NIS Considerations - France An overview of the considerations when conducting Noninterventional

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1 NIS Considerations - France An overview of the considerations when conducting Noninterventional Studies in France Stuart McCully CHCUK Ltd NIS-C-FR-2014 (Mar 2014) Dr Stuart McCully 2014 NIS-C-FR-2014 (Mar 2014)

2 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 1

3 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 2

4 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 CSP and Article R 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 3

5 Simplified Procedure 58 Simplified Formalities to Declare Personal Data Transfers Abroad 58 To Summarise 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 4

6 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 5

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8 Disclaimer Although 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. 7

9 Acknowledgement My 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 8

10 Document History SUMMARY 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 Company Name Change Legislation - Updated Pharmacovigilance Legislation Details Compliance Healthcheck Consulting UK Ltd is now CHCUK Ltd Updated Pharmacovigilance Legislation Decree No 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...] 9

11 Study Classification GENERAL CONSIDERATIONS WHEN PLANNING NIS What are the regulatory requirements for my NIS? It Depends! 15

12 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 Clinical Trials Directive (2001/20/EC) & EC Guidelines Non- Interventional Mandated PASS/PAES EU Pharmacovigilance Legislation & EMA GVP Guidelines Other 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: What? 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? Where? Which countries? How? Submission procedures Notifications Approvals Registration Classification Insurance requirements 16

13 STUDY CLASSIFICATION - USEFUL LINKS Useful Links Accessed From Clinical Trials Directive (2001/20/EC) Pharmacovigilance Directive (2010/84/EU) EMA Good Pharmacovigilance Practices (GVP) EMA Guidance on the 2010 Pharmacovigilance Legislation EMA Guideline on good pharmacovigilance practices (GVP) Module VIII Postauthorisation safety studies (Rev 1 - April 2013) vol-1/dir_2001_20/dir_2001_20_en.pdf vol-1/dir_2010_84/dir_2010_84_en.pdf curl=pages/regulation/document_listing/ document_listing_ jsp&mid=wc0b01 ac05804fcdb1 curl=pages/regulation/general/ general_content_ jsp&mid=wc0b01a c058033e8ad document_library/scientific_guideline/ 2012/06/WC pdf 17

14 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

15 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 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 ). 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 ). 19

16 REGULATORY REQUIREMENTS - USEFUL LINKS Useful Links Accessed From Act No (as amended) - Relating to Computers, Files and Freedoms Agence nationale de sécurité du médicament et des produits de santé (ANSM) Business- Health Transparency Web Portal Unique website managed by French MoH for declaration of data under the French Transparency Act UserSpace=default login.xhtml;jsessionid=4b1fc97c6f4cd26e F8474F60B1ACC915.sunshine-entreprise# [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] Business- Health Transparency Web Portal: Frequently Asked Questions Bylaw of 03 December 2013 reg. the functioning of the single public internet webpage mentioned in Art CSP as published on December 19th, 2013 CCTIRS Manual CCTIRS Submission/ Application Form CNIL - Obligations of Personal Data Controllers CNIL - Practical Information Guide on formalities for the creation (and processing) of data for medical research, of 2008, providing specific information on administrative processes CNIL - Procedures for Doctors and Researchers in the Health sector info_faq.xhtml cidtexte=jorftext &fastpos =2&fastReqId= &c formulaire_cctirs_mai_2008_27723.rtf getnotice.do? cerfaformulaire=10769&cerfanotice=

17 Useful Links Accessed From CNIL - Simplified Declaration Procedure for Biomedical Research CNIL - The Transfer of Data Outside of the European Union CNOM approval required as per the requirements of the Article R of the Public Health Code CNOM Code of Ethics CNOM Model Contracts 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) Commission Nationale de l'informatique et des Libertés (CNIL) CPP Documents and Forms CPP Guidance on the Management of Biomedical Research Declaration of Helsinki (2013) Decree n du 21 mai 2013 Decree No of November 8, 2012 Decree No (as amended) pratique/article/une-procedure-simplifiee-de- affichcodearticle.do? idarticle=legiarti &cidtexte= LEGITEXT &dateTexte= &oldAction=rechCodeArticle groupe/17/tous groupe/33/tous declaration-pour-les-recherches- biomedicales/ accueil.htm accueil.htm 10policies/b3/ cidtexte=jorftext &categori elien=id categorielien=id&cidtexte=jorftext &dateTexte= cidtexte=legitext &datetext e=

18 Study Conduct Considerations CONSIDERATIONS 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 postauthorisation 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 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). 39

