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NIS Considerations - BulgariaAn overview of the considerations when conducting Non-interventional Studies in Bulgaria

Stuart McCully • CHCUK Ltd • NIS-C-BG-2014

©"Dr"Stuart"McCully"2014

NIS"Considera:ons";"Bulgaria2nd"Edi:on";"January"2014

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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



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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



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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



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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



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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.

CopyrightCopyright © 2014 Dr Stuart McCully. All rights reserved.



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NIS DefinitionsEuropean 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).



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








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)



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http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf


http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf






Common NIS TerminologyCommonly Used NIS Terms

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

IMP Investigational Medicinal Product

ISF Investigator Site File

ISPE International Society of Pharmacoepidemiology



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Acronym Term

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

WMA World Medical Association



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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 LinksUseful 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



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Summary of ChangesSummary of country-specific changes implemented since the publication of the 1st Edition of NIS Considerations - Bulgaria in October 2012



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Area Impacted Details

Legislation - Regulation No. 31 for Determining Principles of Good Clinical Practice was Amended in 2012

Regulation No. 31 was Amended in 2012

Article 11 has been repealed: “For non-

interventional 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...]



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http://en.bda.bg/images/stories/documents/legal_acts/ZLPHM_en.pdf




http://www.bda.bg/images/stories/documents/regulations/naredbi/naredba31.pdf










Area Impacted Details

Legislation - Regulation No. 31 for Determining Principles of Good Clinical Practice was Amended in 2012

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...]



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Regulatory Requirements Country-Specific Regulatory Requirements

Regulatory Bodies

Competent Authority

Research Ethics Committees

Data Protection Agency

Pharmaceutical Self-Regulation Body

Pharmaceutical Code of Practice

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)

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)



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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 ✔



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Legal Requirements

Submission Documents for Non-Interventional Studies of Medicinal ProductsThe 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 Details

Application Documents 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)



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Study Conduct ConsiderationsConsiderations when Conducting NIS in Bulgaria

General Considerations for the Conduct of Non-Interventional Studies

Regulation of NISRegarding 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).

PurposeNon-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).



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RemunerationMedical 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).

ApprovalAccording to Article 15a of Regulation No. 31 (as amended):

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.

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;



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Best Practice ConsiderationsBest Practice Considerations when Conducting Non-Interventional Studies in Bulgaria

Criteria for the Conduct of Non-Interventional StudiesAny non-interventional study should meet the following conditions cumulatively (as per Article 14.3 of the ARPharM COE)

Regulation of NISRegarding 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)

PurposeThe study shall be conducted for scientific purposes (as per Article 14.3.1 of the ARPharM COE).



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ProtocolThere shall be a written plan or protocol of the study in place (as per Article 14.3.2 of the ARPharM COE).

Disguised PromotionClinical assessments, post-authorization surveillance, programs concerning experience and studies (including the retrospective ones, if any), non-interventional 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 ServicesContracts 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 ProfessionalCompanies 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



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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)

http://www.arpharm.org/images/stories/attachments/en/En_ARPharM_Disclosure_Code_Final.pdf

ARPharM Code of Ethics of Research-Based Pharmaceutical Industry in Bulgaria (2013)

http://www.arpharm.org/images/stories/attachments/en/En_ARPHARM_Code_of_Ethics_update_2013_Final.pdf

Association of the Research Based Pharmaceutical Manufacturers in Bulgaria (ARPharM)

http://www.arpharm.org/index.php

Good Epidemiological Practice: Proper Conduct in Epidemiologic Research

http://ieaweb.org/2010/04/good-epidemiological-practice-gep/

Guidelines for Good Epidemiology Practices for drug, device, and Vaccine Research in the United States

http://www.rewi.uni-jena.de/rewimedia/Downloads/LS_Ruffert/Ethical_Codes/ISPE_Guidelines%20for%20Good%20Epidemiology%20Practices%20for%20Drug_%20Device_%20and%20Vaccine%20Research%20in%20the%20United%20States.pdf



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