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Clinical Investigations for Medical Devices

and IVD
What are the requirements?
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Clinical Investigations for Medical Devices
and IVD
What are the requirements?
The EU MDR defines a clinical investigation as “any systematic investigation involving one or
more human subjects, undertaken to assess the safety or performance of a device.”

Clinical data (data obtained from use in humans) is a requirement for CE Marking and EU
marketing of all Classes of Medical Devices and Invitro Diagnostic tests. Clinical studies (real-
patient studies) must meet several regulatory standards, many of which must be met before the
study begins.

The EU MDR requires companies to develop a ‘Clinical Development Plan’ (CDP) to map out pre-
clinical and post-market activities to obtain clinical data. This should be the starting point where
manufacturers centralise departmental goals for the product and plan clinical investigations to
meet Good Clinical Practices (GCP's), ICH guidelines, and the regulations that govern clinical trials
in the parts of the world they want to market in, such as EU MDR or the US FDA 21 CFR Parts 50,
56, and 812.

The CDP should intentionally align all clinical investigations on the international standard of
medical devise for human subjects (ISO 14155) which will assure that as well as European
guidance documents such as MEDDEV 2.7/4. This whitepaper outlines the requirements and
considerations manufactures should review to ensure that the Clinical trials they do undertake
is well researched to ensure a return on investment.

Clinical Investigation regulatory pathways in the EU – MDCG 2021-6

guidance
EU MDR has 20 articles that outline the requirements for clinical investigations of medical
devices, spanning articles 62 through 82. Within these articles, the regulation lays out three
regulatory pathways manufacturers can take:
• Article 62 covers investigations that are performed in order to demonstrate conformity
and obtain a CE marking. This is the pathway medical device companies will use if their
device classification (for Class III or Class IIb implantables) requires a clinical investigation.

• Article 74(1) covers the regulatory pathway for devices that already have a CE marking if
the parameters of the investigation are within the device’s intended purpose. In other

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words, if you are conducting a clinical investigation as part of your Post-Market Clinical
Follow-Up (PMCF), then you will be guided by Article 74(1).

• Article 82 covers clinical investigations that are not being performed in order to
demonstrate conformity. Additionally, the Member State in which you hold your study
may have relevant national provisions for you to follow.

To clarify the routes MDCG 2021-1 illustrates this pathway but draws attention to national
guidelines that should be reviewed. Hence again be clear when planning your CDP what
regions you’re considering trials in and why. Consider the long term needs for clinical data as
the MDR states this is an ongoing process throughout the devices’ lifetime. So plan carefully
using your SoTA to ensure you’re not embarking on expensive trials just because you had a
convincing pitch from a CRO.

Clinical Investigation under MDR - regulatory pathways

Stages and types of medical device clinical trials

Clinical investigations (trials) may be carried out during both the premarket and post-market

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phases of the device lifecycle. The graphic below includes the many different types of clinical
activities, including clinical trials, that medical device manufacturers may carry out during the
pre-market and post-market phases.

Clinical trials may occur during the pilot stage, the pivotal stage, or during post-market
surveillance. As previously mentioned, pre-clinical activities do not use human subjects, but this
is not the same as premarket pilot and pivotal studies.

Many of the study descriptor terms are interchangeable, and different descriptors are often used
in different markets to describe the same thing. So, let’s focus on the general types and stages
of studies and their burden to human subjects.

Pilot studies occur early in device development, often before the device design has been
finalized. Pilot studies are used when nonclinical testing is unable to provide preliminary
information on device functionality and clinical safety. These will be conducted with a very small
number of patients - often 10 or fewer. Not to be confused with Usability studies which may be
done in tandem with a pilot study.

The purpose of pilot studies is to gain a broad range of information that may be used to:
• Identify modifications to the device or procedure
• Optimize operator technique
• Refine the intended use population
• Refine nonclinical test plans or methodologies

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• Develop subsequent clinical study protocols

Data obtained from a pilot study is often used to help you design a pivotal study when SoTA data
is insufficient and leaves a lot of questions around suitable safety and performance endpoints. A
pivotal study is used to gather definitive evidence of the safety and effectiveness of your medical
device for a specific intended use. These studies generally use a larger number of subjects than
pilot studies, and you’ll use the results of your pivotal study to gain regulatory approval for your
device.

