Need for cli­ni­cal tri­als in accordance with the MDR

With Regu­la­ti­on (EU) 2017/745 (MDR) coming into force on 26 May 2021, the requi­re­ments for cli­ni­cal evi­dence within the CE con­for­mi­ty assess­ment pro­cess of medi­cal devices have fur­ther increased. The focus on cli­ni­cal tri­als is alre­a­dy clear in the reci­tals of the MDR:

“To ensu­re a high level of safe­ty and per­for­mance, demons­tra­ti­on of com­pli­ance with the gene­ral safe­ty and per­for­mance requi­re­ments laid down in this Regu­la­ti­on [MDR] should be based on cli­ni­cal data that, for class III devices  and implan­ta­ble devices should, as a gene­ral rule, be sourced from cli­ni­cal inves­ti­ga­ti­ons […]” (Reci­tal 63). “The rules on cli­ni­cal inves­ti­ga­ti­ons should be in line with well-established inter­na­tio­nal gui­dance in this field, such as the inter­na­tio­nal stan­dard ISO 14155:2011 on good cli­ni­cal prac­ti­ce for cli­ni­cal inves­ti­ga­ti­ons of medi­cal devices for human sub­jects […]” (Reci­tal 64).

In addi­ti­on, the source of cli­ni­cal data that can be used to demons­tra­te the safe­ty or per­for­mance of a device is expli­cit­ly inten­ded to include post-market cli­ni­cal follow-up of a medi­cal device, so manu­fac­tu­r­ers must also con­sider post-market cli­ni­cal tri­als of their devices.

Cli­ni­cal tri­als at a glance:

1.    Cli­ni­cal tri­al in the con­text of con­for­mi­ty assess­ment for (exten­ded) CE marking

Cli­ni­cal tri­als, which con­sti­tu­te part of the cli­ni­cal eva­lua­ti­on for con­for­mi­ty assess­ment pur­po­ses pur­su­ant to Artic­le 62 MDR, con­cern devices that do not yet have a CE mar­king. They are con­duc­ted in accordance with Artic­le 62 MDR for one or more of the fol­lo­wing purposes:

  • “(a) to estab­lish and veri­fy that, under nor­mal con­di­ti­ons of use,a device is desi­gned, manu­fac­tu­red and packa­ged in  such a way that it is sui­ta­ble for one or more of the spe­ci­fic pur­po­ses lis­ted in point (1) of Artic­le 2, and achie­ves the per­for­mance inten­ded as spe­ci­fied by its manufacturer;
  • (b) to estab­lish and veri­fy the cli­ni­cal bene­fit of a device as spe­ci­fied by its manufacturer;
  • © to estab­lish and veri­fy the cli­ni­cal safe­ty of the device […]”

Appro­pria­te cli­ni­cal tri­als are sub­ject to approval.

This appr­oval requi­re­ment also appli­es to cli­ni­cal tri­als of devices that are alre­a­dy CE mark­ed but are to be used out­side the inten­ded pur­po­se cover­ed by the CE mark. Artic­le 74 (2) MDR is rele­vant in the­se cases: “Whe­re a cli­ni­cal inves­ti­ga­ti­on is to be con­duc­ted to assess, out­side the scope of its inten­ded pur­po­se, a device which alre­a­dy bears the CE mar­king in accordance with Artic­le 20(1), Artic­les 62 to 81 shall apply.”

2.    Post-market cli­ni­cal tri­als with “addi­tio­nal bur­den” for subjects

If a cli­ni­cal tri­al is inten­ded to fur­ther the cli­ni­cal eva­lua­ti­on of a medi­cal device that is alre­a­dy CE-marked, within its inten­ded pur­po­se as defi­ned by the CE-mark, Artic­le 74(1) MDR must be obser­ved “whe­re the inves­ti­ga­ti­on would invol­ve sub­mit­ting sub­jects to pro­ce­du­res addi­tio­nal to tho­se per­for­med under the nor­mal con­di­ti­ons of use of the device and tho­se addi­tio­nal pro­ce­du­res are inva­si­ve or burdensome.”

