Clinical trials in children

British Journal of Clinical Pharmacology

Volumn 79, Issue 3, 2015, Pages 357-369

  Joseph, Pathma D ^a   Craig, Jonathan C ^b   Caldwell, Patrina H Y ^a  

^a UNIVERSITY OF SYDNEY   (Australia)

^b UNIVERSITY OF SYDNEY   (Australia)

Author keywords

Clinical trials; Ethics; Medicines in children; Paediatric drug therapy

Indexed keywords

ARTICLE; BENEFICENCE; BLOOD SAMPLING; CHILD; CHILD HEALTH; CHILD SAFETY; CLINICAL PRACTICE; CLINICAL TRIAL (TOPIC); COMPENSATION; CONFLICT OF INTEREST; DRUG DOSAGE FORM; DRUG EFFICACY; DRUG FORMULATION; DRUG INDUSTRY; DRUG SAFETY; EVIDENCE BASED PRACTICE; FUNDING; HEALTH CARE POLICY; HEALTH PERSONNEL ATTITUDE; HUMAN; INFORMED CONSENT; JUSTICE; LAW; MEDICAL SOCIETY; MEDICATION COMPLIANCE; NON MALEFICENCE; OUTCOME ASSESSMENT; PARENT; PARENTAL CONSENT; PATENT; PATIENT PARTICIPATION; PEDIATRICS; PHARMACOGENOMICS; PHARMACOKINETICS; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); POSTMARKETING SURVEILLANCE; PRIORITY JOURNAL; PROFESSIONAL STANDARD; PUBLICATION; QUALITY OF LIFE; RANDOMIZATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REGISTRATION; REIMBURSEMENT; RESEARCH ETHICS; SAMPLE SIZE; STUDY DESIGN; WELLBEING; DRUG SCREENING; ETHICS; MEDICAL ETHICS; METHODOLOGY; PROCEDURES;

NEW DRUG;

CHILD; CLINICAL TRIALS AS TOPIC; DRUG EVALUATION; DRUGS, INVESTIGATIONAL; ETHICS, MEDICAL; HUMANS; PEDIATRICS; RESEARCH DESIGN;

EID: 84929993788     PISSN: 03065251     EISSN: 13652125     Source Type: Journal    
DOI: 10.1111/bcp.12305     Document Type: Article

References (158)

1. Wilson JT,. An update on the therapeutic orphan. Pediatrics 1999; 104: (Suppl. 3): 585-590.
2. Shirkey H,. Therapeutic orphans. J Pediatr 1968; 72: 119-120.
3. Shirkey H,. Editorial comment: therapeutic orphans. J Pediatr 1999; 104: 583-584.
4. Sammons H, Gray C, Hudson H, Cherrill J, Choonara I,. Safety in paediatric clinical trials-a 7-year review. Acta Paediatr 2008; 97: 474-477.
5. Klassen TP, Hartling L, Hamm M, van der Lee JH, Ursum J, Offringa M,. StaR Child Health: an initiative for RCTs in children. Lancet 2009; 374: 1310-1312.
6. Smyth RL,. Making a difference: the clinical research programme for children. Arch Dis Child 2007; 92: 835-837.
7. Schreiner MS,. Paediatric clinical trials: redressing the imbalance. Nat Rev Drug Discov 2003; 2: 949-961.
8. Dawson L,. The Salk Polio Vaccine Trial of 1954: risks, randomization and public involvement in research. Clin Trials 2004; 1: 122-130.
9. Juskewitch JE, Tapia CJ, Windebank AJ,. Lessons from the Salk Polio Vaccine: methods for and risks of rapid translation. Clin Transl Sci 2010; 3: 182-185.
10. Macy ME, Sawczyn KK, Garrington TP, Graham DK, Gore L,. Pediatric developmental therapies: interesting new drugs now in early-stage clinical trials. Curr Oncol Rep 2008; 10: 477-490.
11. Pritchard-Jones K, Europe S,. Clinical trials for children with cancer in Europe-still a long way from harmonisation: a report from SIOP Europe. Eur J Cancer 2008; 44: 2106-2111.
