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Accountability in Research
Ethics, Integrity and Policy
Volume 15, 2008 - Issue 3
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Original Articles

Clinical Trials of Drugs Used Off-Label in Neonates: Ethical Issues and Alternative Study Designs

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Pages 168-187 | Published online: 08 Jul 2008

References

  • Ahlfors , C.E. 2001 . Benzyl alcohol, kernicterus, and unbound bilirubin . J Pediatr , 139 ( 2 ) : 317 – 319 .
  • Ambalavanan , N. and Whyte , R.K. 2003 . The mismatch between evidence and practice. Common therapies in search of evidence . Clin Perinatol , 30 ( 2 ) : 305 – 331 .
  • Amdur , R.J. and Biddle , C.J. 2001 . An algorithm for evaluating the ethics of a placebo-controlled trial . Int J Cancer , 96 ( 5 ) : 261 – 269 .
  • American Academy of Pediatrics Committee on Drugs (AAPCD) . 1995 . Guidelines for the ethical conduct of studies to evaluate drugs in pediatric populations . Pediatrics , 95 ( 2 ) : 286 – 294 .
  • American Academy of Pediatrics Committee on Drugs (AAPCD) . 1996 . Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: Subject review . Pediatrics , 98 ( 1 ) : 143 – 145 .
  • Avenel , S. , Bomkratz , A. , Dassieu , G. , Janaud , J.C. and Danan , C. 2000 . The incidence of prescriptions without marketing product license in a neonatal intensive care unit . Arch Pediatr , 7 ( 2 ) : 143 – 147 .
  • Banner , W. Jr. 2002 . Off label prescribing in children . Bmj , 324 ( 7349 ) : 1290 – 1291 .
  • Barker , D.J. 2004 . The developmental origins of chronic adult disease . Acta Paediatr Suppl , 93 ( 446 ) : 26 – 33 .
  • Report , Belmont . 1979 . Protection of human subjects: Belmont Report—Ethical principles and guidelines for the protection of human subjects of research . Fed Regist , 44 ( 76 ) : 23192 – 23197 .
  • Berg , J. 2005 . Children and Placebo. Ethics and Research with Children, a Case-Based Approach , Edited by: Kodish , E. Oxford : Oxford University Press .
  • Best Pharmaceuticals for Children Act (BPCA) (2003). 2003 list of drugs for which studies are needed according to Best Pharmaceuticals for Children Act. http://www.fda.gov/cder/pediatric/presentation/ac3-03sm
  • Blumer , J.L. 1999 . Off-label uses of drugs in children . Pediatrics , 104 ( 3 Pt 2 ) : 598 – 602 .
  • Buchanan , D. and Miller , F.G. 2005 . Principles of early stopping of randomized trials for efficacy: a critique of equipoise and an alternative nonexploitation ethical framework . Kennedy Inst Ethics J , 15 ( 2 ) : 161 – 78 .
  • Clark , P.I. and Leaverton , P.E. 1994 . Scientific and ethical issues in the use of placebo controls in clinical trials . Annu Rev Public Health , 15 : 19 – 38 .
  • Coad , D. S. and Ivanova , A. 2005 . The use of the triangular test with response-adaptive treatment allocation . Stat Med , 24 ( 10 ) : 1483 – 93 .
  • Coad , D. S. and Rosenberger , W.F. 1999 . A comparison of the randomized play-the-winner rule and the triangular test for clinical trials with binary responses . Stat Med , 18 ( 7 ) : 761 – 9 .
  • Cooper , W. O. , Griffin , M.R. , Arbogast , P. , Hickson , G.B. , Gautam , S. and Ray , W.A. 2002 . Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis . Arch Pediatr Adolesc Med , 156 ( 7 ) : 647 – 50 .
  • Cuzzolin , L. , Zaccaron , A. and Fanos , V. 2003 . Unlicensed and off-label uses of drugs in paediatrics: a review of the literature . Fundam Clin Pharmacol , 17 ( 1 ) : 125 – 31 .
  • D'Agostino , R. B. Sr. , Massaro , J.M. and Sullivan , L.M. 2003 . Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics . Stat Med , 22 ( 2 ) : 169 – 86 .
  • Djulbegovic , B. and Clarke , M . 2001 . Scientific and ethical issues in equivalence trials . Jama , 285 ( 9 ) : 1206 – 8 .
