Glòria Macià Muñoz

1. Clinical Evaluation

One of the main purposes of the MDR was to amend the current clinical evaluation
procedure under the directives in order to improve the quality, safety and reliability of
medical devices. While mentioned only 23 times in the AIMDD and the MDD together, the
term ‘clinical evaluation’ is given attention 140 times under the MDR.

‘clinical evaluation’ ​means a systematic and planned process to continuously

generate, collect, analyse and assess the ​clinical data pertaining to a device in order to
verify the safety and performance, including clinical benefits, of the device when used as
intended by the manufacturer;

in which, ​‘clinical data’ means information concerning safety or performance that is

generated from the use of a device and is sourced from the following:

● clinical investigation(s) of the device concerned,

● clinical investigation(s) or other studies reported in scientific literature, of a device for
which ​equivalence​to the device in question can be demonstrated,
● reports published in peer review scientific literature on other clinical experience of
either the device in question or a device for which ​equivalence to the device in
question can be demonstrated,
● Clinically relevant information coming from post-market surveillance, in particular the
post-market clinical follow-up​;

In other words, the objective of a clinical evaluation is, based on clinical data, to
provide sufficient clinical evidence to demonstrate conformity to the relevant General Safety
and Performance Requirements (GPRS); to evaluate undesirable side-effects; and to judge
the acceptability of the benefit-risk-ratio​.

Consequently, risk management files and clinical evaluations should not be separate,
stand-alone documents under the MDR. The new Regulation expects a careful alignment of
the risk management system with the clinical evaluation (i.e. clinical risks should be
addressed in clinical investigations, clinical evaluations, and Post-Market Clinical Follow-Up)

Notice also that a clinical evaluation is mandatory for all devices and should be
proportionate to their risk class (e.g. for Class I devices, for instance, clinical evidence might
not be necessary on the basis of a justification). A clinical evaluation must follow a certain
procedure based on either:

● a critical evaluation of the relevant scientific literature of ​equivalen​t devices, if data

demonstrate compliance with the relevant GSPR.
● a critical evaluation of all available clinical investigations, if conducted according the
relevant MDR procedures
● a consideration of all current alternative treatments
 Glòria Macià Muñoz

Due to the laissez-faire attitude of the Commission until very recently (MEDDEV 2.7.1
rev 4 published on July 1, 2016 in the OJEU), using clinical justifications based on device
equivalence has been a standard practice under the MDD for decades. Although still
possible under the MDR, the equivalence argument is going to be less accepted, particularly
for higher risk devices. Even with lower risk devices, equivalence justifications may be
harder to make and must always be endorsed by the manufacturer’s NB. According to Part A
of Annex XIV, more specifically, a clinical evaluation may be based on clinical data from an
equivalent device only if they both have the same technical, biological, and clinical
characteristic. As a result, more clinical data will need to be obtained from clinical
investigations of the device in question.

Another consequence of the easier ‘search literature route’ getting much harder, is
that we can expect many manufacturers to use PMCF data to fulfil the clinical evaluation
requirements. This clearly poses a challenge for new manufacturers with no approved
medical devices on the market under the MDD.

Furthermore, these changes will specially impact manufacturers of implantable

devices and class III devices1, for which clinical investigations will become mandatory.

‘clinical investigation’ means any systematic investigation involving one or more

human subjects, undertaken to assess the safety or performance of a device, ​the so-called
‘investigational device’.

The goals of a clinical investigation are to demonstrate that the device achieves the
performances specified by the manufacturer; to establish and verify the clinical benefit of the
device as predicted by the manufacturer; and to assess whether any side effect constitute
acceptable risks when weighed against the benefits.

These manufacturers will be exempt of clinical investigations only if one of the

following conditions apply:

● the device is a (non-substantial) modification of a device already CE marked

according to the MDR and produced by the same manufacturer, or
● the device is proven to be equivalent to a device already CE marked
according to the MDR produced by another manufacturer with which a
contract is stipulated allowing full access to the relevant data on ongoing
basis ​(it is challenging to picture how such a cooperation within competitors
will work in practice)​, or
● the device was lawfully on the market on the basis of conformity to the
MDD and the manufacturer can produce sufficient clinical data and proof of
conformity to applicable Common Specifications (CS), where these exist.

1
Other categories of devices could need a clinical investigation in the absence of other means to
show clinical evidence (e.g. literature review relating to the safety, performance, design characteristics
and intended purpose of a proven equivalent device)
 Glòria Macià Muñoz

In addition, no obligation of clinical investigation for ‘simple’ class III devices such as
sutures, staples, dental fillings, screws or plates if their clinical evaluation is based on
sufficient clinical data.

