Desborough Lane, Jaffe Karen, Hanna Joseph, Ulloa Johanna, Kaiserman Kevin
Nudge BG, Inc., 725 Old Farm Road, Thousand Oaks, CA, 91360, USA.
MannKind Corporation, 30930 Russell Ranch Road Suite 300, Westlake Village, CA, 91362, USA.
Ann Biomed Eng. 2023 Jan;51(1):137-149. doi: 10.1007/s10439-022-03062-4. Epub 2022 Sep 7.
Computer Modeling and Simulation (CM&S) provides the opportunity to drastically reduce clinical trial patient burden and advance regulatory decision making. At the suggestion of the US Food and Drug Administration (FDA), MannKind Corporation and Nudge BG submitted an application to the FDA Model-Informed Drug Development (MIDD) pilot program to support a label change for the initial dose of Afrezza® (insulin human), a novel inhalable insulin with a rapid pharmacokinetic and pharmacodynamic profile. The MIDD pilot program demonstrates the FDA's commitment to advancing regulatory science through the adoption of evidence generated by CM&S. A simulation framework was developed based on empirical data. It was used to generate evidence to support the label change. Briefing packages and presentations were prepared for two meetings with the FDA, over a period of four months. The model was thoroughly characterized, determined to be low risk for the question of interest, and submitted along with additional clinical evidence for validation. The FDA found the simulation framework to be helpful in providing insights into the question of interest and provides reasonable glycemic outcome predictions. At the conclusion of the MIDD paired meetings, FDA personnel from the Center for Drug Evaluation and Research review team accepted the simulation and requested additional, traditional clinical evidence to support the proposed label change. In the post-meeting comments, the FDA invited MannKind to submit a proposal for a data package including the CM&S evidence in a Type C meeting for further discussion on the label change. This MIDD pilot experience suggests that CM&S is a credible method for evidence generation. Collaboration between sponsor organizations as well as all stakeholders in the FDA, including proponents of CM&S, can further support regulatory decision-making. The learnings from early participants will allow the program to reach its full potential and thereby ultimately benefit patients, sponsors, and FDA.
计算机建模与模拟（CM&S）为大幅减轻临床试验患者负担及推动监管决策提供了契机。在美国食品药品监督管理局（FDA）的建议下，曼金德公司（MannKind Corporation）和努吉BG公司（Nudge BG）向FDA的模型 informed 药物开发（MIDD）试点项目提交了一份申请，以支持对 Afrezza®（人胰岛素）初始剂量进行标签变更，Afrezza®是一种具有快速药代动力学和药效学特征的新型吸入式胰岛素。MIDD 试点项目展示了FDA通过采用CM&S产生的证据来推进监管科学的决心。基于经验数据开发了一个模拟框架。该框架用于生成支持标签变更的证据。在四个月的时间里，为与FDA的两次会议准备了简报包和演示文稿。对该模型进行了全面的特征描述，确定其对于所关注的问题风险较低，并与其他临床证据一同提交以进行验证。FDA发现该模拟框架有助于深入了解所关注的问题，并能提供合理的血糖结果预测。在MIDD配对会议结束时，来自药物评价和研究中心审查团队的FDA人员接受了该模拟，并要求提供更多传统临床证据来支持拟议的标签变更。在会后评论中，FDA邀请曼金德公司在C类会议上提交一份数据包提案，包括CM&S证据，以便就标签变更进行进一步讨论。这次MIDD试点经验表明，CM&S是一种可靠的证据生成方法。申办组织以及FDA的所有利益相关者之间的合作，包括CM&S的支持者，能够进一步支持监管决策。早期参与者的经验教训将使该项目充分发挥其潜力，从而最终使患者、申办者和FDA受益。
