nis considerations - france · final study report 51 notiﬁcation of information that may impact...

NIS Considerations - FranceAn overview of the considerations when conducting Non-interventional Studies in France

Stuart McCully • CHCUK Ltd • NIS-C-FR-2014 (Mar 2014)

© Dr Stuart McCully 2014NIS-C-FR-2014 (Mar 2014)

Table of Contents

Disclaimer 7

Acknowledgement 8

Document History 9

SUMMARY OF CHANGES SINCE PREVIOUS VERSION 9

Study Classification 15

GENERAL CONSIDERATIONS WHEN PLANNING NIS 15

Once you’ve classified your clinical research as a non-interventional study it’s important that you then identify and address the country-specific regulatory requirements: 16

STUDY CLASSIFICATION - USEFUL LINKS 17

Regulatory Requirements 18

COUNTRY-SPECIFIC REGULATORY REQUIREMENTS 18

REGULATORY BODIES 18

DEFINITION 19

Non-Interventional Study for a Marketed Drug 19

Post-Authorisation Efficacy Study (PAES) 19

Post-Authorisation Safety Study (PASS) 19

REGULATORY FRAMEWORK 20

Applicable Legislation & Guidance 20

SUMMARY OF THE NIS REQUIREMENTS IN FRANCE 21

NIS Approval Requirements: Multi-Country Mandated Post-Authorisation Safety Studies (PASS) 21

©"Dr"Stuart"McCully"2014NIS4C4FR42014"(Mar"2014)

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NIS Approval Requirements: France-Only Mandated Post-Authorisation Safety Studies (PASS) 21

NIS Approval Requirements: Other NIS 22

NIS Approval Requirements: Other NIS Involving Collection of Biosamples or Application of Extensive Monitoring 22

APPROVAL & NOTIFICATION REQUIREMENTS 24

Submission Requirements: Multi-Country Mandated Post-Authorisation Study (PASS) 24

Submission Requirements: France-Only Mandated Post-Authorisation Study (PASS) 25

Submission Requirements: Other NIS 26

Submission Requirements: Other NIS Involving Collection of Biosamples or Application of Extensive Monitoring 27

WHO IS RESPONSIBLE FOR WHAT? 28

REGULATORY SUBMISSIONS ROADMAPS 30

Regulatory Map: Multi-Country Mandated Post-Authorisation Safety Studies (PASS) 30

Regulatory Map: France-Only Mandated Post-Authorisation Safety Studies (PASS) 31

Regulatory Map: Other NIS 32

Regulatory Map: Non-Interventional Studies Involving Collection of Biosamples or Application of Extensive Monitoring 33

REGULATORY SUBMISSIONS DOCUMENTS 34

REGULATORY REQUIREMENTS - USEFUL LINKS 36

Study Conduct Considerations 39

GENERIC REQUIREMENTS FOR NIS 39

Authorisation by the Drug Competent Authority (ANSM) 39

Favourable Ethics Opinion 39

CNOM Approval 40

Pharmacovigilance Systems 41

Audits of the Pharmacovigilance System 41

Safety Reporting 41

Healthcare Professionals and Patients 41

Marketing Authorisation Holders 42


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Requirements Regarding the Summary of Product Characteristics (SmPC) 43

Declaration of Transfers of Value 43

Summary 43

Transparency Law References 45

Main Obligations of the Law 45

Items Subject to Disclosure 45

Beneficiaries 46

Publication via the Internet 46

Publication Procedure 47

Identity of the Declaring Organisation 49

Retroactivity 50

Article 4113-6 CSP and Article R 4113-105 CSP - Law Dmos (Anti-Present Law) 51

POST-AUTHORISATION SAFETY STUDIES (PASS) 51

Prohibition of Promotion 51

Progress Reports 51

Final Study Report 51

Notification of Information that May Impact the Risk-Benefit Profile of the Marketed Product 52

