Genea Pty Ltd.

AUSTIN, Texas--( BUSINESS WIRE )-- Gameto , a women’s health biotechnology company dedicated to advancing innovative solutions in reproductive health, has announced a partnership with Australian-based IVF clinic chain, IVFAustralia (IVFA) part of the Virtus Health group. Under this partnership, Gameto’s product, Fertilo, will be available for patients at select IVFA/Virtus clinics. The Virtus Health clinic network is one of the top 5 assisted reproductive services providers in the world. Fertilo is a solution derived from induced pluripotent stem cells (iPSC) and designed to mature eggs outside the body as part of minimal hormonal stimulation cycles for IVF and egg freezing. Unlike traditional methods, which rely on 10-14 days of hormonal stimulation to mature eggs, Fertilo recreates the natural egg maturation process in a laboratory setting. This process replaces 80% of hormone injections required with traditional IVF and reduces the cycle duration and the side effects associated with the patient journey in IVF and/or egg freezing. Dr. Gavin Sacks and Dr. Cheryl Phua, both senior fertility specialists, will be leading Fertilo’s usage at IVFA/Virtus clinics across Australia. Dr. Sacks is the Clinical Director of IVF Australia’s Alexandria and Bondi Clinics, and an Associate Professor at UNSW. He is an innovative leader in the fertility field, internationally renowned for his leading research on the role of the immune system in recurrent miscarriage and IVF. Dr. Sacks has previously pioneered new approaches, including the “Bondi Protocol,” a treatment for implantation failure that has now been adopted by specialists across Australia. “I am thrilled to be leading Fertilo’s usage and implementation in our clinics at IVFA/Virtus,” said Dr. Gavin Sacks. “Throughout my career as a fertility specialist, I have remained dedicated to developing and supporting innovative ways to improve IVF for patients. I am excited to be working with the Gameto team to be pioneering the use of iPSCs in IVF and egg freezing to make the process better for patients.” Gavin will be working closely with Gameto’s Australian Clinical Director, Dr. Tammie Roy, who joins the company after over 15 years at Genea, one of Australia’s highest-performing fertility clinics. At Genea Biomedx, Tammie led the development and commercialization of groundbreaking medical devices, including the world's first automated vitrification instrument for oocyte and embryo preservation and an advanced embryo incubator system that significantly improved IVF pregnancy rates. “We are very excited to be working with Dr. Gavin Sacks and the entire team at IVFA/Virtus,” said Dr. Dina Radenkovic, Gameto’s CEO and Co-founder. “Australia has long been at the forefront of IVF innovation, establishing itself as a global leader in reproductive medicine, as the country was among the first in the world to achieve successful IVF births and has a history of groundbreaking research and clinical advancements dating back to the 1980s. Our partnership with Virtus and IVFA broadens access to Fertilo for patients worldwide, beginning with one of Australia's most respected fertility networks.” With the recent expansion into Australia, Fertilo is now available in four countries, and in the U.S., the company is preparing for Phase 3 trials. If patients are interested in using Fertilo in Australia, they can contact IVFAustralia in Sydney to register interest and find out if they are eligible for the treatment. They will be