A clinical investigation costing millions wasted: Why can EU clinical evaluation cause the entire effort to fall short?

Recently, manycompanieshave approached us saying that they spent several million on a clinical investigation, only to face repeated challenges and major difficulties when applying for EU clinical evaluation.

Business is already challenging enough. If a company invests several million in a clinical investigation only to be blocked at the clinical evaluation stage, it is understandably frustrating. However, this is the reality of medical-device regulatory requirements, and it cannot be ignored. In fact, many of these pain points and potential risks can be mitigated through early planning. Given the time and capital required for a clinical investigation, the burden on a company is substantial,Today, I would like to share some of the key pain points and challenges involved, in the hope of giving companies and industry peers some useful perspective and helping them avoid detours and unnecessary costs.

1. First, let us look at, in the EU clinical evaluation process,which aspects of clinical investigations are most frequently challenged：

A. The endpoints of the clinical investigation are disconnected from the State of the Art (SOTA) in EU clinical evaluation (safety and performance outcome parameters & acceptance criteria). 

This is the most fundamental issue and also the aspect most frequently challenged. The reason is that, during the clinical investigation stage, most companies have not yet taken the requirements of EU clinical evaluation into account,and they have not "built in" the core SOTA requirements for clinical evaluation in advance during the clinical investigation process, resulting in a disconnect between the completed clinical investigation results and the clinical evaluation, making it impossible to map the clinical investigation results that cost several million to support SOTA-based safety and performance in the clinical evaluation. This is where many companies are caught off guard, so the best solution is to ensure that, before initiating a clinical investigation,the requirements of EU clinical evaluation are incorporated into the clinical investigation process as early as possible, which sounds straightforward, but there are still many practical challenges involved.

B. The completed clinical investigation did not take ISO 14155 requirements into account, including alignment with EU clinical investigation expectations and the European population, so the results lack representativeness and coverage。

Items that generally need to be considered in advance or included in a GAP analysis include, but are not limited to, the following (these should be assessed based on whether the target device may be affected by such differences):

Ethics, informed consent (ICF), and ethics committee approval (EC, IRB) procedures versus EU requirements (differences may exist)
Risk management and adverse event (AE, device deficiency) reporting mechanisms are inadequate or insufficiently transparent, with incomplete historical records
Data integrity, quality, monitoring, and audit mechanismsNon-compliance with GCP/ISO 14155 requirements (for example, lack of monitoring, audit trail, source data, or robust data management)
Ifthe study population differs too greatly from the EU target population (in terms of its social context, medical practice (standard of care), and patient population (body habitus (weight, height, BMI), race, comorbidities, lifestyle), and clinical environment (hospital type, standard of care, epidemiology, clinical procedures, standards of medical practice, user training, patterns of use, comorbidity profile), it may still be considered “insufficient to demonstrate safety and effectiveness in the EU population,” including with respect to the specific indication, use environment, and users (patients, healthcare institutions, and healthcare professionals).
The statistical design, analysis, and reporting (sample size, endpoints, follow-up, subgroup analysis, missing data, dropouts, deviations) may also lack sufficient rigor, transparency, and completeness,if the clinical investigation design (methodology, sample size, endpoints, data quality) does not meet EU standards (e.g., bias, inadequate statistical rigor, insufficient monitoring), it may still be rejected even if the data volume is large.
Lack of post-market data, PMCF, long-term follow-up, and real-world data (RWD) is another concern—particularly for high-risk or innovative devices.
Documentation (CIP, IB, CRF, CIR, source data, monitoring records, audit logs, AE reports, device deficiency reports) may be incomplete or fail to meet EU or international requirements for standards, language, and format.

C. There are two additional points that many companies easily overlook: reviewers often pay close attention to whether your clinical investigation has beenregistered on a public platform, and whether your clinical investigation hasAny pubulication? Consider the rationale behind why reviewers ask these two questions.

D. Finally—the real “test of truth”—is to compare the clinical investigation results against the Acceptance Criteria defined by the State of the Art (SOTA), also referred to as thresholds, through a comparative analysis,only if the safety and effectiveness endpoints of the clinical investigation can meet Acceptance Criteria based on SOTA, can it be demonstrated that the device's safety and effectiveness are adequately supported by the clinical investigation data and results.

E. Do not forget: demonstrating the device's Clinical Safety and Performance alone is not enough; measurable or quantitative parameters must also be used to APPROVE Intended Clinical Benefits which Claimed by Manufacture.

So, in closing: the success or failure of EU medical device clinical compliance does not hinge on the clinical investigation, but on the clinical evaluation!