Mandated Non-Interventional Post-Authorisation Safety Studies 52

Multi-Centre Mandated NI PASS 52

France-Only Mandated NI PASS 52

Substantial Amendments 53

End-of-Study Report 53

STUDY CONDUCT CONSIDERATIONS - USEFUL LINKS 54

Data Privacy Considerations 56

DATA PROTECTION 56

Authorisation by the Data Protection Competent Authorities (CCTIRS & CNIL) 56

CCTIRS Approval 57

CNIL Approval 58


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Simplified Procedure 58

Simplified Formalities to Declare Personal Data Transfers Abroad 58

To Summarise... 59

DATA PRIVACY CONSIDERATIONS - USEFUL LINKS 61

Human Tissue Research Considerations 62

DEFINITIONS 62

Biobanks 62

Data Controller 62

Data Processing 63

Recipient of a Processing of Personal Data 63

Sensitive Data 63

REGULATORY FRAMEWORK 63

Informed Consent 64

Consent to Export of Biosamples 64

“Non-Opposition” for Secondary Use of the Biological Material 64

Authorisations and Notifications 65

Collection, Storage, Use of Human Biological Material for Research 65

Export of Human Tissue 65

DATA PROTECTION 67

Data Transfer Requirements 67

Data Controller 67

Data Subject 68

Confidentiality and Security 69

Notification and Authorisation 69

Data Transfer Within the EU 70

Data Transfer Outside of the EU 70

Data Transfer (or Export) Notification for Medical Research Purposes (Simplified Declaration Procedures) 71

Contractual Clauses, Binding Corporate Rules (BCR) and Safe Harbor (for Transfers to USA) Ensuring an Adequate Level of Data Protection in the Export 71


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Advice/Authorisation for the Transfer and Processing of Personal Data Outside the EU for Medical Research Purposes 72

TRANSPORT REQUIREMENTS 73

HUMAN TISSUE RESEARCH CONSIDERATIONS - USEFUL LINKS 75

Best Practice Considerations 76

PHARMACEUTICAL SELF-REGULATION 76

Purpose 76

Prohibition of Promotion 76

Limited Involvement of Medical Representatives 76

Study Protocol 77

Company Oversight 77

Remuneration 78

Use of Consultants 79

Contracts 80

Market Research 80

Prohibition of Gifts 81

Informational or Educational Materials and Items of Medical Utility 81

Study Results 81

Communication of Results Important to the Risk-Benefit Profile of the Marketed Drug 82

Applicability to Other Types of Studies 82

BEST PRACTICE CONSIDERATIONS - USEFUL LINKS 83

NIS Definitions 84

EUROPEAN NIS DEFINITIONS 84

NIS DEFINITIONS 84

Non-interventional Study (NIS) 84

Post-authorisation Safety Study (PASS) 85

Post-authorisation Efficacy Studies (PAES) 86

Common NIS Terminology 87


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DisclaimerAlthough this Compilation contains information of a legal nature, it has been developed for informational purposes only and does not constitute legal advice or opinions as to the current operative laws, regulations, or guidelines of any jurisdiction. In addition, because new standards are issued on a continuing basis, this Compilation is not an exhaustive source of all current applicable laws, regulations, and guidelines relating to non-interventional studies. While reasonable efforts have been made to assure the accuracy and completeness of the information provided, researchers and other individuals should check with local authorities and/or research ethics committees before starting research activities.


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AcknowledgementMy thanks go to Mark Heinemann for his support in researching the updates to the French Laws applicable to non-interventional studies (NIS).

