transition challenges for collaboration agreement of drug regulatory ...

Drug Information Journal, Vol. 35, pp. 935–939, 2001 0092-8615/2001
Printed in the USA. All rights reserved. Copyright © 2001 Drug Information Association Inc.
TRANSITION CHALLENGES FOR
COLLABORATION AGREEMENT OF
DRUG REGULATORY AUTHORITIES IN
EUROPEAN UNION ASSOCIATED
COUNTRIES: FOCUS ON BULGARIA
BORISLAV N. BORISSOV, MD,PHD
Executive Director
MARIA J. POPOVA, MD, PHD
Head of Directorate, Drug Information and Pharmacovigilance
ROZALINA A. KOULAKSAZOVA, MSC PHARM
Head of Department, Specialized Drug Information
Bulgarian Drug Agency, Sofia, Bulgaria
The article focuses on the challenges faced by the Collaboration Agreement of Drug
Regulatory Authorities in European Union Associated Countries (CADREAC) in harmonization
with European Union pharmaceutical standards. The beneficial impact of different
forms of collaboration and the national acheivements of the Bulgarian Drug Agency are
reviewed. In the harmonization process, drug regulatory authorities are dedicated to
collaborating with all stakeholders, starting with industry and ending with consumers.
Key Words: CADREAC; European Union; Bulgarian Drug Agency; Pan European Regulatory
Forum on Pharmaceuticals; Harmonization; Collaboration; Pharmaceutical legislation
INTRODUCTION ority is the preparation of the pharmaceutical
THE COLLABORATION Agreement of Drug
Regulatory Authorities in European Union
Associated Countries was established in
1997. Participating countries—Bulgaria, Czech
Republic, Estonia, Hungary, Poland, Slovakia,
Latvia, Lithuania, Romania, and Slovenia—
shared similar histories and responsibilities
and a common goal—the harmonization of
drug development. CADREAC provided an
sector for accession to the European Union.
This is an intensive process of harmonization
of standards and good practices, introduction
of mutually recognizable procedures, and implementation
of the acceptance of European
Community treaties, regulations, decisions,
and directives by all member states and appli-
cant countries.
informal way to provide mutual assistance in
the harmonization process.
The Bulgarian Drug Agency’s present pri-
IMPACT OF INTERNATIONAL
FORMS OF COLLABORATION
CADREAC Establishment
and Philosophy
Reprint address: Borislav N. Borissov, MD, PhD, Director,
Bulgarian Drug Agency, Yanko Sakazov Blvd., Three meetings were held before CADREAC
1504 Sofia, Bulgaria. E-mail: borisov@bda.bg. was established:
935