12. Stiller CA, Kroll ME, Pritchard-Jones K,. Population survival from childhood cancer in Britain during 1978-2005 by eras of entry to clinical trials. Ann Oncol 2012; 23: 1-6.
13. UK Cancer Research. Childhood cancer survival statistics. Section updated 14/11/11. Available at http://www.cancerresearchuk.org/cancer-info/cancerstats/childhoodcancer/survival/ (last accessed 5 August 2013).
14. Martinez-Castaldi C, Silverstein M, Bauchner H,. Child versus adult research: the gap in high-quality study design. Pediatrics 2008; 122: 52-57.
15. Foex BA,. The ethics of clinical trials. Anaesth Intensive Care Med 2009; 10: 98-101.
16. Sinha I, Jones L, Smyth RL, Williamson PR,. A systematic review of studies that aim to determine which outcomes to measure in clinical trials in children. PLoS Med 2008; 5: e96.
17. Klassen TP, Hartling L, Craig JC, Offringa M,. Children are not just small adults: the urgent need for high-quality trial evidence in children. PLoS Med 2008; 5: e172.
18. Saint Raymond A, Brasseur D,. Development of medicines for children in Europe: ethical implications. Paediatr Respir Rev 2005; 6: 45-51.
19. Amann JP, Dulac O,. Trials in children. Epilepsy Res 2001; 45: 133-136; discussion 7-40.
20. Conroy S, McIntyre J, Choonara I, Stephenson T,. Drug trials in children: problems and the way forward. Br J Clin Pharmacol 2000; 49: 93-97.
21. Rocchi F, Tomasi P,. The development of medicines for children. Part of a series on Pediatric Pharmacology, guest edited by Gianvincenzo Zuccotti, Emilio Clementi, and Massimo Molteni. Pharmacol Res 2011; 64: 169-175.
22. Canadian Paediatric Society. Drug investigation for Canadian children: the role of the Canadian Paediatric Society. Review. 2003 Apr. Report No.: 1205-7088 Contract No.: 4.
23. Contopoulos-Ioannidis DG, Baltogianni MS, Loannidis JPA,. Comparative effectiveness of medical interventions in adults versus children. J Pediatr 2010; 157: 322-330.
24. Noah B,. Just a spoonful of sugar: drug safety for pediatric populations. J Law Med Ethics 2009; 37: 280-291.
25. Pandolfini C, Bonati M, Sammons HM,. Registration of trials in children: update of current international initiatives. Arch Dis Child 2009; 94: 717-719.
26. Institute of Medicines of the National Academies: Committee on Clinical Research Involving Children. The Ethical Conduct of Clinical Research Involving Children. Washington, DC: The National Academies Press, 2004.
27. Ackerman TF,. The ethics of drug research in children. Paediatr Drugs 2001; 3: 29-41.
28. Christensen ML, Helms RA, Chesney RW,. Is pediatric labeling really necessary? Pediatrics 1999; 104: (Suppl. 3): 593-597.
29. Burns LE, Hodgman JE, Cass AB,. Fatal circulatory collapse in premature infants receiving chloramphenicol. N Engl J Med 1959; 261: 1318-1321.
30. Balistreri WF, Farrell MK, Lessons BKE,. From the E-ferol tragedy. Pediatrics 1986; 78: 503-506.
31. Curran WJ,. The thalidomide tragedy in Germany: the end of a historic medicolegal trial. N Engl J Med 1971; 284: 481-482.
32. Cohen E, Uleryk E, Jasuja M, Parkin PC,. An absence of pediatric randomized controlled trials in general medical journals, 1985-2004. J Clin Epidemiol 2007; 60: 118-123.
33. The World Bank. Population ages 0-14 (% of total). The United Nations population division's world population prospects. 2011. Available at http://data.worldbank.org/indicator/SP.POP.0014.TO.ZS/countries/1W?display=default (last accessed 30 May 2013).
34. Joseph DP, Caldwell PHY, Craig JC,. Registered paediatric clinical trials: a global context. Poster presentation International Congress of Pediatrics 2013 (ICP), The 27th Congress of International Pediatric Association 24-29 August 2013 Melbourne, Australia. 2013.
