Clinical Investigations: Requirements and strategy
May 04, 2023
For all clinical investigations starting after May 26, 2021, the stricter requirements of the MDR, compared to the MDD, apply. These requirements are outlined in Articles 62 to 82 and Annex XV. Like the MDD, the MDR fundamentally distinguishes between clinical investigations conducted before and after a device’s CE marking. Investigations conducted after CE marking are further divided into those within the established intended purpose and those aimed at expanding or modifying the intended purpose.
Clinical Investigations: Clinical Data in the MDR
Due to the stricter requirements for clinical data and the equivalence approach for demonstrating safety and performance in clinical evaluation, the need for clinical investigations under the MDR is expected to increase significantly. For implantable devices and Class III devices, it will be mandatory, with few exceptions, to demonstrate the safety and performance of the device with clinical data generated with the device itself (Article 61 MDR).
Clinical Data: The Equivalence Approach
If the equivalence approach is pursued, according to MDR and MDCG 2020-05, sufficient clinical evidence and access to the data of the equivalent devices must be available. In addition to MDCG 2020-05 on equivalence, MDCG 2020-06 on the transfer of clinical data from the MDD era should be consulted to determine the necessity of clinical investigations in individual cases. MDCG 2020-05 sets high requirements for the equivalence of two devices, a standard that was already raised under MDD with Revision 4 of MEDDEV 2.7/1. In certain aspects, the MDR has somewhat relaxed these requirements compared to MEDDEV, as seen in the use of the terms "similar" and "same" in Annex 1 of MEDDEV 2.7.1 and Annex XIV, number 3 of the MDR. MDCG 2020-06 aims to prevent the need for repeated clinical investigations for Class III devices already marketed under the MDD, though this is not always successful since old MDD-compliant clinical data may not meet MDR requirements.
Clinical Data: Legacy Devices
Open questions remain for devices whose previous approach to demonstrating safety and performance no longer meets MDR requirements. Particularly for established devices, conducting a clinical investigation may be impossible due to likely ethics committee disapproval. In other cases, efficacy and performance may be sufficiently demonstrated, but data for specific age groups may be lacking. Depending on the intended age group, generating this data can be challenging. With long market experience, such gaps may sometimes be addressed with existing PMS data. In some cases, data on mechanisms of action can be generated in vitro or ex vivo, especially for material-based medical devices, whose mechanisms often involve forming a protective film, neutralizing stomach acid, or employing other physical or chemical principles.
The Clinical Investigation in the Product Lifecycle / Development Process
When clinical data need to be generated, this can occur at various stages of a medical device's lifecycle. During device development, any gaps should be documented in the clinical development plan, along with strategies for addressing them. During the conformity assessment process, a traditional clinical investigation can be conducted before CE marking. The general requirements for the application, approval, and conduct of clinical investigations before CE marking are regulated by Articles 70 to 72. A simplified procedure exists for investigations of devices within the scope of post-market clinical follow-up (PMCF), provided the investigation is conducted within the intended purpose (Article 74). If the investigation aims to expand or change the intended purpose, the same requirements as for investigations to obtain CE marking apply. In addition to MDR specifications, national requirements must also be considered. Further guidance and requirements for planning and conducting investigations can be found in guidelines or standards such as EN ISO 14155, Good Clinical Practice, the Declaration of Helsinki, and MDCG 2020-10/1.
Post Market Clinical Follow-Up: Collecting Clinical Data
The MDR generally requires the systematic collection of PMCF data for all devices. It is important to note that collecting PMCF data does not necessarily equate to conducting a clinical study. Under the MDD, MEDDEV 2.12/2 rev2, section 5, stated that a clinical investigation for collecting PMCF data could be waived under certain circumstances, such as when the device's safety and performance are sufficiently demonstrated or when sufficient data can be obtained through other market surveillance methods. Although MEDDEV documents are no longer valid under the MDR, it is assumed that this principle still applies. Based on this, PMCF data can be collected through the analysis of registries and databases, user surveys, and the evaluation of complaints/vigilance cases. The reasons for collecting PMCF data via a clinical investigation are diverse, and may include new insights from market experience, device changes, new information about similar devices, or marketing aspects. Regardless of how PMCF data are collected, it is crucial that data collection is systematically planned, conducted, and evaluated in advance. Otherwise, the dataset's significance may be compromised, necessitating further data collection.
Other Clinical Investigations
Article 82 of the MDR defines the requirements for other clinical investigations for the first time. These are studies not conducted for purposes defined in Article 62. According to the definition in §3 of the MPDG, other clinical investigations are primarily studies aimed at answering scientific questions. They are not part of device development or manufacturer product monitoring and are not conducted to demonstrate conformity with the MDR. Nor are they part of the clinical development plan under Annex XIV of the MDR. These investigations are mainly for researching new therapeutic approaches.
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