NIS Considerations - Bulgaria

Transcription

1 NIS Considerations - Bulgaria An overview of the considerations when conducting Noninterventional Studies in Bulgaria Stuart McCully CHCUK Ltd NIS-C-BG

2 Table of Contents Disclaimer 5 Copyright 5 NIS Definitions 6 European NIS Definitions 6 Non-interventional Study (NIS) 6 Post-authorisation Safety Study (PASS) 7 Post-authorisation Efficacy Studies (PAES) 7 Common NIS Terminology 8 Commonly Used NIS Terms 8 Study Classification 10 General Considerations when Planning NIS 10 Study Classification - Useful Links 12 Summary of Changes 13 Regulatory Requirements 37 Country-Specific Regulatory Requirements 37 Regulatory Bodies 37 Definitions 38 Non-Interventional Study (1) 38 Non-Interventional Study (2) 38 Regulatory Framework 39 1

3 Applicable Legislation & Guidance 39 Summary of the Requirements for NIS in Bulgaria 40 Approval and Notification Requirements 41 Who is Responsible for What? 43 Regulatory Submissions Roadmaps 44 Regulatory Submissions Map for Bulgaria-Only Mandated PASS, Voluntary PASS and Other NIS 44 Regulatory Submissions Map for Multi-Country Mandated PASS 45 Legal Requirements 46 Submission Documents for Non-Interventional Studies of Medicinal Products 46 Tabulated Summary of the Regulatory Submission Documents 51 End of Study Notification 55 Summary of the End of Study Notification Requirements 55 Regulatory Requirements - Useful Links 59 Study Conduct Considerations 61 Considerations when Conducting NIS in Bulgaria 61 General Considerations for the Conduct of Non-Interventional Studies 61 Regulation of NIS 61 Purpose 61 Remuneration 62 Approval 62 Substantial Amendments 63 Informed Consent & Compliance with the Data Protection Act 64 Registration of Personal Data Processing 64 Safety Reporting 65 Serious Suspected Adverse Reactions 65 Non-Serious Suspected Adverse Reactions 65 Reporting Information that Might Influence the Benefit/Risk Ratio of the Medicinal Product 65 End of Study Notification 66 2

4 Final Study Report 66 Dissemination of Summary Reports to HCPs 66 Submission of Final Study to the BDA 66 Mandated Non-Interventional Post-Authorisation Safety/ Efficacy Studies 66 Mandated NIS (Post-Approval Commitments) 67 Registration of Mandated NIS in the Risk Management Plan 69 Study Conduct Considerations - Useful Links 70 Best Practice Considerations 72 Best Practice Considerations when Conducting Non-Interventional Studies in Bulgaria 72 Criteria for the Conduct of Non-Interventional Studies 72 Regulation of NIS 72 Purpose 72 Protocol 73 Disguised Promotion 73 Payment for Services 73 Sponsorship of Healthcare Professional 73 Limited Involvement of Sales Reps 74 Scientific Service (Body Responsible for Approval & Supervision of NIS) 74 The Use of Consultants 74 Contracts 75 Remuneration 76 Ban on Gifts 76 Meeting and Events 77 Investigator Meetings 77 Organisation of Events by a Company 77 International Events 78 Hospitality 79 Maximum Permissible Limits for Hospitality 80 Expenses 80 3

5 Presentation/ Lecturer Fees 80 Information and Educational Materials and Items of Medical Utility 81 Questionnaires for Market Research 82 Analysis and Retention of Study Results 82 Reporting Information that Might Influence the Benefit/Risk Ratio of the Medicinal Product 82 Final Study Report 83 Dissemination of Summary Reports to HCPs 83 Submission of Final Study to the BDA 83 Applicability to Other Types of Studies 83 Disclosure of Transfers of Value by Pharmaceutical Companies to Healthcare Professionals and Health Organizations 83 Reporting Period 84 Time of Disclosure 85 Format 85 Platform 85 Applicable National Code 86 Language of disclosure 86 Documentation and retention of records 86 Best Practice Considerations - Useful Links 88 4

6 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. Copyright Copyright 2014 Dr Stuart McCully. All rights reserved. 5

7 NIS Definitions European NIS Definitions Non-interventional Study (NIS) A non-interventional study is a study fulfilling cumulatively the following requirements: 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 the scientific objectives. Non-interventional studies include database research or review of records where all the events of interest have already happened (e.g. case-control, cross-sectional and cohort studies). 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 (as per Section A of EMA GVP Module VIII, Rev 1, April 2013). In this context, interviews, questionnaires and blood samples may be performed as normal clinical practice (as per Section A of EMA GVP Module VIII, Rev 1, April 2013). 6

8 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) 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) 7

9 Common NIS Terminology Commonly Used NIS Terms Acronym Term AE AR CA CI CRA CRF CRO CSR CTD CV DPA EFPIA GCP GPP GVP ICF ICH ICH GCP IEC IMP ISF ISPE 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 Investigational Medicinal Product Investigator Site File International Society of Pharmacoepidemiology 8

