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History

Medicinal regulation is the contemporary internationally adopted term to denote the totality of activities carried out by the state in different spheres of the pharmaceutical sector so as to ensure society with medicines of high quality, efficiency and safety.

In compliance with the adopted terminology nowadays, established on the basis of long scientific and practical experience, a medicine is any finished product which is a substance or combination of substances intended for the treatment or prophylactics of diseases in people and is offered in a finished package, as well as a substance or combination of substances administered to people to diagnose or recover, correct or change man’s physiological functions.

This definition emphasizes the useful and more popular aspect of medicines. Yet the latter is a product which may be dangerous as well.

This was a fact known by the ancient Egyptians and Greeks, who 1000 years B.C. controlled the production of healing remedies. This was a fact known by the muddy ahibi in the Arab countries, who controlled the extracts contained in medicines at that time.

That is what the people of the 20th century recalled, when in the early 60’s, the thalidomide, taken against morning indisposition, led to the birth of more than 6 000 babies with deformities. The thalidomide tragedy made people understand that medicines are products which require an obligatory, constant and stricter control, in compliance with the development of human knowledge.

Bulgaria is a country which in its postliberation history has paid due attention to this process and today, grounded in tradition, is defending its place of a European country with an up-to-date medicinal regulation.

From the first laboratory to the state control institute

From the first laboratory to the state control institute

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The beginning of the state control on medicines in Bulgaria is based on an indispensable prerequisite – the introduction of the official pharmacopoeia. This happened in 1879, only a year after Bulgaria was liberated from the Ottoman rule. The legal document is “Temporary rules on the structure of the medicinal management in Bulgaria”. The date is 1 February 1879. This is the document that lays the basis of the state control on pharmacies.

The birth date of the medicinal regulation in Bulgaria is considered to be 31 October 1904, when together with the publication of Decree 44 of Royal prince Ferdinand by virtue of Art. 169 of the Public Healthcare Protection Act, the chemical laboratory at the Public Healthcare Protection Directorate was established and regulations for its worked were published.

In 1908 the chemical laboratory was transformed into a Chemical Institute at the Public Healthcare Directorate.

In 1935 this institute was set up as a department of the newly-founded Institute of Public healthcare, including a microbiological and hygiene department. The chemical department was presented by four control laboratories then – medicinal control, control of vitamins and food, control of poisonous substances and bacteriological control.

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In 1945 a Central Institute on norms and control of biological substances was founded. In 1949 the institute was renamed in State Control bacteriological Institute. Prof. Dafina Hadzhidimova was its Director.

 

Foundation of the SICM

Foundation of the State Institute for the control of medicines (SICM). Development of the quality control and standardization.

In 1954 the department on the control of medicines at the Central Pharmaceutical Institute (later Scientific-research Chemical-pharmaceutical Institute /SRCPI/) joins the State Control bacteriological Institute and the State Institute for the control of medicines (SICM) was founded.

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Its first Director was Andrea Popov, MD. Later on Directors were prof. Svetoslav Bardarov (1960-1966) and prof. Radi Ovcharov (1966- 1984) and associate prof. Petar Zikolov (1984-1989).

Up to the transition to a market economy the institute developed in an applied-scientific and scientific-research direction, mainly in the sphere of the quality of medicines. The routine activity included the analyses of the raw materials and all medicinal products from import and local produce before registration as well as under a definite order post-registration. The authorization of products for first export was also done after an analytical control in the institute. SICM controlled the finished product on release of each batch of the products of biological origin produced in the country.

The scientific activity in the institute was developed with priority and was viewed as a methodological base of the control-analytical and standardization activity. New alternative methods for control of the quality of medicines were developed. Many of them were acknowledged as rationalizations and inventions. Significant efforts were directed towards to the standardization of the Bulgarian medicinal plants – tens of Bulgarian standardization documents were developed. During this period a scientific Council was actively functioning, which discussed dissertations, scientific discussions were carried out. The research fellows and other specialists in the institute took part in national scientific forums, published both in Bulgarian and international editions.

