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Pediatric Formulations and Dosage Forms and Future Opportunities: Impact of Regulations in the USA and Implementation of Quality by Design

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Pediatric Formulations

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 11))

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Abstract

The advances in pharmaceutical sciences and technology have been so significant that Peter Drucker’s quote that “the future has already happened” applies readily for medicines developed for adults. For pediatric patients, the future is about to happen. The continuation of focused partnerships and knowledge sharing and leveraging are critical to ensure that pediatric patients have timely access to high quality drug products that were developed with pediatric patients in mind. An overview of regulatory efforts, regulations and legislation to address the challenges for pediatric drug development are discussed. The implementation of regulatory incentives, the Pediatric Rule, Best Pharmaceuticals for Children Act, and Pediatric Research Equity Act, is having an impact and has led to incorporation of information for dosing of approximately 500 drug products since 1998 starting with implementation of the Pediatric Rule. There are significant accomplishments and a lot more work ahead for the pediatric community. The labeling information is usually for older pediatric patients and the need for information for safe and effective dosing of patients of 6 years old or younger remains. Some of the study outcomes are inconclusive with respect to safety and efficacy, and support the hypotheses that better understanding of drug delivery to pediatric patients is needed for determining and delivering the right dose to the pediatric patients. The 2012 Food and Drug Administration Safety and Innovation Act and implementation of Quality by Design paradigm focusing on drug product design and manufacturing process are expected to have a synergistic effect for continuing to advance development of pediatric dosage forms and formulations for the benefit of the pediatric patients.

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References

  1. Shirkey H (1968) Therapeutic orphans. J Pediatr 72:119–120, reprinted in 1999 in Pediatrics 104:583–584

    Article  CAS  PubMed  Google Scholar 

  2. Wilson JT (1975) Pragmatic assessment of medicines available for young children and pregnant or breast-feeding women. In: Morselli PL, Garattini S, Sereni F (eds) Basic and therapeutic aspects of perinatal pharmacology. Raven, New York, pp 411–421

    Google Scholar 

  3. American Academy of Pediatrics, Committee on Drugs (1977) Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60:91–101

    Google Scholar 

  4. Munzenberger PJ, McKercher P (1980) Pediatric dosing: the pharmacist dilemma. Contemp Pharm Pract 3:11–14

    CAS  PubMed  Google Scholar 

  5. US Food and Drug Administration (1979) Labeling and prescription drug advertising: content and format for labeling for human prescription drugs. Fed Regist 44:37434–37467

    Google Scholar 

  6. Wilson JT, Kearns GL, Murphy D, Yafee SJ (1994) Pediatric labeling requirements. Implications for pharmacokinetic studies. Clin Pharmacokinet 26:308–325

    Article  CAS  PubMed  Google Scholar 

  7. American Academy of Pediatrics, Committee on Drugs (1995) Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 95:286–295

    Google Scholar 

  8. Wilson JT (1999) An update on the therapeutic orphan. Pediatrics 104:585–590

    CAS  PubMed  Google Scholar 

  9. Coté CJ, Kauffman RE, Troendle GJ, Lambert GH (1996) Is the “Therapeutic Orphan” about to be adopted? Pediatrics 98:118–123

    PubMed  Google Scholar 

  10. American Academy of Pediatrics, Committee on Drugs (1996) Unapproved uses of approved drugs: the physician, the package insert and the Food and Drug Administration: subject review. Pediatrics 98:143–145

    Google Scholar 

  11. Blumer JL (1999) Off-label uses of drugs in children. Pediatrics 104:598–602

    CAS  PubMed  Google Scholar 

  12. Kauffman RE (1991) Fentanyl, fads, and folly: who will adopt the therapeutic orphans? J Pediatr 119:588–589

    Article  CAS  PubMed  Google Scholar 

  13. Wilson JT (1999) Questions and answers on labeling of drugs for children. Drug Inf J 33:375–383

    Google Scholar 

  14. Schirm E, Tobi H, de Vries TW, Choonara I, De Jong-van den Berg LTW (2003) Lack of appropriate formulations of medicines for children in the community. Acta Paediatr 92:1486–1489

    Article  CAS  PubMed  Google Scholar 

  15. Rodriguez W, Roberts R, Murphy D (2001) Adverse drug events in children: the US Food and Drug Administration perspective. Curr Ther Res 62:711–723

    Article  Google Scholar 

  16. Roberts R, Rodriguez W, Murphy D, Crescenzi T (2003) Pediatric drug labeling: improving the safety and efficacy of pediatric therapies. JAMA 290:905–911

