REGULATORY PROBLEMS IN CARING OUT PRE- AND POST- AUTHORISATION CLINICAL TRIALS Dr Penka Decheva GCP Inspector, BDA

New Law on Medicinal Products – 13 April 2007 Main goals Synchronisation of the National Legislation with the European Directives Active implementing of EU Regulations To guarantee quality, efficacy and safety of medicinal products on the Bulgarian, respectively European market. 14 Titles – Title IV Clinical Trials 297 articles

Direct implementation of Directive 2001/20 EC New Law on Medicines… Direct implementation of Directive 2001/20 EC To simplify and harmonise the administrative provisions governing clinical trials by establishing a clear, transparent procedure To facilitate the internal market of medicinal products while at the same time maintain appropriate levels of protection for public health

New Law on Medicines… To provide an environment for conducting clinical research that protects participants without hampering the discovery of new essential medicines To create conditions condusive to the effective co-ordination of such clinical trials in the European Community by the authorities concerned

General provisions Clinical trials in human subjects shall be conducted with observation of the basic principles for the protection of human rights and human dignity in any medico-biological study according to the Declaration of Helsinki. Any clinical trials of medicinal products in human subjects including bioavailability and bioequivalence shall be planned, conducted, and reported in compliance with the principles of Good Clinical Practice. The rules of Good Clinical Practice shall be laid down in an ordinance issued by the minister of health.

General provisions The rights, safety, and health of the subjects in the clinical trials shall be placed above the interests of science and society.

Ethics committee Ethics Committee for multicentre clinical trials shall be established to the minister of health the composition of which shall be determined by an order. Ethics committees shall be established at the healthcare establishments where clinical trials are to be conducted the composition of which shall be determined by an order of the manager of the healthcare establishment.

Ethics committee The BDA shall maintain and keep a public register of ethics committees. Central Ethics Committee shall be established to the Council of Ministers.

Authorisation to conduct a clinical trials The ethics committee shall: 1. give positive opinion; 2. refuse in a motivated manner, or 3. request amendment of a part of the documentation as a condition for obtaining a final opinion.

Authorisation to conduct a clinical trials Within 60 days from the submission of an application, the ethics committee shall pass resolution with an opinion, which shall be sent to the applicant and the BDA.

Authorisation to conduct a clinical trials Where the opinion of the respective ethics committee is negative, the applicant can appeal before the Central Ethics Committee within 90 days of the date of notification. The opinion of the Central Ethics Committee shall be final and binding on the respective ethics committee.

Authorisation to conduct a clinical trials Within 60 days of the date of submission of an application for a clinical trials of medicinal products , the BDA shall notify the applicant that: a. the clinical trials can be conducted on the territory of the Republic of Bulgaria or b. the clinical trials cannot be conducted indicating the reasons therefore. In the cases “в”, the CRO can submit to the BDA an application amended in accordance with the motives set out or submit the required information in accordance with the requirements of the BDA within 30 days.

Authorisation to conduct a clinical trials Within 30 days of the submission of the amended application or the additional information, the BDA shall notify the applicant in writing that: a. the clinical trials can be conducted on the territory of the Republic of Bulgaria or b. that it refuses the conduct of the clinical trials stating the reasons therefore.

Authorisation to conduct a clinical trials The refusal shall be subject to appeal under the terms of the Administrative Procedure Code. The clinical trials can be started provided that within the time limit the BDA has not issued a notification with motives of disapproval of the clinical trials.

Amendments Essential amendment in the conduct of the clinical trials shall be any amendment in the study protocol and/or in the information and the documentation , which can affect: -the safety or the physical and mental immunity of the study subjects; -the scientific value of the clinical trials; -the conduct or the organization of the clinical trials; -the quality or the safety of any study medicinal products.

Premature Termination or Suspension of the Trial The CRO or the investigator can undertake urgent measures to protect the study subjects from suddenly occurred risks for their safety and health. In this cases the CRO shall immediately notify the BDA and the respective ethics committee about the undertaken actions and the reasons for the decision.

Premature Termination or Suspension of the Trial In the cases of cessation the BDA shall immediately notify the respective ethics committee, the other competent authorities, the European Medicines Agency, and the European Commission about the undertaken measures and the reasons therefore.

Pharmacovigilance The sponsor shall notify the BDA, the regulatory bodies of all Member States where the clinical trials is conducted in case of a multicentre trials, and the respective ethics committee of any suspected serious adverse drug reaction occurring in the course of the clinical trials, which has resulted in death or has been life-threatening not later than 7 days of receipt of information thereof.

Pharmacovigilance The sponsor shall provide additional information on the case within 8 days of the date of the notification sent. The sponsor shall notify any other suspected unexpected serious drug reactions occurring in the course of the clinical trials not later than 15 days from the date of receipt of the information for their occurrence.

Pharmacovigilance The BDA shall document any information about suspected unexpected serious adverse drug reactions of the study medicinal products.

Notification of the end of a clinical trial The CRO shall notify in writing the BDA and the respective ethics committee of the end of the clinical trial on the territory of the Republic of Bulgaria The notification shall be submitted within 90 days of the closure of the clinical trials.

Non-interventional study A non-interventional study shall be conducted with medicinal products authorised for use in the Republic of Bulgaria where these are studied to obtain additional information about the product prescribed in the usual manner in compliance with the conditions determined in the marketing authorisation.

Clinical Trials 2006-2007

BDA and Clinical Trials – Current Experience Statistics for 2006-2007 2006 2007 Bioequivalence 23 6 Phase I-I/II 2 Phase II 47 12 Phase III 88 9 Phase IV 3

Main challenges The most important challenge – to transpose the written text into a really functioning system

Main challenges Harmonisation of assessments, with other member states. Development of SOPs and guidelines. Development of “Regulatory Standard” for evaluation . Building up staff abilities.

Main challenges Adequate regulatory approach to the preclinical safety studies, adverse events/adverse drug reactions in clinical trials and post-marketing in terms of evaluation, control, scientific advice. Building up of adequate IT capacity.

Main challenges Exchanche of information, globalisation of regulation at national level . Participation in groups and committees of the European Commission. Scientific assessment of highest quality.

We have the self-confidence that the Bulgarian Drug Agency is able to meet the high requirements and expectations both of the European Union and of all the participants on the medicines market and above all of the Bulgarian citizens.

Thank you!