ANNEX
GUIDELINE
on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical on medicinal products for human use in Romania
Introduction
This Guideline is a translation into Romanian and an adaptation of the Guideline CT-2 of the European Commission (EC) of 2006 on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical on medicinal products for human use.
CHAPTER I
Legal basis
Art. 1. – This Guideline must be correlated with the provisions of Law No. 95/2006 on healthcare reform, Title XVII-The medicinal product, of Minister of Public Health Order No. 904/2006 for the approval of Regulations on the setting up of Good Clinical Practice rules carried out with medicinal products for human use, of Minister of Public Health Order No. 903/2006 on the approval of the Principles and detailed Guidelines on Good Clinical Practice on investigational medicinal products for human use, the requirements for the manufacturing and the importation of these medicinal products, as well as the provisions of other Guidelines on clinical trials.
Art. 2. - (1) In accordance with Art. 36 (1) from the Minister of Public Health Order No. 904/2006, a clinical trial on a medicinal product for human use cannot be started before acquiring a favourable opinion from an Ethics Committee (EC).
(2) According to Art. 45 a) from the Minister of Public Health Order No. 904/2006, the sponsor should notify the EC concerning any major amendment brought to the protocol, after the beginning of the clinical trial.
(3) According to Art. 45 c) from the Minister of Public Health Order No. 904/2006, the sponsor should notify the EC concerning the (premature) closure of a clinical trial.
(4) According to Art. 34 from the Minister of Public Health Order No. 904/2006, the National Medicines Agency takes part in the consultations organised by the European Commission for the elaboration of detailed Guidelines on the application form and documentation which must be submitted in view of the request of the European Commission opinion, especially as regards the information given to the subjects, as well as the adequate measures for the insurance of protection of personal data.
Art. 3. – The application form for the beginning of a clinical trial, for the notification of amendments and notification of trials are common for the competent authority and the ethics committee; in the form filled in by the applicant, the relevant purpose shall be indicated by checking the appropriate box.
CHAPTER II
Scope
Art. 4. – This Guideline establishes the format and the content of the information that must be sent to the Ethics Committee for:
a) request of the EC opinion concerning a proposal for the performance of a clinical trial with a medicinal product for human use;
b) the notification of a substantial amendment and the request of the EC opinion concerning a substantial amendment;
c) notification of the EC concerning the closure or the premature closure of a clinical trial.
Art. 5. – This Guideline contains instructions concerning the format and documentation which accompany the application for the EC opinion concerning a clinical trial with a medicinal product for human use prior to the start of that trial; moreover, the Guideline establishes the documentation which must be submitted to the EC during the conduct and closure of a clinical trial, in order to allow it to fulfil its obligations derived from the Minister of Public Health Order No. 904/2006 and from the Good Clinical Practice principles.
Art. 6. - If, after starting the conduct of the clinical trial, there are substantial amendments necessary to the protocol, the EC must express its opinion on the proposed changes; the documentation which must be submitted to the EC in such cases is, also, mentioned in this Guideline.
Art. 7. – This Guideline specifies the exchange of information between the National Medicines Agency (NMA) and the EC, exchange of information which is one of the requirements of Minister of Public Health Order No. 904/2006 and of other Good Clinical Practice principles.
CHAPTER III
Definitions
Art. 8. - (1) In this Guideline, the definitions included in the Minister of Public Health Order No. 904/2006 are applicable.
(2) Additional terms used in this Guideline are defined in the Guidelines on Good Clinical Practiceapproved through Scientific Council Decision (SCD) No. 39/2006 .
CHAPTER IV
Contacts with the EC
Art. 9. – In case of a multicentre trial, the opinion of the National Ethics Committee must be obtained.
Art. 10. – The opinion concerning the application for authorisation of a clinical trial must be expressed by the EC in the period mentioned in the Minister of Public Health Order No. 904/2006.
Art. 11. – The EC must express its opinion while fulfilling its responsibilities defined in the Minister of Public Health Order No. 904/2006 and in accordance with the national legislation.
Art. 12. – The EC and the NMA may assess the application for authorisations of a sequential or simultaneous clinical trial, depending on the applicant’s opinion.
Art. 13. – EC’s opinion may be requested by its sponsor, its legal representative or by its main investigator (for multicentre studies, by their investigator-coordinator).
CHAPTER V
Form and content of the application submitted to the EC before commencement of a clinical trial: application addressed in view of obtaining EC’s opinion
Art. 14. - The applicant shall submit a valid application to the Ethics Committee in view of obtaining its opinion.
Art. 15. - (1) The application submitted to the EC is considered valid if all requested documents are complete.
(2) In case the application submitted to the EC is valid, the applicant is informed about the validation of the application; thus, the assessment period has started.
(3) If the application is not valid, the EC informs the applicant about the existing findings.
(4) The list mentioned in Annex 1 represents the general information and the specific information for Romania, which must be submitted as part of the valid application as well as of the linguistic requirements.
