本文選題：藥物國際同步研發(fā) + 橋接�。� 參考：《第四軍醫(yī)大學(xué)》2017年博士論文

【摘要】：種族敏感性(Ethnic Sensitivity)是藥物研發(fā)中的重要問題之一,藥物的代謝動(dòng)力學(xué)和藥效學(xué)特征在不同種族間往往具有不同的表現(xiàn)。鑒于這種種族差異,在原區(qū)域(Original Region)批準(zhǔn)上市的藥品,在新區(qū)域(New Region)申報(bào)上市時(shí),需要闡明藥品在種族間的差異,及其對(duì)藥物安全性和有效性的影響。為了充分獲得藥品對(duì)新區(qū)域種族人群最直接的藥動(dòng)/藥效學(xué)、療效、安全性數(shù)據(jù),藥品申辦方往往被監(jiān)管機(jī)構(gòu)要求在新區(qū)域重新進(jìn)行I~IV期臨床試驗(yàn),這種重復(fù)試驗(yàn)不僅浪費(fèi)醫(yī)療資源,更延遲了有效新藥惠及患者的時(shí)間。對(duì)此,ICH E5提出橋接試驗(yàn)(Bridging Study)的概念:如果藥物在不同種族人群具有相似性,即可將該藥物其他種族臨床試驗(yàn)數(shù)據(jù)外推至新區(qū)域的目標(biāo)種族(Targeted Ethnic,TE),根據(jù)情況在新區(qū)域進(jìn)行小規(guī)模附加試驗(yàn),說明藥物對(duì)該區(qū)域人群的安全性、有效性。然而,由于缺乏明確的種族“相似性”定義,這種序貫地國際研發(fā)模式在實(shí)踐中存在諸多亟待解決的問題。隨后,多區(qū)域臨床試驗(yàn)(Multi-regional Clinical Trial,MRCT,又稱為國際多中心臨床試驗(yàn))提出了在國際范圍內(nèi)由多個(gè)區(qū)域共同參與、同步試驗(yàn)的策略,以促進(jìn)藥物在全球范圍內(nèi)的開發(fā)與上市。為使MRCT中每個(gè)區(qū)域符合當(dāng)?shù)厮幤繁O(jiān)管機(jī)構(gòu)的要求,MRCT的設(shè)計(jì)和區(qū)域內(nèi)樣本含量估計(jì)異常復(fù)雜。為確保每個(gè)局部區(qū)域以足夠的把握度確證藥品對(duì)本區(qū)域種族人群的療效,MRCT的樣本含量往往被設(shè)計(jì)得非常龐大。因此,相對(duì)于一個(gè)大規(guī)模MRCT,在適量樣本的MRCT框架外,根據(jù)情況同步或序貫地補(bǔ)充針對(duì)TE人群小規(guī)模的局部區(qū)域臨床試驗(yàn)(Local Clinical Trial,LCT),變成了新藥國際研發(fā)的最新趨勢。而總結(jié)以上現(xiàn)狀,新藥國際研發(fā)項(xiàng)目中有三個(gè)亟待解決的焦點(diǎn)問題:(1)如何估計(jì)局部區(qū)域試驗(yàn)樣本含量;(2)如何分析藥物針對(duì)TE人群的療效;(3)如何解釋局部區(qū)域的試驗(yàn)結(jié)果。針對(duì)這些問題,我們提出一種類三臂非劣效設(shè)計(jì),采用MRCT附加小規(guī)模LCT的橋接設(shè)計(jì),以評(píng)價(jià)國際研發(fā)中局部區(qū)域的藥物療效。具體研究內(nèi)容和結(jié)果如下:1類三臂非劣效設(shè)計(jì)框架的提出假設(shè)已有一個(gè)安慰劑對(duì)照的MRCT,在藥物有效性已確證的基礎(chǔ)上,目標(biāo)區(qū)域?qū)ⅹ?dú)立開展一個(gè)只招募TE人群的臨床試驗(yàn),除區(qū)域不同外,LCT的設(shè)計(jì)要素與MRCT完全一致�；诓煌N族人群的生物共性(Biological Commonality of Humankind),我們假設(shè)在一定程度上LCT與MRCT具有相似的安慰劑效應(yīng),將兩個(gè)安慰劑組類比為三臂非劣效設(shè)計(jì)中的安慰劑臂,對(duì)藥物是否有效進(jìn)行定性判斷;同時(shí),將LCT中的試驗(yàn)組類比為三臂非劣效設(shè)計(jì)中的試驗(yàn)臂;MRCT中的試驗(yàn)組類比為陽性對(duì)照臂(Active Reference Arm),對(duì)藥物的有效性進(jìn)行定量度量。在這個(gè)類三臂(Quasi-three-arm)結(jié)構(gòu)中,假設(shè)LCT的藥物療效是非劣效于MRCT的,以MRCT試驗(yàn)組與安慰劑組療效差的百分比作為非劣效界值,通過非劣效檢驗(yàn)可以確證藥物在LCT的療效:(1)相對(duì)于安慰劑的有效性;(2)保留了MRCT療效的一定百分比;(3)非劣效于MRCT的整體療效。2不同資料類型下類三臂非劣效設(shè)計(jì)的橋接方案基于LCT與MRCT具有相似安慰劑效應(yīng)的假設(shè),本研究針對(duì)不同類型的試驗(yàn)終點(diǎn)(連續(xù)型、二分類和生存資料),基于安慰劑效應(yīng)在LCT與MRCT間相等和不等兩種情況,以LCT與MRCT組間療效差之比的形式構(gòu)建檢驗(yàn)假設(shè),提出橋接設(shè)計(jì)方案和樣本量估計(jì)方法,以一次檢驗(yàn)分別對(duì)藥物療效進(jìn)行定性判斷和定量度量;并通過模擬研究與實(shí)例應(yīng)用探討了各檢驗(yàn)方法的可行性、適用性、穩(wěn)健性,以及樣本含量估計(jì)隨參數(shù)變化的趨勢。(1)連續(xù)型資料:近似正態(tài)假設(shè)下,分別提出安慰劑效應(yīng)相等和不等的非劣效檢驗(yàn)方法和樣本量估計(jì)公式。采用Monte Carlo模擬實(shí)驗(yàn),(1)在單側(cè)檢驗(yàn)水準(zhǔn)α=0.025,目標(biāo)把握度1-β=0.80的設(shè)定下,不同參數(shù)組合109個(gè)模擬情景的平均檢驗(yàn)效能為0.7993±0.0068,平均I類錯(cuò)誤為0.0250±0.0007。(2)樣本含量估計(jì)的模擬研究發(fā)現(xiàn),MRCT樣本含量M_(RCTN)、MRCT組間療效差與方差之比δ_M/σ、LCT與MRCT真實(shí)療效差之比ρ、非劣效界值θ是影響樣本含量的關(guān)鍵因素。其中,隨著θ的增加,N_(LCT)呈明顯的上升趨勢;隨著ρ的增大,N_(LCT)會(huì)逐步下降;當(dāng)固定其他參數(shù)時(shí),δ_M/σ每增大一倍,則N_(LCT)縮小到原來的1/4,而當(dāng)δ_M/σ時(shí),N_(LCT)的下降趨于緩慢,直至δ_M/σ時(shí),N_(LCT)趨于穩(wěn)定;同時(shí),N_(LCT)也隨著MRCTN的增大而減小,但伴隨著/Mds的增大,變化幅度逐步減小。