Predicting harms and benefits in translational trials: Ethics, evidence, and uncertainty

PLoS Medicine

Volumn 8, Issue 3, 2011, Pages

  Kimmelman, Jonathan ^a   London, Alex John ^b  

^a MCGILL UNIVERSITY   (Canada)

^b CARNEGIE MELLON UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CLINICAL RESEARCH; CLINICAL TRIAL (TOPIC); DECISION MAKING; EVIDENCE BASED MEDICINE; HUMAN; MEDICAL ETHICS; MEDICAL RESEARCH; NOTE; PREDICTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RELIABILITY; RISK BENEFIT ANALYSIS; TREATMENT OUTCOME; VALIDATION STUDY; ARTICLE; DRUG SCREENING; ETHICS; EVIDENCE BASED PRACTICE; FORECASTING; ORGANIZATION AND MANAGEMENT; REPRODUCIBILITY; RESEARCH ETHICS; RISK ASSESSMENT; UNCERTAINTY;

CLINICAL TRIALS AS TOPIC; DRUG EVALUATION, PRECLINICAL; ELIGIBILITY DETERMINATION; ETHICS, RESEARCH; EVIDENCE-BASED PRACTICE; FORECASTING; HUMANS; REPRODUCIBILITY OF RESULTS; RISK ASSESSMENT; UNCERTAINTY;

EID: 79953704023     PISSN: 15491277     EISSN: 15491676     Source Type: Journal    
DOI: 10.1371/journal.pmed.1001010     Document Type: Note

References (49)