(5) When needed, before writing the application, the sponsor should check the linguistic requirements of the EC and Romania.
(6) If the applicant has omitted a document, it should be particularly justified.
(7) All sent documents must contain elements of trial identification (the EudraCT number, the number of the protocol given by the sponsor, date and version of the protocol) as well as the version and/or the date of a certain document (for example when there were only revisions of the information for the trial subjects).
Art. 16. - (1) In certain circumstances and in accordance with regulations in force, a simplified authorisation may be taken into consideration (for example, if the EC already owns certain information from a previous research for a clinical trial, submitted by the same applicant, existing documents may be referred to, while mentioning the EudraCT number of that trial).
(2) The procedure of an EudraCT number allocation is described in the European Guideline concerning the EudraCT database.
V.1 Covering letter
Art. 17. - (1) The applicant must send a covering letter together with the application; its superscription must include the EudraCT number and the number given by the protocol’s sponsor, together with the trial name.
(2) The text should highlight the special issues related to the application, such as special population groups included in the trial, the first administration to humans of a new active substance, special investigational medicinal products (IMPs), special trial issues, sub-studies etc. and indicate where relevant information in the application can be found.
(3) The covering letter should specify for each IMP the reference documents chosen by the sponsor in view of identifying an unexpected adverse situation, according to specific guidelines.
(4) Moreover, it should focus on any trial-related or IMP-related scientific opinion coming from the EMEA, the NMA, competent authority (CA) or EC of each Member State (MS) and indicate where an opinion’s copy can be found in the submitted documentation.
V.2. Application Form
Art. 18. - (1) In case of a single-centre clinical trial, the application should be signed by the sponsor or by his legal representative in Romania and/or by the main investigator responsible for the conduct of the trial at that investigational site, in accordance with the national legislation.
(2) In case of a multicentre trial, the application should be signed by the sponsor and by his legal representative and/or by the investigator-coordinator, which is responsible for the coordination of investigators from the various investigational sites.
Art. 19. – In case the application addressed to the EC and the one addressed to the NMA are parallelly sent, both the EC and the NMA should express their opinions taking into consideration the same versions of the submitted documents.
Art. 20. – The application form which must be used for the EC opinion’s request is shown in Annex 6 of the Guideline on the application for authorisation for a clinical trial with a medicinal product for human use, addressed to the competent authority, the notification of certain substantial amendments and declaration of the trial closure in Romania, approved through Scientific Council Decision No. 49/2006.
Art. 21. - (1) The application form addressed to the EC is identical with the one addressed to the NMA, shown in Annex 6 of the Scientific Council Decision No. 49/2006.
(2) The form includes administrative information about the trial, trial site(s), the identification of the sponsor or of the sponsor’s legal representative, as well as the identification of the main sponsor and investigator-coordinator in case of multicentre trials; there are also included information about the protocol’s project and the IMP; these information allow the EC to form an overall image on the trial project and on the prevision of the expertise needed for the documentation’s evaluation.
Art. 22. – In case of multicentre trials, a list containing the main investigators and trial sites planned in order to take place in the trial, must be shown.
V.3. Clinical trial protocol
Art. 23.- (1) The content and format of the clinical trial protocol must respect the provisions of the Scientific Council Decision No. 39/2006.
(2) The clinical trial protocol must be identified through: title, number given by the sponsor, specific for all the versions available, a number and date of the version which shall be updated through the inclusion of the amendments and through a short title or abbreviated name which has been given to it.
(3) The clinical trial protocol should be signed by the sponsor and by the main investigator (or by the investigator-coordinator for multicentre trials).
Art. 24. – The clinical trial protocol should contain the information mentioned in the Scientific Council Decision No. 39/2006.
Art. 25. - (1) The final version should be include all amendments approved up tot hat date.
(2) The protocol should contain a definition of the clinical trial ending; în in case the clinical trial ending is not represented by the last visit of the last subject, this should be argued.
Art. 26. – The clinical trial protocol should also include:
a) anticipated risk/benefit assessment;
b) a justification of the manner of subject selection, especially if there are subjects non-capable of expressing its informed consent, or of the special populations;
c) a description of the recruiting procedures and informed consent procedures, especially if there are temporarily or entirely non-capable of expressing their informed consent or when a procedure implies the witness’ consent;
d) a description of the insurance plan of each additional treatment for subjects once their participation in the trial ends, especially if it differs from the one currently used, depending on the subject’s pathological state;
e) a summary of the protocol in Romanian.
Art.27. - The protocol may include a sub-study, which should be conducted at all investigational sites or only a few of them; the covering letter should focus on any sub-study and the information on this sub-study, shown in section E.2 of the application form or in any other section or joint document, where necessary.
Art. 28. - (1) Certain particular information for each MS or for each investigational site may be included in separate documents.
