Journal of Thrombosis and Haemostasis, 13: 481–484

DOI: 10.1111/jth.12807


Recommendations for the development of new anticoagulant drugs for pediatric use: communication from the SSC of the ISTH C. MALE,* P. MONAGLE,†‡ A. K. C. CHAN§ and G. YOUNG,¶ FOR THE SUBCOMMITTEE ON PEDIATRIC/NEONATAL HEMOSTASIS AND THROMBOSIS *Department of Pediatrics, Medical University of Vienna, Vienna, Austria; †Department of Paediatrics, Murdoch Children’s Research Institute, University of Melbourne; ‡Department of Haematology, Royal Children’s Hospital, Melbourne, Victoria, Australia; §Division of Haematology/ Oncology, McMaster University, McMaster Children’s Hospital, Hamilton, Ontario, Canada; and ¶Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

To cite this article: Male C, Monagle P, Chan AKC, Young G, for the Subcommittee on Pediatric/Neonatal Hemostasis and Thrombosis. Recommendations for the development of new anticoagulant drugs for paediatric use: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13: 481–4.

Introduction There has been a notable increase in the frequency of venous thromboembolism (VTE) and anticoagulant use in children [1]. As a result of new regulations in the USA and Europe [2,3] requiring pharmaceutical companies to develop and license new drugs for children, pediatric investigation programs (PIPs) for several new anticoagulants have begun. The Pediatric/Neonatal Hemostasis and Thrombosis Scientific and Standardization Subcommittee is proposing a guidance paper to ensure a rational and harmonized approach to the introduction of new anticoagulants into pediatrics. The objectives are that these programs address the unique pediatric needs, generate scientifically valid data, and are ethical and feasible. General considerations In principle, PIPs for anticoagulants should be based on the properties of the drugs and built upon the development program in adults, where applicable. Owing to the complexity and risk involved in studying anticoagulants in children, we strongly recommend that development of

Correspondence: Guy Young, Hemostasis and Thrombosis Center, Children’s Hospital Los Angeles, University of Southern California Keck School of Medicine, 4650 Sunset Blvd Mail Stop 54, Los Angeles, CA 90254, USA. Tel.: +1 323 361 5507; fax: +1 323 361 7128. E-mail: [email protected] Received 14 August 2014 Manuscript handled by: W. Ageno Final decision: F. R. Rosendaal, 29 November 2014 © 2014 International Society on Thrombosis and Haemostasis

a PIP should involve pediatric thrombosis experts, and that an independent data safety monitoring board should be appointed for all stages of development. As the etiology of thromboembolism in children is different from that in adults, the following model conditions are suitable for study (Table 1). Primary prevention

Several conditions could be considered to be appropriate targets for studying anticoagulant prophylaxis (Table 1). Given the frequency of central venous catheter (CVC)related thrombosis, a clinical trial aimed at reducing the incidence of CVC-related VTE is feasible and would potentially have a meaningful clinical impact. Other conditions that could be considered for trials aimed at preventing thromboembolism include periprocedural anticoagulation. Treatment

As in adults, VTE and pulmonary embolism should be the model conditions for studying new anticoagulants when considering the treatment of thromboembolism. Development stages Table 2 lists the key components of a PIP for anticoagulants. The usual preclinical data for determining toxicology are required, however, in addition, the need for juvenile animal studies must be considered, especially if preclinical studies indicate toxicity relevant for developing systems or possible effects on growth or development [4]. Furthermore, manufacturers must also develop age-appropriate formulations for all targeted pediatric age groups [5]. Prior to the initiation of pediatric studies, clinical data in adults on safety and pharmacokinetics should be available [6]. Pediatric pharmacokinetic (PK) studies should use a

482 C. Male et al Table 1 Model indications for anticoagulant development for adults and children Prevention Venous TE Adults Orthopedic surgery Major surgery Medically ill patients Children Central venous catheter-related thrombosis Perioperative Periprocedural (e.g. cardiac catheter)

Cardiac and arterial TE


Atrial fibrillation Acute coronary syndrome


Dilated cardiomyopathy Artificial shunts (Fontan) Stent placement Kawasaki syndrome Central arterial lines

DVT/PE Cerebral venous sinus thrombosis Stroke

DVT, deep vein thrombosis; PE, pulmonary embolism; TE, thromboembolism.

