Predicting Harms and Benefits in Translational Trials: Ethics, Evidence, and Uncertainty

J Kimmelman, 2010, Gene transfer and the ethics of first-in-human research: lost in translation.

A Extance, 2010, Alzheimer's failure raises questions about disease-modifying strategies., Nat Rev Drug Discov, 9, 749, 10.1038/nrd3288

1979, The Belmont report: ethical principles and guidelines for the protection of human subjects of research.

1964, Declaration of Helsinki.

H Mann, 2010, ASSERT: a standard for the review and monitoring of randomized clinical trials.

2005, Protection of human subjects: criteria for IRB approval of research., 1

AJ London, 2010, Research ethics. Beyond access vs. protection in trials of innovative therapies., Science, 328, 829, 10.1126/science.1189369

B Djulbegovic, 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, 10.1001/archinte.168.6.632

A Kumar, 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, 10.1136/bmj.38628.561123.7C

HP Soares, 2005, Evaluation of new treatments in radiation oncology: are they better than standard treatments?, JAMA, 293, 970, 10.1001/jama.293.8.970

CP Gross, 2006, Does random treatment assignment cause harm to research participants?, PLoS Med, 3, e188, 10.1371/journal.pmed.0030188

I Kola, 2004, Can the pharmaceutical industry reduce attrition rates?, Nat Rev Drug Discov, 3, 711, 10.1038/nrd1470

MN Pangalos, 2007, Drug development for CNS disorders: strategies for balancing risk and reducing attrition., Nat Rev Drug Discov, 6, 521, 10.1038/nrd2094

DG Contopoulos-Ioannidis, 2003, Translation of highly promising basic science research into clinical applications., Am J Med, 114, 477, 10.1016/S0002-9343(03)00013-5

HB van der Worp, 2010, Can animal models of disease reliably inform human studies?, PLoS Med, 7, e1000245, 10.1371/journal.pmed.1000245

C Kilkenny, 2009, Survey of the quality of experimental design, statistical analysis and reporting of research using animals., PLoS ONE, 4, e7824, 10.1371/journal.pone.0007824

JC Reynolds, 2007, Drug administration in animal studies of cardiac arrest does not reflect human clinical experience., Resuscitation, 74, 13, 10.1016/j.resuscitation.2006.10.032

PM Bath, 2009, Effects of NXY-059 in experimental stroke: an individual animal meta-analysis., Br J Pharmacol, 157, 1157, 10.1111/j.1476-5381.2009.00196.x

M Philip, 2009, Methodological quality of animal studies of neuroprotective agents currently in phase II/III acute ischemic stroke trials., Stroke, 40, 577, 10.1161/STROKEAHA.108.524330

ES Sena, 2010, Publication bias in reports of animal stroke studies leads to major overstatement of efficacy., PLoS Biol, 8, e1000344, 10.1371/journal.pbio.1000344

MR Macleod, 2009, Good laboratory practice. Preventing introduction of bias at the bench., Stroke, 40, e50, 10.1161/STROKEAHA.108.525386

C Kilkenny, 2010, Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research., PLoS Biol, 8, e1000412, 10.1371/journal.pbio.1000412

DB Henley, 2009, Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease., Expert Opin Pharmacother, 10, 1657, 10.1517/14656560903044982

1997, Critical role of phase I clinical trials in cancer treatment., J Clin Oncol, 15, 853, 10.1200/JCO.1997.15.2.853

M Christian, 2002, The investigator's handbook: a manual for participants in clinical trials of investigational agents sponsored by DCTD, NCI.

1996, ICH Harmonized Tripartite Guideline., Guideline for Good Clinical Practice E6(R1)

PR Lowenstein, 2008, A call for physiopathological ethics., Mol Ther, 16, 1771, 10.1038/mt.2008.218

JP Ioannidis, 2010, The need to consider the wider agenda in systematic reviews and meta-analyses: breadth, timing, and depth of the evidence., BMJ, 341, c4875, 10.1136/bmj.c4875

F Mangialasche, 2010, Alzheimer's disease: clinical trials and drug development., Lancet Neurol, 9, 702, 10.1016/S1474-4422(10)70119-8

J Cummings, 2010, What can be inferred from the interruption of the semagacestat trial for treatment of Alzheimer's disease?, Biol Psychiatry, 68, 876, 10.1016/j.biopsych.2010.09.020

C Holden, 2009, Neuroscience. Fetal cells again?, Science, 326, 358, 10.1126/science.326_358

J Kimmelman, 2009, Launching invasive, first-in-human trials against Parkinson's disease: ethical considerations., Mov Disord, 24, 1893, 10.1002/mds.22712

O Lindvall, 2010, Stem cells in human neurodegenerative disorders—time for clinical translation?, J Clin Invest, 120, 29, 10.1172/JCI40543

JA Anderson, 2010, Extending clinical equipoise to phase 1 trials involving patients: unresolved problems., Kennedy Inst Ethics J, 20, 75, 10.1353/ken.0.0307

S Gilman, 2005, Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial., Neurology, 64, 1553, 10.1212/01.WNL.0000159740.16984.3C

HH Feldman, 2010, Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe., Neurology, 74, 956, 10.1212/WNL.0b013e3181d6476a

2010, Elan and Transition Therapeutics announce topline summary results of Phase 2 study and plans for Phase 3 for ELND005 (Scyllo-inositol) [press release]

S Salloway, 2009, A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease., Neurology, 73, 2061, 10.1212/WNL.0b013e3181c67808

B Winblad, 2010, Phenserine efficacy in Alzheimer's disease., J Alzheimers Dis, 22, 1201, 10.3233/JAD-2010-101311

M Gold, 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, 10.1159/000318845

RC Green, 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, 10.1001/jama.2009.1866

2008, Neurochem announces results from Tramiprosate (ALZHEMED(TM)) North American Phase III clinical trial

WJ Marks Jr, 2010, Gene delivery of AAV2-neurturin for Parkinson's disease: a double-blind, randomised, controlled trial., Lancet Neurol, 9, 1164, 10.1016/S1474-4422(10)70254-4

J Nutt, 2003, Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD., Neurology, 60, 69, 10.1212/WNL.60.1.69

AE Lang, 2006, Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease., Ann Neurol, 59, 459, 10.1002/ana.20737

CR Freed, 2001, Transplantation of embryonic dopamine neurons for severe Parkinson's disease., N Engl J Med, 344, 710, 10.1056/NEJM200103083441002

CW Olanow, 2003, A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's disease., Ann Neurol, 54, 403, 10.1002/ana.10720

RL Watts, 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, S87

CW Olanow, 2009, The scientific and clinical basis for the treatment of Parkinson disease., Neurology, 72, S1, 10.1212/WNL.0b013e3181a1d44c