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Enhancing the Pediatric Drug Development Framework to Deliver Better Pediatric Therapies Tomorrow

      Abstract

      Health care professionals involved in the clinical management of children have long appreciated the limited number of therapies suitably evaluated for their optimal use in the pediatric population. In the past century, advances in regulatory policy significantly evolved adult drug evaluation. The scarcity of available patient populations, practical complexities of drug development research, and minimal financial returns have hampered pharmaceutical investment in the study of therapies for children. More recently, pediatric policy and legislation in the United States and Europe have instituted a system of obligations and incentives to stimulate investment in pediatric drug development. These initiatives, in conjunction with a more sophisticated process of drug discovery and development, have led to significant advancements in the labeling of drugs for pediatric use. Facilitated by the emergence of new targets, precision medicine, and innovations in regulatory science, there is now a subtle shift in focus toward drug development research for children rather than simply in children. Although there has been an increase in pediatric studies of investigational agents and labeling of pediatric information for use, there have been unintended consequences of existing policies. As a result, limited progress has been made in certain therapeutic areas and for off-patent therapies. Future policy reform to enhance the availability and accessibility of pediatric medicines should not only reflect an understanding not only of the successes of existing policy and legislative initiatives but also constructively address failures and unintended consequences. Taken together, policy reform, global cooperation, and innovation in regulatory science will more ably deliver better pediatric therapies tomorrow.

      Key words

      Introduction

      Children are subject to many of the same diseases as adults, often leading to clinical treatment that uses the same drugs and biological products. Although the level of relevant research has been increasing, only a fraction of the available therapies in adults have been adequately evaluated in pediatric populations to assess age-appropriate dosing, tolerability, and efficacy.
      American Academy of Pediatrics Committee on Drugs
      Policy Statement: Off-Label Use of Drugs in Children.
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      An update on the therapeutic orphan.
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      • van den Anker J.
      Lack of effect of the European guidance on clinical investigation of medicines in children.
      Because pediatric patients can differ markedly from adults in how medicines are absorbed, metabolized, and excreted, it is not always appropriate to rely on available adult information for use in children. Moreover, numerous diseases in children differ from the adult equivalent or have no adult equivalent disease on which to base assumptions to characterize the potential response to treatment.
      Historically, studies that included children and pregnant women had been conducted with limited regulatory oversight. In some instances, unanticipated mortality (elixir sulfanilamide) and significant developmental toxic effects (thalidomide) resulted.
      • Ballentine C.
      • Kim J.
      • Scialli A.
      Thalidomide: the tragedy of birth defects and the effective treatment of disease.
      These tragedies led to significant policy change governing the testing and marketing of new drugs in the 20th century. This included passage of the 1938 Food, Drug, and Cosmetics (FD&C) Act, which gave the US Food and Drug Administration (FDA) power to monitor the safety profiles of new drugs, and the 1962 Kefauver-Harris Amendments to the FD&C Act, which imposed strict guidelines for the process of drug approval, requiring a drug be tolerable and effective before approval and marketing.
      • Meadows M.
      Promoting Safe and Effective Drugs for 100 Years.
      Although the policies contained protections that were not limited to adults, the tragedies leading to the new legislation had so shocked the societal conscience that the absence of specific requirements to include children led to their routine exclusion from clinical trials. With no pediatric tolerability and efficacy data being generated, children were now exposed to new risks through off-label exposure to drugs as part of clinical practice. In a 1968 Journal of Pediatrics editorial, Harry Shirkey
      • Shirkey H.
      Editorial commentary: therapeutic orphans.
      wrote about this disparity. He highlighted the juxtaposition of pediatric adverse events (AEs) driving new regulatory mandates to strengthen adult drug approval requirements and the absence of adequate labeling for pediatric use, leaving the pediatric population at increased risk for underdosing or overdosing and unanticipated AEs unique to children.
      During the past 2 decades, governments have been addressing the inadequacy of drug testing and insufficient information for use in product labels for children through the introduction of policies intended to stimulate investment in pediatric drug development.
      US Food and Drug Administration
      FDA Status Report to Congress: Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      Among the various policies introduced, laws to provide economic incentives and obligations to require pediatric studies of new drugs in the United States and Europe have had the greatest measurable effect. This review provides a summary of existing pediatric policy initiatives, describes their effect on the availability of new therapies for pediatric use, explains their applicability to today’s drug development portfolios, and introduces considerations for pediatric policy evolution in the years ahead.