35. Bourgeois FT, Murthy S, Pinto C, Olson KL, Ioannidis JP, Mandl KD,. Pediatric versus adult drug trials for conditions with high pediatric disease burden. Pediatrics 2012; 130: 285-292.
36. Mathers C,. Global burden of disease among women, children, and adolescents. In: Maternal and Child Health, ed, Ehiri JE,. New York, NY: Springer Science, Business Media, LLC, 2009; 19-42.
37. Hoppu K,. Can we get the necessary clinical trials in children and avoid the unnecessary ones? Eur J Clin Pharmacol 2009; 65: 747-748.
38. Aripin KNBN, Choonara I, Sammons HM,. A systematic review of paediatric randomised controlled drug trials published in 2007. Arch Dis Child 2010; 95: 469-473.
39. Salazar JC,. Pediatric clinical trial experience: government, child, parent and physician's perspective. Pediatr Infect Dis J 2003; 22: 1124-1127.
40. Sammons HM, Choonara I,. Clinical trials of medication in children 1996-2002. Eur J Clin Pharmacol 2005; 61: 165-167.
41. Aripin KNBN, Choonara I, Sammons HM,. Published paediatric randomized drug trials in developing countries, 1996-2002. Paediatr Drugs 2010; 12: 99-103.
42. Thomson D, Hartling L, Cohen E, Vandermeer B, Tjosvold L, Klassen TP,. Controlled trials in children: quantity, methodological quality and descriptive characteristics of pediatric controlled trials published 1948-2006. PLoS ONE 2010; 5: e13106.
43. Karlberg JPE,. Clinical trials in paediatrics. In: Textbook in Clinical Trials, eds, Machin D, Day S, Green S,. Chichester: John Wiley and Sons, Ltd, 2006; 701-710.
44. Hill P,. Off licence and off label prescribing in children: litigation fears for physicians. Arch Dis Child 2005; 90 (Suppl. I): i17-18.
45. Caldwell PHY, Murphy SB, Butow PN, Craig JC,. Clinical trials in children. Lancet 2004; 364: 803-811.
46. Krekels EHJ, van den Anker JN, Baiardi P, Cella M, Cheng KY, Gibb DM, Green H, Iolascon A, Jacqz-Aigrain EM, Knibbe CAJ, Santen GWE, van Schaik RHN, Tibboel D, Della Pasqua OE,. Pharmacogenetics and paediatric drug development: issues and consequences to labelling and dosing recommendations. Expert Opin Pharmacother 2007; 8: 1787-1799.
47. Lim A, Cranswick N,. Clinical trials, ethical issues and patient recruitment: an australian perspective. Paediatr Perinat Drug Ther 2003; 5: 183-187.
48. Cohen ERM, O'Neill JM, Joffres M, Upshur REG, Mills E,. Reporting of informed consent, standard of care and post-trial obligations in global randomized intervention trials: a systematic survey of registered trials. Developing World Bioeth 2009; 9: 74-80.
49. National Institute of Health. Glossary of terms for human subjects protection and inclusion issues. 2001. Available at http://grants.nih.gov/grants/peer/tree-glossary.pdf (last accessed 4 August 2013).
50. Australian Government National Health and Medical Research Council and Department of Industry, innovation, science, research and tertiary education. Australian Clinical Trials.Phases of clinical trials. Available at http://www.australianclinicaltrials.gov.au/node/5 (last accessed 5 August 2013).
51. US Food and Drug Administration (FDA). Title 21-food and drugs. Chapter 1-Food and Drug administration, Department of Health and Human Services. Subchapter C- drugs: general, code of federal regulations, volume 4, Revised as of 1 April 2011. Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=201.57 (last accessed 10 May 2013).
52. Aleksa K, Koren G,. Ethical issues in including pediatric cancer patients in drug development trials. Paediatr Drugs 2002; 4: 257-265.
53. European Medicines Agency (EMA). Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. Recommendations of the ad hoc group for the development of implementing Guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. 2008. Available at ftp://ftp.cordis.europa.eu/pub/fp7/docs/ethical-considerations-paediatrics-en.pdf (last accessed 5 August 2013).
