Zotarolimus

本次大会的主题为“砥砺深耕·笃行致远”，热情邀请全国相关领域专家、学者、科研骨干、企业代表与会交流。 继上一篇“发育和生殖毒性评估-1”下文概述了测试药物生殖和发育毒性的研究设计的一些考量。 01 特殊考虑 如果某种药物没有或只有非常有限的全身暴露（即，由于其药理、配方或给药途径和递送方式），则可能需要在大鼠和非啮齿动物模型中使用替代配方（alternate formulation）或给药途径来评估其对胚胎-胎儿发育的潜在全身影响。例如，如果一种药物在局部使用或在关节内注射时几乎没有或根本没有可测量的全身暴露，那么该药物可能需要重新配制并通过不同的途径（通常是静脉注射）使用，以实现全身暴露和可能的概念暴露。 如果一种药品被证明有胚胎-胎儿风险，只要在包装说明书中明确强调其致畸性或发育风险，并明确告知孕妇和可能怀孕的妇女不能使用外，该药品仍然可以使用和销售。例如来那度胺，它是沙利度胺的一种强效口服类似物，用于治疗多种血液系统恶性肿瘤；沙利度胺，由于在癌症病人和需要新疗法的适应症中获益与风险比很高，因此作为基本药物被重新启用。 这两种药物的胚胎-胎儿风险在各自的处方信息中都有明确强调，使用这两种药物的妇女或可能怀孕的妇女仍然禁用。此外，这两种药物的使用都要求有一个限制性的销售系统，并制定和严格遵守严格的风险评估和缓解策略。 02 生育力与早期胚胎和胚胎-胎儿发育毒性联合研究 生育力与早期胚胎和胚胎-胎儿发育毒性联合研究（FEED/EFD）测量对生育力、早期妊娠和器官形成的影响。这项综合研究评估的是药物或药品对男性或女性生育力的影响，以及从植入到器官形成期硬腭闭合（涵盖ICH计划的A至D阶段）期间对后代发育的影响（图9-2）。FEED/EFD研究通常在啮齿类动物中进行，特别是在大鼠中对药物进行研究，如果生物制品在大鼠中具有活性，则对生物制品进行研究。对于仅在非人灵长类动物中具有活性的生物制品，由于在实验室环境中交配非人灵长类动物的怀孕率很低，因此不进行生育研究。 03 产前剂量范围毒性研究 在进行明确的EFD研究之前，可能需要进行胚胎-胎儿发育前研究（pre-embryo-fetal development, pEFD），即产前剂量范围探索试验，以选择适当的剂量水平。pEFD研究中的剂量水平可能与重复给药毒理试验中的剂量水平不同，因为怀孕动物的耐受性可能与非怀孕动物不同，而且怀孕动物的毒代动力学可能有很大差异。pEFD研究通常是非GLP研究，每组动物数量较少（例如，6至8只动物，而不是EFD研究中的16至20只动物）。 04 胚胎-胎儿发育研究的剂量选择 应确定用于确定性胚胎-胎儿发育研究的适当剂量水平。ICH S5（R3）和ICH S6（R1）建议，在最大推荐人体剂量（MRHD）或胚胎-胎儿发育研究中使用的高剂量下，暴露比应大于25倍，作为检测任何致畸危害的实用且合理的充足剂量。这一建议是根据对22种已知人体致畸剂的分析得出的，这些致畸剂在最低观测不良效应水平（LOAEL）的暴露量下会出现畸形或胚胎死亡，而最低观测不良效应水平是最高建议人体摄入量（MRHD）暴露量的六倍以下或NOAEL的四倍以下。然而，由于母体剂量限制毒性和饱和毒物动力学等混杂因素的存在，EFD研究中的剂量水平可能低于这一水平。 其他分析还表明，超过人体最大推荐剂量（MRHD）15倍的暴露量可能无法检测出畸形或胚胎致死率。对于高度靶向药物（即单克隆抗体、治疗性蛋白质），ICH S6（R1）23规定，无观测不良效应水平约为临床中人体最大暴露量的10倍，或具有药效学活性的剂量，可能更适合用于EFD研究。 05 产前和产后发育研究 产前和产后发育研究（PPND）研究测量的是研究药物对胎儿晚期发育的影响；它包括妊娠期女性接触药物、植入、分娩和断奶（即图9-1所示ICH方案中的C至F阶段）之后的时期。因此，PPND研究用于评估试验材料对妊娠期、哺乳期以及后代整个发育和性成熟过程的影响。 后者包括对学习和记忆、神经心理学和功能行为以及F1代交配性能的评估，这些评估可能会延迟（图9-3）。PPND研究通常在大鼠中进行，因为使用这种特殊物种有很多优势，如容易接近、妊娠时间短、有广泛的不良结果数据库和历史对照数据。如果某种生物制品仅在非人灵长类动物中具有活性，则也会在非人灵长类动物中进行PPND研究。 对于大鼠PPND研究，通常不进行剂量范围探索试验，因为已经进行了多次重复给药毒理试验和EFD试验。在其他情况下，在幼崽出生前或断奶时进行的初步PPNP试验可有助于提供有关使用的适当剂量水平或后代暴露数据的信息。 对于仅在非人灵长类动物中具有活性的生物制品，则进行ePPND研究，而不是 PPND研究。这是EFD研究和PPND研究的综合研究，剂量给药从植入开始，持续到器官形成、分娩和断奶（即涵盖ICH方案的C至F阶段；Table 9-4）。这是因为猴子的特殊性：繁殖力低，月经周期长，妊娠期分别为35天和165天左右，一般一次只产一个后代，妊娠损失率高。理想情况下所需动物数量为16只左右，而且必须长期累积，因此群体规模往往较小。 非人灵长类ePPND研究是一项长期工作，由于非人灵长类的性成熟较晚，只有3到6岁，因此只能对产后影响进行有限的评估，而不能对后代进行跟踪。尽管存在这些明显的缺点，但非人灵长类动物在胚胎学和生理学方面与人类最为接近，它们对生殖系统损伤的反应相似，可以通过超声波监测妊娠，而且生物制品的免疫原性极低。 绒猴是最常用的种属，因为它们全年都在繁殖，雌性动物有规律的发情周期，产下单个后代（双胞胎的频率与人类大致相同），有大量历史数据表明它们被纳入了非临床研究，而且相对于其他非人灵长类物种，它们更容易获得。 在非人灵长类PPND研究中，至少应设两组动物，其中一组为对照组。在大鼠PPND研究中，给药时间从植入到出生和断奶，从妊娠第六天至第七天开始，持续整个器官形成期、胎儿期（可能通过乳汁接触）到产后第20天。在断奶前和断奶后，对雌性孕妇（F0）和后代（F1）进行评估（Table 9-3）。 F0评估（PPND研究）包括每周母体体重和体重变化、食物消耗量、死亡率以及分娩和尸检期间的临床观察。可以收集毒代动力学数据来测量母体的暴露量，但孕期暴露量通常在EFD研究中测量。在F1断奶前和断奶后，对临床观察、死亡率和存活率进行评估，并将PND4时的幼仔数标准化为约4-5只/性别（见表9-3）。在PND 21时，约16-20只/性别/组（至少一只/性别/窝）。可收集F1后代的毒代动力学数据，并在10周时对性成熟和生殖功能进行评估。 NHP ePPND研究也作为符合GLP标准的研究进行，每组至少有两组，每组至少有16只动物，还有一个对照组。经超声波确认怀孕后，大约从妊娠日（GD）20开始给药，一直持续到分娩和断奶（表9-4）。对母畜（F0）进行临床观察、死亡率、母畜体重和体重变化、食量和分娩观察评估。 如有可能，收集并保存动物的胎盘，并根据需要对尸体解剖时的组织进行评估。F1观察包括从断奶后PND 0开始的每周临床观察、体重和死亡率，但不包括性成熟评估（这需要数年时间）。定期进行体格和功能评估、形态测量和神经行为测试以及外部评估，安乐死后进行骨骼和内脏评估，可能会保存组织进行组织学评估。收集毒代动力学数据以评估接触情况。 06 肿瘤产品的生殖和发育毒性测试 肿瘤产品的生殖与发育毒性测试由ICH S9指南规范。该指南规定，肿瘤产品无需进行生育研究；通常28天的重复给药毒理试验可显示研究药物对生殖器官的潜在毒性。III期临床试验的开展和上市许可的获得都需要进行胚胎-胎儿发育 （EFD）研究，但如果产品明显显示胚胎-胎儿毒性或在某一物种中被证实具有致畸性，则根据ICH S9只需进行一次EFD研究。 如果在重复给药毒理试验中已发现潜在的生殖毒性（如睾丸毒性），则可在临床开发过程的早期进行试验性增强EFD研究。与全面的EFD研究相比，该研究的动物数量较少（例如，每组10只雌性动物，而不是每组20-26只雌性动物）。增强型EFD试验研究的目标是评估对母体和胚胎-胎儿发育终点的影响，与全面 EFD研究类似。如果药物或药品对植入和妊娠结局有明显的不良影响，则无需进行全面的EFD研究，从而减少因肿瘤药物产品的高收益风险比而造成的不必要的动物使用。 根据证据权重和人类获益风险比以及重复给药毒理试验的目标人群，可以推迟 DART研究。 07 生物制品的生殖和发育毒性测试 根据ICH指南S5（R3）2和ICH指南S6（R1），当临床候选药物在啮齿动物、家兔或非人灵长类动物 中具有活性时，需要对生物制品进行生殖和发育毒性评估。如果生物制品在啮齿动物和家兔模型中具有活性，则在大鼠中进行生育力研究，在两个物种中进行EFD研究，除非在一个或其他物种中发现胚胎-胎儿致死性。发育研究可在大鼠PPND或EFD和PPND结合体中进行（即大鼠PPND和EFD结合体）。除非非人灵长类动物是唯一的相关种属（Table 9-3）。 如果生物制品仅在非人灵长类动物中具有活性，则不进行生育力研究，因为在实验室环境中交配的非人灵长类动物怀孕率很低。生殖终点的评估可纳入之前至少为期3个月的重复给药研究中，使用性成熟的雄性和雌性，并对生殖器官进行组织学评估。 在重复给药研究中，如果特别关注对生殖的影响，则应评估精子特征和激素水平，包括测量黄体生成素（LH）和卵泡刺激素（FSH）的水平。如果无法通过实验解决生殖问题，则应在随后的临床试验中处理对生育力的潜在影响，在获得知情同意时提供明确的产品信息，并规定需要采取高效避孕措施。 如果担心对胚胎-胎儿发育和妊娠产生不利影响，那么最好在非人灵长类动物中进行EFD和PPND联合研究（即非人灵长类动物ePPND研究），以评估研究用生物制品的潜在生殖效应。非人灵长类种属的选择取决于目标参与。如本章前文所述，猴是首选的非人灵长类种属，因为雌猴的发情周期更有规律，而且与其他物种相比，猴的历史数据更丰富（Table 9-5）。 一些生物制品已在恒河猴中进行过测试，但由于这些非人灵长类动物是季节性繁殖，因此该种属的可用性有限。同样，狨猴也很少使用，主要原因是雌性狨猴没有月经出血、多排卵、双胎妊娠以及缺乏LH。然而，狨猴被用来测试卡纳金单抗的生殖安全性，因为它是唯一高水平表达白细胞介素-1β的猴种，而白细胞介素-1β是药物的靶点，也是唯一能提供与卡纳金单抗抗体完全交叉反应的猴种。 在没有相关种属（包括非人灵长类动物）的情况下，可使用替代模型，但这些模型必须具有科学依据和充分的特征。替代模型可包括表达靶蛋白或人类蛋白的转基因小鼠、同源分子或替代分子（通常是人类蛋白的小鼠版本）。这些替代或非例行种属或替代分子虽然减少了动物的使用，但只能提供危害评估，而不能提供风险评估。 如果根据药理学、类别效应和作用机制，并考虑到目标人群，有证据表明该生物制品会对生殖和发育产生不利影响，则可能不需要进行DART研究。 当生物制品与啮齿动物、兔子和非人灵长类动物相关，或与啮齿动物和非人灵长类动物相关时，DART研究的时间安排应遵循ICH M3(R2)10-12如 ICH S6（R1）所示。原则是在临床试验中进行与预期患者群相关的DART研究，并确定临床开发的时间。原则是在临床试验中进行与预期患者人群相关的DART研究，并确定临床开发的时机。 通常必须在分别招募150名以上具有生殖或生育潜能的男性或女性患者之前进行确定性DART研究。ICH S5（R3）指南提供了使用扩大剂量范围（eEFD）研究的方案。经过验证的替代模型（如斑马鱼、干细胞、全胚胎或其他检测方法）也可用于在II期临床试验中对超过150名育龄妇女进行超过3个月的评估。 08 疫苗的生殖和发育毒性测试 ICH S5（R3）还特别涵盖了疫苗的生殖和发育毒性测试，如疫苗开发的一般原则规定。该指南规定，对于预防性和治疗性疫苗，在使用和批准上市前都需要进行动物生殖研究。