      Pediatric Policy and Legislative Change

      United States

      To improve the licensing and labeling of products and the availability of age-appropriate formulations for pediatric use, the United States introduced a series of pioneering pediatric regulations and laws (Table I). In 1979, the FDA introduced a pediatric use subsection to the label template. However, manufacturers had little incentive to study pediatric patients because the population affected by the intended use was often limited, yielding a relatively small market. In 1994, the FDA published a final pediatric labeling rule to expand pediatric labeling provisions to require manufacturers of marketed products to review existing data and assess whether it could support pediatric labeling extensions.
      US Food and Drug Administration
      The rule introduced the concept of extrapolation of adult data for pediatric use but did not mandate the conduct of pediatric studies. Although the rule led to the submission of pediatric labeling supplements for a fraction of approved products, the supplements received by the FDA did not substantially improve pediatric use information, failing to adequately address the problem.
      US Federal Register
      Table IKey pediatric policy initiatives in global regions with obligations for pediatric study.
      Figure thumbnail fx1
      BPCA = Best Pharmaceuticals for Children Act; BPCIA = Biologics Price Competition and Innovation Act; FDAAA = FDA Amendments Act; FDAMA = FDA Modernization Act; FDASIA = FDA Safety and Innovation Act; PREA = Pediatric Research Equity Act; USPI = US prescribing information.
      *Invalidated in 2002 by the federal court in the District of Columbia.
      In 1997, US Congress passed the Food and Drug Administration Modernization Act, which created §505A of the FD&C Act, establishing an incentive that granted manufacturers an additional 6 months of marketing exclusivity if they voluntarily performed pediatric studies agreed on under a written request (WR) issued by the FDA.
      US Congress
      One year later, the Pediatric Rule was published as a companion rule designed to require manufacturers of certain new drugs to conduct pediatric studies to support pediatric use for the claimed indication.
      US Food & Drug Administration
      Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients Final Rule.
      Both §505A and the Pediatric Rule were intended to work in conjunction to drive the pediatric study of drugs. However, in 2002, the Federal Court in the District of Columbia invalidated the Pediatric Rule, noting that it exceeded the FDA’s statutory authority. Later that year, the Best Pharmaceuticals for Children Act (BPCA) was enacted, reauthorizing the pediatric exclusivity incentive and establishing a National Institutes of Health process to study off-patent drugs for pediatric use when manufacturers declined to do so.
      US Congress
      In 2003, the US Congress passed the Pediatric Research Equity Act (PREA), which adopted many of the principles that had been introduced under the Pediatric Rule and added a provision that exempted products from the pediatric study requirement when the product had been granted an orphan designation.
      US Congress
      Because the laws had sunset provisions, BPCA and PREA required reauthorization under the FDA Amendments Act in 2007. Under the FDA Amendments Act, the National Institutes of Health process was expanded to allow the National Institutes of Health to draft a proposed pediatric study request for on-patent drugs that the FDA could extend as a WR to sponsors.
      US Congress
      In 2010, pediatric incentives were also made applicable for extension of exclusivity only for biologics under the Biologics Price and Competition Innovations Act.
      US Congress
      Under these policies, modest revenue increases resulted from pediatric labeling extensions. However, the BPCA had proven to be an important stimulus for some blockbuster products whose manufacturers had seen significant incremental revenue gains because of the delayed entrance of generic challengers.
      McKinsey & Company
      McKinsey Center for Government: Do Incentives Drive Pediatric Research?.
      Given this success and to ensure certainty for manufacturers who were investing in pediatric drug development, the BPCA and PREA were made permanent in 2012 under the Food and Drug Administration Safety and Innovation Act (FDASIA). PREA was further amended under the FDASIA to require submission of pediatric study plans by the end of Phase II to hasten the pace of pediatric drug development.
      US Congress
      The FDASIA also added a rare pediatric disease designation process and incentive program (Advancing Hope Act) to the FD&C Act. The Advancing Hope Act offers manufacturers receiving an approval for a rare pediatric disease a voucher (transferable by sale) that can be redeemed for a priority review of a subsequent marketing application for an unrelated product. Since passage, this program has generated significant interest, with numerous sponsors seeking rare pediatric disease designations. As of May 2017, a total of 10 manufacturers have been awarded rare pediatric disease priority review vouchers. In a 2016 report to the US Congress mandated under the FDASIA, the US Government Accountability Office noted that the typical drug development timeline exceeds 10 years; therefore, insufficient time had elapsed to determine whether the program was effective.
      US Government Accountability Office. GAO Report to Congressional Committees

