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Extrapolation as a Default Strategy in Pediatric Drug Development

Abstract

Pediatric drug development lags adult development by about 8 years (Mulugeta et al. in Pediatr Clin 64(6):1185–1196, 2017). In such context, many incentives, regulations, and innovative techniques have been proposed to address the disparity for pediatric patients. One such strategy is extrapolation of efficacy from a reference population. Extrapolation is currently justified by providing evidence in support of the effective use of drugs in children when the course of the disease and the expected treatment response would be sufficiently similar in the pediatric and reference population. This paper’s position is that, despite uncertainties, pediatric drug development programs should initially assume some degree of extrapolation. The degree to which extrapolation can be used lies along a continuum representing the uncertainties to be addressed through generation of new pediatric evidence. In addressing these uncertainties, the extrapolation strategy should reflect the level of tolerable uncertainty concerning the decision to expose a child to the risks of a new drug. This judgment about the level of tolerable uncertainty should vary with the context (e.g., disease severity, existing therapeutic options) and can be embedded into pediatric drug development archetypes to ascertain the extent of studies needed and whether simultaneous development for adults and adolescents be considered.

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Notes

  1. ClinicalTrials.gov search using status = recruiting or not yet recruiting, age = child, study type = interventional, study phase = phase 3–4, funder type = industry. Accessed December 22, 2019.

  2. Belmont Report entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research is codified in HHS regulations as 45 CFR part 46 which includes four subparts. Subpart D pertains to Special Protections for Children as Research Subjects. In the EU, children as vulnerable subjects are covered in Directive 2001/20/EC (Clinical Trials Directive). Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. OJ L 121, 1.5.2001, p. 34.

  3. Both the FDA and EMA define children as the age prior to obtaining the legal age of majority. Physiological development and maturity of organs, pathophysiology and natural history of the disease or condition, available treatment options, and the pharmacology of the

    investigational product are factors to be considered in determining the subgroups in pediatric studies, e.g., adolescents (12 to less than 21 yrs old), children (2 to less than 12 yrs old), infants (29 days to less than 2 yrs old), and neonates (first 28 days of life). These pediatric studies will be interchangeably referred to as pediatric drug development.

  4. Member parties that have implemented the guideline include ANVISA (Brazil), EC (Europe), FDA (US), HSA (Singapore), Health Canada (Canada), MFDS (Republic of Korea), MHLW/PMDA (Japan), NMPA (China), Swissmedic (Switzerland), and TFDA (Chinese Taipei).

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Correspondence to Margaret Gamalo PhD.

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The authors are part of the Biotechnology Innovation Organization’s (BIO) Innovation in Pediatric Drug Development Task Force. This Task Force is a group within the Pediatric Committee, comprised of BIO members working to serve as a resource for BIO members and BIO staff by identifying and responding to key scientific and regulatory issues related to the pediatric drug development. The positions in this paper may not be representative of the full BIO membership. The views and opinions expressed in this paper are those of the authors and do not necessarily reflect the official policy or position of Novartis.

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Gamalo, M., Bucci-Rechtweg, C., Nelson, R.M. et al. Extrapolation as a Default Strategy in Pediatric Drug Development. Ther Innov Regul Sci 56, 883–894 (2022). https://doi.org/10.1007/s43441-021-00367-9

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  • DOI: https://doi.org/10.1007/s43441-021-00367-9

Keywords

  • Pediatric drug development
  • Pediatric regulations
  • Extrapolation
  • Treatment landscape archetypes