1、the professional english of pharmaceutical engineering,wang xinliang east china university of science and technology 05.03.2012,words,attrition rate indications new chemical entities differentiation formulary toxicity toxicology dossier dosage form synergism antagonism genotoxicology carcinogenicity

2、 abnormality pharmacy pharmacognosy pharmacodynamics pharmacokinetics pharmacotherapeutics,淘汰率 n. 適應(yīng)癥 新化學(xué)實(shí)體（新化合物） n. 區(qū)別；變異 n. 公式集；處方集 n. 毒性 n. 毒物學(xué)；毒理學(xué) n. 檔案，卷宗；病歷表冊(cè) 劑型；藥物劑型 n. 協(xié)調(diào)作用 n. 拮抗作用(反協(xié)調(diào)作用) n. 基因毒理學(xué) n. 致癌性；致癌毒性 n. 異常；畸形 n. 藥劑學(xué)；制藥業(yè) n. 生藥學(xué) n. 藥效學(xué) n. 藥物(代謝)動(dòng)力學(xué) n. 臨床藥物治療學(xué),1.引言 藥品開(kāi)發(fā)是一個(gè)非常復(fù)雜的過(guò)程，需要在廣泛

3、的不同功能性團(tuán)隊(duì)之間進(jìn)行大量的協(xié)調(diào)和溝通。這個(gè)過(guò)程是昂貴的，特別是在臨床開(kāi)發(fā)的后期階段，其中涉及到對(duì)數(shù)百名病人的研究。據(jù)目前的估計(jì)，一個(gè)新藥的開(kāi)發(fā)成本約2.3億美元（1987年的美元），并且從起動(dòng)臨床前的開(kāi)發(fā)階段到首次上市（不包括監(jiān)管延遲），需要花費(fèi)7-10年。,1. introduction drug development is a very complex process requiring a great deal of coordination and communication between a wide range of different functional groups.

4、 it is expensive, particularly in the later phases of clinical development, where studies involve hundreds of patients. it is currently estimated that the development of a new drug costs about $ 230 million (1987 dollars) and takes somewhere between 7 and 10 years from initiation of preclinical deve

5、lopment to first marketing (excluding regulatory delays).,unit 5 drugs development (i),藥物開(kāi)發(fā)是一項(xiàng)高風(fēng)險(xiǎn)業(yè)務(wù)，雖然（淘汰）比率不斷上升，在完成了首次人體研究的每十個(gè)新化學(xué)實(shí)體中，大約只有一個(gè)會(huì)成為產(chǎn)品。隨著候選藥物開(kāi)發(fā)的進(jìn)行，失敗的風(fēng)險(xiǎn)在前進(jìn)的道路上，會(huì)象跨欄似的降低。失敗的典型原因包括：不可接受的毒性，缺乏功效，或不比競(jìng)爭(zhēng)產(chǎn)品有優(yōu)勢(shì)（圖1）。,drug development is a high-risk business; although the rate is increasing, only a

6、bout one out of every ten new chemical entities studied in human beings for the first time will ever become a product. as a drug candidate progresses through development the risks of failure decrease as hurdles are overcome along the way. typical reasons for failure include unacceptable toxicity, la

7、ck of efficacy, or inability to provide advantages over competitive products (fig. 1).,圖1. 淘汰率和終止的原因,attrition rate of new chemical entities (nces) entering development. on average only about i in 4001000 compounds.,進(jìn)入開(kāi)發(fā)階段的新化學(xué)實(shí)體（nces）的淘汰率。平均每400 1000個(gè)所合成的化合物只有1個(gè)能進(jìn)入開(kāi)發(fā)過(guò)程。,（不包括抗感染藥）nces開(kāi)發(fā)終止的原因： 1：缺乏療效

