The conduct of Clinical investigations, or Clinical trials involving investigational devices, is another area in which the new European Union Medical Device Regulation (EU MDR) brings current Medical Device Directive (MDD) up to date.  Not only up to date with the European Authorities current expectations for the conduct of clinical investigations, but also brings the European Union requirements into line with the requirements for clinical trials involving investigational devices elsewhere in the world.

The MDD’s sole article on the subject, Article 15 “Clinical investigation” is replaced by twenty articles in new EU MDR, Articles 62 through 82. This global alignment extends to both the requirements and the terminology. For example, the requirements in the new EU MDR are addressed to the “Sponsor”, not the “Manufacturer” as is currently the case in MDD. While the MDD’s current requirement to “notify” the Health Authorities of an intention to perform a clinical investigation, is being replaced with the requirement to submit an application to conduct a clinical investigation. However, for lower risk devices the sponsor can still proceed to start the investigation if the application is not refused. Meaning that in practice, at least for developers of lower risk devices, the new application procedure is unlikely to result in any new delays to starting clinical investigations in the EU.

The new EU MDR Articles 62 through 82 address all the familiar topics related to clinical investigations; the need for informed consent, considerations for vulnerable populations, the application process, requirements for the conduct of the investigation, Adverse Event reporting etc. But while the majority of the requirements are new for clinical investigations conducted in the European Union, sponsors conducting investigations in other regions will find no surprises in these new Articles.

While the new Articles 62 through 82 describe “what” is required, they must be read in conjunction with the more detailed “how” to do of the new Annex on “Clinical investigations”, Annex XV. The new Annex XV updates and extends part 2. of the current MDD’s Annex X “Clinical evaluation”. This new and expanded Annex XV specifies the information to be considered in; (a) the Clinical Investigation Application form, (b) the Investigator’s Brochure, (c) the Clinical Investigation Plan, (d) Sponsors obligations and (e) the Clinical Investigation Report. However, the new MDR’s Annex XV is still far less specific than either ISO14155 or ICH GCP. It therefore appears to be setting only the minimum requirements for conducting clinical investigations in the EU.  Meaning that sponsors should still anticipate that the Authorities will judge their applications by the higher standards of ISO14155 or ICH GCP.

6 thoughts on “Clinical investigations compared to the MDD”

  1. Thank you for claification. I wonder, in the US it is very clear which medical device being in need of clinical investigation (and not only clinical evaluation). In the EU I feel that the requirements on WHICH product has to go through clinical trial is vague. Are there any formulated classifications on which group of products being in need of trials, and when a product can be exempt from the requirement..?
    Thank you,
    Jenny

    1. Thank you for your question. In the EU, the decision whether or not a clinical investigation is required is, in the vast majority of cases, determined by the adequacy of the available clinical data and not by the device class.

      You are probably aware but it’s worth restating: Article 61, 1 sets out the primary elements of the clinical evaluation. Point 1: Conformity with the Annex I requirements and the benefit-risk assessment shall be based on clinical data that provides sufficient clinical evidence (clinical investigations are not mentioned). Point 2: It is the Manufacturer who specifies the level of clinical evidence needed (not the regulation or the notified body), which should be appropriate to the characteristics and intended purpose of device (not its classification). Point 3: The procedure to be followed is the one described in Annex XIV Part A, 1. Note: Clinical investigations are not mentioned among the primary elements of the clinical evaluation process.

      The clinical evaluation process laid down in Annex XIV Part A, 1. The steps are; (a) the clinical evaluation plan, (b) the identification of available data, (c) the appraisal of that data, (d) if needed, the generation of additional data through clinical investigation, (e) the conclusion of the evaluation. Note: Clinical investigations are only mentioned in step (d), as the means by which new or additional clinical data is generated if there are gaps in the available clinical data.

      While Article 61, 4 does set a clear expectation that a clinical investigation should be performed for implantable and class III devices, even for those highest risk class devices, the legislators have included multiple possibilities for being exempt from that requirement (see both clause 4 and clause 6).

      In conclusion: Independent of device class, the Manufacturer determines the level of clinical evidence needed which should be appropriate to the characteristics and intended purpose of device. The starting point for all clinical evaluations, again regardless of device class, should be identification and appraisal of already available data. Only if the available data proves insufficient should a clinical investigation be considered as a means to fill the specific data gaps. While a clinical investigation is an expectation for implantable and class III devices. The legislation contains multiple opportunities, even for the highest risk class devices, to be exempt from the requirement to conduct a clinical investigation.

    1. Thank you for your question about clinical investigations.

      The requirements of the regulation are the same for all clinical investigations, independent of whether it is a first or subsequent investigation. Conformance with ISO 14155 and Articles 62-82.

  2. Hello,
    The Clinical Investigations performed outside of the EU are accepted? They must comply with all the requirements stated in the MDR, Articles 62 through 82? Are there specific requirements for them?
    Also, what kind of clinical data are accepted?
    Thank you,

    1. Thank you for your question.

      While the EU MDR does not specify that clinical investigations must be conducted in the EU, a manufacture’s clinical evaluation (Article 61) would be expected to be based on clinical data from a patient population and medical conditions etc. that are comparable to those in the EU. Additionally, when conducting the clinical evaluation, the manufacturer is required by Article 61, 3(b) to consider whether Articles 62 through 81 were complied with, again independent of geography. The manufacturer, via the clinical evaluation process, determines whether the available clinical data are sufficient or not. However, for devices in Class IIa and above, the notified body’s assessment also includes the clinical evaluation and any clinical investigations.

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