    Article  PubMed  Google Scholar 

  17. Nunn T, Williams J (2005) Formulation of medicines for children. Br J Clin Pharmacol 59:674–676

    Article  PubMed  Google Scholar 

  18. Milne CP (2002) Exploring the frontiers of law and science: FDAMA’s pediatric studies incentive. Food Drug Law J 57:491–517

    PubMed  Google Scholar 

  19. Milne CP, Bruss JB (2008) The economics of pediatric formulation development for off-patent drugs. Clin Ther 30:2133–2145

    Article  PubMed  Google Scholar 

  20. Breitkreutz J (2008) European perspectives on pediatric formulations. Clin Ther 30:2146–2154

    Article  PubMed  Google Scholar 

  21. Mennella JA, Beauchamp GK (2008) Optimizing oral medications for children. Clin Ther 30:2120–2132

    Article  PubMed Central  PubMed  Google Scholar 

  22. US Food and Drug Administration (1994) Specific requirements on content and format of labeling of human prescription drugs: revision of “pediatric use” subsection in the labeling, Final Rule. Fed Regist 59(238):64240–64250

    Google Scholar 

  23. US Food and Drug Administration (1996) Guidance for industry, the content and format for pediatric use supplements

    Google Scholar 

  24. Qualifying for Pediatric Exclusivity Under Section 505A of the Federal Food, Drug and Cosmetic Act (1997) Content and format of pediatric use supplements. Food and Drug Administration. Modernization Act of 1997. Public Law No. 105–115

    Google Scholar 

  25. US Food and Drug Administration (1998) Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients; final rule. Fed Regist 63:66631–66672

    Google Scholar 

  26. US Food and Drug Administration (1999) Guidance for industry: qualifying for pediatric exclusivity under Section 505A of the Federal Food, Drug, and Cosmetic Act. Revised September 1999

    Google Scholar 

  27. Best Pharmaceuticals for Children Act (2002) Public Law No. 107–109

    Google Scholar 

  28. Pediatric Research Equity Act (2003) Public Law No. 108–155

    Google Scholar 

  29. US Food and Drug Administration Amendments Act (FDAAA) of 2007 (September 27, 2007) Public Law No. 110–85 (Best Pharmaceuticals for Children Act, 2007 and Pediatric Research Equity Act of 2007)

    Google Scholar 

  30. US Food and Drug Administration Safety and Innovation Act (FDASIA) (2012) Title V, July 9, 2012 (112th Congress) Public Law 112–144

    Google Scholar 

  31. Standing JF, Khaki ZF, Wong ICK (2005) Poor formulation information in published pediatric drug trials. Pediatrics 116:e559–e562

    Article  PubMed  Google Scholar 

  32. Pandit S, Shah U, Kirby DJ, Nunn T, Tuleu C (2010) Inappropriate oral formulations and information in paediatric trials. Arch Dis Child 95:754–756

    Article  PubMed  Google Scholar 

  33. Standing JF, Tuleu C (2005) Paediatric formulations-getting to the heart of the problem. Int J Pharm 300:56–66

    Article  CAS  PubMed  Google Scholar 

  34. Allen LV Jr (2008) Dosage form design and development. Clin Ther 30:2102–2111

    Article  PubMed  Google Scholar 

  35. Nahata MC, Allen LV Jr (2008) Extemporaneous drug formulations. Clin Ther 30:2112–2119

    Article  PubMed  Google Scholar 

  36. Koren G, Barzilay Z, Greenwald M (1986) Ten-fold errors in administration of drug doses: a neglected iatrogenic disease in pediatrics. Pediatrics 77:848–849

    CAS  PubMed  Google Scholar 

  37. Ross LM, Wallace J, Paton JY (2000) Medication errors in a paediatric teaching hospital in the UK: five years operational experience. Arch Dis Child 83:492–497

    Article  CAS  PubMed  Google Scholar 

  38. Yin HS, Mendelsohn AL, Wolf MS, Parker RM, Fierman A, van Schaick L, Bazan IS, Kline MD, Dreyer BP (2010) Parents’ medication administration errors role of dosing instruments and health literacy. Arch Pediatr Adolesc Med 164:181–186

    Article  PubMed  Google Scholar 

  39. Doherty C, Mc Donnell C (2012) Tenfold medication errors: 5 years’ experience at a university-affiliated pediatric hospital. Pediatrics 129:916–924

    Article  PubMed  Google Scholar 

  40. Abdel-Rahman SM, Reed MD, Wells TG, Kearns GL (2007) Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls. Clin Pharmacol Ther 81:483–494

