How to Create a Biological Sample Collection: Requirements and

Tips from an Academic Research Example in France

M. Medina Calderon

1,2 a

, C. Viennet

, Y. Pellequer

, F. Aubin

3,5 d

, P. Guillem

6,7 e

K. Mouyabi-Nkombo

, T. Lihoreau

1,9 f

and G. Rolin

1,3 g

Inserm CIC 1431, CHU Besançon, F-25000 Besançon, France

UFR Sciences de la Santé, Université de Franche-Comté, Besançon, France

Université de Franche-Comté, UMR 1098 RIGHT INSERM EFS, Besançon, France

Université de Franche-Comté, EA 4267 PEPITE, Besançon, France

Department of Dermatology, University Hospital of Besançon, Besançon, France

Department of Surgery, Clinique du Val d'Ouest, Ecully, France

RésoVerneuil, Paris, France

Department of Clinical Research and Innovation, University Hospital of Besançon, Besançon, France

Tech4Health Network - FCRIN, France

Keywords: Clinical Research, Tissue Collection, Biological Sample, Regulatory Approach.

Abstract: This short paper examines the regulatory needs behind the creation of a biological sample collection in France.

Many research projects, including for medical devices development and evaluation, need biological sample

collections, this article’s ambition is to provide a clear view of the requirements to create such collections.

Numerous laws from the Public Health Code frame research in the health sector in France, starting with the

definition of the research type, and going through the various documents needed, especially securing patient

safety (in link with Good Clinical Practices –GCPs) and data protection. To have a better insight into the

requirements to create a biological sample collection, the use of an on-going academic research will help

illustrate our purpose. This research did not involve human subjects, and therefore had a “simplified” path

regarding national competent authority approval, and what is called “reference methodologies”. Even though

the procedure was labelled “simplified”, numerous interactions are required such as with clinicians,

researchers, the clinical investigation center, the hospital research department, and different public

administrations including the Hospital, the Minister of Higher Education, Research and Innovation, the

National Commission for Data Processing and Liberty (CNIL), and the University of Franche-Comté.

1 INTRODUCTION

Collecting biological samples from patients is a key

for investigating and researching diseases and

treatments. A biological sample can refer to biopsies,

fragments of surgical specimens (tumorous or not),

blood, serum, umbilical cord blood, bone marrow,

bone, stem cells, or microorganisms isolated from

patients (https://www.chu-besancon.fr/la-recherche/

https://orcid.org/0000-0002-8841-2514

https://orcid.org/0000-0002-3538-7837

https://orcid.org/0000-0003-4318-974X

https://orcid.org/0000-0002-1421-4996

https://orcid.org/0000-0002-5449-3897

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

https://orcid.org/0000-0002-6234-869X

faire-de-la-recherche-au-chu/declaration-des-collecti

ons-dechantillons-biologiques.html). It is important

to note that the extraction of samples of tissues and

cells from the human body may only be carried out in

authorised health establishments.

A collection of human biological samples is taken

from a specific group of people identified and

selected according to their clinical or biological

characteristics. This collection must have a scientific

222

Medina Calderon, M., Viennet, C., Pellequer, Y., Aubin, F., Guillem, P., Mouyabi-Nkombo, K., Lihoreau, T. and Rolin, G.

How to Create a Biological Sample Collection: Requirements and Tips from an Academic Research Example in France.

DOI: 10.5220/0011924500003414

In Proceedings of the 16th International Joint Conference on Biomedical Engineering Systems and Technologies (BIOSTEC 2023) - Volume 1: BIODEVICES, pages 222-228

ISBN: 978-989-758-631-6; ISSN: 2184-4305

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

purpose (Légifrance, 2021).

Eventually, a sample collection will help to

understand the changes in tissues and cells related to

a disease, and thus help to develop better treatments,

diagnosis or medical devices specifically designed for

that illness. For exemple PrediMAP an in-vitro

diagnostic medical device in development that uses

collections of vaginal secretions, placenta and

membranes (Assistance Publique - Hôpitaux de Paris,

2022).

The law provides a framework for the collection

and conservation of these samples. However, the

creation of the procedure will involve many

interactions with different partners.

In France, the creation of a biological sample

collection requires a clear understanding of the

scientific and regulatory procedures. Therefore, the

French laws regarding the definition of a study and

the different categories of research are the starting

point. Then, to help illustrate the different interactions

the example of a French academic study that intends

to create a tissue and cell collection to further study a

skin disease will be used.

