Design Approach of Medical Devices for Regulation Compatibility:

A Robotic Rehabilitation Case Study

Raffaele Formicola

, Federica Ragni

, Maurizio Mor

Luciano Bissolotti

and Cinzia Amici

Department of Industrial and Mechanical Engineering, University of Brescia, via Branze 38, 25123, Brescia, Italy

Polibrixia s.r.l., via Branze 43, 25123, Brescia, Italy

Laboratorio Larin, Casa di Cura Domus Salutis, Fondazione Teresa Camplani, via Lazzaretto 3, 25123, Brescia, Italy

Keywords: Design Process, Bio-Medical Devices, MEDDEV, Regulations, CE Mark, Robotic Rehabilitation, Design

Requirements, Bio-Compatible Materials, Selection Criteria.

Abstract: Regulations and normative framework strongly affect requirements and potential design constraints of

devices, especially in critical environments like the medical field, characterized by a complex interaction

among design, therapy procedures and user needs. In order to optimize the design process, the awareness of

the designer about the compound information net generated by the required documentation becomes therefore

fundamental. Depicting a custom mapping of required data and referring documents for the development and

commercialization of a medical device as required by the Conformité Européenne (CE) marking process, this

paper presents a design approach directly suitable for robotic rehabilitation systems, which aims at easing the

regulations compatibility of the designed product. This method is applied to the illustrative case study of the

LEPRE (LEg Programmable REhabilitation) robotic system, with particular attention to data collection and

analysis for the evaluation of clinical background and demonstration of equivalence required by the device

clinical evaluation report, according to MEDical DEVices (MEDDEV) 2.7/1 guidelines. Indications for the

modifications required to adapt it to further application fields are also suggested.

1 INTRODUCTION

Health technologies such as medical devices are

essential to guarantee good health care and the aging

well possibility, and technological innovations in

prevention and rehabilitative fields are gaining

importance in funded research (Amici et al., 2016).

The medical, and in particular the rehabilitative,

environment involves a complex interaction among

design, user needs, and therapy procedures

(Hagedorn et al., 2015). Considering the possible

design methods for medical devices, literature

suggested that both physician and engineer

participate in the design phase of a rehabilitative

device (Amici et al., 2016) since the earlier design

phases: the physician defines the functional

https://orcid.org/0000-0002-5526-0155

https://orcid.org/0000-0002-4186-5356

https://orcid.org/0000-0001-5840-3636

https://orcid.org/0000-0002-5882-645X

https://orcid.org/0000-0001-7426-6029

requirements of the system (i.e. maximum force or

acceleration needed, movement to reproduce with the

device), whereas the engineer develops the technical

specifications of the device (i.e. kind of actuation, or

structure). Then, the final user can support the process

providing feedbacks along the development path.

The necessity of ensuring the patient benefit and

safety led many countries to introduce regulatory

instruments (Henschke et al., 2016) to demonstrate

and guarantee safety and effectiveness of devices to

be launched on the market (Kramer et al., 2020;

Römer and Stuyt, 2007). Given the fundamental role

of regulations in this process (Privitera et al., 2017),

considering them from the earliest stages of the

device design and project management should be

good practice for manufacturers.

146

Formicola, R., Ragni, F., Mor, M., Bissolotti, L. and Amici, C.

Design Approach of Medical Devices for Regulation Compatibility: A Robotic Rehabilitation Case Study.

DOI: 10.5220/0010402801460153

In Proceedings of the 7th International Conference on Information and Communication Technologies for Ageing Well and e-Health (ICT4AWE 2021), pages 146-153

ISBN: 978-989-758-506-7

In the European Union (EU), medical devices can

be marketed across all EU member states after

earning the Conformité Européenne (CE) mark; that

guarantees streamlined trade, safety, and

environmental standards (Council of the European

Union, 1993), and defines essential requirements and

recommendations concerning clinical evaluation and

vigilance (Council of the European Union, 2007).

To obtain the CE mark, the MEDical DEVices

(MEDDEV) set of documents (European

Commission, 2016) is a helpful instrument, since

represents non-binding guidance, which deals with

the application of the directives on medical devices,

such as consensus statements and interpretative

documents (Fraser et al., 2011). Besides, since the

clinical evaluation has become relevant for

manufacturers ((Council of the European Union,

1993) consistent with (European Parliament; Council

of the European Union, 2017)), the MEDDEV

documents state the guidelines to correctly perform

the clinical evaluation of a medical device and sum-

marize it in the Clinical Evaluation Report (CER).

According to MEDDEV 2.7/1, the CER document

includes, among others, two sections: i) clinical

background, and ii) demonstration of equivalence.