Keep in mind, a pivotal study does not necessarily need to be preceded by a pilot study. This is
where a well written SoTA can save time and money in developing your device. If your systematic
review of the SoTA is comprehensive it will provide suitable safety and performance endpoints.
It also will provide prior art (reference range of your performance and safety) effect size, so that
the sample size of your study can be determined.

The types of clinical activities you carry out will depend on your device and the regulatory
pathway you’re taking. It shouldn’t be overlooked that none of the guidance advocates for a
specific study design, unlike drug studies. Meaning you can utilise your SoTA data if you can
justify well-established technology and your CE position in markets outside the EU to obtain
observational post-market clinical data to help your EU MDR clinical data needs.

Do clinical trials happen during post-market surveillance?

As you can see from the graphic, the post-market surveillance stage includes both confirmatory
and observational types of clinical activities. While it may seem odd that you would need to
perform a confirmatory study after receiving approval to place your device on the market, this is
not an irregular occurrence. For example, EU MDR includes a distinct regulatory pathway - Article
74(1) - for conducting a clinical investigation as part of your PMCF.

These post market surveillance studies may be conducted for a number of reasons, including to
confirm the safety and efficacy of the device once it’s on the market or to answer questions
about the long-term safety or performance of the device.

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How much Clinical Data is enough? The Quality and Quantity debate
The EU MDR emphasises clinical evidence quantity and quality as sufficient clinical data. Initially
this was poorly understood but recently with growing notified body feedback, the expectations
are becoming clearer. Clinical data must be assessed against MDCG evidence level,
characteristics, design, statistical power, sample size, follow-up demographics, etc. A dataset's
scientific contribution should be considered alongside its quantity and quality of clinical
evidence.

To justify the ‘Intended Purpose and prove the device's claims, manufacturers must compare the
total amount of data from pre-clinical studies, literature and SoTA sources to ascertain if there is
sufficient clinical evidence. This to the number of datasets and patients enrolled. The data should
include the intended use, indications, clinical claims, contraindications, target groups, and safety
and performance objectives based on the State of the Art. They should all be based on
the manufacturer’s device and any equivalent device if applicable. A pre-specified method
evaluates the identified data sets.

The identified data sets are assessed for data quality to meet General Safety and Performance
Requirements and claims. Scientific surveys can be employed in the PMCF phase to actively
collect clinical evidence. The risk analysis and clinical evaluation must be updated using the data.
Surveys during PMCF take less time than randomised or single-arm clinical investigations and
registry studies.

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Investment in Clinical Investigations – what is at stake?
Sufficient clinical data does not mean all medical devices must do expensive ‘Randomised Control
Trials’. Even in Class III and implantable devices, it should be noted this is not a pre-requisite.
Consider MDCG 2020-6 (see sections below), rank 1-4 studies do not prescribe RCT’s. Although
RCT’s, if designed well, provide high quality evidence. They are the most expensive trial design
types. Costs for clinical trials are quoted by cost per patient, where prospective randomised
designs and difficulty in recruiting patient populations increase the cost. Hence manufacturers
are advised to use the CDP to step back and consider the overall clinical data needs. The goal of
pre-market studies is to access the market, but EU MDR also requires post-market clinical data.
Hence manufacturers will need to invest in further clinical studies post market. Spending most
of the budget on RCT’s might cripple future budgets for PMCF studies which can make the
product more profitable as they can support future claims, broaden the ‘Intended Purpose’ and
differentiate the product in the market.

A manufacturer starting a project must analyse the devices' use and provide a detailed State of
the Art description that explains the devices clinical benefits, risks, safety/performance
endpoints and provide a reference range of the safety/performance effect size. The Notified
Body requires a detailed document and the manufacturer needs to benchmark their device with
objective evidence. MDR requires substantial evidence to prove the device sits within range of
the general safety and performance requirements (GSPR) for the State of the Art.

The State of the Art and the manufacturers technical data must be analysed to define objectives
and study endpoints. Notified Bodies expect patient-level Scientific Surveys for certain devices.
Especially for higher-risk class and long-term use/implantable devices with little clinical evidence.

Generally, surveys can be applied to all risk classes, but the methodology used will be very
different. Manufacturers can’t conduct a simple use-related questionnaire for a IIb class device.
This wouldn’t give information on the hierarchy level of the medical device, the patient, or the
procedure type. Therefore, it would be an invalid way to collect clinical evidence for higher risk
devices.

