The Regulation of Clinical Trials in the Republic of Serbia A

Introduction: Modern trends in drug production and traffi c of drugs as a primary marketing resource of high quality effi cient and safe drugs have an important task to provide safe, eff ective and quality medicines through clinical trials. Topic: Overview of current regulations established in the fi eld of clinical trials of drugs and the importance of carrying out clinical trials is pointed herein. Methods: Pursuant to the applicable regulations in the Republic of Serbia and those established at the level of the European Agency (EMA) is provided an overview of the key elements essential for the objective procedures carried out in clinical trials of drugs in Serbia. Conclusion: Modern drug therapy today is exposed to serious challenges given the numerous studies in the fi eld of medicine and pharmacy carried out in the world today. Clinical trials are particularly vulnerable segment in this area and require the participants in these processes to be highly educated and to have the serious ethical approach to all stages of the process.


INTRODUCTION
Clinical trial -any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic eff ects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or effi cacy his includes clinical trials carried out in either one site or multiple sites, whether in one or more than one Member State.

METHODS
Pursuant to the applicable regulations in the Republic of Serbia and regulations established at the level of the European Agency (EMA) is provided an overview of the key elements essential for the objective procedures carried out in clinical drug trials in Serbia.

TOPIC
Regulations applied within clinical trials [1] in Th ese regulations are determined by the conditions under which clinical trials in Serbia are conducted, the responsibilities of sponsors, ethical committees, researchers, control of clinical trials and other issues in the fi eld of clinical trials.In Republic of Serbia, clinical trials are conducted in accordance with the highest European and international standards or guidelines for good clinical practice representing ethical and scientifi c quality standard in conducting clinical trials.Documentation submitted in the procedure for approving clinical trials is consistent with the documentation required in EU countries.Agency for Medicines and Medical devices (ALIMS) is authorized for tasks related to clinical trials in our country, primarily for the issuance of licenses for clinical trials of medicinal products and medical devices, for issuing a permit to import the drug or medical device clinically tested, monitoring pharmacovigilance in clinical trials and to control implementation of all processes.In average, 90 clinical trials for drugs and medical devices are approved per year in Republic of Serbia.In Serbia, all phases of clinical trials are conducted, but in terms of the number of studies by phases phase III trials are most frequent.
License for the conduct of clinical trials shell be issued within 60 days from the day the application is evaluated to be complete.Sponsors who are not based in the Republic of Serbia can have a legal entity as a representative, or an agent based in the Republic of Serbia, who is responsible for documentation and obtaining authorization for clinical trials and pharmacovigilance in clinical trial conducts.Th e ALIMS shall implement and supervise the conduct of clinical trials to determine whether the approved clinical trials are carried out in accordance with the protocol established by national regulations and guidelines of good clinical practice and in order to protect the health and safety of subjects.
In ALIMS clinical trials of drugs are in the Medical sector which performs the issuance of licenses for clinical trials and control clinical trials, when the Sector for permits authorizing the import of a drug that is in clinical trials.
Clinical trial -any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic eff ects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) with the object of ascertaining its (their) safety and/or effi cacy his includes clinical trials carried out in either one site or multiple sites, whether in one or more than one Member State; Subject is a person participating in the CT of drug confi rms its subject's informed consent on written statement, containing both the date and the signature, on participation in a certain clinical trial, provided by an entity capable of giving consent or, if incapable of giving consent, by its legal representative, in accordance to the Law, given voluntarily aft er being thoroughly informed about the nature, signifi cance, consequences and health risks.
Th e law also defi nes that the clinical trial of drugs (CT), studies performed on humans to determine the clinical, pharmacological or pharmacodynamic eff ects of one or more of the study drugs, or to identify any adverse reactions, to one or more study drugs examine the absorption, distribution, metabolism and excretion in order to determine their safety and effi cacy.
A clinical trial may be conducted if: • Th e benefi ts of the tested drug is greater than its potential risk to the life and health of patients (previously conducted preclinical trials) • Th e Ethics Committee of the legal entity, in which the clinical trial is been conducted, ruled that the therapeutic benefi t of the medicinal product under the trial, and its importance for the protection of life and health of subject, justify its potential risks.
• Subjects, or their legal representatives, are completely informed, in writing and language they can understand, about the clinical trial, and of their right to withdraw their consent to participate in a clinical trial at any time.
• Subjects right to the psychological and physical integrity, privacy and protection of personal data in the procedure of clinical trials are ensured.
Clinical trials must not be carried out on: 1. healthy persons who have not attained the age of 18; 2. healthy pregnant women and nursing mothers; 3. persons accommodated in social care institutions; 4. persons who are placed in health care facilities or institutions for penitentiaries by court decision; 5. persons whose coerced or otherwise induced into giving consent to participate in clinical trials, and to give free consent for participating in clinical trials.
If necessary, and under special precautionary measures, clinical trials can be performed on persons under the age of 18, pregnant and breastfeeding women, suff ering from a disease or condition for which are medical product been clinically investigated, is intended to.
Sponsor in the process of obtaining licence for the implementation of CT, sponsor shall submit to the Agency the fallowing documentation.
A new drug, or a drug already registered, which will be tested in a diff erent way than the approved Summary of Product Characteristics (SPC) to a new indication for a second population, in the new pharmaceutical form.

