When ethics constrains clinical research: Trial design of control arms in "greater than minimal risk" pediatric trials

Human Gene Therapy

Volumn 22, Issue 9, 2011, Pages 1121-1127

  De Melo Martín, Inmaculada ^a   Sondhi, Dolan ^a   Crystal, Ronald G ^a  

^a WEILL CORNELL MEDICAL COLLEGE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CEROID;

ARTICLE; CENTRAL NERVOUS SYSTEM; CONSTRAINT INDUCED THERAPY; GENE TRANSFER; HUMAN; KNOWLEDGE; LIPOFUSCINOSIS; MEDICAL RESEARCH;

ANIMALS; BIOMEDICAL RESEARCH; CENTRAL NERVOUS SYSTEM; CHILD; CONTROLLED CLINICAL TRIALS AS TOPIC; GENE THERAPY; HUMANS; NEURONAL CEROID-LIPOFUSCINOSES; PEDIATRICS; RESEARCH DESIGN; RESEARCH SUBJECTS; TRANSDUCTION, GENETIC;

EID: 80052972993     PISSN: 10430342     EISSN: 15577422     Source Type: Journal    
DOI: 10.1089/hum.2010.230     Document Type: Article

References (74)

1. Agoritsas, T., Deom, M., and Perneger, T.V. (2011). Study design attributes influenced patients' willingness to participate in clinical research: a randomized vignette-based study. J. Clin. Epidemiol. 64, 107-115.
2. Anonymous. (2010). The needs of the few. Nature 466, 160.
3. Arkin, L.M., Sondhi, D., Worgall, S., et al. (2005). Confronting the issues of therapeutic misconception, enrollment decisions, and personal motives in genetic medicine-based clinical research studies for fatal disorders. Hum. Gene Ther. 16, 1028-1036. (Pubitemid 41324562)
4. Bentley, J.P., and Thacker, P.G. (2004). The influence of risk and monetary payment on the research participation decision making process. J. Med. Ethics 30, 293-298. (Pubitemid 38868081)
5. Buckley, B.M. (2008). Clinical trials of orphan medicines. Lancet 371, 2051-2055. (Pubitemid 351799863)
6. Caplan, A.L. (2008). If it's broken, shouldn't it be fixed? Informed consent and initial clinical trials of gene therapy. Hum. Gene Ther. 19, 5-6. (Pubitemid 351171372)
7. Caplan, A., and Levine, B. (2010). Hope, hype and help: ethically assessing the growing market in stem cell therapies. Am. J. Bioeth. 10, 24-25.
8. Crystal, R.G., Sondhi, D., Hackett, N.R., et al. (2004). Clinical protocol. Administration of a replication-deficient adeno-associated virus gene transfer vector expressing the human CLN2 cDNA to the brain of children with late infantile neu-ronal ceroid lipofuscinosis. Hum. Gene Ther. 15, 1131-1154. (Pubitemid 39552294)
9. Deakin, C.T., Alexander, I.E., Kerridge, I. (2009). Accepting risk in clinical research: is the gene therapy field becoming too risk-averse? Mol. Ther. 17, 1842-1848.
10. Department of Health and Human Services (DHHS). (1991). Protection of Human Subjects. Code of Federal Regulations 45 CFR 46 Subpart D-Additional DHHS Protections for Children Involved as Subjects in Research. (Department of Health and Human Services, National Institutes of Health, Office for Protection from Research Risks, Rockville, MD).
11. Derivan, A.T., Leventhal, B.L., March, J., et al. (2004). The ethical use of placebo in clinical trials involving children. J. Child Adolesc. Psychopharmacol. 14, 169-174. (Pubitemid 38988783)
12. Devereaux, P.J., and Yusuf, S. (2003). The evolution of the randomized controlled trial and its role in evidence-based decision making. J. Intern. Med. 254:105-113. (Pubitemid 36900433)
