BACKGROUND: The role of harmonized European standards (HES) is key in the certification of medical devices (MD) in the European Union. When the product is designed and manufactured according to applicable HES, it can benefit from a presumption of conformity (MDCG 2021-5). HES are considered as reflecting the state-of-the-art in the corresponding medical field.

OBJECTIVES: To perform a systematic review to identify guidance on the design, analysis, and reporting of confirmatory pivotal clinical trials for high-risk MD, from the International Standardization Organization (ISO).

METHODS: We included general ISO standards on MD as well as device-specific standards on high-risk cardiovascular, orthopedic, and diabetes MD, if they contained substantial information on clinical investigations.

RESULTS: Twelve ISO standards published between 2016 and 2021 were included: Three relate to MD in general, nine to cardiovascular implants. ISO 14155:2020 on good clinical practice for clinical investigations of MD does not provide a hierarchy of evidence levels by study designs. The recommendation for the choice of study design for a pivotal trial is to derive it from the clinical evaluation necessary to prepare the study. Recommendations are very general and rarely study type specific. The device-specific standards covered heart valves (n=4) and coronary stents (n=5). All heart valve and one other implant standard recommend randomized controlled trials and distinguish between novel and well-established MD. Four standards recommend as a minimum multi-center trials with at least 3 sites and a control group. ISO standards do not report the methods how recommendations were developed. It is unclear, how the state-of-the-art in the medical field is considered.

CONCLUSIONS: Recommendations on the design of pivotal clinical trials for cardiovascular high-risk MD are heterogeneous. Given the importance of ISO standards for the certification of MD, the methods for their development should be explicit, transparent, and based on science.