The first part produces as main output a systematic

review of the current knowledge in the medical field

of interest. Instead, the demonstration of equivalence

can be fulfilled through different possible methods: a)

comparing the new device with an equivalent

certified device, b) collecting clinical evaluations to

certify safety, performance, design characteristics,

and intended purpose of the device, or c) thanks to a

combination of these two options. Among the

considered characteristics, the evaluation of clinical,

technical, and biological factors is specifically

required.

In this complex scenario, the design of

rehabilitative devices should therefore consider not

only technical but also normative requirements,

which could introduce not negligible constraints since

the device conceiving phase. This work presents an

integrated design approach for medical devices,

which aims at easing the regulations compatibility of

the designed product, applied to the illustrative case

study of the LEPRE (LEg Programmable

REhabilitation) robotic system (Amici et al., 2019).

2 MATERIALS AND METHODS

LEPRE (PoliBrixia, Italy) is an end-effector based

robotic device for limb rehabilitation and is

characterized by two degrees of freedom that allow

the implementation of every motion profile in the

desired plane (Ceresoli et al., 2019). Within the

current normative framework, the CER of this device

was performed according to MEDDEV 2.7/1.

2.1 Interpretation of the Normative

Framework

According to the MEDDEV 2.7/1 guidelines, the

CER collects information from several areas of

knowledge. Some of the required data partially

overlap the informative content of other documents,

mandatory as well for the CE mark earning. For

instance, much of the information required in the

device risk assessment is also stated in the risk

analysis document (International Organization for

Standardization, 2019) of the manufacturing

company. For this reason, an analysis of the whole

documentation regarding the device and the quality

system of the manufacturing company (International

Organization for Standardization, 2016) was

performed, looking for consistency between data

required according to MEDDEV 2.7/1 indications

and already existing documents, with the final aim of

optimizing the clinical evaluation process. According

to this custom analysis, a mapping of required data

and referring documents was then performed.

2.2 Clinical Background

The bibliographic research was conducted following

the PICO systematic review strategy

(Patient/Problem, Intervention, Comparison,

Outcome) (Schardt et al., 2007) using as the main

database PubMed (National Center of Biotechnology

Information), and then extended to the ClinicalTrials

(Clinical Trials) and Cochrane (Cochrane Library)

databases. The optional fields Comparison and

Outcome of the PICO technique were omitted. Table

1 collects the selected keywords for the

Patient/Problem and the Intervention fields.

The identified keywords were combined in 5

search strings: s1) neurological AND (robotic AND

rehabilitation); s2) orthopaedic AND (robotic AND

rehabilitation); s3) rehabilitation AND robot-assisted;

s4) upper-limb AND (robotic AND rehabilitation);

s5) lower-limb AND (robotic AND rehabilitation).

For each string and each database, an independent

query was performed.

Inclusion criteria for the selection of the

documents were: i) document type Review or

Systematic Review; ii) document language English or

Italian; iii) publication date between 01.01.1990 -

01.06.2020. Exclusion criteria were: i) references that

Design Approach of Medical Devices for Regulation Compatibility: A Robotic Rehabilitation Case Study

147

are not relevant in terms of population/reference

pathology, ii) non-complete references, iii) too

general references, iv) references without a real

scientific contribution, v) duplicate references. No

further restrictions are reported.

To assure the consistency of the query among the

databases, the search strings were researched in all

fields for PubMed and Cochrane databases. In the

ClinicalTrials database, the query was implemented

by assigning to the “Condition or disease” mask field

the keywords search string of the PICO’s P field, and

to the “Other terms” mask field the keywords search

string of the PICO’s I field. For the Cochrane

database, only intervention documents were selected.

Queries were last updated on the 7

of July 2020.

The results of each query (five search strings for

three databases) were filtered excluding duplicates

and ordered by date (from newest records). Within the

results of each query, the first ten products were

selected, and the final set of documents was then

analyzed by a trained operator. According to

MEDDEV 2.7/1, a quantitative evaluation of the

documents has been performed, considering four

parameters: p1) publication date; p2) accordance

with search string; p3) reference population; and

p4) scientific consistency of the obtained results. For

each of the defined parameters, the operator assigned

a numerical value from 0 to 5 (0 not applicable, 5 fully

consistent for the search), and for each document, a

final score was computed as the sum of all the

parameters’ scores. Table 2 collects a synthesis of the

guidelines for the parameters’ score assignation. Two

evaluators, experienced in clinical and technical

context respectively, further checked the

reasonableness of the results. Only documents

presenting a final score higher than 14 were then

selected and considered as significant for the clinical

background.

