxicology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Correspondence: S Ito ([email protected]) doi:10.1002/cpt.167
222
VOLUME 98 NUMBER 3 | SEPTEMBER 2015 | www.wileyonlinelibrary/cpt
EDITORIAL
On the verge of expiry of BPCA and PREA in 2012, the Institute of Medicine (IOM) published the FDA-commissioned report “Safe and Effective Medicines for Children: Pediatrics Studies Conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.”3 In this 2012 report, the IOM committee concluded that BPCA, PREA, and related policies helped create better information on the efficacy, safety, and appropriate medicine prescribing for children. This is likely to be one of the factors for the US Congress to enact BPCA and PREA as permanent laws. However, the report also argued that some areas require closer attention. One of such “needs improvement” domains was the neonatal population. NEONATES
In this issue, the Review article by Allegaert and van den Anker provides an overview on the challenging aspects of neonatal prescribing and drug development.4 There is no doubt that drug studies in neonates are more difficult than in other age groups. One of the reasons is the rapidly developing pharmacokinetic (PK) and pharmacodynamic (PD) parameters. In other words, the age category of neonates consists of multiple age subgroups, which demand enormous sample sizes in dose-finding PK studies. The neonatal population is the final frontier of therapeutic orphans, but we cannot afford to allow them to continue being the final frontier of therapeutic orphans. This is a question of societal priority we all must answer in full. PEDIATRIC PHARMACOMETRICS
If done properly, a pharmacometrics approach with modeling and simulation is a powerful method that can compensate for a lack of observed data points (to some extent). This is particularly important in the pediatric population, which poses substantial challenges in a conventional PK CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 98 NUMBER 3 | SEPTEMBER 2015
study design of intense time-defined sampling in individual patients. In their Stateof-the-Art article,5 Vinks et al. describe essentials of pediatric pharmacometrics. One of the points they articulate is the importance of accessible pediatric population PK/PD models. If these data in the drug development processes become transparent and easily accessible to the community, the benefits for our children will be tremendous. As our “Systems Approach” theme issue illustrated,6 communal innovation based on shared data seems most appropriate in the pediatric population. TUBERCULOSIS IN CHILDREN
Infection continues to be a significant problem in global health settings. As Schaaf et al. elegantly articulate,7 tuberculosis remains a threat to our children. The authors further indicate lack of PK/PD data for optimal dosing schedules. We may have become too lenient to allow blind use of these drugs, most of which are old drugs with a relatively long history of use. Moreover, tuberculosis is not just the problem in the developing countries. In the era of immunomodulating biologics, pediatric tuberculosis may become the next major infection even in the developed countries, but our therapeutic infrastructure requires intense overhaul. FUTURE
Roughly half of drug use in children is offlabel, and the number is much higher in the advanced care settings and the neonatal population. Although “off-label” and “offevidence” are not necessarily the same thing, “off-label” use of medicines is often based on no or little evidence, associated with more safety issues. We have been making a steady progress over the last decades, but it is time for us to ask ourselves if our effort is sufficient. CONFLICT OF INTEREST The author declares no conflicts of interest. 223
EDITORIAL
C 2015 ASCPT V
1. Shirkey, H. Editorial comment: Therapeutic orphans. Pediatrics. 104, 583–584 (1999). 2. http://www.fda.gov/Drugs/ DevelopmentApprovalProcess/ DevelopmentResources/ucm190622.htm 3. Institute of Medicine: Committee on pediatric studies under BPCA and PREA. Safe and effective medicines for children: pediatrics studies conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act.
224
4. Allegaert, K., van den Anker, J. Neonatal drug therapy: the first frontier of therapeutics for children. Clin. Pharmacol. Ther. (this issue). 5. Vinks, A.A., Emoto, C. & Fukuda, T. Modeling and simulation in pediatric drug therapy: application of pharmacometrics to define the right dose for children. Clin. Pharmacol. Ther. 98, 298–308 (2015). 6. Ito, S. System, crowd, and communal innovation: can the monks solve the elephant?. Clin. Pharmacol. Ther. 93, 369–371 (2013). 7. Shaaf, H.S., Garcia-Prats, A.J. & Donald, P.R. Antituberculosis drugs in children. Clin. Pharmacol. Ther. 98, 252–265 (2015).
VOLUME 98 NUMBER 3 | SEPTEMBER 2015 | www.wileyonlinelibrary/cpt