这些研究必须在用于发育研究的相同种属（如大鼠、小鼠或兔子）中进行，因为免疫反应会略有不同，尽管在所有种属中，针对试验材料的抗体通常会通过胎盘从母体转移给后代。 对于为新生儿、儿童或老年人群开发的疫苗，可能不需要进行DART研究。 最近的一个疫苗开发和DART测试实例是COVID-19疫苗。COVID-19于2019 年12月首次被定义，是2020年肆虐全球的严重急性呼吸系统综合征（SARS）。然而，直到2021年才开发出第一种针对致病冠状病毒（SARS-CoV-2）的COVID-19 mRNA疫苗，并获得了FDA及其他监管机构的成人紧急使用授权（EUA），其他疫苗也根据世界卫生组织的紧急使用清单（EUL）进行了评估 。 为了获得紧急使用授权（EUA）和批准，在雌性大鼠身上进行了发育和生殖研究。在大鼠ePPND研究中，在交配前和妊娠期各注射两次单剂量人用疫苗（包括其所有成分和佐剂），没有证据表明对胎儿会造成不良伤害。需要注意的是，除大鼠外，兔子预计也会引起与人类相同的抗体反应，并被用于ePPND研究（图9-4）。除了这些非临床研究外，还在几个登记处收集了有关妊娠、COVID-19和疫苗接种的数据，以了解COVID-19疫苗的所有不良风险。图9-5描述了使用DART测试的另一个例子。 — 结论 — 在育龄妇女或具有生殖潜能的男性中销售任何新的药物或生物制品时，都必须进行发育和生殖毒性（Developmental and reproductive toxicity, DART）研究。由于DART研究不是在临床试验中进行的，因此非临床DART研究构成了药品或生物药产品使用和批准的危害识别和风险评估的基础，并包含在产品标签或包装插页中，包括所进行的非临床研究的类型和结果。这些专门评估确定了对生育、妊娠和发育的潜在不利影响，并以时间和分段的方式进行，以便对生殖和发育周期各阶段的特定影响进行划分。 DART研究是在药物开发的特定阶段进行的，目的是为安全性提供信息，并为临床试验提供支持。DART研究可以是单独研究，也可以是综合研究，在减少动物数量的同时，合理地使用相关动物种属。 就药品而言，DART研究在啮齿动物（主要是大鼠）和兔子中进行，这些种属也优先用于在大鼠和兔子中具有活性的生物制品。 对于仅在非人灵长类动物中具有活性的生物制品，某些DART研究（如生育力研究）在非人灵长类动物中并不实用，而应纳入亚慢性、重复给药毒理试验，持续时间至少3个月，并使用性成熟的猴子（研究时间会变得很长，费用也很高）。为满足DART要求，可进行非人灵长类 ePPND。 DART研究的开展和时间取决于药物或生物制品的药理学和作用机制、预期目标患者群体以及临床试验的时间安排。当初步研究数据显示对生育能力或胚胎-胎儿致死率有潜在不利影响时，可能不进行DART研究，或只需进行一种研究。反之，如果没有相关的动物种属可进行DART研究，而替代模型又不足以对人类风险进行评估，则可推迟DART研究。对于这些情况，必须从药理学（体外和体内研究）、作用机理、目标参与、暴露和相关动物种属出发，确定证据权重，正如ICH S5（R3）所概述。ICH S5（R3）现已与药品的ICH M3（R2）、生物制品的ICH S6（R1）23和肿瘤产品的ICH S9在开发和生殖毒性方面的要求保持一致。 英文版原文 （上下滑动查看更多） Special considerations If a pharmaceutical has no or very limited systemic exposure (i.e., due to its pharmacology, formulation, or route and mode of delivery), an alternate formulation or route for administering the test substance may be needed in rat and non-rodent models to evaluate its potential systemic effects on embryo-fetal development.  If a pharmaceutical is proven to have an embryo-fetal risk, it can still be used and marketed provided an emphasis on its teratogenicity or developmental risks are clearly stated on the package insert and pregnant women and women who may become pregnant are clearly told not to use it. Examples are lenalidomide, which is a potent oral analog of thalidomide used in the treatment of several hematologic malignancies, and thalidomide, which was revived as an essential medicine because of the high benefit to risk ratio seen in cancer patients and indications requiring novel treatments. The embryo-fetal risks of both drugs are clearly highlighted in their respective prescribing information and their use continues to be contraindicated in women who are, or who may become, pregnant while using them. Moreover, the use of either drug requires a restricted distribution system and that a strict risk evaluation and mitigation strategy is in place and strictly be adhered to. Combined Fertility and Early Embryonic and Embryofetal Development Toxicity Study The combined fertility and early embryonic and embryo-fetal development toxicity study (FEED/EFD) measures the effect on fertility, early establishment of pregnancy, and organogenesis. This combined study assesses the effects of a drug or pharmaceutical on male or female fertility and the development of offspring from implantation through closure of the hard palate at the period of organogenesis, covering stages A to D of the ICH scheme (Figure 9-2). A FEED/EFD study is usually conducted in rodents, specifically in rats for pharmaceuticals, and for biologics if the biologic is active in rats. For biologics that are active only in non-human primates, no fertility studies are conducted due to the low pregnancy rate when non-human primates are mated in a laboratory setting. Prenatal Dose Range-finding Toxicity Study There may be a need to conduct pre-embryo-fetal development (pEFD) studies which are prenatal dose-finding studies to select appropriate dose levels before undertaking definitive EFD studies. Dose levels in pEFD studies may be different from those used in the repeat-dose studies because tolerability of pregnant animals may be different from non-gravid animals, and toxicokinetics may be very different in pregnant animals. pEFD studies are usually non-GLP studies with few animals per group (e.g., six to eight animals rather than 16 to 20 in an EFD study). Dose Selection for Embryo-fetal Development Studies Appropriate dose levels should be determined for use in the definitive EFD studies. ICH S5(R3) and ICH S6(R1) recommend a greater than 25-fold exposure ratio at the maximum recommended human dose (MRHD) or the high dose used in EFD studies, as a pragmatic and reasonably sufficient dose to detect any teratogenic hazard. This recommendation was borne from analyses of 22 known human teratogens which exhibited malformations or embryo-lethality at exposures at the lowest observed adverse effect level (LOAEL) which was at a less than a six-fold the exposure at MRHD or less than four-fold of the no observed adverse effect level (NOAEL). Dose levels in EFD studies may be lower than this, however, due to the presence of confounding factors such as maternal