Acknowledgement: Mark Heinemann, Senior Submission Specialist, Late Stage Group, inVentiv Health Clinical


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Document HistorySUMMARY OF CHANGES SINCE PREVIOUS VERSION

Summary of the changes since the previous of the NIS Considerations: France report (NIS-C-FR-2012)

NOTE: Look for the sections highlighted in the colour on the left. This is a visual indication that a section has been updated or is new

Area Impacted Details

Company Name Change “Compliance Healthcheck Consulting UK Ltd” is now “CHCUK Ltd”

Legislation - Updated Pharmacovigilance Legislation

Updated Pharmacovigilance Legislation

Decree No 2012-1244 of November 8, 2012 relating to the strengthening of the safety provisions of medicinal products for human use subject to market authorization and pharmacovigilance

Transposes Directive 2010/84/EU into national law:

• Serious Adverse Effects (e.g., ADRs) to be notified to the authorities with 15 days (as per current practice)

• Non-serious AEs to be notified to the authorities within 90 days (previously notified only in the PSURs)

• Serious and non-serious AEs to be notified via EudraVigilance by the ANSM and companies by 2015 (at the latest)

[read more...]


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http://www.legifrance.gouv.fr/affichTexte.do?categorieLien=id&cidTexte=JORFTEXT000026592596&dateTexte=




Study ClassificationGENERAL CONSIDERATIONS WHEN PLANNING NIS


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It Depends!

What are the regulatory

requirements for my NIS?

Before starting your clinical research It’s important that it is correctly classified as this that dictates what regulations and guidelines are applicable to the conduct of your clinical research.

For example, in Europe the following applies:

Post-Authorisation Study Interventional

Non-Interventional

Mandated PASS/PAES

Other

Clinical Trials Directive (2001/20/EC) & EC

Guidelines

EU Pharmacovigilance Legislation & EMA GVP

Guidelines

Country-Specific Legislation & Guidelines

Once you’ve classified your clinical research as a non-interventional study it’s important that you then identify and address the country-specific regulatory requirements:

Mandated study? Prospective study? Retrospective study? Is the drug reimbursed? Which patient populations? Are the patients legally competent? Are the patients dead? Tissue collection? Tissue biobanking? Genetic analysis? Secondary use of data or tissues? Submission procedures

Notifications Approvals Registration Classification Insurance requirements

Which countries?

What? Where?

How?


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STUDY CLASSIFICATION - USEFUL LINKS

Useful Links Accessed From

Clinical Trials Directive (2001/20/EC) http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf

Pharmacovigilance Directive (2010/84/EU) http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf

EMA Good Pharmacovigilance Practices (GVP)

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp&mid=WC0b01ac05804fcdb1

EMA Guidance on the 2010 Pharmacovigilance Legislation

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000492.jsp&mid=WC0b01ac058033e8ad

EMA Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 1 - April 2013)

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129137.pdf


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http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf






























Regulatory Requirements COUNTRY-SPECIFIC REGULATORY REQUIREMENTS

REGULATORY BODIES

Competent Authority

Research Ethics Committees

Data Protection Agency

Data Protection Advisory Committee

National Medical Council

Pharmaceutical Self-Regulation Body

Pharmaceutical Code of Practice

Agence nationale de sécurité du médicament et des produits de santé (ANSM)

Comité de Protection des Personnes (CPP)

Commission Nationale de l'Informatique et des Libertés (CNIL)

Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé (CCTIRS)

Conseil National de l'Ordre des Médecins (CNOM)

Les Entreprises du Médicament (LEEM)

LEEM Code of Practice 2014


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http://www.ansm.sante.fr/?UserSpace=default


http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm

http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm

http://www.cnil.fr

http://www.cnil.fr

http://www.enseignementsup-recherche.gouv.fr/cid20537/cctirs.html


http://www.conseil-national.medecin.fr

http://www.conseil-national.medecin.fr

http://www.leem.org

http://www.leem.org

http://www.leem.org/sites/default/files/01%2001%202014%20DDPfinal.pdf


DEFINITION

Non-Interventional Study for a Marketed Drug

A non- interventional study for a marketed drug is defined as a study in the context of which the drug or drugs is (are) prescribed (s) under normal conditions in accordance with the terms of the marketing authorization authorization. The decision to use a particular therapeutic strategy for a patient is not taken in advance as part of a trial protocol but intervenes in the course of the current practice and the prescription drug is not related the decision to include the patient in the study. No additional diagnosis will be performed, no additional monitoring procedure will be implemented for the patient and epidemiological methods shall be used to analyze the data collected (as per paragraph 1.2.6 of the LEEM HCP Code).

