New Experimental Medicine Studies: Fast-Fail Trials in Mood and Anxiety

FAST-MAS计划将重点关注新的分子和临床靶点，这些靶点可能跨越情绪和焦虑谱内的诊断类别，也可能与其他精神疾病相关。如DSM-IV-TR所示，情绪和焦虑谱系障碍是心理健康从业者治疗的最常见和最严重的疾病之一。这些包括重度抑郁症、心境恶劣障碍（一种慢性轻度抑郁症）和双相情感障碍（也称为躁狂抑郁症）。焦虑症有很多种，包括广泛性焦虑症、创伤后应激障碍、强迫症和特殊恐惧症。 该倡议旨在迅速测试和分析新的干预措施（即，化合物）和它们用于治疗精神病理学临床方面的分子和/或临床靶点（例如，快感缺乏、认知功能、社会参与）与传统的情绪和焦虑谱系障碍相关。特别令人感兴趣的是如在当前DSM-IV-TR诊断实体中描述的情绪和焦虑谱系障碍的特征，但通常未被鉴定为当前临床治疗的主要靶标。如上所述，人们对研究跨越传统疾病类别的机制感兴趣，并且直接评估相关机制和临床靶点，而不是通过指定特定诊断来推断。 这一举措的结果，预计将导致这种新的干预措施的具体目标的参与，导致创新的治疗方法的发展与传统的情绪和焦虑谱系障碍相关的精神病理学的临床层面的认识。在这种情况下，新的干预措施（即，化合物）可以指新的化学实体（NCE）或正在考虑从其他适应症中重新利用的化合物。如果最近的基础研究发现表明化合物有可能影响导致精神障碍的生物学机制，并且以前未在临床研究中进行过测试，则对FDA批准用于其他适应症（重新用途）的化合物进行测试是有意义的。本合同对作用于分子靶点的化合物不感兴趣，这些分子靶点与目前市售的精神科药物的分子靶点相似。 本合同的主要目的是迅速进行小规模I期和/或IIa期临床试验（例如，首次人体试验（FIH）、临床机制验证（POCM）、概念验证（POC）），以证明这些有希望的化合物在健康受试者和/或具有与传统情绪和焦虑谱系障碍相关的精神病理学临床维度的患者的良好表征队列中的靶向参与、安全性和早期功效迹象。根据所选化合物的试验数据，每项试验可能是单中心或多中心研究，受试者人数足以成功实现主要目标（例如，药理学剂量范围、在人体中的安全性、分子和/或临床靶标接合、潜在的生物标志物、生物效应、功效的早期迹象），并告知判断特定化合物是否需要进一步评价。

The FAST-MAS initiative will focus will be on novel molecular and clinical targets that may cut across diagnostic categories within the mood and anxiety spectrum, and may also be relevant to other mental disorders. Mood and anxiety spectrum disorders, as represented in the DSM-IV-TR, are among the most common and serious disorders treated by mental health practitioners. These include major depressive disorder; dysthymic disorder (a chronic, mild depression); and bipolar disorder (also called manic depression). There are a wide variety of anxiety disorders, including generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, and special phobias. This initiative seeks to expeditiously test and analyze novel interventions (i.e., compounds) and their molecular and/or clinical targets for treating clinical dimensions of psychopathology (e.g., anhedonia, cognitive function, social engagement) associated with traditional mood and anxiety spectrum disorders. Of particular interest are features of mood and anxiety spectrum disorders as described in the current DSM-IV-TR diagnostic entities, but not typically identified as the primary target of current clinical therapeutics. As described above, there is interest in the study of mechanisms that cut across traditional disorder categories and where relevant mechanisms and clinical targets are assessed directly rather than being inferred through assignment of a particular diagnosis. The outcome of this initiative is expected to lead to enhanced understanding of specific target engagement by such novel interventions, leading to development of innovative treatment approaches for clinical dimensions of psychopathology associated with traditional mood and anxiety spectrum disorders. In this context, novel interventions (i.e., compounds) may refer either to new chemical entities (NCEs) or to compounds that are being considered for re-purposing from other indications. Testing of compounds that have been FDA-approved for other indications (re-purposing) is of interest if recent basic research discoveries suggest that the compound(s) have the potential to affect a biological mechanism contributing to mental disorders and that has previously been untested in clinical studies. Compounds acting on molecular targets that replicate those of currently marketed psychiatric pharmaceuticals are not of interest for this contract. The primary objective of this contract is to expeditiously perform small-scale Phase I and/or Phase IIa clinical trials (e.g., First In Human (FIH), Proof of Clinical Mechanism (POCM), Proof of Concept (POC)) to demonstrate target engagement, safety, and early signs of efficacy of such promising compounds in healthy subjects and/or a well-characterized cohort of patients with clinical dimensions of psychopathology associated with traditional mood and anxiety spectrum disorders. Depending on pilot data available for compounds selected for testing, each trial may be a single-site or multisite study with a number of subjects adequate to successfully address the primary aims (e.g., pharmacologic dose range, safety in humans, molecular and/or clinical target engagement, potential biomarkers, biological effects, early signs of efficacy) and inform a judgment whether the particular compound warrants further evaluation.