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In 1967 the first book of the edition of “Messages of SICM” was published. It was a particular reflection of the development of the medicinal products and biological preparations. Reports and articles on scientific developments by SICM collaborators were published in it, which contributed to the improvement of the control of the quality, the standardization and harmlessness of the medicinal products and biological preparations. Specialists not from the institute also published in it. The establishment of a Pharmacovigilance Center in 1974 and its inclusion in 1975 in the “WHO Drug monitoring programme” was a great achievement of this period and especially of prof. Ovcharov.

In 1976 the Center started to publish annual bulletins “Adverse Drug Reactions”. In 1979 and 1985 editions containing a survey of the respective period were issued.

Thus Bulgaria enjoyed the privilege of having a tradition in the sphere of pharmacovigilance – a direction which is one of the priorities in medicinal regulation today.

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Associate professor Petar Zikolov’s contribution is a great privilege for the future development of the institute. He used to be head of SICM for five years and established a style and school in the control of quality, thanks to which Bulgaria occupied a significant place in this sphere of medicinal regulation.

From SICM to NIMP

From SICM to NIMP

The political and economic changes in 1989 marked the beginning of the transition from a centralized planned to a free market economy. A process of decentralization began in the pharmaceutical sector. The development of the private sector for the pharmaceutical production and distribution was authorized. The number of distributors increased from one to hundreds.

The medicinal market underwent through a serious crisis in 1989, when the import and the local produce were in a condition of deregulation. A lot of medicines, basic for the medicinal practice became deficient, the so-called “suitcase trade” began.

As a result of the lack of regulation, fitting in the new conditions, society was exposed to an unpredictable long stage, characterized by the lack of guarantees for the availability of medicinal products, insecurity in the quality of the ones offered on this deficient market, the occurrence of speculative prices, which made them financially inaccessible etc. A serious necessity of a national institution to regulate and coordinate the relationships between the individual participants in the medicinal sector arose.

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After the demonopolization , the decentralization of the production, supply and distribution of medicines in 1991, SICM turned out to be the only State institution, competent in the medicinal sector. Under the far-sighted leadership of the Director then, prof. Genka Gencheva (1989-1995) international experience was gained and the foundation of a different institute was prepared, an institute which gradually superseded SICM – doubtlessly prestigious in the sphere of the control of quality.

This internal evolution was backed up by a state decision in 1992, when the council of ministers transformed the State Institute for Control of Medicines into a National Institute for Medicinal products (NIMP).

The National Institute for Medicinal products had the status of a scientific organization. It performed the functions of a specialized organ at the Ministry of Healthcare to carry out the state policy and control of medicines for human medicine, expert and control body, national coordinator, methodological manager.

To its functions as an expert and control body of the quality of medicines clearly defined regulatory functions were added for the first time such as: registration and pre-registration of medicines, control of the production, preservation and trade with medicines, coordination of the import, the development of a Bulgarian pharmacopoeia, ensuring information about the medicinal products. These global changes were revolutionary for the pharmaceutical center in Bulgaria. The great process of harmonization with the European medicinal regulation started from here.

The European Union provided serious financial and methodological help to Bulgaria via the PHARE program in order to reconstruct the pharmaceutical sector. Within the program a lot of seminars took place with the participation of over 25 experts from the EU and instruction of the institute staff was carried out in key directions such as: medicinal legislation, control of quality, pharmaceutical inspection especially of the part on Good Manufacturing Practice and Good Distribution Practice, the establishment of a computer information system, price-formation and reimbursement.

The first basic task within the course of reconstruction of the pharmaceutical sector was the establishment of a legal framework. By then there had been no true medicinal legislation in the country. The activities in this sector were regulated by an old and absolutely insufficient for the time text of Ordinance No. 16 of the Public Healthcare Act. The establishment of the new institution was ahead of the creation of a new Act and most probably this was not by chance, since it is this institution that was the nucleus that generated the greater part of the draft-law. This became possible thanks to the accumulated capacity, the wide international support and the presence of a political will to go towards such a change.

Active assistance was provided under the PHARE program by lawyers – consultants from Germany and Spain so as to bring the Bulgarian legislation in line with the European one. Specialists from the institute got a good grounding in the legislations of France, Denmark, Germany, Austria, Portugal, Belgium and other countries.