2.3 Demonstration of Equivalence

For the LEPRE clinical evaluation, a free market

analysis was performed to find potentially equivalent

devices. Once identified the commercial names of

those devices, further bibliographic research was

conducted within the previously presented databases,

to extract the relevant scientific literature currently

available related to safety, performance, design

characteristics, and intended purpose of the devices.

The information gathered from those documents was

then integrated with the data available on the websites

of the manufacturers of the potentially equivalent

devices. The information gathered from those

documents was then integrated with the data available

Table 1: Selected keywords for PICO’s P and I fields.

Patient/Problem fiel

Intervention fiel

neurologic, orthopaedic,

rehabilitation, upper-limb,

lowe

-limb

robotic rehabilitation,

robot-assisted

Table 2: Guidelines for the parameters’ score assignation.

[0-5](points) assignation strateg

Parameter

5: document (published or) updated in

2020

4: document updated in 2019

3: document updated in 2018

2: document updated between 2017-2015

1: document updated between 2014-2010

0: otherwise

5: document very strongly related to the

search string requirements

4: document strongly related to the search

string requirements

3: document moderately related to the

search string requirements

2: document weakly related to the search

string requirements

1: document very weakly related to the

search string requirements

0: document not related to the search string

requirements

5: document with very generic sample of

pathologic subject

4: document with generic sample of

pathologic subject

3: document with moderate generic

sample of pathologic subject

2: document with specific sample of

pathologic subject

1: document with very specific sample of

pathologic subject

0: document with not well-defined sample

of pathologic subject

5: document with very strong theoretical

and practical importance results

4: document with strong theoretical and

practical importance results

3: document with moderate theoretical and

practical importance results

2: document with weak theoretical and

practical importance results

1: document with very weak theoretical

and practical importance results

0: document with no theoretical and

ractical im

ortance results

on the websites of the manufacturers of the

potentially equivalent devices.

According to MEDDEV 2.7/1 indications, the

biological equivalence was omitted, since the user is

strictly required to wear gloves or socks when using

ICT4AWE 2021 - 7th International Conference on Information and Communication Technologies for Ageing Well and e-Health

148

the LEPRE device, therefore no direct user-machine

contact is necessary.

3 RESULTS

3.1 Interpretation of the Normative

Framework

Figure 1 maps the required documents for the CE

marking process. Within the scheme, an example of

the data content interaction is provided, for the

specific case of LEPRE CER. Documents containing

the description of the device present a yellow dot,

whereas data regarding the demonstration of

equivalence are indicated with the green dot. The blue

dot depicts risk analysis-related data, and the red dot

is adopted for post-market surveillance information.

This scheme represents a first level simplification of

the data content interaction among documents sharing

information with CER. For each document within the

dashed boxes, further connections could be also

identified.

3.2 Clinical Background

After the selection process, 37 documents emerged

from the analysis of the PubMed, ClinicalTrials and

Cochrane databases. Table 3 synthesizes overall

results and post-filtering selected documents with

respect to databases and search strings.

Comparing the results of the five queries

performed within each database, 8 duplicated

documents emerged for PubMed, 7 for ClinicalTrials

and 28 for Cochrane, equal to 16,0%, 18,9% and

56,0% of the considered results for the specific

database, respectively.

Figure 2 depicts the trend of the parameters’

scores for all the products of the five queries, with

respect to the three considered databases.

3.3 Demonstration of Equivalence

In order to cover all the functions provided by

LEPRE, three medical devices emerged from the

analysis and were selected as references in the

demonstration of equivalence: device A, suitable for

the evaluation of the functions related to the lower

limb rehabilitation, device B, for the comparison of

the upper limb-related functions, and device C for the

evaluation of the cycloergometer-like features. The

main factors adopted to compare the devices’

characteristics, for both clinical and technical

evaluation, are collected in Table 4.

4 DISCUSSION

The analysis of the informative flow among

documents required by the normative framework

surely can provide the designer with a general

overview of requirements and potential constraints

for the device development. Indeed, the awareness of

the designer about this complex information net can

for instance anticipate potential criticalities in

technical solutions, like suggesting the exclusion of

not biocompatible materials where needed. This

scenario allows reducing resourcing, as time, costs

and human resources otherwise devoted to the

development of first attempt and not optimal

solutions (Amici et al., 2016). Nonetheless, given that

Table 3: Results and post-filtering documents with respect to included databases and selected search strings.