(3)基于錯(cuò)誤的安慰劑效應(yīng)假設(shè),低估的樣本含量引起了條件效能的降低,當(dāng)N_(LCT)=500 1000 1500,,時(shí),條件檢驗(yàn)效能平均降低至69.04%,67.60%,66.02%;而相同條件下,I類錯(cuò)誤并未出現(xiàn)明顯膨脹,維持在名義檢驗(yàn)水準(zhǔn)0.025附近隨機(jī)波動(dòng)。(2)二分類資料:(1)二分類資料樣本含量隨參數(shù)變化的情況與正態(tài)資料類似,且并不會(huì)隨M_(RCT)安慰劑組預(yù)期終點(diǎn)事件發(fā)生率MCp的變化產(chǎn)生明顯改變。(2)大樣本情況下,二分類資料的非劣效檢驗(yàn)統(tǒng)計(jì)量近似正態(tài)分布,然而由于對(duì)統(tǒng)計(jì)量中方差σ~2(?)的估計(jì)依賴于ψ(π)的估計(jì)值(?),有學(xué)者提出用約束極大似然法/限制性極大似然估計(jì)(Restricted Maximum Likelihood Estimation,RMLE)估計(jì)方差更為準(zhǔn)確。因此,本部分采用模擬試驗(yàn),重點(diǎn)比較了基于極大似然估計(jì)(Maximum Likelihood Estimation,MLE)的Wald檢驗(yàn)與RMLE檢驗(yàn)下的條件檢驗(yàn)效能和I類錯(cuò)誤。結(jié)果發(fā)現(xiàn)156個(gè)模擬情景中,Wald檢驗(yàn)的模擬結(jié)果準(zhǔn)確性較差,且變異更大、穩(wěn)定性欠佳。類三臂非劣效設(shè)計(jì)的二分類資料適宜采用RMLE方法,估計(jì)方差及檢驗(yàn)統(tǒng)計(jì)量更加準(zhǔn)確、穩(wěn)健。(3)生存資料:服從指數(shù)分布的生存資料中,試驗(yàn)組與對(duì)照組的風(fēng)險(xiǎn)比(Hazard Ratio,HR)經(jīng)過對(duì)數(shù)轉(zhuǎn)換后呈正態(tài)分布;服從Weibull分布的生存資料,通過Cox比例風(fēng)險(xiǎn)模型,不同處理組間系數(shù)即為對(duì)數(shù)風(fēng)險(xiǎn)比,且近似正態(tài)。通過這種正態(tài)轉(zhuǎn)換,本節(jié)對(duì)服從指數(shù)分布、Weibull分布的非劣效檢驗(yàn)和樣本含量估計(jì)進(jìn)行了理論研究。本研究的主要?jiǎng)?chuàng)新點(diǎn)有:(1)提出一種新的MRCT+LCT橋接思路,由安慰劑、MRCT試驗(yàn)組、LCT試驗(yàn)組構(gòu)造類似于三臂非劣效設(shè)計(jì)的框架,通過一次檢驗(yàn)達(dá)到對(duì)藥物療效的定性判斷和定量度量的目的;(2)探討了不同數(shù)據(jù)資料類型下的統(tǒng)計(jì)分析方法和樣本量估計(jì),給出了影響樣本量估計(jì)的參數(shù)設(shè)置,并推薦了不同條件下的樣本量估計(jì)方案及適用范圍;(3)編寫了基于不同數(shù)據(jù)資料類型下類三臂非劣效設(shè)計(jì)的模擬研究程序,給出可以直接應(yīng)用于臨床實(shí)踐的橋接方案。本文以新藥國際研發(fā)中藥物在目標(biāo)區(qū)域的療效評(píng)價(jià)為研究目的,提出類三臂非劣效設(shè)計(jì)的橋接策略及其在不同數(shù)據(jù)資料類型下的橋接方案和樣本含量估計(jì)公式,重點(diǎn)探討了樣本量估計(jì)的參數(shù)設(shè)置及各種分布檢驗(yàn)統(tǒng)計(jì)量的可行性、準(zhǔn)確性、穩(wěn)健性,以期為橋接試驗(yàn)設(shè)計(jì)提供參考依據(jù),節(jié)約醫(yī)療資源,促進(jìn)有效藥物盡快上市。
[Abstract]:Ethnic Sensitivity is one of the important issues in drug development. Pharmacokinetic and pharmacodynamic characteristics are often different among different races. In view of the racial differences, drugs approved in the original region (Original Region) and the declaration of the new region (New Region) need to be clarified. The differences between races and their effects on drug safety and effectiveness. In order to obtain the most direct pharmacokinetic / pharmacodynamics, efficacy, safety data, and safety data for the new regional population, the drug applicant is often required to reconduct the I~IV clinical trials in the new area, which is not only a waste of medical resources, More delayed the time for effective new drugs to benefit the patient. In this case, ICH E5 proposed the concept of Bridging Study: if the drug is similar in different ethnic groups, other racial clinical trials of the drug can be extrapolated to the target race of the new region (Targeted Ethnic, TE), and in the new area, a small scale is added to the new area. The test shows the