The process’s statistical rationale for the number of patients/surveys should be based on the
study's endpoints, success, and certainty objectives. A biostatistician calculates the number of
patients/surveys needed to prove endpoints from numerous sources which is also needed to
translate CER objectives into endpoints. However, survey data may be relevant but not adequate
evidence.

Manufacturers must use the clinical evaluation process to evaluate the product's stage (time on
the market), information gathered, and clinical gaps in the planning phase. The CEP, CDP, and

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CER must describe the assessment for all devices. Nonetheless, the PMCF plan should
incorporate surveys for post-market clinical evidence collection.

MDCG 2020-6
This guidance is very helpful to understand the hierarchy of data and clinical evidence
requirements.

The MDR does not specify how much evidence is needed or whether a survey, a full clinical study,
or Post Market Surveillance (PMS) data is enough. The MDR requires clinical evidence to support
the devices claims, but the MDCG2020-6 guideline provides useful information. The hierarchy
levels within the guideline contain full clinical studies, randomised studies, registry studies and
high quality surveys shown in the table below

Suggested hierarchy of clinical evidence for confirmation of conformity with relevant GSPRs under the MDR
Rank Types of clinical data and
evidence
1 Results of high quality
clinical investigations
covering all device variants,
indications, patient
populations, duration of
treatment effect, etc
2 Results of high quality
clinical investigations with
some gaps
Considerations / comments
This may not feasible or necessary for certain well-
established devices with broad indications (eg Class IIb
legacy sutures, which could be used in every
conceivable patient population)
Gaps must be justified / addressed with other evidence
in line with an appropriate risk assessment, and clinical
safety, performance, benefit and device claims.

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Rank Types of clinical data and Considerations / comments
evidence
Assuming the gaps can be justified, there should be an
appropriate PMCF plan to address residual risks.
Otherwise, manufacturers shall narrow the intended
purpose of the device until sufficient clinical data has
also been generated.
3 Outcomes from high quality Is there sufficient evidence of the quality of the data
clinical data collection collected by the registry?
systems such as registries Are the devices adequately represented? Are the data
appropriately stratified?
Are the endpoints appropriate to the safety,
performances and endpoints identified in the clinical
evaluation plan?
4 Outcomes from studies with Many literature sources fall into this category, due to
potential methodological limitations such as missing information, publication
flaws but where data can still bias, time lag bias, etc. This applies equally to
be quantified and publications in the peer-reviewed scientific literature.
acceptability justified However, for legacy devices
Class III legacy devices and implantable legacy devices which are not well-established technologies
should have sufficient clinical data as a minimum at level 4. Those devices which are well-
established technologies may be able to confirm conformity with the relevant GSPRs via an
evaluation of cumulative evidence from additional sources as listed below. Reliance solely on
complaints and vigilance is not sufficient.
5 Equivalence data (reliable / Equivalence must meet MDR criteria.
quantifiable) It is normally expected that manufacturers should
gather data on their own devices in the post-market
phase, therefore reliance on equivalence should be
duly justified, and linked to appropriate PMCF or
proactive PMS.
6 Evaluation of state of the art, This is not considered clinical data under the MDR, but
including evaluation of for well-established technologies only can be
clinical data from similar considered supportive of confirmation of conformity to
devices as defined in Section the relevant GSPRs.
1.2 of this document Data from similar devices may be also important to
establish whether the device under evaluation and
similar devices belong to the group of devices
considered as “well established technologies” (WET).
See section 1.2 in this document for the criteria for
WET. Data from similar devices may be used, for
example, to demonstrate ubiquity of design, lack of
novelty, known safety and performance profile of a
generic group of devices, etc.
7 Complaints and vigilance This falls within the definition of clinical data under
data; curated data MDR Article 2(48) but is not generally considered a
high quality source of data due to limitations in
reporting. It may be useful for identifying safety trends
or performance issues. High volume data collected
within a robust quality system may provide supportive
evidence of device safety.
8 Proactive PMS data, such as This falls within the definition of clinical data under
that derived from surveys MDR Article 2(48), but is not generally considered a