  • Ellenberg , S. S. and Temple , R . 2000 . Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 2: practical issues and specific cases . Ann Intern Med , 133 ( 6 ) : 464 – 70 .
  • Emanuel , E. J. , Wendler , D. and Grady , C. 2000 . What makes clinical research ethical? . Jama , 283 ( 20 ) : 2701 – 11 .
  • Ferriman , A. 2001 . World Medical Association clarifies rules on placebo controlled trials . Bmj , 323 ( 7317 ) : 825
  • Field , M. and Behrman , R. 2004 . Ethical conduct of clinical research involving children , Washington, DC : The National Academics Press .
  • Food and Drug Administration (FDA) . 1996 . Protection of human subjects; informed consent–FDA. Final rule . Fed Regist , 61 ( 192 ) : 51498 – 533 .
  • Food and Drug Administration (FDA) . 1997 . Investigational new drug application; exception from informed consent; technical amendment–FDA. Final rule . Fed Regist , 62 ( 115 ) : 32479
  • Food and Drug Administration (FDA) Modernization Act of 1997. (1998). FDA internet index of pediatric issues: FDAMA, 1998 final rule, label changes, exclusivity.
  • Food and Drug Administration (FDA) . 1998 . Regulations requiring manufacturers to assess the safety and effectiveness of new drugs and biological products in pediatric patients–FDA. Final rule . Fed Regist , 63 ( 231 ) : 66631 – 72 .
  • Freedman , B. 1987 . Equipoise and the ethics of clinical research . N Engl J Med , 317 ( 3 ) : 141 – 5 .
  • Gomberg-Maitland , M. , Frison , L. and Halperin , J.L. 2003 . Active-control clinical trials to establish equivalence or noninferiority: methodological and statistical concepts linked to quality . Am Heart J , 146 ( 3 ) : 398 – 403 .
  • Griffin , J. P. 2000 . Prepulsid withdrawn from UK & US markets . Adverse Drug React Toxicol Rev , 19 ( 3 ) : 177
  • Halliday , H. L. and Ehrenkranz , R.A. 2000 . Moderately early (7–14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants . Cochrane Database Syst Rev , : CD001144
  • Harth , S. C. and Thong , Y.H. 1995 . Parental perceptions and attitudes about informed consent in clinical research involving children . Soc Sci Med , 40 ( 11 ) : 1573 – 7 .
  • Henderson-Smart , D. J. and Steer , P. 2000 . Doxapram versus methylxanthine for apnea in preterm infants . Cochrane Database Syst Rev , 4 : CD000075
  • Horng , S. and Miller , F.G. 2003 . Ethical framework for the use of sham procedures in clinical trials . Crit Care Med , 31 ( 3 Suppl ) : S126 – 30 .
  • Hyman , S. E. and Shore , D. 2000 . An NIMH perspective on the use of placebos. National Institute of Mental Health . Biol Psychiatry , 47 ( 8 ) : 689 – 91 .
  • International Conference on Harmonization (ICH) . 2001 . Choice of control group and related issues in clinical trials; availability. Notice . Fed Regist , 66 ( 93 ) : 24390 – 1 .
  • Kearns , G. L. , Abdel-Rahman , S.M. , Alander , S.W. , Blowey , D.L. , Leeder , L.S. and Kauffman , R.E. 2003 . Developmental pharmacology–drug disposition, action, and therapy in infants and children . N Engl J Med , 349 ( 12 ) : 1157 – 67 .
  • Knight , M. 1994 . Adverse drug reactions in neonates . J Clin Pharmacol , 34 ( 2 ) : 128 – 35 .
  • Lorenz , J. M. and Paneth , N . 2003 . When are observational studies adequate to assess the efficacy of therapeutic interventions? . Clin Perinatol , 30 ( 2 ) : 269 – 83 .
  • Manning , D. J. 2000 . Presumed consent in emergency neonatal research . J Med Ethics , 26 ( 4 ) : 249 – 53 .
  • Morley , C. 1997 . Informed consent in medical research. Consent is not always practical in emergency treatments . Bmj , 314 ( 7092 ) : 1480
  • Nelson , R. 2005 . Including children in research: participation or exploitation? Ethics and the pharmaceutical industry , Cambridge : Cambridge University Press .
  • O'Donnell , C. P. , Stone , R.J. and Morley , C.J. 2002 . Unlicensed and off-label drug use in an Australian neonatal intensive care unit . Pediatrics , 110 ( 5 ) : e52