Post-Authorisation Efficacy Study (PAES)

Any biomedical research or observational study on the effectiveness in routine clinical practice on a drug or product (as per Decree No. 2012-1244).

Post-Authorisation Safety Study (PASS)

Any study of a drug or a licensed product to identify, characterize or quantify the relative risk to safety, confirm the safety profile of the drug or to measure the effectiveness of risk management (as per Decree No. 2012-1244).


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REGULATORY REQUIREMENTS - USEFUL LINKS


Act No. 78-17 (as amended) - Relating to Computers, Files and Freedoms

http://www.cnil.fr/documentation/textes-fondateurs/loi78-17/#c329



Business- Health Transparency Web Portal

Unique website managed by French MoH for declaration of data under the French Transparency Act

[Note - You may have difficulty accessing the site as the sites security certificate isn’t currently listed as ‘trusted’ and is therefore regarded by most web browsers as a security threat]

https://www.entreprises-transparence.sante.gouv.fr/flow/login.xhtml;jsessionid=4B1FC97C6F4CD26EF8474F60B1ACC915.sunshine-entreprise#

Business- Health Transparency Web Portal: Frequently Asked Questions

https://www.entreprises-transparence.sante.gouv.fr/flow/info_faq.xhtml

Bylaw of 03 December 2013 reg. the functioning of the “single public internet webpage” mentioned in Art. 1453-4 CSP as published on December 19th, 2013

http://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000028339198&fastPos=2&fastReqId=1620812446&c

CCTIRS Manual http://media.enseignementsup-recherche.gouv.fr/file/84/2/20842.pdf

CCTIRS Submission/ Application Form http://media.enseignementsup-recherche.gouv.fr/file/organigramme/72/3/formulaire_CCTIRS_mai_2008_27723.rtf

CNIL - Obligations of Personal Data Controllers

http://www.cnil.fr/vos-obligations/vos-obligations/

CNIL - Practical Information Guide on formalities for the creation (and processing) of data for medical research, of 2008, providing specific information on administrative processes

https://www.formulaires.modernisation.gouv.fr/gf/getNotice.do?cerfaFormulaire=10769&cerfaNotice=51354

CNIL - Procedures for Doctors and Researchers in the Health sector

http://www.cnil.fr/vos-obligations/declarer-a-la-cnil/mode-demploi/comment-declarer/les-autorisations-du-secteur-sante/


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CNIL - Simplified Declaration Procedure for Biomedical Research

http://www.cnil.fr/les-themes/sante/fiche-pratique/article/une-procedure-simplifiee-de-declaration-pour-les-recherches-biomedicales/

CNIL - The Transfer of Data Outside of the European Union

http://www.cnil.fr/vos-obligations/transfert-de-donnees-hors-ue/

CNOM approval required as per the requirements of the Article R4113-105 of the Public Health Code

http://www.legifrance.gouv.fr/affichCodeArticle.do?idArticle=LEGIARTI000027435590&cidTexte=LEGITEXT000006072665&dateTexte=20140228&oldAction=rechCodeArticle

CNOM Code of Ethics http://www.conseil-national.medecin.fr/groupe/17/tous

CNOM Model Contracts http://www.conseil-national.medecin.fr/groupe/33/tous

Comité Consultatif sur le Traitement de l’Information en matière de Recherche dans le domaine de la Santé (CCTIRS)


Comité de Protection des Personnes (CPP) http://www.recherche-biomedicale.sante.gouv.fr

Commission Nationale de l'Informatique et des Libertés (CNIL)

http://www.cnil.fr

CPP Documents and Forms http://www.recherche-biomedicale.sante.gouv.fr/pro/documents/accueil.htm