54. Bellanti F, Della Pasqua O,. Modelling and simulation as research tools in paediatric drug development. Eur J Clin Pharmacol 2011; 67 (Suppl. 1): 75-86.
55. Shaddy RE, Denne SC, The Committee on Drugs and Committee on Pediatric Research. Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations. Pediatrics 2010; 125: 850.
56. Henschel AD, Rothenberger LG, Boos J,. Randomized clinical trials in children-ethical and methodological issues. Curr Pharm Des 2010; 16: 2407-2415.
57. 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: 76-80.
58. Flynn JT,. Ethics of placebo use in pediatric clinical trials: the case of antihypertensive drug studies. Hypertension 2003; 42: 865-869.
59. Fost N,. Ethical issues in research and innovative therapy in children with mood disorders. Biol Psychiatry 2001; 49: 1015-1022.
60. US Food and Drug Administration. Postmarketing requirements and commitments: Frequently Asked Questions (FAQ). Updated: 02/08/2012. Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Post-marketingPhaseIVCommitments/ucm070766.htm#q15 (last accessed 18 August 2013).
61. Laughon MM, Benjamin DK Jr, Capparelli EV, Kearns GL, Berezny K, Paul IM, Wade K, Barrett J, Smith PB, Cohen-Wolkowiez M,. Innovative clinical trial design for pediatric therapeutics. Expert Rev Clin Pharmacol 2011; 4: 643-652.
62. Johnson TN,. Modelling approaches to dose estimation in children. Br J Clin Pharmacol 2005; 59: 663-669.
63. European Medicines Agency (EMA), Committee for Medicinal Products for Human Use (CHMP). Guideline on the role of pharmacokinetics in the development of medicinal products in the paediatric population. Doc. Ref. EMEA/CHMP/EWP/147013/2004 Corrigendum London, 28 June 2006.
64. Viergever RF, Ghersi D,. The quality of registration of clinical trials. PLoS ONE 2011; 6: 1-8.
65. South African Cochrane Centre. Pan African clinical trials registry (PACTR). Available at http://www.pactr.org (last accessed 9 April 2013).
66. Thomas-Urban KB, Joergensen M, Lynch G, Rubison M, Porter BD, Sayers J, Tesch C,. Clinical trial disclosure: global overview and implications of new laws and guidelines. Drug Inf J 2010; 44: 213-225.
67. International Committee of Medical Journal, ed. Clinical trial registration: a statement from the International Committee of Medical Journal Editors. N Engl J Med 2004; 351: 1250-1251.
68. de Vries TW, van Roon EN,. Low quality of reporting adverse drug reactions in paediatric randomised controlled trials. Arch Dis Child 2010; 95: 1023-1026.
69. Benjamin DK, Smith P, Murphy M, Roberts R, Mathis L, Avant D, Califf RM, Li JS,. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA 2006; 296: 1266-1273.
70. Chalmers I, Glasziou P,. Avoidable waste in the production and reporting of research evidence. Lancet Oncol 2009; 374: 86-89.
71. Cramer K, Wiebe N, Moyer V, Hartling L, Williams K, Swingler G, Klassen TP,. Children in reviews: methodological issues in child-relevant evidence syntheses. BMC Pediatr 2005; 5: 38.
72. Young B, Shilling V, Hickey H, Sowden E, Smyth R, Williamson P,. What parents think about being approached about children's trials, how this differs from what practitioners expect, and what this tells us about enhancing recruitment. Oral presentation: clinical trials methododlogy conference 2011, Bristol UK 4-5 October 2011. Trials. 2011; 12 (Suppl. 1): A116.
73. Morales-Olivas FJ, Morales-Carpi C,. Clinical trials in children. Rev Recent Clin Trials. 2006; 1: 251-258.
74. Deal G, Nikitin N,. European and non-European paediatric clinical trials. Regul Rapportteur 2009; 6: 4-7.
75. Foster BJ, Warady BA,. Clinical research in pediatric nephrology: challenges, and strategies to address them. J Nephrol 2009; 22: 685-693.
