Clinical Trials in Pediatrics and Neonatology: Reasons for Ups and Downs
https://doi.org/10.15690/pf.v13i3.1572
Abstract
The predictability of results of pediatric clinical trials is often limited for a number of reasons. Among the main ones is the imperfect functioning of organ due to immature ontogeny of enzyme and organ systems in children, and the presence of special subpopulations of full-term newborns and preterm neonates sometimes being in a critical condition. The main task of a present-day pediatric investigational plan is to develop drugs and to elaborate doses that are «specifically designed», not simply «suitable» for neonates. Other reasons for limited predictability are as follows: adult data extrapolation constraint due to children’s anatomic and physiological features, the lack of clinical trial subjects resulting in inability to select an optimal dose by its escalation, the absence of consensus on the ethical aspect of pediatric clinical trials, the etiopathogenetic difference of some diseases and conditions depending on subject’s age, and prevalence of placebo-effect in children. Nowadays it is supposed to be very important to publish all, even failed, pediatric trials to improve the accuracy of pharmacological effects modeling in different subpopulations.
About the Authors
A. A. Mosikian
Pavlov First Saint-Petersburg Medical University, Saint-Petersburg, Russian Federation
Russian Federation
Russian Federation
A. O. Tomasheva
Pavlov First Saint-Petersburg Medical University, Saint-Petersburg, Russian Federation
Russian Federation
Russian Federation
T. L. Galankin
Pavlov First Saint-Petersburg Medical University, Saint-Petersburg, Russian Federation
Russian Federation
Russian Federation
A. S. Kolbin
Pavlov First Saint-Petersburg Medical University, Saint-Petersburg, Russian Federation
Saint-Petersburg State University, Saint-Petersburg, Russian Federation
Russian Federation
Russian Federation
References
1. Зырянов С.К. Использование нерекомендованных лекарств в педиатрии // Педиатрия. Журнал им. Г.Н. Сперанского. — 2005. — Т.84. — №5. — С. 19—21. [Zyryanov SK. Usage of nonrecommended drugs in pediatric practice. Pediatriia. 2005;84(5): 19–21. (In Russ).]
2. Turner S. Unregistered and off-label drug use in paediatric patients. Aust J Hosp Pharm. 1999;29(5):265–268. doi: 10.1002/jppr1999295265.
3. Колбин А.С., Шабалов Н.П., Любименко В.А. Частота использования нелицензированных лекарств в неонатологии: данные фармакоэпидемиологического исследования // Педиатрическая фармакология. 2007. — Т.4. — №4. — С. 35–40. [Kolbin AS, Shabalov NP, Lyubimenko VA. Usage rate of the unlicensed medications in neonatology: data of the pharmaco-epidemiological research. Pediatricheskaya farmakologiya. 2007;4(4):35–40. (In Russ).]
4. Завидова С., Намазова-Баранова Л., Тополянская С. Клинические исследования лекарственных препаратов в педиатрии: проблемы и достижения // Педиатрическая фармакология. — 2010. — Т. 7. — № 1. — С. 6–14. [Zavidova S, Namazova-Baranova L, Topolyanskaya S. Clinical trials of drugs in pediatrics: problems and achievements. Pediatric pharmacology. 2010;7(1):6–14. (In Russ).]
5. rosminzdrav.ru [интернет]. Государственный реестр лекарственных средств [доступ от 21.12.2015]. Доступ по ссылке http://grls.rosminzdrav.ru/.
6. fda.gov [Internet]. Pharmacometrics at FDA. Overview [cited 17 Jan 2016]. Available from: http://www.fda.gov/AboutFDA/ CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ ucm167032.htm#Overview.
7. Wang J, Avant D, Green D, et al. A survey of neonatal pharmacokinetic and pharmacodynamic studies in pediatric drug development. Clin Pharmacol Ther. 2015;98(3):328–335. doi: 10.1002/cpt.149.
8. Allegaert K, van den Anker J. Neonatal drug therapy: The first frontier of therapeutics for children. Clin Pharmacol Ther. 2015; 98(3):288–297. doi: 10.1002/cpt.16.
