Functional Analysis to Drive Research and Identify Regulation

Requirements: An Example with a Lithium Monitoring Device

K. Charrière

, C. L. Azzopardi

, M. Nicolier

1,3 c

, T. Lihoreau

, F. Bellivier

4,5,6,7 e

E. Haffen

1,3,8 f

and B. Wacogne

1,2 g

Centre Hospitalier Universitaire de Besançon, Centre d’Investigation Clinique, INSERM CIC 1431, 25030,

Besançon Cedex, France

FEMTO-ST Institute, Univ. Bourgogne Franche-Comte, CNRS, 15B avenue des Montboucons, 25030 Besancon Cedex,

France

Department of Clinical Psychiatry, CHU de Besançon, EA 481 Neurosciences, University Bourgogne Franche-Comté,

25030, Besançon Cedex, France

AP-HP, GH Saint-Louis, Lariboisière, F. Widal, Department of Psychiatry and Addiction Medicine,

75475 Paris cedex 10, France

Inserm, U1144, Paris, F-75006, France

Université Paris Descartes, UMR-S 1144, Paris, F-75006, France

Université Paris Diderot, Sorbonne Paris Cité, UMR-S 1144, Paris, F-75013, France

FondaMental Foundation, Creteil, Hôpital Albert Chenevier, Pôle Psychiatrie, 40 rue de Mesly, 94000 Créteil, France

{emmanuel.haffen, bruno.wacogne}@univ-fcomte.fr, frank.bellivier@inserm.fr

Keywords: Functional Analysis, Medical Device, Lithium Monitoring.

Abstract: Medical device development is often understood as a linear process with design stages occurring sequentially.

First stages are usually performed in order to specify the future device definition through interviews/meetings

of the end-users, researchers and manufacturers. Because the medical device is original, these first stages

mainly involve end-users and researcher. However, regulation constraints and economic reality sometimes

makes manufacturers hesitant to base the industrial development on this initial basis. Functional analysis, well

known by manufacturers, is a method used to accurately define the final functions of a medical device. In this

conference, we estimate that the functional analysis can be put to profit in a more efficient way if researchers

and end-users get familiar with it prior to the interview/meeting stages. Although the results of such

knowledge democratisation is not demonstrated here, we present the function analysis conducted on a lithium

monitoring device according to this multidisciplinary approach. We also show that function analysis can be

used not only to drive research actions but also to identify regulation requirements.

1 INTRODUCTION

Research and development actions in technologies for

health are usually driven by discussions and

experience exchanges between practitioners,

researchers and industrial partners. Because the need

https://orcid.org/0000-0003-4542-8003

https://orcid.org/0000-0003-2147-2042

https://orcid.org/0000-0001-5135-5109

https://orcid.org/0000-0001-8417-6609

https://orcid.org/0000-0002-3660-6640

https://orcid.org/0000-0002-4091-518X

https://orcid.org/0000-0003-1490-5831

to be addressed involves innovations that have never

been studied before, first discussions are often led by

practitioners and researchers with an academic point

of view. However, in the case of medical devices

developments, the main goal is neither to increase

knowledge nor to invent new technologies. The goal

is to answer the need as quickly as possible while

300

Charrière, K., Azzopardi, C., Nicolier, M., Lihoreau, T., Bellivier, F., Haffen, E. and Wacogne, B.

Functional Analysis to Drive Research and Identify Regulation Requirements: An Example with a Lithium Monitoring Device.

DOI: 10.5220/0010382503000307

In Proceedings of the 14th Inter national Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2021) - Volume 1: BIODEVICES, pages 300-307

ISBN: 978-989-758-490-9

proposing a new medical device which not only

addresses the need but also meets the manufacturer

interests and end-users wishes.