seen and treated by Dr. Gavin Sacks or Dr. Cheryl Phua. About Gameto Gameto is a biotechnology company developing novel treatment solutions for women's health, starting with infertility. Gameto brings together an experienced scientific management team with the vision and passion to develop a product suite to support women throughout their reproductive journeys. Gameto's lead program, Fertilo, aims to make IVF and egg freezing shorter, safer, and more accessible through reduced hormonal injections by maturing eggs outside of the body. Gameto is led by physician-turned-entrepreneur Dina Radenkovic as CEO and serial entrepreneur and founder of one of North America's largest fertility networks Prelude Fertility, Martin Varsavsky, as Chairman. For more information, go to gametogen.com or follow us on Twitter and Instagram @gametogen and on LinkedIn . About Virtus/IVFA IVF Australia, part of the Virtus Health network, is a leading provider of fertility care in Australia, offering world-class services to individuals and couples on their journey to parenthood. With state-of-the-art clinics and laboratories, IVF Australia combines compassionate patient care with cutting-edge technologies to achieve exceptional outcomes. As a member of the Virtus Health family, one of the largest assisted reproductive services groups in the world, IVF Australia benefits from a global network of expertise, innovation, and research, solidifying its position as a trusted leader in fertility treatment and reproductive health.

近日，BioBAY园内上市企业贝康医疗自主研发的首个国家创新胚胎植入前染色体非整倍体（PGT-A）试剂盒，在完成10万例临床回顾性样本验证后，成功获得了国家药品监督管理局（NMPA）批准的注册证延续。这意味着该产品的临床有效性再次得到了官方认可，标志着贝康医疗PGT创新医疗产品进入了新的里程碑。 PGT-M/SR试剂盒即将获证，助力市场合规化 除PGT-A试剂盒外，作为“十四五国家重点研发计划重点专项”研发转化成果，贝康医疗自主研发的胚胎植入前地中海贫血检测试剂盒（PGT-M）是中国首个阻断地中海贫血的基因检测试剂盒，目前已完成临床试验；胚胎植入前染色体结构异常检测试剂盒（PGT-SR）能够有效检出以前无法检出的遗传病，正在进行临床试验；这两款产品预计将分别于今年年底和明年陆续获证。贝康医疗凭借其在PGT检测领域的全面获证，正引领着整个行业迈向一个全新的合规化和注册证时代，对提升人口质量和医疗安全具有深远意义。 国家药监局徐景和副局长来贝康医疗调研 DA500&DA5000基因测序平台获证，实现产业创新 贝康医疗推出的中、大通量测序平台DA500和DA5000已获NMPA批准，满足不同规模生殖遗传实验室需求，奠定了基因检测技术创新的硬件基础。依托这些平台，贝康医疗在科研上不断突破，与国内知名生殖中心合作发表多篇学术文章。2022年在《Human Reproduction》上发表了PGT-Plus技术，解决了传统PGT难以检测的复杂遗传疾病；2023年在《Human Reproduction Open》上发表了外周血miRNA在子宫内膜植入周期内动态变化的研究，为了解胚胎着床妇女早孕期的生理变化和胚胎个性化移植提供了重要的理论依据；近些年开展了拉曼光谱技术方向的研究，结合机器学习，实现了对胚胎发育潜力的非侵入性评估，为辅助生殖提供了新工具和生物标志物。截至目前，贝康医疗已发表百余篇科研文章，并将继续致力于技术创新和科研突破，推动生殖遗传领域的发展。 加速全球化进程，布局海外市场 贝康医疗与全球顶尖生育集团Genea达成战略合作协议，通过悉尼IVF中心的平台，将贝康医疗的全场景解决方案推向全球。目前，贝康医疗的PGT完整解决方案已在悉尼IVF中心、泰国和欧洲等地区的顶尖生殖中心成功落地，开启了国际化发展的新篇章。未来，贝康医疗将进一步深化全球合作，持续为全球生殖中心提供最前沿的技术和解决方案，致力于让全球患者从中受益。 ▌文章来源：贝康医疗 责编：何文正 审核：任旭 推荐阅读 上市企业丨信达生物匹康奇拜单抗（IL-23p19抗体）治疗溃疡性结肠炎的II期临床研究达成主要终点 上市企业丨康宁杰瑞HER2双抗KN026联合白蛋白结合型多西他赛新辅助治疗乳腺癌3期临床获批 上市企业丨亚盛医药：APG-2449获CDE许可开展治疗非小细胞肺癌的注册3期临床研究

本次以“突破瓶颈 打造健康产业新引擎”为主题，设一场主论坛和八场主题论坛，从前沿创新突破、临床应用拓展、工艺技术优化、商业化开发等多个全新视角推动CGT技术开发与应用，成就健康产业未来。 发育和生殖毒性（Developmental and reproductive toxicity, DART）研究评估小分子药物及其代谢物以及生物制品对雄性和雌性生育能力、早期胚胎发育以及发育中胚胎、胎儿和后代的生长、成熟和功能的潜在危害。这些研究非常重要，因为孕妇通常不会被纳入新疗法的临床试验中，因此DART研究往往是新药在临床使用、上市批准或同时获得临床使用和上市批准之前有关其潜在生殖和发育风险的唯一信息。 当一种新的药品或生物制品要用于可生育人群时，监管机构要求在动物种属中考察其效果，这涉及到与有生育能力的妇女和有生育能力的男性。这些动物研究的时间安排将取决于正在进行的临床试验阶段。 本章包括对小分子、大分子（生物制品）和疫苗的DART评估。由于细胞和基因治疗产品或组织工程产品被排除在目前的DART试验指导原则之外，因此本章未将其包括在内。关于评估研究药物对幼龄动物的影响以支持可能的儿科用药的青少年研究的讨论也超出了本章的范围。 本章还讨论了针对各种适应症（如肿瘤、疫苗和其他小分子和大分子药物）开发的药品和生物制品的DART战略，如《国际药品生产质量管理规范》（International Council for Harmonisation of Pharmaceuticals for Drugs Technical Requirements）所述。 本章将探讨具体的DART测试策略将如何取决于正在研究的药物、生物制品或疫苗的药理学和作用模式、临床适应症、预期患者人群、临床开发的时间或阶段，以及如何根据不同物种的活性或靶点参与情况进行调整。此外，本章还将详细阐述暴露限度和剂量水平选择、替代检测方法的使用和鉴定以及推迟DART研究的可能性。 