Advertisement

Changes in Drug Development Regulations and Their Impact on Clinical Trials

  • Kevin D. HillEmail author
  • Rachel D. Török
  • Ronald J. Portman
  • Jennifer S. Li
Reference work entry

Abstract

Regulatory changes in the United States and Europe have stimulated major pediatric clinical trials of over 15 different antihypertensive agents over the last two decades. With increased pediatric hypertension trial experience, trial designs have been refined, and we now better understand factors associated with trial success or failure. Appropriate dose range, weight-based dosing, use of a liquid formulation, and use of appropriate blood pressure endpoints are all factors that have been associated with improved trial success. These lessons learned and important modifications in trial design templates are reflected in the United States Food and Drug Administration Written Request criteria. The Written Request provides valuable information that can be used to optimally design future clinical trials of antihypertensive agents as well as other therapeutic agents for use in children.

Keywords

Pediatric hypertension Clinical trials Written Request Pediatric exclusivity Trial design 

References

  1. American Academy of Pediatrics, Committee on Drugs (1977) Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 60:91–101Google Scholar
  2. Batisky DL, Sorof JM, Sugg J et al (2007) Efficacy and safety of extended release metoprolol succinate in hypertensive children 6 to 16 years of age: a clinical trial experience. J Pediatr 150:134–139, 139 e1CrossRefGoogle Scholar
  3. Benjamin DK Jr, Smith PB, Murphy MD et al (2006) Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA 296:1266–1273CrossRefGoogle Scholar
  4. Benjamin DK Jr, Smith PB, Jadhav P et al (2008) Pediatric antihypertensive trial failures: analysis of end points and dose range. Hypertension 51:834–840CrossRefGoogle Scholar
  5. Blowey DL (2012) Update on the pharmacologic treatment of hypertension in pediatrics. J Clin Hypertens (Greenwich) 14:383–387CrossRefGoogle Scholar
  6. Blumer JL, Daniels SR, Dreyer WJ et al (2003) Pharmacokinetics of quinapril in children: assessment during substitution for chronic angiotensin-converting enzyme inhibitor treatment. J Clin Pharmacol 43:128–132CrossRefGoogle Scholar
  7. European Medicines Agency (2016a) Paediatric investigation plans. Accessed at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000293.jsp&mid=WC0b01ac0580025b91. 25 July 2016
  8. European Medicines Agency (2016b) Paediatric-use marketing authorisations. Accessed at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000413.jsp&mid=WC0b01ac0580925c40. 18 Oct 2016
  9. Ferguson MA, Flynn JT (2014) Treatment of pediatric hypertension: lessons learned from recent clinical trials. Curr Cardiovasc Risk Rep 8:399CrossRefGoogle Scholar
  10. Flynn JT (2003) Ethics of placebo use in pediatric clinical trials: the case of antihypertensive drug studies. Hypertension 42:865–869CrossRefGoogle Scholar
  11. Flynn JT, Alderman MH (2005) Characteristics of children with primary hypertension seen at a referral center. Pediatr Nephrol 20:961–966CrossRefGoogle Scholar
  12. Flynn JT, Daniels SR (2006) Pharmacologic treatment of hypertension in children and adolescents. J Pediatr 149:746–754CrossRefGoogle Scholar
  13. Flynn JT, Newburger JW, Daniels SR et al (2004) A randomized, placebo-controlled trial of amlodipine in children with hypertension. J Pediatr 145:353–359CrossRefGoogle Scholar
  14. Flynn JT, Meyers KE, Neto JP et al (2008) Efficacy and safety of the Angiotensin receptor blocker valsartan in children with hypertension aged 1 to 5 years. Hypertension 52:222–228CrossRefGoogle Scholar
  15. Flynn JT, Pierce CB, Miller ER 3rd, Charleston J, Samuels JA, Kupferman J, Furth SL, Warady BA (2012) Chronic kidney disease in children study Group. Reliability of resting blood pressure measurement and classification using an oscillometric device in children with chronic kidney disease. J Pediatr 160(3):434–440CrossRefGoogle Scholar
  16. Full text of European Parliament regulation no. 1901/2006 on medicinal products for paediatric use (2006). Accessed online at: http://ec.europa.eu/health/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. 25 July 2016
  17. Full text of Food and Drug Administration Safety and Innovation Act (2012). Accessed at: http://www.fda.gov/RegulatoryInformation/Legislation/SignificantAmendmentstotheFDCAct/FDASIA/ucm20027187.htm. 16 July 2016
  18. Full text of Pediatric Research Equity Act (2003). Accessed at: http://www.gpo.gov/fdsys/pkg/PLAW-108publ155/html/PLAW-108publ155.htm. 16 July 2016
  19. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Committee on Drugs, American Academy of Pediatrics (1995). Pediatrics 95:286–294Google Scholar
  20. Hammer GB, Lewandowski A, Drover DR et al (2015) Safety and efficacy of sodium nitroprusside during prolonged infusion in pediatric patients. Pediatr Crit Care Med 16:397–403CrossRefGoogle Scholar
  21. Hazan L, Hernandez Rodriguez OA, Bhorat AE, Miyazaki K, Tao B, Heyrman R (2010) A double-blind, dose-response study of the efficacy and safety of olmesartan medoxomil in children and adolescents with hypertension. Hypertension 55:1323–1330CrossRefGoogle Scholar