User driven medical device development is now

widely applied in different collaborative formats likes

Living Labs (Korman, 2016) or Hacking Health

organizations (Chowdhury, 2012). These approaches

have been more or less conceptualized a while ago. In

a well-organized and well-documented paper

(Money, 2011), it is recall that user-centred usability

engineering methods have already been proposed to

improve the Medical Device Design and

Development (MDDD) (Gosbee, 2002). Money and

co-workers describe the MDDD using 4 main

development stages, each of them involving distinct

actions. They can be summarized as follows. Stage 1

identifies the user’s need and involves enquiries and

interviews, both dealing with contextual and usability

issues. This forms the basis for the initial concept

which is further defined during stage 2 which uses

reduced focus groups deepening the initial concept

ideas. This produces requirements documents leading

to stage 3, fully oriented to the device manufacturing.

The device can then be evaluated during stage 4 in

order to check whether or not the users’ requirements

are satisfied. We assume that prototyping actions are

present between stages 2 and 3 or completely

included in stage 3.

In (Money, 2011), what manufacturers think of

the user-driven approach is analysed through

interviews. Instead of trying to rewrite their

conclusion, we simply reproduce the main points they

report. “The findings reveal that despite standards

agencies and academic literature offering strong

support for the employment formal methods,

manufacturers are still hesitant due to a range of

factors including: perceived barriers to obtaining

ethical approval; the speed at which such activity

may be carried out; the belief that there is no need

given the ‘all-knowing’ nature of senior health care

staff and clinical champions; a belief that effective

results are achievable by consulting a minimal

number of champions. Furthermore, less senior

health care practitioners and patients were rarely

seen as being able to provide valuable input into the

process”.

More generally, what is mentioned above also

applies to researchers who often misunderstand both

the manufacturer economic constraints and

patients/practitioners possibilities. Indeed, some

technical or scientific solutions can be incompatible

with a practical use or they can lead to an over-

expensive device. In these 2 cases other and more

realistic solutions must be explored, otherwise,

conditions to be safe, efficient and to match with the

local regulation will be difficult.

Indeed, since the very beginning of the MDDD,

discussions between end-users, researchers and

manufacturers must be somehow oriented/guided

towards realistic solutions. For this a conceptual tool

must be employed and this tool should ideally be

known (even partially) by all the stakeholders.

Functional analysis is a technology design tool

already well known by manufacturers but very rarely

by researchers and the reduced number of end-users

interviewed during the above mentioned stage 2. We

believe that functional analysis should be

pedagogically presented to end-users and researchers

prior to any enquiry. This pedagogical effort should

be clearly codified to allow beginners quickly

understanding main issues of this method and how it

can be used to drive the research and development

actions and to identify the corresponding regulation

issues. In this way interviews conducted to set-up the

initial prototype design can be focused on functional

analysis key points and the “expert” users can be

efficiently involved in stage 3 of the MDDD. At the

end, we think that what was called “end-users’

wishes” at the beginning of this introduction will

become “end-users’ highlights”, that researchers will

directly focus on realistically translatable solutions

and that manufacturers will be less hesitant to these

data into account.

In this conference, we do not present a

retrospective study on how this pedagogic effort is

put to profit to enhance MDDD, but we describe the

functional analysis which has been conducted in the

frame of the H2020 R-LiNK project (grant agreement

n°754907) according to this multidisciplinary

concept. The goal is to present how this analysis

accounts for end-users’ requirements, how it drives

the research actions to be privileged and how it allows

identifying regulation requirements. In the next

section, we rapidly presents the main goals of the R-

LiNK project. The functional analysis is described in

section 3. A short discussion is then proposed in

section 4 before some conclusive remarks are given.

2 THE R-LiNK PROJECT

The consortium of this European project led by Pr.

Franck Bellivier (INSERM UMR-S1144) is

composed of 22 European partners including research

institutes, hospitals, clinical investigation centers and

companies.

The main objective of R-LiNK is to identify the

eligibility criteria for treatment with lithium in bipolar

Functional Analysis to Drive Research and Identify Regulation Requirements: An Example with a Lithium Monitoring Device

301

disorder type 1 (BD1) patients in terms of response,

safety and tolerability. Research actions conducted to

find lithium response biomarkers involve

multidisciplinary research fields like “omics”

investigations, blood analyses, nuclear magnetic

resonance imaging and activity assessment. The

functional analysis presented in this paper is related

to treatment adherence as explained below.