1 发育和生殖毒性测试的基本原则 发育和生殖毒性测试的评估包括从交配和受孕到妊娠、分娩、断奶和后代性成熟的整个生殖和发育周期。ICH S5（R3）将生殖和发育周期划分为精子和卵子的形成、受精、胚胎（胚胎/胎儿）的发育、出生、生长和成熟，然后再重新开始下一代的产生。这一重要概念将DART与一般毒性研究区分开来。周期分为A至F六段（图9-1）。对周期进行分段，可分别评估在发育周期不同阶段接触试验物品的情况。任何特定的不利影响都会被识别出来，而不会与后续阶段的暴露情况相混淆。 分段法是合适的，因为药物是根据其药理和毒性，在规定的时间（或生命周期的一部分）用于某些适应症和病人群体，可以连续给药，也可以不连续给药。 01 非临床DART研究的重要性 由于临床试验通常不包括DART终点（即对生育力的影响或对发育中的胎儿的影响），因此非临床DART研究构成了用于上市审批的药物或生物制品产品的危害识别和风险评估的基础。除了在研发的各个阶段对生殖风险进行评估，并确定将具有生殖潜能的男性和女性纳入临床试验的最合适时间外，还必须在相关动物种属中进行DART研究，以便检测到的任何不良反应都能代表人体安全性。 02 药物或生物制品潜在暴露的发育阶段 生殖和发育周期分为A至F段，以涵盖整个生殖和发育周期。 通常，将进行三种类型的研究来评估药物或生物制品对DART的影响（Figure 9-2）： 生育力和早期胚胎发育（FEED）研究，涵盖生殖和发育周期的A到B阶段； 胚胎-胎儿发育（EFD）研究，涵盖C-D阶段；以及 产前和产后发育（PPND）毒性研究，涵盖C至F阶段。 为了减少动物用量，可以接受组合研究；例如，FEED和EFD组合研究5 （Figure 9-2），或EFD和PPND组合研究合并为ePPND研究6（Figure 9-3）。 DART研究的设计因治疗适应症、目标患者人群和风险效益比的不同而不同，需要支持临床试验、上市批准或两者兼而有之。 只有当生物制品在受试物种中具有活性时，生物制品的DART研究才具有相关性。例如，如果生物制品在啮齿动物和兔子中具有活性，则将在这些种属中进行DART研究。但是，如果生物制品在啮齿动物、非人灵长类动物或两者中均有活性，则DART试验将仅限于使用这些物种进行的研究。如果不适合使用非人灵长类动物（即无目标结合），则可使用替代动物模型或替代试验。在这种情况下，必须对后者进行充分验证或鉴定，以便对危害评估过程中的相关数据进行解释。 作为一般指南，DART研究 • 必须按照良好实验室规范（GLP）或人类风险评估的最高标准进行。 • 通常包括剂量范围探索试验（非GLP）；首次EFD研究通常在兔子身上进行，重复给药毒理试验在啮齿动物上进行。后者为剂量选择（尤其是生育力研究）提供依据。 • 即使将重复给药毒理试验作为DART一部分，也有必要在妊娠动物中进行剂量范围探索试验，因为药物或生物制品在妊娠期间的吸收和耐受性通常不同于生殖周期的其他阶段。 • 与常规毒理学研究相比，DART研究的群体规模更大（20-22只动物，而不是啮齿动物毒性研究中的10只），因为应该有足够数量的仔鼠进行评估。包括16-20只妊娠或产仔的研究通常可提供足够的统计能力来检测相关变化，但这些研究的规模不必过大。 • 应至少包括四个剂量组；在啮齿动物和兔子中应至少包括一个对照组，在非人灵长类动物中应至少包括两个对照组。 • 应保存有关特定试验物种和各种研究设计的所有评估参数的可靠历史数据库。这些数据库对于确定相对罕见的自发不良事件（如胎儿重大畸形）的原因尤为重要，并有助于评估任何可能与试验治疗有关或无关的罕见事件。 2 药物的发育和生殖毒性策略 下文概述了测试药物生殖和发育毒性的研究设计、测试系统和研究终点。 01 生育力和早期胚胎发育研究 生育力和早期胚胎发育试验测量的是研究药物或生物制品对生育力和早期妊娠的影响（Figure 9-2）。FEED研究通常在啮齿动物中进行，大鼠比小鼠更常用。通常在交配前2-4周开始给药，研究可以是雄性和雌性生育力的综合研究，也可以是雄性生育力和雌性生育力的单独研究。 如果在重复给药毒理试验中没有观察到药物或生物制品的毒性迹象（即生殖器官无不良发现），则可进行联合研究。在这种情况下，同一啮齿动物种属的雌雄啮齿动物种属的雄性和雌性在给予药物或生物制品2周后进行交配，评估对早孕的影响。 如果根据药理学预计会产生不良影响，或重复给药毒理试验中发现动物生殖器官有不良组织学发现（如睾丸重量减少、睾丸组织萎缩等），则应单独进行雄性FEED研究。雄性动物的用药时间应延长至交配前10周（最多70-90天），以覆盖整个生精周期（小鼠约56-60天，大鼠约70天）；8只经处理的雄性动物应与未处理的雌性动物交配，以确定父代用药对生育能力和妊娠结果的影响。 同样，如果在雌性生殖器官（如卵巢）中发现不良的组织学结果，将只进行雌性FEED研究。雌性将服用2周，治疗后的雌性将与未治疗的雄性或未治疗的繁殖雄性交配，当交配或通过检测阴道塞确认怀孕时将其分开。 评估雄性的生殖终点包括： • 交配表现和性欲的功能影响； • 附睾精子成熟和射精； • 生育能力； • 生殖器官重量（睾丸和附睾）；以及 • 精子参数，如精子数量、精子形态和精子活力。 在某些情况下，可能需要对精子进行定性或定量分期，以阐明受药物影响的精子成熟阶段。将接受治疗的雄性动物的任何变化与同期对照动物和历史对照进行比较。 雌性动物的生殖终点评估包括： - 交配性能 - 繁殖力和妊娠指数； - 发情周期（首先确定两到三个周期作为基线）； - 生殖器官重量（即卵巢和子宫）；以及 - 卵巢参数，如着床、黄体数量以及着床前后的损失。 根据ICH M3（R2），为药物的非临床开发和人体临床试验的进行提供了指导原则，在进行动物雄性生育能力研究之前，可将人类男性纳入1期和II期临床试验，前提是已完成28天或更长时间的重复给药毒性试验，其中包括对生殖器官进行适当的组织学评估。对雄性和雌性生殖器官进行至少28天暴露后的组织学评估被认为是足够敏感的，可以检测出不良影响。 根据作者的经验，药物或生物制品导致的睾丸毒性比女性生殖毒性更为普遍。这可能是因为在不进行功能评估的情况下，男性生殖器官的不良反应比女性生殖器官的不良反应更容易发现，而在标准的重复给药毒性试验中通常不进行功能评估。虽然男性会持续产生精子，但只有在治疗期间才会出现排卵的最后步骤，而且子宫的变化往往可能很微妙。 1期临床试验通常涉及男性受试者，因此在获得知情同意书时，需要特别警告试验药物对男性生育能力的潜在影响和风险，以及女性伴侣或女性受试者采取有效避孕措施的必要性。男性FEED研究需要在3期开始前进行，因为3期的参与者人数较多。 永久绝育的女性或绝经后的女性由于不再具有生育潜能，因此无需事先进行生育力研究，即可参与I期临床试验。如果临床试验持续时间较短（即少于3个月），且已采取措施防止怀孕（即使用高效节育措施），则ICH M3（R2）允许在进行符合GLP的女性生育力研究之前，纳入数量有限（约150名）的育龄妇女。 这些预防措施旨在限制女性受试者的药物暴露风险和胎儿的意外暴露风险。必须在知情同意书中明确告知生育能力和生殖潜能的风险，并严格遵守研究方案，否则只能招募男性受试者。对于肿瘤药物，不需要进行生育力研究，只需要进行EFD研究（通常在一个种属中进行），以便按照ICH S9的规定进行3期临床试验并获得上市许可。 02 胚胎-胎儿发育研究 胚胎-胎儿发育研究也称为畸胎学或器官发生研究14，评估药物或药品对后代发育的影响，包括从植入到硬腭闭合（即器官发生期；Figure 9-2）。 EFD研究通常在两个种属中进行；对于药物和生物制品而言，通常是啮齿动物（通常是大鼠，但也可以是小鼠）和兔子（非啮齿动物）。生物制品试验可能会使用第三个种属，即非人灵长类动物。 使用两个种属，尤其是非啮齿类动物物种的原因可追溯到20世纪60年代中期沙利度胺的使用，当时该药物被用于孕妇的孕吐治疗，但却被发现会导致服药妇女的婴儿出现严重畸形，包括四肢和下半身畸形15。进一步阐明沙利度胺的作用机理发现，啮齿类动物不表达某些介导沙利度胺作用的蛋白质（即Bmp和DKK1）。 事实上，在FDA于2016年至2021年期间批准的一项药品研究中，63%-84%的小分子药物使用大鼠和兔进行EFD研究，而且跨种属一致性良好。