      Europe

      To evaluate and address the issue in Europe, the European Commission organized a roundtable of experts in 1997. The experts concluded that there was a need to strengthen existing regulation via a formal system of pediatric obligations and incentives. This led to a series of legislative steps that culminated in new legislation governing the development and authorization of medicines by the European Medicines Agency (EMA) for pediatric use in 2006. In the following year, regulation 1901/2006 (Pediatric Regulation) came into force.
      European Parliament and the Council of the European Union
      The Pediatric Regulation introduced a single system of pediatric obligations and incentives to facilitate the evaluation of newly authorized drugs protected by a Supplementary Protection Certificate (SPC). The SPC extends the term of a patent to compensate a manufacturer for the time elapsed between filing of the patent application and granting of the first marketing authorization in Europe. For newly approved products, pediatric investigation plan (PIP) applications are required to be submitted to the EMA no later than on completion of adult human pharmacokinetic studies to ensure that an opinion on use in the pediatric population can be given at the time of the assessment of the marketing authorization.
      European Parliament and the Council of the European Union
      New medicinal products protected by SPC can receive a 6-month extension when completing the commitments as agreed on under a PIP. If manufacturers complete an agreed-on PIP for new orphan medicinal products, they can receive 2 additional years of market exclusivity in addition to the 10 years of orphan market exclusivity. The Pediatric Regulation also introduced a voluntary development pathway for off-patent products that may have a pediatric use, leading to a Pediatric Use Marketing Authorisation (PUMA). Manufacturers who successfully complete a PUMA can receive an additional 8 years of data protection (from generic competitor use of originator drug data in the generic drug filing) and 2 years of market protection (from generic market entry) for the new pediatric use.
      In 2013, the European Commission published a report reviewing the progress made after 5 years of implementation of the Pediatric Regulation.
      European Commission
      Although the report provided promising signs of progress, it also included early acknowledgement that the PUMA concept had so far failed to provide sufficient incentive to outweigh economic risks of investment for industry. Because of the length of a product’s development, the European Commission noted that it would take at least 10 years to gain a “full understanding” of the effect of the regulation. Under article 50(3) of the Pediatric Regulation, a second report assessing the regulation’s effect is planned by the British Parliament in 2017.

      Japan, Canada, and Switzerland

      Although the policies implemented in the United States and Europe have been the primary drivers for pediatric product development globally, other countries have also introduced policies to enhance the labeling of products with information for pediatric use. Historically, penetration of the market by generics in Japan has been low relative to other markets. Therefore, extension of an active patent to protect a marketed drug from generic intrusion had not been foreseen as a valuable incentive for manufacturers. An alternative approach to incentivizing pediatric research has been used in Japan through extension of a product’s reexamination period. During this period, data that have been submitted to Japan’s Pharmaceuticals and Medical Devices Agency for an innovator drug is protected and not available to generic competitors for their regulatory use. Under article 14-4 of the Pharmaceutical Affairs Act (2000/12/27), the reexamination period of an approved drug can be extended from 8 to 10 years on the consideration of pediatric use surveys and clinical studies, if the drug is intended for pediatric use. Currently, this incentive has been of modest value in encouraging investment in pediatric development.
      In Canada, part C of §C.08.004.1 of the Food and Drug Regulations was amended in 2011 to allow manufacturers to receive a 6-month extension of data protection on the provision of results of clinical trials designed to increase knowledge about tolerability and efficacy of a medicine for pediatric use. To qualify for the reward, supplemental filings must be submitted to Health Canada within 5 years of the initial adult marketing approval. In 2014, the Council of Canadian Academies reported that although pediatric medicines research is a strength of the Canadian medical system, the Canadian policy encouraging manufacturers to submit data on pediatric use of drugs has experienced limited success.
      The Council of Canadian Academies
      Most recently, the Swiss have been encouraging pediatric submission of data through an incentive that allows SwissMedic to reduce the user fee by 90% for the authorization of, and major variations to (new indication, dosage recommendation or strength), medicinal products with pediatric-only indications. In addition, the Swiss Parliament recently adopted the revision of the Therapeutic Products Law (March 2016), including an obligation to submit pediatric plans, as well as an incentive extending the SPC by 6 months or extending a free-standing 6-month pediatric SPC, for a medicine if its label includes data from clinical trials conducted in line with an agreed-on PIP. The law also introduced an incentive that allowed manufacturers 10 years of data protection for medicines specifically and exclusively intended for pediatric use. Its impact remains to be seen because the implementing provisions are being drafted.

      The Impact of Policy and Legislative Change on Pediatric Drug Development Today

      Significant progress has been made since pediatric legislation was first enacted 2 decades ago. The FDA and EMA assert that authorities granted them through law have been effective tools, enhancing the quantity and quality of pediatric drug development. There have been >650 labeling changes incorporating pediatric-specific information in the United States since 1997, of which nearly one-third have occurred after the passage of the FDASIA
      US Food and Drug Administration
      FDA Status Report to Congress: Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.

      US Food and Drug Administration New Pediatric Labeling Information Database. https://www.accessdata.fda.gov/scripts/sda/sdnavigation.cfm?sd=labelingdatabase&displayall=false&page=14. Accessed March 30, 2017.

