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Frameworks for Evaluating Medicines in Children

Published:September 26, 2017DOI:https://doi.org/10.1016/j.clinthera.2017.09.003

      Abstract

      Purpose

      To summarise contemporary approaches to evaluating medicines in children, emphasizing topics that are often misunderstood by one or more stakeholder groups.

      Methods

      A narrative review that integrates the literature with experience in multiple settings.

      Findings

      Children and young people need specific approaches to research about drugs because of growth and development. Specific approaches include practicalities such as the volume, frequency and technique of blood samples, and recruitment, including consent by proxy decision-makers and assent by children/young people. The design of drug development programmes includes working with children/young people from an early stage and minimising the burden of research through careful design while optimizing the contribution of extant, high quality information (including extrapolation).Regulators, academics, the pharmaceutical industry and other communities are well-placed to support pediatric drug development. Regulatory challenges include legislation that drives the extension to children of medicines used in adults (rather than a focus on the needs of children) and diversity between jurisdictions. Academics can improve the impact of their work by ensuring that data can be used in drug development programmes after they have answered a well-defined study question. Pharmaceutical companies, and public research funders can promote good return on the investment made in research (including the investment made by children/young people) by supporting data management to allow data reuse.

      Implications

      a greater understanding of pediatric issues is relevant to diverse research communities that work to advance pharmacotherapy.

      Key words

      Introduction

      Children and young people need access to therapeutic agents that have been reliably evaluated, but this population has historically been underserved by efforts to develop drugs.
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      in key jurisdictions. Frameworks for the evaluation of therapeutics include overall therapeutic development planning, academic studies, clinical research operationalization, risk management and ethical oversight, evaluation for marketing authorization, individual therapeutic decision making, public health policy development, purchasing and distribution, and epidemiologic trends. Each of these frameworks needs to adapt to the needs of children and young people. The purpose of this article is to identify exemplar pediatric issues that arise in selected frameworks and research communities.

      Why do Children and Young People Need Special Attention During Drug Development?

      Children and young people have a number of features that influence the design and conduct of studies.
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      For example, the doses of drugs may be different from the doses expected if children are small adults.

      Hawcutt DB, Rose AC, Fuerst-Rectenwald S, et al. (2010). Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates (Chapter) (Eds.), Guide to Pediatric Drug Development and Clinical Research (pp. 96-110).

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      These specificities reflect growth and development: physiological, intellectual, and psychosocial. Relevant aspects of development include cognitive (affecting consent, assent, and agreement), ontogeny of drug disposition and effects, and functional ability that leads to age-specific clinical trial designs and outcome measures. Knowledge about these differences can be used to tailor study designs, most often by using standard age categories such as those defined by the World Health Organization or the International Conference on Harmonisation. Information about the medicinal product in the product label may not match the standard age categories if studies indicate more appropriate age bands. In principle, a drug that could benefit children should be studied in all age groups. Historically, drugs were introduced in adults and then studied in progressively younger people. However, this approach disadvantages younger children, particularly neonates, because the time taken to study new drugs may extend beyond the period of patent protection. In addition, information from adults may not be informative; for example, with respect to safety, and greater understanding of ontogeny allows early-phase trials to be conducted safely in many conditions at all ages. The current orthodoxy is to develop a specific plan for each product. When there is an important clinical need in younger children, and studies can be designed with a good benefit-risk profile, then it is useful to start early-phase work in young children, including neonates, as soon as the information to support the design of trials is available.
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      Given that specific formulations and preclinical studies are needed for many pediatric products, it is prudent to consider age-appropriate formulations and juvenile animal studies during preclinical development of any product that is likely to be used in children.
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      The ability to contribute blood and other biologic samples for pharmacokinetic and toxicity analyses varies with size, although there is no global consensus about the appropriate volumes.

      Hawcutt DB, Rose AC, Fuerst-Rectenwald S, et al. (2010). Points to consider when planning the collection of blood or tissue samples in clinical trials of investigational medicinal products in children, infants and neonates (Chapter) (Eds.), Guide to Pediatric Drug Development and Clinical Research (pp. 96-110).