8、2：藥代動(dòng)力學(xué) 3：動(dòng)物毒性 4：其他因素 5：對(duì)人的不良影響 6：商業(yè)上的原因,reasons for termination of development of nces (excluding anti-infectives) 1: lack of efficacy 2: pharmacokinetics 3: animal toxicity 4: miscellaneous 5: adverse effects in man 6: commercial reasons,2.開(kāi)發(fā)的規(guī)劃 對(duì)候選藥物是否有可能提供有競(jìng)爭(zhēng)力的優(yōu)勢(shì)方面的評(píng)估，首先強(qiáng)調(diào)的需要是達(dá)到一整套的產(chǎn)品目標(biāo)或目標(biāo)產(chǎn)品的特性。

9、應(yīng)當(dāng)特別注意競(jìng)爭(zhēng)者（指藥物）之間的差異。隨著對(duì)有限的處方、醫(yī)療保健費(fèi)用以及藥物經(jīng)濟(jì)學(xué)（本章稍后討論）的日益關(guān)注（強(qiáng)調(diào)），這種情況變得越來(lái)越重要。,2. planning for development assessment of whether a drug candidate is likely to provide competitive advantages highlights the need first to have in place a set of product goals or target product profile. particular attention sh

10、ould be paid to the differentiation from competitors. this is becoming more and more critical with the increasing emphasis on limited formularies，healthcare costs, and pharmacoeconomics (discussed later in the chapter).,包括諸如每日一次給藥、更快的起效作用、比主要競(jìng)爭(zhēng)者具有更低副作用的特性等目標(biāo)在內(nèi)，（藥物開(kāi)發(fā)的）目的特性將定義候選藥物將被開(kāi)發(fā)的（疾病）適應(yīng)癥。隨著候選藥物的開(kāi)

11、發(fā)階段的進(jìn)展，以及候選藥物或競(jìng)爭(zhēng)藥物的新數(shù)據(jù)的獲得，（藥物開(kāi)發(fā)的）目的特性可以再定義或修正。合乎邏輯的下一個(gè)步驟就是明確開(kāi)發(fā)戰(zhàn)略，例如，哪個(gè)（疾病）適應(yīng)癥要優(yōu)先開(kāi)發(fā)，以哪些國(guó)家作為藥物的目標(biāo)市場(chǎng)，然后確定能獲得監(jiān)管機(jī)構(gòu)的批準(zhǔn)和商業(yè)成功的必要核心臨床研究（內(nèi)容）。,a target profile will define the indication(s) that a drug candidate will be developed for, along with goals such as once a day dosing, faster onset of action, better s

12、ide effect profile than a major competitor. the target profile can be refined and revised as a drug candidate moves through development and new data on the drug candidate or competitors become available. the logical next steps are to define the development strategy, for example, which indications to

13、 develop first, which countries to aim to market the drug in and then to define the core clinical studies necessary to achieve regulatory approval and commercial success.,本章將描述一個(gè)新藥成功開(kāi)發(fā)過(guò)程所需的主要活動(dòng)。所有這些活動(dòng)，其中許多是相互依存的，需要認(rèn)真規(guī)劃和協(xié)調(diào)。與高質(zhì)量數(shù)據(jù)的收集打交道的速度是成功的關(guān)鍵。確定需要測(cè)定花費(fèi)時(shí)間來(lái)獲得登記的活動(dòng)的步驟，以項(xiàng)目管理術(shù)語(yǔ)而言，被稱為關(guān)鍵步驟。在研究開(kāi)始之前，計(jì)劃和準(zhǔn)備、并監(jiān)

14、控和管理問(wèn)題以確保關(guān)鍵步驟如期進(jìn)行，這是非常重要。,this chapter will describe the main activities required for successful development of a new drug. all these activities, many of which are interdependent, need to be carefully planned and co-ordinate. speed to market with collection of high quality data is critical for succe

15、ss. the path of activities which determine the time it will take to get to registration is called, in project management terms, the critical path. it is vital to plan and prepare before studies begin and to monitor and manage problems so as to ensure that the critical path remains on schedule.,由于增加的

