A clinical investigation can be well managed, completed according to plan and still leave the manufacturer with an uncomfortable question:
Did we actually generate the evidence we need?
For medical device companies, the purpose of a clinical investigation is not simply to complete a study. The resulting data need to support the wider clinical and regulatory strategy of the device.
Under the EU MDR, clinical evaluation must provide sufficient clinical evidence to support conformity with the relevant safety and performance requirements, and the required level of evidence needs to be appropriate for the characteristics and intended purpose of the device.
When new clinical data are needed, the clinical investigation therefore needs to be designed with the eventual clinical evaluation in mind.
This connection between clinical investigation and Clinical Evaluation Report (CER) should begin long before the first patient is enrolled.
Start with the questions the clinical evaluation needs to answer
Clinical evaluation is not something that starts once the clinical investigation has finished.
The MDR requires manufacturers to plan clinical evaluation around areas including the device’s intended purpose, target patient groups, intended clinical benefits, relevant clinical outcome parameters, safety, benefit-risk considerations and the overall clinical development plan.
These are also exactly the questions that should influence the clinical investigation.
What clinical benefit are we trying to demonstrate? Which claims require clinical support? In which patients? Compared with what current clinical practice? What outcomes would meaningfully demonstrate performance or safety?
If those questions are unclear at the clinical evaluation level, it becomes difficult to design a study that will answer them.
The clinical investigation should therefore be viewed as part of the clinical evidence strategy, not as a separate project that happens to produce data.
Intended purpose and claims need to stay connected to the study
One of the most important links between clinical evaluation and clinical investigation is the manufacturer’s claims.
The MDR requires clinical investigations used for conformity assessment to be designed to confirm or refute claims regarding the device’s safety, performance and benefit-risk profile.
MDCG guidance on Clinical Investigation Plan content similarly states that the objectives of the investigation should describe the claims for clinical performance, effectiveness or safety that are intended to be verified.
This sounds straightforward, but it has significant practical implications.
If the intended purpose says the device is intended to provide a particular clinical benefit, the study needs to generate evidence relevant to that benefit. If the manufacturer intends to make specific performance claims, the endpoints and methodology need to support them.
A successful study of a slightly different question may still produce scientifically interesting results, but those results may have limited value in supporting the intended regulatory claim.
That is why clinical, regulatory and product-development teams should be aligned before the protocol is finalised.
Endpoints determine what the study can ultimately demonstrate
Choosing endpoints is one of the clearest examples of why regulatory planning needs to happen before clinical execution.
An endpoint may be easy to measure and statistically convenient, but that does not automatically make it the right endpoint for the clinical evaluation.
The manufacturer needs to consider whether the selected outcomes actually demonstrate the intended clinical performance or benefit of the device and whether they are meaningful in relation to the current state of the art.
This becomes particularly important when surrogate endpoints or intermediate outcomes are used.
The question is not simply whether the study can demonstrate a statistically significant result. It is whether that result supports the clinical conclusions the manufacturer ultimately needs to make about the device.
Changing the interpretation afterwards can be difficult. Once patients have been enrolled and the data have been collected, there are limits to what can be recovered from a study that was designed around the wrong question.
The patient population also matters
The same principle applies to the population included in the investigation.
The patients studied should be relevant to the intended population of the medical device.
If the intended use covers a particular indication, severity of disease, age range, anatomical situation or clinical environment, the clinical investigation needs to provide evidence that can reasonably support conclusions for that use.
A narrowly selected investigation population may produce very clean data but leave questions about whether the results can be generalised to the intended users or patients.
At the opposite extreme, a very heterogeneous population can sometimes make it difficult to demonstrate a clear effect.
These are clinical design decisions, but they are also regulatory decisions because they influence what conclusions can ultimately be drawn in the CER.
Consider the state of the art before designing the investigation
Clinical evaluation also places the device within the context of current medical knowledge and available treatment alternatives.
This means the clinical investigation should not be designed in isolation from the state of the art.
Understanding current therapies, comparable devices, expected clinical outcomes, known complications and relevant performance benchmarks can help determine what the investigation should actually demonstrate.
This work can influence comparator selection, endpoints, acceptance criteria, follow-up periods and the interpretation of safety and performance outcomes.