      Approaches to sampling blood and other biologic specimens need to be adapted to the size of the child/young person. The ability to collect patient-reported outcomes is a function of developmental age and communication ability. This combination of features mandates that the contributions of children and young people to research are appropriate to their developmental status, and that research is designed and conducted by people with relevant skills and experience in locations with the appropriate support, infrastructure, and protections.
      Children and young people receive extra protections during research because they are (or are perceived to be) vulnerable. The ability to make decisions develops and is captured in the age at which young people can give consent. Age limits are part of the legal fabric but can be out of synch with a young person’s abilities. During clinical trials, it is essential to capture the views of children and young people by seeking their assent to participation and respecting when they dissent from participation (although the concept of assent needs to be clarified).

      Lombardi D, Squires L, Sjostedt P, et al., Industry and Patient Perspectives on Child Participation in Clinical Trials. The Pediatric Assent Initiative Survey Report

      Negative effects of research participation may be heightened in children and young people because they are less able to make sense of the situation than adults; for example, anxiety about blood sampling may make venepuncture in a young child much more difficult than it would be in an adult. Many parents feel more responsibility for the decisions they make about their children than the decisions they make about themselves, which adds to the burdens generated by research that recruits children and young people.
      For all these reasons, the ethical imperative to minimize the burden of research on children, young people, and their families is widely recognized. The burden can be minimized by careful design of the study and its procedures. The number of children recruited to research needs to be sufficient to answer scientific questions that will improve, or clarify, the treatment offered to children and young people, but not more. The number of trials should be minimized. Standard approaches to drug development in adults with common conditions rely on collecting a new, self-contained, and consolidated dataset about a drug used for an indication. Similar to other special and small populations, pediatric drug development requires a different approach. The approach to pediatric drug development includes the following steps.
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      • 1.
        Identify the questions for the development program (based on therapeutic need and the capability of the drug, including its mechanisms of action).
      • 2.
        Establish which information is relevant and already available.
      • 3.
        Define the new information that is needed to answer the questions, define the information gaps.
      • 4.
        Design and implement studies to fill the information gaps (this may include pre-clinical and clinical studies).
      • 5.
        Synthesize new information with existing information.
      • 6.
        Test any assumptions made during these steps.
      • 7.
        Use the information to make decisions.
      A key concept is extrapolation, whereby information from 1 setting is used in another setting. When possible, the use of extant information can significantly reduce the need for the participation of children and young people in research. Extrapolation is implemented in different ways by the US Food and Drug Administration and European Medicines Agency (EMA). Table I describes the different approaches. In any case, effective extrapolation requires high-quality datasets and clear, well-justified assumptions.
      Table IExtrapolation in the United States and Europe.
      CharacteristicUS Food and Drug AdministrationEuropean Medicines Agency
      Source of approachLawA reflection article that proposes a framework
      Citation of sourceTitle 21, Chapter I, Subchapter D, Part 314, Subpart B, §314.55

      Electronic Code of Federal Regulations. Title 21, Chapter I, Subchapter D, Part 314, Subpart B, §314.55. https://www.ecfr.gov/cgi-bin/text-idx?SID=6b1eb4bff359214fbf903c8687292ba8&mc=true&node=se21.5.314_155&rgn=div8. Last accessed August 2nd 2017

      “Reflection paper on extrapolation of efficacy and safety in pediatric medicine development: draft”

      Reflection paper on extrapolation of efficacy and safety in pediatric medicine development: draft. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2016/04/WC500204187.pdf. Last accessed August 2nd 2017