2 DEFINITION OF RESEARCH IN

FRANCE

As mentioned before, the creation of a collection

must have a scientific purpose, and must be part of a

research program, defined as a set of research

activities organized with a goal to facilitate and

accelerate discoveries in a specific scientific field,

defined by an organization carrying out or promoting

research activities (Légifrance, 2021).

In France, research in the health field can be

schematically divided into:

 Research “under Jardé law” or Research

projects Involving Human Subjects (RIPH

Recherche Impliquant la Personne Humaine);

 Research “outside Jardé law” or Research

projects not Involving Human Subjects.

It is to note that for medical devices, research falls

under the European Union Medical Device

Regulation (MDR) (European Parliament, Council of

the European Union, 2017). These categories will

lead to different procedures regarding the

authorisations required to start a biological sample

collection.

2.1 Research Projects Involving

Human Subjects

The research under Jardé law can be divided into

three different categories, each with their own

specifications according to the article L1121-1 from

the public health code (Légifrance, 2022a) :

 “ 1° Interventional research which includes an

intervention on the subject not justified by their

usual treatment;

 2° Interventional research involving only

minimal risks and constraints, the list of which

is specified by […] the Minister of health […];

 3° Non-interventional research that does not

involve any risks or constraints in which all the

medical acts are performed and the products

are used in the usual way.”

These different studies will later need different

authorisations.

For example, a study falling under 1° (or RIPH 1)

can only be conducted after a favourable opinion

from the Ethical Committee “Committee for the

Protection of Persons” (in France Comités de

Protection des Personnes or CPP) and after

authorisation from the national competent authority

(in France the Agence Nationale de Sécurité du

Médicament et des Produits de Santé or ANSM ). On

the other hand, the studies falling under 2° (or RIPH

2) and 3° (or RIPH 3) only need a favourable opinion

from the CPP. Here, the national competent authority

only needs to be informed of the opinion of the CPP

and sent a summary of the research (Légifrance,

2016).

On the same note, to follow the General Data

Protection Regulation (GDPR or RGPD from French

Règlement Général sur la Protection des Données)

different approaches will be required. To help the

implementation of these regulations the National

Commission for Data Processing and Liberty (CNIL

from French Commission Nationale de l'Informatique

et des Libertés) created reference methodologies (MR

from French Méthodologies de Reference) which

offer a framework for the implementation of research

treatments in the field of health. If the research

complies with these reference methodologies, a

referral to the ethic and scientific committee for

research, studies and evaluations in the field of health

(CESREES from French Comité éthique et

scientifique pour les recherches, les études et les

évaluations dans le domaine de la santé) is not

required. For RIPH the reference methodologies are

MR001 or MR003 (Section 3.3) (https://

www.cnil.fr/).

How to Create a Biological Sample Collection: Requirements and Tips from an Academic Research Example in France

223

2.2 Research Projects not Involving

Human Subjects

Research projects not involving human subjects are

studies that do not meet the definition of research

involving human subjects (section 2.1), in particular

studies relating to the reuse of data. The research must

also be in the public interest or a legitimate interest

(GDPR Info, 2016a).

This collection must also be submitted to the

CNIL and comply with the reference methodology

MR004 (Section 3.3) (Commission Nationale de

l’Informatique et des Libertés, 2018a).

3 TISSUES AND CELL

COLLECTION IN FRANCE

To illustrate the establishment of a biological sample

collection the example of a tissue and cell collection

in an academic research project will be used.

This study aimed to better understand the

biological processes that interfere with the

effectiveness of the local treatment of a skin disease.

The project uses tissue samples from a surgery

performed in the normal treatment of the patients in

the hospital in Besançon and a private clinic in Lyon.

In addition, these tissues, after pathological

examination, are considered as biological operative

waste, meaning that if they were not collected for this

research they would be discarded. It must be noted

that these samples can only be used after approval

from the patient.

Once the tissue samples have been gathered,

multiple in vitro and ex vivo tests will be performed.

Afterwards, a tissue (microscope slides) and cell

(primary cell culture) collection will be stored in the

university research laboratory. This research will

allow making numerous analyses for this disease

(Figure 1) from data gathered from the initial testing

but also after the collection has been created. It is

important to note that the objective of this collection

it is not to be distributed to other organizations but

only to be used in the research programs of the

institution (if the aim is to distribute the samples to

other organizations other documents are needed).

3.1 French Laws

Tissues, cells and human products removed during a

medical intervention when stored for later use, are

subject to the public health code (CSP from French

Code de la Santé Publique), and more precisely to

Figure 1: Schematic structure of the proposed academic

research and use of tissue samples.