It is therefore valuable to begin the literature and state-of-the-art work early enough that it can inform the study rather than merely being added to the CER after the investigation has already been completed.
Study design should follow the clinical development strategy
The MDR expects the Clinical Evaluation Plan to include a clinical development plan describing progression from exploratory investigations through confirmatory investigations and into PMCF, including relevant milestones and acceptance criteria.
A clinical investigation should therefore have a clear place within that wider development programme.
- Is it an early feasibility investigation?
- Is it intended to provide pivotal evidence for conformity assessment?
- Is the purpose to confirm a specific safety or performance question?
- Is it a post-market investigation intended to address a residual evidence gap?
The answer affects the level and type of evidence expected from the study.
MDCG guidance also states that the justification for the design of a clinical investigation should be based on the conclusions of the clinical evaluation and should explain where the investigation fits within the clinical development of the device.
This creates an important two-way relationship:
The clinical evaluation helps define what the investigation needs to answer, and the investigation then generates new evidence that feeds back into the clinical evaluation.
Good study design is only useful if the evidence remains reliable
Generating useful evidence also depends on how the investigation is executed.
Once the study begins, monitoring, data management, documentation, protocol compliance and site communication all contribute to whether the resulting dataset can support reliable conclusions.
Protocol deviations, missing data, inconsistent procedures or unresolved site issues can weaken otherwise well-designed evidence.
This is where CRO project management and monitoring connect directly with regulatory strategy.
Monitoring is not simply about checking that the study is progressing. It helps protect the integrity of the evidence that will later be used to support conclusions about device safety and performance.
A strong connection between the sponsor, investigators, monitors and regulatory team also makes it easier to recognise emerging issues that could affect the eventual clinical evaluation.
The Clinical Investigation Report is not the end of the process
At the end of the investigation, the results are documented and analysed in the Clinical Investigation Report.
But from the manufacturer’s regulatory perspective, that is not the final destination of the evidence.
The results need to be interpreted within the wider clinical evaluation.
- How do they compare with the existing literature?
- Do they support the intended clinical benefits?
- Were previously identified clinical evidence gaps addressed?
- Did the investigation reveal new risks or undesirable effects?
- Does the benefit-risk conclusion remain acceptable?
- Are additional data still needed through PMCF?
Under the MDR, the manufacturer is expected to analyse all relevant clinical data in order to reach conclusions about the safety, clinical performance and clinical benefits of the device.
The CER is where the new investigation results are placed into that broader context.
A positive study result therefore does not simply get inserted into the CER. It needs to be critically evaluated alongside the rest of the available evidence.
Clinical evidence continues after market entry
The relationship between clinical investigation and clinical evaluation also continues after CE marking.
Clinical evaluation is an ongoing process, and PMCF is used to proactively collect and evaluate clinical data from the use of a CE-marked device.
The MDR requires the findings from PMCF to be documented in the PMCF Evaluation Report and incorporated into the clinical evaluation and technical documentation.
This is another reason to think in terms of a clinical evidence lifecycle rather than individual documents.
The CEP, clinical investigations, CER, PMS and PMCF should not become isolated activities managed separately from one another. They should continually inform the same overall understanding of whether the device remains safe, performs as intended and provides the expected clinical benefit.
Design the investigation for the evidence you will eventually need
Clinical investigations require significant time, money and coordination.
That makes it especially important to ask the right questions before the protocol is finalised.
What does the clinical evaluation still need to demonstrate? Which claims require additional evidence? Is the population representative of the intended use? Are the endpoints clinically meaningful? Does the follow-up period allow the relevant benefits and risks to be observed? How will the resulting evidence fit alongside the literature, risk management and existing clinical data?
These are not questions for the CER writer to solve after the investigation has finished.
They belong at the beginning of the clinical strategy.
At MDS, our clinical and regulatory teams work across both sides of this process. We support clinical evaluation and evidence planning as well as Clinical Investigation Plan development, regulatory submissions, study project management, monitoring and clinical reporting.
Connecting these activities from the beginning helps ensure that a clinical investigation does more than produce data.
It produces evidence that the manufacturer can actually use.
If you are planning a clinical investigation, reviewing your clinical evidence strategy or updating a CER, MDS can help align the clinical work with the regulatory questions your device needs to answer.
You can contact us at sales@mdsfinland.com or via Book a Meeting.