CPP Guidance on the Management of Biomedical Research

http://www.recherche-biomedicale.sante.gouv.fr/pro/guide/accueil.htm

Declaration of Helsinki (2013) http://www.wma.net/en/30publications/10policies/b3/

Decree n° 2013-414 du 21 mai 2013 http://legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000027434029&categorieLien=id

Decree No 2012-1244 of November 8, 2012 http://www.legifrance.gouv.fr/affichTexte.do?categorieLien=id&cidTexte=JORFTEXT000026592596&dateTexte=

Decree No 2005-1309 (as amended) http://www.legifrance.gouv.fr/affichTexte.do?cidTexte=LEGITEXT000006052581&dateTexte=20090319


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Study Conduct ConsiderationsCONSIDERATIONS WHEN CONDUCTING NIS IN FRANCE

GENERIC REQUIREMENTS FOR NIS

Authorisation by the Drug Competent Authority (ANSM)

There is currently no requirement for NIS to be notified to, or approved by the ANSM, unless they are mandated non-interventional post-authorisation safety studies.

Favourable Ethics Opinion

In countries where ethics committees have jurisdiction to review such studies, the study protocol must be submitted to them (as per paragraph 1.2.6.d of the LEEM HCP Code).

According to the Public Health Code, only biomedical research needs an approval from an IRB/ IEC (Comité de Protection des Personnes: CPP) in France. Non-Interventional Studies do not require CPP review (EFGCP Report, France). Biomedical research is defined as research requiring intervention (like a treatment), or a constraint (e.g., a blood sample), not envisaged in the normal medical follow-up of the patient.

Whereas, research carried out on data from the usual management of the patient is not considered as biomedical research, but as observational research. This involves data obtained retrospectively (e.g., from medical records), post hoc analyses from data obtained for another goal (i.e., data obtained from the patient’s usual care or from other research) or new prospective data (Claudot et al. 2009).


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STUDY CONDUCT CONSIDERATIONS - USEFUL LINKS




Business- Health Transparency Web Portal

Unique website managed by French MoH for declaration of data under the French Transparency Act

[Note - You may have difficulty accessing the site as the sites security certificate isn’t currently listed as ‘trusted’ and is therefore regarded by most web browsers as a security threat]

https://www.entreprises-transparence.sante.gouv.fr/flow/login.xhtml;jsessionid=4B1FC97C6F4CD26EF8474F60B1ACC915.sunshine-entreprise#

Business- Health Transparency Web Portal: Frequently Asked Questions

https://www.entreprises-transparence.sante.gouv.fr/flow/info_faq.xhtml

Bylaw of 03 December 2013 reg. the functioning of the “single public internet webpage” mentioned in Art. 1453-4 CSP as published on December 19th, 2013

http://www.legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000028339198&fastPos=2&fastReqId=1620812446&c

CNOM approval required as per the requirements of the Article R4113-105 of the Public Health Code

http://www.legifrance.gouv.fr/affichCodeArticle.do?idArticle=LEGIARTI000027435590&cidTexte=LEGITEXT000006072665&dateTexte=20140228&oldAction=rechCodeArticle

CNOM Code of Ethics http://www.conseil-national.medecin.fr/groupe/17/tous

CNOM Model Contracts http://www.conseil-national.medecin.fr/groupe/33/tous

Comité de Protection des Personnes (CPP) http://www.recherche-biomedicale.sante.gouv.fr

CPP Documents and Forms http://www.recherche-biomedicale.sante.gouv.fr/pro/documents/accueil.htm

CPP Guidance on the Management of Biomedical Research

http://www.recherche-biomedicale.sante.gouv.fr/pro/guide/accueil.htm

Decree n° 2013-414 du 21 mai 2013 http://legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000027434029&categorieLien=id


