Conditional (European Medicines Agency) or accelerated (U.S. Food and Drug Administration) approval of drugs allow earlier access to promising new treatments that address unmet medical needs. Certain post-marketing requirements must typically be met in order to obtain full approval, such as conducting a new post-market clinical trial. We study the applicability of the recently developed harmonic mean Chi-squared test to this conditional or accelerated approval framework. The proposed approach can be used both to support the design of the post-market trial and the analysis of the combined evidence provided by both trials. Other methods considered are the two-trials rule, Fisher's criterion and Stouffer's method. In contrast to some of the traditional methods, the harmonic mean Chi-squared test always requires a post-market clinical trial. If the p-value from the pre-market clinical trial is << 0.025, a smaller sample size for the post-market clinical trial is needed than with the two-trials rule. For illustration, we apply the harmonic mean Chi-squared test to a drug which received conditional (and later full) market licensing by the EMA. A simulation study is conducted to study the operating characteristics of the harmonic mean Chi-squared test and two-trials rule in more detail. We finally investigate the applicability of these two methods to compute the power at interim of an ongoing post-market trial. These results are expected to aid in the design and assessment of the required post-market studies in terms of the level of evidence required for full approval.
翻译:欧洲药品署(欧洲药品署)或加速(美国食品和药品管理局)批准药物,可以提前获得有希望的新治疗,满足未得到满足的医疗需要。某些后销售要求通常必须满足,才能获得完全批准,例如进行新的市场后临床试验。我们研究最近开发的口音中奇夸德测试是否适用于这一有条件或加速批准框架。拟议的方法既可用于支持后市场试验的设计,也可用于分析两次试验提供的综合证据。考虑的其他方法包括两审判规则、Fisher的标准和Stouffer的可适用性方法。与某些传统方法不同,协调意味着Chi-squared测试总是需要市场后临床试验。如果市场前临床试验的p-价值为0.025,那么后市场临床试验的样本规模可以比两审判规则的样本要小。我们用“口方表示”测试方法来测试一种在两审判后市场设计中获得有条件的药物(以及后来的完全适用性)市场许可。在EMA进行的两个规则的预测性详细的市场试验研究中,我们对这些规则的预测性规则的预测性规则的市场试验的预测性详细研究,就是进行中进行这种试验的双重判断性规则的市场后检验。