9. Benjamin DK Jr, Smith PB, Murphy MD, et al. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA. 2006;296(10):1266–1273. doi: 10.1001/jama.296.10.1266.
10. Wharton GT, Murphy MD, Avant D, et al. Impact of pediatric exclusivity on drug labeling and demonstrations of efficacy. Pediatrics. 2014;134(2):e512–518. doi: 10.1542/peds.2013- 2987.
11. Momper JD, Mulugeta Y, Burckart GJ. Failed pediatric drug development trials. Clin Pharmacol Ther. 2015;98(3):245–251. doi: 10.1002/cpt.142.
12. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology—drug disposition, action and therapy. N Engl J Med. 2003;349(12):1157–1167. doi: 10.1056/nejmra035092.
13. Kearns GL. Selecting the proper pediatric dose: It is more than size that matters. Clin Pharmacol Ther. 2015;98(3):238–240. doi: 10.1002/cpt.168.
14. Holford N. Dosing in children. Clin Pharmacol Ther. 2010; 87(3):367–370. doi: 10.1038/clpt.2009.262.
15. Kleiber M. Body size and metabolism. Hilgardia. 1932; 6(11):315–349. doi: 10.3733/hilg.v06n11p315.
16. Russell J, Baur LA, Beumont PJ, et al. Altered energy metabolism in anorexia nervosa. Psychoneuroendocrinology. 2001;26(1): 51–63. doi: 10.1016/s0306-4530(00)00036-6.
17. Tolbert J, Kearns GL. The challenge of obesity in paediatric leukaemia treatment: it is not just size that matters. Arch Dis Child. 2015;100(1):101–105. doi: 10.1136/archdischild- 2014-307147.
18. U.S. Department of Health and Human Services. FDA. CDER. Guidance for industry, investigators, and reviewers. Exploratory IND studies [Internet]. 2006 [cited 17 Jan 2016]. Available from: http:// www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 078933.pdf.
19. Roth-Cline M, Nelson RM. Microdosing studies in children: A US regulatory perspective. Clin Pharmacol Ther. 2015;98(3):232–233. doi: 10.1002/cpt.165.
20. Sherwin CM, McCaffrey F, Broadbent RS, et al. Discrepancies between predicted and observed rates of intravenous gentamicin delivery for neonates. J Pharm Pharmacol. 2009;61(4):465–471. doi: 10.1211/jpp.61.04.0008.
21. Uppal N, Yasseen B, Seto W, Parshuram CS. Drug formulations that require less than 0.1 mL of stock solution to prepare doses for infants and children. CMAJ. 2011;183(4):E246– 248. doi: 10.1503/ cmaj.100467.
22. Nunn AJ, Richey RH, Shah UU, et al. Estimating the requirement for manipulation of medicines to provide accurate doses for children. Eur. J. Hosp. Pharm. 2013;20(1):3–7. doi: 10.1136/ejhpharm- 2012-000133.
23. Turner MA, Duncan JC, Shah U, et al. Risk assessment of neonatal excipient exposure: lessons from food safety and other areas. Adv Drug Deliv Rev. 2014;73:89–101. doi: 10.1016/j. addr.2013.11.003.
24. Salunke S, Brandys B, Giacoia G, et al. The STEP (Safety and Toxicity of Excipients for Paediatrics) database: part 2. The pilot version. Int J Pharm. 2013;457(1):310–322. doi: 10.1016/ j.ijpharm.2013.09.013.
25. World Health Organization. WHO Model Formulary for Children 2010 [Internet]. WHO; 2010 [cited 24 Jan 2016]. Available from: http://www.who.int/selection_medicines/list/WMFc_2010.pdf.
26. Allegaert K, van de Velde M, van den Anker J. Neonatal clinical pharmacology. Paediatr Anaesth. 2014;24(1):30–38. doi: 10.1111/pan.12176.
27. de Wildt SN, Tibboel D, Leeder JS. Drug metabolism for the paediatrician. Arch Dis Child. 2014;99(12):1137–1142. doi: 10.1136/ archdischild-2013-305212.
