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FDA IVPT 測試 工業指南翻譯稿

更新時間:2023-02-08      點擊次數:2631

In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs Guidance for Industry

工業指南中ANDAs申請提交的外用制劑的體外滲透試驗研究

 

U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) October 2022 Generic Drugs

美(mei)國衛生與公眾服務部食品(pin)和藥(yao)物(wu)管理局藥(yao)物(wu)評估與研究中心(CDER)2022年10月仿制藥(yao)

 

IINTRODUCTION

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called “topical products.” Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro permeation test (IVPT) studies comparing a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD

本指南旨在幫助申請人提交用于皮膚的液體和/或其他半固體產品申請ANDA,包括皮膚和粘膜(如陰道),以下稱為“局部產品”。由于這些產品復雜的遞送途徑,通常是局部起效的,以及某些制劑的潛在復雜性,外用制劑(外用溶液除外)被歸類為復雜制劑。本指南為體外滲透試驗(IVPT)研究提供了建議,該研究比較了擬申報仿制制劑及其參考制劑(RS),以支持證明與參比制劑的(RLD)生物等效性(BE)。參比制劑通常為RLD
 

This guidance does not address drug products that are administered via ophthalmic, otic, nasal, inhalation, oral, or injection-based routes, or that are transdermal or topical delivery systems (including products known as patches, topical patches, or extended release films).

本(ben)指南(nan)不(bu)適(shi)用于通過眼、耳、鼻(bi)、吸(xi)入、口服或(huo)(huo)注(zhu)射途徑給藥(yao)的藥(yao)物,也不(bu)適(shi)用于透皮或(huo)(huo)局部給藥(yao)系(xi)統(包(bao)括貼片、局部貼片或(huo)(huo)緩釋(shi)膜)。



It is beyond the scope of this guidance to discuss specific topical products to which this guidance applies. FDA recommends that applicants consult this guidance and any relevant product-specific guidances (PSGs) and any other relevant guidances for industry, when considering the design and conduct of IVPT studies that, in conjunction with other studies, as deemed necessary, may be appropriate to support a demonstration that a proposed generic topical product and its RLD are bioequivalent. FDA also recommends that applicants routinely refer to FDA’s guidance web pages, because additional guidances may become available that could assist in the development of a generic topical product.

本(ben)指南(nan)(nan)是不討論(lun)適用該指南(nan)(nan)的特(te)定外(wai)用制(zhi)劑(ji)的指南(nan)(nan)。FDA建(jian)議申請人(ren)在考(kao)慮IVPT研(yan)究的設計和實(shi)施時,參考(kao)本(ben)指南(nan)(nan)和任何相關的特(te)定產品(pin)指南(nan)(nan)(PSG)以及(ji)任何其(qi)他(ta)相關的行業指南(nan)(nan),如有(you)(you)必要(yao),結合其(qi)他(ta)研(yan)究,IVPT研(yan)究可能適合支持建(jian)議的通(tong)用外(wai)用制(zhi)劑(ji)及(ji)其(qi)RLD具有(you)(you)生物等效性的證明。FDA還建(jian)議申請人(ren)定期(qi)查(cha)閱FDA的指導網頁,因為可能會有(you)(you)更多的指導,有(you)(you)助于仿制(zhi)藥的開發。



In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.

一般來說,FDA的指(zhi)導文(wen)件并(bing)沒有(you)確立法律上可(ke)強制執行的責任。相反(fan),指(zhi)南描(miao)述了(le)機(ji)構目前對(dui)某一主題的想法,并(bing)且應(ying)僅視為建(jian)議,除非引用了(le)具體的監管或法定要(yao)求。在機(ji)構指(zhi)南中使用“應(ying)該(gai)”一詞意味著有(you)人建(jian)議或建(jian)議,但不是必須的。


 

II. BACKGROUND

This guidance has been developed as part of FDA’s “Drug Competition Action Plan,” which, in coordination with the Generic Drug User Fee Amendments (GDUFA) program and other FDA activities, is intended to increase competition in the market place for prescription drugs, facilitate the entry of high-quality and affordable generic drugs, and improve public health.

本指南是作為FDA“藥品競爭行動(dong)計(ji)(ji)劃(hua)”的(de)(de)一部分制(zhi)定的(de)(de),該(gai)計(ji)(ji)劃(hua)配合GDUFA計(ji)(ji)劃(hua)和其他FDA舉措(cuo),旨在(zai)促進處方藥市場的(de)(de)競爭,促進高質量和實惠的(de)(de)藥品的(de)(de)進入(ru)市場,并改善(shan)公眾醫療。



The Federal Food, Drug, and Cosmetic Act (FD&C Act) generally requires an ANDA to contain, among other things, information to show that the proposed generic drug product 1) is the same as the RLD with respect to the active ingredient(s), conditions of use, route of administration, dosage form, strength, and labeling (with certain permissible differences) and 2) is bioequivalent to the RLD. Thus, an ANDA will not be approved if the information submitted in the ANDA is insufficient to show that the test product is bioequivalent to the RLD.

《聯邦(bang)食品(pin)(pin)、藥品(pin)(pin)和(he)化妝品(pin)(pin)法(fa)案》(FD&C法(fa)案)通常(chang)要求ANDA包含合適的信(xin)息(xi),說明(ming):仿(fang)制藥與(yu)RLD相(xiang)比1)具(ju)(ju)有相(xiang)同活性(xing)成(cheng)分、使用條件、給藥途徑、劑型、規格和(he)標簽(允許(xu)存在某些差異(yi)),和(he)2)與(yu)RLD具(ju)(ju)有生(sheng)(sheng)物等效性(xing)。因此(ci),如果ANDA中提交的信(xin)息(xi)不足以證(zheng)明(ming)自(zi)制制劑與(yu)RLD具(ju)(ju)有生(sheng)(sheng)物等效性(xing),則(ze)ANDA將不予(yu)批(pi)準。



An IVPT study may be used to assess the rate and extent to which a drug (i.e., an active ingredient) from a topical product becomes available at or near a site of action in the skin, and may be used to characterize and compare the rate and extent of bioavailability for a drug from a test topical product and RS. The IVPT flux profiles resemble pharmacokinetic profiles and can be analyzed using unique IVPT endpoints that are somewhat analogous to the pharmacokinetic endpoints of maximum concentration (Cmax) and the area under the concentration-time curve(AUC). Yet, IVPT studies characterize the rate and extent of absorption, not the distribution, metabolism and excretion that occurs in vivo. Therefore, while it is relevant to characterize the kinetics of topical drug bioavailability monitored by IVPT studies, the use in this guidance of the term “cutaneous pharmacokinetics” should not be construed to embody all aspects of pharmacokinetics—only those related to the absorption component that directly controls the rate and extent to which a topically applied drug becomes available locally at the site of action. This guidance focuses on general considerations and recommendations for the method development, method validation, and conduct of IVPT studies that are submitted in ANDAs and intended to support a demonstration of BE.

IVPT研究可用于評估局部產品中的藥物(即活性成分)在皮膚作用部位或附近可用的速率和程度,并可用于表征和比較測試局部產品和RS中藥物的生物利用率和程度。IVPT通量曲線類似于藥代動力學曲線,可以使用*的IVPT終點進行分析,這些終點與最大濃度(Cmax)的藥代動力學終點和濃度-時間曲線下的面積(AUC)有些相似。然而,IVPT研究表征的是吸收的速率和程度,而不是體內的分布、代謝和排泄。因此,雖然表征IVPT研究監測的局部藥物生物利用度的動力學是相關的,本指南中使用的術語“皮膚藥代動力學”不應被解釋為僅體現與吸收成分相關的藥代動力學的所有方面,吸收成分直接控制局部應用藥物在作用部位局部可用的速率和程度。本指南側重于在ANDA中提交的用于支持BE演示的方法開發、方法驗證和IVPT研究的一般考慮和建議。

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III. IVPT METHOD DEVELOPMENT

The development of an IVPT method that is suitable to support a demonstration of BE for a specific topical product routinely involves a systematic series of exploratory studies. Inappropriate or insufficient efforts to develop an IVPT method that is suitable for its intended purpose increases the likelihood that the subsequent IVPT validation, pilot, and pivotal studies will ultimately be inadequate to support a demonstration of BE. By contrast, appropriate and systematic IVPT method development studies help to identify IVPT study designs and protocol (method) parameters which reliably produce flux profiles that can facilitate a comparison of the cutaneous pharmacokinetics of a drug delivered topically to the skin from test topical products and RSs.

IVPT方法的(de)(de)(de)(de)開發適用(yong)于(yu)支持特定(ding)局部產品的(de)(de)(de)(de)BE演示,通常涉及(ji)一系列系統(tong)(tong)的(de)(de)(de)(de)探索性研(yan)(yan)究(jiu)。開發適合(he)其預(yu)期目的(de)(de)(de)(de)的(de)(de)(de)(de)IVPT方法的(de)(de)(de)(de)努力(li)不(bu)當或不(bu)足,增加(jia)了(le)后續IVPT驗證、試點和關鍵研(yan)(yan)究(jiu)最終不(bu)足以支持BE演示的(de)(de)(de)(de)可能(neng)性。相比之(zhi)下,適當和系統(tong)(tong)的(de)(de)(de)(de)IVPT方法開發研(yan)(yan)究(jiu)有(you)助(zhu)于(yu)確定(ding)IVPT研(yan)(yan)究(jiu)設(she)計和方案(方法)參(can)數,這些設(she)計和方案能(neng)夠可靠地產生通量曲(qu)線,從(cong)而有(you)助(zhu)于(yu)比較(jiao)從(cong)測試局部產品和RS局部遞送至皮膚的(de)(de)(de)(de)藥物的(de)(de)(de)(de)皮膚藥代動力(li)學。



A detailed and well-organized IVPT method development report should be submitted in an ANDA to show how the IVPT method was optimized, and to support a demonstration that the method parameters selected for the IVPT are appropriate or necessary, particularly in situations where the method parameters are different from the methods recommended in this guidance). The Agency’s interest in reviewing the method development report is to understand why specific IVPT method parameters were selected and whether the resulting IVPT method is suitably sensitive and reproducible. This method development report should clearly indicate/distinguish the method parameters used for each set of data, illustrate the efforts made to optimize the IVPT method, and demonstrate that the method parameters selected for the IVPT are appropriate.

應(ying)在ANDA中提交一(yi)份詳細且組織良好的(de)(de)(de)(de)IVPT方(fang)(fang)法(fa)開發報告(gao),以說明(ming)IVPT方(fang)(fang)法(fa)是(shi)如何優(you)化的(de)(de)(de)(de),并支持為(wei)IVPT選(xuan)擇(ze)的(de)(de)(de)(de)方(fang)(fang)法(fa)參數(shu)(shu)是(shi)適(shi)當(dang)或必要的(de)(de)(de)(de),特別是(shi)在方(fang)(fang)法(fa)參數(shu)(shu)與(yu)本指南中推薦的(de)(de)(de)(de)方(fang)(fang)法(fa)不同的(de)(de)(de)(de)情況(kuang)下)。機(ji)構審查方(fang)(fang)法(fa)開發報告(gao)的(de)(de)(de)(de)目的(de)(de)(de)(de)是(shi)了解(jie)為(wei)什么選(xuan)擇(ze)了特定的(de)(de)(de)(de)IVPT方(fang)(fang)法(fa)參數(shu)(shu),以及(ji)所得IVPT方(fang)(fang)法(fa)是(shi)否具有(you)適(shi)當(dang)的(de)(de)(de)(de)敏(min)感性和重現性。該方(fang)(fang)法(fa)開發報告(gao)應(ying)明(ming)確指出/區分每組數(shu)(shu)據使用的(de)(de)(de)(de)方(fang)(fang)法(fa)參數(shu)(shu),說明(ming)為(wei)優(you)化IVPT方(fang)(fang)法(fa)所做的(de)(de)(de)(de)努力,并證明(ming)為(wei)IVPT選(xuan)擇(ze)的(de)(de)(de)(de)方(fang)(fang)法(fa)參數(shu)(shu)是(shi)合適(shi)的(de)(de)(de)(de)。



Applicants are encouraged to use the recommendations in this guidance, and if an applicant elects to use methods that are different from those recommended in this guidance, the IVPT method development report should demonstrate why it is scientifically justified to use an alternative approach than what is recommended in this guidance to optimize the IVPT method. Some examples of recommended procedures are described in subsequent sections, to help applicants identify circumstances when information should be submitted in the ANDA to explain why a different procedure was utilized.

鼓勵(li)申(shen)請人使(shi)用(yong)(yong)本(ben)(ben)指南(nan)中(zhong)(zhong)的(de)建(jian)議,如果申(shen)請人選擇使(shi)用(yong)(yong)與本(ben)(ben)指南(nan)中(zhong)(zhong)建(jian)議的(de)方法不同的(de)方法,IVPT方法開發報告應(ying)說明為什么使(shi)用(yong)(yong)本(ben)(ben)指南(nan)推薦的(de)替代方法來優化IVPT方法在科(ke)學上(shang)是合(he)理(li)的(de)。建(jian)議程序(xu)的(de)一(yi)些示例(li)在隨后的(de)章節中(zhong)(zhong)描述,以幫助申(shen)請人確定應(ying)在ANDA中(zhong)(zhong)提(ti)交(jiao)信息的(de)情(qing)況,以解釋為什么使(shi)用(yong)(yong)不同的(de)程序(xu)。



A. IVPT Method Parameters

All relevant parameters of the final IVPT method should be summarized (e.g., in a table) and submitted in the ANDA. Also, information should be provided to briefly explain the choice of the final IVPT method parameters like the equipment (e.g., a vertical diffusion cell (VDC)), skin source (e.g., cadaver), skin type (e.g., posterior torso), skin preparation (e.g., dermatomed), skin barrier integrity test (e.g., trans-epidermal water loss (TEWL) measurement), skin barrier integrity test acceptance criteria (e.g., < 15 grams/meter2 /hour (g/m2 /hr)), topical product dose amount (e.g., 15 milligrams/centimeter2 (mg/cm2 )), dose duration (e.g., 6 hours), study duration (e.g., 24 hours, 48 hours, etc.), receptor solution sampling times (e.g., 1, 2, 4, 6, 8, 12, 16, 20, and 24 hours), etc.

應總(zong)結最終IVPT方法的(de)所有相關參數(shu)(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),在表格中(zhong)(zhong)),并在ANDA中(zhong)(zhong)提(ti)交。此外,應提(ti)供信息,以簡要解釋最終IVPT方法參數(shu)的(de)選擇,如(ru)(ru)(ru)(ru)(ru)設備(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),垂(chui)直擴散池(VDC))、皮膚(fu)源(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),尸體(ti))、皮膚(fu)類型(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),后軀干)、皮膚(fu)準備(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),皮膚(fu)科)、皮膚(fu)屏障完(wan)整(zheng)(zheng)性測(ce)試(shi)(shi)(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),經表皮水分損(sun)失(TEWL)測(ce)量(liang))、,皮膚(fu)屏障完(wan)整(zheng)(zheng)性測(ce)試(shi)(shi)驗收標準(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),<15克(ke)/米2/小(xiao)(xiao)(xiao)時(shi)(g/m2/小(xiao)(xiao)(xiao)時(shi)))、局(ju)部產品劑量(liang)(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),15毫克(ke)/厘米2(mg/cm2))、劑量(liang)持續(xu)時(shi)間(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru),6小(xiao)(xiao)(xiao)時(shi))、研究持續(xu)時(shi)間(如(ru)(ru)(ru)(ru)(ru),24小(xiao)(xiao)(xiao)時(shi)、48小(xiao)(xiao)(xiao)時(shi)等)、受(shou)體(ti)溶液取樣時(shi)間(例(li)(li)(li)(li)如(ru)(ru)(ru)(ru)(ru)1、2、4、6、8、12、16、20和24小(xiao)(xiao)(xiao)時(shi))等。《IVPT測(ce)試(shi)(shi)中(zhong)(zhong)的(de)皮膚(fu)研究》



B. IVPT Method Considerations

The choice of some IVPT method parameters like the equipment, skin source, skin type, skin preparation, and skin barrier integrity test procedures may be based upon investigator experience or convenience, like the availability of specific equipment or instrumentation in a laboratory, established tissue supply agreements, or other logistical considerations. However, if the chosen IVPT method parameters do not appear to be well-suited for a specific IVPT method, it is the applicant’s responsibility to systematically evaluate alternative method parameters, and ultimately, to validate that the IVPT method parameters chosen are suitable for the intended purpose. The recommended procedures for IVPT method validation are detailed in section IV of this guidance.

一些IVPT方法參數的選擇,如設備、皮膚來源、皮膚類型、皮膚準備和皮膚屏障完整性測試程序,可能基于研究人員的經驗或便利性,如實驗室中特定設備或儀器的可用性、既定的組織供應協議或其他后勤考慮。然而,如果選定的IVPT方法參數似乎不適合特定的IVPT法,則申請人有責任系統地評估備選方法參數,并最終驗證選定的IVPT方法參數是否適合預期用途。IVPT方法驗證的推薦程序詳見本指南第四節。

The choice of other IVPT method parameters like the topical product dose amount, dose duration, study duration (which may be longer than the dose duration), sampling schedule, sampling procedures, receptor solution composition, and sample analytical method may be different for each IVPT method, and such parameters of IVPT methods should be systematically developed, optimized, and/or validated for the relevant topical product, as appropriate. The IVPT method development studies should characterize how differences in these method parameters influence the resulting IVPT flux profile so that optimal study conditions can be objectively selected from among those evaluated.

其他IVPT方(fang)法參(can)數(shu)的(de)選(xuan)擇,如(ru)局(ju)部(bu)產品(pin)劑量、劑量持續(xu)時間(jian)、研究(jiu)持續(xu)時間(jian)(可能長(chang)于劑量持續(xu)時間(jian))、取樣(yang)計劃、取樣(yang)程序、受體(ti)溶液組成和樣(yang)品(pin)分析(xi)方(fang)法,對(dui)于每種(zhong)IVPT方(fang)法可能有(you)所不同,應系統開(kai)發、優化IVPT方(fang)法的(de)此類參(can)數(shu),和/或(huo)對(dui)相(xiang)關局(ju)部(bu)產品(pin)進行驗(yan)證。IVPT方(fang)法開(kai)發研究(jiu)應描述這(zhe)些方(fang)法參(can)數(shu)的(de)差(cha)異(yi)如(ru)何影(ying)響最終的(de)IVPT通量分布,以便從評估的(de)條件中客觀選(xuan)擇最佳研究(jiu)條件。



The selection of the dose amount used in the study should be assessed for each IVPT method based upon studies performed during IVPT method development. Different dose amounts may be compared in parallel on replicate skin sections from the same set of donors to optimize the dose amount for the IVPT study. Considerations for selecting an optimal dose amount may include (1) the consistency with which the dose can be applied (potentially using different dispensing and/or spreading techniques), (2) the reproducibility of the flux profiles, (3) the influence of dose amount and dose duration on the shape of the flux profile, and (4) the approximate range of drug concentrations in receptor solution samples at different time points (relative to the sample analytical method limits of quantification).

應根據(ju)IVPT方法開發期間(jian)進行的(de)(de)研究,評估(gu)每種IVPT方法在研究中使用的(de)(de)劑(ji)(ji)(ji)量(liang)選(xuan)擇(ze)(ze)。可(ke)以(yi)在來自同一組(zu)供體(ti)(ti)的(de)(de)復(fu)制(zhi)皮膚切片上(shang)平行比較(jiao)不(bu)同劑(ji)(ji)(ji)量(liang),以(yi)優化IVPT研究的(de)(de)劑(ji)(ji)(ji)量(liang)。選(xuan)擇(ze)(ze)最佳劑(ji)(ji)(ji)量(liang)的(de)(de)考慮因素可(ke)以(yi)包括(kuo)(1)可(ke)以(yi)施加劑(ji)(ji)(ji)量(liang)的(de)(de)一致(zhi)性(可(ke)能(neng)使用不(bu)同的(de)(de)分(fen)配和/或散布(bu)技術),(2)通(tong)量(liang)分(fen)布(bu)的(de)(de)再(zai)現性,(3)劑(ji)(ji)(ji)量(liang)和劑(ji)(ji)(ji)量(liang)持續時間(jian)對(dui)通(tong)量(liang)分(fen)布(bu)形狀的(de)(de)影響,和(4)不(bu)同時間(jian)點受(shou)體(ti)(ti)溶液樣品中藥物濃度的(de)(de)近似范(fan)圍(相對(dui)于樣品分(fen)析(xi)方法的(de)(de)定量(liang)限值)。



The selected sampling schedule and study duration should be sufficient to characterize the cutaneous pharmacokinetics of the drug, which ideally includes a sufficiently complete flux profile to identify the maximum (peak) flux and a decline in the flux thereafter across multiple subsequent time points. A dose that remains on the skin for the duration of the study may continue to deliver the drug for a sustained period and may not necessarily exhibit a suitable decline in the flux at later time points. In such instances, it may be appropriate to develop an IVPT method that involves wiping off the applied dose after a suitable duration on the skin and continuing to monitor the receptor solution for an extended period thereafter, during which the decline in the flux profile can be characterized. The sampling frequency should be selected to provide a suitable resolution for the flux profile, and a minimum of eight non-zero sampling time points is recommended across the study duration (e.g., 48 hours).

所選(xuan)擇的(de)(de)采樣(yang)時(shi)間(jian)(jian)表(biao)和研究(jiu)(jiu)持續(xu)時(shi)間(jian)(jian)應足(zu)以表(biao)征(zheng)藥(yao)物的(de)(de)皮(pi)膚(fu)藥(yao)代動(dong)力學,理想情(qing)況下,包(bao)括(kuo)足(zu)夠完整的(de)(de)通量(liang)曲線,以確定最大(峰值)通量(liang)以及(ji)隨后(hou)在(zai)(zai)(zai)多(duo)個(ge)后(hou)續(xu)時(shi)間(jian)(jian)點(dian)(dian)的(de)(de)通量(liang)下降。在(zai)(zai)(zai)研究(jiu)(jiu)持續(xu)時(shi)間(jian)(jian)內(nei)留在(zai)(zai)(zai)皮(pi)膚(fu)上的(de)(de)劑量(liang)可(ke)能(neng)(neng)會持續(xu)給藥(yao)一段(duan)時(shi)間(jian)(jian),并(bing)且(qie)不一定會在(zai)(zai)(zai)以后(hou)的(de)(de)時(shi)間(jian)(jian)點(dian)(dian)出現適(shi)當的(de)(de)流(liu)量(liang)下降。在(zai)(zai)(zai)這種情(qing)況下,開發IVPT方法可(ke)能(neng)(neng)是合(he)適(shi)的(de)(de),該方法包(bao)括(kuo)在(zai)(zai)(zai)皮(pi)膚(fu)上適(shi)當的(de)(de)持續(xu)時(shi)間(jian)(jian)后(hou)擦去施用的(de)(de)劑量(liang),并(bing)在(zai)(zai)(zai)此(ci)后(hou)的(de)(de)較長時(shi)間(jian)(jian)內(nei)繼續(xu)監測(ce)受體溶(rong)液,在(zai)(zai)(zai)此(ci)期間(jian)(jian)可(ke)以表(biao)征(zheng)通量(liang)分布的(de)(de)下降。應選(xuan)擇采樣(yang)頻(pin)率,以便(bian)為通量(liang)分布提(ti)供合(he)適(shi)的(de)(de)分辨率,并(bing)且(qie)建議在(zai)(zai)(zai)整個(ge)研究(jiu)(jiu)持續(xu)時(shi)間(jian)(jian)內(nei)(例如,48小(xiao)時(shi))至(zhi)少八個(ge)非零采樣(yang)時(shi)間(jian)(jian)點(dian)(dian)。



C. IVPT Method Procedures and Controls

Suitable technical procedures and control parameters should be established during method development. These may include procedures for preparing and mounting the skin on the diffusion cell in a consistent manner, determining the instrument settings that regulate the skin surface temperature within the specified range, performing the barrier integrity test appropriately, controlling the accuracy and precision of the dose amount dispensed on each skin section.

在(zai)方法開發過程中(zhong),應建(jian)立適當的(de)技(ji)術(shu)程序和控制參數(shu)。這些(xie)可以包括以一致(zhi)的(de)方式(shi)制備皮(pi)膚并將(jiang)其安(an)裝在(zai)擴散(san)池上的(de)程序,確定將(jiang)皮(pi)膚表面溫度調節(jie)在(zai)規(gui)定范圍內的(de)儀器(qi)設置(zhi),適當地進(jin)行屏障完整性測試,控制分配到每(mei)個(ge)皮(pi)膚部分的(de)劑(ji)量的(de)準(zhun)確性和精密(mi)度。



For example, a dosing procedure may be developed that uses a positive displacement pipette to dispense a volumetrically controlled amount of a topical product, targeting the deposition on the skin of a certain mass (e.g., 15 mg/cm2 ) of topical product. If the inner diameter of the orifice in the dosing compartment of the diffusion cell is 15 millimeters (mm), and the effective dose area is ~1.77 cm2 , this would indicate a target dose of ~26.5 mg of topical product per diffusion cell. Experiments during method development may establish that, based upon the density of the topical product, a specific volumetric setting on a specific model of positive displacement pipette with a specific pipette tip repeatedly dispenses ~27.5 mg of topical product (e.g., characterized by multiple replicate pipette dispensations into a weigh boat on a fine balance). This pipette setting may be optimal for a dosing procedure where the dose spreading instrument, like the flat bottom of a high performance liquid chromatography (HPLC) glass vial, or the rounded end of a glass rod or capillary tube, is subsequently used to spread the dispensed dose evenly upon the skin section mounted in the diffusion cell, and where repeatedly weighing the dose-spreading instrument before and after the dose spreading indicates that the residual topical product remaining on the bottom of the glass vial after the dose spreading reproducibly amounts to ~1.0 mg of topical product (indicating that ~26.5 mg of the topical product would reproducibly be dosed to each skin section). Such characterizations of the technical procedures and control parameters for the IVPT method, like the reproducibility of the dosing procedure, should be established during method development and may not need to be demonstrated thereafter each time the same procedure is used.