10 Acronym Term 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 WMA 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 World Medical Association 9

11 Study Classification General Considerations when Planning NIS What are the regulatory requirements for my NIS? It Depends! 10

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 11

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 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 12

14 Summary of Changes Summary of country-specific changes implemented since the publication of the 1st Edition of NIS Considerations - Bulgaria in October

15 Area Impacted Legislation - Regulation No. 31 for Determining Principles of Good Clinical Practice was Amended in 2012 Details Regulation No. 31 was Amended in 2012 Article 11 has been repealed: For noninterventional trial on medicinal product under art. 145 of LMPHM the sponsor should submit to BDA and the EC in accordance with art. 103 of LMPHM an application form for conduct of clinical trials Requirements for Observational Studies are now contained in Article 15a of Regulation No. 31 (as amended): The sponsor or agent of the non-interventional study of art. 145 LMPHM shall submit to the BDA and the ethics committee of art. 103 LMPHM the application form to conduct an observational study Administrative documents for studies in Article 145 of the LMPHM shall contain: 1. Cover letter; 2. Application form; 3. List of all centers and principal investigators for the territory of Republic of Bulgaria; 4. A copy of the recommendations of the scientific committee of the European Medicines Agency consultation on planning studies, from the process; 5. Letter of assignment or contract authorizing the person submitting application on behalf of the entity, if the applicant is not a contractor 6. A registration document issued by the competent authority of the contracting authority and the applicant within the European Union where the contractor or applicant individual, data - name, address, telephone and fax; [read more...] 14

16 Area Impacted Legislation - Regulation No. 31 for Determining Principles of Good Clinical Practice was Amended in 2012 Details Information on the Observational Study Participant Information on the Observational Study Participant Shall Include: 1. Information about the patient / participant; 2. Informed consent form, except when treated retrospective and anonymous medical information; 3. Description of the procedures for recruitment of patients / subjects; 4. Description of the procedures for obtaining informed consent from the legal representative, if provided; 5. Ethical justification for enrollment of patients / participants who are not able to give informed consent in accordance with Art. 98 LMPHM; 6. Copy of any other information that will be used to raise patients / subjects and / or given to the patient / participant before or during observational study (as per Article 15c of Regulation No.31, as amended) [read more...] 15

17 Regulatory Requirements Country-Specific Regulatory Requirements Regulatory Bodies Competent Authority Research Ethics Committees Bulgarian Drug Agency (BDA Local Ethics Committee (LEC) (All trials are approved by the local ethics committee at the trials site regardless of the specificity of the trial) Data Protection Agency Pharmaceutical Self-Regulation Body Pharmaceutical Code of Practice Commission for Personal Data Protection (CPDP) Association of the Research Based Pharmaceutical Manufacturers in Bulgaria (ARPharM) ARPharM Code of Ethics of Research-Based Pharmaceutical Industry in Bulgaria (2013) ARPharM Code for Disclosure of Transfers of Value by Pharmaceutical Companies to Healthcare Professionals and Health Organizations (Nov 2013) 37

18 Who is Responsible for What? The following table provides an overview of the tasks that need to be undertaken when conducting a non-interventional study in Bulgaria. The responsibilities for each of the task have been defined below. Study Tasks Sponsor Principal Investigator Study Documentation Prepare (and translate) the regulatory submission documents in accordance with the regulatory requirements (see below) Contracts & Agreements Set-up a contractual agreement between study Sponsor and Investigator/Institution where the study will be conducted Competent Authority (BDA) Submit observational study application documents Request changes to the approved research End os study notification Data Protection Agency (CPDP) Registration Research Ethics Committee (REC) Obtain REC Approval Submit annual progress reports to the REC Request changes to the approved research Submit an end-of-study notification to the REC 43

19 Legal Requirements Submission Documents for Non- Interventional Studies of Medicinal Products The approval of non-interventional studies is regulated through Article 145 of the Medicinal Products in Human Medicines Act (LMPHM) and Article 15 of Regulation 31 for Determining the Principles for Good Clinical Practice of the Ministry of Health of 12 August 2007 (as per the BDA Website - Approval of Observational Studies of Medicines). According to Article 15 of the Regulation 31 (as amended): NIS Requirements Application Documents Details The sponsor or agent of the non-interventional study of Article 145 LMPHM shall submit to the BDA and the ethics committee of Article 103 LMPHM the application form to conduct an observational study Administrative documents for studies in Article 145 of the LMPHM shall contain: 1. Cover letter; 2. Application form; 3. List of all centers and principal investigators for the territory of Republic of Bulgaria; 4. A copy of the recommendations of the scientific committee of the European Medicines Agency consultation on planning studies, from the process; 5. Letter of assignment or contract authorizing the person submitting application on behalf of the entity, if the applicant is not a contractor 6. A registration document issued by the competent authority of the contracting authority and the applicant within the European Union where the contractor or applicant individual, data - name, address, telephone and fax; 7. A declaration that the application to BDA and to the ethics committee comprises the same information (as per Article 15c of Regulation No.31, as amended) 46

