Cole Susan, Pertinez Henry, Butler Andrew S, Kerwash Essam, Bhat Swati, El-Khateeb Eman, Owen Andrew
Medicines and Healthcare Products Regulatory Agency, Canary Wharf, London E14 4PU, UK.
Centre of Excellence for Long-Acting Therapeutics University of Liverpool, Liverpool L69 3BX, UK.
Pharmaceuticals (Basel). 2024 Dec 6;17(12):1640. doi: 10.3390/ph17121640.
The development of long-acting products of a characterized drug substance is of great interest. It is possible to support the development of these products with available clinical data by matching the exposure to a predefined bracket of a minimal concentration for efficacy and a maximal concentration for safety. This bracketing approach would cut down on the time and cost of new long-acting contraceptive products progressing to market. The current study describes the assessment of the data available to support a bracketing approach to conclude comparable levels of efficacy and safety for a postulated novel long-acting reversible contraceptive (LARC) product of levonorgestrel.
Literature evidence of levonorgestrel efficacy, as quantified by the Pearl Index, was utilized and modeled by incorporating three LARC products for the estimation of a minimal concentration required for efficacy. Further literature was reviewed to quantify the maximal concentration required to ensure product safety. Additionally, a review of the regulatory precedence for the approach was conducted using European and UK databases.
There was a reasonable definition of the minimal concentrations for efficacy where the target concentrations of levonorgestrel were in the range of 200-400 pg/mL. Maximum concentrations for safety were less well defined. Although regulatory guidance supports the bracketing approach, there is little precedence for licensing new products based on pharmacokinetic data only, despite much reduced clinical and non-clinical packages being evidenced.
Understanding of the exposure response is not currently considered sufficient to support a bracketing approach for a new levonorgestrel product. If additional safety data are established, current regulations may allow for a reduced application package. Additional work is needed to support the approach, and this could utilize the wealth of information in real-world datasets combined with systems models.
开发具有特定特征的药物的长效产品备受关注。通过将暴露量与预定义的疗效最低浓度范围和安全性最高浓度范围相匹配，利用现有临床数据来支持这些产品的开发是可行的。这种分组方法将减少新型长效避孕产品进入市场的时间和成本。本研究描述了对现有数据的评估，以支持采用分组方法来推断假定的新型左炔诺孕酮长效可逆避孕（LARC）产品具有可比的疗效和安全性水平。
利用以Pearl指数量化的左炔诺孕酮疗效的文献证据，并通过纳入三种LARC产品进行建模，以估计疗效所需的最低浓度。进一步查阅文献以量化确保产品安全所需的最高浓度。此外，使用欧洲和英国数据库对该方法的监管先例进行了审查。
对于疗效的最低浓度有合理的定义，左炔诺孕酮的目标浓度范围为200 - 400 pg/mL。安全性的最高浓度定义不太明确。尽管监管指南支持分组方法，但仅基于药代动力学数据批准新产品的先例很少，尽管有证据表明临床和非临床资料包已大幅减少。
目前认为对暴露反应的了解不足以支持对新的左炔诺孕酮产品采用分组方法。如果建立了更多的安全性数据，现行法规可能允许减少申报资料包。需要开展更多工作来支持该方法，这可以利用真实世界数据集中的丰富信息并结合系统模型。