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Decree No. 2012-1244 of November 8th 2012 - Relating to the Strengthening of the Safety Provisions of Medicinal Products for Human Use Subject to Market Authorization and Pharmacovigilance

http://legifrance.gouv.fr/affichTexte.do?cidTexte=JORFTEXT000026592596&fastPos=1&fastReqId=1082519980&categorieLien=cid&oldAction=rechTexte

Explanatory note « Circulaire N° DSG/PF2/2013/224 » of 29 May 2013

http://circulaire.legifrance.gouv.fr/pdf/2013/06/cir_37074.pdf

LEEM Code of Practice 2014 http://www.leem.org/sites/default/files/01 01 2014 DDPfinal.pdf

Les Entreprises du Médicament (LEEM) http://www.leem.org

List of CPPs http://www.recherche-biomedicale.sante.gouv.fr/pro/comites/coordonnees.htm

The Public Health Code (NIS are currently governed by Article L1121-1 of the Public Health Code)

http://www.legifrance.gouv.fr/affichCodeArticle.do?idArticle=LEGIARTI000006686056&cidTexte=LEGITEXT000006072665&dateTexte=20140228&fastPos=17&fastReqId=432819206&oldAction=rechCodeArticle


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Data Privacy ConsiderationsCONSIDERATIONS WHEN CONDUCTING NIS IN FRANCE

DATA PROTECTION

Laws and regulations regarding the protection of personal data must be respected (as per paragraph 1.2.6.e of the LEEM HCP Code).

NIS in France must comply with Act No. 78-17 (as amended) and the requirements of the French National Commission for Data Protection (CNIL).

Where the research requires the collection of identifying biological samples, the informed and express consent of data subjects must be obtained prior to the implementation of data processing (Article 56 of Act No. 78-17 (as amended)).

Information in relation to deceased persons, including that mentioned on death certificates, may be subjected to data processing unless the person in question expressed his refusal in writing before his death (Article 56 of Act No. 78-17 (as amended)).

Authorisation by the Data Protection Competent Authorities (CCTIRS & CNIL)

All NIS must be approved by/ receive a favourable opinion from the CCTIRS and authorised by the CNIL (as per


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Articles 25 and 53 of Act No. 78-17 (as amended)).

CCTIRS Approval

For each application for the processing of personal data, a “Comité Consultatif sur le Traitement de l’information en matière de Recherche dans le domaine de la Santé” (CCTIRS - an advisory committee on the processing of information for medical research), established by the Ministry in charge of research and composed of competent persons as regards medical research, epidemiology, genetics and biostatistics, shall express its opinion on the methodology of the research with respect to the provisions of this Act, the necessity of recourse to personal data and their relevance to the purpose of the research, prior to submission to the “Commission Nationale de l’informatique et des Libertés” (CNIL) (Articles 53 and 54 of Act No. 78-17 (as amended)).

The CCTIRS examines the scientific basis for data collection (especially for data on genetics, ethnicity, political and religious opinion), the adequacy of the CRF (no more data recorded than required by the objectives of the project) and the conformity of the information given to subjects on the protocol (all major data are described in the subject’s information form).

The advisory committee shall send its opinion to the applicant within one month, failing which, the opinion shall be deemed positive. In case of emergency, this time limit may be reduced to fifteen days (Article 54 of Act No. 78-17 (as amended)).

Useful Links:

• CCTIRS Manual (In French)

• CCTIRS Submission/Application Form (In French)


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Human Tissue Research ConsiderationsCONSIDERATIONS WHEN COLLECTING BIOSAMPLES DURING NIS IN FRANCE

DEFINITIONS

Biobanks

Biobanks are privately or publicly maintained institutions for the long-term storage of human bodily substances and for the storage of personal data and information on the donors of these substances. Bodily substances include cells, tissue and blood, as well as DNA, the physical medium of genetic information. Data and information are deemed to comprise both genetic information from individuals and health- and lifestyle-related information on those individuals. The particularity of the biobanks to which these opinions are devoted lies in this twofold character: the specific importance of the collections of samples stems from the combination of samples with such data and information. Since any collection may become the subject of genetic research at some point, attention must also be given to the regulation of genetic research in the context of biobanks (as per CCNE Advice No. 77 of 2003).

