Background:
Newly emerging products which combine drugs, devices, and biologics are expected to provide new opportuni- ties in bridging device and drug capabilities and establish synergies while bringing sophisticated combination products to consumers. The emergence of these novel products has triggered new regulatory, strategic, and technological challenges. While progress has been made at clarifying the issues that arise most frequently, regulatory authorities and product developers continue to struggle with complex regulatory and technical issues encompassing the development programs for combina- tion products. A risk-based approach requires not only a strategy but also tools to define key indicators to measure specific risks. Key risk indicators (KRIs) and risk-based quality management systems should focus on safety of research subjects and data integrity.
Methods:
We analyzed current regulatory guidelines throughout the life cycle of combination products and compared old and new approaches to risk-based quality and compliance management for current good manufacturing practices and during pre-clinical and clinical phases of combination products development. Cause–effect analysis for two major risk categories in clinical trials with combination products was performed.
Results:
The results of our analysis are based on observations from 15 clinical trials, which were conducted with combination products. Based on our findings, we proposed practical recommendations for the development of KRIs to improve conduct and ensure safety of research subjects in trials with combination products by utilizing risk-based quality management approach. 
Conclusion:
Combination products, due to their specific nature, can increase risks while being tested in clinical trials. Metrics critical to risks and quality management should be linked to particular processes within development program for combination products. Ongoing collaboration between regulators, industry, and other stakeholders is essential to streamlining of the global combination entities development and approval process in a way that will produce safe and effective products for consumers.

Risk-Based Quality and Safety Management in Clinical Trials with Combination Products in Global Regulatory Environment.