      (Figure 1). In Europe, the number of new pediatric medicines, new pediatric indications, and new age-appropriate forms is increasing
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      (Figure 2). The FDA and EMA highlight the large number of studies proposed by manufacturers since laws were implemented as evidence of the adequacy of the policies in stimulating the evaluation of therapies for pediatric use. Since the passage of the FDASIA (through June 2015), the FDA has received 569 pediatric study plans from manufacturers in compliance with PREA.
      US Food and Drug Administration
      FDA Status Report to Congress: Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.
      Since entry into force of the Pediatric Regulation (through December 31, 2015), the EMA has granted >840 positive opinions on PIPs that include pediatric commitments.
      Figure 1
      Figure 1Pediatric labeling changes in the United States since the passage of pediatric-specific legislation, including the Best Pharmaceuticals for Children Act, the Pediatric Research Equity Act, and the Pediatric Rule. Center for Biologics Evaluation and Research and Center for Drug Evaluation and Research regulated biologics with pediatric labeling changes before September 27, 2007, are not included in the US Food and Drug Administration (FDA) database. Data are from the FDA New Pediatric Labeling Information Database.

      US Food and Drug Administration New Pediatric Labeling Information Database. https://www.accessdata.fda.gov/scripts/sda/sdnavigation.cfm?sd=labelingdatabase&displayall=false&page=14. Accessed March 30, 2017.

      Figure 2
      Figure 2Number of new pediatric products, indications, and posologies via the centralized procedure at the European Medicines Agency in the 3 years before and after the entry into force of the Pediatric Regulation. Data are from European Medicines Agency.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      As drug developers have gained pediatric drug development experience under these policies, they have begun to translate and apply their knowledge to investigational drugs designed to address diseases observed primarily in pediatric populations. In parallel, pharmaceutical pipelines now include highly targeted therapies and use precision medicine approaches that take into account genetic variability, environment, and lifestyle to treat or prevent disease. Exciting progress in the development of cystic fibrosis transmembrane conductance regulator modulators, small molecules that target specific mutations caused by different defects in the protein made by the cystic fibrosis gene may indicate that precision medicine and personalized approaches are just the thing necessary to trigger a new era ahead for pediatric drug development. In 2016 alone, 8 of 22 new drug and biologics applications (36%) approved by the FDA included a pediatric indication for use.
      US Food & Drug Administration
      Although 2 of the 8 products, eteplirsen and nusinersen, were awarded with pediatric rare disease priority review vouchers on approval, none had agreed-on commitments under PREA or a WR under BPCA. In Europe, 6 of 27 new active substances (22%) received marketing authorization, including a pediatric indication for use.
      European Medicines Agency
      EMA Annual Report to the European Commission (EC) 2016 (WC500227334).
      Only 2, migalastat and eftrenonacog alfa, had an agreed-on PIP at the time the positive opinion was received for the marketing authorization. Although these new products for pediatric use represent only a portion of all new drug and biologic approvals, the investment despite high disease complexity, scarcity of available patients, and modest commercial upside in relation to adult marketplaces reflects an important shift in thinking on drug development for pediatric patients.
      Pediatric policy initiatives have been complemented by other policy initiatives in shaping and reframing pediatric pipeline considerations for today’s pharmaceutical portfolios. In 1983, the US Congress passed the Orphan Drug Act to stimulate the development of treatments for rare diseases where there was “no reasonable expectation” that the commercial marketplace could support development.
      • Kesselheim A.
      An empirical review of major legislation affecting drug development: past experiences, effects, and unintended consequences.
      Since then several other countries and regions have established regulations to incentivize the development of orphan, drugs including the EU in 2000.
      • Hall A.
      • Carlson M.
      The current status of orphan drug development in Europe and the US.
      An analysis of the FDA database of products developed under the Orphan Drug Act found that 38 of 148 orphan product approvals (26%) in the United States between 2000 and 2009 were for pediatric indications.
      • Thorat C.
      • Xu K.
      • Freeman S.
      • et al.
      What the Orphan Drug Act has done lately for children with rare diseases: a 10-year analysis.
      The authors found that the proportion of pediatric rare disease product approvals had increased in the first half to the second half of the decade (17.5% to 30.8%). Although children constitute a subset of the rare diseases community who have benefited, significant need still exists for tolerable and efficacious therapies for the pediatric rare diseases population.

