Preclinical & Clinical Trial Requirements
The ins and outs of preclinical & clinical trial requirements: Bulgaria. Prepared in association with Kinstellar and PharmDedict, this is an extract from The Pharma Legal Handbook: Bulgaria, available to purchase here for GBP 75.
1. Are clinical trials required to be conducted locally as a condition (stated or implicit) for marketing approval?
There is no requirement for clinical trials to be conducted locally as a condition for obtaining market authorisation. However, if the clinical trials have been conducted outside of the European Union, the applicant for market authorisation shall submit a declaration that the trials meet the ethical requirements of the Good Clinical Practice set forth in the applicable Bulgarian legislation.
2. How are clinical trials funded?
Clinical trials are usually funded by a sponsor. The sponsor is an individual, a company, a healthcare institution or an organization which initiates, organizes and/or funds the clinical trial. Non-profit organizations sponsoring a clinical trial have to provide evidence for the sources of funding for the clinical trial. The sponsor is liable for the compliance of all aspects of the clinical trial and the conduct thereof.
3. What are the requirements for preclinical and clinical trial protocols? Who must approve the protocols?
The protocol shall describe the objective, design, methodology, statistical considerations, purpose and organization of the clinical trial. The protocol is identified by: (a) the title of the clinical trial; (b) the EU trial number; (c) the sponsor’s protocol code number specific for all versions of it (if relevant); (d) the date and number of the version, to be updated when it is amended; (e) a short title or name assigned to the protocol; and (f) the name and address of the sponsor, as well as the name and function of the representative or representatives of the sponsor authorised to sign the protocol or any substantial modification to the protocol.
The protocol has to include at least: (a) assessment of the expected benefits and risks; (b) a description of the subject inclusion and exclusion criteria; (c) a justification for including subjects, especially in cases where subjects who are incapable of giving informed consent or other special populations, will be included; (d) a detailed description of the recruitment and informed consent procedure, especially when subjects are incapable of giving informed consent and when it is envisaged the consent to be given by an independent witness; (e) a description of the arrangements for taking care of the subjects after their participation in the clinical trial has ended; (f) a description of arrangements for monitoring the conduct of the clinical trial; and (g) a description of the publication plan. Upon Regulation (EU) No 536/2014 1 (the “Clinical Trials Regulation”) becoming applicable 2, the protocol and its content has to be made in compliance with the requirements of Part D (Protocol) of Annex I of that Regulation.
The protocol needs to receive a positive opinion by the respective Ethics Committee for Clinical Trials 3 (either local Ethics Committee 4 at the site where the trial will be conducted or the Ethics Committee at the Ministry of Health, in case of multicenter clinical trials). The protocol has to be approved also by the Executive Director of the Bulgarian Drug Agency.
4. What are the requirements for consent by participants in clinical trials?
There are no restrictions with respect to who can participate in clinical trials, as long as the participants have given their consent for participating. Participant of full age can give their consent freely, while the consent of under-aged participants and incapacitated participants of full age is given by their parents or custodians.
There are several requirements, which the consent should meet:
- the participants should receive clear, comprehensive and concise information which enables them to understand the nature, objectives, implications, risks and inconveniences of the clinical trial;
- the participants should receive information on their rights and guarantees regarding their protection, in particular the right to refuse to participate and the right to withdraw from the clinical trial at any time without any resulting detriment and without having to provide any justification;
- the consent should be obtained in writing. 5
5. May participants in clinical trials be compensated?
Participants in clinical trials may receive compensation for their participation in a clinical trial. This can be contractually arranged. Information regarding such compensation has to be included in the documentation for the trial and reviewed and approved by the respective Ethics Committee. The Ethics Committee should review both the amount and method of payment to subjects to assure that neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be prorated and not wholly contingent on completion of the trial by the subject.
No incentives or financial inducements are given except compensation in case of clinical trial on minors or clinical trials on incapacitated adults not able to give informed legal consent (vulnerable subjects).
6. How are participants in clinical trials protected and indemnified against any harm that arises as a result of participation in the trial?
Under Bulgarian law, the sponsor of the clinical trial and the investigator are required to conclude a civil liability insurance, which covers the pecuniary and non-pecuniary damage that might be caused during the trial.
Apart from this, participants in clinical trials (or their families, in cases of death) are entitled to receive compensations in cases of death or health detriment due to the clinical trial.
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC.;
Regulation (EU) No 536/2014, including the requirements regarding the protocol, will become applicable six months after the European Commission publishes a notice under Article 82(3) of the Regulation.
The Ethical Commission for Clinical Trials is a commission established at the Bulgarian Ministry of Health.
The amendments of LMPHM from October 2018 replaced the existing local Ethics Committees at the healthcare establishments (LEC) by a “contact person” appointed at each site. The contact person will have monitoring functions and will partially take over the functions of the former LECs. The change is supposed to enter into force simultaneously with the Clinical Trials Regulation (expected to become applicable in 2021). For centres with operative LECs – they will operate according to the old rules until replaced with a contact person. It is not possible to establish new LECs any more, as the legal basis for this is no longer available.
Certain deviations from this rule are envisaged in cases when the participant cannot write, e.g. the consent can recorded in another suitable way.