跨种属和跨研究一致性（即DART、生育力和EFD研究之间的一致性）表明，大多数对生育力和胚胎发育的不良影响均可识别。 在EFD研究中，孕妇在妊娠期（即Figure 9-1所示ICH方案中的C至D阶段）用药，妊娠期因物种而异（Table 9-1）。 EFD研究中收集的发育终点包括母体终点和胎儿终点。 • 母体终点包括母体体重和体重变化、进食量、临床观察、临床病理学、存活率、宏观检查、胎盘大体评估和有时重量、妊娠子宫重量、尸检结果、器官重量以及黄体和植入部位计数。 • 胎儿终点包括胎儿存活率（活胎/死胎）、胎儿数量或窝产仔数、胎儿性别（男/女）、胎儿体重、植入后丢失（早期/晚期再植），以及胎儿畸形和胎儿发育变异发生率评估。 发育毒性最敏感的指标是存活率改变（胚胎或胎儿存活/死亡）、结构改变（变异或畸形，包括胎儿外部、软组织和骨骼改变）和发育迟缓（最敏感的终点是胎儿体重和大小）。 就生物制品而言，虽然一般需要进行两项EFD研究，但只需测试活性种属。例如，如果只在大鼠身上发现活性，而在兔子身上没有发现活性，则只进行大鼠的EFD研究。另一方面，如果生物制品只在非人灵长类动物身上有活性，则按照ICH S6（R1）的规定，在食蟹猴（Cynomolgus monkey）上进行EFD和PPND联合研究。 虽然这样做的好处是减少了所需动物的数量（表9-2），但对过去20年批准的生物制品许可申请（BLA）进行的分析表明，在生物制品DART研究中使用非人灵长类动物的比例已从2002-2015年的62%大幅下降到2020-2021年的22%。2020-2021年间进行的大多数BLA（37%）使用啮齿类动物进行DART研究。 — 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，明智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）所概述的那样。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。 (本章较长，未完待续) 英文版原文 （上下滑动查看更多） Chapter 9 Developmental and Reproductive Toxicity Assessments Developmental and reproductive toxicity (DART) studies evaluate the potential hazards of small molecule pharmaceuticals and their metabolites, and biopharmaceuticals, on male and female fertility, the ability to produce children, and the growth, maturation and function of the developing embryo, fetus, and offspring. These studies are important because pregnant women are usually not included in clinical trials of new therapeutics, so DART studies may often provide the only information on the potential reproductive and developmental risks of a new drug before its clinical use, marketing approval, or both. When a new pharmaceutical or biopharmaceutical is to be used in fertile populations, regulatory agencies require that its effects are tested in an animal species that relates to women of childbearing potential and men of reproductive potential. The timing of these animal studies will depend on the phase of clinical trial testing that is in progress.1 This chapter covers DART assessment of small and large molecules (biopharmaceuticals), and vaccines. As cell and gene therapy products, or tissue-engineered products, are excluded from current DART testing guidelines, they are not included. The discussion of juvenile studies that assess the effects of investigational drugs on young animals to support possible pediatric use is also beyond the scope of this chapter. The chapter also includes discussion of DART strategies for pharmaceuticals and biologics being developed for various indications, such as oncology, vaccines, and other small and large molecules as outlined in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) safety (S)5 revision 3 (R3).2 It will examine how the specific DART strategy for testing will depend on the pharmacology and mode of action of the pharmaceutical, biologic or vaccine under investigation, as well as the clinical indication, intended patient population, the timing or phase of clinical development, and how this will be tailored based on the activity or target engagement in different species. In addition, this chapter will elaborate on exposure margins and dose-level selection, as well as the use and qualification of alternative assays, and the potential for deferral of DART studies. Underlying Principles of Developmental and Reproductive  Toxicity Testing Evaluation of DART encompasses the entire reproductive and developmental cycle from mating and conception through to gestation, parturition, weaning, and sexual maturity of the offspring. ICH S5(R3) divides the reproductive and