      Neonates

      Many conditions for which pharmacologic therapy is used in neonatal medicine are unique to the neonatal period because of the distinctive developmental status of newborns, characterized by immaturity and transitional physiology. The immaturity of this population causes unique drug disposition and sometimes unique organ responsiveness that differ considerably from older pediatric and adult populations.
      • Ku L.
      • Smith P.B.
      Dosing in neonates: special considerations in physiology and trial design.
      Furthermore, neonatal diseases may not have an analogous condition in the adult population (eg, bronchopulmonary dysplasia). Therefore, the existing regulatory paradigm that ties pediatric incentives and obligations to the submission of a product intended for adult use may not yield therapies that address the specific needs of neonates. In fact, despite the impressive progress of pediatric policies and legislation, evaluation of products for use in neonates remains minimally affected.
      Most drugs used in this highly vulnerable population have not undergone sufficient study, and as many as 90% of the therapies used in neonatal intensive care units have not been authorized for neonatal use.
      • Davis J.
      • Connor E.
      • Wood A.
      The need for rigorous evidence on medication use in preterm infants: is it time for a neonatal rule?.
      In Europe, 26.3% of pediatric programs agreed on under the Pediatric Regulation include neonates, although none have been completed to date.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      Although a number of neonatal studies have been conducted under US policies, a significant portion of the drugs studied were for therapies that are not used clinically in neonatal intensive care units to treat neonatal patients.
      • Laughon M.
      • Avant D.
      • Tripathi N.
      • et al.
      Drug labeling and exposure in neonates.
      This finding suggests that the drugs studied were not directed at the greatest neonatal public health need.

      Pediatric Cancer

      Pediatric policy initiatives have been designed to integrate pediatric needs onto a backbone of adult drug development. Because of their construct, however, these laws have not provided the necessary structure to successfully bridge differences that exist in the etiology, biology, and treatment goals (cure vs palliation) between childhood and adult cancer. In the United States, PREA contains a provision that restricts its application to the intended adult indication. As a result, PREA requirements rarely apply as most new cancer therapies are intended for adult cancers (eg, breast, lung) that do not occur in children. Since passage, just one approved therapy, imatinib mesylate, includes pediatric labeling for studies conducted under PREA.

      US Food and Drug Administration New Pediatric Labeling Information Database. https://www.accessdata.fda.gov/scripts/sda/sdnavigation.cfm?sd=labelingdatabase&displayall=false&page=14. Accessed March 30, 2017.

      The BPCA, on the other hand, was designed with the understanding that many childhood diseases are unique to children. It grants the FDA the authority to extend a WR to sponsors for a pediatric indication different from the intended adult indication. Since passage of the BPCA, however, only 20 products have had their labels updated to include important information for use for pediatric cancers.

      US Food and Drug Administration New Pediatric Labeling Information Database. https://www.accessdata.fda.gov/scripts/sda/sdnavigation.cfm?sd=labelingdatabase&displayall=false&page=14. Accessed March 30, 2017.

      In their 2016 Report to Congress, the FDA noted the role precision medicine is playing in driving targeted therapy development and the identification of cellular pathways or genetic mutations and/or deletions associated with the growth or progression of pediatric cancers. As a result, the rate of WRs (54 before the FDASIA and 19 after the FDASIA through the end of 2016) extended to sponsors to study pediatric cancer has increased
      US Food and Drug Administration
      FDA Status Report to Congress: Best Pharmaceuticals for Children Act and Pediatric Research Equity Act.

      US Food and Drug Administration Written Requests Issued. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm050002.htm. Accessed March 30, 2017.

      (Figure 3).
      Figure 3
      Figure 3Number of written requests issued by the US Food and Drug Administration (FDA) for pediatric cancer since the passage of the Food and Drug Administration Safety and Innovation Act (through December 31, 2016). Source: FDA web-site. Data are from FDA.

      US Food and Drug Administration Written Requests Issued. https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/ucm050002.htm. Accessed March 30, 2017.