16、經(jīng)濟(jì)壓力和競(jìng)爭(zhēng)強(qiáng)度，企業(yè)探索如何縮短這一關(guān)鍵步驟是重要的。并行開(kāi)展這些活動(dòng)，或?qū)⑼ǔ０错樞蜷_(kāi)展的研究進(jìn)行重疊，往往會(huì)涉及到風(fēng)險(xiǎn)的增加；但節(jié)省時(shí)間的紅利可以使這種戰(zhàn)略值得做。 新藥開(kāi)發(fā)的關(guān)鍵步驟貫穿于化合物的初期合成、亞急性毒理學(xué)研究和隨后的臨床計(jì)劃。一個(gè)展示典型的候選藥物的關(guān)鍵步驟活動(dòng)的圖表如fig. 2所示。,with increased economic pressures and competitive intensity it is important for companies to explore ways to shorten this critical path. runnin

17、g activities in parallel, or overlapping studies which would usually run sequentially, often involves an increase in risk but the dividends in time-saving can make such strategies worthwhile. the critical path for development of a new drug generally runs through the initial synthesis of compound, su

18、bacute toxicology studies, and the clinical program. a chart showing the critical path activities for a typical drug candidate is shown in fig. 2.,11,adme is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a ph

19、armaceutical compound within an organism. the four criteria all influence the drug levels and kinetics of drug exposure to the tissues and hence influence the performance and pharmacological activity of the compound as a drug.,12,“adme”即“毒藥物動(dòng)力學(xué)”，指機(jī)體對(duì)外源化學(xué)物的吸收、分布、代謝及排泄等過(guò)程；這些過(guò)程可能同時(shí)發(fā)生?？筛爬樗幬锏霓D(zhuǎn)運(yùn)和轉(zhuǎn)化，或稱為機(jī)體

20、對(duì)藥物的處置。 藥動(dòng)學(xué)研究所反映出的藥物在動(dòng)物或者人體內(nèi)的動(dòng)態(tài)變化規(guī)律，除了可作為藥效學(xué)和毒理學(xué)研究的借鑒外，也是指導(dǎo)新藥研究與開(kāi)發(fā)，進(jìn)行先導(dǎo)化合物的設(shè)計(jì)和篩選，以及申報(bào)臨床研究或進(jìn)一步申報(bào)生產(chǎn)所必須提交的重要資料。 對(duì)外源化學(xué)物adme過(guò)程的研究有重要意義： 1、可能用來(lái)確定與毒性發(fā)生有關(guān)的靶器官或組織的暴露特征。 2、可能為在其他的毒性研究的劑量選擇提供有用數(shù)據(jù)。 3、有助于闡明兩種或兩種以上外源化學(xué)物聯(lián)合毒作用的機(jī)制。 4、可通過(guò)改變外源化學(xué)物adme過(guò)程，以預(yù)防和治療外源化學(xué)物中毒。,下列各部分突出了和藥物開(kāi)發(fā)工作的具體目標(biāo)和活動(dòng)內(nèi)容。在每個(gè)技術(shù)學(xué)科里的活動(dòng)按時(shí)間前后排列的順序大致作了

21、介紹。在任何時(shí)候，在所有這些領(lǐng)域的工作可能是平行進(jìn)行。這些大多數(shù)工作的時(shí)序和所出成果對(duì)其他學(xué)科里的工作有著直接的影響。,the following sections highlight the objectives and activities of drug development work. activities within each technical discipline are described broadly in chronological order. at any one time, work in all these disciplines may be proceed

22、ing in parallel. the timing and outcome of much of the work has direct impact on work in other disciplines.,藥物開(kāi)發(fā)的主要階段是臨床前期（化合物可給人體服藥前的所需的研究）、i階段（通常在健康志愿者身上的臨床研究）、期（病人身上的初期療效和安全性和治療劑量調(diào)查研究）和期（在幾百個(gè)病人的研究）。然后附述一個(gè)由國(guó)家監(jiān)管當(dāng)局隨后審查的上市申請(qǐng)檔案的匯編。,the major phases of drug development are preclinical (studies required