76. Bavdekar SB,. Pediatric clinical trials. Perspect Clin Res 2013; 4: 89-99.
77. The Children's Oncology Group (COG). Available at http://www.childrensoncologygroup.org/ (last accessed 2 August 2013).
78. Children's Cancer and Leukaemia Group (CCLG). Available at http://www.cclg.org.uk/ (last accessed 2 August 2013).
79. Paediatric Rheumatology International Trials Organisation (PRINTO). Available at http://www.printo.it/ (last accessed 3 August 2013).
80. Ruperto N, Martini A,. Networking in paediatrics: the example of the Paediatric Rheumatology International Trials Organisation (PRINTO). Arch Dis Child 2011; 96: 596-601.
81. Paediatric European Network for the Treatment of AIDS (PENTA). Available at http://www.pentatrials.org/network.htm (last accessed 5 August 2013).
82. Paediatric Emergency Care Applied Research Network (PECARN). Available at http://www.pecarn.org/ (last accessed 1 August 2013).
83. Shilling V, Young B,. How do parents experience being asked to enter a child in a randomised controlled trial? BMC Med Ethics 2009; 10: 1.
84. Martin K,. Current issues in paediat ric clinical trials. Meeting report. Available at http://www.abpi.org.uk (last accessed 3 October 20136).
85. Singhal N, Oberle K, Burgess E, Huber-Okrainec J,. Parents' perceptions of research with newborns. J Perinatol 2002; 22: 57-63.
86. Woolfall K, Shilling V, Hickey H, Smyth RL, Sowden E, Williamson PR, Young B,. Parents' agendas in paediatric clinical trial recruitment are different from researchers' and often remain unvoiced: a qualitative study. PLoS ONE 2013; 8: e67352.
87. Caldwell PHY, Butow PN, Craig JC,. Parents' attitudes to randomised controlled trials involving children. J Pediatr 2003; 145: 555-560.
88. Caldwell PHY, Hamilton S, Tan A, Craig JC,. Strategies for increasing recruitment to randomised controlled trials: systematic review. PLoS Med 2010; 7: 1-16.
89. Tarnowski KJ, Allen DM, Mayhall C, Kelly PA,. Readability of pediatric biomedical research informed consent forms. Pediatrics 2007; 119: 849-859.
90. Masty J, Fisher C,. A goodness-of-fit approach to informed consent for pediatric intervention research. Ethics Behav 2008; 18: 139-160.
91. Why fair tests are needed. Available at http://www.jameslindlibrary.org/essays/fair-tests/why-fair-tests-are-needed.html (last accessed 2 November 2013).
92. Allmark P, Spedding M,. Clinical trials in neonates: ethical issues. Semin Fetal Neonatal Med 2007; 12: 318-323.
93. Caldwell P, Butow P, Craig J,. Parents' attitudes to children's participation in randomized controlled trials. J Pediatr 2003; 142: 554-559.
94. Snowdon C, Elbourne D, Garcia J,. Zelen randomization: attitudes of parents participating in a neonatal clinical trial. Control Clin Trials 1999; 20: 149-171.
95. Culbert A, Davis DJ,. Parental preferences for neonatal resuscitation research consent: a pilot study. J Med Ethics 2005; 31: 721-726.
96. Abdel-Rahman SM, Reed MD, Wells TG, Kearns GL,. Considerations in the rational design and conduct of phase I/II pediatric clinical trials: avoiding the problems and pitfalls. Clin Pharmacol Ther 2007; 81: 483-494.
97. de Wildt SN, Ito S, Koren G,. Challenges for drug studies in children: CYP3A phenotyping as example. Drug Discov Today 2009; 14: 6-15.
98. Caldwell PHY, Dans L, de Vries MC, Newman J, Sammons H, Spriggs M, Tambe P, Van't Hoff W, Woolfall K, Young B, Offringa M,. Standard 1: consent and recruitment. Pediatrics 2012; 129 (Suppl. 3): S118-123.
99. NHS National Institute for Health Research. Medicines for children research network. Available at http://www.mcrn.org.uk/ (last accessed 12 April 2012).