PubMed ClinicalTrials Cochrane

Keywords Search String

Found

results

Compatible

results

Found

results

Compatible

results

Found

results

Compatible

results

s1: neurological AND (robotic AND rehabilitation) 149 6 29 5 24 2

s2: orthopaedic AND (robotic AND rehabilitation) 29 2 0 0 10 1

s3: rehabilitation AND robot-assisted 118 5 58 4 16 0

s4: upper-limb AND (robotic AND rehabilitation) 176 2 55 4 19 0

s5: lower-limb AND (robotic AND rehabilitation) 76 4 7 2 14 0

Total 548 19 149 15 83 3

Design Approach of Medical Devices for Regulation Compatibility: A Robotic Rehabilitation Case Study

149

Figure 1: Schematization of information content and

mandatory documents required for the CE marking process.

The dashed boxes identify on the left the device-related

information expected within the technical file, and on the

right the manufacturer-related information required by the

System Quality ISO 13485 regulation. The yellow dots

indicate information referring to the description of the

LEPRE device, the green dots data related to the

demonstration of equivalence, finally the blue and red ones

depict risk analysis and post-market surveillance

information respectively.

those constraints derive from field-related regulatory

instruments, analogous analyses should be performed

when considering devices designed for different

operational environments, e.g. industrial applications,

according to a task-driven design strategy (Amici et

al., 2020), or more in general, a design-for-X

approach (Bause et al., 2019; Huang, 1996). In fact,

the scheme depicted in Figure 1 represents a custom

interpretation of the normative framework,

specifically developed within the scenario of medical

devices, designed for rehabilitative purposes, but also

provides an illustrative application of a generally

valid methodological approach. Besides, the need for

the same informative content among documents

suggests aiming for an optimization strategy also at a

process management level, in the documents’

definition. As a matter of fact, repeating the same

information in multiple instances should be a

deprecated strategy, since it leaves room for potential

mistakes or incongruences. Conversely, overall

knowledge of what information is required, for which

document, and with which level of detail, allows the

possibility of creating multi-purpose texts, suitable

for integration in different documents, with a modular

rationale.

Focusing on the illustrative case depicted in

Figure 1, LEPRE CER emphasizes strong first-level

connections with at least seven documents: for

instance, the device description is expected in User

and Maintenance Manual, Technical Documentation

(Drawings and Bill Of Materials – BOM), Firmware

and Software Documentation, Safety Prescriptions

(CEI EN 60601), as well as Usability document

within the documentation required by the device’s

technical file. In the same way, information related to

the demonstration of equivalence will be surely

included in the User and Maintenance Manual,

Technical Documentation (Drawings and BOM) and

Firmware and Software Documentation, although

differences apply also at this first approximation

level; for example, Firmware and Software

Documentation deals with both clinical and technical

equivalence, whereas the Technical Documentation

mainly focuses on the technical characteristics.

Besides, these interactions could be graphically

schematized as double arrowed connections between

two documents, since those relations should be

considered mutual. In the same way, schemes and

connections should be considered dynamic objects,

since they evolve with the design phase along the

development process. For instance, the introduction

of a new attachment able to provide new training

exercises would require an update of all the

documents device- and company-related, but P01

Procedure Index and P02 Quality Policy and

Objectives. Besides, also modifications at a software

level only, like the introduction of a new training

exercise which does not directly affect the device

hardware, would affect all the documents but

Technical Documentation (Drawings and BOM) in

addition to the previously cited P01 and P02. Still,

this result should not surprise, given that the data

interactions’ net reflects the complexity of the design

process (A.F. De Toni, 2007; A.F. De Toni and

Tonchia, 2002). Within this scenario, methodological

approaches aiming at the optimization of the design

process such as concurrent engineering solutions

could introduce considerable improvements in the

overall efficiency of the design process (Loureiro and

Curran, 2007).

Considering the CER developed for LEPRE, the

PubMed, ClinicalTrials and Cochrane databases have

been analyzed. Those databases present different

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150

characteristics and aims, and collect therefore

different kinds of data: the absence of duplicate

documents in the results of the corresponding search

strings among databases indicates that those

databases integrate each other, supporting the

appropriateness of analyzing them all. The analysis of

the clinical background emphasized the interest of

scientific research on this topic, especially in the last

years, as the ascending trend of the parameter p1

scores for the PubMed and ClinicalTrials databases

highlights. For the Cochrane database, a peak is

revealed for value 2; this behavior can be justified

considering that 2 points are assigned to a range of

years (2015-2017), unlike higher values, which refer

to single years. The high values of the p3 and p4

parameters support the suitability of the identified

search strings as detectors of the results’ clinical and

technical relevance respectively, since they allow

assessing population dimension, and importance and

applicability of the proposed scientific results.