例如,可(ke)(ke)以開發(fa)一種劑(ji)(ji)(ji)量(liang)(liang)(liang)程(cheng)序,其使用(yong)(yong)(yong)正(zheng)位移(yi)(yi)移(yi)(yi)液(ye)(ye)(ye)(ye)管來分(fen)(fen)(fen)配(pei)(pei)體(ti)積(ji)(ji)(ji)控(kong)制量(liang)(liang)(liang)的(de)(de)(de)(de)(de)(de)(de)(de)局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin),靶向一定(ding)(ding)(ding)質量(liang)(liang)(liang)(例如,15mg/cm2)的(de)(de)(de)(de)(de)(de)(de)(de)局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin)在皮膚(fu)上的(de)(de)(de)(de)(de)(de)(de)(de)沉積(ji)(ji)(ji)。如果(guo)擴(kuo)散(san)池(chi)給(gei)(gei)藥室的(de)(de)(de)(de)(de)(de)(de)(de)孔口(kou)內徑為(wei)15毫米(mm),有(you)效劑(ji)(ji)(ji)量(liang)(liang)(liang)面積(ji)(ji)(ji)約為(wei)1.77 cm2,則表(biao)明(ming)每個擴(kuo)散(san)池(chi)的(de)(de)(de)(de)(de)(de)(de)(de)目標劑(ji)(ji)(ji)量(liang)(liang)(liang)為(wei)約26.5 mg局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin)。方(fang)法開發(fa)過(guo)程(cheng)中的(de)(de)(de)(de)(de)(de)(de)(de)實(shi)驗可(ke)(ke)以確定(ding)(ding)(ding),基于外用(yong)(yong)(yong)產(chan)品(pin)的(de)(de)(de)(de)(de)(de)(de)(de)密(mi)度,具有(you)特(te)(te)定(ding)(ding)(ding)移(yi)(yi)液(ye)(ye)(ye)(ye)管的(de)(de)(de)(de)(de)(de)(de)(de)特(te)(te)定(ding)(ding)(ding)型號正(zheng)移(yi)(yi)液(ye)(ye)(ye)(ye)管的(de)(de)(de)(de)(de)(de)(de)(de)特(te)(te)定(ding)(ding)(ding)體(ti)積(ji)(ji)(ji)設置可(ke)(ke)重(zhong)復(fu)分(fen)(fen)(fen)配(pei)(pei)約27.5 mg外用(yong)(yong)(yong)產(chan)品(pin)(例如,以多(duo)次重(zhong)復(fu)移(yi)(yi)液(ye)(ye)(ye)(ye)管分(fen)(fen)(fen)配(pei)(pei)為(wei)特(te)(te)征,將其分(fen)(fen)(fen)配(pei)(pei)到(dao)(dao)精密(mi)天(tian)平上的(de)(de)(de)(de)(de)(de)(de)(de)稱量(liang)(liang)(liang)舟中)。這種移(yi)(yi)液(ye)(ye)(ye)(ye)管設置對于劑(ji)(ji)(ji)量(liang)(liang)(liang)分(fen)(fen)(fen)配(pei)(pei)過(guo)程(cheng)可(ke)(ke)能是(shi)最(zui)佳的(de)(de)(de)(de)(de)(de)(de)(de),其中劑(ji)(ji)(ji)量(liang)(liang)(liang)分(fen)(fen)(fen)配(pei)(pei)儀器,如高效液(ye)(ye)(ye)(ye)相色(se)譜(HPLC)玻璃瓶(ping)(ping)的(de)(de)(de)(de)(de)(de)(de)(de)平底,或(huo)玻璃棒或(huo)毛細管的(de)(de)(de)(de)(de)(de)(de)(de)圓(yuan)形端,隨后(hou)用(yong)(yong)(yong)于將分(fen)(fen)(fen)配(pei)(pei)的(de)(de)(de)(de)(de)(de)(de)(de)劑(ji)(ji)(ji)量(liang)(liang)(liang)均勻地分(fen)(fen)(fen)配(pei)(pei)到(dao)(dao)安裝在擴(kuo)散(san)池(chi)中的(de)(de)(de)(de)(de)(de)(de)(de)皮膚(fu)部(bu)(bu)(bu)分(fen)(fen)(fen)上,并且其中在劑(ji)(ji)(ji)量(liang)(liang)(liang)散(san)布之(zhi)前和之(zhi)后(hou)重(zhong)復(fu)稱量(liang)(liang)(liang)劑(ji)(ji)(ji)量(liang)(liang)(liang)散(san)布儀器表(biao)明(ming),在劑(ji)(ji)(ji)量(liang)(liang)(liang)散(san)布之(zhi)后(hou)殘(can)留在玻璃瓶(ping)(ping)底部(bu)(bu)(bu)的(de)(de)(de)(de)(de)(de)(de)(de)殘(can)留局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin)可(ke)(ke)重(zhong)復(fu)地達(da)到(dao)(dao)約1.0mg局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin)(表(biao)明(ming)將可(ke)(ke)重(zhong)復(fu)地將約26.5mg局(ju)(ju)部(bu)(bu)(bu)產(chan)品(pin)施用(yong)(yong)(yong)到(dao)(dao)每個皮膚(fu)部(bu)(bu)(bu)分(fen)(fen)(fen))。IVPT方(fang)法的(de)(de)(de)(de)(de)(de)(de)(de)技術程(cheng)序和控(kong)制參數的(de)(de)(de)(de)(de)(de)(de)(de)此類特(te)(te)征,如給(gei)(gei)藥程(cheng)序的(de)(de)(de)(de)(de)(de)(de)(de)再現性(xing),應(ying)在方(fang)法開發(fa)過(guo)程(cheng)中確定(ding)(ding)(ding),此后(hou)可(ke)(ke)能不(bu)需要在每次使用(yong)(yong)(yong)相同程(cheng)序時進行證(zheng)明(ming)。‍

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D. ‍‍IVPT Skin Barrier Integrity Testing: Common Methods

The technical procedures for the skin barrier integrity test should be established during IVPT method development. Three types of barrier integrity tests are common, however, there are currently no applicable compendial standard protocols or acceptance criteria for any of these three types of human skin barrier integrity tests. Nonetheless, recommended parameters for the three common types of barrier integrity tests are discussed below.

應(ying)在IVPT方法開(kai)發(fa)期間制定皮膚屏(ping)障(zhang)完(wan)整性(xing)(xing)測試(shi)(shi)的(de)(de)技術程序。三(san)種類(lei)(lei)型(xing)的(de)(de)屏(ping)障(zhang)完(wan)整性(xing)(xing)測試(shi)(shi)是常見的(de)(de),然而,目前沒有適用于這三(san)種類(lei)(lei)型(xing)人體皮膚屏(ping)障(zhang)完(wan)整性(xing)(xing)檢測的(de)(de)藥典(dian)標準協議(yi)或驗收標準。盡管如此,下面討論(lun)了三(san)種常見類(lei)(lei)型(xing)的(de)(de)屏(ping)障(zhang)完(wan)整性(xing)(xing)測試(shi)(shi)的(de)(de)推(tui)薦參(can)數。IVPT測試(shi)(shi)中的(de)(de)皮膚研(yan)究



1. Trans-Epidermal Water Loss Skin Barrier Integrity Test

A TEWL skin barrier integrity test involves a measurement near the outer surface of the skin of the rate at which water (vapor) is fluxing through the skin barrier from the underside of the skin section. For the test, the skin section is mounted in a diffusion cell (e.g., clamped in place between the donor and receptor compartments), with the underside of the skin in contact with the receptor solution in the receptor compartment (e.g., phosphate buffered saline, pH 7.4), and equilibrated to a skin surface temperature of 32°C ± 1°C. If skin sections are cut large enough to cover the flange of the diffusion cell in which they are mounted, then after they have equilibrated for several hours at a skin surface temperature of 32°C ± 1°C, it may be feasible to gently remove the donor compartment without disrupting a skin section’s adherence to the lower flange of the diffusion cell, thereby allowing the TEWL probe to be placed directly on the skin surface, instead of being placed atop the donor compartment. Typically, a minimum of three replicate measurements are made on each skin section, which are recorded after the measurements have stabilized.

TEWL皮(pi)膚屏(ping)障完整性(xing)測試包括在皮(pi)膚外表面(mian)(mian)附近(jin)測量水(蒸汽)從(cong)皮(pi)膚部(bu)(bu)分(fen)下(xia)(xia)側(ce)流過皮(pi)膚屏(ping)障的速率。對于試驗(yan),將皮(pi)膚部(bu)(bu)分(fen)安(an)(an)裝(zhuang)在擴(kuo)散(san)池(chi)中(zhong)(例如,夾(jia)在供(gong)體(ti)和受體(ti)室之間的適(shi)當位置),皮(pi)膚下(xia)(xia)側(ce)與受體(ti)室中(zhong)的受體(ti)溶液(例如,磷酸鹽緩沖鹽水,pH 7.4)接觸,并平(ping)衡至32°C±1°C的皮(pi)膚表面(mian)(mian)溫度(du)。如果皮(pi)膚部(bu)(bu)分(fen)被切(qie)割(ge)得(de)足夠大(da),足以覆蓋其所安(an)(an)裝(zhuang)的擴(kuo)散(san)池(chi)的法蘭,那么(me)在皮(pi)膚表面(mian)(mian)溫度(du)為32°C±1°C的條件下(xia)(xia)平(ping)衡數小時后,可以在不破壞皮(pi)膚部(bu)(bu)分(fen)與擴(kuo)散(san)池(chi)下(xia)(xia)法蘭的粘附性(xing)的情(qing)況下(xia)(xia)輕輕移除(chu)供(gong)體(ti)隔(ge)室,從(cong)而(er)允許TEWL探針直(zhi)接放置在皮(pi)膚表面(mian)(mian)上(shang)而(er)不是放置在供(gong)體(ti)隔(ge)室的頂部(bu)(bu)。通常(chang),在每個(ge)皮(pi)膚部(bu)(bu)分(fen)上(shang)至少進行三次重(zhong)復測量,并在測量穩(wen)定后進行記(ji)錄。(下(xia)(xia)圖,皮(pi)膚測試用經(jing)皮(pi)水分(fen)流失測量儀(yi))

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Commercially available devices to measure TEWL may differ in design and operational principles. The TEWL measured by devices with certain designs (e.g., an open chamber versus a closed chamber) may be relatively more susceptible to the influence of environmental conditions. Therefore, environmental temperature and humidity are typically controlled as precisely as possible (e.g., a temperature range of 21°C ± 2°C and a humidity range of 50% ± 20% relative humidity are ideal, if feasible). More precise control of the relative humidity (e.g., in the range of 40% – 50%) may reduce the variability of TEWL measurements for devices with certain designs. Certain designs of measurement probes and adapters for in vitro use are available by the manufacturers of TEWL devices, and may be appropriate to use. Inconsistency in the diameters for the measurement probe chamber, the measurement probe orifice, the in vitro adapters, and the skin area being measured, as well as variation in the distance of the probe sensor(s) from the skin surface, potentially because of the (variable) height of donor compartments (when applicable), could increase the variability of TEWL measurements. Inconsistent control of the alignment of the TEWL measurement device in relation to the donor compartment and/or the skin section may also increase the variability of TEWL measurements. Also, the TEWL measured by devices with certain designs may be relatively more susceptible to the influence of heat transfer from the hand that holds the probe. Applicants should follow relevant instructions in the manufacturer’s user manual for the specific TEWL measurement device used.

用(yong)(yong)于(yu)(yu)測(ce)量(liang)(liang)(liang)(liang)TEWL的(de)(de)(de)(de)(de)(de)市(shi)售設備在設計(ji)和(he)操作原理上(shang)可(ke)(ke)(ke)(ke)能(neng)(neng)有(you)所(suo)不(bu)(bu)同。由(you)(you)具有(you)特(te)(te)定(ding)(ding)設計(ji)(例(li)(li)如(ru),開放室(shi)與封(feng)閉室(shi))的(de)(de)(de)(de)(de)(de)裝(zhuang)置(zhi)測(ce)量(liang)(liang)(liang)(liang)的(de)(de)(de)(de)(de)(de)TEWL可(ke)(ke)(ke)(ke)能(neng)(neng)相(xiang)對(dui)(dui)更(geng)容易受(shou)到環境條件的(de)(de)(de)(de)(de)(de)影響。因此,通常盡(jin)可(ke)(ke)(ke)(ke)能(neng)(neng)精確(que)地(di)控(kong)(kong)制環境溫度(du)(du)和(he)濕度(du)(du)(例(li)(li)如(ru),如(ru)果可(ke)(ke)(ke)(ke)行,理想的(de)(de)(de)(de)(de)(de)溫度(du)(du)范(fan)圍(wei)為(wei)21°C±2°C,濕度(du)(du)范(fan)圍(wei)為(wei)50%±20%相(xiang)對(dui)(dui)濕度(du)(du))。更(geng)精確(que)地(di)控(kong)(kong)制相(xiang)對(dui)(dui)濕度(du)(du)(例(li)(li)如(ru),在40%–50%的(de)(de)(de)(de)(de)(de)范(fan)圍(wei)內)可(ke)(ke)(ke)(ke)以(yi)減少具有(you)特(te)(te)定(ding)(ding)設計(ji)的(de)(de)(de)(de)(de)(de)設備的(de)(de)(de)(de)(de)(de)TEWL測(ce)量(liang)(liang)(liang)(liang)的(de)(de)(de)(de)(de)(de)可(ke)(ke)(ke)(ke)變(bian)(bian)(bian)性(xing)。TEWL裝(zhuang)置(zhi)的(de)(de)(de)(de)(de)(de)制造商可(ke)(ke)(ke)(ke)提(ti)供(gong)用(yong)(yong)于(yu)(yu)體外使用(yong)(yong)的(de)(de)(de)(de)(de)(de)測(ce)量(liang)(liang)(liang)(liang)探(tan)針和(he)適配器的(de)(de)(de)(de)(de)(de)某些設計(ji),并且可(ke)(ke)(ke)(ke)能(neng)(neng)適合使用(yong)(yong)。測(ce)量(liang)(liang)(liang)(liang)探(tan)頭(tou)室(shi)、測(ce)量(liang)(liang)(liang)(liang)探(tan)頭(tou)孔(kong)口、體外適配器和(he)被(bei)測(ce)皮膚面(mian)積的(de)(de)(de)(de)(de)(de)直徑不(bu)(bu)一(yi)致,以(yi)及探(tan)頭(tou)傳感器與皮膚表面(mian)的(de)(de)(de)(de)(de)(de)距離變(bian)(bian)(bian)化,可(ke)(ke)(ke)(ke)能(neng)(neng)是(shi)由(you)(you)于(yu)(yu)供(gong)體隔室(shi)的(de)(de)(de)(de)(de)(de)(可(ke)(ke)(ke)(ke)變(bian)(bian)(bian))高度(du)(du)(如(ru)適用(yong)(yong)),可(ke)(ke)(ke)(ke)能(neng)(neng)會增(zeng)(zeng)加(jia)TEWL測(ce)量(liang)(liang)(liang)(liang)的(de)(de)(de)(de)(de)(de)變(bian)(bian)(bian)異性(xing)。TEWL測(ce)量(liang)(liang)(liang)(liang)裝(zhuang)置(zhi)相(xiang)對(dui)(dui)于(yu)(yu)供(gong)體隔室(shi)和(he)/或皮膚部分的(de)(de)(de)(de)(de)(de)對(dui)(dui)準(zhun)的(de)(de)(de)(de)(de)(de)不(bu)(bu)一(yi)致控(kong)(kong)制也可(ke)(ke)(ke)(ke)能(neng)(neng)增(zeng)(zeng)加(jia)TEWL測(ce)定(ding)(ding)的(de)(de)(de)(de)(de)(de)可(ke)(ke)(ke)(ke)變(bian)(bian)(bian)性(xing)。此外,由(you)(you)具有(you)特(te)(te)定(ding)(ding)設計(ji)的(de)(de)(de)(de)(de)(de)設備測(ce)量(liang)(liang)(liang)(liang)的(de)(de)(de)(de)(de)(de)TEWL可(ke)(ke)(ke)(ke)能(neng)(neng)相(xiang)對(dui)(dui)更(geng)容易受(shou)到握住探(tan)頭(tou)的(de)(de)(de)(de)(de)(de)手的(de)(de)(de)(de)(de)(de)熱傳遞的(de)(de)(de)(de)(de)(de)影響。申請人(ren)應遵循制造商用(yong)(yong)戶手冊中關(guan)于(yu)(yu)所(suo)用(yong)(yong)特(te)(te)定(ding)(ding)TEWL測(ce)量(liang)(liang)(liang)(liang)設備的(de)(de)(de)(de)(de)(de)相(xiang)關(guan)說明。



No more than approximately 15 grams of water per square meter per hour (i.e., ≤ 15 g/m2 /hr) could be a reasonable skin barrier integrity acceptance (cutoff) criterion for a TEWL barrier integrity test on human torso or thigh skin; if this was selected as the cutoff criterion, skin sections with a TEWL > 15 g/m2 /hr would fail the test. Skin sections that fail a barrier integrity test should not be dosed, but may serve as non-dosed control skin sections. A higher cutoff (e.g., ≤ 20 g/m2 /hr) may also be reasonable if justified by experimental data demonstrating that the selected acceptance criterion appropriately discriminates skin sections with a compromised barrier integrity from those with a competent barrier integrity.

每(mei)平方米每(mei)小時不(bu)超過(guo)約15克水(例(li)如,≤ 15g/m2/hr)可能是(shi)人體軀干(gan)或大腿(tui)皮(pi)膚(fu)上TEWL屏(ping)障(zhang)完(wan)整性(xing)測(ce)試的(de)(de)合(he)理皮(pi)膚(fu)屏(ping)障(zhang)完(wan)整性(xing)驗(yan)收(截止(zhi))標準;如果(guo)將(jiang)此作為截止(zhi)標準,TEWL>15 g/m2/hr的(de)(de)皮(pi)膚(fu)切片將(jiang)無(wu)法通(tong)過(guo)測(ce)試。未通(tong)過(guo)屏(ping)障(zhang)完(wan)整性(xing)測(ce)試的(de)(de)皮(pi)膚(fu)部(bu)分不(bu)應給藥(yao),但可作為未給藥(yao)的(de)(de)對照(zhao)皮(pi)膚(fu)部(bu)分。較高的(de)(de)截止(zhi)(例(li)如,≤ 20g/m2/hr)也(ye)可能是(shi)合(he)理的(de)(de),如果(guo)實驗(yan)數(shu)據證(zheng)明所選(xuan)驗(yan)收標準適當地區分屏(ping)障(zhang)完(wan)整性(xing)受損的(de)(de)皮(pi)膚(fu)部(bu)分和(he)屏(ping)障(zhang)完(wan)整性(xing)合(he)格(ge)的(de)(de)皮(pi)膚(fu)部(bu)分。



However, TEWL measurements for skin sections with a competent barrier integrity can vary depending upon the TEWL measurement device, the manner in which it is operated, and the environmental conditions (e.g., higher ambient humidity or greater distance from the skin surface may decrease the value of the TEWL measurement). Precise control of environmental and device/operational factors can minimize variability in TEWL measurements. Therefore, the technical procedures for measuring TEWL should be optimized during IVPT method development (or based upon prior optimization in the laboratory performing the test). Also, the TEWL measurement device should be appropriately calibrated (by the manufacturer, and for some devices, also before each set of tests). Applicants may provide information about the relevant calibration procedures specified by the manufacturer for the specific TEWL device used; this can be submitted in the ANDA along with the IVPT method development report, to support the appropriateness of the technical procedures established by the laboratory for TEWL measurements. When a TEWL barrier integrity test is used in any study phase (IVPT method development, pilot study, validation, and/or pivotal study) the ambient laboratory temperature and humidity during the TEWL barrier integrity test should be monitored and reported.

然而(er),對于(yu)具有合格屏障完(wan)整性(xing)的(de)皮膚(fu)部分的(de)TEWL測(ce)(ce)(ce)量可(ke)以(yi)根據TEWL測(ce)(ce)(ce)試(shi)設(she)備、其操作方(fang)(fang)式和環(huan)(huan)(huan)(huan)境(jing)(jing)條件而(er)變化(hua)(例(li)如,較高的(de)環(huan)(huan)(huan)(huan)境(jing)(jing)濕度或(huo)離皮膚(fu)表面更(geng)大(da)的(de)距離可(ke)能(neng)會降低TEWL的(de)測(ce)(ce)(ce)量值)。精確控制(zhi)環(huan)(huan)(huan)(huan)境(jing)(jing)和設(she)備/操作因素可(ke)以(yi)最大(da)限度地減少TEWL測(ce)(ce)(ce)量的(de)變化(hua)。因此,應在(zai)IVPT方(fang)(fang)法開(kai)發過程(cheng)中(zhong)(zhong)優(you)化(hua)TEWL測(ce)(ce)(ce)量的(de)技(ji)術程(cheng)序(xu)(或(huo)基于(yu)實驗(yan)(yan)室(shi)進行(xing)試(shi)驗(yan)(yan)的(de)事先(xian)優(you)化(hua))。此外,TEWL測(ce)(ce)(ce)量設(she)備應進行(xing)適當校(xiao)準(由制(zhi)造商(shang)進行(xing)校(xiao)準,對于(yu)某些設(she)備,也應在(zai)每組測(ce)(ce)(ce)試(shi)之前進行(xing)校(xiao)準)。申請人可(ke)提供制(zhi)造商(shang)為(wei)所用特定TEWL裝置規定的(de)相關(guan)(guan)校(xiao)準程(cheng)序(xu)的(de)信(xin)息(xi);這可(ke)以(yi)與IVPT方(fang)(fang)法開(kai)發報(bao)告一起提交(jiao)在(zai)ANDA中(zhong)(zhong),以(yi)支持(chi)實驗(yan)(yan)室(shi)為(wei)TEWL測(ce)(ce)(ce)量建立(li)的(de)技(ji)術程(cheng)序(xu)的(de)適當性(xing)。當TEWL屏障完(wan)整性(xing)測(ce)(ce)(ce)試(shi)用于(yu)任何(he)研究(jiu)(jiu)階段(IVPT方(fang)(fang)法開(kai)發、試(shi)點研究(jiu)(jiu)、驗(yan)(yan)證和/或(huo)關(guan)(guan)鍵研究(jiu)(jiu))時,應監(jian)測(ce)(ce)(ce)和報(bao)告TEWL阻隔完(wan)整性(xing)測(ce)(ce)(ce)試(shi)期間(jian)的(de)實驗(yan)(yan)室(shi)環(huan)(huan)(huan)(huan)境(jing)(jing)溫度和濕度。



2.Tritiated Water Skin Barrier Integrity Test

An example of a recommended approach to a tritiated water skin barrier integrity test would be to mount the skin in a diffusion cell (e.g., clamped in place between the donor and receptor compartments) and allow it to equilibrate to a skin surface temperature of 32°C ± 1°C with the stratum corneum exposed to the air in the donor compartment and the underside of the skin in contact with the receptor solution (e.g., phosphate buffered saline, pH 7.4).

氚化水-皮膚(fu)屏障完整性測試的推薦方法的一個例(li)子是(shi)將皮膚(fu)安(an)裝在擴散池中(zhong)(zhong)(例(li)如,夾在供(gong)體(ti)和受體(ti)室(shi)之間(jian)的適當位置),并使其平(ping)衡至32°C±1°C的皮膚(fu)表面(mian)溫度,使角質層暴露在供(gong)體(ti)室(shi)中(zhong)(zhong)的空氣中(zhong)(zhong),皮膚(fu)下側與受體(ti)溶液(例(li)如磷(lin)酸鹽緩沖鹽水,pH 7.4)。



A small amount of tritiated water (sufficient to cover the entire surface of the skin section) would be briefly dosed on the stratum corneum. This dose of tritiated water would be left on the surface for a precisely controlled and relatively brief period (e.g., 5 minutes) after which it would be removed from the skin surface (e.g., using a pipette to remove the bulk volume and then an absorbent low lint laboratory tissue to gently blot dry). The receptor solution would then be sampled at a precise duration after the removal of the tritiated water from the skin surface (e.g., 30 minutes after the removal of the 5-minute dose of tritiated water from the skin surface).