19 STUDY CONDUCT CONSIDERATIONS - USEFUL LINKS Useful Links Accessed From Agence nationale de sécurité du médicament et des produits de santé (ANSM) Business- Health Transparency Web Portal Unique website managed by French MoH for declaration of data under the French Transparency Act UserSpace=default login.xhtml;jsessionid=4b1fc97c6f4cd26ef 8474F60B1ACC915.sunshine-entreprise# [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] Business- Health Transparency Web Portal: Frequently Asked Questions Bylaw of 03 December 2013 reg. the functioning of the single public internet webpage mentioned in Art CSP as published on December 19th, 2013 CNOM approval required as per the requirements of the Article R of the Public Health Code CNOM Code of Ethics CNOM Model Contracts Comité de Protection des Personnes (CPP) CPP Documents and Forms CPP Guidance on the Management of Biomedical Research Decree n du 21 mai cidtexte=jorftext &fastpos= 2&fastReqId= &c affichcodearticle.do? idarticle=legiarti &cidtexte= LEGITEXT &dateTexte= &oldAction=rechCodeArticle groupe/17/tous groupe/33/tous accueil.htm accueil.htm cidtexte=jorftext &categori elien=id 54

20 Useful Links Accessed From Decree No of November 8th Relating to the Strengthening of the Safety Provisions of Medicinal Products for Human Use Subject to Market Authorization and Pharmacovigilance Explanatory note «Circulaire N DSG/ PF2/2013/224» of 29 May cidtexte=jorftext &fastpos= 1&fastReqId= &categorieLien=cid &oldaction=rechtexte /06/cir_37074.pdf LEEM Code of Practice DDPfinal.pdf Les Entreprises du Médicament (LEEM) List of CPPs The Public Health Code (NIS are currently governed by Article L of the Public Health Code) coordonnees.htm affichcodearticle.do? idarticle=legiarti &cidtexte= LEGITEXT &dateTexte= &fastPos=17&fastReqId= &oldA ction=rechcodearticle 55

21 Data Privacy Considerations CONSIDERATIONS WHEN CONDUCTING NIS IN FRANCE DATA PROTECTION Laws and regulations regarding the protection of personal data must be respected (as per paragraph e of the LEEM HCP Code). NIS in France must comply with Act No (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 (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 (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 56

22 Articles 25 and 53 of Act No (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 (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 (as amended)). Useful Links: CCTIRS Manual (In French) CCTIRS Submission/Application Form (In French) 57

23 Human Tissue Research Considerations CONSIDERATIONS 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 of 197) 62

24 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 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 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 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). 63

25 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 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. 64

26 Best Practice Considerations BEST 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 of the LEEM HCP Code). Purpose The study should be conducted for scientific purposes (as per paragraph 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 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 ) 76

27 NIS Definitions Considerations 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 84

28 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 nonexposed 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 85

29 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) 86

30 Common NIS Terminology Acronym AE AR CA CI CRA CRF CRO CSR CTD CV DPA EFPIA GCP GPP GVP ICF ICH ICH GCP IEC Term Adverse Event Adverse Reaction Competent Authority (e.g., MHRA) Chief Investigator Clinical Research Associate Case Report Form Contract Research Organisation Clinical Study Report Clinical Trials Directive (2001/20/EC) Curriculum Vitae Data Protection Agency European Federation of Pharmaceutical Industries and Associations Good Clinical Practice Good Pharmacoepidemiology Practice Good Pharmacovigilance Practice Informed Consent Form The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH Good Clinical Practice Guidelines Independent Ethics Committee 87

31 Acronym IMP ISF ISPE MA MAH NCA NIS NTF PAS PAES PASS PI PIL PV QA QC QMS QoL QP REC SAE SAR SDV SIF SmPC SOP SUSAR TMF Term Investigational Medicinal Product Investigator Site File International Society of Pharmacoepidemiology Marketing Authorisation Marketing Authorisation Holder National Competent Authority Non-interventional Study Note to the File Post-authorisation Study Post-authorisation Efficacy Study Post-authorisation Safety Study Principal Investigator Patient Information Leaflet Pharmacovigilance Quality Assurance Quality Control Quality Management System Quality of Life Qualified Person Research Ethics Committee Serious Adverse Event Serious Adverse Reaction Source Data Verification Subject Information Form Summary of Product Characteristics Standard Operating Procedure Suspected Unexpected Serious Adverse Reaction Trial Master File 88

32 Acronym WMA Term World Medical Association 89