Table 2 Key components of a pediatric investigation plan for an anticoagulant drug Preclinical data (? consider juvenile animal studies) Development of pediatric formulation(s) Adult data Phase 1: PK/PD studies and safety In vitro concentration–response studies Physiologically based PK prediction models Population pharmacokinetics/pharmacodynamics and modeling Phase 2: Dose-finding/dose confirmation and safety Phase 3: Efficacy and safety Prevention (CVC, cardiac disease) Treatment (VTE/PE) Phase 4: postmarketing surveillance CVC, central venous catheter; PD, pharmacodynamic; PE, pulmonary embolism; PK, pharmacokinetic; VTE, venous thromboembolism.

stepwise approach, starting with adolescents and proceeding to younger age groups. There are age-dependent differences in the coagulation system that are most significant in infants aged < 6 months and neonates. These differences may affect the anticoagulant effect of the drug at a given plasma concentration, and will also impact on laboratory monitoring. Therefore, pediatric PK studies should also obtain pharmacodynamic (PD) parameters. An initial step to estimate the age-dependent drug concentration–anticoagulant response relationship may be the performance of in vitro studies with plasma from healthy children of different age groups spiked with the anticoagulant at several concentrations, to assess the effects on various coagulation parameters [7]. To what extent such in vitro parameters correlate with clinical outcome needs to be established in later clinical development. The choice of age strata will depend on the pharmacologic properties of the drug and the target disease(s), but, given the age-dependent coagulation system, there should always be a distinction between older children and infants aged < 6 months. The choice of appropriate efficacy and safety outcomes for clinical trials in thromboembolism in children is of utmost importance, but, for a detailed discussion of outcomes, readers should refer to a recent ISTH position

paper [8]. The following are some basic criteria for each stage of development. Phase 1

A phase 1 study implies ‘first in child’ drug administration with the main goals of establishing a basic level of safety and determining PK parameters, PD parameters, and dosing. The ethical challenges of phase 1 studies are that they cannot involve healthy children and offer only short-term drug exposure, providing little individual benefit. We recommend that phase 1 studies be performed in children who have completed their course of anticoagulation for a VTE, as these patients have a relatively high risk of recurrence [9], and thus there is a potential benefit. Study designs should be open-label and non-comparative, using single-dose PK/PD assessment whenever possible, and may include one or more dose levels. A critical issue is the number and volume of blood samples collected, particularly in young children and neonates. Therefore, sophisticated tools to optimize pediatric PK studies should be applied. Physiologically based PK models using PK data from adults and physiologic information for children may be used to predict doses for different pediatric age groups and to optimize sampling schemes in advance [10]. Pediatric PK studies should proceed in a staggered fashion from adolescents to younger age groups, thereby gradually improving the prediction for younger age groups. This approach may also involve population PK modeling, which allows sparse sampling in individual patients [11]. Finally, micro-methods for laboratory analyses should be used to minimize sample volumes. Safety data must be carefully collected. At phase 1 completion, there should be increased confidence in the safety of the agent and a clear understanding of the dose (s) to be used in subsequent phases. Phase 2

The goal of this phase is to confirm safety in a larger patient population and to establish the best dose. Addi© 2014 International Society on Thrombosis and Haemostasis

Development of new anticoagulants in pediatrics 483

tional PK evaluation, focusing in particular on repeated dose administration, should be performed, and dose-ranging or dose titration in the individual patient based on an appropriate PD parameter should also be performed. The study design may include a comparison arm using standard anticoagulants or placebo. Although various designs are possible, we recommend that a phase 2 study be conducted during the late phase of anticoagulant treatment of a VTE after a period of treatment with standard agents. Phase 3

The objective of phase 3 studies is to establish efficacy, safety, and a positive benefit-to-risk ratio. In adult studies, a phase 3 study is intended to prove that the new agent is at least non-inferior to standard therapy, and usually requires thousands of patients. Such fully powered studies in children are not feasible, owing to numerous barriers [12]. Therefore, a PIP will have to build on the data available from adults. The plan should outline how data extrapolated from adult studies will inform the design and complement the results of the pediatric study [13]. The pediatric study should still include a randomized comparison with standard anticoagulants as a frame of reference regarding frequencies of VTE and bleeding in the pediatric setting. For treatment of VTE, phase 3 studies should comprise the entire treatment period, with randomization occurring early, i.e. within 1 week of initiating anticoagulation. The assessment of primary outcome should be performed after 3–6 months of treatment, and patients requiring longer anticoagulation can be followed further for secondary outcomes. It is important that phase 3 studies continue to collect PK and/or PD data from children of different ages to correlate these with clinical outcomes. For studies of prophylactic anticoagulation, the study duration will depend on the time period for which patients are at risk. For periprocedural anticoagulation, the time period is relatively easy to identify; however, for patients on long-term prophylactic anticoagulation, a relevant and feasible time period for study needs to be defined. For studies of CVC-related thromboembolism prophylaxis, imaging studies are required in order to assess clinically asymptomatic thromboembolism. Phase 4