23、 before the compound can be dosed in humans), phase i (clinical studies usually in healthy human volunteers), phase ( initial efficacy and safety and dose finding studies in patients)，and phase (studies in several hundred patients). there then follows assembly of a marketing application dossier for

24、subsequent review by country regulatory authorities.,3化學(xué)品的開(kāi)發(fā) 候選藥物的快速開(kāi)發(fā)是取決于足夠數(shù)量的化合物的可獲得性。該化合物的純度需要達(dá)到一定的標(biāo)準(zhǔn)，以便它用于安全性（毒理學(xué)）、藥學(xué)的和臨床的研究。最初，化學(xué)家將進(jìn)行小到中等規(guī)模的研究，考察采用幾種不同方法制備該化合物，以便確定該化合物的最佳合成路線。,3. chemical development rapid development of a drug candidate is dependent on the availability of sufficient quantity

25、of the compound. the purity of compound needs to reach certain standards in order for it to be used in safety (toxicology), pharmaceutical, and clinical studies. initially, chemists will work on a small to medium scale to investigate production of the compound by several different methods so as to i

26、dentify the optimum route for synthesizing the compound.,這里“最佳” 可能意味著多種因素的組合，例如，最有效，最便宜的安全，或產(chǎn)生最少的廢物。最終產(chǎn)品和中間體及雜質(zhì)的分析在確定最佳的合成方法起著關(guān)鍵作用。分析方法的開(kāi)發(fā)和驗(yàn)證對(duì)于支持工藝開(kāi)發(fā)和保證原料藥的純度是必要的。,optimum here may mean a combination of several factors, for example, most efficient, cheapest safe, or that producing minimal waste. ana

27、lysis of the final product as well as intermediates and impurities plays a key role in identifying the best method of synthesis. development and validation of analytical methods are necessary to support process development and guarantee the purity of the drug substance.,在某些情況下，雜質(zhì)的含量可能高得令人無(wú)法接受，要么需要開(kāi)發(fā)

28、改進(jìn)的純化程序，要么需要對(duì)合成過(guò)程大量調(diào)整。其主要目的是確?；衔锏某煞挚芍?，最終所制備的物料盡可能的純凈。,in some cases levels of impurities may be unacceptably high and either improved purification procedures will need to be developed or the synthetic process may require significant alterations. the main aim is to ensure that the composition of com

29、pound is understood and that ultimately the material that is prepared is as pure as possible.,隨著候選藥物開(kāi)發(fā)的進(jìn)展，所需化合物的數(shù)量越來(lái)越大。不同測(cè)試所需的物料的數(shù)量，往往取決于化合物的實(shí)際效力和劑型。中試工廠可以被看作是一個(gè)小型規(guī)模的制造機(jī)構(gòu)。在轉(zhuǎn)入中試工廠前，需要對(duì)化學(xué)合成進(jìn)行廣泛的評(píng)估和測(cè)試，以確保任何的改變和危害降至最低。,as a drug candidate progresses through development, larger and larger amounts of comp

30、ound are required. the amount of material required for different tests will often depend on the actual potency and dosage form of the compound. a pilot plant can be regarded as a mini-manufacturing set-up. before transferring to a pilot plant, extensive evaluation and testing of the chemical synthes

31、is is undertaken to ensure that any changes and hazards are minimized.,（制備）程序要優(yōu)化，特別注重開(kāi)發(fā)環(huán)境可接受的處置廢棄物的方法。一旦被批準(zhǔn)和銷(xiāo)售，藥品的生產(chǎn)所用的大量原料藥，其商業(yè)化生產(chǎn)將可能采取更大規(guī)模進(jìn)行或在登記的制造工廠進(jìn)行。,procedures are optimized, particular attention being paid to developing environmentally acceptable ways of disposing of waste products. commercia