將少量(liang)(liang)(liang)的(de)氚水(足以(yi)覆蓋皮(pi)膚(fu)部(bu)分(fen)的(de)整個表面(mian))短暫地施加(jia)于角質層。該劑量(liang)(liang)(liang)的(de)氚水將在表面(mian)上停留一(yi)段精確控制(zhi)且相對較短的(de)時間(例如,5分(fen)鐘),之(zhi)后(hou)將其(qi)從皮(pi)膚(fu)表面(mian)去(qu)(qu)除(chu)(例如,使用(yong)移液管去(qu)(qu)除(chu)大量(liang)(liang)(liang)體(ti)積,然后(hou)使用(yong)實驗室吸水紙輕(qing)輕(qing)吸干)。然后(hou)在從皮(pi)膚(fu)表面(mian)去(qu)(qu)除(chu)氚水之(zhi)后(hou)的(de)精確持續(xu)時間(例如,從皮(pi)膚(fu)表面(mian)除(chu)去(qu)(qu)5分(fen)鐘劑量(liang)(liang)(liang)的(de)氚水后(hou)30分(fen)鐘)對受(shou)體(ti)溶(rong)液進行取樣(yang)。



While the entire volume of the receptor compartment may be removed and replenished, typically only an aliquot of the receptor solution (e.g., phosphate buffered saline, pH 7.4) is transferred to a suitable volume of scintillation fluid for counting. The volume of the aliquot typically depends upon the type of scintillation fluid used and the maximum amount of aqueous fluid that is suitable to mix with the scintillation fluid. A scintillation counter is then used to quantify the amount of radioactivity in the aliquot sampled, which can be used to calculate the amount of tritiated water that permeated into the larger (entire) volume of receptor solution; the calculation is performed using the specific activity of the tritiated water to equate a given amount of radioactivity to the equivalent volume of tritiated water that permeated per square centimeter of skin surface area.

雖然可(ke)以(yi)(yi)移除并補充整個體(ti)積(ji)(ji)的(de)受(shou)體(ti)室,但通常(chang)僅將一等分的(de)受(shou)體(ti)溶液(ye)(例如,磷酸(suan)鹽緩沖鹽水(shui),pH 7.4)轉移到合(he)適體(ti)積(ji)(ji)的(de)閃(shan)爍(shuo)液(ye)中進行(xing)計數(shu)。等分試(shi)樣的(de)體(ti)積(ji)(ji)通常(chang)取決于所使(shi)(shi)用的(de)閃(shan)爍(shuo)流體(ti)的(de)類型以(yi)(yi)及適合(he)與閃(shan)爍(shuo)流體(ti)混合(he)的(de)水(shui)性(xing)流體(ti)的(de)最大(da)量(liang)。然后(hou),使(shi)(shi)用閃(shan)爍(shuo)計數(shu)器來(lai)定(ding)量(liang)取樣的(de)等分試(shi)樣中的(de)放射性(xing)量(liang),可(ke)用于計算滲入(ru)較大(da)(整個)體(ti)積(ji)(ji)的(de)受(shou)體(ti)溶液(ye)中的(de)氚(chuan)水(shui)的(de)量(liang);使(shi)(shi)用氚(chuan)水(shui)的(de)比活度進行(xing)計算,以(yi)(yi)將給定(ding)的(de)放射性(xing)量(liang)等同(tong)于每(mei)平方厘米皮膚(fu)表面積(ji)(ji)滲透的(de)氚(chuan)水(shui)當量(liang)體(ti)積(ji)(ji)。



Approximately 1.5 equivalent(eq.) microliter (µL) of tritiated water per cm2 (i.e., ~1.5 eq. µL/cm2 or ~1.5 eq. mg/cm2 ) would be a reasonable skin barrier integrity acceptance (cutoff) criterion for a tritiated water barrier integrity test that involves a 5-minute dose followed by a 30- minute sampling duration (i.e., sampling 30 minutes after dose removal) on human torso or thigh skin. Skin sections with a tritiated water test result of > 1.5 eq. mg/cm2 would fail the test and be excluded from the population of skin sections dosed with the topical product; skin sections that fail a barrier integrity test should not be dosed, but may serve as non-dosed control skin sections. Other acceptance criteria may also be reasonable if justified by experimental data demonstrating that the selected acceptance criterion appropriately discriminates skin sections with a compromised barrier integrity from those with a competent barrier integrity.

人(ren)體(ti)軀干或大腿(tui)皮(pi)(pi)膚(fu)(fu)(fu)上氚(chuan)(chuan)水屏障(zhang)(zhang)(zhang)完整(zheng)性測試的(de)合理(li)皮(pi)(pi)膚(fu)(fu)(fu)屏障(zhang)(zhang)(zhang)完整(zheng)性驗(yan)收(shou)(截止)標(biao)準是每cm2約1.5當量(eq)微(wei)升(sheng)(µL)的(de)氚(chuan)(chuan)水(例如(ru),約1.5 eq. µL/cm2或約1.5 eq. mg/cm2)。該測試涉(she)及5分(fen)(fen)鐘(zhong)劑量,隨后30分(fen)(fen)鐘(zhong)采樣持續時(shi)間(即(ji),去除劑量后30分(fen)(fen)鐘(zhong)采樣)。氚(chuan)(chuan)水測試結果大于1.5 eq. mg/cm2的(de)皮(pi)(pi)膚(fu)(fu)(fu)切片判(pan)定為(wei)未(wei)(wei)通過(guo)測試,并(bing)被排除在使用局部(bu)產品的(de)皮(pi)(pi)膚(fu)(fu)(fu)切片人(ren)群(qun)之外;未(wei)(wei)通過(guo)屏障(zhang)(zhang)(zhang)完整(zheng)性測試的(de)皮(pi)(pi)膚(fu)(fu)(fu)部(bu)分(fen)(fen)不應給藥,但可(ke)(ke)作為(wei)未(wei)(wei)給藥的(de)對照皮(pi)(pi)膚(fu)(fu)(fu)部(bu)分(fen)(fen)。如(ru)果實驗(yan)數(shu)據證明所選驗(yan)收(shou)標(biao)準能(neng)夠適當區(qu)分(fen)(fen)屏障(zhang)(zhang)(zhang)完整(zheng)性受(shou)損(sun)的(de)皮(pi)(pi)膚(fu)(fu)(fu)部(bu)分(fen)(fen)和屏障(zhang)(zhang)(zhang)完整(zheng)性合格的(de)皮(pi)(pi)膚(fu)(fu)(fu)部(bu)分(fen)(fen),則其他驗(yan)收(shou)標(biao)準也可(ke)(ke)能(neng)合理(li)。(下(xia)圖,放(fang)射性測試用閃點計數(shu)器)



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When calculating the results for a tritiated water barrier integrity test, it may be important to account for the surface area dosed. For example, if using an acceptance criterion of 1.5 eq. mg/cm2 with a diffusion cell that has an orifice diameter of 15 mm and a skin surface area of 1.77 cm2 , the mass of tritiated water that would be calculated to have permeated into the receptor compartment would be ~2.7 eq. mg/cm2 of tritiated water.

當(dang)計(ji)算(suan)氚(chuan)水屏障完整性測試的(de)(de)(de)結果(guo)時,給藥表(biao)面積(ji)(ji)是一個很重要的(de)(de)(de)影響(xiang)因素。例如,如果(guo)使用1.5 eq. mg/cm2的(de)(de)(de)驗收標(biao)準和孔直(zhi)徑為(wei)15 mm、皮膚表(biao)面積(ji)(ji)為(wei)1.77 cm2的(de)(de)(de)擴散池,則(ze)計(ji)算(suan)出滲入受體室的(de)(de)(de)氚(chuan)水質(zhi)量為(wei)約2.7 eq. mg/cm2的(de)(de)(de)氚(chuan)。



3.Electrical Based Skin Barrier Integrity Tests

There are several variations of electrical based skin barrier integrity tests that report the test result as a measure of the resistance, conductance, or a related electrical concept that characterizes the bulk flow of electrical current across the skin. Transepithelial electrical resistance tests involving the skin may be referred to more specifically as Trans-Epidermal Electrical Resistance (TEER) skin barrier integrity tests. The test results may be described in units of conductance, which is the reciprocal of resistance. Electrical based skin barrier integrity tests often use instruments that are designed to measure the inductance (L), capacitance (C), and resistance (R) of electronic circuits or electrical components; these instruments are commonly known as LCR meters and have different settings (test parameters) that can be adjusted.

基(ji)于(yu)電(dian)(dian)(dian)(dian)(dian)的(de)皮(pi)膚屏(ping)障完(wan)整性(xing)測(ce)(ce)試(shi)(shi)(shi)有(you)幾種(zhong)變體(ti)(ti),將測(ce)(ce)試(shi)(shi)(shi)結果(guo)報(bao)告為(wei)電(dian)(dian)(dian)(dian)(dian)阻(zu)(zu)、電(dian)(dian)(dian)(dian)(dian)導或相關電(dian)(dian)(dian)(dian)(dian)概念的(de)測(ce)(ce)量(liang)值,以表(biao)征穿過皮(pi)膚的(de)整體(ti)(ti)電(dian)(dian)(dian)(dian)(dian)流。涉(she)及皮(pi)膚的(de)經(jing)上皮(pi)電(dian)(dian)(dian)(dian)(dian)阻(zu)(zu)測(ce)(ce)試(shi)(shi)(shi)可(ke)以更具(ju)體(ti)(ti)地稱(cheng)為(wei)經(jing)表(biao)皮(pi)電(dian)(dian)(dian)(dian)(dian)阻(zu)(zu)(TEER)皮(pi)膚屏(ping)障完(wan)整性(xing)測(ce)(ce)試(shi)(shi)(shi)。測(ce)(ce)試(shi)(shi)(shi)結果(guo)可(ke)用(yong)電(dian)(dian)(dian)(dian)(dian)導單(dan)位表(biao)示(shi),電(dian)(dian)(dian)(dian)(dian)導是電(dian)(dian)(dian)(dian)(dian)阻(zu)(zu)的(de)倒數。基(ji)于(yu)電(dian)(dian)(dian)(dian)(dian)氣的(de)皮(pi)膚屏(ping)障完(wan)整性(xing)測(ce)(ce)試(shi)(shi)(shi)通常使用(yong)設計用(yong)于(yu)測(ce)(ce)量(liang)電(dian)(dian)(dian)(dian)(dian)子電(dian)(dian)(dian)(dian)(dian)路或電(dian)(dian)(dian)(dian)(dian)氣部件(jian)的(de)電(dian)(dian)(dian)(dian)(dian)感(L)、電(dian)(dian)(dian)(dian)(dian)容(C)和(he)電(dian)(dian)(dian)(dian)(dian)阻(zu)(zu)(R)的(de)儀器;這些儀器通常被稱(cheng)為(wei)LCR儀表(biao),并具(ju)有(you)可(ke)調整的(de)不同(tong)設置(zhi)(測(ce)(ce)試(shi)(shi)(shi)參數)。



An example of a recommended approach to a TEER skin barrier integrity test would be to mount the skin in a diffusion cell (e.g., clamped in place between the donor and receptor compartments) and allow it to equilibrate to a skin surface temperature of 32°C ± 1°C with the stratum corneum exposed to the air in the donor compartment and the underside of the skin in contact with an ionic solution (e.g., phosphate buffered saline, pH 7.4).

TEER皮(pi)膚屏障完整性測試(shi)推薦方(fang)法的一個示例(li)是(shi)將(jiang)皮(pi)膚安裝在擴散池(chi)中(zhong)(zhong)(例(li)如,夾在供(gong)體和受體隔室之(zhi)間的適(shi)當位置),并(bing)使其恒(heng)定在32°C&plusmn;1°C的皮(pi)膚表面溫(wen)度,角質層暴(bao)露于供(gong)體隔室中(zhong)(zhong)的空(kong)氣中(zhong)(zhong),皮(pi)膚下(xia)側與離子(zi)溶液(ye)接觸(例(li)如,磷酸鹽緩沖(chong)鹽水,pH 7.4)。



A small amount of the ionic solution (sufficient to cover the entire surface of the skin section) would be briefly dosed on the stratum corneum. Then, one lead/electrode from an LCR meter would be placed in contact with the solution in the receptor compartment while the other lead/electrode would be placed in contact with the solution in the donor compartment. After measuring the resistance across the skin (e.g., in kΩ, normalized for area, noting that resistance is inversely proportional to area) the solution in the donor compartment would be removed and the skin surface would be gently blotted dry with an absorbent low lint laboratory tissue. The skin (still mounted in the diffusion cell) would then be allowed to equilibrate with the dry air above for a sufficient duration to normalize the hydration state of the stratum corneum before being dosed with the test topical product or RS.

將(jiang)少量離子(zi)溶液(ye)(足以覆蓋皮(pi)(pi)膚部分(fen)的(de)(de)(de)整個表(biao)面(mian))短暫地施加到角(jiao)質(zhi)層上(shang)。然(ran)后,LCR測(ce)(ce)量儀(yi)的(de)(de)(de)一根導線/電(dian)極(ji)與受體(ti)室(shi)(shi)中(zhong)(zhong)的(de)(de)(de)溶液(ye)接觸,而另一根導線或電(dian)極(ji)與供(gong)體(ti)室(shi)(shi)中(zhong)(zhong)的(de)(de)(de)液(ye)體(ti)接觸。測(ce)(ce)量皮(pi)(pi)膚上(shang)的(de)(de)(de)電(dian)阻(例(li)如(ru),kΩ,按面(mian)積(ji)歸一化(hua),注(zhu)意電(dian)阻與面(mian)積(ji)成(cheng)反比(bi))后,除去供(gong)體(ti)室(shi)(shi)中(zhong)(zhong)的(de)(de)(de)溶液(ye),并用(yong)吸(xi)水(shui)性低皮(pi)(pi)棉(mian)實驗室(shi)(shi)紙巾輕(qing)(qing)輕(qing)(qing)吸(xi)干皮(pi)(pi)膚表(biao)面(mian)。然(ran)后讓皮(pi)(pi)膚(仍安裝在擴散池中(zhong)(zhong))與上(shang)面(mian)的(de)(de)(de)干燥空氣平(ping)衡(heng)足夠長的(de)(de)(de)時間,以使角(jiao)質(zhi)層的(de)(de)(de)水(shui)合狀態正常化(hua)。



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The results for a TEER skin barrier integrity test can vary substantially depending on the LCR meter settings (e.g., frequency) and the technical procedures used for the test. The acceptance criterion for a specific electrical based skin barrier integrity test method may be justified by experimental data demonstrating that the selected acceptance criterion appropriately discriminates skin sections with a compromised barrier integrity from those with a competent barrier integrity.

TEER皮(pi)膚屏(ping)障(zhang)完整(zheng)性測試(shi)的(de)結(jie)果可能會根據LCR儀表設置(例如(ru)頻率(lv))和(he)測試(shi)使用的(de)技(ji)術程(cheng)序而產生較(jiao)大差異。可以通過(guo)實驗(yan)數(shu)據證(zheng)明,特定基于(yu)電氣的(de)皮(pi)膚屏(ping)障(zhang)完整(zheng)性測試(shi)方法的(de)驗(yan)收標準可以適(shi)當區分屏(ping)障(zhang)完整(zheng)性受損的(de)皮(pi)膚部(bu)分和(he)屏(ping)障(zhang)完整(zheng)性合格的(de)皮(pi)膚部(bu)分。



E.IVPT Skin Barrier Integrity Testing: General Considerations

There are three general considerations for the development or adoption of technical procedures for any skin barrier integrity test method during IVPT method development:

在(zai)IVPT方法開(kai)發(fa)過程中,開(kai)發(fa)或采用任何皮膚屏障完整(zheng)性(xing)測試方法的技(ji)術程序有三個一般(ban)考慮(lv)因(yin)素:



i. The technical procedures should not irreversibly alter the skin barrier. It may be acceptable to temporarily alter the hydration state of the stratum corneum by briefly depositing an aqueous solution on the surface of the skin, as long as sufficient time is afforded for the hydration of the stratum corneum to normalize before dosing of the topical product. The procedure described above for a brief (e.g., 5-minute) exposure of the skin surface to tritiated water followed by a 30-minute duration during which the hydration state of the stratum corneum is re-equilibrating would likely be appropriate. By contrast, a 30-minute exposure of the skin surface to an aqueous solution for an electricalbased test method, followed within 5 minutes by dosing of the topical product, may not be appropriate without further characterization of the influence of the hydration state of the stratum corneum on the discrimination sensitivity of the skin to differences in topical bioavailability. Similarly, if a portable lamp were placed close to the skin to improve visibility while study procedures were being performed, the heat from the lamp may alter the local (micro)environment of the skin in a manner that is not representative of the ambient environmental conditions in the laboratory; this should be avoided.

i、 技(ji)術程序(xu)不應(ying)給皮(pi)膚(fu)(fu)屏障造成(cheng)不可逆轉地改(gai)變(bian)。只要有足(zu)夠的(de)(de)(de)(de)時(shi)間使角質(zhi)層的(de)(de)(de)(de)水(shui)合(he)作用正常(chang)化,就(jiu)可以通過(guo)在皮(pi)膚(fu)(fu)表(biao)面(mian)短(duan)暫(zan)沉積水(shui)溶(rong)液來暫(zan)時(shi)改(gai)變(bian)角質(zhi)層的(de)(de)(de)(de)水(shui)合(he)狀態。上述將(jiang)皮(pi)膚(fu)(fu)表(biao)面(mian)短(duan)暫(zan)(例(li)如5分(fen)鐘)暴(bao)露于(yu)(yu)氚水(shui),然(ran)后持續30分(fen)鐘,在此期間角質(zhi)層的(de)(de)(de)(de)水(shui)合(he)狀態重新(xin)平(ping)衡的(de)(de)(de)(de)過(guo)程可能(neng)(neng)是合(he)適的(de)(de)(de)(de)。相比之下,如果不進一步表(biao)征角質(zhi)層的(de)(de)(de)(de)水(shui)合(he)狀態對(dui)(dui)皮(pi)膚(fu)(fu)對(dui)(dui)局部(bu)生(sheng)物利用度(du)差異的(de)(de)(de)(de)辨別敏(min)感性(xing)的(de)(de)(de)(de)影響,將(jiang)皮(pi)膚(fu)(fu)表(biao)面(mian)暴(bao)露于(yu)(yu)基于(yu)(yu)電(dian)的(de)(de)(de)(de)測試(shi)方(fang)法的(de)(de)(de)(de)水(shui)溶(rong)液中30分(fen)鐘,然(ran)后在5分(fen)鐘內給藥局部(bu)產品可能(neng)(neng)是不合(he)適的(de)(de)(de)(de)。類似地,如果在研(yan)究時(shi)將(jiang)便攜式燈靠近(jin)皮(pi)膚(fu)(fu)放置以提(ti)高能(neng)(neng)見度(du),燈的(de)(de)(de)(de)熱(re)量可能(neng)(neng)會(hui)改(gai)變(bian)皮(pi)膚(fu)(fu)的(de)(de)(de)(de)局部(bu)(微)環境(jing),而這種方(fang)式不能(neng)(neng)代表(biao)實驗室中的(de)(de)(de)(de)環境(jing)條件,應(ying)該避免(mian)。



ii. The acceptance criterion should be a cutoff value for the test result, at which a skin section fails the test. Skin sections that fail a barrier integrity test should not be dosed but may serve as non-dosed control skin sections. Skin sections with a passing barrier integrity test result may be considered to have a competent barrier integrity and may be dosed. This acceptance criterion should be selected based upon an understanding of the distribution of test results (among multiple replicate skin sections from multiple donors) for the specific barrier integrity test procedure performed with the specific type and preparation of skin under conditions relevant to the IVPT pivotal studies submitted in the ANDA. The intention of the barrier integrity test is to identify (and exclude) skin sections whose barrier integrity (intactness) is compromised. The intent is not to reduce the inherent variability in barrier function (permeability) in human skin that is representative of real variation in the human population. Also, the relative permeability of the skin to a drug from a topical product may not necessarily correlate with the permeability of the skin to water, and therefore, constraining the variability of the skin permeability to water (using a stricter acceptance criterion that excludes a larger number of skin sections) may not necessarily reduce the variability in the IVPT study results.

ii.驗收標準(zhun)(zhun)應(ying)為(wei)皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen)未(wei)通過測(ce)(ce)(ce)試(shi)結果(guo)時的(de)(de)(de)臨界(jie)值。未(wei)通過屏(ping)(ping)障(zhang)(zhang)(zhang)完整(zheng)性(xing)(xing)(xing)測(ce)(ce)(ce)試(shi)的(de)(de)(de)皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen)不(bu)應(ying)給(gei)藥,但可作為(wei)未(wei)給(gei)藥的(de)(de)(de)對照皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen)。屏(ping)(ping)障(zhang)(zhang)(zhang)完整(zheng)性(xing)(xing)(xing)測(ce)(ce)(ce)試(shi)結果(guo)合(he)格的(de)(de)(de)皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen)可被視(shi)為(wei)具有合(he)格的(de)(de)(de)屏(ping)(ping)障(zhang)(zhang)(zhang)完整(zheng)性(xing)(xing)(xing),并可給(gei)藥。應(ying)基(ji)于(yu)對測(ce)(ce)(ce)試(shi)結果(guo)分(fen)布(來(lai)自(zi)多(duo)個(ge)供體(ti)的(de)(de)(de)多(duo)個(ge)重復皮(pi)(pi)(pi)膚(fu)切(qie)片(pian))的(de)(de)(de)理解來(lai)選(xuan)擇此(ci)接(jie)(jie)受(shou)標準(zhun)(zhun),該測(ce)(ce)(ce)試(shi)程序是在與ANDA中提交的(de)(de)(de)IVPT關鍵研究相關的(de)(de)(de)條件下,使(shi)(shi)用(yong)特定(ding)(ding)類(lei)型和制備的(de)(de)(de)皮(pi)(pi)(pi)膚(fu)進行的(de)(de)(de)。屏(ping)(ping)障(zhang)(zhang)(zhang)完整(zheng)性(xing)(xing)(xing)測(ce)(ce)(ce)試(shi)的(de)(de)(de)目的(de)(de)(de)是識別(并排(pai)除(chu)(chu))屏(ping)(ping)障(zhang)(zhang)(zhang)完整(zheng)性(xing)(xing)(xing)(完整(zheng)性(xing)(xing)(xing))受(shou)損的(de)(de)(de)皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen)。其目的(de)(de)(de)并不(bu)是減少人體(ti)皮(pi)(pi)(pi)膚(fu)屏(ping)(ping)障(zhang)(zhang)(zhang)功能(滲(shen)透性(xing)(xing)(xing))的(de)(de)(de)固有變(bian)異性(xing)(xing)(xing),這這代表了人群的(de)(de)(de)真實(shi)變(bian)化。此(ci)外,皮(pi)(pi)(pi)膚(fu)對局部(bu)(bu)產品的(de)(de)(de)藥物的(de)(de)(de)相對滲(shen)透性(xing)(xing)(xing)可能不(bu)一定(ding)(ding)與皮(pi)(pi)(pi)膚(fu)對水的(de)(de)(de)滲(shen)透性(xing)(xing)(xing)相關,因(yin)此(ci),限制皮(pi)(pi)(pi)膚(fu)對水滲(shen)透性(xing)(xing)(xing)的(de)(de)(de)可變(bian)性(xing)(xing)(xing)(使(shi)(shi)用(yong)更嚴格的(de)(de)(de)接(jie)(jie)受(shou)標準(zhun)(zhun),排(pai)除(chu)(chu)更多(duo)的(de)(de)(de)皮(pi)(pi)(pi)膚(fu)部(bu)(bu)分(fen))不(bu)一定(ding)(ding)會降(jiang)低IVPT研究結果(guo)的(de)(de)(de)可變(bian)性(xing)(xing)(xing)。



iii. The acceptance criterion should be able to discriminate skin sections with a compromised barrier integrity. This may be demonstrated by measuring the barrier integrity of skin sections mounted and equilibrated in a diffusion cell before and after deliberately compromising the skin barrier (e.g., by repeatedly using adhesive tape to strip away increasing amounts of the stratum corneum, piercing the skin several times with a 30 gauge needle, or using other physical or chemical insults to damage the skin barrier). Based upon the acceptance criterion selected, the test result for skin sections that pass the test before being damaged should fail the test after the damage.

iii.驗收標準應能夠區分屏(ping)障完(wan)整(zheng)性受損(sun)的皮(pi)(pi)(pi)膚(fu)(fu)部分。這可以通過在(zai)故意破壞(huai)皮(pi)(pi)(pi)膚(fu)(fu)屏(ping)障之(zhi)前和(he)之(zhi)后(hou)測量在(zai)擴散池中安裝和(he)平衡的皮(pi)(pi)(pi)膚(fu)(fu)部分的屏(ping)障完(wan)整(zheng)性來(lai)證明(例如(ru),通過反復使(shi)(shi)用(yong)(yong)膠帶剝離(li)越來(lai)越多的角質層(ceng),用(yong)(yong)30號(hao)針(zhen)刺(ci)穿皮(pi)(pi)(pi)膚(fu)(fu)幾次,或(huo)使(shi)(shi)用(yong)(yong)其他物(wu)理(li)或(huo)化(hua)學侮(wu)辱來(lai)破壞(huai)皮(pi)(pi)(pi)膚(fu)(fu)屏(ping)障)。根(gen)據選定的接受標準,受損(sun)前測試結果(guo)合格(ge)的皮(pi)(pi)(pi)膚(fu)(fu),破損(sun)后(hou)的測試結果(guo)應不合格(ge)。



F.Differences Between IVPT Method Development and Validation

1.Optimization of an IVPT Method Prior to Advancing to IVPT Method Validation

Different study designs and method parameters may be evaluated during the IVPT method development phase. For example, if the selected study parameters initially involve a dose duration of 48 hours and a study duration of 48 hours, and the flux profile is measurable, but it is not feasible to identify the maximum (peak) flux and a decline in the flux thereafter across multiple subsequent time points, then it may be appropriate to evaluate other study parameters as part of the IVPT method development. For example, a different target dose of the topical product and/or a longer sampling duration may be evaluated. An alternate study design may involve a shorter dose duration (e.g., 4–6 hours) after which the applied dose is removed from the skin, and the receptor solution continues to be sampled across a study duration that is sufficient to identify the maximum (peak) flux and a decline in the flux thereafter across multiple subsequent time points. While shorter dose durations can help to improve the shape of IVPT flux profiles, the removal of the topical product dose from the skin surface can be challenging and often requires its own method development and optimization. Also, the design of sensitivity studies for such an IVPT study design may require a more sophisticated understanding of IVPT studies. While reasonable efforts should be made to develop an IVPT method that produces a well-defined maximum (peak) flux and a decline in the flux thereafter across multiple subsequent time points, this may not be feasible for certain topical products even with study durations of 96 hours, or, at least, may not be feasible to produce reliably in all donors. In such circumstances, the IVPT method development report should detail the systematic efforts made to optimize the IVPT method.