developmental cycle from formation of the sperm and egg, fertilization, development of the conceptus (embryo/fetus), birth, growth and maturation, and then the process starts over again if a next generation is produced. This important concept differentiates DART from general toxicity studies. The cycle is divided into six segments, A to F (Figure 9-1). This segmentation of the cycle allows exposure to a test article at various stages of the developmental cycle to be evaluated separately. Any specific adverse effects are identified without being confounded by exposure in subsequent segments. The segmented approach is appropriate as drugs are given for certain indications, and to patient populations based on their pharmacology and toxicity at defined times (or portions of the life cycle) and may or may not be continuously administered. Importance of Nonclinical DART Studies As clinical trials do not routinely include DART endpoints (i.e., regarding the effects on fertility, or on the developing conceptus), nonclinical DART studies form the basis of hazard identification and risk assessment for pharmaceutical or biologic drug products used for marketing approval. In addition to assessing reproductive risk at all stages of development and determine the most appropriate time to include men and women of reproductive potential in clinical trials, it is important to conduct DART studies in a relevant animal species so that any adverse effects detected are representative for human safety. Developmental Stages for Potential Exposures of Drugs or Biopharmaceuticals The reproductive and developmental cycle are divided into segments A to F to encompass the entire reproductive and developmental cycle. Typically, three types of studies will be conducted to assess a drug or biopharmaceutical’s effects on DART (Figure 9-2): 3-4 1.Fertility and early embryonic development (FEED) studies, which cover stages A to B of the reproduction and development cycle; 2.Embryo-fetal development (EFD) studies, which cover stages C-D; and 3.Pre-and postnatal development (PPND) toxicity studies, which cover stages C-F. Combination studies are acceptable to reduce animal usage; for example, a combined FEED and EFD study5 (Figure 9-2), or a combined EFD and PPND study that merges into ePPND study6 (Figure 9-3). DART study designs vary according to the therapeutic indication, intended patient population, and the risk-benefit ratio, needed to support clinical trials, marketing approval, or both. DART studies for biologics are only relevant when the biologic is active in the test species. For example, if the biologic is active in rodents and rabbits, DART studies will be conducted in these species. However, if the biologic is active in rodents, non-human primates, or both, then DART testing will be confined to studies which use these species. In cases where non-human primate is not appropriate (i.e., no target binding) then an alternative animal model or surrogate assays may be used. If so, the latter must be fully validated or characterized to enable data interpretation relevant to the hazard assessment process. As a general guide, DART studies: • Must be conducted according to good laboratory practice (GLP),7 or to the highest standards for human risk assessments. • Usually include dose-range finding studies (non-GLP); first-time EFD studies are usually in rabbits, with repeat-dose toxicity studies performed in rodents. The latter provide the basis for dose selection (especially in fertility