In　clinical　development　of　a　test　treatment,　clinical　trials　are　usually　conducted　to　collect　data　for　evaluation　of　safety　and　efficacy　of　the　test　treatment　under　investigation.　To　provide　accurate　and　reliable　assessment,　well-controlled　clinical　trials　under　valid　study　designs　are　necessarily　conducted.　The　clinical　trial　process　is　lengthy　and　costly,　consisting　of　protocol　development,　trial　conduct,　data　collection,　statistical　analysis　and　interpretation,　and　reporting.　In　practice,　some　controversial　issues　are　commonly　encountered　regardless　of　compliance　with　good　clinical　practice.　These　issues　include,　but　are　not　limited　to,　statistical　hypotheses　for　clinical　evaluation,　instability　of　classical　sample　size　calculation,　integrity　of　blinding,　clinical　strategy　for　endpoint　selection,　impact　of　protocol　amendments,　flexibility　and　feasibility　of　adaptive　design　methods,　multiplicity　in　clinical　trials,　and　independence　of　data　monitoring　committees.　In　this　article,　these　issues　are　briefly　outlined.　The　impact　of　these　issues　on　the　evaluation　of　the　safety　and　efficacy　of　the　test　treatment　under　investigation　is　assessed　and　discussed　with　examples　whenever　applicable.　Recommendations　regarding　possible　resolutions　of　these　issues　are　also　provided　whenever　possible.