    Article  CAS  PubMed  Google Scholar 

  41. Knellwolf AL, Bauzon S, Della Casa Alberighi O, Lutsar I, Bácsy E, Alfarez D, Panei P (2011) Framework conditions facilitating paediatric clinical research. Ital J Pediatr 37:12

    Article  PubMed Central  PubMed  Google Scholar 

  42. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL (2007) Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 59:1043–1055

    Article  CAS  PubMed  Google Scholar 

  43. Tuleu C, Breitkreutz J (2013) Educational paper: formulation-related issues in pediatric clinical pharmacology. Eur J Pediatr 172:717–720

    Article  CAS  PubMed  Google Scholar 

  44. Mandel D, Littner Y, Mimouni FB, Lubetzky R (2006) Conclusiveness of the cochrane neonatal reviews: a systematic analysis acta. Paediatrica 95:1209–1212

    Article  Google Scholar 

  45. Benjamin DK Jr, Smith PB, Murphy MD, Roberts R, Mathis L, Avant D, Califf RA, Li JS (2006) Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA 296:1266–1273

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Temeck J (2010) Pediatric product development in the U.S. FDA Seminar, Copenhagen. http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/UCM262309.pdf

  47. FDA Pediatrics Page (2013) Labeling database as of March 2013. http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase

  48. Sachs AN, Avant D, Lee CS, Rodriguez W, Murphy DM (2012) Pediatric information in drug product labeling. JAMA 307:1914–1915

    Article  CAS  PubMed  Google Scholar 

  49. Regulation No. EC 1901/2006 (2006) European parliament and the council, European Commission (Brussels), December 12, 2006

    Google Scholar 

  50. Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA) (2006) Reflection paper: formulations of choice for the paediatric population

    Google Scholar 

  51. International Conference on Harmonization (ICH) Topic E-11 (2001) Clinical investigation of medicinal products in the pediatric population. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002926.pdf

  52. Sixtieth World Health Assembly, Better Medicines for Children (May 2007) WHA60.20

    Google Scholar 

  53. World Health Organization (2011) Essential medicines for children. http://www.who.int/childmedicines/en/

  54. Beggs SA, Cranswick NE, Reed MD (2005) Improving drug use for children in the developing world. Arch Dis Child 90:1091–1093

    Article  CAS  PubMed  Google Scholar 

  55. Permala J, Hassali MA, Awaisu A, Shafie AA (2010) Dosing information in a standard drug reference: are pediatrics still therapeutically neglected? Pediatr Int 52:290–295

    Article  PubMed  Google Scholar 

  56. McNally GP, Railkar AM (2009) In: Mulberg AE, van den Anker JN, Silber SA (eds) Formulation of pediatric dosage forms in pediatric drug development, concepts and applications. Wiley, New York, pp 553–566

    Google Scholar 

  57. Krause J, Breitkreutz J (2008) Improving drug delivery in paediatric medicine. Pharmaceut Med 22:41–50

    Google Scholar 

  58. Breitkreuz J, Tuleu C, Solomonidou D (2007) Paediatric formulations. In: Rose K, van den Anker JN (eds) Guide to paediatric clinical research. Karger AG, Basel

    Google Scholar 

  59. Smyth RL, Edwards AD (2006) A major new initiative to improve treatment for children. Arch Dis Child 91:212–213

    Article  CAS  PubMed  Google Scholar 

  60. Walsh J, Bickmann D, Breitkreutz J, Chariot-Goulet M, on behalf of the European Pediatric Formulation Initiative (EUPFI) (2011) Delivery devices for the administration of pediatric formulations: overview of current practices, challenges and recent developments. Int J Pharmaceut 415:221–231

    Article  CAS  Google Scholar 

  61. Guidance for Industry (2009) ICH Q8(R2) Pharmaceutical Development, Revision 2. http://www.fda.gov/downloads/Drugs/…/Guidances/ucm073507.pdf

  62. Potter C (2009) PQLI application of science- and risk-based approaches (ICH Q8, Q9, and Q10) to existing products. J Pharm Innov 4:4–23. doi:10.1007/s12247-009-9051-9

    Article  Google Scholar 

  63. Winkle H (2011) Key note “QbD and Pediatric Drug Development” application of QbD to development of pediatric formulations and dosage forms. In: Mini-symposium, CRS 38th annual meeting & exposition of the controlled release society, Gaylord National Hotel & Convention Center, National Harbor, MD