dose-limiting toxicities and saturation toxicokinetics. Additional analyses also have indicated that a greater than 15-fold exposure at the maximum recommended human dose (MRHD) may not detect malformations or embryo-lethality. For highly targeted pharmaceuticals (i.e., monoclonal antibodies, therapeutic proteins), ICH S6(R1)23 provides that exposures at the NOAEL approximately 10 times more than the human maximum exposures achieved in the clinic, or at a dose that exhibits pharmacodynamic activity, may be more appropriate for EFD studies. Pre- and Post-Natal Development Study A PPND study measures the effect of an investigational pharmaceutical on late fetal development; it encompasses the period following exposure of the pregnant female and implantation through parturition and through weaning (i.e., stages C to F of the ICH scheme shown in Figure 9-1). As such, a PPND study is used to assess the effects of test material on pregnancy, during lactation, and throughout the development and sexual maturity of the offspring. The latter includes the assessment of learning and memory, neuropsychology and functional behavior, and mating performance of the F1 generation, which can be delayed (Figure 9-3). A PPND study is usually conducted in rats due to the many advantages of using this particular species, such as accessibility, short gestation time, and an extensive database of adverse findings and historical control data. A PPND study will also be conducted in non-human primate if a biologic is being tested and it is only active in non-human primate. For a rat PPND study, dose-range finding studies are usually not done because several repeat-dose toxicity studies and EFD studies will have already been performed. In other cases, a preliminary PPNP study, conducted up to the birth of the pups or at weaning, could help provide information on the appropriate dose levels to use or exposure data in the offspring. For biologics that are active only in non-human primate, a modified or ePPND study is conducted instead of a PPND study. This is a combined study of an EFD study and a PPND study, and dose administration starts at implantation, continues through organogenesis, and into parturition and weaning (i.e., covering stages C to F of the ICH scheme; Table 9-4). This is due to the unique differences of monkeys exhibiting low fecundity, long menstrual cycles and gestation times of 35 days and around 165 days, respectively, generally producing only one offspring at a time, and a high rate of pregnancy loss. The number of animals needed is ideally around 16 which must be accrued over time, so group sizes tend to be small. A non-human primate ePPND study is a long-term endeavor and will deliver only a limited assessment of postnatal effects without follow-up of the offspring due to the late sexual maturity of non-human primate which is between 3 to 6 years of age. Despite these apparent disadvantages, non-human primates are the closest to humans in terms of their embryology and physiology, they respond similarly to reproductive insults, pregnancy can be monitored by ultrasound, and there is minimal immunogenicity with biologics. Cynomolgus monkeys are the most frequently used species because they breed all year around, females have a regular estrous cycle, they produce a single offspring (and twins at about the same frequency as humans), there is a large amount of historical data on their inclusion in nonclinical studies, and they are more easily sourced relative to other non-human primate species.20-22 PPND and ePPND are conducted as GLP-compliant studies with ideally four groups of animals with at least 16 pregnant females per group, which includes the control group. In non-human primate PPND, there should be at least two groups of animals, one of which will be the control group. For rat PPND studies, dosing is from implantation through to birth and weaning and starts on the sixth to seventh gestational day and continues throughout organogenesis, the fetal period (with potential exposure through the milk) to postnatal day 20. Assessments are done on the pregnant females (F0) and the offspring (F1) before and after weaning (Table 9-3). F0 assessments (PPND study) include weekly maternal body weight and body weight change, food consumption, mortality and clinical observations during parturition and necropsy. Toxicokinetics to measure maternal exposures can be collected but exposure during pregnancy is usually measured in the EFD studies. In F1 pre-weaning and post-weaning, clinical observations, mortality and survival are evaluated, and litter size are standardized to approximately 4-5 pups/sex at PND4 (see Table 9-3). At PND 21, approximately 16-20 animals/sex/group (with at least one/sex/litter) are formed. Toxicokinetics in F1 offspring may be collected, and sexual maturation and reproductive function are assessed at 10 weeks. A NHP ePPND study is also conducted as a GLP-compliant study with at least two groups