Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
Janssen-Cilag France, Paris, France.
Respir Med Res. 2022 May;81:100893. doi: 10.1016/j.resmer.2022.100893. Epub 2022 May 4.
Developing a new medication in a rare disease indication like pulmonary arterial hypertension (PAH) is very challenging. This is especially true now that clinical trials often employ time to clinical worsening (TTCW) as an endpoint (thus requiring a relatively large and lengthy trial) and since patients are more frequently prescribed combination therapy. During the last few decades, several tools have been developed to predict mortality in PAH and have demonstrated generally good discrimination. The objective of this review article is to assess the available data on the different tools and methods described in the literature and identify potential candidates that could be used as surrogate endpoints in pivotal randomized clinical trials in future. Some of these tools have been validated in various registries and in post-hoc analyses of clinical trial data, but none have been assessed in a prospective clinical trial and we still lack the evidence necessary for endorsement by health authorities. In this review, we identify several promising options that warrant further investigation as potential surrogate endpoints in clinical trials to replace TTCW or 6-minute walk distance. Prospective inclusion of such tools in new clinical trials may help build a stronger surrogacy for prognosis of disease progression and mortality.
在肺动脉高压（PAH）等罕见疾病适应症中开发新药物极具挑战性。由于临床试验通常采用临床恶化时间（TTCW）作为终点（因此需要相对较大和较长的试验），并且患者经常接受联合治疗，情况尤其如此。在过去的几十年中，已经开发出了几种工具来预测 PAH 患者的死亡率，并且已经证明这些工具具有较好的区分能力。本文的目的是评估文献中描述的不同工具和方法的可用数据，并确定可能在未来的关键性随机临床试验中用作替代终点的潜在候选方法。其中一些工具已在各种登记处和临床试验数据的事后分析中得到验证，但尚无工具在前瞻性临床试验中进行评估，我们仍然缺乏获得卫生当局认可的必要证据。在本综述中，我们确定了一些有前途的选择，这些选择需要进一步研究，作为替代 TTCW 或 6 分钟步行距离的临床试验替代终点。将此类工具前瞻性纳入新的临床试验中，可能有助于为疾病进展和死亡率的预后建立更强的替代关系。