20 Study Conduct Considerations Considerations when Conducting NIS in Bulgaria General Considerations for the Conduct of Non- Interventional Studies Regulation of NIS Regarding the regulation of non-interventional studies, the Bulgarian law must be respected (as per Article 14.1 of the ARPharM COE): Medicinal Products in Human Medicines Act (as amended) Regulation No.31 of August 12, 2007 Designation of Rules for Good Clinical Practice (as amended) (in Bulgarian) Law for the Protection of Personal Data (as amended) (LPPD) Non-interventional studies in the territory of the Republic of Bulgaria shall be conducted in compliance with Articles 145c -145e of the LMPHM, as amended). Purpose Non-interventional post-marketing safety studies shall be conducted on the initiative of the market authorisation holder or pursuant to the conditions under Articles 55a and 56a (e.g., post-authorisation commitments), and shall be connected with gathering of drug safety data from patients and medical specialists (as per Article 145a(1) of the LMPHM, as amended). 61

21 Remuneration Medical specialists shall not receive financial or other incentives for participation in non-interventional safety studies, except for compensations for the time and means spent (as per Article 145a(3) of the LMPHM, as amended). Approval According to Article 15a of Regulation No. 31 (as amended): observational study. The sponsor or agent of the noninterventional study of Article 145 LMPHM shall submit to the BDA and the ethics committee of Article 103 LMPHM the application form to conduct an The application documents should include: Cover letter; Application form; List of all centers and principal investigators for the territory of Republic of Bulgaria; A copy of the recommendations of the scientific committee of the European Medicines Agency consultation on planning studies, from the process; Letter of assignment or contract authorizing the person submitting application on behalf of the entity, if the applicant is not a contractor A registration document issued by the competent authority of the contracting authority and the applicant within the European Union where the contractor or applicant individual, data - name, address, telephone and fax; 62

22 Best Practice Considerations Best Practice Considerations when Conducting Non-Interventional Studies in Bulgaria Criteria for the Conduct of Non-Interventional Studies Any non-interventional study should meet the following conditions cumulatively (as per Article 14.3 of the ARPharM COE) Regulation of NIS Regarding the regulation of non-interventional studies, the Bulgarian law must be respected (as per Article 14.1 of the ARPharM COE): Medicinal Products in Human Medicines Act (as amended) Regulation No.31 of August 12, 2007 Designation of Rules for Good Clinical Practice Law for the Protection of Personal Data (as amended) (LPPD) Purpose The study shall be conducted for scientific purposes (as per Article of the ARPharM COE). 72

23 Protocol There shall be a written plan or protocol of the study in place (as per Article of the ARPharM COE). Disguised Promotion Clinical assessments, post-authorization surveillance, programs concerning experience and studies (including the retrospective ones, if any), noninterventional studies performed after the grant of marketing authorization must not be a disguised promotion and advertising. Such assessments, programs and studies should be conducted primarily with a scientific and educational purpose (as per Article 8.2 of the ARPharM COE). The hiring of the healthcare professional to provide the relevant service is not an inducement to recommend, prescribe, purchase, supply, sell or administer a particular medicinal product (as per Article 13.3 of the ARPharM COE). Payment for Services Contracts between companies and institutions or organisations of healthcare professionals are only allowed if contracts cover services, which are provided for the purpose of supporting healthcare or research; and do not constitute an inducement to recommend, prescribe, purchase, supply, sell or administer specific medicinal products (as per Articles 12.1 and 14.3 of the ARPharM COE). Sponsorship of Healthcare Professional Companies comply with the applicable codes in the selection and sponsorship of healthcare professionals to participate in training and events. Healthcare professionals can not be provided compensation only for participating in events. In the case of sponsorship of healthcare professionals to participate in an international event, the provisions of the national code of 73

24 Best Practice Considerations - Useful Links Useful Links Accessed From ARPharM Code for Disclosure of Transfers of Value by Pharmaceutical Companies to Healthcare Professionals and Health Organizations (Nov 2013) ARPharM Code of Ethics of Research-Based Pharmaceutical Industry in Bulgaria (2013) Association of the Research Based Pharmaceutical Manufacturers in Bulgaria (ARPharM) Good Epidemiological Practice: Proper Conduct in Epidemiologic Research Guidelines for Good Epidemiology Practices for drug, device, and Vaccine Research in the United States attachments/en/ En_ARPharM_Disclosure_Code_Final.pdf attachments/en/ En_ARPHARM_Code_of_Ethics_update_201 3_Final.pdf Downloads/LS_Ruffert/Ethical_Codes/ ISPE_Guidelines%20for%20Good %20Epidemiology%20Practices%20for %20Drug_%20Device_%20and%20Vaccine %20Research%20in%20the%20United %20States.pdf 88