of at least 16 animals per group, with one control group. Dosing starts approximately on gestation day (GD) 20 after pregnancy has been confirmed by ultrasound and continues through parturition and weaning (Table 9-4). Maternal animals (F0) are assessed for clinical observations, mortality, maternal body weight and body weight change, food consumption and parturition observations. The placentas of animals are collected and preserved if possible and tissues at necropsy evaluated as warranted. F1 observations include weekly clinical observations, body weight and mortality from PND 0 postweaning but without sexual maturation evaluation (which will take several years). Physical and functional assessments, morphometry and a neurobehavioral test battery as well as external evaluations are done at regular intervals, and skeletal and visceral evaluations conducted after euthanasia, wherein tissues may be preserved for possible histological evaluation. Toxicokinetic data are collected to assess exposure. Reproductive and Developmental Toxicity Testing for Oncology Products Reproductive and developmental toxicity testing for oncology products is covered by the ICH S9 guideline.13 This states that there is no need for fertility studies for oncology products; usually repeat-dose toxicity studies of 28 days’ duration can inform on an investigational drug’s potential toxicity on the reproductive organs. EFD studies are needed for Phase 3 clinical trials to go ahead and for marketing approval to be obtained, but if the product clearly has embryo-fetal toxicity or proven teratogenicity in one species, only one EFD study is required according to ICH S9. If potential reproductive toxicity has already been noted (e.g., testicular toxicity) in repeat-dose toxicity studies, a pilot enhanced EFD study may be conducted early in clinical development process. This can include a smaller number of animals than a full EFD study (e.g., 10 test material-naïve females per group rather than 20-26 females per group). The goal of a pilot enhanced EFD study is to assess the effects on maternal and embryo-fetal development endpoints, similar to a full EFD study. If the drug or pharmaceutical has clear adverse effects on implantation and pregnancy outcomes, conducting a full EFD study is not necessary, thus reducing unnecessary animal use due to a high benefit-to-risk ratio of oncology drug products.  Based on weight-of-evidence and human benefit-risk ratio and the intended population in repeat-dose toxicity studies, deferral of DART studies may be possible. Reproductive and Developmental Toxicity Testing for Biologics Reproductive and developmental toxicity assessments are required for biologics when the clinical candidate is active in rodents, rabbits, or non-human primates, according to ICH guidelines S5(R3)2 and ICH S6(R1).23 If the biologic is active in rodent and rabbit models, then fertility studies are conducted in the rat and EFD studies are done in both species, unless embryo-fetal lethality has been identified in one or other species. Developmental studies can be conducted in rat PPND or a combined EFD and PPND (i.e., a rat ePPND study) unless non-human primate is the only relevant species (Table 9-3). If the biologic is active only in non-human primates, fertility studies are not conducted because of the low pregnancy rate in non-human primates mated in a laboratory setting. Evaluation of reproductive endpoints may be incorporated in the preceding repeat-dose studies of at least 3 months’ duration instead, using sexually mature males and females with histological evaluation of the reproductive organs. Within the repeat-dosing studies,and if there are specific concerns on the effects on reproduction, sperm characterization and hormone levels should be assessed, which includes measuring levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).20-22 If reproduction concerns cannot be addressed experimentally, potential effects on fertility should be managed in subsequent clinical trials by giving clear product information when obtaining informed consent and stipulating the need for highly effective contraception. A combined EFD and PPND in non-human primates (i.e., an NHP ePPND study) is preferred to assess the potential reproductive effect of an investigational biologic, unless there is a concern for adverse effects on embryo-fetal development and pregnancy. The choice of non-human primate species is dependent on target engagement. As stated previously in this chapter, Cynomolgus monkeys are the preferred non-human primate species due to females having a more regular estrous cycle and there being a larger amount of historical data on them than for other species (Table 9-5). Some biologics have been tested in Rhesus monkeys, but the availability of this species is limited as these non-human primates are seasonal breeders.20,28 Similarly, the marmoset monkey is rarely used, mainly due to the lack of menstrual bleeding