13. Emanuel, E.J., and Miller, F.G. (2001). The ethics of placebo-controlled trials: a middle ground. N. Engl. J. Med. 345, 915-919.
14. Emanuel, E.J., Wendler, D., and Grady, C. (2000). What makes clinical research ethical? JAMA 283, 2701-2711. (Pubitemid 30337334)
15. Feng, L.R., Maguire-Zeiss, K.A. (2010). Gene therapy in Parkinson's disease: rationale and current status. CNS Drugs. 24, 177-192.
16. Fisher, C.B., Kornetsky, S.Z., and Prentice, E.D. (2007). Determining risk in pediatric research with no prospect of direct benefit: time for a national consensus on the interpretation of federal regulations. Am. J. Bioeth. 7, 5-10. (Pubitemid 46417411)
17. Flynn, J.T. (2003). Ethics of placebo use in pediatric clinical trials: the case of antihypertensive drug studies. Hypertension 42, 865-869. (Pubitemid 37413721)
18. Freedman, B., Weijer, C., and Glass, K.C. (1996). Placebo orthodoxy in clinical research I: empirical and methodological myths. J. Law Med. Ethics 24, 243-251. (Pubitemid 126434957)
19. Glass, K.C., and Binik, A. (2008). Rethinking risk in pediatric research. J. Law Med. Ethics 36, 567-576.
20. Griggs, R.C., Batshaw, M., Dunkle, M., et al. (2009). Rare Diseases Clinical Research Network. Clinical research for rare disease: opportunities, challenges, and solutions. Mol. Genet. Metab. 96, 20-26.
21. Guyatt, G.H., Haynes, R.B., Jaeschke, R.Z., et al. (2000). Users' Guides to the Medical Literature: XXV. Evidence-based medicine: principles for applying the Users' Guides to patient care. Evidence-Based Medicine Working Group. JAMA 284, 1290-1296.
22. Hackett, N.R., Redmond, D.E., Sondhi, D., et al. (2005). Safety of direct administration of AAV2(CU)hCLN2, a candidate treatment for the central nervous system manifestations of late infantile neuronal ceroid lipofuscinosis, to the brain of rats and nonhuman primates. Hum. Gene Ther. 16, 1484-1503. (Pubitemid 41829023)
23. Haltia, M. (2003).The neuronal ceroid-lipofuscinoses. J. Neuro-pathol. Exp. Neurol. 62, 1-13. (Pubitemid 36068888)
24. Horng, S., and Miller, F.G. (2002). Is placebo surgery unethical? N. Engl. J. Med. 347, 137-139. (Pubitemid 34753486)
25. Howson, C., and Urbach, P.M. (1993). Scientific Reasoning-The Bayesian Approach. 2nd ed. (Open Court, Chicago and La Salle).
26. Iltis, A. (2007). Pediatric research posing a minor increase over minimal risk and no prospect of direct benefit: challenging 45 CFR 46.406. Account Res. 14, 19-34.
27. Janson, C., McPhee, S., Bilaniuk, L., et al. (2002). Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain. Hum Gene Ther. 13, 1391-1412. (Pubitemid 35034518)
28. Kimmelman, J. (2008).The ethics of human gene transfer. Nat. Rev. Genet. 9, 239-244. (Pubitemid 351271801)
29. Kipnis, K. (2003). Seven vulnerabilities in the pediatric research subject. Theor. Med. Bioeth. 24, 107-120. (Pubitemid 36966179)
30. Kopelman, L.M. (2004). What conditions justify risky nonthera-peutic or "no benefit" pediatric studies: a sliding scale analysis. J. Law Med. Ethics 32, 749-758. (Pubitemid 40238823)
31. Kulynych, J., and Korn, D. (2002). The effect of the new federal medical-privacy rule on research. N. Engl. J. Med. 346, 201-204. (Pubitemid 34438889)
32. Lantos, J.D. (2007). Research in wonderland: does "minimal risk" mean whatever an institutional review board says it means? Am. J. Bioeth. 7, 11-12. (Pubitemid 46417412)
