Clinical investigations are defined within both FDA and EU MDR as the systematic investigation involving one or more human subjects, undertaken to collect data and assess the safety or performance of a device. Using the clinical data to demonstrate that the device meets the safety and effectiveness considerations is an important step in the device lifecycle.
Here, we will look at some of the differences between FDA and EU MDR process and requirements for clinical investigations.
Establishing clinical equivalence against a similar device allows manufacturers to use existing clinical data to evaluate the device’s safety and effectiveness, removing the need for an in-depth clinical investigation.
EU MDR’s definition for equivalence is more rigid than that of FDA. Clinical equivalence is justified under EU MDR only if the similar device is reviewed to deliver similar critical performance:
- expected clinical effect,
- specific intended purpose,
- duration of use, etc
And the device is to be used for the same:
- Clinical condition or purpose – similar severity and stage of disease.
- Intended purpose – professional use, home use, etc.
- Site/location in the body
- Population – age, gender, anatomy and physiology
On top of these requirements, EU MDR also requires manufacturers to demonstrate technical and biological equivalence in addition to clinical equivalence, to justify usage of the same data. Due to these rigid requirements, it is often impossible for manufacturers to establish equivalence unless the similar device is owned by them.
Exceptions under EU MDR apply for devices that have been CE marked and placed on the market under MDD. For such devices, a Post-Market Clinical Follow-Up (PMCF) investigation is conducted. PMCF allows manufacturers to collect data from the device use in the market under the intended condition, and establish safety and effectiveness. However, there are some limitations to using this pathway.
FDA allows manufacturers to claim substantial equivalence for some devices under premarket notification submission eliminating the need for an in-depth clinical investigation. Substantial equivalence is to be established with respect, but not limited to, intended use, design, energy transfer, performance, safety, effectiveness, labeling, biocompatibility, standards, and other characteristics. Manufacturers are required to effectively address the differences between the similar device and their device and justify that the differences do not compromise device safety and effectiveness. However, Class III devices will almost always require a clinical investigation unless equivalence can be established with a device that was in the market prior to the Medical Device Amendments (1976).
Changes to Clinical Investigation
In some cases, ongoing clinical investigations may require a change to the plan or conditions. A major or substantial1 change to the clinical investigation should be communicated to the regulatory body.
FDA identifies major changes to the clinical investigation for changes related to indication, study control, primary endpoint variable, sample size, method of estimation and early termination.
FDA and/or IRB approval2 is required for implementation of major changes in the clinical investigation. For IDE, some developmental device changes may be implemented without prior notification. Deviations from the plan to protect the life or physical well-being of a subject in an emergency are allowed to be implemented without prior notification. In such cases, the manufacturer needs to submit a notice of change or modification within 5 days of implementation.
EU MDR defines substantial change as one that has a high impact on one or both of the following:
- Safety or health or rights of the subject
- Robustness or reliability of the clinical data generated by the investigation.
In cases where the design or scientific outcomes of the clinical investigations may be seriously impacted, manufacturers should evaluate if there is a need to initiate a new investigation.
Unlike FDA, EU MDR allows implementation of substantial changes once the deadline has expired, if there is no notification from the Competent Authority3. The Competent Authority has 38 days to respond to the change notification submitted by the manufacturer and may request a 7-day extension. Upon the expiration of this deadline, the manufacturer may implement the changes to the ongoing clinical investigation.
Clinical Investigation Monitoring
Clinical investigations are to be monitored to ensure that the investigation activities are being carried out as planned. A risk-based approach to monitoring clinical investigations is a common theme with both FDA and EU MDR. A monitoring plan is included in the clinical investigation plan that is submitted to the regulatory body during the application process. The clinical investigation report compiled at the end of the investigation is required to have the results of the executed monitoring plan.
In cases where the clinical investigation takes longer than one year, the IRB and FDA require manufacturers to generate an annual summary report of the investigation and the progress, even if there is no change to the clinical investigation plan. In case there are any minor changes to the investigation plan, the changes shall be summarized in this report.
However, with EU MDR, there is no requirement to submit progress reports if there are changes to the clinical investigation plan. This requirement under EU MDR is subject to change with the implementation of EUDAMED, which will allow manufacturers to keep the database updated.
In addition to the notifications discussed in the previous sections, manufacturers are also required to notify the regulatory body when the clinical investigation has ended.
EU MDR and FDA (in some cases) require manufacturers to issue a notification and submit the clinical investigation report after the completion or termination of the clinical investigation. The differences in the requirement appear in timelines. See Table 1 below for a summary of the timelines.
|FDA (if requested)||EU MDR|
|Completion of clinical investigation – notification||30 working days||15 days|
|Clinical investigation report||6 months||One year|
|Termination of the clinical investigation – notification||30 working days||None – clinical investigation report is to be submitted|
|Termination of the clinical investigation – notification||30 working days||3 months|
Table 1: Timelines for notifications and reporting the end of clinical investigations.
While this is not an exhaustive list of the differences between FDA and EU MDR Clinical Requirements, it highlights some of the main differences to consider when developing Clinical investigations for both FDA and EU MDR.
Acronyms and Notes:
EU MDR: European Medical Device Regulations
EUDAMED: European Database on Medical Devices
FDA: Food and Drug Administration
IRB: Investigation Review Board
1 FDA categorizes changes to be either minor or major. EU MDR categorizes changes to be either substantial or non-substantial.
2 FDA approval is required for changes that may affect the scientific soundness of the clinical investigation. Both FDA and IRB approval is required for changes that involve the rights, safety or welfare of subjects.
3 Competent Authority is a body with authority to act on behalf of the government of the member state to ensure that the Medical Devie Requirements are transposed into National Law and are applied.
Image: iStock Photo
Dhruvitha Krishna is a QA/RA Specialist at StarFish Medical with a M.S degree in Biomedical Engineering. She has worked in manufacturing, new product implementation, software deployment, project management and regulatory areas in medical device companies. Dhruvitha is dedicated to quality, regulatory and continuous process improvement for the manufacturer.