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Th e documentation for the approval of clinical trials of medicines shall contain: 1. Covering letter by the sponsor; 2. Protocol; 3. Protocol Synopsis in the Serbian language; 4. Information on adverse reactions to the medicine, unless part of the Investigator's Brochure; 5. Investigator's Brochure; 6. Investigational Medicinal Product Dossier (IMPD), i.e. the documentation from the investigational medicinal product dossier in another format if the sponsor does not have the required documentation prepared in the IMPD format; 7. Summary of Product Characteristics with authorization; 8. Case Report Form (CRF); 9. Decision of the ethics committee of the healthcare institution that will implement the clinical trials, and/or ethics committees if they are multicentre clinical trials; 10.Written consent by the general manager of the healthcare institution, and/or healthcare institutions wherein the clinical trials of the medicine will take place; 11.Documentation on the investigational medicine, Good Manufacturer Practice certificate of a European Union country or another country with the same or similar requirements regarding Good Manufacturer Practices, and/ or a certifi cate on the application of Good Manufacturer Practice issued by the competent ministry pursuant to the law, and/or a report by the inspection for medicines of the competent ministry on compliance with the conditions for the manufacture of medicines for clinical trials, no older than six months, an analysis certifi cate, labelling for the medicine in the Serbian language and the original language, both for the medicine being tested, as well as the comparative medicine; 12. Certifi cate confi rming that the material of animal or human origin being used in the production of the medicine does not pose a risk of transmission of spongiform encephalopathy -TSE certifi cate, if required; 13.Additional requirements for medicines with specifi c characteristics (genetically modifi ed organisms, radiopharmaceuticals); 14.Certifi cate of Good Manufacturing Practice for the location of the production of the active biological substance of a European Union country or another country with the same requirements regarding Good Manufacturer Practice, and/or a statement by a person qualifi ed for releasing a series of medicines for clinical trials confi rming the active biological substance was manufactured pursuant to Good Manufacturing Practices for active substances, and/or a report by the inspection of the competent ministry on the compliance of the manufacturing of the active biological substance with the Guidelines of Good Manufacturing Practice for active substances no older than six months, 15.Written statement by the principal investigator of being familiar with the properties of medicines in clinical trials and the goal of the clinical trials, as well as on conducting the trials pursuant to the regulations in eff ect and the principles of Good Clinical Practice; 16.Evidence of the importer of the medicine for clinical trials holding an authorization for the wholesale of medicines issued by the competent ministry; 17.Brief resume and references for the principal investigator; 18.Evidence of the sponsor insuring persons undergoing clinical trials in case of health damage to subjects for the period of the implementation of clinical trials; 19.Form for subject information and written consent signed by the subjects, in the Serbian language; 20.Validated copy of the contract on the transfer of authorization to the contract research organization; 21.Other subject information (patient journal, instructions, etc. in the Serbian language); 22. List of countries where the medicine obtained authorization; 23.List of countries where clinical trials for the same medicine were approved, and/or approvals of ethics committees and authorized bodies; 24.List of places where the same clinical trials of medicines are being conducted, if the trials are multicentre trials; 25.Additional information related to the protection of subject health, at the request of the Agency; 26.Evidence of having paid the prescribed tariff s to the Agency for issuing authorizations for the clinical trials of the medicine.
Th e agency assesses the content of the request for CT, documentation and render a decision within approximately 60 days from the day the documentation is evaluated to be complete.
Th e Agency in this process shall issue www.hophonline.orgapproval for substantial amendment within 30 days.Amendment may essentially relate to: the protocol implementation CT, study drug, preclinical pharmacological and toxicological data and clinical data.
Sponsor is obliged to inform the Agency and the EC on the completion of CT ,within 90 days.In case of early completion of CT, this period shall be reduced to 15 days and the reason for completion must be clearly explained.