Conversely, the p2 parameter can be considered a

valid indicator of methodological quality of the

investigation, since it expresses the correlation

between expected requirements imposed by the

search strings and actual content of the obtained

documents. A potential limitation of the proposed

approach is given by the evaluation of the ten most

recent documents for each query and each database,

but preliminary investigations suggested that this

value represented a reasonable compromise between

analysis quality and computational time. According

to this rationale, the number of evaluated documents

should be likely modified in case of analyses

performed on different fields, for instance, increased

when dealing with more traditional fields, like the

mechanical or the industrial one, which could

reasonably present a wider quantity of relevant

documents.

For the demonstration of equivalence, three

different devices had to be evaluated in order to

provide for a complete analysis of LEPRE device’s

functions, since no device currently on the market

provided a comparable set of features. The

comparison between LEPRE and device A allowed

demonstrating the clinical and technical equivalence

of the functions related to the mobilization of the

subject’s lower limb, since no differences

significantly affecting the equivalence can be

detected between the devices. In the same way, the

comparison with device B and device C allowed

fulfilling the clinical and technical equivalence for the

upper limb-related functions and the cycloergometer-

like features respectively. No demonstration of

biological equivalence was required since the user

shall wear gloves or socks while performing the

rehabilitative training with the LEPRE device. In fact,

in case of direct contact between patient and device,

MEDDEV 2.7/1 suggests the use of a biocompatible

material (International Organization for

Standardization, 2020) at a design process level, or

Figure 2: Bar plots of the assigned parameters’ scores in

aggregate form. From the top, the number of documents

with respect to the score and database, for a) publication

date (p1); b) accordance with search string (p2); c)

reference population (p3); and d) scientific consistency

(p4).

Design Approach of Medical Devices for Regulation Compatibility: A Robotic Rehabilitation Case Study

151

Table 4: Schematic comparison between LEPRE

characteristics and devices A, B and C respectively, with

respect to the parameters required for the clinical and

technical evaluation. Green checkmarks indicate a

complete overlapping of the characteristics between the

devices, whereas yellow checkmarks indicate a partial

equivalence: in the lower row of the table the detail of the

observed differences is presented.

A B C

Parameters for

Clinical Evaluation

Clinical condition

Intended purpose

Site of the body

involved

Reference

population

Parameters for

Technical Evaluation

Design structure

Conditions of use

Specifications and

properties

Deployment

methods

Principles of

operation

Differences Details

1. Device B can be adopted to also treat

pathologies related to the pelvic diaphragm

(e.g. incontinentia), currently excluded for

LEPRE device.

2. Device C can be adopted to also treat

pathologies such as hemodialysis, Alzheimer’s

disease/dementia,

percutaneous coronary

intervention (PCI), respiratory rehabilitation,

or poliomyelitis/post-poliomyelitis syndrome,

currently excluded for LEPRE device.

3. Reference population for the device also

includes pediatric subjects, currently excluded

for LEPRE device.

4. Device A presents overall dimensions and

weight remarkably higher than LEPRE device,

since it includes a seating system and supports

for the patient, unnecessary in LEPRE device.

the demonstration of biological equivalence at the

final stage. Nevertheless, the no-contact operational

condition assured by LEPRE also represents a

favorable asset for the use of rehabilitation devices

within the current scenario of the COVID-19

pandemic, easing the implementation of hygienizing

and sanitizing protocols.

5 CONCLUSIONS

The design process of medical devices must integrate

and optimize requirements related to technical and

clinical factors, user needs, therapy procedures, and

regulations’ constraints. The optimization of the

design process can be eased by the awareness about

the complex information net required by the

normative framework. Within this scenario, this

paper presents a design approach which aims at

easing the regulations compatibility of the designed

product, based on the custom mapping of required

data and referring documents for the development and

commercialization of a medical device according to

the CE marking process. This method is applied to the

illustrative case study of the LEPRE robotic system,

describing the data collection and analysis for the

device CER, as suggested MEDDEV 2.7/1

guidelines, with particular a focus on the evaluation

of clinical background and demonstration of

equivalence. Since the proposed method grounds on

the analysis of documentation that are strongly

dependent on the product operational conditions,

indications for the modifications required to adapt it

to further application fields are also suggested.

ACKNOWLEDGEMENTS

LEPRE was developed within the SIMeRiON project

(Innovative Mechatronics System for Orthopedic and

Neurological Rehabilitation), funded by Regione

Lombardia (bando FRIM FESR Aggregazioni

2016/18).

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