safety and effectiveness of the drug for the population in the region. However, there are many problems to be solved in the practice of the sequential international R & D model due to the lack of a clear definition of racial "similarity". Then, multi regional clinical trials (Multi-regional Clinical Trial, MRCT, also known as international multicenter clinical trials) In order to make every region of MRCT conform to the requirements of local drug regulators, the design of MRCT and the estimation of the sample content in the region are very complex to ensure that each local area is sure enough. The sample content of MRCT is often very large in assessing the effectiveness of drugs for ethnic groups in the region. Therefore, relative to a large-scale MRCT, a small scale local regional clinical trial (Local Clinical Trial, LCT) for the TE population (Local Clinical Trial, LCT) has been transformed into a new drug international research. There are three key issues in the new drug international R & D project: (1) how to estimate the content of local regional test samples; (2) how to analyze the efficacy of drugs for the TE population; (3) how to explain the experimental results in the local area. In view of these problems, we propose a non inferiority complex of three arms. The MRCT plus small scale LCT bridge design is used to evaluate the drug efficacy of the local area in international R & D. The specific research content and results are as follows: the 1 category of three arm non inferiority design framework has a placebo-controlled MRCT. On the basis of the validation of the drug effectiveness, the target area will be independently recruited to recruit only TE The clinical trials of the population, except for regional differences, are exactly the same as the LCT design elements. Based on the Biological Commonality of Humankind of different racial groups, we assume that LCT and MRCT have a similar placebo effect to a certain extent, and the two placebo groups are analogized to the placebo arm in the three arm non inferiority design. Qualitative judgment of the effectiveness of the drug was made; at the same time, the experimental group in the LCT group was analogous to the three arm non inferiority design arm; the test group in MRCT was analogous to the positive control arm (Active Reference Arm) to measure the effectiveness of the drug. In this class of three arm (Quasi-three-arm) structure, the efficacy of the LCT was assumed to be not inferior. MRCT, the percentage of the difference between the MRCT test group and the placebo group was a non inferiority value, and the efficacy of the drug in LCT was confirmed by the non inferiority test: (1) the efficacy of the placebo relative to the placebo; (2) a certain percentage of the efficacy of the MRCT was retained; (3) the non inferiority of the three arm non inferiority design under the different data types of