在(zai)IVPT方(fang)(fang)法開發階(jie)段(duan),可(ke)(ke)以(yi)評(ping)估(gu)不(bu)同(tong)的(de)(de)(de)研(yan)究(jiu)設(she)(she)計和方(fang)(fang)法參(can)數。例如(ru),如(ru)果(guo)所選的(de)(de)(de)研(yan)究(jiu)參(can)數最(zui)初(chu)涉及48小(xiao)時(shi)(shi)(shi)(shi)的(de)(de)(de)劑(ji)量(liang)(liang)(liang)(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)和48小(xiao)時(shi)(shi)(shi)(shi)的(de)(de)(de)研(yan)究(jiu)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian),并且(qie)通量(liang)(liang)(liang)(liang)分布是(shi)可(ke)(ke)測量(liang)(liang)(liang)(liang)的(de)(de)(de),但無法確(que)定最(zui)大(da)(da)(峰值)通量(liang)(liang)(liang)(liang)和通量(liang)(liang)(liang)(liang)下(xia)(xia)降,則可(ke)(ke)以(yi)評(ping)估(gu)其他研(yan)究(jiu)參(can)數作為(wei)IVPT方(fang)(fang)法開發的(de)(de)(de)一部(bu)分。例如(ru),可(ke)(ke)以(yi)評(ping)估(gu)局(ju)(ju)部(bu)產(chan)(chan)品的(de)(de)(de)不(bu)同(tong)目標劑(ji)量(liang)(liang)(liang)(liang)和/或更長的(de)(de)(de)取樣持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)。另一種研(yan)究(jiu)設(she)(she)計可(ke)(ke)能(neng)(neng)(neng)涉及更短的(de)(de)(de)劑(ji)量(liang)(liang)(liang)(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)(例如(ru),4-6小(xiao)時(shi)(shi)(shi)(shi)),之后(hou)(hou)(hou)(hou)去除(chu)(chu)皮膚的(de)(de)(de)上樣劑(ji)量(liang)(liang)(liang)(liang),并且(qie)在(zai)研(yan)究(jiu)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)內繼續(xu)(xu)(xu)對受體(ti)溶液進行(xing)采(cai)樣,該(gai)研(yan)究(jiu)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)足(zu)以(yi)確(que)定最(zui)大(da)(da)(峰值)通量(liang)(liang)(liang)(liang)以(yi)及隨(sui)后(hou)(hou)(hou)(hou)在(zai)多(duo)個(ge)(ge)后(hou)(hou)(hou)(hou)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)點的(de)(de)(de)通量(liang)(liang)(liang)(liang)下(xia)(xia)降。雖然更短的(de)(de)(de)劑(ji)量(liang)(liang)(liang)(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)有(you)助于(yu)(yu)改善(shan)IVPT通量(liang)(liang)(liang)(liang)分布曲線的(de)(de)(de)形狀(zhuang),但從(cong)皮膚表(biao)面去除(chu)(chu)局(ju)(ju)部(bu)產(chan)(chan)品劑(ji)量(liang)(liang)(liang)(liang)可(ke)(ke)能(neng)(neng)(neng)具有(you)挑戰(zhan)性(xing),通常需(xu)(xu)要自己(ji)開發方(fang)(fang)法和優化。此外,此類IVPT研(yan)究(jiu)設(she)(she)計的(de)(de)(de)敏感(gan)性(xing)研(yan)究(jiu)設(she)(she)計可(ke)(ke)能(neng)(neng)(neng)需(xu)(xu)要對IVPT研(yan)究(jiu)有(you)更復雜(za)的(de)(de)(de)理解。盡(jin)管應盡(jin)合理努(nu)力開發一種IVPT方(fang)(fang)法,該(gai)方(fang)(fang)法可(ke)(ke)在(zai)隨(sui)后(hou)(hou)(hou)(hou)的(de)(de)(de)多(duo)個(ge)(ge)時(shi)(shi)(shi)(shi)間(jian)(jian)點產(chan)(chan)生明確(que)定義的(de)(de)(de)最(zui)大(da)(da)(峰值)通量(liang)(liang)(liang)(liang)和通量(liang)(liang)(liang)(liang)下(xia)(xia)降,但這對于(yu)(yu)某些(xie)局(ju)(ju)部(bu)產(chan)(chan)品來說可(ke)(ke)能(neng)(neng)(neng)不(bu)可(ke)(ke)行(xing),即使研(yan)究(jiu)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)(shi)(shi)間(jian)(jian)為(wei)96小(xiao)時(shi)(shi)(shi)(shi),或者(zhe)至(zhi)少不(bu)可(ke)(ke)能(neng)(neng)(neng)在(zai)所有(you)供體(ti)中(zhong)穩(wen)定地產(chan)(chan)生。在(zai)這種情況下(xia)(xia),IVPT方(fang)(fang)法開發報告應詳(xiang)細說明為(wei)優化IVPT方(fang)(fang)法所做的(de)(de)(de)系統努(nu)力。



The IVPT method development studies, being exploratory in nature, are often performed using a sample analytical method that is not validated (e.g., an HPLC or ultrahigh performance liquid chromatography (UPLC) method, often involving mass spectrometry (MS)); also, IVPT method development studies are often conducted in a manner that is not compatible with a quality management system which would otherwise make the evidence generated suitable to support valid conclusions. Such method development studies would not be suitable to demonstrate the validity of an IVPT method, or associated results. Therefore, although it may appear to be redundant, certain experiments performed during IVRT method development may need to be repeated during IVPT method validation, using appropriate controls, like a validated analytical method and procedures that are compatible with a suitable quality management system.

IVPT方(fang)法(fa)(fa)(fa)開發(fa)研究本質(zhi)上是探索性(xing)的,通常(chang)使(shi)用未經(jing)(jing)驗證的樣品分析(xi)方(fang)法(fa)(fa)(fa)(例(li)如,HPLC或(huo)超高效(xiao)液相(xiang)色譜(UPLC)方(fang)法(fa)(fa)(fa),通常(chang)涉(she)及質(zhi)譜(MS));此外,IVPT方(fang)法(fa)(fa)(fa)開發(fa)研究通常(chang)與質(zhi)量(liang)(liang)管理體(ti)系不兼容,否則會使(shi)生成的證據適(shi)合(he)支持有(you)(you)效(xiao)結(jie)論。此類方(fang)法(fa)(fa)(fa)開發(fa)研究不適(shi)合(he)證明IVPT方(fang)法(fa)(fa)(fa)或(huo)相(xiang)關(guan)結(jie)果的有(you)(you)效(xiao)性(xing)。因此,盡管IVRT方(fang)法(fa)(fa)(fa)開發(fa)過程(cheng)中(zhong)進行(xing)(xing)的某些實驗看起(qi)來可能是多余的,但(dan)在IVPT方(fang)法(fa)(fa)(fa)驗證過程(cheng)中(zhong)可能需要重復(fu)進行(xing)(xing),使(shi)用適(shi)當的控制(zhi),如經(jing)(jing)過驗證的與合(he)適(shi)的質(zhi)量(liang)(liang)管理系統兼容的分析(xi)方(fang)法(fa)(fa)(fa)和程(cheng)序(xu)。。



It is important to clearly segregate and consistently identify those experiments and results that were part of IVPT method development separately from those that were part of IVPT method validation. It is also important to consistently identify all relevant method parameters and experimental conditions/controls for each set of IVPT results. Information in the method development report should clearly identify/distinguish when the results for apparently similar sets of experiments may have been obtained using different method parameters. Method development reports should clarify which sets of diffusion cells were run in parallel or separately (e.g., on separate days). In addition, the sample analytical method parameters used to analyze the samples from each set of IVPT experiments should be specified, and the report should indicate whether or not the sample analytical method was validated (either at the time of sample analysis or subsequently).

重(zhong)要(yao)(yao)的(de)(de)(de)(de)(de)是(shi)要(yao)(yao)明確的(de)(de)(de)(de)(de)將IVPT方(fang)法(fa)(fa)開(kai)發(fa)中的(de)(de)(de)(de)(de)實(shi)驗(yan)(yan)和結(jie)果(guo)與(yu)IVPT方(fang)法(fa)(fa)驗(yan)(yan)證中的(de)(de)(de)(de)(de)實(shi)驗(yan)(yan)與(yu)結(jie)果(guo)分(fen)(fen)(fen)開(kai),并加以一致識別。對于(yu)每組IVPT結(jie)果(guo),一致識別所有相關的(de)(de)(de)(de)(de)方(fang)法(fa)(fa)參(can)數(shu)和實(shi)驗(yan)(yan)條(tiao)件/對照同(tong)樣重(zhong)要(yao)(yao)。方(fang)法(fa)(fa)開(kai)發(fa)報(bao)(bao)告中的(de)(de)(de)(de)(de)信息應(ying)清(qing)楚(chu)地識別/區分(fen)(fen)(fen)什么時候明顯相似的(de)(de)(de)(de)(de)實(shi)驗(yan)(yan)結(jie)果(guo)可能是(shi)使用(yong)不(bu)同(tong)的(de)(de)(de)(de)(de)方(fang)法(fa)(fa)參(can)數(shu)獲(huo)得的(de)(de)(de)(de)(de)。方(fang)法(fa)(fa)開(kai)發(fa)報(bao)(bao)告應(ying)闡明哪(na)些(xie)擴散測(ce)試池組是(shi)平行或單(dan)獨(du)運行的(de)(de)(de)(de)(de)(例(li)如,在不(bu)同(tong)的(de)(de)(de)(de)(de)日子)。此(ci)外,應(ying)規定(ding)用(yong)于(yu)分(fen)(fen)(fen)析(xi)每組IVPT實(shi)驗(yan)(yan)樣品的(de)(de)(de)(de)(de)樣品分(fen)(fen)(fen)析(xi)方(fang)法(fa)(fa)參(can)數(shu),報(bao)(bao)告應(ying)說明樣品分(fen)(fen)(fen)析(xi)方(fang)法(fa)(fa)是(shi)否經(jing)過驗(yan)(yan)證(在樣品分(fen)(fen)(fen)析(xi)時或隨后)。



IV.IVPT METHOD VALIDATION

When all the relevant parameters of the IVPT method have been established, a pilot study should be performed using the final IVPT method and using a validated sample analytical method. The purpose of the pilot study is to validate the suitability of the selected IVPT method parameters by demonstrating that the performance characteristics of the IVPT method are appropriate to compare the cutaneous pharmacokinetics of a drug delivered topically from a test product and RS. The results from the pilot study, thereby, support the systematic validation of the IVPT method, which proceeds as a distinct study phase following IVPT method development.

當IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)的(de)所(suo)有相關參(can)數都已確定后(hou),應(ying)使用(yong)(yong)最(zui)終IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)和經(jing)驗證(zheng)的(de)樣品(pin)分(fen)析方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)進行(xing)試點研(yan)(yan)究。試點研(yan)(yan)究的(de)目的(de)是通(tong)過(guo)證(zheng)明IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)的(de)性能特征適(shi)用(yong)(yong)于比(bi)較在測試產品(pin)和RS中局部(bu)傳遞的(de)藥物的(de)皮膚藥代動力學(xue),來(lai)驗證(zheng)所(suo)選IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)參(can)數的(de)適(shi)用(yong)(yong)性。因此,試點研(yan)(yan)究結果支持(chi)IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)系(xi)統(tong)驗證(zheng),這在IVPT方(fang)(fang)法(fa)(fa)(fa)(fa)(fa)開發之(zhi)后(hou)作(zuo)為一個特殊的(de)研(yan)(yan)究階段進行(xing)。



The results from this IVPT pilot study can help to estimate the number of donors that may be needed to adequately power the IVPT pivotal study. In addition to the test topical product and RS evaluated in the pilot study, a parallel assessment should be performed with a third topical product or formulation that is known or designed to be different from the RS, to validate the selectivity of the IVPT method to discriminate differences in bioavailability. The IVPT pilot study results should be plotted with error bars, comparing the permeation profiles for the three treatment groups in the pilot study. Separate plots should be prepared for average flux results and average cumulative permeation results. These data can be used to support specific IVPT method validation parameters (e.g., permeation profile and range).

IVPT試點(dian)研(yan)(yan)究的(de)(de)(de)結(jie)(jie)果有助于估計(ji)可能需要的(de)(de)(de)供體數(shu)量(liang)(liang),以(yi)充分支(zhi)持(chi)IVPT關鍵研(yan)(yan)究。除(chu)了試點(dian)研(yan)(yan)究中評估的(de)(de)(de)試驗(yan)外(wai)(wai)用(yong)(yong)產品(pin)(pin)和RS外(wai)(wai),還應(ying)使用(yong)(yong)已知或設計(ji)與RS不同的(de)(de)(de)第三種外(wai)(wai)用(yong)(yong)產品(pin)(pin)或配方進(jin)行平行評估,以(yi)驗(yan)證IVPT方法對區分生物利用(yong)(yong)度差異的(de)(de)(de)選(xuan)擇性。IVPT試點(dian)研(yan)(yan)究結(jie)(jie)果應(ying)繪制誤差條,比較(jiao)中試研(yan)(yan)究中三個治(zhi)療組的(de)(de)(de)滲(shen)(shen)透(tou)曲線。應(ying)為平均通量(liang)(liang)結(jie)(jie)果和平均累(lei)積滲(shen)(shen)透(tou)結(jie)(jie)果繪制單獨的(de)(de)(de)圖。這些數(shu)據可用(yong)(yong)于支(zhi)持(chi)特定(ding)的(de)(de)(de)IVPT方法驗(yan)證參數(shu)(例如滲(shen)(shen)透(tou)圖譜和范圍)。



A pilot IVPT study performed with multiple skin donors (e.g., 4–6 skin donors) and a minimum of four replicate skin sections per donor per treatment group is recommended. As skin from an increasing number of donors is evaluated in the pilot study, the accuracy of the estimated number of donors needed to adequately power the IVPT pivotal study may improve. While skin from the same donors evaluated in the pilot study may also be used in the IVPT pivotal study, the results from the pilot study should not be combined with the results from the IVPT pivotal study for the purpose of statistical analysis.

建議對(dui)多(duo)個皮(pi)(pi)膚(fu)(fu)供者(例如4-6個皮(pi)(pi)膚(fu)(fu)捐贈者)進行IVPT試(shi)(shi)驗研(yan)(yan)(yan)究(jiu)(jiu),每(mei)個治療組每(mei)個供者至(zhi)少四個重(zhong)復皮(pi)(pi)膚(fu)(fu)切片(pian)。隨(sui)著越來越多(duo)的(de)供者的(de)皮(pi)(pi)膚(fu)(fu)在試(shi)(shi)點(dian)(dian)研(yan)(yan)(yan)究(jiu)(jiu)中得到評(ping)估,為(wei)IVPT關(guan)鍵研(yan)(yan)(yan)究(jiu)(jiu)提供足夠(gou)動力所需捐獻(xian)者估計數量的(de)準確(que)性可(ke)能(neng)會提高。雖然在試(shi)(shi)點(dian)(dian)研(yan)(yan)(yan)究(jiu)(jiu)中評(ping)估的(de)同一供者的(de)皮(pi)(pi)膚(fu)(fu)也可(ke)用(yong)于IVPT關(guan)鍵研(yan)(yan)(yan)究(jiu)(jiu),但試(shi)(shi)點(dian)(dian)研(yan)(yan)(yan)究(jiu)(jiu)的(de)結果不應與(yu)IVPT關(guan)鍵性研(yan)(yan)(yan)究(jiu)(jiu)的(de)結果結合起來進行統計分析(xi)。



The equipment, methodologies, and study conditions used in the IVPT pilot study (and the eventual IVPT pivotal study) should be appropriately validated or qualified. If an applicant elects to use equipment, methodologies, or study conditions that are different from those recommended in this guidance, the applicant should demonstrate why it was necessary and scientifically justified to do so. Detailed protocols and well-controlled study procedures are recommended to ensure the precise control of dosing, sampling, and other IVPT study parameters, as well as potential sources of experimental bias.

IVPT試(shi)點研(yan)究(jiu)(jiu)(以及最終的IVPT關鍵研(yan)究(jiu)(jiu))中使用(yong)的設備、方(fang)法和(he)研(yan)究(jiu)(jiu)條件應經過適當驗(yan)證或(huo)鑒定。如果申請(qing)人選擇使用(yong)與本指(zhi)南中建議的不同的設備、方(fang)法或(huo)研(yan)究(jiu)(jiu)條件,申請(qing)人應證明(ming)這樣(yang)做(zuo)的必要性(xing)和(he)科學(xue)合理性(xing)。建議采用詳細的方案和控制良好的研究程序,以確保精確控制給藥、取樣和其他IVPT研究參數,以及實驗偏差的潛在來源。

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The validation of the IVPT method should incorporate specific qualifications and controls (described below), performed using a validated sample analytical method, as applicable. The qualification of an IVPT method parameter refers to the process of defining what attributes make it suitable to perform its function in the IVPT method. For example, when repeated measurements of the temperature at the surface of skin mounted in a diffusion cell demonstrate that an IVPT equipment can maintain the skin surface temperature in the range of 32°C ± 1°C, the results can support a demonstration that the equipment is qualified to perform its function in an IVPT method for which a method parameter is the control of skin surface temperature in the range of 32°C ± 1°C across the relevant study duration.

IVPT方(fang)(fang)法(fa)的(de)(de)驗(yan)證應包括具(ju)體的(de)(de)限(xian)定(ding)(ding)條件(jian)和控制(zhi)(如(ru)下所(suo)述),如(ru)適用,使用經驗(yan)證的(de)(de)樣(yang)品分析方(fang)(fang)法(fa)進行(xing)。IVPT方(fang)(fang)法(fa)參數的(de)(de)限(xian)定(ding)(ding)指的(de)(de)是(shi)定(ding)(ding)義哪些屬性適合在IVPT方(fang)(fang)法(fa)中(zhong)執行(xing)其功能(neng)(neng)的(de)(de)過(guo)程。例(li)如(ru),當對安裝在擴散(san)池中(zhong)的(de)(de)皮(pi)膚(fu)表(biao)面溫(wen)(wen)度重復測(ce)量的(de)(de)結果(guo)(guo)表(biao)明IVPT設(she)備可(ke)以(yi)將皮(pi)膚(fu)表(biao)面溫(wen)(wen)度保持在32°C±1°C的(de)(de)范(fan)圍(wei)內時,結果(guo)(guo)可(ke)以(yi)證明該設(she)備有資格在IVPT方(fang)(fang)法(fa)中(zhong)執行(xing)其功能(neng)(neng),其中(zhong)方(fang)(fang)法(fa)參數是(shi)在相(xiang)關研究持續時間內將皮(pi)膚(fu)表(biao)面溫(wen)(wen)度控制(zhi)在32°C±1°C范(fan)圍(wei)內。



A.Equipment Qualification

Suitable equipment for the IVPT method includes various models of VDCs and flow-through diffusion cells. The operating principles and specific test procedures differ among the various equipment; relevant procedures from the manufacturer may be used for installation, operational, and performance qualifications. The laboratory qualification of each diffusion cell should, at minimum, include 1) measurements of the diffusional area of the orifices of the donor and receptor compartments between which the skin is mounted, 2) the empirically measured volume of the receptor solution compartment in each VDC or the empirically measured outflow tube length for each flow-through diffusion cell, 3) the stability of the temperature measured at the skin surface (e.g., 32°C ± 1°C) across a relevant duration (e.g., 48 hours), and 4) the rate of stirring or agitation in VDCs, or the flow rate for flow-through diffusion cells, as applicable.

適用于IVPT方(fang)法(fa)的(de)(de)(de)(de)設(she)備包(bao)括各種型(xing)號(hao)的(de)(de)(de)(de)VDC和(he)流通擴散(san)(san)池。不(bu)同(tong)設(she)備的(de)(de)(de)(de)工作原(yuan)理和(he)具體(ti)測(ce)試程序不(bu)同(tong);制(zhi)造商的(de)(de)(de)(de)相關程序可用于安裝、操作和(he)性(xing)能鑒(jian)定。每個擴散(san)(san)池的(de)(de)(de)(de)實驗室鑒(jian)定至少應包(bao)括:1)測(ce)量(liang)皮膚(fu)安裝在(zai)供(gong)體(ti)和(he)受體(ti)隔間(jian)(jian)的(de)(de)(de)(de)孔口擴散(san)(san)面積,2)每個VDC中受體(ti)溶液隔間(jian)(jian)的(de)(de)(de)(de)經(jing)驗測(ce)量(liang)體(ti)積或(huo)每個流通擴散(san)(san)池的(de)(de)(de)(de)經(jing)驗測(ce)量(liang)流出管長度,3)在(zai)相關持(chi)續時間(jian)(jian)(例如48小時)內(nei)在(zai)皮膚(fu)表面測(ce)量(liang)的(de)(de)(de)(de)溫(wen)度(例如32°C±1°C)的(de)(de)(de)(de)穩(wen)定性(xing),以(yi)及4)VDC中的(de)(de)(de)(de)攪拌或(huo)攪拌速率,或(huo)流通擴散(san)(san)池的(de)(de)(de)(de)流速(如適用)。



If information related to the diffusional area of the orifices and the volume of the receptor solution compartment for each diffusion cell is available from the manufacturer, that information should be provided for each relevant diffusion cell, in addition to the empirical measurements made by the laboratory performing the IVPT studies. The equipment should control the diffusion cell temperature so that the skin surface temperature is verified to be stable (e.g., 32°C ± 1°C) for each diffusion cell before dosing (e.g., measured by a calibrated infrared thermometer), and monitored periodically throughout the duration of the experiment by repeatedly measuring the skin surface temperature of a non-dosed control diffusion cell that is run in parallel with the other replicate dosed diffusion cells and connected to the same water bath or thermoregulation system.

如果制造商提供了與每個擴散池的孔口擴散面積和受體溶液隔室體積相關的信息,則除了實驗室進行IVPT研究的經驗測量之外,還應提供每個相關擴散池的信息。設備應控制擴散池溫度,以便在給藥前驗證每個擴散池的皮膚表面溫度穩定(例如,32°C±1°C)(例如,通過校準的紅外溫度計測量),并在整個實驗期間通過重復測量非劑(ji)量控制擴散池(chi)的皮膚表面溫度進(jin)行周期(qi)性監測,該擴散池與其他(ta)重復劑量給藥擴散池并聯(lian)運行(xing)并連接到相同的水(shui)浴或溫(wen)度調節系統(tong)。



B.Membrane (Skin) Qualification

Excised human skin is recommended as the membrane for the IVPT study. The validity of each skin section dosed in the study should be qualified using an appropriate test procedure to evaluate the stratum corneum barrier integrity. Acceptable barrier integrity tests may be based upon tritiated water permeation, TEWL, or electrical impedance/conductance measured across the skin. The test parameters and acceptance criteria used for the skin barrier integrity test should be justified for the specific method and instrumentation that is used during the study. The skin from all donors whose skin is included in the study should be prepared in a consistent manner and dermatomed to a relatively consistent thickness, within limits specified in the study protocol. The skin thickness should be measured and reported for each skin section included in the study. The assignment of replicate skin sections from a donor to each treatment group should be randomized, as feasible. It is acceptable to balance the distribution of skin thicknesses in each treatment group (test topical product or RS) by a procedure specified in the study protocol.