936 Borislav N. Borissov, Maria J. Popova, and Rozalina A. Koulaksazova
• The European Union Associated Countries procedure for centralized authorized prod-
of Central and Eastern Europe meeting on ucts (2). This procedure, a serious step in the
pharmaceutical issues in Brussels on Octo- preparation for EU accession, was effective
ber 25, 1995,
as of January 1, 1999. Under this procedure,
• A roundtable of European Union/Central CADREAC countries accept the European
and Eastern European countries on the Medicine Evaluation Agency’s (EMEA’s)
pharmaceutical industry in Brussels on June evaluation of centrally authorized products
27, 1996, and
and issue a decision on granting a marketing
• An informal meeting between some Central authorization within 90 days.
and Eastern European countries and the Euro- The implementation of the procedure is
pean Union in London in December 1996. important for marketing application holders,
drug regulatory authorities, and patients.
CADREAC was inaugurated during the Marketing application holders benefit from
first meeting of the drug regulatory authori- faster access to the market and lower fees.
ties of Central and Eastern Europe in Sofia, Drug regulatory authorities benefit from
Bulgaria in 1997 (1). Ten countries signed more experience and resource savings. Fi-
the agreement: Bulgaria, Czech Republic, nally, patients benefit by fast availability of
Estonia, Hungary, Poland, Slovakia, Latvia, innovative products on the market. General
Lithuania, Romania, and Slovenia; Cypress registration statistics about centrally authorjoined
CADREAC in 1998. Together, these ized products for 1999 and 2000 show the
countries represent a significant pharmaceu- contribution of the simplified centralized
tical market of more than 100 million people. procedure (Table 1).
CADREAC is a voluntary agreement for Another ambitious task of the agreement
mutual assistance of the European Union As- is the elaboration of a common simplified
sociated Countries. It is supported by Euro- procedure for products subject to the Mutual
pean Union (EU) officials and encouraged Recognition Procedure in the EU. For these
by the World Health Organization. The key products, CADREAC countries look for a
aims of the agreement are to: successful balance between their national responsibilities
and European requirements.
1. Enhance implementation of EU standards Participation in the work of the EMEA
and requirements, and the Committee for Proprietary Medicinal
2. Create a better environment for EU to in- products is a serious tool for accelerating EU
volve Central and Eastern European coun- harmonization. CADREAC is represented by
tries,
two observers on each topic: quality, efficacy,
3. Facilitate the introduction of mutually rec- safety, Good Manufacturing Practice, Good
ognizable procedures,
Clinical Practice, Mutual Recognition Facili-
4. Establish a forum to discuss strategies for EU tating Group, information technology, Notice
accession (avoiding duplication of work),
5. Organize meetings of Central and Eastern
to Applicants, and so forth.
European countries’ drug regulatory authorities
and between Central and Eastern
European countries and the EU, and
The Pan European Regulatory Forum
on Pharmaceuticals
6. Participate in the European network of regu- The Pan European Regulatory Forum on
latory information on medicinal products. Pharmaceuticals develops strategies to meet
emerging political and economic changes
National Achievements due to the
CADREAC Collaboration
(3). It is an open, constructive dialogue that
analyzes the situation and, at the same time,
determines mechanisms for fulfilling techni-
One of the major achievements of the collabcal requirements of the white paper, which
oration is the elaboration of the simplified outlines the principal requirements govern-

Challenges for Eastern European Associated EU Countries: Bulgaria 937
TABLE 1
Medicinal Products in Bulgaria, Centrally Authorized in the EU
Number of
Number of Registered
Year/Kind of Procedure in Bulgaria Applications Medical Products
1995–98/National Procedure 55 53
1999–2000/Simplified Centralized Procedure 72 56 + 16 in progress
ing the preparation for integration to the for products using the national proce-
Community Market of the European Comdure,munity Associated Countries. The forum is • Medical devices and in vitro diagnostics
funded by the EU project Poland Hungary are included in the scope of the Medici-
Albania Romania Estonia (PHARE) and was nal Act. Specific requirements for granting
established in 1999. It focuses on the follow- marketing applications of medical devices
ing priority action areas: and in vitro diagnostics were stipulated in
a separate regulation of August 2000. The
1. Acceptance of European Community trea- requirements of the three relevant Euroties,
regulations, decisions, and directives pean directives (93/42, 90/385, and 98/79)
by all member states and applicant coun- have been incorporated into national legistries,lation.
The Bulgarian Drug Agency is re-
2. Quality, efficacy, safety,
sponsible for granting marketing applica-
3. Good Manufacturing Practice,
tions for these products. The Conformitee
4. Responsibilities and mandate of the com- Europeene (CE) mark is respected; for
petent authorities, and
products with the CE mark the procedure
5. Information technology.
lasts two months.
• An additional point of over-the-counter
Interagency training is considered a future sales was established. The revised law aptopic
of collaboration for the Pan European proves medicinal product sales in drug
Regulatory Forum on Pharmaceuticals. stores, which were established in Bulgaria
in 2000. A sublaw regulation with a general
sale list was published. The list comprises
IMPORTANT REGULATORY a limited number of products from the over-
CHANGES IN BULGARIA’S the-counter list including some medical de-
PHARMACEUTICAL SECTOR vices and in vitro diagnostics, and
DURING 2000 • Conduct of clinical trials. The regulation
on clinical trials was amended in Septem-
The Medicinal Act of February 2000 revised
the 1995 law (4). Several topics that were
already harmonized with European legislation
were not changed. Others were amended
to reach compliance with EU legislation.
Some new provisions were introduced. Important
new provision in the revised law and
sublaw regulations are:
ber 2000. Annex 1 is an adopted translation
of the International Conference on Harmo-
nization tripartite Guideline for Good Clin-
ical Practice and Annex 2 is the notification
form (5). The duration of this approval procedure
is two months for Phases II and
III and one month for Phase IV. Detailed
information is available on the Bulgarian
Drug Agency Web site (www.bda.bg/Doc-
• The timeframe for assessment and umentsonMainImportance). Experience in
granting of marketing applications was clinical trials is gradually growing (Figures
shortened from 12 months to 7 months
1 and 2).