the MRCT was not inferior to the overall efficacy of MRCT. The bridging scheme is based on the hypothesis that LCT and MRCT have similar placebo effect. This study aims at different types of test endpoints (continuous, two classification and survival data), based on the placebo effect equal and unequal between LCT and MRCT, and constructs a bridge design scheme based on the ratio of the difference of the curative effect between the LCT and the MRCT group. And the method of sample size estimation, the qualitative judgment and quantitative measurement of the drug effect are carried out by one test, and the feasibility, applicability, robustness, and the trend of the sample content estimation with the parameter change are discussed by the simulation study and the case application. (1) the continuous data, under the approximate normal assumption, the placebo The effect equality and unequal non inferiority test method and the sample size estimation formula. Using the Monte Carlo simulation experiment, (1) in the unilateral test level alpha =0.025, the target grasp degree 1- beta =0.80 is set, the average test efficiency of the 109 simulated scenarios with different parameters combination is 0.7993 + 0.0068, the average I type error is 0.0250 + 0.0007. (2) sample content estimation The simulation study found that the MRCT sample content is M_ (RCTN), the ratio of the curative effect and the variance of the MRCT group is delta _M/ sigma, LCT and the true effect of MRCT, and the non inferiority boundary value theta is the key factor affecting the sample content. Among them, N_ (LCT) increases with the increase of theta; N_ (LCT) decreases gradually with the increase of P, when other parameters are fixed. When delta _M/ is doubled, then N_ (LCT) is reduced to the original 1/4, and when N_ (LCT) decreases slowly when delta _M/ sigma, N_ (LCT) tends to stabilize until Delta _M/ sigma; meanwhile, N_ (LCT) decreases with the increase, but with the increase, the variation amplitude decreases gradually. (3) based on the false placebo-effect hypothesis, the undervalued sample contains The quantity caused the reduction of the condition efficiency. When N_ (LCT) =500 10001500, the condition test efficiency was reduced to 69.04%, 67.60%, 66.02%; and under the same condition, the I class error did not expand obviously, and maintained at the nominal test level 0.025 random fluctuation. (2) two classification data: (1) two classification data sample content varies with parameter. The normal data is similar and does not change significantly with the change of the incidence of the expected end point of the M_ (RCT) placebo group. (2) the non inferiority test statistics of the two classification data are approximately normal distribution under the large sample case. However, some scholars put forward the constraints due to the estimation of the difference of the Chinese difference ~2 (?) on the statistics. The maximum likelihood method / restrictive maximum likelihood estimation (Restricted Maximum Likelihood Estimation, RMLE) is more accurate in estimating the variance. Therefore, the simulation experiment is used in this part to compare the condition test effectiveness and the I class error based on the Wald test and RMLE test based on the maximum likelihood estimation (Maximum Likelihood Estimation, MLE). In the present 156 simulated scenarios, the accuracy of the simulation results of the Wald test is poor, and the variation is greater and the stability is not good. The two classification data of the three arm non inferiority design are suitable for the use of the RMLE method, and the estimation variance and the test statistics are more accurate and robust. (3) the survival data: the risk ratio of the experimental group and the control group in the subsistence data of the digital distribution (Hazard Ratio, HR) is a normal distribution after logarithmic conversion; subsistence data obeys Weibull distribution, and through Cox proportional hazard model, the coefficient between different processing groups is the logarithmic risk ratio, and it is approximately normal. Through this normal transformation, this section has a theory that obeys the exponential distribution, the non inferiority test and the sample content estimation of the Weibull distribution. The main innovations of this study were as follows: (1) a new MRCT+LCT bridging idea was proposed, which consisted of a placebo, MRCT test group, and the LCT test group structure similar to the three arm non inferiority design framework to achieve qualitative judgment and quantitative measurement of the efficacy of the drug by one test; (2) the statistical analysis under different data types was discussed. The method and sample quantity estimate, give the parameter setting of the estimation of sample size, and recommend the sample size estimation scheme under different conditions and the scope of application. (3) the simulation research program based on the three arm non inferiority design based on different data types is written, and the bridging scheme which can be directly applied to clinical practice is given. The therapeutic evaluation of drugs in the target area in international R & D is the purpose of research. The bridging strategy of three arm non inferiority design and its bridge scheme and sample content estimation formula under different data types are proposed. The parameters setting of the sample size estimation and the feasibility, accuracy and robustness of various distribution test statistics are discussed. In order to provide reference for bridge test design, save medical resources and promote effective drug listing as soon as possible.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R95
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本文編號(hào)：1999966