      Scope“Where the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, [Food and Drug Administration] may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies. Studies may not be needed in each pediatric age group, if data from one age group can be extrapolated to another”“This approach is intended to contribute to decision-making about appropriate doses in the various age groups; and efficacy and safety, and the benefit-risk balance in the target population”
      ComponentsExamine 3 assumptions (using well-reasoned arguments based on data):Extrapolation concept: To build on a systematic synthesis of all available data, including the use of modelling and simulation approaches, with the aim of developing explicit predictions regarding differences of pharmacokinetics/pharmacodynamics, disease progression, and clinical response to treatment between source and target populations
      • 1.
        Is the course of the disease sufficiently similar in adults and children?
      Extrapolation plan: To propose optimal studies in the target population in accordance with the degree of predicted similarities and certainty of predictions as identified by the extrapolation concept
      • 2.
        Is the response to treatment sufficiently similar in adults and children?
      Confirmation & extrapolation: To confirm the extrapolation concept by relevant emerging data as it is obtained in studies and to interpret the data in the target population in the context of information extrapolated from the source population(s). If the extrapolation concept cannot be confirmed in its entirety, it should be updated and the extrapolation plan revised accordingly
      • 3.
        Do adults and children have a sufficiently similar exposure-response relationship OR can the pediatric dose to match the adult exposure be determined in cases when certainty already exists on response?
      Mitigating uncertainty and risk: The limited data generated in the target population may not be sufficient to resolve all uncertainties and assumptions underlying the extrapolation concept by the time of marketing authorisation. Additional follow-up data, may be necessary to address uncertainties and to further evaluate assumptions. Measures to generate these data need to be proposed.
      Publication by agency staffReference
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      Extrapolation of adult data and other data in pediatric drug-development programs.
      Reference
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      Extrapolation in the development of pediatric medicines: examples from approvals for biological treatments for pediatric chronic immune-mediated inflammatory diseases.
      Children and young people may also be perceived as vulnerable due to the effects of the drugs. This apparent vulnerability stems from a lack of understanding about the drugs and is not intrinsic to children and young people. Children and young people are vulnerable to new drugs because of a lack of research. The way to protect children from harm arising from drugs is to conduct good research, not shield children from research or deny them access to new drugs that have been evaluated.

      Improving medicines for children In Canada The Expert Panel on Therapeutic Products for Infants, Children, and Youth. http://www.scienceadvice.ca/uploads/eng/assessments%20and%20publications%20and%20news%20releases/therapeutics/therapeutics_fullreporten.pdf. Last accessed August 2nd 2017

      All pediatric drug development involves coinvestment. No commercial, or publically funded, study covers all the costs met by the research community. All pediatric studies depend on goodwill, time, and other in-kind resources from the institutions that host research and the individuals that conduct research. The most important type of coinvestment comes from research participants and their families. It is generally considered unethical to reward children and young people for their participation in research (beyond meeting their costs, and, possibly, making a token gesture of limited financial value). The return on the investment in research made by children and their families comes in benefiting others. This drives reuse of data and the reduction of inefficiencies that arise from ad hoc research collaborations.
      Within each framework for the evaluation of drugs, decision making is based on a stable collection of assumptions, policies, and cultural norms. The historic neglect of children and young people during regulated drug development means that this collection is not yet stable in pediatrics.

      Frameworks for Evaluating Drugs in Children and Young People

      Information Relevant to Regulating Marketing Authorization

      Regulation started many centuries ago with descriptions of how to prepare drugs (pharmaceutical quality).
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      It is ironic that common methods to prepare drugs for children, namely manipulation of a dosage form at the point of administration, remain largely unstudied.
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      A systematic review of the use of dosage form manipulation to obtain required doses to inform use of manipulation in pediatric practice (Journal article).
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      Manipulation of drugs to achieve the required dose is intrinsic to pediatric practice but is not supported by guidelines or evidence.
      Modern regulatory developments were often stimulated by harm that fell disproportionately on children. In the United States, legislation to regulate the development and licensing drugs evolved during the 19th and 20th centuries. An initial stimulus for regulation was safety issues arising from poor pharmaceutical quality of vaccines (1890s) and drugs (1930s). Subsequently it became clear that it was necessary to regulate claims about the effects of drugs. In Europe, the thalidomide disaster was a strong stimulus for regulation.
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      The regulatory approach is about meeting explicit, legally mandated standards.

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      Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (Consolidated version : 16/11/2012). https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf. Last accessed May 19th 2017. Last accessed August 2nd 2017

      The standard of evidence needed for licensing and marketing drugs in children is similar to that in adults, taking account of considerations that are relevant to small or special populations. However, the issues summarized in the previous section mean that the design of programs and protocols is adapted to children and young people. Pediatric development plans are defined as Pediatric Investigation Plans in Europe and Pediatric Study Plans in the United States.