938 Borislav N. Borissov, Maria J. Popova, and Rozalina A. Koulaksazova
FIGURE 1. Clinical trials conducted in Bulgaria between 1995 and 2000.
THE NATIONAL INFORMATION • Optic archive of packages, and
SYSTEM ON PHARMACEUTICALS • Information technology.
An important responsibility of the Bulgarian The agency’s Web site (www.bdg.bg/
Drug Agency is to maintain a national infor- bulletin) includes all registered drugs,
mation system on pharmaceuticals. An Ora- searchable by trade name, international non-
cle-based drug database was established in proprietary name, Anatomical Therapeutic
1998, comprising nine modules covering ar- Chemical (ATC) code, and manufacturer.
eas of activity within the agency:
The site also contains lists of over-the-
counter drugs and licensed wholesalers with
• Marketing authorization,
essential information on their licenses, and
• Manufacturing authorization, information on current information recalls.
• Wholesaling authorization,
Basic registration and sales statistics are pub-
• Import and sales, lished annually. The top 50 ethical and over-
• Medicinal products advertising,
the-counter products are listed by number of
• Adverse drug reactions register, packs and revenue. The Web site is updated
• Medical devices,
weekly.
FIGURE 2. Phase II and III clinical trials conducted in Bulgaria between 1995 and 2000.

Challenges for Eastern European Associated EU Countries: Bulgaria 939
The agency publishes three quarterly bul- Forum on Pharmaceuticals is another impor-
letins for prescribers and retail pharmacists: tant form of partnership between regulators
Newly Registered Drugs Bulletin, Bulletin on on an international basis. These collabora-
Adverse Drug Reactions, and Specialized tions that CADREAC takes part in play an
Drug Bulletin. The guiding principal of important role in bridging the gaps and build-
Specialized Drug Bulletin is to classify auing a common network of competence, confithorized
medicinal products according to the dence, and credibility in pharmaceutical reg-
internationally accepted classification, allowing
comparisons among countries; this is
ulation.
the philosophy of the International Society
of Drug Independent Bulletins. The analysis
REFERENCES
of drug consumption based on the ATC/defined
daily dose methodology became an im-
1. Collaboration Agreement between Drug Regulatory
Authorities in European Union Associated Countries,
portant tool for determining trends in the pre- June 14, 1997, Sofia, Bulgaria.
scribing profile and for starting a national 2. European Commission. Procedure on the Granting of
dialogue on rational and cost-effective drug
use.
Marketing Authorization by Central and East Euro-
pean Countries for Medicinal Products for Human
Use Authorized in the European Union Following the
Centralized Procedure and the Variations and Re-
CONCLUSION
newal of such Marketing Authorizations. http://phar
macos.eudra.com.
The implementation of EU standards in
CADREAC is a consequence of the effort
3. Organization of a Pan European Regulatory Forum
on Pharmaceuticals. Terms of Reference, PRAQIII.
Pan European Regulatory Forum on Pharmaceuticals.
of all countries and their drug regulatory http://perf.eudra.org.
authorities, and collaborative activity among 4. Revised Version of the Bulgarian Medicinal Act. State
CADREAC countries. Essential support
from the EU—both financial and professional—has
also had a positive impact on
Gazette. Bulgarian National Assembly: February 4,
2000.
5. Regulation No. 14 of the Conditions and the Order
for Conducting Clinical Trials of Drugs on Human
this process. The Pan European Regulatory
Subjects. State Gazette. July 31, 2000.