建議(yi)將切(qie)除的(de)人體(ti)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)作為IVPT研(yan)究(jiu)的(de)膜。通過(guo)適當的(de)測(ce)(ce)(ce)試(shi)(shi)程(cheng)序(xu)來(lai)評(ping)估角質層屏障的(de)完(wan)(wan)整(zheng)性(xing),來(lai)鑒定(ding)研(yan)究(jiu)中(zhong)使(shi)用(yong)(yong)的(de)每(mei)個(ge)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)切(qie)片(pian)的(de)有效性(xing)。可(ke)(ke)(ke)接受的(de)屏障完(wan)(wan)整(zheng)性(xing)測(ce)(ce)(ce)試(shi)(shi)可(ke)(ke)(ke)基于氚(chuan)水滲(shen)透、TEWL或(huo)(huo)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)上測(ce)(ce)(ce)量(liang)的(de)電阻抗/電導(dao)。用(yong)(yong)于皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)屏障完(wan)(wan)整(zheng)性(xing)測(ce)(ce)(ce)試(shi)(shi)的(de)測(ce)(ce)(ce)試(shi)(shi)參數和(he)驗收標準(zhun)應(ying)針對(dui)研(yan)究(jiu)期間(jian)使(shi)用(yong)(yong)的(de)特定(ding)方(fang)(fang)法(fa)和(he)儀(yi)器進行驗證。研(yan)究(jiu)中(zhong)包括的(de)所(suo)有捐獻者的(de)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)應(ying)以一致(zhi)的(de)方(fang)(fang)式制(zhi)備,并在(zai)研(yan)究(jiu)方(fang)(fang)案(an)(an)中(zhong)規定(ding)的(de)范圍內保持相(xiang)對(dui)一致(zhi)的(de)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)厚(hou)度(du)。應(ying)測(ce)(ce)(ce)量(liang)并報告研(yan)究(jiu)中(zhong)每(mei)個(ge)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)切(qie)片(pian)的(de)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)厚(hou)度(du)。在(zai)可(ke)(ke)(ke)行的(de)情況(kuang)下,應(ying)將供(gong)體(ti)的(de)復制(zhi)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)切(qie)片(pian)隨機(ji)分配給每(mei)個(ge)治(zhi)療組。也可(ke)(ke)(ke)以通過(guo)研(yan)究(jiu)方(fang)(fang)案(an)(an)中(zhong)規定(ding)的(de)程(cheng)序(xu)來(lai)平(ping)衡每(mei)個(ge)治(zhi)療組(測(ce)(ce)(ce)試(shi)(shi)局(ju)部(bu)產品(pin)或(huo)(huo)RS)的(de)皮(pi)(pi)(pi)膚(fu)(fu)(fu)(fu)厚(hou)度(du)分布(bu)。



C.Receptor Solution Qualification

The composition and pH of the receptor solution used for the IVPT study should be qualified in relation to its compatibility with the skin as well as the stability and solubility of the drug in that receptor solution. The stability of the drug in the receptor solution samples should be validated as part of the receptor sample analytical method validation. The solubility of the drug in the IVPT receptor solution should be empirically determined in triplicate, to illustrate that the solubility of the drug in the receptor solution exceeds the highest sample concentration in the IVPT pivotal study, ideally by an order of magnitude. The solubility of the drug in the IVPT receptor solution should be sufficient to characterize the higher amounts of drug permeating from the increased drug delivery condition evaluated in the IVPT sensitivity assessment during IVPT method validation.

用于IVPT研(yan)究的(de)(de)(de)(de)(de)受(shou)(shou)體(ti)溶(rong)(rong)液(ye)的(de)(de)(de)(de)(de)組成和pH應符合其(qi)與(yu)皮膚的(de)(de)(de)(de)(de)相容性以(yi)及藥(yao)(yao)物(wu)在該(gai)受(shou)(shou)體(ti)溶(rong)(rong)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)穩(wen)定性和溶(rong)(rong)解(jie)(jie)度(du)(du)。受(shou)(shou)體(ti)溶(rong)(rong)液(ye)樣(yang)品(pin)中(zhong)(zhong)藥(yao)(yao)物(wu)的(de)(de)(de)(de)(de)穩(wen)定性應作為(wei)(wei)受(shou)(shou)體(ti)樣(yang)品(pin)分(fen)析方(fang)法驗證的(de)(de)(de)(de)(de)一部分(fen)進行驗證。藥(yao)(yao)物(wu)在IVPT受(shou)(shou)體(ti)溶(rong)(rong)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)溶(rong)(rong)解(jie)(jie)度(du)(du)應根據(ju)經驗確定三份,以(yi)說明(ming)藥(yao)(yao)物(wu)在受(shou)(shou)體(ti)溶(rong)(rong)液(ye)中(zhong)(zhong)溶(rong)(rong)解(jie)(jie)度(du)(du)超過(guo)IVPT關鍵研(yan)究中(zhong)(zhong)的(de)(de)(de)(de)(de)最高樣(yang)品(pin)濃(nong)度(du)(du),理想(xiang)情況下為(wei)(wei)一個數量級。藥(yao)(yao)物(wu)在IVPT受(shou)(shou)體(ti)溶(rong)(rong)液(ye)中(zhong)(zhong)的(de)(de)(de)(de)(de)溶(rong)(rong)解(jie)(jie)度(du)(du)應足以(yi)表征(zheng)IVPT方(fang)法驗證期(qi)間IVPT敏感性評估中(zhong)(zhong)評估的(de)(de)(de)(de)(de)藥(yao)(yao)物(wu)遞送(song)條件增加導(dao)致(zhi)的(de)(de)(de)(de)(de)藥(yao)(yao)物(wu)滲透量增加。



The inclusion of 0.1% polyoxyethylene[20]oleyl ether (also known as Oleth-20, Volpo-20, or Brij-20; CAS number 9004-98-2) is recommended to enhance the solubility of physiological buffer based (aqueous) receptor solutions for hydrophobic drugs. If additional solubility is needed, small increases in the concentration of polyoxyethylene[20]oleyl ether (e.g., from 0.1% or 0.2%, which is typically adequate for most hydrophobic drugs, to higher concentrations) are recommended, but should not exceed 6% polyoxyethylene[20]oleyl ether. Other strategies to improve the solubility of the drug in the receptor solution that may have the potential to alter the permeability of the skin (e.g., inclusion of organic solvents and alcohols in the receptor solution) are not recommended and may invalidate the IVPT method.

建(jian)議加入0.1%聚(ju)氧乙(yi)烯(xi)[20]油酸酯(也稱(cheng)為Oleth-20、Volpo-20或Brij-20;CAS號9004-98-2),以提高(gao)疏水(shui)性藥(yao)物(wu)生理(li)緩沖液基(水(shui))受體溶(rong)(rong)液的(de)(de)溶(rong)(rong)解度(du)(du)。如果需(xu)要額(e)外的(de)(de)溶(rong)(rong)解度(du)(du),建(jian)議將聚(ju)氧乙(yi)烯(xi)[20]油酸酯的(de)(de)濃(nong)度(du)(du)小幅度(du)(du)增加(例(li)如,從(cong)0.1%或0.2%,這對于大多數疏水(shui)性藥(yao)物(wu)來(lai)說通常是足夠的(de)(de),到更高(gao)的(de)(de)濃(nong)度(du)(du)),但不(bu)應超過6%的(de)(de)聚(ju)氧乙(yi)烯(xi)[20]油酸酯。不(bu)建(jian)議采用其他可能改變(bian)皮(pi)膚滲透性的(de)(de)提高(gao)藥(yao)物(wu)在(zai)受體溶(rong)(rong)液中溶(rong)(rong)解度(du)(du)的(de)(de)策略(例(li)如,在(zai)受體溶(rong)(rong)液內加入有(you)機溶(rong)(rong)劑和醇),可能使(shi)IVPT方法無效。

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The inclusion of an anti-microbial agent in the receptor solution (e.g., ~0.1% sodium azide or ~ 0.01% gentamicin sulfate) is recommended to mitigate potential bacterial decomposition of the dermis and/or epidermis in the diffusion cell, regardless of the study duration. Other antimicrobial agents may also be acceptable, and if used, information should be included in the ANDA to explain the reason for their selection (and for the concentration at which they were used).

無論研究持續時間如何,建議在受體溶液中加入抗菌劑(例如,約0.1%*氮化(hua)鈉或約0.01%硫(liu)酸慶大霉素),以減(jian)輕擴散測(ce)試池中真(zhen)皮和/或表皮的潛在細菌分解。其他(ta)抗菌劑也可以接(jie)受(shou),如果(guo)使用,應(ying)在ANDA中包(bao)含相(xiang)關信息(xi),以解釋(shi)選擇的原因(以及使用的濃度)。



D.Receptor Solution Sampling Qualification

The accuracy and precision of receptor solution sample collection at each time point should be appropriately qualified. Evidence to qualify a sampling procedure should illustrate that the sampling technique can reliably collect a consistent volume of the sample from the well-mixed volume of the receptor compartment at each sampling event, and that no artifacts are likely to be created by the sampling technique. Information should be included describing the equipment manufacturer’s specification for the accuracy and precision of receptor solution sampling, when available.

應(ying)適當限定每個時(shi)間(jian)點受(shou)(shou)體(ti)溶(rong)液樣品采集的準(zhun)確(que)度(du)(du)和(he)精密度(du)(du)。鑒定采樣程(cheng)序(xu)的證據應(ying)表明,采樣技(ji)術可以(yi)在每次(ci)采樣中從一(yi)定體(ti)積(ji)、均勻混合的受(shou)(shou)體(ti)室中收集一(yi)致(zhi)體(ti)積(ji)的樣品,并且(qie)采樣技(ji)術不(bu)會(hui)產(chan)生(sheng)污染。如果(guo)可用(yong),應(ying)包括(kuo)描述(shu)設備制造商關于(yu)受(shou)(shou)體(ti)溶(rong)液取樣準(zhun)確(que)性和(he)精密度(du)(du)的規(gui)范的信(xin)息(xi)。



For IVPT studies using a flow-through diffusion cell, it may be appropriate to qualify the lengths of tubing, and their associated dead volumes, to accurately calculate the lag time before a sample elutes through the tubing and is collected. For IVPT studies using a VDC, removal of the entire receptor solution volume and full volume replacement of the receptor solution at each time point may provide optimal solubility sink conditions. The sampling of small aliquots of the receptor solution for an IVPT study may introduce anomalous measurements of apparently negative flux in certain regions of the IVPT study and produce flux profiles that are difficult to interpret.

對于使用流通擴散池的IVPT研究,可能需要確定管道長度及其相關死體積,以準確計算樣品通過管道洗脫并收集之前的滯后時間。對于使用VDC的IVPT研究,在每個時間點去除整個受體溶液體積并(bing)全部置換受(shou)體溶(rong)液(ye)可(ke)以(yi)提供最(zui)佳溶(rong)解(jie)度漏(lou)槽條件(jian)。在IVPT研(yan)究(jiu)中對受(shou)體溶(rong)液(ye)的(de)小(xiao)等份取樣可(ke)能會在IVPT研(yan)究(jiu)某(mou)些區域引入明顯負通量的(de)異常測量,并(bing)產生(sheng)難以(yi)解(jie)釋的(de)通量分布。



E.Environmental Control

Ambient laboratory temperature and humidity during the study should be monitored and reported. An environmentally controlled temperature range of 21°C ± 2°C is recommended, and a humidity range of 50% &plusmn; 20% relative humidity is recommended, if feasible.

研究期間應監測和報告實驗室環境溫度(du)(du)和濕度(du)(du)。環境溫度(du)(du)宜控制在21°C±2°C,相對濕度(du)(du)宜控制在為50%±20%。



F.Permeation Profile and Range

The flux profile and cumulative permeation profile for the IVPT pilot study should be plotted across a range of sampling times, which corresponds to the IVPT pivotal study duration. The calculation of flux and cumulative total permeation is discussed in more detail below. The results of the IVPT pilot study should validate that the selected study parameters are suitable to adequately characterize the permeation profile (the cutaneous pharmacokinetics) of the drug within the selected study duration (the range of sampling time points).

IVPT試點(dian)(dian)研究(jiu)的(de)(de)(de)通(tong)量(liang)分布(bu)和累(lei)積滲(shen)(shen)(shen)透分布(bu)應(ying)在一定取(qu)樣(yang)時(shi)(shi)間范圍內繪制,這(zhe)與(yu)IVPT關鍵研究(jiu)持(chi)續時(shi)(shi)間相對(dui)應(ying)。下(xia)面將更詳細(xi)地討論通(tong)量(liang)和累(lei)積總滲(shen)(shen)(shen)透的(de)(de)(de)計(ji)算。IVPT先導研究(jiu)的(de)(de)(de)結果應(ying)驗證所選研究(jiu)參數適合于在所選研究(jiu)時(shi)(shi)間(采(cai)樣(yang)時(shi)(shi)間點(dian)(dian)范圍)內充分表(biao)征藥物的(de)(de)(de)滲(shen)(shen)(shen)透特性(皮(pi)膚藥代動力(li)學)。



A sufficiently complete flux profile should be adequate to identify the maximum (peak) flux and a decline in the flux thereafter across multiple subsequent time points in the IVPT pilot study. The results of the IVPT pilot study should also validate that the sampling frequency provides suitable resolution to adequately characterize the permeation profile (particularly the flux profile).

在IVPT試點(dian)(dian)研究中(zhong),一個足(zu)夠(gou)完(wan)整(zheng)的通量分布(bu)應足(zu)以確(que)定多個后續時(shi)間點(dian)(dian)的最大(峰值)通量和此(ci)后通量的下降。IVPT試點(dian)(dian)研究的結果(guo)還應驗證采樣頻率提供了適當的分辨率,以充(chong)分表征滲透曲線(xian)(尤其是通量曲線(xian))。



G.Precision and Reproducibility

The flux and cumulative permeation results from the IVPT pilot study (and the eventual IVPT pivotal study) should be calculated, tabulated, and reported for each diffusion cell at each time point, with summary statistics to describe the intra-donor average, standard deviation, and percent coefficient of variation (%CV) among replicates, as well as the inter-donor average, standard error, and %CV. Complete results for all data values used in the calculations should be reported in a clear and organized manner, to facilitate the reconstruction of the flux and cumulative permeation results. The design of the study should be detailed and clear, and data values should be clearly associated with specific donors, replicates, treatment groups, time points, etc

IVPT先導(dao)研究(jiu)(jiu)(以(yi)及最(zui)終的(de)IVPT關(guan)鍵研究(jiu)(jiu))的(de)通量和(he)累(lei)積滲透結(jie)果應(ying)在每個(ge)時間(jian)點(dian)為每個(ge)擴(kuo)散(san)池進行計算、制表和(he)報(bao)告(gao),并提供(gong)(gong)匯總統計數據,以(yi)描(miao)述(shu)供(gong)(gong)體內平均值、標準偏(pian)差(cha)和(he)重(zhong)(zhong)(zhong)復之(zhi)間(jian)的(de)變異系數百分比(%CV),以(yi)及供(gong)(gong)體間(jian)平均值和(he)%CV。計算中使用(yong)的(de)所(suo)有數據值的(de)完整(zheng)結(jie)果應(ying)以(yi)清(qing)(qing)晰和(he)有組(zu)織的(de)方式報(bao)告(gao),以(yi)便于重(zhong)(zhong)(zhong)建通量和(he)累(lei)積滲透結(jie)果。研究(jiu)(jiu)的(de)設(she)計應(ying)詳細、清(qing)(qing)晰,數據值應(ying)與特定捐獻者(zhe)、重(zhong)(zhong)(zhong)復、治療組(zu)、時間(jian)點(dian)等(deng)明確相關(guan)。



H.Dose Depletion

The recovery of permeated drug in the receptor solution should be characterized in each diffusion cell as the cumulative total permeation of the drug in the receptor solution over the IVPT duration. This may be expressed as a percentage of the nominal amount of drug in the applied dose (which may be estimated based upon the nominal strength of the drug in the topical product and the approximate mass of topical product dosed on the skin).

受(shou)(shou)體(ti)溶液(ye)中(zhong)(zhong)(zhong)滲(shen)透藥(yao)物(wu)的(de)(de)回收應為(wei)在每個擴散池中(zhong)(zhong)(zhong)表征為(wei)藥(yao)物(wu)在IVPT持續時間內(nei)在受(shou)(shou)體(ti)溶液(ye)中(zhong)(zhong)(zhong)的(de)(de)累(lei)積(ji)總(zong)滲(shen)透。這可以(yi)表示為(wei)藥(yao)物(wu)標稱量(liang)(liang)在應用劑(ji)量(liang)(liang)中(zhong)(zhong)(zhong)的(de)(de)百分比(可以(yi)基于(yu)局(ju)(ju)部(bu)產品中(zhong)(zhong)(zhong)藥(yao)物(wu)的(de)(de)標稱強度和皮膚上施用的(de)(de)局(ju)(ju)部(bu)產品的(de)(de)近似質(zhi)量(liang)(liang)來(lai)估計)。



For example, if 10 mg of a topical product containing 5% drug was dosed on the membrane, the amount of drug in the applied dose may be estimated to be 0.5 mg (or 500 µg). If a cumulative total of 10 µg of drug diffused into the receptor solution across a 48-hour duration of the IVPT, it would be possible to estimate that the 500 µg dose would have been depleted by approximately 10 µg, amounting to an approximately 2% dose depletion. The average percentage dose depletion may thereby be estimated (not accounting for skin content) and should be reported.

例如,如果(guo)將含有5%藥(yao)物的(de)(de)10mg局(ju)部產品應(ying)用在(zai)膜上,則(ze)應(ying)用劑量(liang)(liang)中的(de)(de)藥(yao)物量(liang)(liang)估(gu)計(ji)為(wei)0.5mg(或500&micro;g)。如果(guo)在(zai)IVPT的(de)(de)48小(xiao)時持續時間內,累計(ji)10&micro;g藥(yao)物擴散到受(shou)體(ti)溶液中,可以(yi)(yi)估(gu)計(ji)500µg劑量(liang)(liang)將消耗約(yue)10µg,相(xiang)當于約(yue)2%的(de)(de)劑量(liang)(liang)消耗。由此(ci)可以(yi)(yi)估(gu)計(ji)平均劑量(liang)(liang)消耗百分(fen)比(不考慮皮膚含量(liang)(liang)),并應(ying)予以(yi)(yi)報(bao)告(gao)。



I.Discrimination Sensitivity and Selectivity

The discrimination ability of the IVPT method may be described using two concepts: sensitivity and selectivity. The IVPT sensitivity studies are necessarily performed during IVPT method development to establish IVPT method parameters like the dose amount, dose duration, study duration, etc. However, the analysis of the results from these studies is qualitative in nature, and they need not be repeated during the IVPT method validation phase.

IVPT方法的(de)鑒(jian)別能(neng)力可以(yi)用兩個概念(nian)來描述:靈(ling)敏(min)(min)度和選(xuan)擇性。IVPT方法開發期間(jian)必(bi)須進行IVPT靈(ling)敏(min)(min)性研究(jiu),以(yi)確定IVPT方法參數,如(ru)劑量、劑量持(chi)續時間(jian)、研究(jiu)持(chi)續時間(jian)等。然而,這(zhe)些(xie)研究(jiu)結果的(de)分析本質(zhi)上是定性的(de),在IVPT方法驗(yan)證(zheng)階段(duan)無需重(zhong)復驗(yan)證(zheng)。



The IVPT sensitivity studies are typically performed toward the end of the IVPT method development phase, and a key purpose of these studies is to incorporate the final IVPT method parameters for the target dose and dose duration to be used in the pivotal study so that the IVPT sensitivity studies can support a demonstration of the validity of the final IVPT method. Therefore, IVPT sensitivity studies are described within this section of the guidance in the context of IVPT validation (rather than method development) to avoid dissociating the discussions of IVPT sensitivity (which is performed to establish the suitability of the final IVPT method parameters) and IVPT selectivity (which is performed once the final IVPT method parameters are established, and which is based upon the IVPT pilot study that is performed as part of the IVPT method validation). With the exception of the alternative dose amounts or dose durations used in the IVPT sensitivity study, it is important that the IVPT method parameters are consistent across the IVPT sensitivity, pilot, and pivotal studies (including the anatomical region specified in the study protocol (e.g., posterior torso), the skin source, and skin preparation).

IVPT靈敏(min)度研(yan)(yan)究(jiu)(jiu)通(tong)常(chang)在(zai)IVPT方(fang)(fang)法(fa)開發階(jie)段的(de)(de)(de)(de)(de)末尾進(jin)行(xing),這些研(yan)(yan)究(jiu)(jiu)的(de)(de)(de)(de)(de)一個(ge)關(guan)(guan)鍵(jian)目(mu)的(de)(de)(de)(de)(de)是(shi)將最(zui)終IVPT方(fang)(fang)法(fa)參數(shu)的(de)(de)(de)(de)(de)目(mu)標劑量和(he)劑量時間用(yong)于(yu)(yu)關(guan)(guan)鍵(jian)研(yan)(yan)究(jiu)(jiu),IVPT靈敏(min)性研(yan)(yan)究(jiu)(jiu)可以支持(chi)證(zheng)(zheng)明最(zui)終IVPT方(fang)(fang)法(fa)的(de)(de)(de)(de)(de)有(you)效性。因此本節指南在(zai)IVPT驗證(zheng)(zheng)(而(er)非方(fang)(fang)法(fa)開發)的(de)(de)(de)(de)(de)背景下描述了(le)IVPT靈敏(min)度研(yan)(yan)究(jiu)(jiu),以避免將IVPT靈敏(min)度(用(yong)于(yu)(yu)確定(ding)最(zui)終IVPT方(fang)(fang)法(fa)參數(shu)的(de)(de)(de)(de)(de)適用(yong)性)和(he)IVPT選擇性(一旦確定(ding)了(le)最(zui)終IVPT方(fang)(fang)法(fa)參數(shu),即進(jin)行(xing)該(gai)試(shi)驗,并(bing)基于(yu)(yu)IVPT試(shi)驗研(yan)(yan)究(jiu)(jiu),該(gai)試(shi)驗研(yan)(yan)究(jiu)(jiu)是(shi)IVPT方(fang)(fang)法(fa)驗證(zheng)(zheng)的(de)(de)(de)(de)(de)一部分(fen))的(de)(de)(de)(de)(de)討論分(fen)開。除了(le)IVPT敏(min)感性研(yan)(yan)究(jiu)(jiu)中(zhong)(zhong)使(shi)用(yong)的(de)(de)(de)(de)(de)替代劑量或劑量持(chi)續時間外(wai),重要的(de)(de)(de)(de)(de)是(shi)IVPT方(fang)(fang)法(fa)參數(shu)在(zai)IVPT靈敏(min)度、先導性和(he)關(guan)(guan)鍵(jian)性研(yan)(yan)究(jiu)(jiu)(包括研(yan)(yan)究(jiu)(jiu)方(fang)(fang)案中(zhong)(zhong)規定(ding)的(de)(de)(de)(de)(de)解(jie)剖區域(如軀干后部)、皮膚(fu)來源(yuan)和(he)皮膚(fu)制備)中(zhong)(zhong)保持(chi)一致(zhi)。



1.IVPT Sensitivity

IVPT sensitivity is the ability of the IVPT method to detect changes in the cutaneous pharmacokinetics of the drug as a function of differences in drug delivery. If the IVPT method consistently demonstrates higher and lower flux profiles (i.e., higher and lower values for IVPT endpoints) in response to increased and decreased drug delivery, respectively (or in response to other conditions expected to increase and decrease drug delivery, respectively), the IVPT method may be considered sensitive.

IVPT靈敏度(du)是IVPT方(fang)法(fa)(fa)檢測藥(yao)(yao)物的(de)皮膚(fu)藥(yao)(yao)代動力(li)學變化作(zuo)(zuo)為(wei)藥(yao)(yao)物傳遞(di)差(cha)異的(de)功能的(de)能力(li)。如(ru)果IVPT方(fang)法(fa)(fa)始(shi)終(zhong)(zhong)顯示出較高(gao)(gao)和(he)較低的(de)通量(liang)分(fen)布(即IVPT終(zhong)(zhong)點(dian)的(de)高(gao)(gao)和(he)低),分(fen)別對藥(yao)(yao)物遞(di)送的(de)增加(jia)和(he)減少作(zuo)(zuo)出反應(或對預期分(fen)別增加(jia)和(he)減少藥(yao)(yao)物遞(di)送量(liang)的(de)其他條件(jian)作(zuo)(zuo)出反應),則IVPT方(fang)法(fa)(fa)可能被認為(wei)是靈敏的(de)。



There are a few potential approaches by which to produce the differences in drug delivery that can be differentiated by a suitably discriminating IVPT method. Regardless of the approach used, the differences in the IVPT permeation profiles are not necessarily expected to be specifically proportional to differences in the dose amount, dose duration, or product strength. For example, three-fold differences in the dose amount (even if outside the recommended target dose range) may provide distinct flux curves but may not result in three-fold differences in the IVPT endpoints because the skin barrier may be rate-limiting both in vitro and in vivo.

有(you)幾種潛(qian)在的(de)方(fang)(fang)法可以(yi)產(chan)生藥物遞送的(de)差(cha)(cha)異(yi),這些差(cha)(cha)異(yi)可以(yi)通過適當鑒(jian)別(bie)的(de)IVPT方(fang)(fang)法進行(xing)區分。無論采用何種方(fang)(fang)法,IVPT滲透曲線(xian)的(de)差(cha)(cha)異(yi)不一定與(yu)劑(ji)量(liang)、劑(ji)量(liang)持續時(shi)間或產(chan)品強度的(de)差(cha)(cha)異(yi)成正比。例如(ru),劑(ji)量(liang)的(de)三倍(bei)差(cha)(cha)異(yi)(即(ji)使在推薦(jian)的(de)目標劑(ji)量(liang)范圍之外)可以(yi)提(ti)供不同的(de)通量(liang)曲線(xian),但不會導致IVPT終點的(de)三倍(bei)差(cha)(cha)別(bie),因為皮(pi)膚屏障在體外和體內都(dou)可能是限制速(su)率的(de)因素。



In other words, if the target dose for the pivotal IVPT study was 10 mg/cm2 , a 3-fold lower dose would be ~3 mg/cm2 and a 3-fold higher dose would be 30 mg/cm2 ; thus, an IVPT sensitivity study might compare the flux profiles from 3, 10, and 30 mg/cm2 doses of the topical product. Similarly, if the target dose for the pivotal IVPT study was 15 mg/cm2 , a 3-fold lower dose would be 5 mg/cm2 and a 3-fold higher dose would be 45 mg/cm2 ; thus, an IVPT sensitivity study might compare the flux profiles from 5, 15, and 45 mg/cm2 doses of the topical product. An IVPT sensitivity study performed with multiple skin donors (e.g., 4–6 skin donors) and a minimum of four replicate skin sections per donor per treatment group is recommended.