      Challenges within the Regulatory Framework

      Current legislation is based around extending to children and young people the use of drugs available to adults for specific indications, following the same indications in all age groups. This can mean that the needs of children and young people are not the primary driver for research that they participate in. One way to address this tension is to examine the pharmacologic mechanisms of action that are relevant to children, rather than only pursuing development for the same indications in all age groups.
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      One aspect of this challenge is that for conditions that are common in adults, but relatively rare in children (such as diabetes type 2 or hepatitis C) there are many drugs available to study. Each sponsor pursues its own development program. The relatively small number of patients can mean that none of the programs is completed. This tension can be addressed through shared drug development programs, such as master protocols.
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      Some growth points in regulatory science and practice are particularly relevant to pediatrics, including evidence-based design and feasibility,

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      adaptive licensing,
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      integration of real-world evidence,
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      and consistent approaches across regulatory jurisdictions.

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      Off-label use in children is common. The population in which a treatment has been studied may not have included children or addressed the needs (or wishes) of a specific child. When considering off-label use it is important to apply a benefit-risk analysis with appropriate mitigating measures. Off-label use may, or may not, require consent from the families, depending on the additional risks that arise from using off-label drugs once mitigating strategies have been applied. There is tension between accepting that off-label use is sometimes necessary and then ensuring it is safe, and minimizing off-label use in the hopes of stimulating on-label use and related research. This is a complex issue that needs interventions across multiple areas of policy and practice. Simple approaches such as banning off-label use or making off-label use burdensome at the point of prescribing can harm children by preventing access to necessary drugs and do not necessarily lead to improved access to appropriate drugs.
      The institutional arrangements within regulatory agencies contribute to the challenges they face. The pediatric office of the US Food and Drug Administration has limited power, but broad advisory capabilities. The EMA pediatric office is involved in all decisions about pediatric investigation plans, but relies on advice from the European regulatory network. Many other regulators do not have a specific pediatric office. This divergence is addressed by the Pediatric Cluster.

      International Collaboration/Pediatric Cluster. https://www.fda.gov/scienceresearch/specialtopics/pediatrictherapeuticsresearch/ucm106621.htm. Last accessed August 2nd 2017

      Wider discussion is also valuable, involving sponsors, regulators, research participants and their advocates, and investigators. A successful example of this approach is the International Neonatal Consortium because the involved parties are committed to address specific problems using real-time and face-to-face interactions.
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      Harmonization across jurisdictions can be facilitated by consensus documents such as International Conference on Harmonisation 11.

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      Academic-led Research

      Academics contribute to drug development in several ways, including clinically driven research, science-driven research, and promotion of a research and evidence-based culture. Some clinical academic researchers conduct work that is targeted at the regulatory framework

      Mochly-Rosen D, Grimes K. A Practical Guide to Drug Development in Academia the SPARK Approach Springer. ISBN 978-3-319-02201-7

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      Academic, Foundation, and Industry Collaboration in Finding New Therapies.
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      Optimizing operational efficiencies in early phase trials: The Pediatric Trials Network experience
      Best Pharmaceuticals for Children Act — Pediatric Trials Network Administrative Core Committee.
      or contributes to a programmatic approach to drugs evaluation.
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      However, these approaches have not been adopted widely.
      Clinical research-driven studies are often more pragmatic than regulatory studies. The usual goals for such research are publications, individual professional advancement, and potential influence on clinical practice. Academic-driven clinical evaluation of drugs usually addresses a single, carefully chosen question about a specific context. This is often summarized in the PICO format: population, intervention, control, outcome. Each trial is designed to answer a focused clinically relevant question rather than contribute to a broad dossier of information about multiple questions. Science-driven clinical research often aims to develop methodologies or theoretical frameworks, or to test hypotheses. Individual studies that are driven by clinical or scientific interest may not contribute to the systematic approach to pediatric drug development described above. When possible, academics should consider preparatory work about formulations, dosage regimens, inclusion criteria, and outcomes before designing a clinical trial. Academics should also consider how to ensure their studies generate data that can be used for multiple purposes.
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      Usage of unpublished pediatric data.
      Academics need to learn more about regulatory processes to support sponsors and regulators

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      and improve the generalizability and influence of their work.

