ANNEX REGULATIONS on the authorisation by the NMA of clinical trials/notification to the National Medicines Agency of non-interventional studies on medicinal products for human use in Romania CHAPTER I General principles Art. 1. - (1) Clinical trials which are undertaken within Romania are authorised by the National Medicines Agency (NMA) in compliance with Law No. 95/2006 on healthcare reform, Title XVII The medicinal product. (2) Non-interventional studies are an exception to provisions of paragraph (1), as defined in the Norms relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, approved through Minister of Public Health Order No. 904/2006 on the approval of the Norms on the implementation of GMP rules in clinical trials carried out on medicinal products for human use, which shall be notified to the NMA. Art. 2. - Clinical trials must be conducted in accordance with all regulations in force relating to clinical trials. CHAPTER II Authorisation procedures for clinical trials Art. 3. - (1) In view of starting an authorisation procedure for a clinical trial, the applicant shall submit to the NMA, after having assessed the existence of all documents an application in the format of SCD No. 49/2006 provided in the Guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authority, notification of substantial amendments and declaration of the end of the trial in Romania, modified through SCD No. 27/28.09.2007. (2) On request, the documents mentioned in Annex 1 which is integral part of these regulations are attached. (3) Documentation must be provided in either English or Romanian. (4) The label of the medicinal products used in clinical trials (investigational medicinal product, reference medicinal product, placebo)
should be given in Romanian and English (only for the NMA use, so that the translation may be verified); clinical trials shall only use the label in Romanian, and if the sponsor/investigator is Romanian, the label may only be presented in Romanian. (5) The information for the subject and the informed consent form should be presented in Romanian (and in the language of ethnic minorities, if required) and in English, so that the translation may be verified by the NMA; in case the sponsor/investigator is Romanian, the information for the subject and the informed consent form should only be presented in Romanian. (6) The documents mentioned in Art. 3 (2) should be set up in accordance with the provisions of SCD No. 49/2006. Art. 4. - (1) Documentation and Sample Admission Compartment of the Evaluation-Authorisation Department verifies the existence of all solicited documents according to Annex 1. (2) If the documentation presented by the applicant is not complete, the application for authorisation is suspended. (3) If the documentation is complete, the application is accepted and it shall receive a NMA registration number. Art. 5. The authorisation tariff for admission, established through the Minister of Public order in force, shall be paid after having accepted the application for authorisation. Art. 6. After the money enters into the NMA account, the evaluation procedure of the documentation needed in clinical trial authorisation shall start. Art. 7. - (1) If, following evaluation of documentation, additional information is needed, the NMA shall thereof inform the applicant in writing. (2) The authorisation/rejection of the clinical trial authorisation is extended compared to the deadline mentioned in Minister of Public Health Order No. 904/2006 with the duration of time elapsed as of admission of the application letters containing applications issued by the applicant and until the NMA receipt of the solicited information. Art. 8. - In case the documentation is set up in compliance with provisions of SCD No. 49/2006, the NMA forwards the authorisation for clinical trial conduct in the format shown in Annex 2 which is integral part of these Regulations, according to the term mentioned in Art. 39 of the Minister of Public Health Order No. 904/2006. Art. 9. - Art. 9. - If, following the documentation s evaluation, it is observed that it is not set up according to regulations in force and not
sufficiently justified, according to the term mentioned in the Minister of Public Health Order No. 904/2006, the applicant shall be informed by the NMA about the authorisation s rejection, which shall be accompanied by an evidence report. Art. 10. - (1) The applicant may require the revision of the rejection decision in maximum 30 days as of the NMA decision being shown; the review request must be accompanied by support documentation. (2) The NMA shall analyse the application and then express its point of view in maximum 30 days as of admission to the NMA. Art. 11. The authorisation is valid during the conduct of a clinical trial, approved by the NMA; the trial shall start maximum 6 months after the date of the approval. Art. 12. - A clinical trial may be started only if the NMA has not forwarded any motivated objections and after having obtained National Ethics Committee favourable opinion, in multicentre studies, or the Institutional Ethics Committee favourable opinion, in single-centre studies. CHAPTER III Importation of investigational medicinal products Art. 13. - The notification of investigational medicinal products (IMPs) importation shall be done in compliance with legislation in force. CHAPTER IV Analysis of biological samples Art. 14. - Analysis of biological samples collected during the clinical trials may be carried out in certified or accredited laboratories in Romania or other countries. Art. 15. In case the analysis of biological samples is not performed in Romania, these shall be sent to another member states/the exportation in third countries shall be done in compliance with legal provisions in force. CHAPTER V GCP inspection Art. 16. - GCP inspection is conducted in accordance with legal provisions in force. CHAPTER VI Requests concerning ways of trial subjects recruitment