換言之,如(ru)果關(guan)鍵(jian)IVPT研究(jiu)(jiu)的目標劑(ji)(ji)量(liang)為(wei)10 mg/cm2,則低3倍(bei)的劑(ji)(ji)量(liang)為(wei)~3 mg/cm2且高3倍(bei)的濃度為(wei)30 mg/cm2;因此(ci),IVPT敏感性研究(jiu)(jiu)可(ke)以比(bi)較3、10和(he)30 mg/cm2劑(ji)(ji)量(liang)的局部產(chan)品的通量(liang)分(fen)(fen)布。類似地,如(ru)果關(guan)鍵(jian)IVPT研究(jiu)(jiu)的目標劑(ji)(ji)量(liang)為(wei)15 mg/cm2,低3倍(bei)的劑(ji)(ji)量(liang)為(wei)5 mg/cm2而高3倍(bei)的濃度為(wei)45 mg/cm2;因此(ci),IVPT敏感性研究(jiu)(jiu)可(ke)能會比(bi)較5、15和(he)45 mg/cm2劑(ji)(ji)量(liang)的局部產(chan)品的通量(liang)分(fen)(fen)布。建議對多個(ge)皮(pi)(pi)(pi)膚捐獻(xian)者(例如(ru)4-6個(ge)皮(pi)(pi)(pi)膚捐贈者)進行IVPT靈敏度研究(jiu)(jiu),每個(ge)治療(liao)組每個(ge)捐獻(xian)者至少四個(ge)重復皮(pi)(pi)(pi)膚切片(pian)。



Modulation of Dose Amount: An IVPT method development study with different dose amounts may provide supportive evidence that the IVPT methodology is sensitive to differences in drug delivery.

劑量調(diao)節:不(bu)同劑量的IVPT方法開發研究(jiu)可能提供支持性證據,證明IVPT方法對藥物遞送的差異(yi)敏感。



This approach is well suited to topical products that contain volatile components that evaporate from the formulation following dose application to the skin. Modulating the dose amount for such topical products effectively alters the thickness of the applied dose. The majority of volatile components from a thinner dose will tend to evaporate more rapidly (compared to a thicker dose), and a thinner dose will tend to deliver less drug into the skin (and/or for a shorter duration) compared to a thicker dose.

這種方(fang)(fang)法非常適合于含(han)有揮發(fa)性(xing)成(cheng)(cheng)分的(de)局(ju)部(bu)產(chan)(chan)品,這些揮發(fa)性(xing)成(cheng)(cheng)分在涂抹到皮(pi)膚(fu)后從配方(fang)(fang)中蒸發(fa)。調節這種局(ju)部(bu)產(chan)(chan)品的(de)劑量(liang)有效地改變了(le)應用劑量(liang)的(de)厚度(du)。較(jiao)薄劑量(liang)的(de)大部(bu)分揮發(fa)性(xing)成(cheng)(cheng)分往往會(hui)蒸發(fa)得更快(與(yu)較(jiao)厚劑量(liang)相比),較(jiao)薄劑量(liang)進入(ru)皮(pi)膚(fu)的(de)藥(yao)量(liang)較(jiao)少(和(he)/或持續時間更短)。



Modulating the dose amount can be an effective technique to modulate differences in drug delivery for formulations with volatile components, like gels, lotions, and many creams. However, modulating the dose amount may not necessarily produce perceptible differences in drug delivery for topical products like petrolatum-based ointments, or other types of topical products that do not evaporate on the skin, or that may not experience dose-dependent differences in metamorphosis that can alter the rate and extent of drug delivery.

調節劑量可以是一種有效的技術,可以調節含有揮發性成分的制劑(如凝膠、乳液和許多乳膏)的藥物遞送差異。然而,調節劑量并不一定會對局部產品(如基于凡士林的軟膏)或其他類型的局部產品(不會在皮膚上蒸發)產生明顯的藥物遞送差異,或者可能不會經歷可改變藥物遞送速率和程度的劑量依賴(lai)性**差(cha)異。



Modulation of Dose Duration: For many topical products, it may be more effective to modulate the dose duration, instead of the dose amount, to produce differences in drug delivery and associated changes in the cutaneous pharmacokinetics of the drug.

劑量(liang)持(chi)(chi)續時間的調節(jie):對(dui)于許多外用產品,調節(jie)劑量(liang)持(chi)(chi)續時間而不是劑量(liang)可能更有效,以產生藥(yao)物遞送的差異和藥(yao)物的皮膚藥(yao)代動力學的相(xiang)關變化(hua)。



An IVPT method development study with a controlled dose amount (e.g., 15 mg/cm2 ) dosed for different durations (e.g., 2 hours, 6 hours, and 12 hours) may be well suited to provide supportive evidence that the IVPT methodology is sensitive to differences in drug delivery from many topical products. The scenario described in this example would support an IVPT study design where a topical product dose of 15 mg/cm2 is dosed for 6 hours (the target duration for the IVPT study) and then wiped off. The applied dose may be removed with a series of cotton-tipped swabs, one or more of which may be dry and one or more of which may be moistened (e.g., with a soap solution or water). The initial (dry) swab typically removes the bulk of the dose and subsequent swabs are used to remove the residual dose (i.e., the residue of the topical product which may otherwise continue to deliver drug into the skin) and/or to rinse the skin.

具有不同持(chi)續(xu)時間(jian)(jian)(例(li)(li)如(ru),2小時、6小時和12小時)的(de)(de)(de)(de)受控劑量(liang)(例(li)(li)如(ru),15 mg/cm2)的(de)(de)(de)(de)IVPT方(fang)法開發(fa)研究可(ke)能非常(chang)適合提供支持(chi)性證據,證明IVPT方(fang)法對許(xu)多局(ju)部產(chan)品(pin)的(de)(de)(de)(de)藥物(wu)遞送差異敏感。本例(li)(li)中描述的(de)(de)(de)(de)方(fang)案將支持(chi)IVPT研究設計,其(qi)中局(ju)部產(chan)品(pin)劑量(liang)為15 mg/cm2,持(chi)續(xu)6小時(IVPT研究的(de)(de)(de)(de)目標持(chi)續(xu)時間(jian)(jian)),然(ran)后擦掉。可(ke)使用(yong)一系列棉簽去(qu)除(chu)(chu)應用(yong)的(de)(de)(de)(de)劑量(liang),其(qi)中一個或多個棉簽可(ke)能干(gan)燥,一個或更多棉簽可(ke)能濕潤(例(li)(li)如(ru),用(yong)肥皂溶(rong)液或水)。初始(干(gan))拭子通常(chang)去(qu)除(chu)(chu)大部分劑量(liang),隨后的(de)(de)(de)(de)拭子用(yong)于去(qu)除(chu)(chu)剩(sheng)余劑量(liang)(即(ji),局(ju)部產(chan)品(pin)的(de)(de)(de)(de)殘留物(wu),否則可(ke)能繼續(xu)將藥物(wu)輸送到皮膚中)和/或沖(chong)洗皮膚。



To support a demonstration of the sensitivity of the IVPT study, the permeation profile produced by the target dose duration for the IVPT study (e.g., 6 hours) should be compared with a shorter dose duration (e.g., 2 hours) that is expected to perceptibly decrease the drug delivery, and also be compared with a longer dose duration (e.g., 12 hours) that is expected to perceptibly increase the drug delivery. Thereby, the three dose durations compared in the IVPT sensitivity study are designed to produce perceptible changes in the cutaneous pharmacokinetics of the drug as a function of differences in drug delivery, and thereby support a demonstration of the sensitivity of the IVPT method.

為了證(zheng)明(ming)IVPT研(yan)究的(de)(de)靈(ling)敏(min)度,應將IVPT研(yan)究目(mu)標劑量(liang)持(chi)續(xu)(xu)時(shi)間(例如(ru)6小時(shi))產生的(de)(de)滲透曲線與(yu)預(yu)期明(ming)顯降低藥物遞送(song)的(de)(de)更(geng)短劑量(liang)持(chi)續(xu)(xu)時(shi)間進(jin)行比(bi)較(jiao),并且(qie)還(huan)與(yu)預(yu)期顯著(zhu)增(zeng)加藥物遞送(song)的(de)(de)更(geng)長劑量(liang)持(chi)續(xu)(xu)時(shi)間(例如(ru)12小時(shi))相比(bi)較(jiao)。因此,IVPT靈(ling)敏(min)度研(yan)究中(zhong)比(bi)較(jiao)的(de)(de)三個(ge)劑量(liang)持(chi)續(xu)(xu)時(shi)間旨在根據藥物遞送(song)差(cha)異產生藥物的(de)(de)皮膚(fu)藥代(dai)動(dong)力(li)學的(de)(de)明(ming)顯變化,從而支(zhi)持(chi)IVPT方法(fa)的(de)(de)靈(ling)敏(min)度證(zheng)明(ming)。



The specific dose durations may be selected based upon an initial exploratory IVPT study performed during IVPT method development that characterizes the permeation profile when the dose is left on the skin for a longer duration (e.g., 24 or 48 hours). An important feature of the results from such an IVPT study is the duration of the initial phase of the permeation profile, when the flux is increasing at a relatively rapid rate.

具體劑量(liang)持續時(shi)(shi)(shi)間(jian)(jian)可以(yi)基于IVPT方法開發期間(jian)(jian)進行(xing)的(de)初始(shi)探索(suo)性IVPT研(yan)(yan)究來(lai)選擇,該研(yan)(yan)究表征(zheng)了當劑量(liang)在皮膚(fu)上停留更長時(shi)(shi)(shi)間(jian)(jian)(例如24或48小時(shi)(shi)(shi))時(shi)(shi)(shi)的(de)滲透曲(qu)線。這種(zhong)IVPT研(yan)(yan)究結果的(de)一個重要(yao)特征(zheng)是當通(tong)量(liang)以(yi)相對較快的(de)速率增加時(shi)(shi)(shi),滲透曲(qu)線初始(shi)階段的(de)持續時(shi)(shi)(shi)間(jian)(jian)。



For example, if such an exploratory study indicates that the flux increases on a steep slope until approximately 12 hours, and then continues to deliver the drug at a gradually increasing rate thereafter, it may suggest that the permeation profile for a dose duration of longer than 12 hours (e.g., 24 hours) may not be perceptibly different from that of the 12- hour dose duration, especially when compared in a relatively small number of donors and replicates (e.g., four donors with four replicates each per dose duration). It may also suggest that a 12-hour dose duration may be a good choice for the longest of the three dose durations in the IVPT sensitivity study.

例如(ru),如(ru)果這(zhe)樣(yang)的(de)(de)(de)探(tan)索性研究(jiu)表(biao)明(ming),通(tong)量(liang)以(yi)陡峭的(de)(de)(de)斜率(lv)增(zeng)加(jia),直到(dao)大約12小(xiao)時(shi)(shi),然后繼續(xu)(xu)(xu)以(yi)逐(zhu)漸增(zeng)加(jia)的(de)(de)(de)速率(lv)遞送藥物,這(zhe)可能表(biao)明(ming),超過12小(xiao)時(shi)(shi)(例如(ru)24小(xiao)時(shi)(shi))的(de)(de)(de)劑量(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)間(jian)(jian)(jian)的(de)(de)(de)滲透曲(qu)線可能與12小(xiao)時(shi)(shi)劑量(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)間(jian)(jian)(jian)沒有明(ming)顯差(cha)異(yi),特別(bie)是(shi)在(zai)相對(dui)較(jiao)少數量(liang)的(de)(de)(de)供(gong)體(ti)和復(fu)制體(ti)(例如(ru)每(mei)個(ge)(ge)劑量(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)間(jian)(jian)(jian)具有四個(ge)(ge)復(fu)制體(ti)的(de)(de)(de)四個(ge)(ge)供(gong)體(ti))中(zhong)(zhong)進行(xing)比較(jiao)時(shi)(shi)。這(zhe)也(ye)可能表(biao)明(ming),在(zai)IVPT敏感性研究(jiu)中(zhong)(zhong),12小(xiao)時(shi)(shi)的(de)(de)(de)劑量(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)間(jian)(jian)(jian)可能是(shi)三個(ge)(ge)劑量(liang)持(chi)(chi)續(xu)(xu)(xu)時(shi)(shi)間(jian)(jian)(jian)中(zhong)(zhong)最長的(de)(de)(de)一(yi)個(ge)(ge)很好的(de)(de)(de)選(xuan)擇(ze)。



The target dose duration should be selected based upon considerations like the sensitivity of the sample analytical method, the ability to produce a permeation profile that can be perceptibly discriminated from that produced by the longer (12 hour) dose duration, and/or the labeled use of the topical product (which may indicate that the topical product should be reapplied every 4–6 hours).

目標劑(ji)量持(chi)續時(shi)(shi)間的(de)(de)選擇應(ying)基于以下(xia)考慮(lv)因素,如樣品(pin)分析方(fang)法的(de)(de)靈敏度、產(chan)(chan)生(sheng)滲透曲(qu)線的(de)(de)能(neng)力,該滲透曲(qu)線可明(ming)顯區別于較長(12小時(shi)(shi))劑(ji)量持(chi)續時(shi)(shi)間產(chan)(chan)生(sheng)的(de)(de)滲透曲(qu)線,和(he)/或局部產(chan)(chan)品(pin)的(de)(de)標記使用(這(zhe)可能(neng)表明(ming)局部產(chan)(chan)品(pin)應(ying)每(mei)4-6小時(shi)(shi)重新給(gei)藥一(yi)次)。



The shortest of the three dose durations in the IVPT sensitivity study should be selected based upon the sensitivity of the sample analytical method and its ability to produce a permeation profile that can be perceptibly discriminated from that produced by the target (6 hour) dose duration.

在(zai)IVPT靈敏度(du)研究(jiu)中(zhong)(zhong),三個劑量持續時間中(zhong)(zhong)最短(duan)的(de)時間選擇(ze),應(ying)根據樣品分析方法的(de)靈敏度(du),以及可明顯區(qu)別于目標維持時間(6小時)所(suo)產生的(de)滲透曲線的(de)能力(li)來選擇(ze)。



· Modulation of Product Strength: To validate the sensitivity, specificity, and selectivity of an in vitro release test (IVRT) method, altered strength formulations are routinely prepared. While it may seem convenient to use these altered strength formulations in an attempt to demonstrate the sensitivity and selectivity of an IVPT method, doing so may not produce the desired outcomes. There may be circumstances when this strategy may produce perceptibly different permeation profiles, however, in many instances, the resulting permeation profiles may not be perceptibly different when compared in a relatively small number of donors and replicates (e.g., four donors with four replicates each per topical product strength). In general, the modulation of topical product strength to support a demonstration of IVPT sensitivity is not recommended because it may not consistently produce the expected increase or decrease in drug delivery; however, in certain situations, higher and lower strength formulations (relative to the nominal strength of the RS) may suitably increase and decrease the drug delivery and cutaneous pharmacokinetics relative to that from the nominal strength topical product.

•調(diao)節產(chan)品規(gui)(gui)格(ge)(ge):為驗證(zheng)(zheng)IVRT方法的(de)(de)(de)(de)(de)靈敏度、專屬性(xing)(xing)和(he)(he)(he)選(xuan)擇性(xing)(xing),通常(chang)采(cai)用(yong)改變配方制(zhi)劑規(gui)(gui)格(ge)(ge)的(de)(de)(de)(de)(de)方法。雖然采(cai)用(yong)改變配方制(zhi)劑的(de)(de)(de)(de)(de)規(gui)(gui)格(ge)(ge)的(de)(de)(de)(de)(de)方法來證(zheng)(zheng)明(ming)(ming)IVPT方法的(de)(de)(de)(de)(de)靈敏度和(he)(he)(he)選(xuan)擇性(xing)(xing)似乎很方便,但這種(zhong)(zhong)方式可能不(bu)會產(chan)生預期的(de)(de)(de)(de)(de)結果。在(zai)(zai)(zai)某(mou)些情(qing)況下(xia),這種(zhong)(zhong)策略可能會產(chan)生明(ming)(ming)顯不(bu)同的(de)(de)(de)(de)(de)滲透(tou)曲(qu)線(xian),然而,在(zai)(zai)(zai)很多情(qing)況下(xia),由于(yu)(yu)在(zai)(zai)(zai)對(dui)比(bi)研究(jiu)中采(cai)用(yong)的(de)(de)(de)(de)(de)供體(ti)組(zu)和(he)(he)(he)重復數較(jiao)(jiao)(jiao)少(shao)(如(ru),每(mei)種(zhong)(zhong)外用(yong)制(zhi)劑規(gui)(gui)格(ge)(ge)采(cai)用(yong)4個供體(ti)組(zu),每(mei)組(zu)供體(ti)4個重復),并(bing)不(bu)能產(chan)生明(ming)(ming)顯不(bu)同的(de)(de)(de)(de)(de)滲透(tou)曲(qu)線(xian)。通常(chang),不(bu)建議(yi)通過調(diao)整(zheng)外用(yong)制(zhi)劑規(gui)(gui)格(ge)(ge)的(de)(de)(de)(de)(de)方法以證(zheng)(zheng)明(ming)(ming)IVPT的(de)(de)(de)(de)(de)靈敏度,因(yin)為它可能不(bu)會持續產(chan)生預期的(de)(de)(de)(de)(de)增加(jia)或減少(shao)的(de)(de)(de)(de)(de)藥物遞送;然而,在(zai)(zai)(zai)某(mou)些情(qing)況下(xia),相較(jiao)(jiao)(jiao)于(yu)(yu)外用(yong)制(zhi)劑的(de)(de)(de)(de)(de)目標規(gui)(gui)格(ge)(ge),較(jiao)(jiao)(jiao)高和(he)(he)(he)較(jiao)(jiao)(jiao)低規(gui)(gui)格(ge)(ge)的(de)(de)(de)(de)(de)配方制(zhi)劑(相對(dui)于(yu)(yu)對(dui)照制(zhi)劑(RS)的(de)(de)(de)(de)(de)規(gui)(gui)格(ge)(ge))可以適(shi)當地增加(jia)和(he)(he)(he)降低藥物遞送和(he)(he)(he)皮膚藥代(dai)動力學。



2.IVPT Selectivity/IVPT選擇性

IVPT selectivity is the ability of the IVPT method to discriminate the cutaneous pharmacokinetics of the drug between the RS and a topical product or formulation that exhibits differences in drug delivery relative to the RS. The IVPT pilot study with the parallel assessment of the RS, the test topical product, and a third topical product or formulation that is known or designed to be different from the RS may provide supportive evidence that the IVPT methodology is selective for differences in drug delivery. Topical product batch information for all topical product lots used in IVPT method development, validation and pilot studies, as applicable, should be submitted in the study reports. The topical product information should include, but not be limited to, information about the batch formula, manufacturing date, batch size, altered manufacturing processes (if applicable) and, if available, potency and content uniformity. The evaluation of inequivalence may be based upon a qualitative or quantitative comparison of the permeation profiles and/or the IVPT endpoints.

IVPT選擇性(xing)是IVPT方(fang)法區分“對(dui)照制劑(RS)“和(he)“與RS在(zai)藥(yao)物(wu)遞送方(fang)面存在(zai)差(cha)異(yi)的(de)(de)外(wai)(wai)用(yong)制劑或配(pei)方(fang)”在(zai)藥(yao)物(wu)皮膚藥(yao)代動力(li)學差(cha)異(yi)的(de)(de)能力(li)。在(zai)IVPT初(chu)步(bu)研究(jiu)(jiu)中(zhong),通過將(jiang)RS、自研外(wai)(wai)用(yong)制劑和(he)“已知或設計不(bu)同于RS”的(de)(de)第三種外(wai)(wai)用(yong)制劑或配(pei)方(fang)進行(xing)(xing)平行(xing)(xing)評(ping)估,提(ti)供(gong)支持性(xing)證據,說(shuo)明IVPT方(fang)法對(dui)藥(yao)物(wu)遞送的(de)(de)差(cha)異(yi)具有(you)選擇性(xing)。如適用(yong),應在(zai)研究(jiu)(jiu)報告中(zhong)遞交,IVPT方(fang)法開發(fa)、驗證和(he)初(chu)步(bu)研究(jiu)(jiu)中(zhong)用(yong)到的(de)(de)所有(you)外(wai)(wai)用(yong)制劑的(de)(de)相關批(pi)信息,包括但(dan)不(bu)限于:批(pi)配(pei)方(fang)、生產(chan)日期、批(pi)量、變更的(de)(de)生產(chan)工藝(如適用(yong)),以(yi)及效價和(he)含量均勻度(du)(如有(you))。可(ke)基于滲透曲(qu)線和(he)/或IVPT終(zhong)點的(de)(de)定性(xing)或定量比較(jiao)進行(xing)(xing)不(bu)等效性(xing)評(ping)估。



J.Robustness/耐用性

A primary assumption related to robustness testing is that the test system performs consistently when all system variables (e.g., temperature, stirring rate) are at nominal settings. A value of robustness testing is that it can verify whether the system continues to provide a consistent output when specific variables are slightly altered, thereby qualifying operational ranges for those variables. However, the variability inherent in the permeability of human skin, whether in vitro or in vivo, may not be compatible with the primary assumption related to the consistency of the test system.

與(yu)耐用性(xing)(xing)測(ce)試(shi)相(xiang)關的(de)(de)一個主要(yao)假設是(shi)(shi)(shi),當(dang)所有(you)(you)系(xi)(xi)(xi)統變(bian)量(liang)(如:溫度、攪拌(ban)速率)處于標準(zhun)設置時,測(ce)試(shi)系(xi)(xi)(xi)統的(de)(de)性(xing)(xing)能一致。耐用性(xing)(xing)測(ce)試(shi)意義在于,它可以(yi)驗證當(dang)特定變(bian)量(liang)略有(you)(you)改變(bian)時,系(xi)(xi)(xi)統是(shi)(shi)(shi)否能提供一致的(de)(de)輸(shu)出結果,從而確定這些變(bian)量(liang)的(de)(de)操作范圍(wei)。然(ran)而,無論是(shi)(shi)(shi)體外(wai)還是(shi)(shi)(shi)體內,人體皮膚滲透(tou)性(xing)(xing)固有(you)(you)的(de)(de)變(bian)異性(xing)(xing)可能與(yu)與(yu)測(ce)試(shi)系(xi)(xi)(xi)統一致性(xing)(xing)相(xiang)關的(de)(de)主要(yao)初(chu)始的(de)(de)假設不(bu)兼容。



Nonetheless, results from studies during IVPT method development that appear to support the robustness of the IVPT method or system should be reported, if relevant. For example, an IVPT method may be robust to substantial variations in the stirring rate of the receptor compartment. Similarly, the permeation profile of a drug into and through human skin may appear to be robust to certain differences in the topical product strength. Ultimately, because it may not always be feasible to validate the robustness of IVPT method parameters, IVPT study procedures should be controlled as precisely as possible.

盡管如此,如果(guo)相(xiang)關,應報告IVPT方法(fa)開(kai)發期間得到的(de)關于(yu)支持(chi)IVPT方法(fa)或系統耐用性(xing)的(de)研究結果(guo)。例如,IVPT方法(fa)對(dui)于(yu)接收室(shi)攪拌(ban)速率的(de)顯著(zhu)變(bian)化具有耐用性(xing)。與其(qi)類似地(di),藥物進入并通過人體皮膚的(de)滲(shen)透曲線,可(ke)能(neng)對(dui)外用制劑規格的(de)改變(bian)表現(xian)出耐用性(xing)。所以(yi),對(dui)于(yu)驗證IVPT方法(fa)參數的(de)耐用性(xing)并不總(zong)是(shi)可(ke)行(xing)的(de),在(zai)IVPT研究中(zhong)應盡可(ke)能(neng)精準地(di)控制IVPT研究程序。



V. SAMPLE ANALYTICAL METHOD VALIDATION/樣品分析方法驗證

While exploratory studies performed during IVPT method development may use an unvalidated sample analytical method, it is essential that all studies conducted as part of the IVPT method validation use a validated sample analytical method. A validated IVPT method should use a validated sample analytical method (e.g., HPLC/MS or UPLC/MS). Therefore, a discussion of the sample analytical method for the IVPT method is included in this guidance under this section on IVPT method validation

雖然在IVPT方(fang)(fang)法開(kai)發的(de)(de)探索性研(yan)究中,可采用未經驗(yan)(yan)證(zheng)的(de)(de)樣品(pin)分(fen)析方(fang)(fang)法,但(dan)作(zuo)為IVPT方(fang)(fang)法驗(yan)(yan)證(zheng)的(de)(de)一部分(fen),所進行的(de)(de)IVPT研(yan)究都必須(xu)采用經過驗(yan)(yan)證(zheng)的(de)(de)樣本分(fen)析方(fang)(fang)法。經驗(yan)(yan)證(zheng)的(de)(de)IVPT方(fang)(fang)法應使(shi)用已(yi)驗(yan)(yan)證(zheng)的(de)(de)樣品(pin)分(fen)析方(fang)(fang)法(如:HPLC/MS或UPLC/MS)。因此,本指南中關于(yu)IVPT方(fang)(fang)法驗(yan)(yan)證(zheng)的(de)(de)章節中包含了對IVPT方(fang)(fang)法樣品(pin)分(fen)析方(fang)(fang)法的(de)(de)討(tao)論。



However, the study protocols and reports related to the IVPT method are distinct from those for the sample analytical method that is used to quantify drug concentrations in IVPT receptor solution samples. The validation of a sample analytical method, in and of itself, does not demonstrate the validity of an IVPT method. Separate and specific reports should be submitted for the validation of the sample analytical method (e.g., HPLC/MS or UPLC/MS) and for the validation of the IVPT method.