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Thus as a result of the efforts of many people, with political will and capacity, the Pharmaceuticals and Pharmacies Serving Human Medicine Act was adopted in 1995 (PPSHMA). It is the real basis of the further restructure of the pharmaceutical sector. This Act regulates all basic activities, related to medicinal products. It is followed by 32 ordinances and secondary legislative acts, the greater part of which adapt the provisions of more than 10 European Directives and Good international Practices. For the first time society gets a law that establishes the norms, rules and responsibilities in the medicinal sector and this law is in line to a maximum extent with the European legislation.

Via the new Act and a restructuring of the state control institute in a regulatory medicinal institution Bulgaria takes the first serious steps, which according to the “The White Book” it must perform as an associated EU member-state:

  1. To harmonize its pharmaceutical legislation with the EU one;
  2. To establish a national regulatory body similar to the ones of the European Medicines Agencies, which could adapt the EU norms and standards and guarantee the quality, efficiency and safety of the medicinal products offered to society.

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The evolution of the medicinal regulatory institution created was especially intensive after the Act was adopted. Practically, it reflects the “White book” philosophy, according to which a formal transposition of no Act is possible without an adequate infrastructure available, which could apply it in practice. The implementation of the Act without the experience and motivation of the staff, without the ongoing dynamic restructuring of NIMP was impossible. During this period the head of the institute was Zhasmina Mircheva, MD, the first of a number of young directors of the institute.

In these new conditions the necessity of an operative national pharmaceutical inspection system of a new type was especially pressing. A special unit was established in NIMP, the number of members of which increased from one to eight specialists, who attended training courses in leading European countries. On a regional level units in the Hygiene-epidemic institutes (HEC) were established and inspector-pharmacists. Widely-attended seminars on “Good practices” were held, with participants-experts from Denmark, Great Britain, France and Ireland. Later on handbooks on “Good manufacturing Practice”, “Good Laboratory Practice”, “Good clinical practice”, “Good donation practice” were developed and published. National requirements for opening the pharmaceutical manufacture and authorizing manufacturers and wholesalers were prepared on the basis of the European norms and standards.

In 1994 the first scroll of the Bulgarian pharmacopoeia was published, which is followed by two more, which are an adapted translation of the European pharmacopoeia. The European pharmacopoeia was introduced as official for Bulgaria in 1995. The advertisement of medicines was made possible for the first time in Bulgaria.

The control of the advertisement of medicines, fully in line with the EU requirements, implemented in the Act and Ordinance No. 13 of 14th July 2000, was under way. The council, approving a priori the advertisement proposals was composed only of professionals in the sphere of Healthcare and non-professionals of different professions and performing different social functions. This model provided the opportunity for an unbiased assessment of the advertisement materials and was a prerequisite for objectivity.

The medicinal products registration procedure was set on a completely new basis. It already included not only an assessment of the quality, but also of the efficiency and safety. The requirements for the dossier of the offered products were harmonized with the European ones. The process of forming internal experts for the assessment of the products – applicants for authorization entered its real-phase development. On the basis of the documentation applied by the manufacturer, the internal experts prepared a written statement on the efficiency, its place in therapy and the safety profile. The safety of the product statement was the basic emphasis in the assessment on this level.

The institute started, following the European example, a wider cooperation with external experts. The specialized commissions, reviewing the product after a positive assessment of NIMP held their meetings in the premises of the institute and by rule the secretary was an official working for NIMP. The territorial concentration of the regulatory activities and capacities regarding medicines: manufacturing authorizations, marketing authorizations, trade in medicines, post-marketing control, quality control, control of the advertisements are all markers of the European model of a medicines agency to which NIMP comes closer.

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This abrupt increase of the number of newly-authorized medicines necessitates providing regular information about the pharmaceutical sector, medicines specialists and society as a whole. The issuance of a number of references on the medicinal products with marketing authorizations began. These are the issues of 1992, 1993 (via this issue the anatomic-therapeutic-chemical (ATC) classification was introduced for the first time, 1994 and 1996, as well as two supplements of 1997 and 1999. In the periods between these two issues bulletins-supplements were issued every three months which provided non-interruption of the information flow on medicinal products with marketing authorizations.