among females, multiple ovulations, twin pregnancies, and a lack of LH. However, marmoset monkey was used to test reproductive safety of canakinumab because it was the only monkey species that expressed a high level of interleukin-1β, which is the drug target, and the only monkey species that provided full cross-reactivity to canakinumab antibodies. In cases where there are no relevant species, including non-human primates, alternative models can be used provided they are scientifically justified and adequately characterized. Alternative might include transgenic mice expressing the target or human proteins, homologous molecules or surrogate molecules (typically the mouse version of the human protein). These alternative or non-routine species or surrogate molecules may provide hazard assessments only and not risk assessments, although they reduce animal use. If based on the pharmacology, class effect and mechanism of action, and considering the target population, there is evidence that the biologic will have adverse effects on reproduction and development, DART studies may not be needed. When the biologic is relevant in rodents, rabbits and non-human primates, or relevant in rodents and non-human primates, the timing of DART studies follows ICH M3(R2) guidance,10-12 as indicated in the ICH S6(R1).23 The principle is to conduct the DART studies relevant to the intended patient population in the clinical trials and timing of clinical development. Definitive DART studies usually must be conducted before enrolling more than 150 men or women of reproductive or childbearing potential, respectively. ICH S5(R3) guidance2 provides schemes for using expanded dose-range (eEFD) studies. Validated alternative models (e.g., Zebrafish, stem cells, whole embryos, or other assays) also can be used to allow more than 150 women of childbearing potential to be evaluated for longer than 3 months in Phase 2 clinical trials. Reproductive and Developmental Toxicity Testing for Vaccines Reproductive and developmental toxicity testing for vaccines is also specifically covered by ICH S5(R3),2 as provided in the general principles for the development of vaccines.30 This guidance states that for both preventive and therapeutic vaccines, animal reproductive studies need to be conducted before their use and marketing approval. These studies must be performed in the same species used for developmental studies (i.e., rat, mouse, or rabbit) as immune responses will be slightly different, although antibodies against the test material will usually transfer through the placenta from mother to offspring in all species. For vaccines being developed for neonates, children or geriatric populations, DART studies may not be required. A recent example of vaccine development and DART testing is that of the COVID-19 vaccines. First described in December 2019, COVID-19 is a severe acute respiratory syndrome (SARS) that ravaged the world in 2020.31 It was not until 2021, however, that the first COVID-19 mRNA vaccine against the causative coronavirus (SARS-CoV-2) was developed32 and received Emergency Use Authorization (EUA) for adults from the FDA,33 among other regulatory bodies, and other vaccines were assessed under the WHO’s Emergency Use Listing (EUL).31 For the EUA and approval, developmental and reproductive studies were conducted in female rats.32 In the rat ePPND study, a single human dose of the vaccine (with all its components and adjuvants) was given twice at pre-mating and twice at gestation, and there was no evidence of adverse harm to the fetus. Note that, in addition to rats, rabbits are expected to elicit the same antibody responses as human and are also used for ePPND studies (Figure 9-4). In addition to these nonclinical studies, data on pregnancy, COVID-19, and vaccinations was collected in several registries to inform of all the adverse risks of the COVID-19 vaccine.34 An additional example on the use of DART testing is described in Figure 9-5. Conclusion DART studies are required for the marketing of any new pharmaceutical or biologic drug in women of child-bearing potential or men of reproductive potential. As DART studies are not conducted in clinical trials, nonclinical DART studies form the basis of hazard identification and risk assessment for pharmaceutical or biologic drug products’ use and approval and are included in the product label or packaging insert, including the type and results of nonclinical studies conducted. These specialized assessments identify potential adverse effects on fertility, pregnancy and development, and are conducted in a temporal and segmented fashion to allow delineation of effects specific for various stages of the reproductive and developmental cycle. DART studies are conducted at specific stages in drug development to inform safety and support clinical trials, and either separate or combined studies with the judicious use of relevant animal species while reducing animal numbers. For