In addition to the comprehensive traditional development program described above, it should be understood that, when a novel anticoagulant is approved for pediatric use, a post-licensing surveillance program should be given strong consideration. The potential for anticoagulant drugs to have non-hematologic effects that are not readily identified in earlier phases is high, and studies assessing

© 2014 International Society on Thrombosis and Haemostasis

outcomes such as bone density, neuropsychological development and growth are critical. Conclusions The proposed guideline intends to provide a basis for drug investigation programs studying new anticoagulants in children and to achieve some degree of uniformity in the approach. It is expected that the regulatory authorities and pharmaceutical industry will view this document as a template for the design and approval of PIPs, and ultimately the licensing of new anticoagulants for pediatric use. Addendum C. Male and G. Young conceived the project and drafted the manuscript. P. Monagle and A. K. C. Chan critically reviewed and finalized the manuscript. Disclosure of Conflict of Interests C. Male was a member of Steering Committees for Bristol-Myers Squibb and Bayer, outside the submitted work. The other authors state that they have no conflict of interest. References 1 Raffini L, Huang Y, Witmer C, Feudtner C. Dramatic increase in venous thromboembolism in children’s hospitals in the United States from 2001–2007. Pediatrics 2009; 124: 1001–8. 2 United States Food and Drug Administration. Pediatric Research Equity Act (PREA) and Best Pharmaceuticals for Children Act (BPCA). 2007. Accessed 27 June 2014. 3 Regulation (EC) No. 1901/2006 and 1902/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for pediatric use. Pediatric regulation. Official Journal of the European Union 18: L378/1. 2006. 4 European Medicines Agency, Committee for Human Medicinal Products. Guideline on the Need for Non-clinical Testing in Juvenile Animals on Human Pharmaceuticals for Pediatric Indications. 2008. EMEA/CHMP/SWP/169215/2005. 5 European Medicines Agency, Committee for Medicinal Products for Human Use. Reflection paper: formulations of choice for the pediatric population. 2006. EMEA/CHMP/PEG/194810/2005. 6 European Medicines Agency, Committee for Medicinal Products for Human Use. Guideline on the role of pharmacokinetics in the development of medicinal products in the pediatric population. 2006. EMEA/CHMP/EWP/147013/2004. 7 Attard C, Monagle P, Kubitza D, Ignjatovic V. The in-vitro anticoagulant effect of rivaroxaban in neonates. Blood Coagul Fibrinolysis 2014; 25: 237–40. 8 Mitchell LG, Goldenberg NA, Male C, Kenet G, Monagle P, Nowak-G€ ottl U, on behalf of the Perinatal and Pediatric Hemostasis Subcommittee of the SSC of the ISTH. Definition of clinical efficacy and safety outcomes for clinical trials in deep venous thrombosis and pulmonary embolism in children. J Thromb Haemost 2011; 9:1856–8.

484 C. Male et al 9 Young G, Albisetti M, Bonduel M, Brandao L, Chan A, Friedrichs F, Goldenberg N, Grabowski E, Heller C, Journeycake J, Kenet G, Krumpel A, Kurnik K, Male C, Manco-Johnson M, Mathew P, Monagle P, van Ommen H, Simioni P, Svirin P, et al. Impact of inherited thrombophilia on venous thromboembolism in children: a systematic review and meta-analysis of observational studies. Circulation 2008; 118: 1378–82. 10 Bj€ orkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. Br J Clin Pharmacol 2004; 59: 691–704.

11 Anderson BJ, Allegaert K, Holford NH. Population clinical pharmacology of children: general principles. Eur J Pediatr 2006; 165: 741–6. 12 Massicotte MP, Sofronas M, de Veber G. Difficulties in performing clinical trials of antithrombotic therapy in neonates and children. Thromb Res 2006; 118: 153–63. 13 European Medicines Agency. Concept paper on extrapolation of efficacy and safety in medicine development. 2012. EMA/129698/ 2012.

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Recommendations for the development of new anticoagulant drugs for pediatric use: communication from the SSC of the ISTH.

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