studies). • Dose-range finding studies in pregnant animals may be necessary even if repeat-dose toxicity studies are included as part of the DART strategy, as a drug or biopharmaceutical’s absorption and tolerability are usually different during pregnancy as compared to the rest of the reproductive cycle. • Compared to regular toxicology studies, group sizes in DART studies are larger (20-22 animals instead of 10 in a rodent toxicity study) because there should be sufficient number of litters to evaluate. Studies that include 16-20 pregnancies or litters usually provide sufficient statistical power to detect relevant change, but these are not unnecessarily large. • Should include at least four dose groups; this should include at least one vehicle group as a control in rodents and rabbits and at least two vehicle control groups in non-human primate. • Should maintain robust, historical databases of all the parameters being evaluated in the particular test species, and the various study designs. Such databases are especially relevant for determining the cause of relatively rare and spontaneous adverse events, such as major fetal malformations, and can aid in the evaluation of any rare event that may or may not be related to the test treatment. Developmental and Reproductive Toxicity Strategies for Pharmaceuticals An overview of study designs, test systems and study endpoints for testing the reproductive and developmental toxicity of pharmaceuticals is given below. Fertility and Early Embryonic Development Study FEED studies measure the effects of an investigational drug or biopharmaceutical on fertility and the early establishment of pregnancy (Figure 9-2). FEED studies are usually conducted in rodents, and rats are used more often than mice. Dosing usually starts 2-4 weeks before mating, and studies can be either be a combined male and female fertility study or separate male fertility and female fertility studies. If there is no indication of toxicity due to the drug or biopharmaceutical observed in repeat-dose toxicity studies (i.e., no adverse findings in reproductive organs), then a combined study can be conducted. This is where males and females from the same rodent species are given the drug or biopharmaceutical for 2 weeks and are then mated, with the effects on early pregnancy evaluated. If adverse effects based on pharmacology are expected or repeat-toxicity studies uncover adverse histological findings in the animal reproductive organs (e.g., reduced testicular weights, testicular tissue atrophy, etc.) then a male FEED study should be conducted separately. Dosing in males should be extended to 10 weeks prior to mating (up to 70-90 days) to cover a full spermatogenic cycle (~56-60 days in mouse and ~70 days in rat);8 and treated males should be mated with untreated females to determine the effect of paternal dosing on fertility and pregnancy outcomes. Similarly, a female only FEED study will be conducted if there are adverse histological findings in the female reproductive organs (e.g., ovaries). Females will be dosed for 2 weeks and treated females will be mated with untreated males or untreated breeder males and separated when mating or pregnancy is confirmed by detection of a vaginal plug. Reproductive endpoints evaluated for males are: • Mating performance and the functional effects of libido; • Epididymal sperm maturation and ejaculation; Fertility; • Reproductive organ weights (testicular and epididymal); and • Sperm parameters such as sperm count, sperm