      Policy Development and Health Technology Assessment

      Similar considerations apply to health technologies and health economic studies. One factor that limits the utility of health economic assessments of drugs and devices in children is the time horizon used for the assessment. A benefit in infancy may have implications for 6 or 7 decades. These long-term benefits are not always captured due to policy decisions and methodologic difficulties.

      Communities

      Academics and Other Clinicians

      Academics are only 1 element of the clinical research enterprise. Other clinical staff have a significant role to play in clinical drug development. Large clinical centers outside academic settings can contribute to clinical trials very effectively, if appropriate resources are in place.
      Academic leaders need to promote therapeutic development and evaluation. Tenure and promotion are powerful drivers for academics so that contribution to regulatory-grade studies could become a valued part of the assessment of academics.

      International Conference on Harmonisation. CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E11/Step4/E11_Guideline.pdf. Last accessed August 2nd 2017

      Familiarity and conformance with regulatory and health technology assessment logic is necessary for academic innovations to contribute to therapeutic developments that improve clinical care. In particular, clinical academics need to consider how to evaluate parameters such as dosing, formulations, developmentally appropriate outcome measures, and safety when planning to address their clinical questions.
      In general, the pharmaceutical industry and regulators now understand the need for pediatric-specific drug development. In some cases, the rate limiting steps to adequate drug development for children do not lie with the industry or the regulators, but with the clinical community. Useful information about drugs depends on comparisons. Comparisons need to be consistent. Divergence in standards of care prevents consistent comparisons. Quite often divergence in standards of care is based on local circumstances and opinion rather than evidence. More fundamentally, the clinical community does not have standard approaches to outcome assessments and data management, which leads to problems with feasibility assessment, study design, study implementation, and long-term follow-up of benefits and harms of drugs. The clinical community needs to address these issues. However, overcoming these challenges will not be cost-neutral and other stakeholders need to support the clinical community.

      Owner of an Asset such as a Therapeutic Product

      The proprietor of a product can be a pharmaceutical company, a nonprofit organization, or a spinoff from an academic institution. Recently, patient groups have developed assets.
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      Companies deal with the costs of drug assessment in pediatrics by either assuming that they will generate an appropriate return on investment, or that the costs of not complying with the regulatory requirements will be greater than the costs of doing the research. Return on investment may be measured in several ways—most commonly as financial value but clinical or social value may also be important.
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      There may be a concern that commercial entities may make unjustified profits out of drugs used in children. However, this is unlikely to be relevant to the vast majority of drugs used in children because of market size. Indeed, recognition of this fact and the attendant market failures has driven the changes in the regulatory environment in the United States and Europe over the past 2 decades. The regulatory changes have not addressed issues relating to the availability of drugs to children. Even if drugs can be placed on the market, access of children to those drugs depends on decisions about pricing and reimbursement at national, regional, and institutional levels. There is growing concern among owners of assets that the effort that goes into drugs development will not be rewarded by access. This concern is shared by investigators and participants in research—what is the point of involvement in research if the drugs cannot be used by people who would benefit from them.

      Children, Young People, and Families

      Patients, families, and other nonprofessional care providers need to be central to the evaluation of drugs in a proportionate way that respects the other demands on their time while avoiding parentalism and tokenism.

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      It is increasingly recognized that participant centricity is efficient and effective for research funders.
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      Public and patient involvement in pediatric research.
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      Improving Surgical Research by Involving Stakeholders.
      The value of working with children and young people is increasingly recognized. For example, the EMA actively encourages the engagement of children and young people in drug development.