然而,與(yu)IVPT方法相關的(de)研(yan)究方案和(he)報告與(yu)用于量(liang)化IVPT接收(shou)液(ye)樣(yang)品(pin)(pin)定(ding)量(liang)的(de)分(fen)(fen)析方法不同(tong)。樣(yang)品(pin)(pin)分(fen)(fen)析方法的(de)驗(yan)證(zheng)(zheng)本身并不能證(zheng)(zheng)明IVPT方法的(de)有效性(xing)。因此,應分(fen)(fen)別提(ti)交IVPT方法驗(yan)證(zheng)(zheng)報告和(he)樣(yang)品(pin)(pin)分(fen)(fen)析方法(如:HPLC/MS或UPLC/MS)。



Any results from studies of the IVPT method that are performed during method development using a different sample analytical method than that which is ultimately validated, cannot support a demonstration of the validity of the IVPT method. Information should be provided in the IVPT method validation report referencing the (separate) sample analytical method validation, and clearly indicate that all relevant results in the IVPT method validation report were obtained using a validated sample analytical method (as opposed to a sample analytical method with different parameters than those which were validated).

如果(guo)在(zai)方(fang)(fang)法開發(fa)過程中,使用(yong)的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)方(fang)(fang)法與(yu)最(zui)終驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)方(fang)(fang)法不(bu)(bu)(bu)同,那么與(yu)其相(xiang)關的(de)(de)IVPT方(fang)(fang)法研究(jiu)結(jie)果(guo)則不(bu)(bu)(bu)能用(yong)于支持論證(zheng)(zheng)(zheng)(zheng)IVPT方(fang)(fang)法的(de)(de)有(you)效性。應在(zai)IVPT方(fang)(fang)法驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)報(bao)(bao)告中,提供參(can)考的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)方(fang)(fang)法驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)的(de)(de)信息(xi),并明(ming)確表明(ming)IVPT方(fang)(fang)法驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)報(bao)(bao)告中的(de)(de)所有(you)相(xiang)關結(jie)果(guo)均采用(yong)經(jing)驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)方(fang)(fang)法(不(bu)(bu)(bu)是與(yu)經(jing)驗(yan)(yan)證(zheng)(zheng)(zheng)(zheng)的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)法有(you)不(bu)(bu)(bu)同參(can)數(shu)的(de)(de)樣(yang)(yang)品(pin)分(fen)析(xi)放法)獲(huo)得(de)的(de)(de)。



The receptor sample analysis procedures (e.g., typically involving an HPLC/MS or UPLC/MS system) should be performed using chromatography software (e.g., a chromatography data system) with audit trails, and should include a multi-point (6–8 concentration) calibration curve with suitable quality control samples, and should be validated in a manner compatible with the FDA guidance for industry Bioanalytical Method Validation (May 2018).

接收液樣品的(de)分析方法(如(ru):通常為HPLC/MS或UPLC/MS系(xi)統(tong)),應(ying)使用具有(you)(you)審計(ji)追蹤(zong)的(de)色(se)譜軟件(如(ru),色(se)譜數據系(xi)統(tong)),并(bing)應(ying)包括具有(you)(you)適當(dang)質量控(kong)制樣品的(de)多點(6~8個)校準曲線,并(bing)應(ying)符合FDA生物(wu)分析方法驗證行業指南(nan)要求。



The validation of the receptor sample analytical method should include relevant qualifications of dilution integrity, if applicable, as well as stability assessments with the highest relevant temperature in the receptor solution for the longest relevant duration; the highest relevant temperature may be warmer than 32°C because the temperature of the receptor solution is often higher than the temperature at the surface of the skin, and the longest relevant duration may be the longest interval between sampling time points for methods in which the entire receptor solution is replaced at each sampling time point, or it could be longer in scenarios with only partial sampling of the receptor solution (e.g., 34°C for 48 hours).

接(jie)(jie)收(shou)液中樣(yang)品(pin)分(fen)析方法(fa)的(de)驗證應包括(kuo)稀釋完(wan)整性確認(ren)(如適用),以及樣(yang)品(pin)在最(zui)高相(xiang)關(guan)溫(wen)(wen)度(du)(du)的(de)接(jie)(jie)收(shou)液中放置最(zui)長(chang)時(shi)間的(de)穩定性評估;最(zui)高相(xiang)關(guan)溫(wen)(wen)度(du)(du)可略高于(yu)(yu)32°C,因為接(jie)(jie)收(shou)液的(de)溫(wen)(wen)度(du)(du)通(tong)常高于(yu)(yu)皮(pi)膚表面的(de)溫(wen)(wen)度(du)(du)。對(dui)于(yu)(yu)在每個取樣(yang)時(shi)間點替換整個接(jie)(jie)收(shou)液的(de)情況,最(zui)長(chang)相(xiang)關(guan)時(shi)間為各相(xiang)鄰取樣(yang)時(shi)間點中,間隔最(zui)長(chang)時(shi)間;但(dan)對(dui)于(yu)(yu)接(jie)(jie)收(shou)液部分(fen)取樣(yang)的(de)情況,時(shi)間可能更長(chang)(例(li)如34°C放置 48h)。



If the samples are processed in specific ways for analysis (e.g., by drying and reconstituting the receptor samples in a smaller volume to concentrate the sample and increase the effective analytical sensitivity, or by dilution of receptor solution samples into the validated curve range of the sample analytical method) those procedures should be validated (e.g., by qualifying the dilution integrity during the sample analytical method validation). The stability of the drug in the receptor solution sample should be validated in a receptor solution matrix that has been exposed to the underside of the skin in a diffusion cell under conditions relevant to the IVPT pivotal study.

如果(guo)樣(yang)品(pin)以(yi)特定的(de)(de)分(fen)(fen)析方(fang)法進行處理(li)(如:通過將樣(yang)品(pin)干燥后(hou)重新以(yi)較小的(de)(de)體積溶劑配制(zhi)以(yi)提高(gao)有效分(fen)(fen)析靈敏度,或通過稀釋(shi)接(jie)收(shou)液(ye)樣(yang)品(pin),使其(qi)達到已驗(yan)證(zheng)分(fen)(fen)析方(fang)法的(de)(de)曲線范(fan)圍(wei)內),則應確(que)認其(qi)處理(li)方(fang)法(如:在(zai)樣(yang)品(pin)分(fen)(fen)析方(fang)法驗(yan)證(zheng)期間確(que)認稀釋(shi)完(wan)整性)。接(jie)收(shou)液(ye)樣(yang)品(pin)中藥物的(de)(de)穩定性,應在(zai)與(yu)IVPT正式研究相關的(de)(de)條件下(xia),在(zai)擴散池中皮(pi)膚下(xia)側接(jie)觸的(de)(de)接(jie)收(shou)液(ye)基質中進行。



VI. IVPT PIVOTAL STUDY/IVPT正式研究

The IVPT pivotal study protocol should incorporate considerations relevant to BE studies, in general

IVPT正式研究方案通常應包括(kuo)與BE研究相(xiang)關的(de)考慮(lv)因素



A. Handling and Retention of Samples/樣品的處理與保存

Refer to 21 CFR 320.38, 320.63 and the FDA guidances for industry Handling and Retention of BA and BE Testing Samples (May 2004) and Compliance Policy for the Quantity of Bioavailability and Bioequivalence Samples Retained Under 21 CFR 320.38(c) (August 2020), as applicable, regarding considerations for retention of study drug samples and to 21 CFR 320.36 for requirements for maintenance of records of BE testing. Retention samples should be randomly selected from the drug supplies received before allocating topical product units for use in an IVPT study in which the test topical product and RS are compared.

參考(kao)21 CFR 320.38,320.63和(he)(he)FDA行業指南《生(sheng)物(wu)利(li)用度(BA)和(he)(he)生(sheng)物(wu)等效(xiao)性(BE)研(yan)究(jiu)中(zhong)試驗樣品的(de)(de)處理和(he)(he)保(bao)存》(2004年5月)和(he)(he)《21CFR 320.38(c) BE樣品留存的(de)(de)數(shu)量及生(sheng)物(wu)利(li)用度》(2020年8月),關于保(bao)留研(yan)究(jiu)藥物(wu)樣品的(de)(de)考(kao)慮以及21 CFR 320.36關于保(bao)存BE檢測記錄的(de)(de)要求(如適用)。在采用自(zi)研(yan)外(wai)用制劑和(he)(he)RS進行IVPT對(dui)比研(yan)究(jiu)前,應(ying)從收(shou)到的(de)(de)藥品中(zhong)隨機選擇(ze)樣品進行留樣。



B. Control of Study Procedures/研究程序的控制

Study procedures that have the potential to influence the results of the study should be appropriately controlled. Also, experimental observations that may have the potential to influence the interpretation of the study results, as well as any protocol or standard operating procedure (SOP) deviations, should be reported.

應(ying)對可能(neng)影(ying)響研(yan)(yan)(yan)究(jiu)結(jie)果的(de)(de)研(yan)(yan)(yan)究(jiu)程(cheng)序進行適(shi)當控制。此外,應(ying)報告可能(neng)影(ying)響研(yan)(yan)(yan)究(jiu)結(jie)果解釋(shi)的(de)(de)實(shi)驗觀察結(jie)果,以及任何方(fang)案(an)或標準操作程(cheng)序(SOP)發生偏差。



Control of procedures related to the skin include the consistent control across the study of the skin preparation (e.g., dermatoming of skin sections) and the thickness of skin sections mounted on diffusion cells, as well as the skin storage conditions, including the duration for which the skin was frozen and the number of freeze-thaw cycles to which the skin was exposed. Skin from the same anatomical location should be used from all donors, and the demographics (age, race, sex) should be reported for all donors. Also, the IVPT sensitivity, pilot, and pivotal studies should use skin from the same anatomical site; otherwise, if skin from different anatomical sites is used across the different study phases, it may not be possible for the results of the IVPT sensitivity and pilot studies to support a demonstration of the discrimination ability of the IVPT method used for the pivotal study because the method parameters would not be aligned across the respective studies. Similarly, if a non-rate-limiting support membrane is used beneath the skin section (e.g., a filter membrane used in a validated IVRT method for the same topical product) then it should be used in a consistent manner for the IVPT sensitivity, pilot, and pivotal studies.

與皮(pi)膚(fu)相關的(de)(de)程序(xu)的(de)(de)控制,包(bao)括相同(tong)(tong)的(de)(de)皮(pi)膚(fu)處理方(fang)法(fa)(如:皮(pi)膚(fu)的(de)(de)剝離)和安裝在擴(kuo)散測試(shi)(shi)池上的(de)(de)皮(pi)膚(fu)切(qie)片的(de)(de)厚(hou)度的(de)(de)研究(jiu)(jiu)(jiu)中(zhong)(zhong)的(de)(de)一致(zhi)性(xing)(xing),及皮(pi)膚(fu)儲存條件,例如皮(pi)膚(fu)冷凍(dong)的(de)(de)儲存時間和取出的(de)(de)凍(dong)融循環次數。所(suo)有供給皮(pi)膚(fu)均應(ying)采用(yong)相同(tong)(tong)解(jie)剖(pou)位(wei)置(zhi),并報告所(suo)有供體的(de)(de)人口統計信息(xi)(年齡、種族、性(xing)(xing)別)。此外,在IVPT靈(ling)敏度、初步實驗(yan)和正(zheng)式(shi)研究(jiu)(jiu)(jiu),應(ying)采用(yong)同(tong)(tong)一解(jie)剖(pou)部位(wei)的(de)(de)皮(pi)膚(fu);否(fou)則(ze)(ze),如果在不同(tong)(tong)的(de)(de)研究(jiu)(jiu)(jiu)階段使用(yong)不同(tong)(tong)位(wei)置(zhi)解(jie)剖(pou)部位(wei),IVPT靈(ling)敏度和初步試(shi)(shi)驗(yan)的(de)(de)結果可能不足以支持用(yong)于正(zheng)式(shi)研究(jiu)(jiu)(jiu)的(de)(de)IVPT方(fang)法(fa)的(de)(de)區分(fen)力的(de)(de)論證,因為(wei)方(fang)法(fa)參數在各(ge)個研究(jiu)(jiu)(jiu)中(zhong)(zhong)不一致(zhi)。同(tong)(tong)樣,如果在皮(pi)膚(fu)部分(fen)下方(fang)使用(yong)非速(su)率限(xian)制性(xing)(xing)支撐膜(如:同(tong)(tong)類IVRT方(fang)法(fa)驗(yan)證研究(jiu)(jiu)(jiu)中(zhong)(zhong)使用(yong)的(de)(de)濾膜),則(ze)(ze)與IVPT靈(ling)敏度、初步試(shi)(shi)驗(yan)和正(zheng)式(shi)研究(jiu)(jiu)(jiu)中(zhong)(zhong)一致(zhi)。



Control of procedures related to the dose include the control of the area of dose application, the dose amount, the dosing technique, the dose duration, and the blinding and randomization procedures for dosing. The test topical product and RS should be dosed in an identical and consistent manner for all diffusion cells in the study. Differences in dosing technique may alter the metamorphosis of the dosage form on the skin, and inconsistencies in the diameter of the area dosed on each diffusion cell may significantly influence the dosed area and contribute to errors in the calculation of flux.

與劑量(liang)或上(shang)(shang)(shang)樣(yang)相關的(de)(de)(de)控(kong)制程序,包括:對(dui)上(shang)(shang)(shang)樣(yang)面積、上(shang)(shang)(shang)樣(yang)量(liang)、上(shang)(shang)(shang)樣(yang)技術、劑量(liang)維(wei)持時間的(de)(de)(de)控(kong)制,以及在研究中每(mei)個擴散(san)池(chi)采用的(de)(de)(de)盲法(fa)和隨機化(hua)方法(fa)的(de)(de)(de)一致(zhi)性。不同的(de)(de)(de)上(shang)(shang)(shang)樣(yang)技術可(ke)能改變上(shang)(shang)(shang)樣(yang)到皮膚上(shang)(shang)(shang)劑型的(de)(de)(de)形態,擴散(san)池(chi)孔(kong)口擴散(san)面積的(de)(de)(de)不一致(zhi)可(ke)能會顯著(zhu)影響(xiang)上(shang)(shang)(shang)樣(yang)面積,從而(er)導致(zhi)通量(liang)計算的(de)(de)(de)偏差。



Control of procedures related to sampling include the control of sampling time precision, the sampling technique, the duration of sampling and replacement of receptor solution, the sample volume or flow rate, and sample handling and storage.

與取(qu)樣(yang)相關的程序控制包括(kuo)取(qu)樣(yang)時間精度、取(qu)樣(yang)技術、取(qu)樣(yang)和替換接收液的時間間隔、取(qu)樣(yang)體積或流速(su),以及樣(yang)品的處理和存(cun)儲。



Control of procedures related to the pivotal study should include a non-dosed control skin section from each skin donor, which should be mounted in a diffusion cell and otherwise treated identically to the dosed skin sections, including sampling of the receptor solution at all time points to ensure that drug concentrations monitored in the receptor solution are associated with the dose applied in the IVPT pivotal study, and not drug contamination in the skin from that donor that might permeate into the receptor solution across the duration of the study. A pre-dose “zero” sample collected from each diffusion cell is also recommended, which may identify potential contamination associated with each skin section and/or each diffusion cell.

與正式研究(jiu)相(xiang)關的(de)控制程序,應包(bao)括來自每個(ge)皮膚(fu)供體(ti)的(de)非劑(ji)量(liang)(liang)對照皮膚(fu)部分,包(bao)括在(zai)所有時(shi)間點對接(jie)收液進行取(qu)樣(yang),以確保接(jie)收液中監測的(de)藥(yao)物濃度與IVPT正式研究(jiu)中應用的(de)劑(ji)量(liang)(liang)相(xiang)關,而不是(shi)研究(jiu)期間由于(yu)皮膚(fu)的(de)藥(yao)物污染滲透進入。建議從每個(ge)擴散(san)池(chi)中采(cai)集“零”濃度樣(yang)品,用于(yu)識別每個(ge)皮膚(fu)切(qie)片和/或(huo)每個(ge)擴散(san)池(chi)的(de)潛在(zai)污染。

圖片

 

In addition, investigators should perform the IVPT validation and pivotal studies within a quality management system that includes, but is not limited to, documented procedures for:

此外,研(yan)究(jiu)人員應在一(yi)定的(de)質量管理體系(xi)條(tiao)件下,進行IVPT驗證(zheng)和正式研(yan)究(jiu),該體系(xi)包括但不限(xian)于:



·Study personnel identification, training, qualification, and responsibilities/ 研究人員的識別、培(pei)訓、資格和職責

·Study management and study management personnel responsibilities/研(yan)究(jiu)管理和研(yan)究(jiu)管理人員職責(ze)

· Quality control (QC) and QC personnel responsibilities/質(zhi)量控制(zhi)(QC)和QC人(ren)員職(zhi)責

· Quality assurance (QA) and QA personnel responsibilities/質量(liang)保證(QA)和(he)QA人員職責

·Use of SOPs /標準操作規程(SOP)的(de)制定

· Use of study protocols/研(yan)究方案的(de)制定

· Use of study reports/研(yan)究報告(gao)的制定(ding)

· Maintenance and control of the study facility environment and systems/研究設施環境和系統的維護(hu)和控(kong)制。

·Qualification and calibration of instruments and computerized systems/儀(yi)器和計(ji)算機(ji)系統(tong)的(de)鑒定和校準。

·Good documentation practices including, but not limited to, contemporaneous documentation of study procedures and recording of experimental observations or deviations from procedures specified in the study protocol or in relevant SOPs/良好(hao)的(de)文件規范,包括但不限于:研究程(cheng)序(xu)的(de)及(ji)時記(ji)錄(lu)、實驗觀察及(ji)相關SOPs中規定的(de)程(cheng)序(xu)的(de)偏(pian)差。

· Maintenance of suitable records that facilitate the reconstruction of study events and procedures, including study sample handling and storage records (e.g., sample tracking logs), audit trails for sample analysis procedures, control of study materials and reagents, and electronic data control/維護有助(zhu)于重(zhong)建(jian)研究事(shi)件和(he)程序的適(shi)當記(ji)錄(lu),包括研究樣(yang)(yang)本(ben)處(chu)理和(he)存儲記(ji)錄(lu)(如:樣(yang)(yang)本(ben)跟蹤(zong)日志)、樣(yang)(yang)本(ben)分析過程的審計跟蹤(zong)、研究物料(liao)和(he)試劑的控(kong)制以及電(dian)子(zi)數據(ju)控(kong)制。

·Archival of study records研究記錄(lu)存檔(dang)



C. Blinding Procedure/盲法程序

A detailed description of the blinding procedure should be provided in the study protocol and final report. The packaging of the test topical product and RS should be similar in appearance to maintain adequate blinding of the investigator and any experimental operators.

研究(jiu)方案和(he)最終報告中應提供(gong)盲(mang)法(fa)程序的(de)詳細說明。試驗外用制劑和(he)RS的(de)包裝應保(bao)(bao)持相似的(de)外,以確保(bao)(bao)研究(jiu)者(zhe)和(he)任何實驗操作人員的(de)充(chong)分致盲(mang)。



D.Randomization/隨機化

The method of randomization should be described in the protocol of the IVPT study and the randomization schedule provided, preferably in a SAS data set in .xpt format (created using the SAS XPORT procedure). It is recommended that an independent third party generate and hold the randomization code throughout the conduct of the study to minimize bias. The applicant may generate the randomization code if not involved in the packaging and labeling of the test topical product and RS dosed in the study. A sealed copy of the randomization scheme should be retained at the study site and should be available to FDA investigators at the time of site inspection to allow for verification of the treatment identity of each skin section.

應(ying)在IVPT研究(jiu)方案中(zhong)描述隨機(ji)(ji)化方法并(bing)提(ti)供隨機(ji)(ji)化計劃表,推薦以(yi).xpt格(ge)式(shi)的(de)SAS數據集形(xing)式(shi)(使用SAS XPORT程序創建)。建議由獨立的(de)第三方在整個(ge)研究(jiu)過程中(zhong)生成并(bing)保(bao)存隨機(ji)(ji)化代碼(ma),以(yi)減(jian)少偏差。如果(guo)研究(jiu)中(zhong)未涉及自(zi)(zi)研外用制(zhi)劑和RS的(de)包(bao)裝和標簽,申(shen)請人可以(yi)自(zi)(zi)行生成隨機(ji)(ji)代碼(ma)。隨機(ji)(ji)方案的(de)密封副本應(ying)保(bao)存在研究(jiu)現場,并(bing)應(ying)在現場檢(jian)查時提(ti)供給FDA研究(jiu)人員,以(yi)便(bian)確認每個(ge)皮膚(fu)切片的(de)具體信息。



E.Dosing/上樣

In the IVPT pivotal study, the test topical product and RS should be dosed in an alternating pattern on successive diffusion cells (skin sections) from each donor. One of two dosing sequences (illustrated below) may be randomly assigned for each donor:

在(zai)(zai)IVPT正(zheng)式(shi)研究中(zhong),對于(yu)每(mei)個供(gong)體組(zu),可以在(zai)(zai)擴散(san)池(皮膚切片)上以交替給藥方式(shi)依次放置自研外用制劑和(he)RS。對于(yu)每(mei)個供(gong)體組(zu),可采(cai)用下述兩個方式(shi)中(zhong)的一(yi)個進行(xing)隨機放樣(如(ru)下所(suo)示):

a. ABABAB…

b. BABABA…



F. Study Design/  研究設計

The IVPT pivotal study should compare the cutaneous pharmacokinetics of the drug from the test topical product versus that from the RS using excised human skin with a competent skin barrier mounted on a qualified diffusion cell system. The IVPT pivotal study should use a design that directly compares the test topical product and RS on skin from the same set of donors, each with the same number of replicate skin sections per donor per treatment group (dosed with either test topical product or RS topical), using the same IVPT method parameters.

在IVPT正式研究中,應(ying)采用皮(pi)膚(fu)屏障完整性(xing)良好的離(li)體人類皮(pi)膚(fu)和經驗(yan)證(zheng)的擴(kuo)散池系統,對(dui)自(zi)研外(wai)用制劑(ji)和RS的皮(pi)膚(fu)藥代動(dong)力(li)學進行對(dui)比研究。在自(zi)研外(wai)用制劑(ji)和RS的對(dui)比研究中,每個試驗(yan)組(zu)應(ying)采用相同(tong)(tong)的皮(pi)膚(fu)供體、相同(tong)(tong)的皮(pi)膚(fu)切片重復數,并采用相同(tong)(tong)的IVPT方(fang)法參數。



The IVPT pivotal study design, methodology, and diffusion cell equipment considerations relating to sampling precision should be controlled as precisely as possible. For example, it may be appropriate to stagger the dose application on successive diffusion cells and to synchronize the sampling time points with the dosing time for that diffusion cell, to ensure consistent durations between dosing and sampling of all diffusion cells.

應盡可(ke)能精確地控制IVPT正式研(yan)究設計、方法和(he)與擴(kuo)散(san)(san)池(chi)設備(bei)取(qu)(qu)樣(yang)精度。例如,在連(lian)續(xu)的擴(kuo)散(san)(san)池(chi)上(shang)(shang),錯開上(shang)(shang)樣(yang)時(shi)(shi)間點,根據(ju)上(shang)(shang)樣(yang)時(shi)(shi)間的差異,從而同步(bu)取(qu)(qu)樣(yang)時(shi)(shi)間,以(yi)確保所有擴(kuo)散(san)(san)池(chi)給藥和(he)取(qu)(qu)樣(yang)之間的時(shi)(shi)間間隔一致(zhi)。



G. Inclusion Criteria/納入標準

In general, the following inclusion criteria should apply: healthy, normal, barrier-competent skin from male and/or female donors of at least 18 years of age. Inclusion criteria related to donor demographics (e.g., age, race, sex) should be specified in the study protocol and demographic information should be reported for each donor. Additional criteria may be added by the applicant

通常,以(yi)(yi)下入選標準應適用:來自至少18歲的(de)健康、正常、屏障功能皮(pi)膚,雄性和(he)/或雌性供體。應在研究方案中規(gui)定符合納入標準的(de)人(ren)口統計信息(xi)(如(ru),年齡、種(zhong)族、性別(bie)),并報告每個(ge)供體的(de)個(ge)人(ren)信息(xi)。申請人(ren)可以(yi)(yi)增加其它(ta)納入標準。



The skin may be harvested following excision from patients undergoing a surgical procedure or excised from cadavers. A consistent source is recommended for all the skin used. The anatomical region specified in the study protocol (e.g., posterior torso) should be consistent for all donors whose skin is included in the study.

皮(pi)膚(fu)(fu)可以(yi)在(zai)外科手術(shu)的患者或尸(shi)體(ti)上(shang)獲(huo)取(qu)。所(suo)有使用(yong)的皮(pi)膚(fu)(fu)應(ying)有一致的來源(yuan)。研究方(fang)案中規定的解剖區域(如軀干后部)應(ying)與研究中包括皮(pi)膚(fu)(fu)的所(suo)有供體(ti)一致。



The study protocol should specify the inclusion (acceptance) criteria for skin sections based upon the barrier integrity test result, which should be reported for each skin section.