      Although the Pediatric Regulation includes a provision that allows for a waiver from pediatric study if the intended adult condition is listed on a class waiver list, the EMA adopted a policy in 2012 that established a framework expanding its scope.
      European Medicines Agency
      EMA Policy on the determination of the condition(s) for a Pediatric Investigation Plan/Waiver (scope of the PIP/waiver) (EMA/272931/2011).
      Under this policy, a PIP condition can be determined based on the (1) intended indication, (2) mode or mechanism of action that determines the expected activity of the product, (3) unmet pediatric need, and (4) an independent hierarchical classification of diseases relevant to adult and pediatric diseases. On its practical application, the policy requires sponsors to submit a PIP that addresses a pediatric need identified through the broader condition of the intended adult indication or a product’s mechanism of action. As of December 2015, a total of 83 PIPs for 68 different cancer therapies have been agreed on with sponsors by the EMA, of which 41 PIPs are intended to address cancers that primarily affect pediatric patients.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      Furthermore, 14 voluntary PIPs targeting the treatment of a pediatric solid malignant tumor have been agreed on with the EMA.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      Since entry into force, 7 pediatric cancer PIPs have been completed, and 5 new anticancer therapies and 6 new pediatric cancer indications for previously authorized medicines have been authorized in Europe.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      The development of pediatric cancer therapies is complicated by the small number of eligible children for evaluation in early phase trials because childhood cancers are a collection of rare and ultrarare diseases. As a result, only a limited number of pediatric cancer trials can be conducted at any one time. Currently, there are hundreds of products within industry pipelines competing for the same pediatric cancer populations.
      Pharmaceutical Research and Manufacturers of America
      Therefore, a highly organized system of evaluation for new pediatric cancer therapies is crucial to ensuring that translational and clinical research can be efficiently and effectively implemented.
      • Smith M.
      • Ho P.T.
      Pediatric drug development: a perspective from the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI).
      • Smith M.
      • Reaman G.
      Remaining challenges in childhood cancer and newer targeted therapeutics.
      However, existing laws are structured to facilitate agreement between sponsors and regulatory agencies on a product-by-product and indication-by-indication basis. Reflecting on this complexity, a diverse set of stakeholders across the European pediatric cancer community are collaborating to identify and propose pragmatic solutions to address these challenges and facilitate a more efficient pediatric cancer drug development.
      • Vassal G.
      • Rousseau R.
      • Blanc P.
      • et al.
      Creating a unique, multi-stakeholder Pediatric Oncology Platform to improve drug development for children and adolescents with cancer.

      Off-patent Products for Pediatric Use

      Pediatric policy and legislative change has primarily redirected research attention to new investigational products. It has minimally affected the evaluation of off-patent drugs, which continue to be used widely outside their labeled use in the clinical management of children. Under the BPCA, the National Institutes of Health (in consultation with the FDA) develops and publishes a priority list of needs in pediatric therapeutics annually. The list consists of key pediatric therapeutic needs and is organized into 17 therapeutic areas, which include a list of off-patent drugs that lack adequate pediatric labeling. Since its introduction in 2002, this program has led to labeling extension for 2 therapies for pediatric use (sodium nitroprusside in the pediatric population and meropenem for injection for neonates and infants <3 months of age).

      US Food & Drug Administration NIH Funded Pediatric Labeling Changes. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm379088.htm. Accessed May 1, 2017.

      Similar to the pathway established in the United States, funding is available for studies on medicines that are not covered by a patent or a SPC in the European Union. This funding provided through the Seventh Framework Programme for Research for the development of pediatric medicines may lead to the submission of an application for a PUMA. Five project calls have been launched to develop off-patent products for pediatric use, resulting in 20 projects being granted to evaluate 24 medicines.
      • Ruggieri L.
      • Giannuzzi V.
      • Baiardi P.
      • et al.
      Successful private–public funding of pediatric medicines research: lessons from the EU programme to fund research into off-patent medicines.
      An important success of this program has been the creation of varied collaborative international research consortia. The PUMA pathway was envisaged to improve information on, and the development of, off-patent medicinal products for the pediatric population. Since passage of the Pediatric Regulation, however, none of the PIPs agreed on as part of the Seventh Framework Programme for Research projects and only 2 industry-sponsored PUMA authorizations have been granted—for midazolam (oromucosal use) and propranolol hydrochloride (oral use).
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      When off-patent drugs are entrenched as the standard of care and broadly considered to be effective with minimal risk, certain design considerations (placebo control) to properly evaluate the drug may be problematic and handicap enrollment.
      • Bavdekar S.
      Pediatric clinical trials.
      There are also a host of other critical roadblocks that hinder the industry investment in new pediatric uses for off-patent medicines. Importantly, as products reach their patent and SPC expiry, the pharmaceutical research infrastructure necessary for evaluation of further clinical and technical development is dismantled. In the marketplace, reimbursement strategies have not been established to value the role of age-appropriate formulations in relation to cheaper unlicensed or extemporaneously prepared alternatives. Finally, current incentives are insufficient to overcome the cost associated with investment in further lifecycle development and manufacturing supply.

      Collaboration and Innovation in Optimizing Pediatric Drug Development Tomorrow

      The American Academy of Pediatrics’ Committee on Drugs landmark policy statement that “It is not only ethical but also imperative that new drugs to be used in children, be studied in children … So the benefits of therapeutic advances will become available to all who may need them” remains as true today as it was 40 years ago.
      American Academy of Pediatrics Committee on Drugs
      Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations.
      Pediatric policy initiatives have made significant progress in advancing a global understanding that evaluation of new medicines should include assessments that address pediatric need. Policy and legislative reform have led to an increase in the number of therapies being evaluated in pediatric populations, the number of adult drugs labeled to include adequate pediatric tolerability and effectiveness data,
      • Yao L.
      FDA takes steps to encourage pediatric drug studies.
      and the institution and expansion of research infrastructures to support pediatric drug development.