  22. Li JS, Berezny K, Kilaru R et al (2004) Is the extrapolated adult dose of fosinopril safe and effective in treating hypertensive children? Hypertension 44:289–293CrossRefGoogle Scholar
  23. Li JS, Eisenstein EL, Grabowski HG et al (2007) Economic return of clinical trials performed under the pediatric exclusivity program. JAMA 297:480–488CrossRefGoogle Scholar
  24. Li JS, Flynn JT, Portman R et al (2010) The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension: a randomized, double-blind, dose-response study. J Pediatr 157:282–287CrossRefGoogle Scholar
  25. Meyers KE, Lieberman K, Solar-Yohay S, Han G, Shi V (2011) The efficacy and safety of valsartan in obese and non-obese pediatric hypertensive patients. J Clin Hypertens (Greenwich) 13:758–766CrossRefGoogle Scholar
  26. Pasquali SK, Sanders SP, Li JS (2002) Oral antihypertensive trial design and analysis under the pediatric exclusivity provision. Am Heart J 144:608–614CrossRefGoogle Scholar
  27. Rodriguez W, Selen A, Avant D et al (2008) Improving pediatric dosing through pediatric initiatives: what we have learned. Pediatrics 121:530–539CrossRefGoogle Scholar
  28. Regulation (EC) No 1901/2006 of the European Parliament and of the council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004. http://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2006_1901/reg_2006_1901_en.pdf. Accessed 4 Jan 2016
  29. Sakarcan A, Tenney F, Wilson JT et al (2001) The pharmacokinetics of irbesartan in hypertensive children and adolescents. J Clin Pharmacol 41:742–749CrossRefGoogle Scholar
  30. Schaefer F, van de Walle J, Zurowska A et al (2010) Efficacy, safety and pharmacokinetics of candesartan cilexetil in hypertensive children from 1 to less than 6 years of age. J Hypertens 28:1083–1090CrossRefGoogle Scholar
  31. Schaefer F, Litwin M, Zachwieja J et al (2011) Efficacy and safety of valsartan compared to enalapril in hypertensive children: a 12-week, randomized, double-blind, parallel-group study. J Hypertens 29:2484–2490CrossRefGoogle Scholar
  32. Shahinfar S, Cano F, Soffer BA et al (2005) A double-blind, dose-response study of losartan in hypertensive children. Am J Hypertens 18:183–190CrossRefGoogle Scholar
  33. Skirton H, Chamberlain W, Lawson C, Ryan H, Young E (2011) A systematic review of variability and reliability of manual and automated blood pressure readings. J Clin Nurs 20:602–614CrossRefGoogle Scholar
  34. Smith PB, Li JS, Murphy MD, Califf RM, Benjamin DK Jr (2008) Safety of placebo controls in pediatric hypertension trials. Hypertension 51:829–833CrossRefGoogle Scholar
  35. Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S (2003) A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hypertens 16:795–800CrossRefGoogle Scholar
  36. Sorof JM, Cargo P, Graepel J et al (2002a) Beta-blocker/thiazide combination for treatment of hypertensive children: a randomized double-blind, placebo-controlled trial. Pediatr Nephrol 17:345–350CrossRefGoogle Scholar
  37. Sorof JM, Poffenbarger T, Franco K, Bernard L, Portman RJ (2002b) Isolated systolic hypertension, obesity, and hyperkinetic hemodynamic states in children. J Pediatr 140:660–666CrossRefGoogle Scholar
  38. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents (2004). Pediatrics 114:555–576Google Scholar
  39. Trachtman H, Frank R, Mahan JD et al (2003) Clinical trial of extended-release felodipine in pediatric essential hypertension. Pediatr Nephrol 18:548–553PubMedGoogle Scholar
  40. Trachtman H, Hainer JW, Sugg J, Teng R, Sorof JM, Radcliffe J (2008) Efficacy, safety, and pharmacokinetics of candesartan cilexetil in hypertensive children aged 6 to 17 years. J Clin Hypertens (Greenwich) 10:743–750CrossRefGoogle Scholar
  41. U.S. Food and Drug Administration (2016a) New pediatric labeling information database. Accessed online at: http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase. 25 July 2016
  42. U.S. Food and Drug Administration (2016b) Pediatric product development. Accessed online at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm. 18 Oct 2016
  43. Wells T, Frame V, Soffer B et al (2002) A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharmacol 42:870–880CrossRefGoogle Scholar
  44. Wells TG, Portman R, Norman P, Haertter S, Davidai G, Fei W (2010) Safety, efficacy, and pharmacokinetics of telmisartan in pediatric patients with hypertension. Clin Pediatr (Phila) 49:938–946CrossRefGoogle Scholar
  45. Wells T, Blumer J, Meyers KE et al (2011) Effectiveness and safety of valsartan in children aged 6 to 16 years with hypertension. J Clin Hypertens (Greenwich) 13:357–365CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Kevin D. Hill
    • 1
    • 2
    Email author
  • Rachel D. Török
    • 1
  • Ronald J. Portman
    • 3
  • Jennifer S. Li
    • 1
    • 2
  1. 1.Department of PediatricsDuke Clinical Research InstituteDurhamUSA
  2. 2.Department of PediatricsDuke University Medical CenterDurhamUSA
  3. 3.Pediatric Therapeutic AreaNovartis Pharmaceutical CorporationEast HanoverUSA

Personalised recommendations