morphology, and sperm motility. In some cases, qualitative or quantitative sperm staging9may be desired to elucidate the stage of sperm maturation affected by the pharmaceutical. Any changes in the treated males are compared with the concurrent control animals and historical control. Reproductive endpoints evaluated for females are: • Mating performance; • Fertility and pregnancy indices; • Estrous cycling (establish two to three cycles as baseline first); • Reproductive organ weights (i.e., ovary and uterus); and • Ovarian parameters such as implantation, number of corpora lutea, and pre- and post-implantation loss. Human males can be enrolled in Phase 1 and 2 clinical trials prior to the conduct of an animal male fertility study according to ICH M3(R2), 10-12 which provide guidelines to the nonclinical development and conduct of human clinical trials for pharmaceuticals, provided that a 28-day or longer repeat-dose study has been completed and which included appropriate histological evaluation of the reproductive organs. The histological evaluation of male and female reproductive organs after a minimum of 28-days of exposure is considered sensitive enough to detect adverse effects. In the authors’ experience, testicular toxicity due to a drug or biopharmaceutical is more prevalent than female reproductive toxicity. This may be because adverse effects in the male reproductive organs are more easily discerned than those in the female reproductive organs without evaluation of function, which is not typically conducted in standard repeat-dose toxicity studies. While there is the continuous production of sperm in the male, only the final steps in ovulation occur during treatment and changes in the uterus may often be subtle. Phase 1 clinical trials typically involve male subjects and obtaining informed consent requires that specific warnings about the potential effects and risks of the testing agent on male fertility are given, as well as need for effective contraception by female partners or female test subjects. A male FEED study will need to be conducted before the initiation of Phase 3, which has a larger number of participants included. Women who are permanently sterilized or who are postmenopausal can be included in Phase 1 clinical trials without prior fertility studies being conducted as they are no longer of childbearing potential. When clinical trials are of short duration (i.e., less than 3 months) and steps are in place to prevent pregnancies (i.e., using highly effective birth control), ICH M3(R2)10-12 allows for the inclusion of a limited (approximately 150) number of women of childbearing potential before the conduct of GLP-compliant female fertility studies. These precautions are to limit the risk of drug exposure in female subjects and the unintentional exposure to the fetus. Risks to fertility and reproductive potential need to be communicated clearly in the informed consent, and strict adherence to the study protocol is expected, otherwise, only male subjects are enrolled. For oncology drugs, fertility studies are not required, only an EFD study (usually in one species) is necessary and to enable Phase 3 clinical trials and marketing approval, as outlined in ICH S9. Embryo-fetal Development Study EFD studies, also known as teratology or organogenesis studies,14 assess the effects of a drug or pharmaceutical on the development of offspring, from implantation through to closure of the hard palate (i.e., the period of organogenesis; Figure 