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evidence
9 Individual case reports on
the subject device
10 Compliance to non-clinical
elements of common
specifications considered
relevant to device safety and
performance
11 Simulated use / animal /
cadaveric testing involving
healthcare professionals or
other end users
12 Pre-clinical and bench
testing / compliance to
standards
Considerations / comments
high quality source of data due limitations associated
with sources of bias and
quality of data collection. It may be useful for
This falls within the definition of clinical data under
MDR Article 2(48), but is not considered a high quality
source of data due to limitations in generalising
findings to a wider patient population, reporting bias,
etc. It may provide supportive or illustrative
information with respect to specific claims.
Common specifications which address clinical
investigation or data requirements directly would rank
higher in this hierarchy. Common specifications may
address clinically relevant endpoints through non-
clinical evidence such as mechanical testing for
strength and endurance, biological safety, usability,
etc.
This is not clinical data but may be considered evidence
of confirmation of conformity to relevant GSPRs,
particularly in terms of usability, such as for accessories
or instruments.
Pre-clinical and bench testing may address clinically
relevant endpoints through non-clinical evidence such
as mechanical testing for strength and endurance,
biological safety, usability, etc.

Manufacturers must consider their device's class in order to understand the sufficient amount
of evidence that’s required.

The manufacturer may combine clinical evidence collection methods depending on the device
class. Manufacturers should assess each method for the specific claim or objective, using the
MDCG guideline to determine which information is sufficient for the device.

ISO 14155:2020
ISO 14155 provides guidance and requirements for the design, conduct, recording and reporting
of clinical investigations in accordance with the MDR and the ethical principles set out in
the Declaration of Helsinki.

The manufacturer must consider the applicable part of the ISO 14155 standard. By doing so, the
manufacturer understands what data is needed for surveys and the final report. The
manufacturer should describe if they met the proposed endpoints and their data findings. This
data is included in the CER and PMCF.

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Benefits and Claims

In accordance with the MDR, the performance of a device is its ability to achieve its intended
purpose as stated by the manufacturer. By extension, the clinical performance of a medical
device is the ability of the device to achieve its intended purpose, thereby leading to a clinical
benefit when used as intended. ‘Clinical benefit’ means the positive impact of a device on the
health of an individual, expressed in terms of a meaningful, measurable, patient-relevant clinical
outcome(s), including outcome(s) related to diagnosis, or a positive impact on patient
management or public health.

Claims can be both clinical and technical. Technical claims may pertain to the design of the
device, aka it is reusable, sterile. Whereas any clinical claim but be measurable in-patient
outcomes. It will not be accepted by the notified authority or the national marketing claims
regulator if you infer a clinical benefit. For instance you cannot say “our device is sold sterile and
hence prevents infections” unless you can prove in a study that the rates of infections is lower in
your device versus a competitor that is not sold sterile. But it may be that the state of the art
requires all devices in your device category to be sold sterile, so it’s better to claim in the
intended use that the device is sold sterile.

Notified Bodies state that medical device safety and performance claims, as well as clinical
benefit and claims are relevant. Benefits must be measurable, patient-oriented, and meaningful.
When the device indirectly benefits a procedure, it should be mentioned. Nonetheless,
manufacturers must limit their claims and identify mandatory from complementary information
as clinical evidence must substantiate the device's benefits.

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MDCG 2021-6 outlines the difference between performance, clinical performance and clinical benefit

CLIN-r+ Recommendations
Notified bodies are given the authority to define state-of-the-art in accordance with their
expertise and understanding of the law. Where the manufacturer provides no or an ill-defined
SoTA, it opens the door for the Notified Body to impose their interpretation of the SoTA.
Uncertainty could result in the need for expensive clinical trials, or worse no CE mark being
granted.

Hence defining the ‘state of the art’ should be the starting point in the development process by
any manufacturer or innovator in MedTech. If a manufacturer cannot demonstrate to the
Notified Body a clear understanding of what is the SoTA for your device, it will leave various areas
in your Technical Document exposed to scrutiny and sow uncertainty if conformity is achieved.

A state of the art literature review gives a wealth of information by overviewing the performance
and safety data, as well as defining the technology’s clinical benefits, disadvantages, risks, and
limitations. It contains powerful strategic insight on if a clinical investigation is needed, what type
of design would be best to address your gaps, help support your ‘Intended Purpose’ and help
keep your trial budget in check.

Manufacturers without this expertise should consider partnering with an experienced

consultancy when assessing standards, risk, clinical data and considering what clinical studies are
best suited for your devices CE marking needs. Consultancies also come with resources such as
clinical study designers, statisticians and experienced SoTA medical writers systematic review

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helping expand your companies’ capabilities cost-effectively.

Should you have any questions or need professional assistance, CLIN-r+ has a wealth of
experience in clinical investigations and literature searches to call upon. Get in touch!

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