2. Clinical Investigation

In case a clinical investigation is needed, there is a new possibility for manufacturers

of implatable and Class III devices to voluntarily obtain scientific advice from an expert
panel (not yet constituted) designated by the Commission. Manufacturers may use it to
receive ​voluntary early scientific advice regarding their Intended clinical development
strategy and their proposals for clinical investigation(s).

Another significant change of the MDR is the ​greater emphasis it places on

patients in terms of protection of their rights, safety, dignity and well-being​. It details,
for example, ​specific requirements for vulnerable socials groups ​such as incapacitated
subjects, minors and pregnant or breastfeeding women. In addition, ​patients must be well
informed and give their consent prior to the start of the clinical investigation and are
entitled to a ​damage compensation ​(i.e. insurance) by the sponsor2.

‘sponsor’ ​means any individual, company, institution or organisation which takes

responsibility ​(i.e. liability) for the initiation, for the management and setting up of the
financing of the clinical investigation;

In cases where the sponsor is the same medical device manufacturer, the obligations
listed in Chapter III of Annex XV will apply to the later too.

As previously mentioned, a clear improvement of the MDR was the strengthening of

the transparency of information. Hence, data concerning clinical investigations needs to be
entered into the Eudamed. This includes the application documents (i.e. application form,
investigator's brochure, clinical investigation plan and the other documents listed in Chapter
II of Annex XV) which will remain confidential. Additionally, irrespective of the outcome of the
clinical investigation, a clinical investigation report must be produced and accompanied by a
summary presented in terms that are easily understandable to the intended user. For all
clinical investigations started after the MDR application date, these two documents are
compulsory and will become publicly available in the Eudamed ​at the latest before the
device is placed on the market. In addition, serious adverse events should be also reported
through the Eudamed according to the timeline.

Finally, one exciting change for sponsors under the MDR is that in the case of clinical
trials taking place in more than one Member State, they will be able to submit a single

2
It should be possible both for the manufacturer and for another natural or legal person to be the
​
sponsor taking responsibility for the clinical investigation. Similarly to ARs, if the sponsor of a clinical
investigation is not established in the EU, a natural or legal person established in the EU must act as
its legal representative.
 Glòria Macià Muñoz

application in order to reduce administrative burden3. Applications will be hence subject to

one single coordinated assessment instead of multiple national assessments.

3. Clinical Evaluation and Clinical Investigations - Implications for Industry

● Improvement on the quality, safety and reliability of medical devices ​⎼rebuilded trust
and reputation of the industry.
● The equivalence argument and the literature route will become unavailable for many
manufacturers ⎼need for other sources of clinical data (e.g. clinical investigations or
PMCF).
● Clinical data definition excludes some sources of valid but unpublished data such as
registries or patient feedback.
● New equivalence definition may lead to unnecessary clinical investigations.
● Clinicians may be reluctant to conduct studies where the outcome data is commonly
anticipated
● Manufacturers may use PMCF data to comply with the new MDR clinical evaluation
requirements ⎼clinical investigations may be the only valid option for new
manufacturers and existing manufacturers who aim to innovate.
● Clinical investigations will be required more often ⎼mandatory for implantable devices
and Class III with some envisaged exemptions.
● New possibility for manufacturers of implatable and Class III to receive voluntary
early scientific advice from an expert panel.
● Stricter requirements for clinical investigations ⎼greater emphasis on patients rights,
safety, dignity and well-being.
● Clinical investigations will take more time and will be more expensive ⎼increased
R&D costs.
● Potential for cash-flow problems due to delay in releasing a new product or
re-certifying an existing one.
● Potential increased costs for NB review of clinical evaluations.
● Strengthening of the transparency of information regarding clinical investigations.
Previously confidential documents will become publicly available in the Eudamed
⎼manufacturer’s sensitive information may be exposed.
● Faster serious adverse events reporting in the Eudamed.
● Easier registration of clinical trials that take place in more than one Member State.
● … any other remarks?

Which are going to be the requirements regarding clinical evaluations (AND clinical
investigations) for....

● aesthetics products (Annex XIV)?

● custom-made devices (Annex XIII)?
● in-house use devices?

3
Notice though that coordinated assessments of clinical investigation applications will be of voluntary
​
participation for each Member State. They will not become compulsory until after 7 years of the MDR
Application Date.