pharmaceuticals, DART studies are conducted in rodents (mostly in rat) and rabbits, and these species are also preferentially used for biologics that are active in rats and rabbits. For biologics that are active only in non-human primates, some DART studies such as fertility studies are not practical in non-human primates and instead should be incorporated into subchronic, repeat-dose toxicity studies of at least 3 months duration with the use of sexually mature monkeys (studies become very long and expensive). To fulfill the DART requirements, a non-human primate ePPND may be conducted. The conduct and timing of DART studies depends upon the pharmacology and mechanism of action of the pharmaceutical or biologic, the intended target patient population and the timing of clinical trials. DART may not be conducted, or only one species is necessary, when data from initial studies indicate potential adverse effects on fertility or embryo-fetal lethality. Conversely, DART studies may be deferred if there are no relevant animal species in which to perform them and alternative models are not sufficiently characterized for the assessment of human risk. For these scenarios, a weight-of-evidence must be established starting from the pharmacology (both in vitro and in vivo studies), mechanism of action, target engagement, exposures and relevant animal species, as outlined in ICH S5(R3).2 ICH S5(R3) is now aligned with development and reproductive toxicity requirements with ICH M3(R2)10,11 for pharmaceuticals, ICH S6(R1)23 for biologics and ICH S913 for oncology products. 参考文献：（上下滑动查看更多） All references verified 23 February 2023. 1. Faqi AS, ed. A Comprehensive Guide to Toxicology in Nonclinical Drug Development. 2nd ed. Elsevier B.V.; 2016. 2. International Council for Harmonisation. Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals: S5(R3). Current as of 18 February 2020. Accessed 23 February 2023. https://database.ich.org/sites/default/files/S5-R3_Step4_ Guideline_2020_0218_1.pdf 3. Lerman SA, Hew KW, Stewart J, et al. The nonclinical fertility study design for pharmaceuticals. Birth Defects Res B Dev Reprod Toxicol. 2009;86(6):429-436. 4. Colerangle JB. Preclinical development of nononcogenic drugs (small and large molecules). In: Faqi AS, ed. A Comprehensive Guide to Toxicology in Nonclinical Drug Development. 2nd ed. Elsevier, B.V.; 2016: 659-683. 5. Reynaud L, Marsden E. Combined fertility and embryotoxicity study. Methods Mol Bio. 2013; 947:125-137. 6. Bailey GP, Wise DL, Buschmann J, et al. Pre- and postnatal developmental toxicity study design for pharmaceuticals. Birth Defects Res B Dev Reprod Toxicol. 2009;86(6):437-445. 7. 21 CFR Part 58: Good Laboratory Practice. Current as of 24 October 2022. Accessed 23 February 2023. https://www.ecfr.gov/current/ title-21/chapter-I/subchapter-A/part-58 8. Perrard ML, Sereni N, Schulth-Bolard C, et al. Complete human and rat ex vivo spermatogenesis from fresh or frozen testicular tissue. Biol Reprod. 2016;95(4):89. 9. Xua J, Lu H, Li H, et al. Computerized spermatogenesis staging (CSS) of mouse testis sections via quantitative histomorphological analysis. Med Image Anal. 2021;70:1-40:101835. 10. European Medicines Agency. ICH M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Current as of December 2009. Accessed 23 February 2023. https://www.ema.europa.eu/ en/documents/scientific-guideline/ich-guideline-m3r2-nonclinical-safety-studies-conduct-human-clinical-trials-marketingauthorisation_en.pdf 11. Food and Drug Administration. Guidance For Industry: M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Current as of January 2010. Accessed 23 February 2023. https://www.fda.gov/media/71542/download 12. Food and Drug Administration. Guidance for Industry. M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Questions and Answers. Current as of February 2013. Accessed 23 February 2023. https://www.fda.gov/media/82725/download 13. International Council for Harmonisation. ICH Harmonised Tripartite Guideline. Nonclinical Evaluation for Anticancer Pharmaceuticals S9. Current as of 29 October 2009. Accessed 23 February 2023. https:// database.ich.org/sites/default/files/S9_Guideline.pdf 14. Allais L, Reynaud L. Teratology studies in the rabbit. Methods Mol Bio. 2013; 947:139-156. 15. Drobeck HP, Coulson F, Cornelius D. Effects of thalidomide on fetal development in rabbits and on establishment of pregnancy in monkeys. Toxicol App Pharmacol. 1965;7(2):165-178. 16. Tantibanchachai C, Joanna Y. Studies of thalidomide’s effects on rodent embryos from 1962-2008. Embryo Project Encyclopedia (2014-03-07). ISSN: 1940-5030. http://embryo.asu.edu/ handle/10776/7642 17. Barrow P. Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2016 and 2017. Reprod Toxicol. 2018;80:117-125. 18. Barrow P. Review of embryo-fetal developmental toxicity studies performed for pharmaceuticals approved by FDA in 2020 and 2021. Reprod Toxicol. 2022;112:100-108. 