2.1 Origin of the Project

Bipolar disorders (BD) are prevalent mental disorders

and a leading cause of suicide. Bipolar disorders are

lifelong lasting, with an episodic course of the illness

in most cases. Mood stabilizers are the mainstay of

treatment of BD and lithium is the gold standard

(Sani, 2017).

Indeed, a substantial minority of individuals

remain asymptomatic for years on lithium (about

20%) but most show only partial response and up to

one third do not respond (Burgess, 2001).

Furthermore, in current clinical practice, lithium

exposure is poorly controlled using laboratory tests.

First, it is usually verified only once or twice a year.

Second, adherence to chronic treatment is known to

be poor. Meanwhile, the prescription of lithium

remains delicate. For the treatment to be effective,

serum concentrations 10-14 h after the last dose taken

must reach 0.5 to 1.0 mEq/L. If plasmatic

concentration exceeds 1.2 mEq/L, toxic effects are

likely to occur (Amdisen, 1967; Baldessarini, 2013;

Bauer, 2016; Tondo, 2019).

Therefore, there is an important medical need to

first, provide the patients/practitioners with a simple

tool which could allow patients to become actor of

her/his treatment, hence improving the adherence to

treatment and second, to increase the frequency with

which the lithium level can be assessed in a non-

invasive manner. To this end, the device is intended

to be used at home by patients, so it’s a class C in vitro

medical device, according the European regulation

(EU 2017/746). The idea is not to replace laboratory

lithium dosing techniques but to create a simple

home-based lithium level indicator so that the patient

can check if her/his lithium level is below, within or

above the therapeutic window. A rapid analysis of the

home-based usability possibilities led us to consider

the detection of lithium in saliva. Also, because it will

be used at home by patients or by non-specifically

trained medical staff, the device must be carefully

designed and a complete functional analysis must be

performed.

3 FUNCTIONAL STATEMENT OF

THE NEED

Functional specifications documents are well

codified, even if different methodologies can be used

to write them. They can be separated in three parts:

 need analysis

 functional analysis

 technical specification

Before and during constitution of functional

specifications, studies are carried out to better

understand the needs of potential customers.

3.1 Analysis of the Need

Analysis of the need is an essential phase because it

dictates the direction of the future work. The needs

and the objectives should be clearly identified and

formalized.

To do this, different tools can be used; one of them

is the APTE® method (see for example (APTE, no

date)). This method starts from the expression of a

need, without considering any technical solutions. It

constitutes the first phase of design leading to the

edition of the functional specifications. Three

questions have to be considered.

 To whom is the “product” useful?

 What does the “product” acts on?

 What is the purpose of the “product”?

3.1.1 Expression and Characterization of

the Need for R-LiNK Monitoring

Device

In our project, the “product” is the monitoring device.

To whom is the “product” useful? The R-LiNK

monitoring device is useful to patients suffering from

bipolar disorder and the medical staff. What does the

“product” acts on? It acts on patients’ saliva to assess

lithium levels. What is the purpose of the “product”?

It aims at improving treatment adherence and to avoid

relapse by self-monitoring and self-management.

Furthermore, it aims at minimizing (avoid if possible)

the risk of lithium overdose. This is illustrated in

figure 1.

This first expression of the need is of course

essential but not sufficient. Indeed, the need will be

correctly addressed only if the expected performances

of the device are obtained. Therefore, the need has to

be clearly characterized specifying qualification and

quantification to estimate measurable quantities.

For the R-LiNK monitoring device, the need will

be satisfied if the device allows lithium detection

ClinMed 2021 - Special Session on Dealing with the Change in European Regulations for Medical Devices

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between 0.5 and 4 mM, with 0.2 mM accuracy and

improve treatment adherence, among others.

Figure 1: R-LiNK monitoring device: expression of the

need.