28. Smits A, Kulo A, de Hoon JN, Allegaert K. Pharmacokinetics of drugs in neonates: pattern recognition beyond compound specific observations. Curr Pharm Des. 2012;18(21):3119–3146. doi: 10.2174/1381612811209023119.
29. Schreuder MF, Bueters RR, Allegaert K. The interplay between drugs and the kidney in premature neonates. Pediatr Nephrol. 2014;29(11):2083–2091. doi: 10.1007/s00467-013-2651-0.
30. Girardi A, Raschi E, Galletti S, et al. Drug-induced renal damage in preterm neonates: state of the art and methods for early detection. Drug Saf. 2015;38(6):535–551. doi: 10.1007/s40264-015- 0288-6.
31. McCune SK, Mulugeta YA. Regulatory science needs for neonates: a call for neonatal community collaboration and innovation. Front Pediatr. 2014;2:135. doi: 10.3389/fped.2014.00135.
32. Weimer K, Gulewitsch MD, Schlarb AA, et al. Placebo effects in children: a review. Pediatr Res. 2013;74(1):96–102. doi: 10.1038/ pr.2013.66.
33. King BH, Dukes K, Donnelly CL, et al. Baseline factors predicting placebo response to treatment in children and adolescents with autism spectrum disorders: a multisite randomized clinical trial. JAMA Pediatr. 2013;167(11):1045–52. doi: 10.1001/jamapediatrics. 2013.2698.
34. Zhang B, Schmidt B. Do we measure the right end points? A systematic review of primary outcomes in recent neonatal randomized clinical trials. J Pediatr. 2001;138(1):76– 80. doi: 10.1067/ mpd.2001.110299.
35. fda.gov [Internet]. Executive summary FDA background package for Advisory Committee Meeting November 05, 2010 [updated 2010 Sep 27; cited 24 Jan 2016]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/ Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM232026.pdf
36. Blake MJ, Abdel-Rahman SM, Pearce RE, et al. Effect of diet on the development of drug metabolism by cytochrome P-450 enzymes in healthy infants. Pediatr Res. 2006;60(6):717– 723. doi: 10.1203/01.pdr.0000245909.74166.00.
37. Allegaert K. Tailored tools to improve pharmacotherapy in infants. Expert Opin Drug Metab Toxicol. 2014;10(8):1069–1078. doi: 10.1517/17425255.2014.931937.
38. fda.gov [Internet]. The Code of Federal Regulations (CFR), Title 21 Food and Drugs, Chapter I.50 Protection of human subjects in clinical trials [updated 2015 Aug 21; cited 24 Jan 2016]. Available from: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=50.
39. fda.gov [Internet]. Pediatric Ethics Subcommittee of the Pediatric Advisory Committee Meeting Announcement. Bethesda, MD; May 11, 2011 [updated 2011 Apr 19; cited 24 Jan 2016]. Available from: http:// www.fda.gov/AdvisoryCommittees/Calendar/ucm251844.htm.
40. Shinwell ES, Eventov-Friedman S. Impact of perinatal corticosteroids on neuromotor development and outcome: review of the literature and new meta-analysis. Semin Fetal Neonatal Med. 2009;14(3):164–70. doi: 10.1016/j.siny.2008.12.001.
41. Leeder JS, Kearns G. Interpreting pharmacogenetic data in the developing neonate: the challenge of hitting a moving target. Clin Pharm Ther. 2012;92(4):434–436. doi: 10.1038/clpt.2012.130.
42. Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther. 2008;83(2):234– 242. doi: 10.1038/sj.clpt.6100406.
43. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376–382. doi: 10.1038/clpt.2013.254.
44. Shah RR, Smith RL. Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine. Drug Metab Dispos. 2015;43(3): 400–410. doi: 10.1124/dmd.114.061093.
Review
For citations:
Mosikian A.A., Tomasheva A.O., Galankin T.L., Kolbin A.S. Clinical Trials in Pediatrics and Neonatology: Reasons for Ups and Downs. Pediatric pharmacology. 2016;13(3):232-238. (In Russ.) https://doi.org/10.15690/pf.v13i3.1572
Views:
1223
Email this article 