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\begin{document}

\title{Question-based development of high-risk medical devices: A proposal for
a structured design and review process.}



\author[1]{Nicholas White}%
\author[2]{Joric Oude Vrielink}%
\author[2]{Koen van der Bogt}%
\author[3]{Adam Cohen (EMA-commentaries only)}%
\author[2]{Joris Rotmans}%
\author[1]{Tim Horeman}%
\affil[1]{Delft University of Technology}%
\affil[2]{Leiden University Medical Center}%
\affil[3]{Centre for Human Drug Research}%


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  \date{March 14, 2025}


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\begin{abstract}
The recent introduction of the European Medical Device Regulation poses
stricter legislation for manufacturers developing medical devices in the
EU. Many devices have been placed into a higher risk category, thus
requiring more data before market approval, and a much larger focus has
also been placed on safety. For implantable and Class III devices, the
highest risk class, clinical evidence is a necessity. However, the
requirements of clinical study design and developmental outcomes are
only described in general terms due to the diversity of devices. A
structured approach to determining the requirements for the clinical
development of high-risk medical devices is introduced, utilising the
question-based development framework, which is already used for
pharmaceutical drug development. An example of a novel implantable
device for haemodialysis demonstrates how to set up a relevant target
product profile defining the device requirements and criteria. This can
then be used to define specific questions to be answered during clinical
development, based upon 5 general questions as specified by the
question-based framework. The result is a clear and evaluable overview
of requirements and methodologies to verify and track these requirements
in the clinical development phase. Development organisations will be
guided to the optimal route, also to abandon projects destined for
failure in an early stage to minimise development risks. Moreover, the
framework facilitates communication with funding agencies, regulators
and clinicians, while highlighting remaining ``known unknowns'' that are
to be answered in the post-market phase after sufficient benefit has
been established relative to the risks.%
\end{abstract}%



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