3.1.2 Validation of the Need

Here, the questions to be answered are defined as

follows. What is the origin of the need or why is the

device wanted? What can change the need or even

makes the need disappear?

The need of detecting lithium with a simple

monitoring device comes from practitioner facing

some clinical issues.

First, as described above, 30-55% of individuals

selected for treatment with lithium will not have the

predicted outcome. One possible cause to the non-

efficacy of the treatment is the non-adherence to

treatment. Second, lithium can be toxic and the

therapeutic window is limited, between 0.5 and 1.2

mM in plasma with toxic effects above the maximum

value.

These two issues will not disappear but

technological or pharmaceutical developments may

change clinical practices. One major evolution has

been identified: emergence of new medicine for

bipolar disorder leading to stopping the use of lithium

therapy.

Taking these elements into account, it is therefore

unlikely that the need for a new lithium monitoring

device disappears completely.

3.2 Establishment of Service Functions

and Constraints

Since the need has been validated, the functional

analysis can continue and a list of functions can be

established. First, it’s important to better understand

what a function is. Looking normative definition

issued from the French Association for

Standardization (AFNOR), a function is an action of

a product or one of its constituents expressed

exclusively in terms of purpose.

Therefore, it is required to disregard technological

solutions. In order to help defining these functions, an

interactions diagram of the device with its

environment can be drawn. The diagram defines the

limits of the device and specifies the life situation

being studied. This is presented in figure 2. In this

figure, bubbles represent the physical elements of the

environment that have impact on the device. Lines

characterize functions linking the system to its

environment.

Figure 2: R-LiNK monitoring device interaction diagram

for the “normal use” life situation.

Two types of functions exist: the main function

and constraint functions. The main function reflects

actions performed by the device, the constraint

functions reflect an adaptation of the device to its

environment. Therefore, the environment has to be

defined for a specified life situation. In our R-LiNK

example, the diagram represents the life situation

“normal use”.

Environment of the R-LiNK monitoring device

consists of:

 users

 biological sample

 user’s place

 European standards (IVD MD 2017/746)

 European market

Functions are defined as follows.

Main function:

 MF1: the device indicates the level of lithium in

the biological sample.

Functional Analysis to Drive Research and Identify Regulation Requirements: An Example with a Lithium Monitoring Device

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Constraint functions:

 CF1: the device is suitable for all users

 CF2: the device is suitable for home use

 CF3: the device respects the regulations in force

 CF4: the device integrates the European market

at a reasonable cost

Note that the market is not a physical element, but

cost is really a constraint to take in account at the

beginning of the development. That’s why we chose

to include this notion in our functional analysis of the

need.

3.2.1 Justifications of Functions

To ensure the function is really necessary, it’s

possible to ask, as for the need: what is the purpose,

the origin and the probability to disappear for each

function?

For the R-LiNK device, the purpose of MF1 is to

improve treatment adherence by self-monitoring and

to minimize or avoid the risk of lithium overdose or

under dosing. New medicine for bipolar disorder

leading to the stopping lithium therapy can make the

function disappear. Eliminating the function is

unlikely. The function is validated.

The purpose of CF1 is to meet the expectations of

user comfort whatever the patient's physical condition

is because: the patient can use the product easily and

quickly so they can monitor themselves without

demotivation, the patient is looking for effective

products that provide him with a certain comfort of

use. Eliminating the function is unlikely. The

function is validated.

The purpose of CF2 is to meet the expectations of

user comfort whatever the place of use because

patients have to regularly monitor themselves at home

or at their place of holiday, during their work travels.

Eliminating the function is unlikely. The function is

validated.

The purpose of CF3 is to be able to commercialize

the device and to assure the user that the product has

been approved and that he can therefore use. The

products sold must be certified by standards of quality

and safety. Eliminating the function is unlikely. The

function is validated.

The goal of CF4 is to enable the use of the device

throughout the European Union at a reasonable cost

because all patients are concerned and reimbursement

rules are not identical for the entire European

community. Eliminating the function is unlikely. The

function is validated.