Good Clinical Practice
Good Clinical Practice (GCP) in clinical trials of drugs is an international ethical and scientifi c quality standard for designing, implementing, recording and reporting the tests conducted on humans.Compliance with these standards ensures public confi dence in the rights, safety and welfare of subjects protected in accordance with the principles of Helsinki Declaration and that data from clinical trials is authentic.
Good Clinical Practice guidelines regulate the liability of participants in a clinical trial as: • Ethics Committee • Sponsor • Principal Investigator Guidelines defi ne the basic documentation , consisting of documents that individually or collectively permit evaluation of the conduct of clinical trials and the quality of data obtained throughout clinical trial.Th ese documents shell demonstrate that the investigator, sponsor and monitor respected Good Clinical Practice and applicable regulations.
Continuous monitoring of the conduct of clinical trials by the sponsor through monitoring and audit by the competent authority through control / inspection ensures quality of implementation of the clinical trials, primarily in relation to the monitoring of safety, respect for the rights and welfare of subjects.
Beside industrial initiated commercial clinical trials, academic investigator initiated studies are the very important area of interest for applied science progress in Europe and Planet too.

CONCLUSION
Th e process of approval and conduct of clinical trials in Serbia complies with the regulations that apply in the EU, in particular, as regards compliance with the highest international ethical and scientifi c standards -Guidelines for Good Clinical Practice, and in order to enable patients in Serbia with the latest modern diagnostics and therapy in the treatment of.
Th e Agency for Medicines and Medical Devices of Serbia (ALIMS), on the basis of well-established professional documentation base on drugs in a relatively short time of its existence, invested their professional capacity and with the support of eminent experts develop this activity and improves procedures according to the latest regulations to scientifi c and professional achievements.
Serbia are in line with European regulations more precisely with the Main EU Directive-EU DIRECTIVE 2001/20 / EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 and THE COM-MISSION DIRECTIVE 2005/28/EC of 8 April 2005 Clinical trials in Republic of Serbia are laid down by following regulations: • Th e Law on Medicines and Medical Devices (''Offi cial Gazette of RS "Nr.30/2010 and 107/12).• Regulations on the contents of the request and documentation for the approval of clinical trials of medicinal products and medical devices and conducting clinical trials of medicinal products and devices (''Offi cial Gazette of RS'' ,Nr.64/211 and 91/2013),including ICH /E11 guidelines on Clinical testing of drugs on children.• Regulations on the methods of reporting, collecting and monitoring adverse drug reactions ( ''Offi cial Gazette of RS '' ,Nr.64/211).• DKP Guidelines, ICH-E6 (''Offi cial Gazette of RS'' , Nr.28/2008).• Annex 13-Production of clinically tested drug (''Offi cial Gazette of RS'' , Nr.28/2008).

Vučinić
ZM et al: The Regulation of Clinical Trials in the Republic of Serbia