In December 2016, the United States Congress passed the 21st Century Cures Act to accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently. For implementation of the 21st Century Cures Act, the FDA has kicked off several critical clinical initiatives to accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently. These critical clinical initiatives include (i) complex innovative design (CID), (ii) model-informed drug development (MIDD), (iii) biomarker-development, (iv) real-world data (RWD) and real-world evidence (RWE), (v) artificial intelligence (AI) and machine learning (for imaging medicine and mobile individualized medicine), (vi) flexible and efficient assessment of biosimilar products, (vii) statistical methods for complex generic drug products, (viii) patient-based risk assessment, (ix) big data center and analytics, and (x) rare diseases drug development. In practice, however, controversial and/or challenging issues are inevitably encountered during the implementation of these critical clinical initiatives. This presentation is multi-fold. First, several controversial and challenging issues that are commonly encountered in the review and approval process will be identified. Second, I will focus on statistical methodology development for implementation of these critical clinical initiatives.