3.2.2 Functional Analysis and Usability

At this stage of the functional analysis, details can be

provided to really meet the end-users’ need. It is often

made by brainstorming or interview with the various

stakeholders. In our project, these investigations led

to the conclusions given below.

 The device must measure lithium quickly (5

minutes if patients have to wait for results, more

if the result is recorded).

 The device must to detect lithium in the

therapeutic window (ideally 0.5 mM to 5 mM,

with an accuracy of 0.2 mM in saliva).

 The device must be non-invasive (use of saliva

instead of blood).

 The device has to deliver the results in an

understandable manner.

 The device must be easy to use, compact and

mobile.

 Finally, the device must be easily stored after

use.

3.2.3 Characterization of Service Functions

and Constraints

Based on all these indications, the functions are then

defined with criteria, levels, and tests to be

performed. This is summarized in table 1.

Note that in table 1, we inserted a column titled

“flexibility”. This estimates how negotiable can be

the results expected in columns “criteria” and

“levels”. Flexibility is defined as follows:

 F0 means zero flexibility, imperative level

 F1 means low flexibility, little negotiable level

 F2 means good flexibility, negotiable level

 F3 means strong flexibility, very negotiable

level.

After this functional analysis of the need,

technological solutions can be envisaged. At this

stage, it is essential to think about the solutions

objectively and without restrictions. To do this, a

Functional Analysis System Technique (FAST) is

useful (FAST1, FAST2, FAST3, no date). Among

other methods, the use of FAST allows a highly

multidisciplinary consortium to speak the same

language. Structured analysis and design technique,

also termed SADT (Ross, 1985), may be used too, but

we think it is more adapted when the technical

solution is already chosen.

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Table 1: Definition of the functions.

N° Function Criteria / standard Levels Flexibility Tests

MF1

Monitor the level of salivary

lithium

Indicate the level of lithium

in saliva comprehensively

for the patient

0,5 mM to 5 mM

100 µL saliva

Without

contamination

Accuracy 0.2 mM

Performance tests in the

laboratory on artificial samples

then on real calibrated samples.

Tests in real conditions of use

CF1 Suitable for all users

The patient easily uses the

device without errors

Pass the aptitude

to use tests

Formative and summative

evaluation tests

CF2 Suitable for home use

The device works in the

patient's environment:

home, holidays

Pass the aptitude

to use tests

Formative and summative

evaluation tests

CF3

Respect the regulations in

force

Complies with the new

European IVMD regulation

(auto-monitoring)

UE 2017/746 F0 Respect the regulation in force

CF4

Integrate the European

market at a reasonable cost

The cost is not a hindrance

for the patient or the

institutions

Consumable 10 €

Cartridge reader

300 €

Estimated costs by item,

including raw materials and an

estimate of manufacturing costs

FAST allows, among other things, organizing and

understanding relationship between functions. It

helps identifying missing or redundant functions. All

functions can be analyzed in the same way. The

method consists in asking, for each of them: why do

you do [Function], how do you do [Function] and

when you do [Function] is there another function that

occur together with or as a result of [Function]? This

can be formalized using the codified diagram

presented in figure 3.

Figure 3: General principle for establishing a FAST

diagram.

The FAST diagram corresponding to the device

developed in the frame of the R-LiNK project is

presented in figure 4. In this figure, the first column

(on the left hand side) corresponds to functions.

Identification of these functions should ideally take

place during the stage 1 of the MDDD described in

the introduction of this document. The identification

of the items presented in the second columns should

be made during stage 2. The third and fourth columns

should be filled during the end of stage 2 or the

beginning of stage 3 depending on where the

prototyping actions are performed. The idea of this

conference is not to go through each items depicted

in figure 4. However, we shortly describe how the

main function analysis lead to “usability” solutions.

The MF1 function is analyzed as follows.

 In order to assess the lithium level in the

biological sample it is necessary to put the

saliva in contact with the sensor’s reagents.

