The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials.
The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials.
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FDA和EMEA指南对药物开发与0期试验有关的影响。
DOI：
10.1038/sj.bjc.6603925
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发表时间：
2007-09-03
影响因子：
8.8
通讯作者：
Schellens, J H M
中科院分区：
文献类型：
--
作者：
Marchetti, S;Schellens, J H M
通过最近的生物医学研究，确定的治疗癌症靶点的数量有所增加，这导致了需要进一步测试的大量分子的产生。目前（抗癌）药物的开发是一个相当低效的过程，平均一个新分子需要大约10-15年。这也是一个具有挑战性的过程，因为它与高成本和低批准率有关。众所周知，进入临床I期试验的新分子实体中，只有不到10%的进展超出了研究计划并进入市场；对于抗癌药物来说，这种可能性甚至更低。2003年，美国食品和药物管理局（FDA）宣布迫切需要新的工具包，以改善从科学发现到患者的关键发展路径。在这种情况下，0期（零）试验应该允许通过亚药理学剂量给药，在短时间内对少量人进行测试化合物的药代动力学和药效学特征的早期评估。通常，0期研究没有治疗或诊断目的。由于给药剂量低，毒性风险低，需要较短的临床前包装来支持这些研究。0期临床试验被建议用于帮助早期选择有希望的候选药物，以便在I-III期临床试验中进行进一步评估，为药物发现提供潜在的有用工具，特别是在肿瘤学领域。0期研究有望降低药物开发成本，并限制临床前体外和体内测试以及药物开发的时间。然而，也有人担心第0阶段研究的效用和可行性。2006年1月，美国食品和药物管理局发布了关于人类新药探索性研究的指导方针，目前国家癌症研究所正在进行一项0期计划，以评估0期研究对药物开发的影响（可行性和实用性）。在欧洲，2004年由药品评价（EMEA）编制的立场文件提出了减少临床前安全包以支持早期微剂量临床研究的可能性，并且，正如EMEA人用药品委员会最近发表的一份关于药品的概念文件所宣布的那样，EMEA关于0期研究的指南预计很快就会出台。0期研究对药物开发过程和安全性的真正影响需要仔细探讨。
An increase in the number of identified therapeutic cancer targets achieved through recent biomedical research has resulted in the generation of a large number of molecules that need to be tested further. Current development of (anticancer) drugs is a rather inefficient process that for an average new molecule takes around 10–15 years. It is also a challenging process as it is associated with high costs and a low rate of approval. It is known that less than 10% of new molecular entities entering clinical Phase I testing progress beyond the investigational programme and reach the market; this probability is even lower for anticancer agents. In 2003, the US Food and Drug Administration (US FDA) declared the urgent need for new toolkits to improve the critical development path that leads from scientific discovery to the patient. In this scenario, Phase 0 (zero) trials should allow an early evaluation in humans of pharmacokinetic and pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of humans. Typically, Phase 0 studies have no therapeutic or diagnostic intent. Owing to the low doses administered and the low risk of toxicity, shorter preclinical packages to support these studies are required. Phase 0 trials have been proposed to help in making an early selection of promising candidates for further evaluation in Phase I–III trials, providing a potentially useful instrument for drug discovery, particularly in the field of oncology. Phase 0 studies are expected to reduce costs of drug development, and to limit the preclinical in vitro and in vivo testing and the time period of drug development. However, there are also concerns about the utility and feasibility of Phase 0 studies. In January 2006, guidelines on exploratory investigational new drug studies in humans have been published by the US FDA, and currently a Phase 0 programme is ongoing at the National Cancer Institute to evaluate the impact (feasibility and utility) of Phase 0 studies on drug development. In Europe, a Position Paper produced by the Evaluation of Medicinal Products (EMEA) in 2004 raised the possibility of a reduced preclinical safety package to support early microdose clinical studies, and, as announced by a recent Concept Paper on medicinal products published by the committee for medicinal products for human use of the EMEA, EMEA's guidelines on Phase 0 studies are expected shortly. The true impact of Phase 0 studies on the drug development process as well as on the safety needs to be carefully explored.