19. Andrews PA, Blanset D, Costa PL, et al. Analysis of exposure margins in developmental toxicity studies for detection of human teratogens. Regul Toxicol Pharmacol. 2019;105:62-68. 20. Bowman CJ, Weinbauer GF. Reproductive, developmental, and juvenile toxicity assessments. In: Cavagnaro JA, Cosenza ME, eds. Translational Medicine: Optimizing Preclinical Safety Evaluation of Biopharmaceuticals. 1st ed. CRC Press;2021:131-148. 21. Chellman GJ, Bussiere JL, Makori N, et al. Developmental and reproductive toxicology studies in nonhuman primates. Birth Defects Res B Dev Reprod Toxicol. 2009;86(6):446-462. 22. Faqi AS. A critical evaluation of developmental and reproductive toxicology in nonhuman primates. Sys Biol Reprod Med. 2012;58(1):23-32. 23. International Council for Harmonisation. ICH Harmonised Tripartite Guideline. Preclinical Safety Evaluation of Biotechnology Derived Pharmaceuticals S6 (R1). Current as of 12 June 2011. Accessed 23 February 2023.https://database.ich.org/sites/default/files/S6_R1_Guideline_0.pdf 24. Chapman KL, Holzgrefe H, Black LE, et al. Pharmaceutical toxicology: designing studies to reduce animal use while maximizing human translation. Regul Toxicol Pharmacol. 2012;66(1):88-103. 25. Revlimid [prescribing information]. Bristol Myers Squibb; 2022. Accessed 23 February 2023. https://packageinserts.bms.com/pi/ pi_revlimid.pdf 26. Brynner R, Stephens TD. Dark remedy: the impact of thalidomide and its revival as a vital medicine. Perseus Books; 2001. 27. Luetgens CM, Weinbauer GF. Functional assessment of sexual maturity in male macaques (Macaca fascicularis). Regul Toxicol Pharmacol. 2012;63(3):391-400. 28. VandeVoort CA, Mtango NR, Midic U, Latham KE, et al. Disruptions in follicle cell functions in the ovaries of rhesus monkeys during summer. Physiol Genomics. 2015;47(4):102-112. 29. ILARIS (canakinumab) [prescribing information]. Drugs@ FDA: FDA-Approved Drugs; 2020. Accessed 23 February 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125319s100lbl.pdf 30. Food and Drug Administration. Guidance for Industry. General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases. Current as of December 2011. Accessed 23 February 2023. https://www.fda.gov/media/82306/download 31. World Health Organization. Timeline: WHO’s COVID-19 response. Accessed 23 February 2023. https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/interactive-timeline 32. Comirnaty (COVID-19 vaccine, mRNA) [prescribing information]. Pfizer; 2022. Accessed 23 February 2022. https://labeling.pfizer.com/ShowLabeling.aspx?id=16351&format=pdf 33. Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent COVID-19. Guidance for Industry. Current as of 31 March 2022. Accessed 23 February 2023. https://www.fda.gov/media/142749/download 34. The Organization of Teratology Information Specialists. Mother to Baby. COVID-19 Vaccines. Accessed 23 February 2023. https:// mothertobaby.org/ongoing-study/covid19-vaccines/ 35. Food and Drug Administration. Guideline for Industry: Detection of Toxicity to Reproduction for Medicinal Products. ICH S5A. Current as of September 1994. Accessed 23 February 2023. https://www.fda. gov/media/72009/download 36. Food and Drug Administration. Guideline for Industry. Detection of Toxicity to Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility. ICH S5B. Current as of April 1996. Accessed 23 February 2023. https://www.fda.gov/media/72019/download 37. European Medicines Agency / Committee for Medicinal Products for Human Use. Guideline on The Exposure to Medicinal Products During Pregnancy: Need to Post-Authorisation Data. Current as of May 2006. Accessed 23 February 2023. https://www.ema.europa.eu/ en/documents/regulatory-procedural-guideline/guideline-exposuremedicinal-products-during-pregnancy-need-post-authorisationdata_en.pdf 38. European Medicines Agency / Committee for Medicinal Products for Human Use. Guideline on Risk Assessment of Medicinal Products on Human Reproduction and Lactation: From Data to Labelling. Current as of January 2009. Accessed 23 February 2023. https://www. ema.europa.eu/en/documents/scientific-guideline/guideline-riskassessment- medicinal-products-human-reproduction-lactation-datalabelling_ en.pdf 39. Food and Drug Administration. Testicular Toxicity: Evaluation During Drug Development. Guidance for Industry. Current as of October 2018. Accessed 23 February 2023. https://www.fda.gov/ media/117948/download 40. Food and Drug Administration. Guideline for Industry. Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies. ICH S3A. Current as of March 1995. Accessed 23 February 2023. https://www. fda.gov/media/71990/download 41. Food and Drug Administration. S3A Guidance: Note for Guidance on Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies: Focus on Microsampling. Questions and Answers. Guidance for Industry. Current as of May 2018. Accessed 23 February 2023. https://www.fda.gov/media/100027/download 声明：原英文原文版权归美国法规事务协会（RAPS）所有，本译文供参考，如有任何建议，请联系我们。 同写意媒体矩阵，欢迎关注↓↓↓