Articles L1241-1 to L1245-8 about “Tissues, cells,

products of the human body and their derivatives”.

(Légifrance, 2022b).

During the establishment of a biological sample

collection within the context of an RIPH, the

collection no longer must be declared to the Ministry

of Higher Education, Research and Innovation

(Figure 2). However, the declaration of these samples

is necessary if they are stored following the study and

if this is the case, a requalification of the collection

before a CPP will be needed (Lemaire, 2019).

If the collection is formed during research

“outside Jardé law”, the collection must be declared

to the Ministry of Higher Education, Research and

Innovation but does not require the opinion of a CPP

(although it is recommended to have an opinion from

a local ethics committee for research).

This academic research project is listed as a study

“outside Jardé law”. It will then need (Figure 2):

 The approval of the Ministry of Higher

Education, Research and Innovation ;

 Compliance with the CNIL Reference

Methodology MR004 (Section 3.3);

 A favourable opinion from a local ethics

committee (not mandatory but recommended).

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Figure 2: Non-exhaustive diagram about the requirements

for the creation of a biological sample collection with

research “under Jardé law” and “outside Jardé law”.

3.2 Ministry of Higher Education,

Research and Innovation

To have the approval of the Ministry of Higher

Education, Research and Innovation for the

conservation of elements of the human body a

declaration must be made. This declaration consists

of a letter signed by the legal representative of the

applicant organization and a supporting document.

These two documents must be transmitted to the

Ministry of Higher Education, Research and

Innovation using the online webpage to submit the

files: “CODECOH” (from French COnservation

d'Eléments du COrps Humain) (https://

appliweb.dgri.education.fr/appli_web/codecoh/Ident

Codec.jsp).

The supportive document as explained by the

CODECOH has three essential parts: administrative,

methodologic, and scientific. The administrative part

will provide the basic information of the organization.

The methodologic part however needs the expertise

of field investigators familiar with the structure and

procedures of the laboratory where the samples will

be stored. Lastly, the scientific part guarantees the

compliance with the law; for example justifying the

importance of the envisioned research, data

protection procedures, or patient consent. Overall, the

procedure and information needed for the document

is documented by the Ministry of Higher Education,

Research and Innovation.

After the submission of a complete file, the

Ministry of Higher Education, Research and

Innovation has two months to notify its disagreement.

If there is no feedback during those months, the

project is allowed to start. (Ministère de

l’Enseignement supérieur, recherche et innovation,

2018).

3.3 CNIL

The CNIL is an administrative authority that helps

organizations comply with the RGPD (section 2.1).

This study “outside Jardé law” will need to act in

accordance with the CNIL reference method 004

(Commission Nationale de l’Informatique et des

Libertés, 2018a). To fulfil the MR004, multiple

procedures will have to be considered (Table 1).

This study will only collect the needed

information from the patient, more specifically

information about the progression of the disease and

the drugs the patient administered to treat it.

Additionally, this information will only be used by

the laboratory of the University to create a correlation

between the tissue structures and the progression of

the disease.

Concerning the reference method MR004, the

study must justify in the protocol why this

information about the patient must be collected.

Additionally, a procedure must be put together in

order to protect the privacy and data of the patients:

the information must be anonymised, the

correspondence table (patient-code) must be kept

secure and whoever has access to the information

must be identified from the beginning and be bound

to professional secrecy.

How to Create a Biological Sample Collection: Requirements and Tips from an Academic Research Example in France

225

Table 1: Non-exhaustive comparison of the different reference methodologies by the CNIL. (Commission Nationale de

l’Informatique et des Libertés, 2018b).

MR001 MR003 MR004

Data controlle

Stud

onso

Health Data Hub

registration

No Yes

Patient information

Only necessary information may be collected and a scientific justification in the protocol is

needed.

Duration of data

storage

Until the market launch of the

studied product or the same

duration as MR003 and

MR004.

Two years after the last publication of the research results or

until the release of the final research report.

Access to the data

Clear distinction between accesses to directly and indirectly identifying data. Whoever has

access to the information must be identified and be bound to professional secrecy.

Informing people and

res

ectin

their ri

hts

Written, free and informed

consent from the

atient.

Patient does not object to participating after having been

individuall

informed.

Security and Privacy

Data protection impact assessment carried out by the data controller.

Implement and monitor the application of a security and confidentiality policy.

Also, for this study, in order to comply with the

provisions of Article 13 of the GDPR (GDPR Info,

2016b), the patient must be notified of the

information that will be collected and its purposes.

