Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies
June 2021 – Our three (3) step ‘How To’ guide for conducting prospective voluntary NIS in Bulgaria:
- Study Classification – Clinical Trial or Non-Interventional Study?
- Submission Requirements – Approvals, Notifications and Registration
- Submission Documents – Initial Application and Substantial Amendments
Definition: A non-interventional study shall be conducted with medicinal products authorised for use in the Republic of Bulgaria where these are studied in order to obtain additional information about the product prescribed in the usual manner in compliance with the conditions determined in the marketing authorisation. No additional diagnostic or monitoring procedures, different from the usual practices shall be applied to the patients in non-interventional studies, and epidemiological methods should be used for the analysis of the collected data (as per Article 145(1) of the Medicinal Products in Human Medicine Act)[1].
Regulatory Consideration 1: Study Classification – Is your study a non-interventional study or a clinical trial?
Use the following simple decision tree to determine whether your proposed clinical study is a clinical trial or a non-interventional study
Regulatory Consideration 2: Approvals, Notifications and Registration
Bulgaria is one of the few European countries where the competent authority for medicinal products (Bulgarian Drug Agency)[2] must approve non-interventional studies (see below).
Approvals:
Notifications: Not Applicable
Registration: EU PAS Register (Optional)
Fee: BGN 400
Regulatory Consideration 3: Submission Documents
Initial Application[4]:
1. Administrative documentation
. Administrative documentation
– Application form^
– Cover letter
– List of the regulatory bodies to which an application has been submitted and their decision
– List of all planned centers, principal investigators and research teams for the territory of the Republic of Bulgaria
– Copy of the recommendations of the Scientific Committee of the European Medicines Agency for consultation on trial planning (if applicable)
– Assignment letter or contract for authorization of the person who submits the application on behalf of the sponsor, when the applicant is not the sponsor
– Document for current registration, issued by a competent authority, to the contracting authority and the applicant on the territory of the European Union
– Declaration that the documentation submitted to the BDA and the Ethics Commission contains the same information.
2. Information for Participant:
– Information about the patient / participant and a form of informed consent – original and in Bulgarian
– Description of the procedures for recruiting patients / participants
– Description of the procedures for obtaining informed consent from a legal representative, where foreseen
– Ethical justification in case of recruitment of participants who are not able to give informed consent
– Any other information that will be used to recruit participants and / or provide to a participant before or during the non-interventional study.
3. The protocol documentation:
– Protocol of the study with all current changes
– Summary of the protocol in Bulgarian
– Assessment of the scientific value of the study by a specialist in the relevant field, when available
– Ethical evaluation of the protocol by the principal or coordinating researcher, when it is not part of the protocol
– A page of the protocol, signed by the sponsor and the principal investigator for each of the proposed centers
4. Documentation for the Medicinal Product:
– Current brief description of the product (SmPC)
5. The Documentation for the Technical Requirements and the Personnel:
– Description of the necessary equipment and / or technical requirements for implementation of the protocol
– Documents certifying the available technical possibilities for implementation of the protocol
– Permit for carrying out medical activity under Art. 47, para. 1 of the PPA / registration certificate under Art. 40, para. 1 of the Health Insurance Act for the medical institution – center of the non-interventional research.
6. Financing and Administrative Organization of the Study:
– Insurance
– Contract between the sponsor and the medical institution
– Contract between the sponsor and the researcher
– Data on the source of funding of the study, when the contracting authority is a non-profit legal entity
– Documentation that the fee has been paid = 400 BGN
Substantial Amendments[5][*]:
1. Application form^^
2. Cover letter
3. Summary of the planned change
4. List of the updated documents
5. The updated documentation reflecting the changes
6. Pages from the documentation with marked changes, comparing the current and the new texts
7. Justification of the changes
8. Documentation that the fee has been paid = 120 BGN
9. A copy of the positive opinion of the ethics committee, when it becomes available.
* Both the BDA and ECKI need to approve any substantial amendments: https://iisda.government.bg/adm_services/services/service_provision/6858
^ NIS Application Form: https://iisda.government.bg/adm_services/service_sample_file/6844_76240
^^ NIS Substantial Amendment Application Form: https://iisda.government.bg/adm_services/service_sample_file/6858_76336
References
1. Article 145(1) of the Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf
2. Bulgarian Drug Agency (BDA)
Link: https://www.bda.bg/bg/
3. Ethical Commission for Clinical Trials (ECKI)
Link: https://www.bda.bg/bg/%d0%b7%d0%b0-%d0%b8%d0%b0%d0%bb/%d0%b4%d1%80%d1%83%d0%b3%d0%b8-%d0%ba%d0%be%d0%bc%d0%b8%d1%81%d0%b8%d0%b8/67-cemi
4. BDA/ECKI – Approval of a Non-Interventional Study of a Medicinal Product
Link: https://iisda.government.bg/adm_services/services/service_provision/6844
5. BDA – Issuance of Approval for a Significant Change in a Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/6858
Useful Resources:
ECKI – Issuance of an Opinion by the Ethics Committee for Clinical Trials for Making a Significant Change in a Clinical Trial or Non-Interventional Study
Link: https://iisda.government.bg/adm_services/services/service_provision/92971
NIS Ordinance – Ordinance № 8 of March 31, 2021 on the terms and conditions for conducting non-interventional studies of medicinal products on the territory of the Republic of Bulgaria
Link [Bulgarian]: https://www.bda.bg/images/stories/documents/regulations/naredbi/20210415/%D0%9D%D0%90%D0%A0%D0%95%D0%94%D0%91%D0%90%20%E2%84%96%208%20%D0%9E%D0%A2%2031%20%D0%9C%D0%90%D0%A0%D0%A2%202021%20%D0%93..pdf
Link [English]: https://nis-regs.com/wp-content/uploads/2021/06/NIS-Ordinance-2021.pdf
Medicinal Products in Human Medicine Act (ZLPHM)
Link: https://www.bda.bg/images/stories/documents/legal_acts/20210208_ZLPHM_English.pdf
Note1: Articles 81 to 144 = Clinical Trials
Note2: Article 145 = Non-interventional Studies.
Note3: Articles 183 to 194 = Pharmacovigilance
Guideline on good pharmacovigilance practices (GVP) – Module VIII Addendum I – Requirements and recommendations for the submission of information on non-interventional post-authorisation safety studies (Rev 3) (EMA/395730/2012 Rev 3; 15 June 2020)
Link: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-gvp-module-viii-addendum-i-requirements-recommendations_en-1.pdf