33. Litton, P. (2008). Non-beneficial pediatric research and the best interests standard: a legal and ethical reconciliation. Yale J. Health Policy Law Ethics 8, 359-420.
34. London, A.J., and Kadane, J.B. (2002). Placebos that harm: sham surgery controls in clinical trials. Stat. Methods Med. Res. 11, 413-427.
35. Lynch, H.F. (2007). Give them what they want? The permissibility of pediatric placebo-controlled trials under the best pharmaceuticals for children act. Ann. Health Law 16, 79-138.
36. Macklin, R. (1999).The ethical problems with sham surgery in clinical research. N. Engl. J. Med. 341, 992-996.
37. Martin, R.A., and Robert, J.S. (2007). Is risky pediatric research without prospect of direct benefit ever justified? Am. J. Bioeth. 7, 12-15. (Pubitemid 46417413)
38. Meldrum, M.L. (2000). A brief history of the randomized controlled trial. From oranges and lemons to the gold standard. Hematol. Oncol. Clin. North Am. 14, 745-760, vii.
39. Miller, F.G. (2003). Sham surgery: an ethical analysis. Am. J. Bioethics. 3, 41-48.
40. Miller, F.G., and Brody, H. (2002). What makes placebo-controlled trials unethical? Am. J. Bioeth. 2, 3-9.
41. Miller, F.G., Wendler, D., and Wilfond, B. (2003). When do the federal regulations allow placebo-controlled trials in children? J. Pediatr. 142, 102-107. (Pubitemid 36232895)
42. Mitsumoto, J., Dorsey, E.R., Beck, C.A., Kieburtz, K., and Griggs, R.C. (2009). Pivotal studies of orphan drugs approved for neurological diseases. Ann. Neurol. 66, 184-190.
43. Mole, S.E., and Williams R.E. (2001). Neuronal ceroid-lipofusci-noses. In GeneReviews. R.A. Pagon, T.C. Bird, C.R. Dolan, and K. Stephen, eds, Available at www.ncbi.nlm.nih.gov/books/NBK1428/(accessed August 2010).
44. Morton, N.S. (2008). Injection pain due to propofol in children and the ethics of placebo. Br. J. Anaesth. 101, 878-879.
45. Mueller, C., Flotte, T.R. (2008). Clinical gene therapy using re-combinant adeno-associated virus vectors. Gene Ther. 15, 858-863. (Pubitemid 351712619)
46. National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (NCPHSBBR). (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. (U.S. Government Printing Office, Washington, DC).
47. Orentlicher, D. (2005). Making research a requirement of treatment: why we should sometimes let doctors pressure patients to participate in research. Hastings Center Rep. 35, 20-28. (Pubitemid 43167977)
48. Passini, M.A., Dodge, J.C., Bu, J., et al. (2006). Intracranial delivery of CLN2 reduces brain pathology in a mouse model of classical late infantile neuronal ceroid lipofuscinosis. J. Neu-rosci. 25, 1334-1342. (Pubitemid 43237004)
49. Polgar, S., and Ng, J. (2005). Ethics, methodology and the use of placebo controls in surgical trials. Brain Res. Bull. 67, 290-297. (Pubitemid 41354778)
50. Qiu, J. (2009). Trading on hope. Nat. Biotechnol. 27, 790-792.
51. Robinson, E.J., Kerr, C.E., Stevens, A.J., et al. (2005). Lay public's understanding of equipoise and randomisation in randomised controlled trials. Health Technol. Assess. 9, 1-192, iii-iv.
52. Sackett, D.L., Rosenberg, W.M., Gray, J.A., et al. (1996). Evidence based medicine: what it is and what it isn't. BMJ 312, 71-72.
53. Sadelain, M., Rivière, I., Wang, X., et al. (2010). Strategy for a multicenter phase I clinical trial to evaluate globin gene transfer in beta-thalassemia. Ann. N. Y. Acad. Sci. 1202, 52-58.
