傳統新藥研發的第一期臨床試驗主要是針對劑量相關毒性決定藥品的最大耐受劑量，第二期臨床試驗的病人則接受此一最大耐受劑量，然後檢定藥品的短期藥效。一般而言，藥品產生毒性反應的機率低於目標毒性機率為可接受的毒性，而產生藥效的機率低於某一門檻值則是不可接受的藥效。此二年期計畫擬針對毒性反應為二元資料及藥效反應為二元或存活資料的情形分別研究二階段早期或合併前二期臨床試驗的調適型設計，以獲得具有可接受毒性及最高藥效的最佳劑量，提供第三期臨床試驗使用。第一階段將循序的觀測資料，計算藥品具可接受毒性的後驗機率，據以升降藥品劑量，然後估計最大耐受劑量。第二階段則以該最大耐受劑量及相鄰劑量進行多臂的循序隨機化設計，根據所獲得的毒性與藥效反應資料，分別計算藥品具可接受毒性的後驗機率及可接受藥效的後驗機率，以便同時考量藥品的毒性及藥效，進行最佳藥品劑量的選擇。本計畫第一年針對毒性與藥效反應皆為二元資料進行研究最佳藥品劑量的鑑別，第二年則針對毒性與藥效反應分別為二元資料及存活資料的情形鑑別最佳藥品劑量。預期本計畫所提出的合併前二期的臨床試驗更能快速且有效的鑑別最佳藥品的劑量。 ;In the development of a new drug, the major purpose of the phase I clinical trial is to identify the maximum tolerated dose (MTD) with respective to the dose-limiting toxicity (DLT). In the phase II clinical trial, the short-term efficacy of the drug is then evaluated for patients taking the MTD. In general, the toxicity is acceptable if the resulted toxicity probability is less than the target toxicity probability (TTP). Moreover, the efficacy is not acceptable if the corresponding efficacy probability is less than a threshold. This 2-year project considers finding the optimal dose of the drug that has an acceptable toxicity and reaches the maximum efficacy based on a two-stage adaptive design for the early-phase or phase I/II clinical trial when binary toxicity responses and efficacy responses of binary data or survival times are available. At the first stage, the MTD is identified after a dose-escalation procedure based on a sequentially computed posterior probability of acceptable toxicity. At the second stage, a multi-arm randomized design is sequentially used to collect toxicity and efficacy responses where the MDT identified at the first stage and the adjacent doses are under investigation. The optimal dose is then determined based on the posterior probabilities of the acceptable toxicity and acceptable efficacy. In the first year, the project takes into account of identifying the optimal dose based on the binary toxicity and efficacy responses. In the second year, the project then considers identifying the optimal dose based on the binary toxicity response together with the survival time for efficacy response. This project gives new designs of the phase I/II clinical trial that identify the optimal dose of the drug under study more efficient and quickly.
