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Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies


Summary of the requirements for conducting prospective non-interventional studies (NIS) in Bulgaria. Includes the updates implemented by the recent NIS Ordinance (Ordinance № 8 of March 31, 2021).

June 2021 – Our three (3) step ‘How To’ guide for conducting prospective voluntary NIS in Bulgaria:

  1. Study Classification – Clinical Trial or Non-Interventional Study?
  2. Submission Requirements – Approvals, Notifications and Registration
  3. 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).


  1. Bulgarian Drug Agency (BDA)[2]
  2. Ethical Commission for Clinical Trials (ECKI)[3]

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:
^ NIS Application Form:
^^ NIS Substantial Amendment Application Form:


1. Article 145(1) of the Medicinal Products in Human Medicine Act (ZLPHM)

2. Bulgarian Drug Agency (BDA)

3. Ethical Commission for Clinical Trials (ECKI)

4. BDA/ECKI – Approval of a Non-Interventional Study of a Medicinal Product

5. BDA – Issuance of Approval for a Significant Change in a Non-Interventional Study

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

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]:
Link [English]:

Medicinal Products in Human Medicine Act (ZLPHM)
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)

Insights | Bulgaria – ‘How To’ Guide for Non-Interventional Studies2022-08-07T17:27:58+00:00

Insights | Real World Research in Mental Health


RWR, when done properly, is a low-cost / high-quality alternative to traditional research.  Improving mental health across the board needs to focus not just on pharmaceutical interventions.  Strengthening the implementation of research evidence and good practice into a range of settings where people seek support is equally important.

June 2021 – Mental health disorders remain the highest unmet medical need, surpassing cancer.  One in four of us is affected by mental illness.  That’s a friend, a partner, a child or maybe even you.  Fortunately, health crises this prevalent attract large budgets and significant awareness campaigns.


In 2019, $3.7 billion was spent around the world researching mental health, which sounds big, but that is only 4% of total global health research.  It’s too little, unchanging over time, and disproportionate to the burden of suffering attributable to mental health disorders globally.

It is also too inequitable, with less than 10% of funding being spent in countries that have 90% of global health problems. And more importantly it is too skewed, with more than 50% devoted to biological and aetiological research, and about 7% allocated to health services research, clinical research, and prevention[1].  We continue to chase a pharmaceutical solution to a human problem, with little sign of the kind of success seen in virtually any other disease.

And then came COVID-19.  We now have a pandemic within a pandemic.  Everywhere you look there is evidence of the massive impact on mental health that lockdowns, loss of loved ones, loss of jobs or just being on the front line of healthcare has had.  In 2019, 8% of the US population thought mental health was the most important health issue, 13% thought it was cancer.  In 2020 that flipped on its head – 13% now say it’s mental health and 9% say it’s cancer[2].
So, being realistic, mental health will never get the kind of funding that it deserves, so how can we make the most of what funding is available?

Researchers and scientists are expanding current approved therapeutics in new indications as well as looking at non-traditional technologies to help patients dealing with mental health issues and they are increasingly doing this by turning to real-world research (RWR) data. There is a significant opportunity to generate insights from real-world data on mental health disorders to get a much better understanding of the issues facing individuals on a day-to-day level and then to develop novel, scalable solutions to address this increasing burden.

RWR, when done properly, is a low-cost / high-quality alternative to traditional research.  Improving mental health across the board needs to focus not just on pharmaceutical interventions.  Strengthening the implementation of research evidence and good practice into a range of settings where people seek support is equally important.

A key part of enabling this will be to support mental health delivery staff to be research literate, encourage RWR at the front line and then making research findings accessible and relevant for local implementation.  Unfortunately, within the clinical research world the experience and expertise required to deliver high quality real-world research lags behind randomised clinical trials in the same way mental health is the poor cousin to oncology.  Developing systems and processes to ensure that money spent on RWR data in mental health carries the same reliability as randomised controlled trials (RCTs) will be equally important.

Although RCTs remain crucial for coverage and reimbursement decisions by payers, RWR can be employed to assess clinically meaningful endpoints, gauge the impact of interventions on the quality of healthcare, and help payers make appropriate data-driven decisions.

The future for mental health research may well be Real.


1. Vikram Patel. Mental Health Research Funding: Too little, too inequitable, too skewed
Lancet, Volume 8, Issue 3, P171-172, March 01, 2021

2. America Speaks – Survey data reflecting the views of Americans on medical, health, and scientific research. Poll Data Summary, Volume 20.

Insights | Real World Research in Mental Health2022-08-07T17:28:48+00:00
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