Data Controller

Means, unless expressly designated by legislative or regulatory provisions relating to this processing, a person, public authority, department or any other organisation who determines the purposes and means of the data processing (as per Data Protection Act n.78-17 of 197)


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Data Processing

Collection, recording, use, transfer or disclosure of personal information, and any operating files or databases, including interconnections (as per Data Protection Act n.78-17 of 197)

Recipient of a Processing of Personal Data

Is any authorised person to whom the data are disclosed, other than the data subject, the data controller, the sub-contractor and persons who, due to their functions, are in charge of processing the data. However, the authorities who are legally entitled to ask the data controller to send them the personal data, in the context of a particular mission or that of the exercise of a right to receive such data, shall not be regarded as recipients (as per Data Protection Act n.78-17 of 197)

Sensitive Data

Personal data that reveals, directly or indirectly, the racial and ethnic origins, the political, philosophical, religious opinions or trade union affiliation of persons, or which concern their health or sexual life (as per Data Protection Act n.78-17 of 197)

REGULATORY FRAMEWORK

France has a specific framework to organise import/export of human samples for research. It is described under law and other regulations. They indicate the French agency delivering an authorisation and the different requirements to be fulfilled (HSERN, 2011).


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The regulation excludes gametes, gene and cell therapies. A new regulation has covered these activities since May 2008, but is only concerning therapeutic uses (HSERN, 2011).

Informed Consent

The biobank establishment applicant must obtain prior informed consent from the donor of the biological material. Written consent must be established after clear information. The consent can always be withdrawn (as per Article L 1211-2 of the Public Health Code) (HSERN, 2011).

The donor has to give his consent for the storage, the handle, the use and the research purpose for which he has given its tissues and cells AND associated data (HSERN, 2011).

Consent to Export of Biosamples

Export of the human biological material and linked personal data has to be mentioned in the original consent form. In addition, the consent has to mention the processing of associated personal data for research purposes. Transfer of personal data to a non-European country must be specifically mentioned and approved by the data subject in the informed consent process. The CNIL provides models of mentions .

When the samples are exchanged for the purposes of biomedical research this mention is evaluated by a Committee on Protection of Individuals (CPP) (HSERN, 2011).

“Non-Opposition” for Secondary Use of the Biological Material

The consent for secondary use of human biological material is under a legal regime of “non-opposition” (opt-out) : After information for new use from researchers, human biological samples can be used except in case of opposition from the donor.


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Best Practice ConsiderationsBEST PRACTICE CONSIDERATIONS WHEN CONDUCTING NIS IN FRANCE

PHARMACEUTICAL SELF-REGULATION

Non-interventional studies that are prospective in nature and involve collecting data on patients with , or on behalf of , health professionals , acting individually or in groups, specifically for the needs of the study must meet in all of the following conditions (as per paragraph 1.2.6 of the LEEM HCP Code).

Purpose

The study should be conducted for scientific purposes (as per paragraph 1.2.6.a of the LEEM HCP Code).

Prohibition of Promotion

The study should not be an incentive to advise, prescribe, purchase, supply, sell or administer medication (as per paragraph 1.2.6.f of the LEEM HCP Code).

Limited Involvement of Medical Representatives

Medical representatives can not be involved in the development of studies (pre- recruitment and recruitment and financial relationships with physicians )


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NIS DefinitionsConsiderations when providing access to unapproved drugs

EUROPEAN NIS DEFINITIONS

NIS DEFINITIONS

Non-interventional Study (NIS)

A study is non-interventional if the following requirements are cumulatively fulfilled [Volume 10 of The Rules Governing Medicinal Products in the European Union, Questions and Answers, Version 9.0, August 2011, Question 1.9]1:

the medicinal product is prescribed in the usual manner in accordance with the terms of the marketing authorisation;

the assignment of the patient to a particular therapeutic strategy is not decided in advance by a trial protocol but falls within current practice and the prescription of the medicine is clearly separated from the decision to include the patient in the study; and

no additional diagnostic or monitoring procedures are applied to the patients and epidemiological methods are used for the analysis of collected data.