Furthermore, the patient must be “not opposed” to the

collection of the biological sample or of data

concerning the disease in order to be included in the

study. For this, a patient information notice and non-

opposition will be written and handed in to the doctor

for the patient.

If information regarding the patient or doctors is

shared in the European Union, the reasons must also

be justified (Commission Nationale de l’Informatique

et des Libertés, 2018a).

3.4 University

The University of Franche-Comté (UFC) not only has

various research laboratories but also an ethical

committee for research.

This research project will take place in the

university laboratories with the required material for

ex vivo and in vitro sample testing and storage of

samples.

Even though is not legally needed to have an ethics

committee’s approval to perform the study, having one

will allow the publication of the study in American

journals too (Lemaire, 2006). The local ethical

committee for research will make sure the patients

included in the study are protected. For example, they

will assess the potential effect on patients, evaluate the

information given to participants, the treatment of

personal data and the potential threat of identification

(https://www.ubfc.fr/en/research/ethical-committee-

for-research/).

3.5 Hospital

The sponsor of this study is the University Hospital

of Besançon. Additionally, the tissue samples used in

this project will be acquired in the hospital and clinic.

The hospital department of Clinical Research and

Innovation (DRCI from French Délégation à la

recherche clinique et à l'innovation) and the Clinical

Investigation Centre (Inserm CIC 1431) have an

undeniable role in the regulatory aspect of the study.

The legally defined purposes of the DRCI are

(Légifrance, 2011) :

 “Promotion (organization, administration,

management, control, technical regulatory

support for clinical trials);

 Methodological assistance, data management;

and biostatistics (editorial help, clinical trial

design, database management)”.

According to the same legal document

(Légifrance, 2011), the CIC is a research structure of

the hospital that helps to develop studies by relying

on one side on an efficient research environment with

multiple parties and on the other side on the

recruitment of patients.

Thus, the multiple files needed will be handled by

the DRCI and the CIC: protocol, resume, budget,

patient notice, CODECOH, local ethics committee

document and partnership document between

hospital and university but also with the private clinic.

It must be noted that having more than one research

location (in this case hospital, university and private

clinic) will need more procedures regarding storage

and transport of the biological samples but also

legal documents confirming the agreements and

partnerships with the different sites.

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On the same note, it must not be forgotten to

classify the biological sample especially if it could be

an infectious substance and if it might go across

country borders. The rules on storage, packaging and

transportation (Genève : Organisation mondiale de la

Santé, 2019) are to be taken into account for the

protocol, partnership and CODECOH documents.

Overall, writing the protocol needed not only

information exchange with the DRCI and the CIC but

also with the hospital and the clinic doctors, as well

as with the university researchers, in order to provide

a strong clinical and scientific justification (the

“rational” of the study).

Figure 3: List summarizing the documents needed and the

exchanges of information: example from our proposed

academic research.

4 CONCLUSIONS

Biological sample collections are important to help

increase the understanding of a disease and eventually

improve patient care. The process needs to be part of

a clinical study, and as such various procedures and

documents are required to collect biological samples

from patients, posing an entry barrier.

In France, the procedure is regulated in a very

specific way that requires multiple contributors with

different skills in order to complete the project. There

is no “simple” way to obtain approvals, but this work

hopes to facilitate the approach.

It must be noted that this is only an example for a

French study, many of these procedures are not yet

harmonised in the European Union.

Even if there are tools to help identify the

applicable laws (http://campus.ecrin.org/) or to

identify the administrative authorities in the European

countries (such as the national competent authority

(https://www.ema.europa.eu/en/partners-networks/

eu-partners/eu-member-states), the ethics committee

(http://www.eurecnet.org/) or the data protection

authority (https://edpb.europa.eu/about-edpb/about-

edpb/members_en)), the research project’s specific

regulatory requirements need to be evaluated case by

case. Therefore, it is not surprising that the regulatory

needs of a study are dependent on the nature of the

research, the countries involved and the timing of

application of new regulations (the laws regarding

European clinical trials and clinical investigations are

constantly changing and databases might not be up-

to-date yet). Some examples of these complex

procedures can be seen in retrospective studies in

Europe (Houg, Lihoreau, Hennessy, Mouyabi, et al.,

2022), non-interventional studies in the European

Union (Ramirez, 2015) or multinational clinical

investigations for medical devices (Houg, Lihoreau,

Hennessy, Esperou, et al., 2022).

Consequently, for a multicentre and international

study aiming to create a biological sample collection

from different countries, the procedure will have a

tendency to become more complex. The study will

need to comply with multiple competent authorities

and possibly adapt to local requirements too (center

dependant).

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