100. Caldwell PHY, Butow PN, Craig JC,. Paediatricians' attitudes to randomised controlled trials involving children. J Pediatr 2002; 141: 798-803.
101. Wax PM,. Elixirs, diluents, and the passage of the 1938 Federal Food, Drug and Cosmetic Act. Ann Intern Med 1995; 122: 456-461.
102. Ernest TB, Elder DP, Martini LG, Roberts M, Ford JL,. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007; 59: 1043-1055.
103. US Food and Drug Administration (FDA). FDA Amendments Act of 2007 (FDAAA),Title IV: Pediatric Research Equity Act of 2007 (PREA) and Title V: Best Pharmaceuticals for Children Act of 2007 (BPCA). September 27, 2007. (Public Law No. 110-85). Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.htm (last accessed 25 January 2013).
104. World Health Organization. Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children. Geneva: WHO, 2008. Available at http://www.who.int/selection-medicines/committees/expert/17/application/paediatric/Dosage-form-reportDEC2008.pdf (last accessed 12 August 2013).
105. von Baeyer CL,. Children's self-reports of pain intensity: scale selection, limitations and interpretation. Pain Res Manag 2006; 11: 157-162.
106. Ligi I, Boubred F, Grandvuillemin I, Simeoni U,. Clinical research in newborn infants: difficulties and specificity. Eur J Clin Pharmacol 2011; 67 (Suppl. 1): 29-32.
107. Abbott J, Gee L,. Quality of life in children and adolescents with cystic fibrosis: implications for optimizing treatments and clinical trial design. Paediatr Drugs 2003; 5: 41-56.
108. O'Lonergan TA, Milgrom H,. Ethical considerations in research involving children. Curr Allergy Asthma Rep 2005; 5: 451-458.
109. Ross LF, Newburger JW, Sanders SP,. Ethical issues in pediatric trials. Am Heart J 2001; 142: 233-236.
110. Dixon-Woods M, Ashcroft RE, Jackson CJ, Tobin MD, Kivits J, Burton PR, Samani NJ,. Beyond ′misunderstanding′: written information and decisions about taking part in a genetic epidemiology study. Soc Sci Med 2007; 65: 2212-2222.
111. Hirtz DG, Gilbert PR, Terrill CM, Buckman SY,. Clinical trials in children-How are they implemented? Pediatr Neurol 2006; 34: 436-438.
112. Spriggs M, Caldwell P,. The ethics of paediatric research. J Paediatr Child Health 2011; 47: 664-667.
113. Mason SA, Allmark PJ,. Obtaining informed consent to neonatal randomised controlled trials: interviews with parents and clinicians in the Euricon study. Lancet 2000; 356: 2045-2051.
114. World Medical Association. Declaration of Helsinki, 2008. Available at http://www.wma.net/en/30publications/10policies/b3/index.html (last accessed 9 February 2013).
115. Eder M, Yamokoski A, Wittmann P, Kodish E,. Improving informed consent: suggestions from parents of children with leukemia. Pediatrics 2007; 119: e849-859.
116. Davidson AJ, O'Brien M,. Ethics and medical research in children. Paediatr Anaesth 2009; 19: 994-1004.
117. Wendler D, Rackoff JE, Emanuel EJ, Grady C,. The ethics of paying for children's participation in research. J Pediatr 2002; 141: 166-171.
118. Dobson R,. Lump sums for children taking part in research may distort parents' judgment. BMJ 2002; 325: 796.
119. Tishler CL, Reiss NS,. Pediatric drug-trial recruitment: enticement without coercion. Pediatrics 2011; 127: 949-954.
120. Glasser S, Howard G,. Clinical trial design issues: at least 10 things you should look for in clinical trials. J Clin Pharmacol 2006; 46: 1106-1115.
121. United Nations General Assembly. ′Convention on the rights of the child′ Part 1, Article1, A/RES/44/25, 61st plenary meeting. 20 November 1989. Available at http://www.un.org/documents/ga/res/44/a44r025.htm (last accessed 4 April 2013).