54. Shilling, V., and Young, B. (2009). How do parents experience being asked to enter a child in a randomised controlled trial? BMC Med. Ethics 10:1.
55. Simonelli, F., Maguire, A.M., Testa, F., et al. (2010). Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration. Mol. Ther. 18, 643-650.
56. Sondhi, D., Peterson, D.A., Giannaris, E.L., et al. (2005). AAV2-mediated CLN2 gene transfer to rodent and non-human primate brain results in long-term TPP-I expression compatible with therapy for LINCL. Gene Ther. 12, 1618-1632. (Pubitemid 41670352)
57. Sondhi, D., Hackett, N.R., Peterson, D.A., et al. (2007). Enhanced survival of the LINCL mouse following CLN2 gene transfer using the rh.10 rhesus macaque-derived adeno-associated virus vector. Mol Ther. 15, 481-91.
58. Souweidane, M.M., Fraser, J.F., Arkin, L.M., et al. (2010). Gene therapy for late infantile neuronal ceroid lipofuscinosis: neu-rosurgical considerations. J. Neurosurg. Pediatr. 6, 115-122.
59. Urbach, P.M. (1985). Randomization and the design of experiments. Philos. Sci. 52, 256-273.
60. Vines, D.J., and Warburton, M.J. (1999). Classical late infantile neuronal ceroid lipofuscinosis fibroblasts are deficient in ly-sosomal tripeptidyl peptidase I. FEBS Lett. 443, 131-135. (Pubitemid 29078617)
61. Weijer, C. (2002). I need a placebo like I need a hole in the head. J. Law Med. Ethics 30, 69-72. (Pubitemid 39277859)
62. Weleber, R.G. (1998). The dystrophic retina in multisystem disorders: the electroretinogram in neuronal ceroid lipofusci-noses. Eye 12, 580-590. (Pubitemid 28356668)
63. Wendler, D., and Emanuel, E.J. (2005). What is a "minor" increase over minimal risk? J. Pediatr. 147, 575-578. (Pubitemid 41598326)
64. Williams, D.A. (2009). Gene therapy continues to mature and to face challenges. Mol. Ther. 17, 1305-1306.
65. Williams, R.E., Gottlob, I., Lake, B.D., et al. (1999). CLN 2: classic late infantile NCL. In The Neuronal Ceroid Lipofuscinoses (Batten Disease). H.H. Goebel, S.E. Mole, and B.D. Lake, eds. (IOS Press, Amsterdam, the Netherlands), pp. 37-54.
66. Wilson, J.M. (2009). Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol. Genet. Metab. 96, 151-157.
67. Wisniewski, K.E., Kida, E., Golabek, A.A., et al. (2001). Neuronal ceroid lipofuscinoses: classification and diagnosis. Adv. Genet. 45, 1-34.
68. Worgall, S., Kekatpure, M.V., Heier, L., et al. (2007). Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology 69, 521-535. (Pubitemid 47357259)
69. Worgall, S., Sondhi, D., Hackett, N.R., et al. (2008). Treatment of late infantile neuronal ceroid lipofuscinosis by CNS administration of a serotype 2 adeno-associated virus expressing CLN2 cDNA. Hum. Gene Ther. 19, 463-474. (Pubitemid 351748791)
70. World Medical Association (WMO). (2000). Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 284, 3043-3045.
71. Worrall, J. (2002). What evidence in evidence-based medicine? Philos. Sci. 69, S316-330.
72. Worrall, J. (2008). Evidence and ethics in medicine. Perspect. Biol. Med. 51, 418-431.
73. Worrall, J. (2010). Evidence: philosophy of science meets medicine. J. Eval. Clin. Pract. 16, 356-362.
74. Zarzeczny, A., and Caulfield, T. (2010). Stem cell tourism and doctors' duties to minors-a view from Canada. Am. J. Bioeth. 10, 3-15.