  • Osborn , D. A. 2005 . Diagnosis and treatment of preterm transitional circulatory compromise . Early Hum Dev , 81 ( 5 ) : 413 – 22 .
  • Palmer , C. R. and Rosenberger , W.F. 1999 . Ethics and practice: alternative designs for phase III randomized clinical trials . Control Clin Trials , 20 ( 2 ) : 172 – 86 .
  • Perlman , J. M. 2006 . Summary proceedings from the neurology group on hypoxic-ischemic encephalopathy . Pediatrics , 117 ( 3 Pt 2 ) : S28 – 33 .
  • Report and Recommendations of the National Bioethics Advisory Commission (2001). Ethical and Policy Issues in Research involving Human Participants. http://bioethics.georgetown.edu/nbac/overvoll.html (Accessed: August 2001 ).
  • Roberts , R. , Rodriguez , W. , Murphy , D. and Crescenzi , T. 2003 . Pediatric drug labeling: improving the safety and efficacy of pediatric therapies . Jama , 290 ( 7 ) : 905 – 11 .
  • Rogers , C. G. , Tyson , J.E. , Kennedy , K.A. , Broyles , R.S. and Hickman , J.F. 1998 . Conventional consent with opting in versus simplified consent with opting out: an exploratory trial for studies that do not increase patient risk . J Pediatr , 132 ( 4 ) : 606 – 11 .
  • Rosenberger , W. F. 1999 . Randomized play-the-winner clinical trials: review and recommendations . Control Clin Trials , 20 ( 4 ) : 328 – 42 .
  • Roth , S. J. , Adatia , I. and Pearson , G.D. 2006 . Summary proceedings from the cardiology group on postoperative cardiac dysfunction . Pediatrics , 117 ( 3 Pt 2 ) : S40 – 6 .
  • Rothman , K. J. and Michels , K.B. 1994 . The continuing unethical use of placebo controls . N Engl J Med , 331 ( 6 ) : 394 – 8 .
  • Schmidt , B. , Roberts , R.S. , Davis , P. , Doyle , L.W. , Barrington , K.K. , Ohlsson , A. , Solimano , A. and Tin , W. 2006 . Caffeine therapy for apnea of prematurity . N Engl J Med , 354 ( 20 ) : 2112 – 21 .
  • Shamoo , A.E. 2006 . Letter to the Editor: Emergency research consent waiver- a proper way . Am J Bioeth , 6 ( 4 ) : W48 – W51 .
  • Short , B. L. , Van Meurs , K. and Evans , J.R. 2006 . Summary proceedings from the cardiology group on cardiovascular instability in preterm infants . Pediatrics , 117 ( 3 Pt 2 ) : S34 – 9 .
  • Snowdon , C. , Garcia , J. and Elbourne , D. 1997 . Making sense of randomization; responses of parents of critically ill babies to random allocation of treatment in a clinical trial . Soc Sci Med , 45 ( 9 ) : 1337 – 55 .
  • Steinbrook , R. 2002 . Testing medications in children . N Engl J Med , 347 ( 18 ) : 1462 – 70 .
  • Subhedar , N. V. and Shaw , N.J. 2003 . Dopamine versus dobutamine for hypotensive preterm infants . Cochrane Database Syst Rev , 3 : CD001242
  • t Jong , G. W. , Eland , I.A. , Sturkenboom , M.C. , van den Anker , J.N. and Strickerf , B.H. 2004 . Unlicensed and off-label prescription of respiratory drugs to children . Eur Respir J , 23 ( 2 ) : 310 – 3 .
  • Temple , R. and Ellenberg , S.S. 2000 . Placebo-controlled trials and active-control trials in the evaluation of new treatments. Part 1: ethical and scientific issues . Ann Intern Med , 133 ( 6 ) : 455 – 63 .
  • United States. Congress. Senate. Committee on Health Education Labor and Pensions. (2001). Best Pharmaceuticals for Children Act : report (to accompany S. 838). [Washington, D.C., U.S. G.P.O.
  • Ward , R. M. 2006 . Drug disposition in the late preterm (“near-term”) newborn . Semin Perinatol , 30 ( 1 ) : 48 – 51 .
  • Whitehead , J. 1997 . The Design and Analysis of Sequential Clinical Trials, , 2nd , Chichester : Wiley .
  • World Medical Association (WMA) . 1994 . Declaration of Helsinki. Recommendations guiding physicians in biomedical research involving human subjects . J Med Liban , 42 ( 2 ) : 88 – 9 .
  • World Medical Association (WMA) . 2002 . Declaration of Helsinki. Ethical principles for medical research involving human subjects . Nurs Ethics , 9 ( 1 ) : 105 – 9 .

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