9-2). EFD studies are usually conducted in two species; this is usually the rodent (usually the rat but can also be done in the mouse) and the rabbit (non-rodent) for both pharmaceuticals and biologics. A third species, non-human primates, may be used for testing a biologic. The reason for using two species, especially a non-rodent species, stems back to the use of thalidomide in the mid-1960s when the drug was given to pregnant women as treatment for morning sickness but was found to cause major malformations including limb and lower body malformations in the babies of women who had taken the drug.15 EFD studies had been conducted in rats and mice but had not revealed any embryo-fetal risk until additional EFD studies were conducted in rabbits a few years later that the risk was confirmed. Further elucidation of the mechanism of action of thalidomide found that rodents do not express certain proteins (i.e., Bmp and DKK1) that mediate the effect of thalidomide.16 Hence, using a rodent and nonrodent species is now the standard strategy for EFD studies. In fact, in a study of pharmaceuticals approved by FDA between 2016 to 2021, 63-84% small molecules used the rat and rabbit for EFD studies, and there was good cross-species concordance.17-19 Cross-species and cross-study concordance (i.e., between DART, fertility and EFD studies) indicates that most adverse effects on fertility and embryofetal development can be identified. In EFD studies, pregnant females are dosed during the during the gestation period (i.e., stages C to D of the ICH scheme shown in Figure 9-1), which varies between species (Table 9-1).  The developmental endpoints collected in the EFD studies include both maternal and fetal endpoints. • Maternal endpoints include maternal body weight and body weight change, food consumption, clinical observations, clinical pathology, survival, macroscopic examinations, gross evaluation and sometimes weight of placenta, gravid uterine weight, necropsy findings, organ weights, and corpora lutea and implantation site count. • Fetal endpoints include fetal viability (live/dead fetuses), the number of fetuses or litter size, fetal sex (male/female), fetal body weights, post-implantation loss (early/late resorptions), and an evaluation of the incidence of fetal malformations and fetal developmental variations. The most sensitive indicators of developmental toxicity are altered survival (live/dead embryos or fetuses), structural changes (either variations or malformations including fetal external, soft tissue and skeletal alterations), and developmental delays (with the most sensitive endpoint being fetal body weight and size). In the case of biologics, although two EFD studies are generally required, only the active species needs to be tested. For example, if activity is seen only in rats but not in rabbits, only a rat EFD study is conducted;20 if, on the other hand, a biologic is active only in non-human primate, then a combined EFD and PPND study will be conducted in Cynomolgus monkey21-22, as described in ICH S6(R1).23 While this has the advantage of reducing the number of animals required,24 (Table 9-2) an analysis of Biologics License Applications (BLA) approved in the past 20 years shows that the use of non-human primates for biologic DART studies has dropped substantially from 62% in 2002-2015 to only 22% in 2020-2021. Most of the BLAs (37%) conducted between 2020- 2021 used rodents for DART studies. 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↓↓↓