      Collaboration

      In certain regions, it is now routine for sponsors to meet with regulatory agencies to discuss pediatric plans for investigational agents within their pipelines. In response, there has been an increasing demand for expert trialists and networks cognizant of the demands of Good Clinical Practice and the need for greater efficiency and expertise in pediatric drug development. This should help to address the high rate of failure of pediatric studies conducted under agreed-on pediatric initiatives. In an analysis of products evaluated under US initiatives between 2007 and 2014, a total of 42% of completed pediatric trials failed to establish tolerability or efficacy, leading to an inability to label the product for use in children.
      • Momper J.D.
      • Mulugeta L.
      • Burckart G.J.
      Failed pediatric drug development trials.
      Recently, a host of pediatric research consortia and networks have been established to facilitate the development and validation of pediatric and neonatal-specific biomarkers and end points; provide access to pediatric-specific expertise to enhance the design, initiation, and conduct of pediatric clinical trials; and facilitate the timeliness, quality, and medical impact of clinical trials of drugs and biologics on child health.
      Press Release
      Press Release
      Press Release
      These collaborative approaches and enhancements to underlying pediatric research infrastructure are essential to better inform design considerations, enhance efficiency, and increase the likelihood of success of programs conducted under pediatric policy and legislative initiatives.
      Most children are healthy and therefore have limited to no need for many investigational therapies. Thus, one of the greatest challenges facing pediatric drug development is that patients are a precious commodity, which prohibits the accommodation of multiple competing drug development programs for most pediatric diseases. Existing legislation in the United States and Europe has been implemented without a system of prioritization of disease based on unmet need or a data-driven process that can equitably identify and prioritize drugs for study. As a result, significant concerns regarding feasibility have emerged. Some densely competitive therapeutic areas, where there is a low pediatric prevalence of the respective diseases, are struggling to complete pediatric studies that are part of an agreed-on obligation.
      • Karres J.
      • Pratt V.
      • Guettier J.M.
      • et al.
      Joining forces: a call for greater collaboration to study new medicines in children and adolescents with type 2 diabetes.
      • Rose K.
      • Walson P.
      Do the European Medicines Agency decisions hurt pediatric melanoma patients?.
      Overcrowding and misalignment among stakeholders on what constitutes a feasible research plan have also led to significant procedural rework to facilitate regulatory agreement of program modifications.
      European Medicines Agency
      10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Pediatric Regulation (EMA/231225/2015).
      In 2013, the EMA held a workshop in response to the glut of pediatric studies required under the Pediatric Regulation for several new type 2 diabetes mellitus drugs.
      European Medicines Agency
      EMA Report of the workshop on pediatric investigation plans in type 2 diabetes mellitus (EMA/272764/2013).
      At the time, 16 PIPs (31 studies) had been agreed on across the class of glucagon-like peptide-1 analogues, dipeptidyl peptidase 4 inhibitors, and sodium-glucose co-transporter 2 inhibitors, of which none had been able to progress. The workshop highlighted the need for rational, collaborative, data-driven approaches to identifying and prioritizing products for study that are within the scope of pediatric legislative requirements. In addition, it focused attention on the critical need for innovative analytical approaches to facilitate data generation in pediatrics.