      Principles on the involvement of young patients/consumers within EMA activities. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2017/07/WC500231645.pdf. Last accessed August 2nd 2017

      The risks of working with children, such as capture by commercial interests, can be mitigated by working through trusted third parties that act as honest brokers.
      Individuals can comment on aspects of clinical trials; for example, researchers asking their own children to comment on information sheets or consent forms. Experience shows that more formal approaches are more useful. Young People’s Advisory Groups provide input to many aspects of trial design and implementation through a forum that allows training and meetings to be organised in a child-friendly way. Some aspects of trials can be addressed by members of Young People’s Advisory Groups with training in clinical trials, other aspects need input from people with experience with the condition under investigation. Families who manage high levels of burden may not be able to attend formal meetings and need bespoke approaches developed through expertise gained in other settings. In all cases, high-quality advice needs to be paid for not only to cover the costs incurred by young people and their families, but also to develop and maintain the infrastructure needed to obtain advice.
      Coercion may be a concern in this population but can be managed using well-designed consent processes and paying due attention to assent. Implicit coercion that arises from divergent access to health care services is more difficult to address but is usually managed by ensuring that study participants continue to have the same access to the services provided during the research once the research has been completed.
      Some drug development occurs in the setting of treatment for life-threatening diseases. Decisions about the use of drugs in children are based on similar principles to the principles that apply in other populations. The need to use proxy decision makers and respect the autonomy of the child/young person is an additional level of complexity, particularly when the legal requirements do not match the capability of the sick person. Life expectancy influences these decisions in the same way that is does in other populations.

      Public Research Funders

      Public research funders are generally driven by a mission. Project selection will be primarily determined by mission goals, which can vary from the interests and priorities of other communities. In some cases, the mission of public funders includes comprehensive approaches to pediatric drug development.
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      However, most funders consider projects and programs in isolation from drug development. As discussed above, this does not make the best use of investments in research. Public funders should consider the broader picture and include resources to allow the reuse of data in drug development programs by the broader research community.
      • Warren E.
      Strengthening Research through Data Sharing.

      Discussion: Common Features between Frameworks and Communities

      Some authors have estimated that 85% of life sciences research is nonproductive. All research frameworks and communities contribute to research waste (and resulting delays in the provision of effective drugs).
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      Overcoming this waste is particularly important for children and young people because of the investment that children and young people make in research participation, the limited availability of children eligible for any particular study, and the narrow margin for error in study implementation. Multistakeholder forays are important and potentially productive ways to minimize research waste and maximize the benefits of research.
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      The International Neonatal Consortium: collaborating to advance regulatory science for neonates.
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      Members of Working Group 1 of the Pediatric Platform of ACCELERATE. Implementation of mechanism of action biology-driven early drug development for children with cancer.
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      TACT
      The TREAT-NMD advisory committee for therapeutics (TACT): an innovative de-risking model to foster orphan drug development.
      Work toward a shared and interoperable framework at strategic
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      and practical levels
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      is an important goal and pediatrics is at the forefront of these activities. Data sharing requires technical and semantic interoperability, which is under development in pediatrics.

      Benson T, Grieve G. Principles of Health Interoperability: SNOMED CT, HL7 and FHIR (Health Information Technology Standards) Paperback Springer; 3rd ed. 2016 edition (1 July 2016).

      • Kahn M.G.
      • Bailey L.C.
      • Forrest C.B.
      • et al.
      Building a common pediatric research terminology for accelerating child health research.
      • Haumont D.
      • NguyenBa C.
      • Modi N.
      eNewborn: The Information Technology Revolution and Challenges for Neonatal Networks.
      For pediatric research in particular, an international cooperative effort to develop a concept and terminology resource is readily and freely available.
      • Gipson D.S.
      • Kirkendall E.S.
      • Gumbs-Petty B.
      • et al.
      Development of a Pediatric Adverse Events Terminology.

      Conclusions

      Pediatric drug development needs to take account of specificities relating to growth, development, decision making, and the burdens imposed by research. Researchers need to be part of a team that includes expertise in overcoming these challenges.

      Conflicts of Interest

      The authors have indicated that they have no conflicts of interest regarding the content of this article.

      Acknowledgments

      Dr. Turner developed the concept and wrote the drafts. Dr. Hirschfeld enriched the concept and made substantial amendments to the drafts.

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