32、l production of bulk drug substance for production of a drug, once approved and marketed, will likely take place on a larger scale or at a registered manufacturing plant.,4配方開(kāi)發(fā) 藥物的劑型，是指病人服用藥物的方式。存在形式繁多的從貼劑到吸入到鼻腔內(nèi)藥品的可能的劑型。較常見(jiàn)的劑型包括口服片劑或膠囊、口服液、外用藥膏或霜?jiǎng)?、和注射劑?；蛱囟ê蜻x藥物所的劑型或形態(tài)的選擇在將目標(biāo)特性中也要被定義。,4. formulation

33、development the dosage form of a drug is the form by which it is administered to the patient. there are a vast array of possible dosage forms ranging from transdermal patches to inhalers to intranasal medicines. the more common dosage forms include oral tablets or capsules, oral liquids, topical oin

34、tments or creams, and injectables. the dosage form or forms chosen for a particular drug candidate will be defined in the target profile.,有時(shí)，一個(gè)更簡(jiǎn)單的劑型，例如口服液，會(huì)被選擇來(lái)進(jìn)行早期人類臨床研究。在藥物開(kāi)發(fā)過(guò)程的早期的、高風(fēng)險(xiǎn)階段，這可以節(jié)省時(shí)間和預(yù)付成本。后期的臨床研究將使用預(yù)期要銷(xiāo)售的劑型。,sometimes a more simple dosage form, for example, an oral solution, is chosen

35、 for early clinical studies in human beings. this may save time and upfront costs at an early, high-risk stage of the drug development process. later clinical studies would use the expected marketed dosage form.,無(wú)論是什么劑型，藥物和其他物料的組合構(gòu)成它必須符合一定標(biāo)準(zhǔn)。最重要的標(biāo)準(zhǔn)之一是有足夠的穩(wěn)定性。這意味著，預(yù)先確定的效力水平必須，例如，兩年或三年后，能繼續(xù)保持。一種劑型所產(chǎn)生的

36、穩(wěn)定劑數(shù)據(jù)將決定它的保質(zhì)期（貯藏壽命）和推薦的儲(chǔ)存條件。在開(kāi)發(fā)的早期，其保質(zhì)期可能僅限于數(shù)月。只要藥品的使用期限足以超過(guò)臨床研究或研究的階段，這就不會(huì)是個(gè)問(wèn)題。,whatever the dosage form, the combination of drug and other materials which constitute it must fulfil certain criteria. one of the most important is that of adequate stability. that means a predetermined potency level m

37、ust remain after, for example, two or three years. the stability data generated on a dosage form will determine its shelf-life and recommended storage conditions. early in development the shelf-life may be limited to several months. this will not be a problem provided it is sufficient to cover use o

38、f the drug over the duration of the clinical study or studies.,5藥理學(xué) 在候選藥物考慮到人之前，它對(duì)主要系統(tǒng)的藥理作用研究往往在大量的物種上進(jìn)行了研究。所研究的身體系統(tǒng)包括心血管的，呼吸的和神經(jīng)系統(tǒng)；對(duì)總體行為的影響也會(huì)研究。,5. pharmacology before a drug candidate is given to man，its pharmacological effects on major systems are often investigated in a number of species. the bo

39、dy systems studied include cardiovascular, respiratory, and nervous systems; the effects on gross behavior can also be studied.,由于它們的特殊的作用或者因?yàn)樗鼈兊墓餐褂?，有時(shí)進(jìn)行實(shí)驗(yàn)是為了理解候選藥物是否對(duì)其他藥物的作用有干擾，這些藥物可能要與候選藥物同時(shí)服用。應(yīng)當(dāng)對(duì)藥物的任何協(xié)同作用或拮抗作用進(jìn)行研究，任何必要的警告必須發(fā)布給臨床研究者。（這可能被認(rèn)為有必要在臨床研究進(jìn)一步研究這些作用，以及任何潛在的或已被證明的藥物相互作用可能記錄在藥物的產(chǎn)品標(biāo)簽上。）,expe