Art. 17. Recruitment of subjects for clinical trials conducted in Romania can only be done via advertisements/leaflets which can only be distributed in hospitals/medical cabinets; healthy volunteers may also be recruited via other means excepting the media. CHAPTER VII Reporting of adverse situations occurring in clinical trials Art. 18. It is the sponsor s obligation to report to the NMA adverse reactions and other information according to the provisions of SCD No. 26/2007 on the approval of the Guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use, occurring during clinical trials conducted at Romanian sites and on the electronic applications submitted by the NMA published on the EudraVigilance website. Art. 19. Serious suspected and unexpected adverse reactions, ending in death or life-threatening, shall be reported to the NMA only by the sponsor, in accordance with Minister of Public Health Order No. 904/2006. Art. 20. Reporting of adverse reactions occurring in clinical trials conducted in Romania shall be done according to the form of the Council for International Organisations of Medical Sciences, 2 nd version. Art. 21. In non-commercial studies, as defined in Minister of Public Health Order No. 904/2006, serious suspected and unexpected adverse reactions shall be reported to the NMA by the investigator within the time frames mentioned in the provisions of SCD No. 26/2007. CHAPTER VIII Requests on investigator s qualification Art. 22. Requests on investigator s qualification are mentioned in Art. 37 of the SCD 39/2006 on the approval of the Guideline on Good Clinical Practice. Art. 23. The application for authorisation of a clinical trial is accompanied by the form concerning qualification of each main investigator at the respective trial sites and his/her consent for participating in the clinical trial according to Annex 4, which is integral part of these Regulations. Art. 24. In case of non-commercial studies, the investigator who initiates the trial receives the responsibilities of the sponsor. CHAPTER IX Authorisation of institutions where clinical trials may be conducted
Art. 25. Clinical trials may be conducted only in institutions authorised by the Ministry of Public Health, in accordance with provisions of Minister of Public Health Order No. 912/2006 in force on approval of Regulations for authorisation of units which may carry out clinical trials on medicinal products for human use. Art. 26. The authorisation is granted by the Ministry of Public Health on request of the interested institution, in compliance with legal regulations in force. CHAPTER X Notification procedure for non-interventional studies Art. 27. The notification of non-interventional studies resides in submission by an applicant to the NMA of a notification address, made according to provisions of Annex 5, which is integral part of these Regulations, accompanied by the following documents: - copy of the study project; - list of the sites where the trial will be conducted; - information on the duration of the trial and number of patients who will enrol; - list of the investigators containing their names, surnames and workplaces; - trial objectives: a) The scientific objectives of the trial should be clearly stated, as well as the relevance for the medical practice of the data obtained during the trial s conduct; b) The assessment indicators of the trial objectives should be specified. Art. 28. The clinical trial proposer is responsible for transmitting to the NMA the results of the non-interventional study, as well as the interpretation and the statistical significance of results in one year after the cessation of the study. Art. 29. In case of non-interventional studies, the NMA does not request any tariff for the activity undertaken. Art. 30. The NMA shall host a particular database containing noninterventional studies which shall also contain the results of noninterventional trials carried out in Romania. Art. 31. In case the NMA hasn t submitted to the clinical trial proposer in written form the necessity of transmitting additional data in 60
days as of the notification s submission, the trial initiation notification is considered accepted and the trial may start. ANNEX 1 to Regulations DOCUMENTS accompanying the application for authorisation of a clinical trial to the NMA 1. General information 1.1. Confirmation of receipt of the EudraCT number 1.2. Covering letter 1.3. Application form 1.4. List of competent authorities (CA) in the EU to whom the application and the decision details have been submitted, when available 1.5. Copy of the Ethics Committee opinion, if available 1.6. Copy/summary of any scientific counselling 1.7. If the applicant is not the sponsor, a legal authorisation letter from the sponsor, allowing the applicant to act on behalf of the sponsor 1.8. Acceptance of the application in English 2. Information on the trial subjects 2.1. Informed consent form 2.2. Document containing information for the subject 2.3. Contracts of recruiting subjects 3. Information on the protocol 3.1. Protocol containing all amendments 3.2. Summary of the protocol in Romanian 3.3.Re-evaluation of the trial (Peer review), when available 3.4.Opinion of the main investigator/coordinator on the ethical aspects of the trial 4. Information on the investigational medicinal product (IMP) 4.1. Investigator s Brochure 4.2. Investigational Medicinal Product Simplified Dossier (IMPSD) 4.3. Simplified Investigational Medicinal Product Dossier (IMPD) 4.4. Summary of Product Characteristics (SPC) (for medicinal products which own a marketing authorisation in Romania or in the EU)