The enormous number of new products appearing on our market necessitated the provision of independent, critically presented information on medicinal products, which would stimulate rational pharmacotherapy. In cooperation with the then present pharmaceutical – therapeutical commission in 1993 NIMP started the creation and distribution of the independent issue “Medicinal bulletin”, which since1998 became an independent issue of NIMP.

The necessity of presenting the information, used and kept in the institute, on a more up-to-date basis became obvious. With the financial and methodological help of the PHARE program a computerized information system was established in NIMP, working under ORACLE. It included 10 modules, keeping detailed information on medicinal products registration; control of import and sales; licensing of manufacturers, retailers and wholesalers, control of the advertisements, adverse drug reactions. Since January 2000 everyone who wants gets a free access via internet to this data base, in its section providing information for medicinal products with marketing authorizations and licensed wholesalers of medicines.

Intensive changes and a tendency for harmonization with the European legislation were observed in the other associated EU member-states. They all worked to achieve one and the same aim – to protect the health of society by providing it with medicines, covering the international quality, efficiency and safety standards. All of them have similar contacts with the European institutions and they are all interested in intensifying the process of joining them. All of them taken together comprise an impressive enormous pharmaceutical market (population of more than 100 000 000) and the joining of this market obviously requires a better collaboration, harmonization and mutual assistance in all spheres of the pharmaceutical sector.

Thus the objective realities, the EU support and the encouraging help of WHO lead to the historical decision for the establishment of an informal union of the regulatory bodies of these countries. In 1997 the first official meeting was held in Sofia which aims at creating CADREAC (Collaboration Agreement of Drug Regulatory authorities in European Union Associated Countries).

There are six objectives that the union sets before itself:

  1. To facilitate the implementation of the European standards and requirements;
  2. To create an appropriate atmosphere which could facilitate EU in the process of the accession of the Central and East European countries;
  3. To facilitate the process of implementing new procedures that are mutual recognition;
  4. To create a forum for discussing the strategy of joining the European Union ( by avoiding the duplication of the activities);
  5. To prepare meetings of the regulatory bodies participating in the agreement among themselves and with the European Union;
  6. To participate in the European network for regulatory medicinal information.

An active cooperation started between the European Medicines Agency (EMEA) and the Central and East European countries via CADREAC on three levels:

  1. The implementation of a commonly accepted simplified procedure of the medicines registered in the EU under the centralized procedure;
  2. Exchange of information on the safety of these medicines.
  3. Participation of CADREAC observers in the working groups of the Committee for Proprietary Medicinal products (CPMP) and EMEA.

FROM NIMP TO BDA

FROM NIMP TO BDA

The medicinal sector is extremely dynamic. The adaptation of the European pharmaceutical legislation in 1995 via its implementation is the basis of the first pharmaceutical Act – the Pharmacies and Pharmaceuticals Serving Human Medicine Act and the 32 ordinances following it were the first step of the process of European harmonization. In the 1995-2000 period the regulatory policy was marked by the necessity to solve in a step-by-step manner narrowly national problems, the improvement of the legislation respectively. This was a normal, expected process and the respective changes were put forward before the Parliament.

Together with that of extreme importance and priority in this period was the regular transposition of the amendments of the European pharmaceutical legislation and the adoption of the complete philosophy in the management of the pharmaceutical sector. Adopting such a philosophy, such a common model was a process taking place not only in Bulgaria, but also in all Central and East European countries and which is still ongoing in the member-states themselves.

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Since 1997 the management of NIMP was taken over by Borislav Borisov, MD. In 1999 the Pan-European Regulatory forum was launched and it gathered the intellectual potential of the whole European pharmaceutical regulation and a dialogue began, in which positions were harmonized, priorities were outlined and the policy for this sector was laid down. The participation of Bulgaria and the other associated countries was planned as a form of training and gaining experience, but as a partnership as well, in which the opinion of all countries was valuable.

What is important for the institution is the participation in joint trials within the framework of European Network of Official Medicines Control Laboratories (OMCL) and the European Directorate for the Quality of Medicines (EDQM) at the Council of Europe. It became a member in the structure of this network almost four years ago. More than 40 joint trials of the suitability of the laboratories have been conducted by now (PTS), new monographs and chemical standards of the European pharmacopoeia were developed, observation of the national pharmaceutical market was carried out (MSS).