122. Tassinari MS, ed. Pediatric Regulations in the US and Europe. Silver Spring, MD: FDA Office of New Drugs, ODAC Pediatric Subcommittee, November 2010. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM236390.pdf (last accessed 1 July 2013).
123. Office of the Secretary: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report: ethical principles and guidelines for the protection of human subjects of research. 18 April 1979. Available at http://science.education.nih.gov/supplements/nih9/bioethics/guide/teacher/Mod5-Belmont.pdf (last accessed 9 July 2013).
124. World Medical Association I. WMA Declaration of Ottawa on child health. Available at http://www.wma.net/en/30publications/10policies/c4/ (last accessed 3 August 2013).
125. The European Agency for the Evaluation of Medicinal Products (EMA). Evaluation of medicines for human use. ICH Topic E11 Clinical Investigation of Medicinal Products in the Paediatric Population. CPMP/ICH/2711/99. 2000: 1-12.
126. US Food and Drug Administration (FDA). Fact sheet: pediatric provisions in the Food and Drug Administration Safety and Innovation Act (FDASIA). 07092012. Available at http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm311038.htm (last accessed 6 July 2013).
127. US Food and Drug Administration. Running clinical trials. Additional protections for children. Last update 08/05/2010. Available at http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ucm119111.htm (last accessed 31 July 2013).
128. National Health and Medical Research Council. Clinical trials. Available at http://www.nhmrc.gov.au/health-ethics/human-research-ethics/clinical-trials (last accessed 10 August 2013).
129. Smit-Marshall P,. Pediatric clinical trials: a worldview. Appl Clin Trials 2010; 19: 32-37.
130. Smyth AR, Barbato A, Beydon N, Bisgaard H, de Boeck K, Brand P, Bush A, Fauroux B, de Jongste J, Korppi M, O'Callaghan C, Pijnenburg M, Ratjen F, Southern K, Spencer D, Thomson A, Vyas H, Warris A, Merkus PJ,. Respiratory medicines for children: current evidence, unlicensed use and research priorities. Eur Respir J 2010; 35: 247-265.
131. Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, Knoeppel C, Seyberth H, Pandolfini C, Raffaelli MP, Rocchi F, Bonati M, Jong G, de Hoog M, van den Anker J,. Survey of unlicenced and off label drug use in paediatric wards in European countries. BMJ 2000; 320: 79-82.
132. Permanand G, Mossialos E, McKee M,. The EU's new paediatric medicines legislation: serving children's needs? Arch Dis Child 2007; 92: 808-811.
133. Sammons H,. Ethical issues of clinical trials in children: a European perspective. Arch Dis Child 2009; 94: 474-477.
134. Greener M,. Bitter medicine. New regulations aim to address the dearth of clinical safety trials for drugs used in children. EMBO Rep 2008; 9: 505-508.
135. European Medicines Agency (EMA). Paediatric regulation. Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document-listing/document-listing-000068.jsp (last accessed 5 August 2013).
136. Li J, Eisenstein E, Grabowski H, Reid E, Mangum B, Schulman K, Goldsmith J, Murphy MD, Califf R, Benjamin D,. Economic return of clinical trials performed under the pediatric exclusivity program. JAMA 2007; 297: 480-488.
137. US Food and Drug Administration (FDA). New pediatric labeling information database. Available at http://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase (last accessed 22 May and 19 July 2013).
138. WHO and StaR Child Health. Report of the WHO and StaR Child Health Paediatric Trials in Developing Countries Meeting: Use of Standards in Paediatric Clinical Trials in Developing Countries Meeting. Amsterdam, The Netherlands: WHO and StaR Child Health, 28 October 2009. Available at http://www.who.int/childmedicines/progress/Amsterdam-Meeting.pdf (last accessed 5 May 2013).
139. US Food and Drug Administration. Database is one-stop resource on kids' medications. Available at http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm305040.htm?source=govdelivery (last accessed 30 May 2012).
140. Boots I, Sukhai RN, Klein RH, Holl RA, Wit JM, Cohen AF, Burggraaf J,. Stimulation programs for pediatric drug research-do children really benefit? Eur J Pediatr 2007; 166: 849-855.