4.5. Information about all active clinical trials on the same IMP 4.6. If the IMP is manufactured in the EU and doesn t own an MA in the EU 4.6.1. Copy of the manufacturing authorisation according to Art. 13 of Directive 2001/20/EC, mentioning the application field of the authorisation 4.7. If the IMP is not manufactured in the EU and doesn t have an MA in the EU 4.7.1. Certification of the qualified person referring to the fact that the manufacturing site is compliant with the Good Manufacturing Practice (GMP)/at least equivalent to the GMP-EU or referring to the fact that each manufacturing batch has been submitted to testings, analysis or controls needed in view of confirming the quality 4.7.2. GMP certificate for the active substance 4.7.3. Copy of the manufacturing/importation authorisation in accordance with Art. 13 of Directive 2001/20/EC. 4.8. IMP analysis certificate in exceptional cases: 4.8.1. When the impurities are not specifically justified or if unexpected impurities are justified, not covered by specification 4.9. Viral safety studies, if needed 4.10. Applicable authorisations for trials or medicinal products having special features, such as genetically modified organisms (GMOs), radiopharmaceuticals. 4.11. TSE certificate, if needed 4.12. Labelling examples in Romanian and English 5.Information on the staff and facilities 5.1. Facilities made available for the trial (Authorisation of the sanitary unit for the conduct of clinical trials, Consent of the sanitary unit s director on the conduct of the clinical trial) 5.2. CV of the coordinator-investigator in Romania (for multicentre trials) 5.3. CV of each investigator responsible for conducting the trial at Romanian investigational sites (main investigator) 5.4. Information about the support personnel (Form on the qualification of the main investigator)
ANNEX 2 to Regulations AUTHORISATION for the conduct of the clinical trial The National Medicines Agency, based on Art. 37 of the Minister of Public Health Order No. 904/2006, authorises the conduct of a clinical trial according to Protocol No.: EudraCT No.: Title: Sponsor: Investigators: Institution (trial site): Remarks: PRESIDENT,...
FORM for reporting severe suspected adverse reactions ANNEX 3 to Regulations Suspected adverse reaction Protocol No. Notification No. Investigational Medicinal Product Patient No. I. Information on the adverse reaction 1.Patient s initials 1.Country 2.Birthplace 2.a. Age 3. Sex 4.-6. Manifestation of the adverse reaction Day Month Year Day Month Year 8-12 7.Reaction s description (including relevant outcomes/laboratory Fill in testings) accordingly: [ ] Death [ ] Lifethreatening [ ] Extension of hospitalisation [ ] Invalidating [ ] Congenital disorders/ cancer [ ] Other important requirements
II. Information about the suspected investigational medicinal product 14.Name of the investigational medicinal product 15. Daily dose 16. Route of administration 20. The adverse reaction has subsided after the discontinuation of the trial [ ] Yes [ ] No 21. The adverse reaction has reoccurred after the second administration of the investigational medicinal product [ ] Yes [ ] No 17. Administration indications 18. Period of administration (from/until) 19.Duration of the administration III. Simultaneous medication and history 22.Simultaneous medication and administration data (excluding that one meant for the reaction s treatment) 23. Other relevant anamnesis data (such as diagnosis, allergic reactions, pregnancy etc.) IV Information about the sponsor and the investigator 24.a. Name and address of the sponsor 24.b. Name of the investigator 24.c. Date of receipt by the sponsor 25.a. Type of information [ ] Initial [ ] Sequential 25.b. Manner of informing the sponsor Date of notification Date of receipt [ ] Additional information shall be attached Sponsor s signature
ANNEX 4 to Regulations FORM Concerning qualification of the main investigator/coordinator and arrangements made for participation in the clinical trial Investigational medicinal product... Protocol No.... Name of the main investigator/coordinator...... Investigator s....... address. Curriculum Vitae/summary:... YES [ ] Qualification.... Attached (profession) Experience in clinical trials:... Experience with other relevant medicinal products for the proposed trial......... Common tasks: Involvement in other clinical trials : Necessary time for this protocol: Availability of subjects suitable for the clinical trial: I hereby accept to participate as main investigator/coordinator in the clinical trial mentioned: I hereby agree to allow control of all documents: I hereby agree to allow access to basic documentation:
I hereby agree to sign the engagement form and conduct the trial according to the approved protocol, in compliance with the revised Declaration of Human Rights of Helsinki and Good Clinical Practice in Romania. During the trial, the following shall participate as sub-investigators : Signature Name Date... (day/month/year) Title (Monitor) ANNEX 5 to Regulations NOTIFICATION on the conduct of a non-interventional trial in Romania To the NATIONAL MEDICINES AGENCY APPLICANT SPONSOR INVESTIGATOR CRO* Name and surname Profession Institution Address Telephone/Fax number *) Contract Research Organisation We hereby inform you about the conduct of a non-interventional study for a medicinal product authorised for marketing in Romania: Title of the clinical trial :........
- Country Information about the investigational medicinal product - Commercial name/code - Active substances - CTA code - Pharmaceutical form - Doses - Route of administration - Manufacturer This notification is accompanied by: Copy of the trial object Study objectives List of the sites where the trial shall be conducted; Information about the trial duration and number of patients to be enrolled. List of investigators containing the names and surnames of the investigators and their workplaces