MILPITAS, Calif.--( BUSINESS WIRE )-- Elixir Medical , a developer of disruptive technologies to treat cardiovascular disease, today announced it will present one-year clinical outcomes from the 2,400 patient INFINITY-SWEDEHEART Randomized Clinical Trial (RCT), a prospective, multi-center, single-blind, clinical trial comparing the drug-eluting DynamX Coronary Bioadaptor System with the contemporary Resolute Onyx TM zotarolimus drug-eluting stent (DES), at a late-breaking Hot Line session at ESC Congress 2024 in London. “Today’s minimally invasive coronary artery disease (CAD) treatments are limited to only establishing a fixed flow lumen in the artery which re-narrows over time presenting an unacceptable major adverse event rate (MACE) of 20% by five years 1 and up to 50% by 10 years 2 , increasing annually without a plateau 3 . The DynamX bioadaptor was developed to address and surpass the limitations of CAD treatments by not only being capable of establishing a flow lumen, but also uniquely restoring the essential attributes of vessel function to adapt and maintain the established flow lumen, restore hemodynamic modulation of the artery, and reduce plaque progression to deliver a sustained, low adverse event rate that plateaus after six months,” said Motasim Sirhan, CEO of Elixir Medical. “Building on the exceptional results of the BIOADAPTOR-RCT study, where we observed a statistically significant 65% reduction in clinical events in de novo lesions by two years compared to Resolute Onyx DES 4 , the INFINITY-SWEDEHEART RCT will provide evidence of the DynamX bioadaptor performance in a broader, real-world patient population, including a large cohort of patients with acute coronary syndrome (ACS).” The INFINITY-SWEDEHEART RCT enrolled 2,400 patients from 20 sites in Sweden. The trial is executed through the SWEDEHEART registry program in Sweden, a national collaborative research program supporting the evidence-based development of therapies for heart disease. Study management is conducted in collaboration with Uppsala Clinical Research Center (UCR), a non-profit organization providing clinical research services for the development and improvement of health care in Sweden and worldwide. The data will be presented by David Erlinge, M.D., Ph.D., head of the Cardiology Department at Skane University Hospital, Lund, SE, in the Hot Line session “INFINITY-SWEDEHEART - Percutaneous coronary intervention with a bioadaptor compared to a contemporary drug-eluting stent – one-year primary outcomes.” The presentation will also include a discussant review and panel discussion. Presentation details : HOT LINE 11 Title : “INFINITY-SWEDEHEART - Percutaneous coronary intervention with a bioadaptor compared to a contemporary drug eluting stent- one-year primary outcomes” Principal investigator : David Erlinge, M.D., Ph.D., head of the Cardiology Department at Skane University Hospital, Lund, SE. Date : Monday, September 2, 2024 Time : 13:45 - 14:45 BST Location : Main Auditorium About the INFINITY-SWEDEHEART Trial The INFINITY-SWEDEHEART Trial is a prospective, multi-center, single-blind, randomized (1:1), registry-based clinical trial comparing a sirolimus-eluting bioadaptor with a contemporary zotarolimus-eluting stent (DES) in 2,400 patients. The trial is executed in partnership with the ongoing SWEDEHEART registry program in Sweden, a national collaborative research program launched in 2009 to support the evidence-based development of therapies for heart disease. DynamX Coronary Bioadaptor System The DynamX bioadaptor is designated by the U.S. Food and Drug Administration (FDA) as a breakthrough technology and is the first coronary implant designed to restore coronary artery hemodynamic modulation as demonstrated by restored vessel pulsatility, compliance, adaptive increase in blood flow volume, and to provide plaque stabilization and regression. With this unique mechanism of action (MOA), bioadaptor addresses the shortcomings of drug-eluting stents and bioresorbable scaffolds, translating to remarkably low clinical event rates that showed a plateau between one-year and two-year clinical follow-up in the BIOADAPTOR RCT study. The DynamX Coronary Bioadaptor System is CE-marked. Not available for sale in the U.S. About Elixir Medical Elixir Medical Corporation, a privately-held company based in Milpitas, California, develops disruptive platforms to treat coronary and peripheral artery disease. Our transformative technologies have multiple applications across the cardiovascular space capable of delivering improved clinical outcomes for millions of patients. Visit us at www.elixirmedical.com and on LinkedIn and X . References: 1. Iqbal et al. Final 5-Year Report of the RESOLUTE All-comers Trial. Circ Cardiovasc Interv. 2015. 2. Kufner et al. ISAR-TEST 4 Trial. Circulation, 2019. 3. Madhavan MV et al. J Am Coll Cardiol 2020;75:590-604 4. Saito S. Two-year clinical outcomes of the BIOADAPTOR RCT study. EuroPCR 2024.