Addi­tio­nal pro­ce­du­res that are bur­den­so­me may take a varie­ty of forms and may include, for exam­p­le, pro­ce­du­res that cau­se pain, dis­com­fort, anxie­ty, poten­ti­al risks, or complications/side effects. The pre­sence of a “bur­den” is deter­mi­ned from the per­spec­ti­ve of the sub­jects. Other inva­si­ve pro­ce­du­res include pene­tra­ti­on of the body through the body sur­face as well as through the mucous mem­bra­nes of the body orifices.

Cor­re­spon­ding cli­ni­cal tri­als are not sub­ject to appr­oval, but are sub­ject to notification.

3.    Post-market cli­ni­cal tri­als wit­hout “addi­tio­nal bur­den” for subjects

If a cli­ni­cal tri­al is con­duc­ted with a device that is alre­a­dy CE-marked to eva­lua­te its per­for­mance when used within the defi­ned inten­ded pur­po­se wit­hout (having to) use addi­tio­nal bur­den­so­me or inva­si­ve pro­ce­du­res, the MDR rules for cli­ni­cal tri­als are not rele­vant. The­r­e­fo­re, the­re is neither an appr­oval nor a noti­fi­ca­ti­on requi­re­ment in the­se cases.

4.    Other cli­ni­cal tri­als accor­ding to Artic­le 82 MDR

Artic­le 82 of the MDR also regu­la­tes cli­ni­cal inves­ti­ga­ti­ons of medi­cal devices that are not initia­ted by the manu­fac­tu­rer or are not con­duc­ted in con­nec­tion with a con­for­mi­ty assess­ment. Mini­mum requi­re­ments are also impo­sed on the­se other cli­ni­cal tri­als. Thus, in par­ti­cu­lar, accor­ding to Artic­le 62(2) and (3) MDR, the­se must also be “desi­gned and con­duc­ted in such a way that the rights, safe­ty, digni­ty and well-being of the sub­jects par­ti­ci­pa­ting in a cli­ni­cal inves­ti­ga­ti­on are pro­tec­ted and pre­vail over all other inte­rests and the cli­ni­cal data gene­ra­ted are sci­en­ti­fi­cal­ly valid, relia­ble and robust.” They, too, are “sub­ject to sci­en­ti­fic and ethi­cal review.” The spe­ci­fic requi­re­ments for other cli­ni­cal tri­als are defi­ned in accordance with Artic­le 82 (2) MDR in § 47 of the Medi­cal Device Law Imple­men­ta­ti­on Act (MPDG) (PDF only in Ger­man) appli­ca­ble in Ger­ma­ny. The­re, too, a distinc­tion is made bet­ween “other cli­ni­cal tri­als” of pro­ducts with and wit­hout CE mar­king, the use within or out­side the inten­ded pur­po­se alre­a­dy cover­ed by the CE mar­king, and the use of addi­tio­nal­ly inva­si­ve or stressful procedures.

Recom­men­ded action for sponsors

Cli­ni­cal tri­als are time-consuming and cos­t­ly, but essen­ti­al to demons­tra­te the cli­ni­cal bene­fit or added value of a medi­cal device. In spe­ci­fic cases, espe­ci­al­ly in the case of tests with CE-marked pro­ducts, ques­ti­ons may ari­se as to the scope of duties of the spon­sor, and deli­mi­ta­ti­on pro­blems may ari­se. The­r­e­fo­re, befo­re con­duc­ting cor­re­spon­ding stu­dies, spon­sors should careful­ly check the inten­ti­on pur­sued and the given frame­work con­di­ti­ons in order to com­ply with their respec­ti­ve obli­ga­ti­ons and the requi­re­ments for the cli­ni­cal tri­al in each case, thus avo­i­ding lia­bi­li­ty risks.


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