1. Kimmelman J, (2010) Gene transfer and the ethics of first-in-human research: lost in translation. Cambridge Cambridge University Press.
2. Extance A, (2010) Alzheimer's failure raises questions about disease-modifying strategies. Nat Rev Drug Discov 9: 749-751.
3. The National Commission for the Protection of Human Subjects of Biomedical and Behavioural Research (1979) The Belmont report: ethical principles and guidelines for the protection of human subjects of research. Bethesda Department of Health Education and Welfare.
4. World Medical Association (1964) Declaration of Helsinki. Helsinki 18th World Medical Assembly.
5. Mann H, (2010) ASSERT: a standard for the review and monitoring of randomized clinical trials. Available: http://www.assert-statement.org/. Accessed 31 January 2011.
6. Department of Health and Human Services (2005) Protection of human subjects: criteria for IRB approval of research. Title 45 CFR 46.111(a)(1) pp. 1-12.
7. London AJ, Kimmelman J, Emborg ME, (2010) Research ethics. Beyond access vs. protection in trials of innovative therapies. Science 328: 829-830.
8. Djulbegovic B, Kumar A, Soares HP, Hozo I, Bepler G, et al. (2008) Treatment success in cancer: new cancer treatment successes identified in phase 3 randomized controlled trials conducted by the National Cancer Institute-sponsored cooperative oncology groups, 1955 to 2006. Arch Intern Med 168: 632-642.
9. Kumar A, Soares H, Wells R, Clarke M, Hozo I, et al. (2005) Are experimental treatments for cancer in children superior to established treatments? Observational study of randomised controlled trials by the Children's Oncology Group. BMJ 331: 1295.
10. Soares HP, Kumar A, Daniels S, Swann S, Cantor A, et al. (2005) Evaluation of new treatments in radiation oncology: are they better than standard treatments? JAMA 293: 970-978.
11. Gross CP, Krumholz HM, Van Wye G, Emanuel EJ, Wendler D, (2006) Does random treatment assignment cause harm to research participants? PLoS Med 3: e188 doi:10.1371/journal.pmed.0030188.
12. Kola I, Landis J, (2004) Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 3: 711-715.
13. Pangalos MN, Schechter LE, Hurko O, (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6: 521-532.
14. Contopoulos-Ioannidis DG, Ntzani E, Ioannidis JP, (2003) Translation of highly promising basic science research into clinical applications. Am J Med 114: 477-484.
15. van der Worp HB, Howells DW, Sena ES, Porritt MJ, Rewell S, et al. (2010) Can animal models of disease reliably inform human studies? PLoS Med 7: e1000245 doi:10.1371/journal.pmed.1000245.
16. Kilkenny C, Parsons N, Kadyszewski E, Festing MF, Cuthill IC, et al. (2009) Survey of the quality of experimental design, statistical analysis and reporting of research using animals. PLoS ONE 4: e7824 doi:10.1371/journal.pone.0007824.
17. Reynolds JC, Rittenberger JC, Menegazzi JJ, (2007) Drug administration in animal studies of cardiac arrest does not reflect human clinical experience. Resuscitation 74: 13-26.
18. Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, et al. (2009) Effects of NXY-059 in experimental stroke: an individual animal meta-analysis. Br J Pharmacol 157: 1157-1171.
19. Philip M, Benatar M, Fisher M, Savitz SI, (2009) Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials. Stroke 40: 577-581.
20. Sena ES, van der Worp HB, Bath PM, Howells DW, Macleod M, (2010) Publication bias in reports of animal stroke studies leads to major overstatement of efficacy. PLoS Biol 8: e1000344 doi:10.1371/journal.pbio.1000344.
21. Macleod MR, Fisher M, O'Collins VE, Sena ES, Dirnagl U, et al. (2009) Good laboratory practice. Preventing introduction of bias at the bench. Stroke 40: e50-e52.
22. Kilkenny C, Browne W, Cuthill I, Emerson M, Altman D, (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8: e1000412 doi:10.1371/journal.pbio.1000412.
23. Henley DB, May PC, Dean RA, Siemers ER, (2009) Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease. Expert Opin Pharmacother 10: 1657-1664.
24. American Society of Clinical Oncology (1997) Critical role of phase I clinical trials in cancer treatment. J Clin Oncol 15: 853-859.
25. Christian M, Shoemaker D, (2002) The investigator's handbook: a manual for participants in clinical trials of investigational agents sponsored by DCTD, NCI. Bethesda Cancer Therapy Evaluation Program.
26. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) (1996) ICH Harmonized Tripartite Guideline. Guideline for Good Clinical Practice E6(R1).
27. Lowenstein PR, (2008) A call for physiopathological ethics. Mol Ther 16: 1771-1772.
28. Ioannidis JP, Karassa FB, (2010) The need to consider the wider agenda in systematic reviews and meta-analyses: breadth, timing, and depth of the evidence. BMJ 341: c4875.
29. Mangialasche F, Solomon A, Winblad B, Mecocci P, Kivipelto M, (2010) Alzheimer's disease: clinical trials and drug development. Lancet Neurol 9: 702-716.
30. Cummings J, (2010) What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease? Biol Psychiatry 68: 876-878.
31. Holden C, (2009) Neuroscience. Fetal cells again? Science 326: 358-359.
32. Kimmelman J, London AJ, Ravina B, Ramsay T, Bernstein M, et al. (2009) Launching invasive, first-in-human trials against Parkinson's disease: ethical considerations. Mov Disord 24: 1893-1901.
33. Lindvall O, Kokaia Z, (2010) Stem cells in human neurodegenerative disorders-time for clinical translation? J Clin Invest 120: 29-40.
34. Anderson JA, Kimmelman J, (2010) Extending clinical equipoise to phase 1 trials involving patients: unresolved problems. Kennedy Inst Ethics J 20: 75-98.
35. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, et al. (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64: 1553-1562.
36. Feldman HH, Doody RS, Kivipelto M, Sparks DL, Waters DD, et al. (2010) Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74: 956-964.
37. Elan Corporation (2010) Elan and Transition Therapeutics announce topline summary results of Phase 2 study and plans for Phase 3 for ELND005 (Scyllo-inositol) [press release].
38. Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, et al. (2009) A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 73: 2061-2070.
39. Winblad B, Giacobini E, Frolich L, Friedhoff LT, Bruinsma G, et al. (2010) Phenserine efficacy in Alzheimer's disease. J Alzheimers Dis 22: 1201-1208.
40. Gold M, Alderton C, Zvartau-Hind M, Egginton S, Saunders AM, et al. (2010) Rosiglitazone monotherapy in mild-to-moderate alzheimer's disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement Geriatr Cogn Disord 30: 131-146.
41. Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, et al. (2009) Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA 302: 2557-2564.
42. Bellus Health Inc (2008) Neurochem announces results from Tramiprosate (ALZHEMED(TM)) North American Phase III clinical trial.
43. Marks WJ Jr, Bartus RT, Siffert J, Davis CS, Lozano A, et al. (2010) Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial. Lancet Neurol 9: 1164-1172.
44. Nutt J, Burchiel KJ, Comella CL, Jankovic J, Lang AE, et al. (2003) Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 60: 69-73.
45. Lang AE, Gill S, Patel NK, Lozano A, Nutt JG, et al. (2006) Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 59: 459-466.
46. Freed CR, Greene PE, Breeze RE, Tsai WY, DuMouchel W, et al. (2001) Transplantation of embryonic dopamine neurons for severe Parkinson's disease. N Engl J Med 344: 710-719.
47. Olanow CW, Goetz CG, Kordower JH, Stoessl AJ, Sossi V, et al. (2003) A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease. Ann Neurol 54: 403-414.
48. Watts RL, Freeman TB, Hauser RA, Bakay RAE, Ellias SA, et al. (2001) A double-blind, randomised, controlled, multicenter clinical trial of the safety and efficacy of stereotaxic intrastriatal implantation of fetal porcine ventral mesencephalic tissue (Neurocelli-PD) vs. imitation surgery in patients with Parkinson's disease (PD). Parkinsonism Relat Disord 7 (Suppl): S87.
49. Olanow CW, Stern MB, Sethi K, (2009) The scientific and clinical basis for the treatment of Parkinson disease. Neurology 72 (21 Suppl 4): S1-S136.