研究方(fang)案應根據屏障(zhang)完整性測試結果(guo)規定皮(pi)膚部分的納入(接受(shou))標準。



The study protocol should specify inclusion criteria related to the temperature and duration of skin storage as well as the number of freeze-thaw cycles, all of which should be reported for each donor&rsquo;s skin.

研究方案應規定與皮膚儲(chu)存(cun)(cun)的溫度和儲(chu)存(cun)(cun)時間(jian)以及凍融循(xun)環次數納入相(xiang)關的標(biao)準。



The study protocol should specify the inclusion criteria related to the skin harvesting/processing procedures and skin thickness (e.g., dermatomed skin of 500 μm ± 250 μm thickness) used in the IVPT study.

研究(jiu)方案應規(gui)定與IVPT研究(jiu)中使用(yong)的皮膚采集(ji)/處理程序和(he)皮膚厚度(例如,500μm±250μm厚度的皮膚)。



H. Exclusion Criteria/排除標準

In general, the following exclusion criteria should apply. Skin from subjects with a known (history of) dermatological disease should be excluded from the study. Skin with tattoos, stretch marks, or any visible sign of abnormality should be excluded from the study. Skin exhibiting a significant density of terminal hair is not recommended and should be excluded from the study. Additional criteria may be added by the applicant.

通常,采用以下排除標(biao)準(zhun)(zhun)。患有(you)已知皮膚病(bing)(病(bing)史)的(de)供體皮膚;有(you)紋身、妊娠紋或(huo)任何明顯異常跡象的(de)皮膚應;皮膚表現(xian)出(chu)明顯的(de)末梢(shao)毛發(fa)密度等。申(shen)請(qing)人可(ke)增加其他標(biao)準(zhun)(zhun)。



While gentle washing or rinsing of the skin surface is appropriate, submerging the skin in an aqueous solution for more than a few minutes may damage the skin barrier and should be avoided; such skin sections should be excluded from the study. Also, skin that has been subjected to shaving with a blade; abrasive polishing; tape-stripping; or cleansing with alcohols, solvents, or other strong solutions that could damage the skin barrier should be excluded from the study.

雖然可以采用(yong)(yong)溫和地清洗或(huo)漂洗皮膚表面,但(dan)將皮膚浸泡在水溶(rong)液中幾分鐘以上可能(neng)會破壞皮膚屏障(zhang),應避(bi)免該方式。另外,不(bu)建議采用(yong)(yong)用(yong)(yong)刀片刮過的(de)皮膚;磨料拋光(guang);膠帶剝離;或(huo)使用(yong)(yong)酒精、溶(rong)劑(ji)或(huo)其他可能(neng)破壞皮膚屏障(zhang)的(de)強極性溶(rong)液進行(xing)清潔。

 

Skin from donors with significant background levels of the drug or other compounds that may interfere with the quantification of the drug in receptor solution samples should be excluded from the study.

來(lai)自供體的皮(pi)膚(fu)具有顯著的藥(yao)物(wu)背景(jing)水(shui)平或其他(ta)可能干擾受體溶液(ye)樣(yang)品中藥(yao)物(wu)定量的化合物(wu)應(ying)排(pai)除在(zai)研究之(zhi)外。



Skin from donors exhibiting a high barrier integrity test failure rate among replicate skin sections may be excluded from the study, and skin from an alternative donor may be used instead.

重復皮(pi)(pi)膚切片中屏障完整性測(ce)試失敗率高的供(gong)(gong)體皮(pi)(pi)膚可能被排除在研究之外,應采用替代供(gong)(gong)體皮(pi)(pi)膚。



I. IVPT Endpoints/  IVPT終點

The endpoints for the IVPT pivotal study are based upon parameters that characterize the rate and extent to which the drug permeates into and through the skin and becomes available in the receptor solution. Specifically, the rate of drug permeation is characterized by the flux (J) and the extent of drug permeation is characterized by the total cumulative amount (AMT) of drug permeated into the receptor solution across the study duration.

IVPT正式研究的(de)(de)終點,是基于表(biao)征藥(yao)物(wu)滲(shen)透(tou)和(he)通(tong)過皮膚中,并(bing)進入接收(shou)(shou)液的(de)(de)速率和(he)程度的(de)(de)參數。具體來說,藥(yao)物(wu)滲(shen)透(tou)速率以(yi)通(tong)量(J)進行表(biao)征,而藥(yao)物(wu)滲(shen)透(tou)程度采用整個(ge)研究期(qi)間滲(shen)透(tou)到接收(shou)(shou)液中的(de)(de)藥(yao)物(wu)的(de)(de)總累積量(AMT)進行表(biao)征。



The flux (rate of drug permeation) should be plotted as J on the Y-axis in units of mass/area/time (e.g., nanograms (ng)/cm2 /hr) versus time on the X-axis. Flux profiles commonly resemble plasma pharmacokinetic profiles, however, it is important to distinguish that the flux is a rate, rather than a concentration. The extent of drug permeation should also be plotted, as the total cumulative amount (AMT) of drug permeated on the Y-axis in units of mass/area (e.g., ng/cm2 ) versus time on the X-axis.

以通量(藥(yao)物(wu)滲透速率)為縱(zong)(zong)坐(zuo)標(biao)Y-軸(zhou)(zhou)(zhou),時間(jian)為橫坐(zuo)標(biao)X-軸(zhou)(zhou)(zhou)作圖(tu)(tu);其中Y-軸(zhou)(zhou)(zhou)用“J”標(biao)識,以質(zhi)量/面積(ji)/時間(jian)(如(ru),納克/平方厘米(mi)/小時)為單(dan)(dan)位(wei)。通量分布模型(xing)通常類(lei)似于血漿藥(yao)代動力(li)學分布模型(xing),盡管(guan)通量是(shi)一個速率單(dan)(dan)位(wei),并不代表濃(nong)度。也應對藥(yao)物(wu)的(de)滲透程度作圖(tu)(tu),以藥(yao)物(wu)累積(ji)滲透量(單(dan)(dan)位(wei)為質(zhi)量/面積(ji),如(ru)納克/平方厘米(mi))為縱(zong)(zong)坐(zuo)標(biao)Y-軸(zhou)(zhou)(zhou),時間(jian)為橫坐(zuo)標(biao)X-軸(zhou)(zhou)(zhou)。



The flux should be calculated based upon: the receptor sample concentration (e.g., 2.0 ng/mL) at each time point; the precise, empirically measured volume of that specific diffusion cell (e.g., 6.0 mL) which may vary between individual cells; the area of dose application (e.g., 1 cm2 ); and the duration for which the receptor volume was accepting the drug. For example, if the sample exemplified here represented a 2-hour period following dosing, then J would be calculated based upon the values above as:

流(liu)量的(de)計算應基于(yu):每個時間點的(de)接收(shou)液(ye)中的(de)樣(yang)品(pin)濃(nong)度(如(ru)(ru)(ru):2.0 ng/mL);精確、經驗性的(de)測量擴(kuo)散池(chi)的(de)體(ti)積(ji)(如(ru)(ru)(ru):6.0mL),每個擴(kuo)散池(chi)體(ti)積(ji)或有不同(tong);上樣(yang)區(qu)域(yu)面積(ji)(如(ru)(ru)(ru):1cm2);研究(jiu)的(de)持續時間。例如(ru)(ru)(ru),如(ru)(ru)(ru)果這里例舉的(de)樣(yang)品(pin)表示(shi)給藥(yao)后2小時內的(de)情況,則J將基于(yu)上述值計算為:J = [(2.0 ng/mL) x (6.0 mL)]/(1 cm2 )/(2 hrs) = 6 ng/cm2 /hr



This flux should be calculated and reported for each diffusion cell for each sampling interval and plotted across the entire study duration to generate the flux profile for each diffusion cell. The rate calculated above may be plotted at the 2-hour time point, or at the midpoint between 0 and 2 hours (i.e., 1 hour).

應(ying)計算并報告(gao)各(ge)擴(kuo)散池(chi)的(de)(de)所有(you)相鄰(lin)采樣點之(zhi)間的(de)(de)通量,并繪制整個研究期間所有(you)擴(kuo)散池(chi)的(de)(de)通量曲線。上面計算的(de)(de)速率(lv)可以在2小時(shi)的(de)(de)實際時(shi)間點進行繪制,或者在0到2小時(shi)(即1小時(shi))之(zhi)間的(de)(de)中點繪制。



In addition, the AMT should be calculated and reported for each diffusion cell. This cumulative amount of drug that has permeated (in total across the entire study) should be reported as the AMT endpoint, rather than using a trapezoid rule to calculate the area under the flux curve.

此外,應計算并報告每個擴散池的總累計滲透量(AMT)。AMT終點為藥物滲透的累計量(整個研究期間的滲透總量),而不是采用梯形法則計算的通量曲線下的面積。

圖片

The maximum flux (Jmax) at the peak of the drug flux profile and the AMT should both be compared for locally-acting test topical products and RSs. This is somewhat analogous to the comparison of the Cmax and AUC for systemically-acting test products and RSs, inasmuch as the pair of endpoints in each case facilitates a comparison of the rate and extent to which the drug from each type of product (locally-acting or systemically-acting) becomes available at the site of action.

應將局部(bu)起效(xiao)(xiao)的自(zi)研制(zhi)劑和RSs的最大通量(Jmax,藥物通量曲線的最高峰)和AMT進(jin)行對比。這類似于全身起效(xiao)(xiao)的自(zi)研制(zhi)劑和RSs的Cmax和AUC的比較,因為(wei)這些終(zhong)點可分別用(yong)于表(biao)征(zheng)各劑型(xing)(局部(bu)起效(xiao)(xiao)或全身起效(xiao)(xiao))藥物到(dao)達作用(yong)部(bu)位的速(su)率和程(cheng)度。



A confidence interval (CI) should be calculated for each IVPT endpoint: 應計算(suan)每個IVPT終點的(de)置信(xin)區(qu)間(jian)(CI):

a. the natural log-transformed maximum flux (Jmax) 自然對數(shu)換(huan)算后的最大(da)通量(Jmax)

b. the natural log-transformed total cumulative amount (AMT) permeated自(zi)然對數(shu)換算后的總(zong)累積滲透量(AMT)



It is the responsibility of the applicant to determine the number of donors required to adequately power the IVPT pivotal study, however, a minimum of four dosed replicates per donor per treatment group (test product or RS) is recommended.

申請人有責任確定足以支(zhi)持IVPT關鍵研究(jiu)所需的供(gong)體數(shu)量,然而,建(jian)議每(mei)(mei)個試驗(yan)組(自研制劑或(huo)RS)每(mei)(mei)個供(gong)體至(zhi)少4個重復劑量。



At the completion of the study, if the number of skin replicates is the same for all donors in the test topical product and RS treatment groups in the IVPT study, a statistical analysis for a balanced design is recommended. If skin sections or diffusion cells are excluded from the final statistical analysis because of experimental loss/issues, and the resulting data set is unbalanced, a statistical analysis for an unbalanced design is recommended.

在IVPT研究結束時,如果自研外用制劑和(he)RS試驗組中(zhong)所有(you)供體的(de)皮膚(fu)(fu)切片(pian)重復數均一致,建(jian)議(yi)(yi)采(cai)用平衡設計(ji)(ji)法進(jin)(jin)行統(tong)計(ji)(ji)分析。如果皮膚(fu)(fu)切片(pian)或(huo)擴(kuo)散測(ce)試池因實驗損失/問題而被排除在最終統(tong)計(ji)(ji)分析之外,且所得(de)數據集不平衡,則建(jian)議(yi)(yi)對不平衡設計(ji)(ji)進(jin)(jin)行統(tong)計(ji)(ji)分析。



Approaches to statistical analysis of the pivotal study are described in section VIII of this guidance. Appendix I provides example SAS code for determining BE with both a balanced dataset and an unbalanced dataset. Appendix II provides numerical examples with simulated data sets. Appendix III provides example R code for determining BE.

在本指南的(de)(de)第VIII部分(fen),對正(zheng)式(shi)研究的(de)(de)統計分(fen)析(xi)方法進行(xing)了(le)描述。附錄I中(zhong)提(ti)供了(le)用(yong)于測定平衡(heng)數(shu)(shu)據(ju)集(ji)和非平衡(heng)數(shu)(shu)據(ju)集(ji)BE的(de)(de)SAS代(dai)碼示(shi)(shi)例。附錄II中(zhong)提(ti)供了(le)模擬數(shu)(shu)據(ju)集(ji)的(de)(de)具體(ti)示(shi)(shi)例。附錄III中(zhong)提(ti)供了(le)測定BE的(de)(de)R代(dai)碼示(shi)(shi)例。



VII. SUBMITTING INFORMATION ON IVPT STUDIES IN AN ANDA/ANDA中遞交(jiao)的IVPT研究信息

For IVPT studies with topical products submitted in ANDAs that are intended to support a demonstration of BE, detailed study protocols, relevant SOPs, and detailed reports should be submitted for the IVPT method validation (including the IVPT pilot study) and the IVPT pivotal study. In addition, a detailed report describing the IVPT method development should be submitted. These protocols, SOPs, and reports should be submitted in module 5.3.1.2 of the electronic Common Technical Document (eCTD) and should describe experimental procedures, study controls, quality management procedures, and data analyses.

對(dui)于(yu)在(zai)ANDA中(zhong)提(ti)交的(de)(de)(de)用(yong)于(yu)支持(chi)BE演示的(de)(de)(de)外用(yong)制劑的(de)(de)(de)IVPT研究,應(ying)提(ti)交詳(xiang)(xiang)細的(de)(de)(de)研究方案(an)、相(xiang)關SOP和(he)詳(xiang)(xiang)細的(de)(de)(de)報(bao)告,用(yong)于(yu)IVPT方法(fa)驗證(包括IVPT初步(bu)研究)和(he)IVPT關鍵(jian)研究。此外,還應(ying)提(ti)交一份(fen)詳(xiang)(xiang)細的(de)(de)(de)IVPT方法(fa)開發報(bao)告。這些方案(an)、SOPs和(he)報(bao)告應(ying)在(zai)電子通用(yong)技術文件(eCTD)的(de)(de)(de)模(mo)塊5.3.1.2中(zhong)遞(di)交,并對(dui)相(xiang)關的(de)(de)(de)試驗方法(fa)、研究控制、質量管理(li)程序(xu)和(he)數據分(fen)析進行描(miao)述(shu)。



Note that the study protocols, SOPs, and reports related to the IVPT method are distinct from those for the sample analytical method that is used to quantify drug concentrations in IVPT receptor solution samples (e.g., an HPLC/MS or UPLC/MS method). Separate protocols and SOPs should be submitted for the sample analytical method validation. Sample analytical method development and validation reports, pilot and pivotal IVPT study sample analysis reports, as well as associated SOPs and protocols relevant to the sample analysis of an IVPT study with human skin should be submitted in Module 5.3.1.4 of the eCTD.

注意,用于IVPT接收液中樣品濃度(du)的(de)(de)定量分(fen)(fen)析方(fang)法(fa)(如,HPLC/MS或(huo)UPLC/MS方(fang)法(fa))與IVPT方(fang)法(fa)相(xiang)(xiang)關(guan)(guan)的(de)(de)研究(jiu)方(fang)案(an)、SOPs和報告(gao)不同。樣品分(fen)(fen)析方(fang)法(fa)驗(yan)證(zheng)應提(ti)交單獨的(de)(de)方(fang)案(an)和標準操作規程。樣本分(fen)(fen)析方(fang)法(fa)開發和驗(yan)證(zheng)報告(gao)、試點和關(guan)(guan)鍵IVPT研究(jiu)樣本分(fen)(fen)析報告(gao)以及與人體(ti)皮膚IVPT研究(jiu)的(de)(de)樣本分(fen)(fen)析相(xiang)(xiang)關(guan)(guan)的(de)(de)相(xiang)(xiang)關(guan)(guan)SOP和協議應在eCTD的(de)(de)模塊(kuai)5.3.1.4中提(ti)交。



VIII.IVPT PIVOTAL STUDY STATISTICAL ANALYSIS/IVPT正式研究統計分析

The two treatment groups would correspond to the test topical product (T) and the RS (R). The statistical analysis should consider a sample of n donors, for which rT replicate skin sections from the j thdonor (j = 1, ? , n) are available for the T group and rR replicate skin sections from the j th donor (j= 1, ? , n) are available for the R group. Each replicate (i) from each donor (j) should have been randomly assigned to each product.

兩個治療組將對應于自研外用制劑(T)和RS(R)。進行統計分析應考慮以下樣本n 組供體,其中rT復制第j個供者的皮膚切片(j = 1.? , n) 適用于T組和rR復(fu)制第j個供體的皮膚切片(j = 1.? , n) 可用(yong)于(yu)R組。每(mei)個供體(j)的每(mei)個復(fu)制品(i)應隨機分配給每(mei)個產品。

 

Define the following quantities: 定義(yi)如下:

Tij= the natural log-transformed IVPT endpoint (Jmax or AMT) dosed with the test topical product for the ith skin replicate from the jth donor (i = 1, 2, ? ,rT,j =1, 2, ? , n)

Tij=第j個供體的第i個皮膚復制品的試驗外用產品給藥的自然對數轉換IVPT終點(Jmax或AMT)(i = 1, 2, ? , rT,j =1, 2, ? , n)

Rij = the natural log-transformed IVPT endpoint( Jmax or AMT) dosed with the RS for the ith skin replicate from the jth donor (i= 1, 2, ? , rR

j = 1, 2, ? , n)

Rij=第j個供體第i次皮膚復制的RS給藥的自然對數轉換IVPT終點(Jmax或AMT)(i= 1, 2, ? , rR,j= 1, 2, ? , n)

rTj= the number of skin replicates from the j th donor dosed with the test topical product ( j = 1, 2, ? , n)

rTj=第j個供(gong)體用外(wai)用制劑(j = 1, 2, ? , n)

rRj = the number of skin replicates from the j th donor dosed with the RS ( j=1, 2, ? , n)

rRj=第j個(ge)供體用(yong)RS( j=1, 2, ? , n)給藥(yao)的皮膚(fu)切(qie)片的重(zhong)復數

r=rR1+rR2+……+rRn = the total number of skin replicates in the R group

r =rR1+rR2+……+rRn=R組皮膚切片總數

n = the number of donors

n = 供(gong)體組的(de)數量

If the numbers of skin replicates available for the final statistical analysis are the same for the n donors for the T group and the R group, the resulting data set is balanced. For simplicity of notation, the common number of skin replicates for one donor for one treatment group in a balanced data set is denoted as r=rT1+rT2+……=rTn=rR1+rR2=……rRn

如果可用于最終統計分析的皮膚切片重復次數相同的n 組和T組和R組的供體中,所得數據集是平衡的。為方便標記,在平衡數據集中,一個供體對一個治療組的皮膚重復次數表示為r=rT1+rT2+……=rTn=rR1+rR2=……rRn

 

A diffusion cell may be excluded from among the replicates in a data set when there is a documented observation of a failure (e.g., visual observation that a skin section tears and leaks during the study) or a protocol deviation (e.g., the receptor compartment in a diffusion cell is discovered to be empty at the first sampling time point). In such instances, if sufficient skin remains from the same donor, and no samples from that diffusion cell have been analyzed, a replacement diffusion cell can be set up and studied. Otherwise (if the diffusion cell cannot be replaced) the resulting data set becomes unbalanced.

當有(you)失敗的(de)(de)觀察(cha)記錄(如(ru):在研(yan)究期間(jian)觀察(cha)到皮膚可(ke)見(jian)撕裂(lie)和泄漏)或方案的(de)(de)偏差(cha)(如(ru):擴散(san)測試池中的(de)(de)接收室在第一個(ge)取(qu)樣(yang)時間(jian)點被發(fa)現為(wei)空(kong))時,擴散(san)測試池可(ke)從(cong)數據集(ji)中的(de)(de)重復數中排除(chu)。在這種情(qing)況下,如(ru)果來自同一供體的(de)(de)足夠(gou)皮膚仍充足,并且沒(mei)有(you)對(dui)該(gai)(gai)擴散(san)池的(de)(de)樣(yang)品進行分析,則(ze)可(ke)以(yi)采(cai)用替代擴散(san)池。若沒(mei)有(you)可(ke)替代擴散(san)池,則(ze)該(gai)(gai)結果數據集(ji)是不平衡的(de)(de)。



The statistical analysis methods for assessing BE in the cases of a balanced data set and an unbalanced data set are described below. For a donor to be included in the statistical analysis, there should be at least 3 replicate skin sections from the donor for each (T and R) treatment group.

下文描述了在(zai)平(ping)衡(heng)數據集和非平(ping)衡(heng)數據集情況下評估BE的統計分(fen)析方法。對(dui)于納入統計分(fen)析的供體,每個(T和R)治療組的供體應至少有3個重復皮膚切片。



Step 1. Determine Swr,the estimated within-donor standard deviation of the RS, for each of the natural log-transformed IVPT endpoints Jmax and AMT:

步驟1.確定Swr,,每個自(zi)然對數(shu)變換(huan)IVPT終點Jmax和AMT的(de)RS的(de)估計供(gong)體內標準偏(pian)差:

圖片

 

(a) If Swr≥0.294, use the scaled average BE (SABE) approach to determine BE for the individual IVPT endpoint(s) in Steps 2, 3.1, and 4.1

(a) 如果Swr ≥0.294,使用縮放平均BE(SABE)方法確(que)定(ding)步驟2、3.1和4.1中(zhong)單個IVPT終點的(de)BE

(b) If Swr<0.294, use the regular average BE (ABE) approach through the two one-sided tests (TOST) procedure (Schuirmann, 1987) to determine BE fo the individual IVPT endpoint(s) in Steps 2, 3.2, and 4.2

(b) 如果Swr<0.294,使用常規平均BE(ABE)方法(fa),通過(guo)兩個單(dan)側測試(TOST)程序(Schuirmann,1987),在步驟2、3.2和4.2中確定單(dan)個IVPT終(zhong)點的(de)BE

圖片

 

Step 2. Determine the point estimate for the mean difference of T and R products (I^), its standard error (se(I^)), and the corresponding degrees of freedom (df∗).

確定T和R乘積平均差的點估計(I^), 其標準誤差(se(I^)),以及(ji)相(xiang)應的自(zi)由度(df∗)

For a balanced data set, determine I^, se(I^) and df∗ by the following: 對于平衡數據集,確定I^, se(I^)和(he)df∗通過以(yi)下方式:

圖片

 

For an unbalanced data set, approximate I^, se(I^) and df∗ by using PROC MIXED  (or PROC GLM) in SAS. The example code is provided in Appendix I.

對于不平衡數據集,近似I^, se(I^)和df∗ 在SAS中(zhong)使用(yong)PROC MIXED(或(huo)PROC GLM)。附錄I中(zhong)提供了示例代碼。



Step 3.1. Scaled Average BE (SABE) Approach標度(du)平(ping)均BE(SABE)方法

In the SABE approach, the hypotheses to be tested are: 在SABE方法中,要測試(shi)的(de)假設(she)是(shi):

圖片

Rejection of the null hypothesis supports the conclusion of equivalence of the two products. 否定(ding)零假設(she)支持兩種(zhong)產品等價的結論。

Determine (1-α)*100% upper confidence bound for (μT-μR)2-θσ2WRbased on Howe’s Approximation (Howe, 1974) (α = 0.05):

圖片

Note that t(1-α),df∗ is (1-α) ∗ 100th percentile of the Student’s t-distribution with df∗ degrees of freedom and x2(1-α),(r*-n) is (1-α) ∗ 100th percentile of the Chi- square distribution with (r*-n)degrees of freedom

Step 3.2. Regular Average BE (ABE) Approach常規平均BE(ABE)方法

In the ABE approach, the hypotheses to be tested are: 在ABE方法(fa)中,要測試(shi)的假(jia)設是:

圖片

 

Rejection of the null hypothesis supports the conclusion of equivalence of the two products. 否定零(ling)假設(she)支持兩(liang)種(zhong)產品(pin)等價的結(jie)論。

Determine the (1 − 2α)*100% confidence interval for μT-μR (α = 0.05):

圖片

where t(1-&alpha;),df∗ is (1-α) ∗ 100th  percentile of the Student’s t-distribution with df∗ degrees of freedom.

 

Step 4.1. BE Determination with SABE Approach用SABE方(fang)法確定(ding)BE

For the test product to be bioequivalent to the reference standard, both of the following conditions must be satisfied for each IVPT endpoint tested: 為使自制(zhi)(zhi)制(zhi)(zhi)劑與參比制(zhi)(zhi)劑具有生物等效性(xing),每個IVPT試驗終(zhong)點必(bi)須滿足(zu)以(yi)下(xia)兩個條件:

a.the 95% upper confidence bound for (μT-μR)2-θσ2WR must be less than or equal to zero (numbers should be kept to a minimum of four significant figures for comparison).

b.the point estimate of the T/R geometric mean ratio must fall within the pre- specified limits [1/m,m], where m = 1.2500.

 

Step 4.2. BE Determination with ABE Approach 采用ABE法確定(ding)BE測定(ding)

For the test product to be bioequivalent to the reference standard, the 90% confidence interval for μT-μR must be contained within the limits [1/m,m] in the original scale for each IVPT endpoint tested, where m = 1.2500.

在IVPT重點測試中,如果μT-μR的90%置信區間(jian)必(bi)須(xu)包(bao)含在每個測試IVPT終點(dian)原始(shi)量表中的限值(zhi)[1/m,m]內,其中m=1.2500,則證明自研(yan)制劑與對照制劑具有(you)生物等(deng)效

圖片

 

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