 For this, the user must be able to collect the

saliva.

 In order to collect the saliva, different

technical solutions can be used: use an existing

saliva sampling device (Salivette® type) or

spit in a recipient.

Here, we recall that the scientific or technological

solutions are listed in column 4 but the final choice is

not yet made. This is because, in the frame of our

functional analysis, the goal is not yet to select the

final solutions but to identify all of them as we already

mentioned above while writing that we should

disregards technological solutions.

Indeed, when the FAST diagram is finalized,

practical work can start. This is the prototyping phase

which should take place during stage 2 or 3 of the

MDDD method already mentioned. Choice of the

technical solutions or specialty areas where research

efforts should be put can now be finalized in

accordance with the end-users’ “highlights” and

regulation constraints. Because our device is intended

to be used in the European community, the regulation

documents listed in figure 4 correspond to a part a part

of required standards to comply with the European

Regulation.

Functional Analysis to Drive Research and Identify Regulation Requirements: An Example with a Lithium Monitoring Device

305

4 A BIT OF DISCUSSION

We have seen that the functional analysis allows

defining what a medical device should be in order to

meet requirements of end-users, researchers and

manufacturers in accordance with the regulation

constraints. The FAST diagram summarizes these

aspects. Including this diagram in the general MDDD

plane proposed elsewhere, we understand that the

functional analysis takes place at the beginning of the

development, mainly during stages 1 and 2.

In order to be efficiently conducted, the functional

analysis must involve all the stakeholders which

includes not only manufacturers who already know

this kind of analysis but also end-users and

researchers. For this, a pedagogic effort must be made

which is not in the scope of this conference.

However, if we only stick to this understanding,

there is a risk that the functional analysis is

considered as a background task which extends over

the beginning of the MDDD process. The

consequence could likely be that important

information highlighted during the functional

analysis are under-estimated during the prototyping

phase, if not simply forgotten. It is therefore crucial

that actors try to consider the development of a

medical device not like a process linear in time but as

a whole.

The linear perception of technological

developments is nowadays probably due to the

importance that the TRL scale has gained these last

decades. This “Readiness Technology Level” scale

was originally proposed by the NASA to improve

technology developments. However, the NASA

proposed a more general and less linear development

model with the so-called CML scale, namely the

“Concept Maturity Level” scale (Ziemer, 2013).

Readers interested in this method can refer to (CML1,

CML2, no date). The CML scale has recently been

adapted to the medical device development (Béjean,

2019). The development is now not only described

but also driven through 3 main dimensions: need,

science and technology, programmatic.

We think that the functional analysis can

efficiently be used to link the above mentioned 3-

dimensional development descriptions.

Figure 4: FAST diagram obtained for the home-based lithium monitoring device of the R-LiNK project.

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5 CONCLUSION

In this paper, we have presented how function

analysis can be used to drive research and

development actions and to identify regulation

constraints during the development of medical

devices. An example of functional analysis conducted

to design a home-based lithium monitoring device is

given. It is shown that function must be identified and

characterized and that technological solutions and

regulation constraints arise from this analysis. At this

stage, scientific or technological techniques used in

the final medical device are not yet chosen. They will

be chosen during the subsequent prototyping phase

according to the identified regulation constraints.

But, beyond the only description of a functional

analysis, we pointed out that an efficient design of a

medical device implies controlled discussion between

end-users, researchers and manufacturers. In order to

ensure these fruitful discussions and exchanges of

experience, a common innovation frame must be

adopted. The idea here is that functional analysis can

be this common frame to the condition that it is

pedagogically explained and presented to

stakeholders less familiar with it than manufacturers.

Functional analysis can then be regarded as a

common thread in the design and development

process.

This methodology is currently applied to the

lithium monitoring device developed in the frame of

the H2020 R-LiNK project and results of this

development will be available soon.

ACKNOWLEDGEMENTS

R-LiNK has received funding from The European

Union’s Horizon 2020 Research and Innovation

program Under Grant Agreement N° 754907.

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