40、riments are sometimes conducted to see whether the drug candidate interferes with the actions of other medicines which, because of their specific effects or because of their common use, are likely to be taken concurrently with the drug candidate. any synergism or antagonism of drug effects should be

41、 investigated, and any necessary warning issued to clinical investigators. (it may be judged necessary to investigate such effects further in clinical studies, and any potential or proven drug interactions are likely to be noted in the product labeling for the drug.),特別是如果該候選藥物的治療窗寬很小時(shí)，確定一種物質(zhì)可能應(yīng)用于過(guò)劑

42、量的管理的情況，這也可能是適當(dāng)?shù)摹?it may also be appropriate to identify a substance for possible use in the management of overdosage, particularly if the therapeutic margin of the drug candidate is small.,6安全性評(píng)價(jià) 在藥品開(kāi)給人服用前所開(kāi)展的動(dòng)物毒理學(xué)測(cè)試的目標(biāo)，是為了排除不可接受的毒性化合物，識(shí)別潛在的靶器官和藥物不良反應(yīng)的時(shí)序。這意味著，在早期人類研究中這些器官和組織可以特別注意而得到監(jiān)測(cè)。對(duì)有毒作用是可逆的還是不

43、可逆轉(zhuǎn)的、它們是否可以預(yù)防的、（如果可能的話）毒理學(xué)作用機(jī)制的確定，是重要的。使藥物在人類的血中濃度和各種動(dòng)物物種的血中濃度的響應(yīng)建立相互關(guān)聯(lián)也是重要的。,6. safety evaluation the objective of animal toxicology testing, carried out prior to the administration of a drug to man, is to reject compounds of unacceptable toxicity and to identify potential target organs and timings

44、 for adverse effects of the drug. this means that in early human studies these organs and tissues can be monitored with particular attention. it is important to establish whether toxic effects are reversible or irreversible, whether they can be prevented and, if possible, the mechanism of the toxico

45、logical effects. it is also important to interrelate drug response to blood levels in humans and blood levels in various animal species.,對(duì)于在人候選藥物評(píng)價(jià)所需的毒理學(xué)研究，將與所推薦的臨床應(yīng)用時(shí)的給藥途徑和臨床研究的治療持續(xù)時(shí)間有關(guān)。劑量的大小和使用頻率，以及毒理學(xué)研究的持續(xù)時(shí)間在人體獲準(zhǔn)測(cè)試的主要決定因素。許多國(guó)家，包括英國(guó)、美國(guó)、澳大利亞和北歐國(guó)家，都有涉及在人類治療持續(xù)時(shí)間和需要在兩個(gè)物種中進(jìn)行的毒性研究的時(shí)間長(zhǎng)短的監(jiān)管指南。指南的要點(diǎn)引用在隨后的章

46、節(jié)里。,the toxicological studies required for the evaluation of a drug candidate in man will be relevant to its proposed clinical use in terms of route of administration and duration of treatment of the clinical studies. the size and frequency of the doses and the duration of the toxicology studies are

47、 major determinants of permissible tests in man. countries, including uk, usa, australia, and nordic countries, have regulatory guidelines which relate the duration of treatment allowed in man to the length of toxicity studies required in two species. points from the guidelines are referenced in the

48、 subsequent sections.,最初，增加測(cè)試物質(zhì)劑量的藥理作用建立于少量動(dòng)物的急性毒性研究，一般采用兩種給藥途徑（一種用于人體）。（所得的）結(jié)果給隨后的慢性毒性試驗(yàn)，提供了一個(gè)最大耐受劑量的參考值，有助于劑量水平的選擇，以及確定靶標(biāo)器官。,initially, the pharmacological effects of increasing doses of the test substances are established in acute toxicity studies in small numbers of animals, generally using two