The legal framework of the necessity to amend and supplement legislation in Bulgaria was outlined when the Act for the amendment and supplementation of the Pharmaceuticals and Pharmacies Serving Human medicine Act was passed. The Act was renovating in the following aspects: new terms for “medicine”, “medicinal product”, “medicinal substance” were introduced; medical devices were included in the range of the Act; the texts, concerning clinical trials were up-dated.

By virtue of the Act the Bulgarian Drug Agency at the Ministry of Healthcare was established, which was defined as a body for the supervision of the quality, efficiency and safety of medicines. It has extended rights and functions, including the ones on the issuance of manufacturing authorizations, marketing authorizations under art. 3, par. 3 and 5, (medical devices and in vitro diagnostic means), keeping different registers, registration of drugstores etc.

The Ministry of Healthcare and the Bulgarian Drug Agency are indicated as the two institutions, conducting the pharmaceutical policy of the country. The basic functions of the Agency according to the Act are the following:

  1. To issue manufacturing authorizations of medicines.
  2. To put forward proposals before the Minister of Healthcare for the issuance of marketing authorizations and for the wholesale trade in medicines.
  3. To carry out a chemical and pharmaceutical expertise for the assessment of the quality regarding the marketing authorizations and to register the clinical trials with medicines conducted in the country.
  4. To register drugstores.
  5. To coordinate the import and issue sales authorizations of medicines.
  6. To issue certificates of medicines and the origin of medicines.
  7. To control the manufacture, retail and wholesale trade with medicines, clinical trials and the advertisement of medicines.
  8. To make laboratory analyses when doubting a deviation from the quality, efficiency and safety of medicines and to undertake the measures stipulated in the Act.
  9. To organize a system for the registration, analysis and summary of the adverse drug reactions, as well as the medicinal interactions, arising when using medicines and to undertake the respective measures.
  10. To perform the functions of a national coordinator and consultant on the problems, related to the quality, efficiency and safety of medicines.
  11. To carry out a consultancy, scientific, information and editor’s activity in the sphere of the pharmaceutical sector.
  12. To participates in activities in the sphere of medicines, related to the work of international bodies, organizations and agreements, to which Bulgaria is a party.

In December 2003 amendments were made to the PPSHMA, the aim of which was to reduce the differences with the European legislation. By virtue of these changes BDA presented by its General Executive acquired the authority to issue marketing authorizations of medicinal products. This agency acquired independence for the first time in its competence, bearing both serious rights and unambiguous responsibility. The Act introduced the concepts and the procedures respectively regarding the “essentially similar medicinal product” and “familiar medicinal substances”, the way the European legislation interprets them. This revision of the Act includes the European principle of respecting the data exclusivity, which a lot of joining countries refuse to include in advance. The Bulgarian legislation includes the “Bolar” amendment too and thus fits the requirements of both the innovative and generic industry. Standards are made uniform with Europe regarding pharmacovigilance – even more serious requirements are set before the marketing authorization holders.

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Since April 2004 Director of the Agency has been Emil Hristov, MD. Challenge has offered him the chance and responsibility to be head of BDA during the final period of Bulgaria’s EU accession – 2007.

The doubtless success of BDA during the latest years includes:

  • The Ethics Code approved by an order of the General Executive of BDA in 2000.
  • The invitation made to experts from the Agency to participate as observers in the working committees at EMEA of September 2003.
  • In June 2004 the Act for ratification of Convention 50 for developing the European pharmacopoeia was approved. After presenting the accession documents of the General Secretary of the Council of Europe in September, Bulgaria’s membership will come into force on 22 December 2004.
  • The participation of the Agency’s representatives in different programs and projects is ongoing, the more large-scale of which are the Pan-European Regulatory Forum (PERF), the working groups at EMEA, WHO, the Drug Information Association (DIA), the European pharmacopoeia – in the sphere of the control of the manufacture, OMCL and other working meetings, conferences and training.
  • The publications of BDA’s employees under the form of reports and articles in the most prestigious issues in the sphere of medicinal regulation and other specialized spheres.
  • BDA’s hosting of a couple of international inspections by EMEA, WHO, the European pharmacopoeia – in the sphere of the control of the manufacture, the administrative capacity of the Agency, in the sphere of the control of the clinical trials, to ensure high quality in its laboratory activity. Bulgaria has been the host of a number of working committees under PERF.
  • The free Internet access provided via the Agency’s web site to a large amount of information related to its activity. The data base of the medicines with marketing authorizations is up-dated weekly, the new normative documents are published both in English and Bulgarian and allow access to forms and applications (in pdf format), approved by PPSHMA and its ordinances.
  • BDA’s information system, which was supplemented by up-dated hardware and software. An opportunity was provided for the industry to follow the course of the operating procedures on granting marketing authorizations of medicinal products. This system (Drug Dossier Tracking and Traceability) is the only one of its kind by now and raises interest.
  • Signing an agreement with the European Medicines Agency (EMEA) within the PHARE program:
    1. Reimbursement of the expenses for the participation of the BDA representatives as active observers in the following committees and workshops of EMEA:
      1. Committee for Human Medicine Products, plenary (CHMP plenary).
      2. Committee for Human Medicine Products Biotech (CHMP Biotech).
      3. Efficiency working group at CHMP.
      4. Safety working group.
      5. Pharmacovigilance working group.
      6. Pediatric expert group.
      7. Herbal Medicinal Products Committee, plenary (HMPC, Plenary).
      8. Committee for orphan Medicinal Products, plenary (COMP Plenary).
      9. Scientific Advice Working Group.
      10. Inspectors on Good Manufacturing Practice (AD hoc meeting of the inspector’s offices on Good manufacturing Practice).
      11. Inspectors on Good Clinical Practice (AD hoc meeting of the inspector’s offices on Good Clinical Practice).
      12. Inspectors on Good Laboratory Practice, CHMP/CVMP Quality (united working group on the quality of medicinal products – human/veterinary).
      13. Quality Review of documentation group (QRD).
      14. Eudranet telematic group.
      15. Europharm telematic group.
      16. Eudravigilance telematic group.
      17. Eudra telemetric group for clinical trials.
      18. Management board.
  • BDA integration if the EU telematic system.
  • Conducting a pre-accession linguistic check of the Bulgarian variant of the information (Product information) of the medicinal products (Summary of products characteristics, leaflet and package labeling), having a marketing authorization under the centralized procedure of the European Union.
  • Conducting an analytical control within the joint trials (departments of the Chemical-Physical Expertise of medicines and Pharmacovigilance), organized by the European Directorate on the Quality of Medicines (EDQM) on the monitoring of the market (MSS), qualification trials (PTS) and chemical comparative substances (CRS) of the European pharmacopoeia. The BDA laboratories have been included for ten years in the network of the European Network of Official Medicines Control Laboratories (OMCL) at EDQM.
  • Medical devices – inclusion of BDA employees in the following working groups of the European Commission related to the medical devices:
    • Consultancy Committee for approximating the laws related to the medical devices in the member-states.
    • Medicines and medical devices.
    • Working group on monitoring the market.
    • Expert group on medical devices – classification and border products.
    • Expert group on medical devices – vigilance.
    • Working group at the notified bodies.
  • Participation in the development of the new Pharmaceuticals and Pharmacies Serving Human Medicine Act and new Medical devices Act.

BDA performs its regulatory activity in cooperation with the following specialized commissions, established under art. 21 of PPSHMA at the Ministry of Healthcare:

  1. Specialized Commission for Assessment of the Therapeutic Efficiency and Safety of the Medicinal Products (SCATESMP).
  2. Specialized Commission for Assessment of the Therapeutic Efficiency and Safety of the Medicinal Products – phytogalenic and homeopathic (SCATESMP – PHGH).
  3. Specialized Commission for the Authorization of the Conduction of Clinical Trials (SCACCT).
  4. Central Ethics Commission (CEC).
  5. Specialized Commission for Assessment of the Therapeutic Efficiency and Safety of the Medicinal products – vaccines and medicines under art.3, par. 3 (SCATESMP – V).
  6. Specialized Commission for Assessment of Medical Devices (SCAMD).
  7. Specialized Commission for determining the belonging of the products (SCDBP).