Non-interventional studies are defined by the methodological approach used and not by its scientific objectives. Non-interventional studies include database research or review of records where all the events of interest have already happened (this may include case-control, cross-sectional, cohort or other study designs making secondary use of data). Non-interventional studies also include those involving primary data collection (e.g. prospective observational studies and registries in which the data collected derive from routine clinical care), provided that the conditions set out above are met. In these studies, interviews, questionnaires and blood samples may be


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performed as part of normal clinical practice (as per Section A of GVP Module VIII).

Post-authorisation Safety Study (PASS)

Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or of measuring the effectiveness of risk management measures (Article 1(c)(15) as 2001/83/EC as amended by Directive 2010/84/EU)

A post-authorisation study should be classified as a PASS when the main aim for initiating the study includes any of the following objectives:

to quantify potential or identified risks, e.g. to characterise the incidence rate, estimate the rate ratio or rate difference in comparison to a non-exposed population or a population exposed to another drug or class of drugs, and investigate risk factors and effect modifiers;

to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (e.g. pregnant women, specific age groups, patients with renal or hepatic impairment);

to evaluate the risks of a medicinal product after long-term use;

to provide evidence about the absence of risks;

to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (e.g. indication, dosage, co-medication, medication errors);

to measure the effectiveness of a risk minimisation activity.

Whereas the PASS design should be appropriate to address the study objective(s), the classification of a post-authorisation study as a PASS is not constrained by the type of design chosen if it fulfils the criteria as set in DIR Art 1(15). For example, a systematic literature review or a meta-analysis may


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be considered as PASS depending on their aim (as per Section B.3 of GVP Module VIII).

Post-authorisation Efficacy Studies (PAES)

Any study conducted where concerns relating to some aspects of the efficacy of the medicinal product are identified and can only be resolved after the medicinal product has been marketed (Article 21(a) as 2001/83/EC as amended by Directive 2010/84/EU)


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Common NIS Terminology

Acronym Term

AE Adverse Event

AR Adverse Reaction

CA Competent Authority (e.g., MHRA)

CI Chief Investigator

CRA Clinical Research Associate

CRF Case Report Form

CRO Contract Research Organisation

CSR Clinical Study Report

CTD Clinical Trials Directive (2001/20/EC)

CV Curriculum Vitae

DPA Data Protection Agency

EFPIA European Federation of Pharmaceutical Industries and Associations

GCP Good Clinical Practice

GPP Good Pharmacoepidemiology Practice

GVP Good Pharmacovigilance Practice

ICF Informed Consent Form

ICH The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use

ICH GCP ICH Good Clinical Practice Guidelines

IEC Independent Ethics Committee


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Acronym Term

IMP Investigational Medicinal Product

ISF Investigator Site File

ISPE International Society of Pharmacoepidemiology

MA Marketing Authorisation

MAH Marketing Authorisation Holder

NCA National Competent Authority

NIS Non-interventional Study

NTF Note to the File

PAS Post-authorisation Study

PAES Post-authorisation Efficacy Study

PASS Post-authorisation Safety Study

PI Principal Investigator

PIL Patient Information Leaflet

PV Pharmacovigilance

QA Quality Assurance

QC Quality Control

QMS Quality Management System

QoL Quality of Life

QP Qualified Person

REC Research Ethics Committee

SAE Serious Adverse Event

SAR Serious Adverse Reaction

SDV Source Data Verification

SIF Subject Information Form

SmPC Summary of Product Characteristics

SOP Standard Operating Procedure

SUSAR Suspected Unexpected Serious Adverse Reaction

TMF Trial Master File


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Acronym Term

WMA World Medical Association


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