    Google Scholar 

  64. Becker ML, Leeder SJ (2010) Identifying genomic and developmental causes of adverse drug reactions in children. Pharmacogenomics 11:1591–1602. doi:10.2217/pgs.10.146

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  65. Bartelink IH, Rademaker CMA, Schobben AFAM, van den Anker JN (2006) Guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations. Clin Pharmacokinet 45:1077–1097

    Article  CAS  PubMed  Google Scholar 

  66. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Drug therapy: developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167

    Article  CAS  PubMed  Google Scholar 

  67. Rodriguez W, Selen A, Avant D, Chaurasia C, Crescenzi T, Gieser G, Di Giacinto J, Huang SM, Lee P, Mathis L, Murphy D, Murphy S, Roberts R, Sachs HC, Suarez S, Tandon V, Uppoor RS (2008) Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics 121:530–539

    Article  PubMed  Google Scholar 

  68. Abdel-Rahman SM, Amidon GL, Kaul A, Lukacova V, Vinks AA, Knipp GT, and Members of the BCS Task Force (2012) Summary of the national institute of child health and human development-best pharmaceuticals for children act pediatric formulation initiatives workshop––pediatric biopharmaceutics classification system working group. Clin Ther 34:S11–S24

    Article  PubMed Central  PubMed  Google Scholar 

  69. Giacoia GP, Taylor-Zapata P, Mattison D (2008) Eunice Kennedy Shriver national institute of child health and human development pediatric formulations initiative: selected reports from working groups. Clin Ther 30:2097–2101

    Article  PubMed  Google Scholar 

  70. Giacoia GP, Taylor-Zapata P, Zajicek A (2012) Eunice Kennedy Shriver national institute of child health and human development pediatrics formulation initiative: proceedings from the second workshop on pediatric formulations. Clin Ther 34:S1–S10

    Article  PubMed  Google Scholar 

  71. Shaddy RE, Denne SC, the Committee on Drugs and Committee on Pediatric Research (2010) Clinical report—guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 125:850–860

    Article  PubMed  Google Scholar 

  72. Gray VA (2009) Meeting report: University of Wisconsin/AAPS/FDA workshop applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit. Dissolution Technol 16:35–39

    Google Scholar 

  73. Selen A, Cruañes MT, Müllertz A, Dickinson PA, Cook JA, Polli JE, Kesisoglou F, Crison J, Johnson KC, Muirhead GT, Schofield T, Tsong Y (2010) Meeting report: applied biopharmaceutics and Quality by Design for dissolution/release specification setting: product quality for patient benefit. AAPSJ 12:465–472

    Article  PubMed  Google Scholar 

  74. Murphy D (2011) Key note (pediatric product development: the path to the present) application of QbD to development of pediatric formulations and dosage forms. In: CRS 38th annual meeting & exposition of the controlled release society, Gaylord National Hotel & Convention Center, National Harbor, MD

    Google Scholar 

  75. Stella VJ (2001) My mentors. J Pharm Sci 90:969–978

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This chapter is dedicated to Dianne Murphy, Rosemary Roberts, Shirley Murphy, William Rodriguez, ShaAvhrée Buckman-Garner, and Lisa Mathis with gratitude for their illuminating leadership and to all members of the pediatric community at large for their inspiring, diligent and focused efforts in advance of the pediatric medicines.

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Authors and Affiliations

  1. Office of New Drug Quality Assessment/CDER/FDA, 10903 New Hampshire Ave., Building #21, Room 1604, Silver Spring, MD, 20993, USA

    Arzu Selen

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  1. Arzu Selen
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Correspondence to Arzu Selen .

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Editors and Affiliations

  1. Department of Pharmaceutics Department of Analytical Chemistry, University of Copenhagen, Denmark

    Daniel Bar-Shalom

  2. Pediatric Drug Development & More, klausrose Consulting, Riehen, Switzerland

    Klaus Rose

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Disclaimer: The findings and conclusions in this chapter are the views of the author and have not been formally disseminated by the US Food and Drug Administration and should not be construed to represent any Agency determination or policy. No official endorsement by the FDA is intended or should be inferred.

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© 2014 American Association of Pharmaceutical Scientists

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Selen, A. (2014). Pediatric Formulations and Dosage Forms and Future Opportunities: Impact of Regulations in the USA and Implementation of Quality by Design. In: Bar-Shalom, D., Rose, K. (eds) Pediatric Formulations. AAPS Advances in the Pharmaceutical Sciences Series, vol 11. Springer, New York, NY. https://doi.org/10.1007/978-1-4899-8011-3_26

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