49、routes of administration (one being that used in man). results provide a guide to the maximum tolerated doses in subsequent chronic toxicity tests, aid selection of dose levels, and identify target organs.,隨后的亞急性毒性試驗(yàn)的主要目的是確定候選藥物在動(dòng)物長(zhǎng)期給藥后是否有足夠的耐受性，從而作為對(duì)人類可能產(chǎn)生的不良反應(yīng)的參考。使用與人相同的給藥途徑，在先于人的該化合物的給藥前，兩個(gè)物種（一個(gè)為

50、非嚙齒類）的兩到四個(gè)星期（每日劑量）的研究是必需的。三個(gè)劑量水平通常是必要的：每天的低劑量應(yīng)是所期望的治療劑量的低一數(shù)量級(jí)，最高劑量應(yīng)顯示出一定的毒性。,the main aim of the subsequent sub-acute toxicity tests is to determine whether or not the drug candidate is adequately tolerated after administration to animals for a prolonged period as a guide to possible adverse reactio

51、ns in man. two to four week (daily dosing) studies are required, using the same route of administration as in man, in two species (one non-rodent) prior to administration of the compound to man. three dose levels are usually necessary: the low daily dose should be a low multiple of the expected ther

52、apeutic dose, and the highest dose should demonstrate some toxicity.,評(píng)價(jià)新化學(xué)實(shí)體的通用指南應(yīng)該是一個(gè)為期14天以上毒理學(xué)研究需要支持正常的志愿者在第i階段的單劑量接觸一個(gè)新的候選藥物。支持7至10天時(shí)間的臨床研究，要求為期30天的毒理學(xué)研究。而超過(guò)7至10天直至30天的臨床研究則需要有至少90天的毒理學(xué)研究的支持。,a general guide for the evaluation of new chemical entities would be that toxicology studies of a minimum

53、 duration of 14 days are required to support single-dose exposure of a new drug candidate in normal volunteers in phase i. toxicology studies of 30 days duration are required to support clinical studies of 7 to 10 days duration. clinical studies of greater than 7 to 10 days up to 30 days duration re

54、quire the support of at least 90 days toxicology studies.,這些要求應(yīng)在計(jì)劃藥物開(kāi)發(fā)之前就明確說(shuō)明。未來(lái)臨床試驗(yàn)的持續(xù)時(shí)間和大概的時(shí)序安排需要提前好好地深思熟慮，以便做好安排并進(jìn)行適當(dāng)?shù)亩纠韺W(xué)研究，以支持臨床計(jì)劃并避免任何延誤。,these requirements illustrate the need to plan ahead in drug development. the duration and approximate timings for future clinical trials need to be consider

55、ed well in advance in order to schedule and conduct the appropriate toxicology studies to support the clinical program and avoid any delays.,兩種類型的安全測(cè)試是用來(lái)檢測(cè)候選藥物在人體產(chǎn)生腫瘤的能力。第一類是短期的體外遺傳毒性試驗(yàn)，例如細(xì)菌試驗(yàn)。第二類是是在小鼠和大鼠身上進(jìn)行的動(dòng)物長(zhǎng)期致癌性研究；他們往往二年的時(shí)間長(zhǎng)度覆蓋了動(dòng)物壽命的很大一部分。小鼠和大鼠的使用，因?yàn)樗麄兊膲勖鄬?duì)較短，體積小，容易獲得。此外，有關(guān)這些物種的特定種族的自發(fā)疾病及腫瘤所積累的

56、知識(shí)，大大有助于解釋研究結(jié)果。,two types of safety test are used to detect the ability of the drug candidate to produce tumours in man. the first are short-term in vitro genotoxicity tests, for example bacterial tests. the second are long-term animal carcinogenicity studies which are conducted in mice and rats; their length of often 2 years covers a large part of the lifespan of the animal. mice and rats are used because of their relatively short life span, small size, and ready availability. also, knowledge, which has accu