本文關(guān)鍵詞：靶向藥物全球同步研發(fā)設(shè)計中的幾個問題　出處：《南京醫(yī)科大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 靶向藥物 全球同步研發(fā)項目 檢驗效能 樣本量估計

【摘要】：目的:近年來靶向藥物研發(fā)和藥物全球同步研發(fā)項目越發(fā)受到關(guān)注。靶向藥物的臨床試驗設(shè)計仍僅限于單個地域,如果要在新地域上市,需要進(jìn)行一個新的確證性臨床試驗,用于評價藥物的有效性和安全性,這必將會延長藥物研發(fā)周期,浪費大量人力物力。本文提出了靶向藥物的全球同步研發(fā)項目方法設(shè)計,并對該方法的統(tǒng)計學(xué)性能(檢驗效能、一類錯誤)進(jìn)行評價。此外,本文提出的設(shè)計在LCT(local clinical trial)部分僅需要較少的TE(target ethnic)人群樣本,第二部分給出了不同參數(shù)設(shè)置下LCT所需的樣本量大小,以期為實際工作提供指導(dǎo)意見。方法:將全人群分為NTE(non-target ethnic)人群和TE人群,其中又包括靶點陽性人群和靶點陰性人群,MRCT(multi-regional clinical trial)和LCT可以同時進(jìn)行也可以序貫進(jìn)行,分別采用全隨機(jī)設(shè)計或富集設(shè)計,最終的分析將人群歸類為NTE人群和TE人群,并將各自的檢驗統(tǒng)計量進(jìn)行加權(quán)合并。對于LCT部分樣本量的估計,考慮終點指標(biāo)為連續(xù)性或二分類指標(biāo),TE人群與NTE人群的效應(yīng)比值和權(quán)重對樣本量的影響,并進(jìn)行比較。結(jié)果:觀察不同靶點人群比例和LCT樣本量對兩種設(shè)計檢驗效能的影響,結(jié)果顯示,當(dāng)TE人群與NTE人群、靶點陽性與靶點陰性人群效應(yīng)相等時,相同分配樣本量情況下全隨機(jī)設(shè)計與富集設(shè)計的檢驗效能最高,經(jīng)過篩選的富集設(shè)計檢驗效能最低;當(dāng)靶點陰性人群效應(yīng)較低時,富集設(shè)計的分配樣本量與全隨機(jī)設(shè)計相等時,富集設(shè)計的檢驗效能較高,經(jīng)過篩選的富集設(shè)計檢驗效能最低;靶點陽性人群比例增大,檢驗效能隨之增大;兩種設(shè)計的一類錯誤均較為穩(wěn)定,不隨權(quán)重及靶點比例變化而變化。當(dāng)TE人群與NTE人群的效應(yīng)比值較大時,本研究方法的樣本量較為貼合實際,當(dāng)效應(yīng)比值較小,尤其是二分類資料,樣本量異常大。另外,隨著權(quán)重的增加,樣本量變化率增加明顯。結(jié)論:在靶向藥物全球同步研發(fā)項目中,根據(jù)種族因素及靶向藥物針對不同靶點人群的效應(yīng)差異,當(dāng)有足夠的證據(jù)表明靶向藥物對靶點陽性人群有更好的療效且擁有可靠的靶點檢測方法時,我們建議采用富集設(shè)計。當(dāng)不能確定靶向藥物對陰性人群是否有效或無可靠地靶點檢測方法時,建議采用全隨機(jī)設(shè)計。采用富集設(shè)計可以減少樣本量,降低研究成本,但是也要考慮篩選過程花費,以及倫理學(xué)是否可行。
[Abstract]:Objective: in recent years, more and more attention has been paid to the research and development of targeted drugs and their global synchronization. The clinical trials of targeted drugs are still limited to a single region, if they are to be listed in new regions. A new corroborative clinical trial is needed to evaluate the efficacy and safety of drugs, which is bound to prolong the drug development cycle. Waste a lot of manpower and material resources. In this paper, we propose a global synchronous research and development project design of targeted drugs, and evaluate the statistical performance of the method (test effectiveness, a class of errors). The design proposed in this paper requires only a small number of TE(target ethnic population samples in the LCT(local clinical Trial part. In the second part, the sample size required by LCT with different parameters is given. Methods: the whole population was divided into NTE(non-target ethnic group and te group. These include target positive and target negative groups. MRCT(multi-regional clinical trialand LCT can be carried out simultaneously or sequentially, using full random design or enrichment design, respectively. The final analysis classifies the population as NTE population and te population, and combines their test statistics weighted. For the estimation of partial sample size of LCT, the endpoint index is considered as continuity or two-classification index. The effect ratio and weight of te population and NTE population on sample size were compared. Results: the effects of different target population ratio and LCT sample size on the effectiveness of two design tests were observed. When the effect of target positive and target negative was equal between te and NTE, the test efficiency of full random design and enrichment design was the highest when the sample size was the same. The efficiency of enrichment design was the lowest. When the target negative population effect is low and the sample size of enrichment design is equal to that of full random design, the test efficiency of enrichment design is higher and that of enrichment design selected is the lowest. The proportion of target positive population increased and the test efficiency increased. The two kinds of errors are stable and do not change with weight and target ratio. When the ratio of effect between te population and NTE population is large, the sample size of this method is more practical. When the effect ratio is small, especially the two-classification data, the sample size is unusually large. In addition, with the increase of weight, the sample size change rate increases obviously. Conclusion: in the target drug global synchronization research and development project. According to the racial factors and the effects of targeting drugs on different target populations, when there is sufficient evidence that targeted drugs have better efficacy on target positive people and have reliable target detection methods. We recommend the use of enrichment design. When it is not certain whether the targeted drug is effective for negative population or there is no reliable target detection method, we recommend the full random design. The enrichment design can reduce the sample size. Reduce the cost of research, but also consider the cost of the screening process and the feasibility of ethics.
【學(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R91

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