Predicting Harms and Benefits in Translational Trials Ethics, Evidence, and Uncertainty 英文参考文献.docVIP

Essay PredictingHarmsandBenefitsinTranslationalTrials: Ethics,Evidence,andUncertainty JonathanKimmelman1,AlexJohnLondon2* 1BiomedicalEthicsUnit,DepartmentofSocialStudiesofMedicine,McGillUniversity,Montreal,Quebec,Canada,2DepartmentofPhilosophy,CarnegieMellonUniversity, Pittsburgh,Pennsylvania,UnitedStatesofAmerica Introduction withanticipatedbenefitstosocietyand,if applicable, to the volunteers themselves [4,6]. Accurate prediction plays a critical roleinthisprocess.Whenresearchteams underestimatetheprobabilityoffavorable clinical or translational outcomes, they underminehealthcaresystemsbyimped- ingclinicaltranslation.Wheninvestigators overestimate the probability of favorable outcomes,theypotentiallyexposeindivid- ualstounjustifiedburdens,whichmaybe considerableforphase1studiesinvolving unprovendrugs.Inbothcases,misestima- tionthreatenstheintegrityofthescientific enterprise, because it frustrates prudent allocationofresearchresources[7]. that a systematic investigation is overdue. Highly promising preclinical findings in cancer, stroke, HIV vaccines, and neuro- degenerative diseases frequently fail clini- cal translation. In cancer, only 5% of products entering trials are eventually licensed [12,13]. In one study, approxi- mately 5% of high impact basic science reportswereclinicallytranslatedwithin10 years [14]. We suggest that these disap- pointments partly reflect two problems in the way evidence is used in predicting clinicaloutcomes. First-in-humanclinicaltrialsrepresenta critical juncture in the translation of laboratory discoveries. However, because theyinvolvethegreatestdegreeofuncer- tainty at any point in the drug develop- mentprocess,theirinitiationisbesetbya series of nettlesome ethical questions [1]: has clinical promise been sufficiently demonstrated in animals? Should trial access be restricted to patients with refractorydisease?Shouldtrialsbeviewed as therapeutic? Have researchers ade- quatelyminimizedrisks? PreclinicalReportingand Validi