141. Hoppu K, Anabwani G, Garcia-Bournissen F, Gazarian M, Kearns G, Nakamura H, Peterson R, Sri Ranganathan S, Wildt S,. The status of paediatric medicines initiatives around the world-what has happened and what has not? Eur J Clin Pharmacol 2012; 68: 1-10.
142. Flynn JT,. Successes and shortcomings of the Food and Drug Modernization Act. Am J Hypertens 2003; 16: 889-891.
143. World Health Organisation (WHO). Essential medicines for children. Available at http://www.who.int/childmedicines/ (last accessed 12 April 2013).
144. World Health Organisation. Medicines for children:Resources, progress reports and scientific publications: medicines: medicines for children.Fact sheet N°34, 1 June 2010. Available at http://www.who.int/mediacentre/factsheets/fs341/en/index.html (last accessed 9 April 2013).
145. Institute DtM. Pediatric Trials Network funded with $95M NIH grant, has FDA approval to study 4 drugs, now enrolling. Available at https://www.dtmi.duke.edu/news-publications/news/dtmi-news-archives/putting-an-end-to-2018ballpark-dosing2019-in-children (last accessed 20 October 2013).
146. Benjamin D,. Clinical Trials Approach and the Pediatric Trials Network. American Society for Clinical Pharmacology and Therapeutics (ASCPT) conference, 12-17 March 2012. Available at https://pediatrictrials.org/background/ptn-news-papers/ptn-presentations (last accessed 20 October 2013).
147. European Medicines Agency (EMA). Network of paediatric research at the European Medicines Agency (Enpr-EMA). Available at http://www.ema.europa.eu/ema/index.jsp?curl=pages/partners-and
148. The Global Research in Paediatrics (GRIP) network for excellence. Available at http://www.grip-network.org/index.php/cms/en/paediatric-clinical-pharmacology (last accessed 15 August 2011).
149. Star Child Health. Standards for research in child health. Available at http://ifsrc.org/ (last accessed 30 July 2013).
150. Frakking FNJ, Van der Lee JH, Klassen JH, Offringa M, for the StaR-Child Health Group. Report: survey of current guidance for child health clinical trials. The star child health project: standards for research with children. 2009. Available at http://www.who.int/childmedicines/publications/GUIDANCECHILDHEALTH.pdf (last accessed 5 August 2013).
151. Hartling L, Wittmeier KDM, Caldwell P, van der Lee H, Klassen TP, Craig JC, Offringa M, for the StaR Child Health Group. StaR child health: developing evidence-based guidance for the design, conduct, and reporting of pediatric trials. Pediatrics 2012; 129 (Suppl. 3): S112-117.
152. International Pediatric Association. IPA Statement on equity and quality healthcare for children of the world. Fifty-seventh Session of the WHO Regional Committee for the Western Pacific Auckland, New Zealand, 18-22nd September 2006. Agenda Item 7: Report of the Regional Director. Available at http://www.ipa-world.org/uploadedbyfck/WSO-0001.pdf (last accessed 3 August 2013).
153. National Institutes of Health. NIH policy and guidelines on the inclusion of children as participants in Research involving human subjects. 6 March 1998. Available at http://grants.nih.gov/grants/guide/notice-files/not98-024.html (last accessed 10 August 2013).
154. National Institute of Health (NIH) and Child Development (NICHD). Clinical trials & clinical research. Available at http://www.nichd.nih.gov/health/clinicalresearch/ (last accessed 5 July 2013).
155. UK Medical Research Council. MRC ethics guide. Medical research involving children. 2004. Available at http://www.mrc.ac.uk/consumption/idcplg?IdcService=GET-FILE&dID=11512&dDocName=MRC002430&allowInterrupt=1 (last accessed 10 August 2013).
156. Brooke A,. Paediatric clinical research manual. Arch Dis Child 2006; 91: 951-952.
157. Devine S, Dagher RN, Weiss KD, Santana VM,. Good clinical practice and the conduct of clinical studies in pediatric oncology. Pediatr Clin North Am 2008; 55: 187-209, xi-xii.
158. Tunis SR, Stryer DB, Clancy CM,. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003; 290: 1624-1632.