(2) For example, the financial agreements between the sponsor and main investigator or clinical investigation centre, the policy of the publishing clinical trial results and the investigator’s access to data may be described in separate protocol contracts; these agreements may be included in the documents which accompany the application addressed to the EC or may subsequently be solicited by the EC.
V.4. Data on the investigational medicinal product
Art. 29. – The application form contains the necessary information in order to identify the IMP, the pharmaceutical form(s) and strength(s), dose(s), route(s) of administration, as well as the treatment period(s).
Art. 30. – More information about the IMP are provided in the Investigator’s Brochure (IB) which must contain all clinical and non-clinical data on the relevant IMPs for the trial and must offer proofs that support the adequate reasoning for the proposed clinical trial, as well as the safe use of the IMP in the trial.
Art. 31. – If the IMP owns a marketing authorisation (MA) in any MS and if it will be used in accordance with the MA terms, the IB may be replaced by the approved Summary of product Characteristics (SPC).
V.5. Manners of subject recruitment
Art. 32. - (1) The procedure on the enrolment of subjects must be accurately described in the clinical trial protocol or in separate documents, if it differs depending on the trial site.
(2) The manner of the subjects’ enrolment together with the motivation concerning the selection of the group of subjects are very important in case of trials which include subjects which are non-capable of expressing their informed consent.
Art. 33. - (1) In case it is intended that the subjects’ recruitment is done via publicity, copies of the materials used in this purpose, including printing materials, registrations or video tapes must also be attached to documents used in view of obtaining the EC’s opinion.
(2) Moreover, the procedures proposed for the management of answers to announcements should be specified.
(3) These procedures shall include the manners which shall be used in order to inform/counsel the non-eligible trial subjects; Annex 5 provides additional information about some main issues which may be considered relevant depending on the trial type.
V.6.Information about the trial subject and procedure of obtaining the informed consent
Art. 34. – The information which must belong to the informed consent are defined in Art. 21 (j) from the Minister of Public Health Order No. 904/2006.
Art. 35. – The informed consent form, as well as any information which shall be provided to the subject (and/or, when needed, to his parents/legal representative) before they decide to participate or not in the trial, must be annexed to the shown documents in view of obtaining the EC’s opinion.
Art. 36. - (1) The information existing in these documents must be based on the elements mentioned in the Scientific Council Decision No. 39/2006.
(2) Furthermore, these documents must describe the insurance plan of each additional treatment of the patients once their participation in the trial ends, if this treatment differs from the current one, depending on the subject’s pathological state.
Art. 37. – The document which contains the information addressed to the subject and/or parent/legal representative should be concise, clear, relevant and coherent to the subject; the document must be written in Romanian and, when needed, in the languages of the national minorities.
Art. 38. - (1) The measures taken in order to grant the subject’s right to intimity and data preserving, in accordance with provisions of Law No. 677/2001, with further completions of Law No. 46/2003, should be detailed.
(2) Information about the codification, archiving and preservation of data concerning the subject’s identity, of any other personal data registered and of the biological materials’ storage gathered from the subject, should be included.
(3) Likewise, information should be given concerning the persons who will have access to the codification list, about the place, duration and person responsible for the archiving of that list.
4) According to the national legislation in force, the subject’s rights should be stated: to ask for updated information about the personal data registered, to demand the rectification of errors, to be aware of who will be responsible for the preservation of data and who will have access to them.
Art. 39. - (1) The subject should be informed about the possibility of withdrawing his informed consent without giving any explanation and that of requiring that all biological evidences previously recollected to be destroyed so that it will prevent their examination in the future.
(2) The document should include a declaration attesting that, subsequent to the withdrawal of the informed consent by the subject, the new information from the subject shall not be collected any longer, and attached to the existent data/database.
Art. 40. - (1) Information shall be provided about the contact person which can provide additional information on the trial and the rights of the subjects involved in that trial.
(2) Likewise, information about the person which can be contacted in case an affectation caused by the study occurs shall be provided.
Art. 41. - (1) In case the inclusion in the trial of minor subjects or subjects who are no table to express their informed consent is taken into account, the procedures needed in view of obtaining their informed consent as well as the informed consent of the parents/legal representative must be described.
(2) The situation described in (1) may require two sets of documents containing information for the subject: apart from the information presented to the parents or the legal representative, the subject should be informed in accordance with his ability of understanding; when needed, the declaration attesting that the subject’s decision to not take part in the trial or to withdraw from the trial shall be respected, even if the consent is given by the parent/legal representative, must be included in this document.
(3) The protocol should contain a development plan of such situations.
Art. 42. – When the informed consent is gained in the presence of a witness, the trial subject should receive relevant information about the reasons for involving the witness, the procedure of selecting the witness, as well as the procedure used in view of obtaining the informed consent.
Art. 43. - (1) The procedure of gaining the legal representative’s informed consent for patients who are temporarily no table to express their informed consent, should be described.