      Innovation

      Pharmaceutical research has driven unimaginable innovation in regulatory and development science, which is rapidly revolutionizing how treatments for the most complex diseases can be developed. Regulatory agencies have been working to evaluate and evolve tools that can bridge the gap and facilitate the evaluation of cutting-edge therapeutic discoveries.
      US Food & Drug Administration
      Although development of new adult therapies often requires substantial evidence of tolerability and efficacy through randomized and well-controlled trials, the scarcity of affected pediatric patients often limits the ability to use this approach. For older drugs, extensive information on adult drug disposition is often available, which may allow for approaches (modeling and simulation, extrapolation) that maximize preexisting data to enhance the efficiency and success of a pediatric drug development program.
      • Huang S.M.
      • Abernethy D.
      • Wang Y.
      • et al.
      The utility of modeling and simulation in drug development and regulatory review.
      • Manolis E.
      • Osman T.
      • Koenig F.
      • et al.
      Role of modeling and simulation in pediatric investigation plans.
      For investigational drugs, early-phase drug development is typically conducted in adult healthy volunteers and adult patients as part of the proof-of-concept evaluation. For certain diseases and population subsets (adults and adolescents), there may be little difference in renal capacity or hepatic enzyme expression, leading to a high degree of congruence on dosing
      • Momper J.
      • Mulugeta Y.
      • Green D.
      • et al.
      Adolescent dosing and labeling since the Food and Drug Administration Amendments Act of 2007.
      and allowing for the inclusion of some pediatric subsets within the adult Phase II and III program. This may lead to the inclusion of some pediatric subsets within the indication for use statements of newly approved therapies, facilitating earlier pediatric access to new medicines. In planning pediatric programs for new investigational therapies, consideration of the similarity of the natural history of disease, pathophysiology and clinical characteristics of the disease among different populations, and the role of developmental and maturational changes related to a drug’s target may allow for extrapolating inferences from a reference population to the target pediatric population.
      • Mulugeta Y.
      • Barrett J.S.
      • Nelson R.
      • et al.
      Exposure matching for extrapolation of efficacy in pediatric drug development.
      • Hlavin G.
      • Koenig F.
      • Male C.
      • et al.
      Evidence, eminence and extrapolation.
      This approach balances the need to generate pediatric information for use when the patients are scarce and makes more efficient use of preexisting data, limiting unnecessary pediatric studies. In 2016, both the EMA and FDA held public workshops on the role of extrapolation in pediatric drug development,
      European Medicines Agency
      US Food and Drug Administration-University of Maryland CERSI Workshop
      and the EMA took steps to develop a more structured framework for pediatric extrapolation when it released a Reflection paper on the topic.
      European Medicines Agency
      EMA Reflection paper on extrapolation of efficacy and safety in pediatric medicine development (EMA/199678/2016).
      Taken together, these analytic approaches may hasten the labeling of new information for pediatric use. Importantly, these pragmatic considerations are science based and do not require legislative change to be implemented.

      The Way Forward

      Two decades of pediatric policy and legislative change has left an indelible mark on pediatric drug development. Regional laws implementing a system of obligations and incentives for pediatric drug development are responsible for driving a fundamental shift in mindset that children are better protected through drug development research than from it. Although conditions that affect child health continue to be studied in de novo drug development less frequently than new medicine development for adults, the parallel emergence of targeted therapies and innovation in regulatory science has led to pharmaceutical pipelines peppered with investigational drugs targeted to address pediatric diseases. As children continue to be affected by conditions with significant disease burden, there is a persistent need to identify better pathways to facilitate the development of therapies for pediatric use.
      The Pediatric Regulation in Europe is currently being analyzed as part of a planned 10-year review with a view to potential amendment, and Switzerland is drafting implementing guidelines for new pediatric requirements. In other regions, including the United States, Japan, and Canada, advocacy groups have challenged policymakers to analyze existing policy and their consequences for children. As we look toward the future of pediatric policy and legislative change, we must carefully consider the impact that they have on pediatric public health in the region to which policies and laws have been directed and their impact globally. As regional governments grapple with laws, guidelines, or regulations to address the unique needs of their constituents, there must be an acknowledgment that the relative scarcity of pediatric populations afflicted by disease dictate global solutions, including regulatory convergence on key program considerations. Regionally, there must be a conscious effort to ensure that new policy proposals do not unwittingly hinder pediatric drug development due to an inability to converge regulatory requirements for pediatric program development.
      Although legislation is responsible for the increase in labeling medicines for pediatric use in Europe and the United States, poor implementation and failure to amend problematic implementation has led to considerable consequence for pediatric drug development and, importantly, patients. Therefore, policymakers must ensure that reevaluation of existing policy and new policy proposals are influenced by data that have indicated a positive policy effect on public health outcomes. Meaningful policy considerations should be based on quantitative and qualitative reviews and, where possible, conducted by independent bodies to minimize any risk of bias in an analysis that may be introduced when conducted by an affected stakeholder group.
      Although policy and legislative change has not and cannot meaningfully address all the gaps that exist for pediatric drug development, we should ensure every opportunity for stakeholders to engage and collaborate to identify and recommend practical, pragmatic, and meaningful solutions for program development. These opportunities include the following: public-private partnerships to identify and prioritize unmet medical need, trial designs, and innovative approaches to data generation; identification and construction of international databases to facilitate data sharing; implementation of innovative analytic strategies to maximize the use of preexisting data; and investment in efficient preclinical and clinical research infrastructures to facilitate innovation for medicines for children. These pragmatic solutions, incorporated onto a framework of meaningful and flexible policy initiatives, can address the nuanced complexities of pediatric drug development that will bring children the therapies of tomorrow.

      Conflicts of Interest

      Christina Bucci-Rechtweg is a full-time employee and stockholder of Novartis Pharmaceuticals Corporation. The author has indicated that she has no other conflicts of interest regarding the content of this article.

      ACKNOWLEDGMENTS

      None.

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