Cabinet Regulations No 289




Yüklə 94.53 Kb.
tarix10.04.2016
ölçüsü94.53 Kb.
Cabinet Regulations No 289

Riga, 23 March 2010 (Minutes No 15, § 34)


Procedures for Clinical Trials and Observational Studies of Administration of Medicinal Products, Marking of Investigational Medicines and Assessment of Conformity to Good Clinical Practice
Issued in accordance with the Pharmacy Law,

Article 5, Paragraphs 3, 6 and 15

I. General Provisions

1. These Regulations provide for the procedure of clinical trials (including multi-centre trials) of medicines (except veterinary drugs) in conformance with the good clinical practice requirements, the procedure of observational studies of administration of medicines, marking of investigational medicinal products, as well as the procedure for assessment of conformity to the good clinical practice requirements.


2. ‘Trial subject’ is an individual who participates in a clinical trial as either a recipient of the investigational medicinal product or a control.
3. ‘Investigational medicinal product’ is a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already having a marketing authorisation but whose application, form, packing or indication differ from the authorised ones, or which are used to gain further information about the authorised form.
4. ‘Investigator’ is a medical person (physician) who, by virtue of the normative acts regulating medical treatment, is entitled to perform medical treatment independently and has a practical experience in the field of medical treatment, which is related to the subject matter of the given clinical trial.
5. ‘Sponsor’ is a physical person or a legal entity which takes responsibility for the initiation, management and/or financing of a clinical trial.
6. ‘Protocol’ (and any amendments thereof) is a document that describes the objective, design, methodology, statistical considerations and organisation of a trial, determines the prerequisites for inclusion or non-inclusion of trial subjects, and the procedure for trial surveillance and publication of the results.
7. A multi-centre clinical trial is conducted according to a single trial protocol but at more than one site and by more than one investigator. The trial sites may be located in one or several member-states of the European Union (hereinafter referred to as ‘Member State’) or in Member States and third countries.
8. Clinical trials of gene- or somatic cell-related therapeutic medicines may only be performed at specialized medical centres of clinical university hospitals.
9. The available non-clinical and clinical information on an investigational medicinal product shall be sufficient to substantiate the necessity of a proposed clinical trial.
10. The rights, safety and well-being of trial subjects shall prevail over the interests of science and society.
11. Each individual involved in conducting a trial shall be qualified by education, training and experience to perform his/her tasks.
12. Clinical trials shall be scientifically sound and guided by ethical principles in all aspects.
13. Clinical trials, including bioavailability and bioequivalence studies, shall be designed, conducted and reported in accordance with the good clinical practice principles.
14. Good clinical practice is a set of internationally recognised ethical and scientific quality requirements which must be observed for designing, conducting, recording of and reporting on clinical trials involving human trial subjects.
15. Information gained in a clinical trial must be recorded in a protocol, processed and stored in such a way as to ensure precise information presentation, interpretation and verification, at the same time ensuring protection of trial subjects’ personal data.

II. Responsibility of Sponsor and Investigator

16. When commencing and conducting a clinical trial, the investigator and sponsor shall observe these regulations and all other normative acts providing for healthcare and protection of personal data of individuals.


17. The investigator is responsible for the medical treatment of a trial subject and all medical decisions related to the clinical trial. The investigator is also responsible for the conduct of a clinical trial at a trial site. If a trial is conducted by a team of individuals at a trial site, the investigator who is responsible for the team shall be called the principal investigator.
18. An investigator shall be selected by the sponsor with regard to the qualification and experience of the former. The sponsor may arrange for further training for the investigator, if required.
19. The investigator may take part in the first phase studies if he/she has had previous experience of clinical trials of medicinal products.
20. A sponsor may delegate any or all of its functions to a physical person or a legal entity (hereinafter referred to as ‘Sponsor’s Authorized Person’). In such cases, however, the sponsor shall remain fully responsible for the conduct of the clinical trial and the compliance of trial data generation with the provisions hereof.
21. The investigator and the sponsor may be the same person.
22. The sponsor shall cause to insure its own and the investigator’s civil liability providing for insurance or indemnity terms and conditions. The sponsor shall not be held liable for the injury caused to the trial subjects by the investigator or other persons involved in the clinical trial, either intentionally or due to negligence.
23. The sponsor or its legal representative must be registered in any of the member-states. If the sponsor or its representative is a physical person, his/her declared domicile must be located in the European Union.
24. The sponsor shall ensure delivery of the necessary investigational medicinal product for the clinical trial that were manufactured and underwent quality control in compliance with good manufacturing practice.
25. The sponsor is responsible for the quality of the investigational product and its delivery to the clinical trial site (hereinafter referred to as ‘trial site’), for determination of the storage conditions and shelf life for the investigational product, and, if necessary, dilutions and appliances for product infusion. Every person involved in the clinical trial shall be informed about the said terms and conditions. It is the duty of these persons to observe the storage conditions for the investigational product.

26. The investigator shall be responsible for the storage and inventory accounting of the investigational product at the trial site.


27. The investigational medicinal product and, if necessary, appliances for its infusion shall be delivered by the sponsor free of charge.

III. Investigator’s Brochure

28. Investigator’s brochure is a compilation of clinical and preclinical information about the previous investigational product research involving human subjects. The information in the investigator’s brochure shall be presented in a concise, simple, objective, balanced and non-promotional way enabling a clinician or potential investigator to understand it and make an unbiased feasibility study of the proposed clinical trial in view of potential risks and benefits. These requirements also apply to any updates of the investigator’s brochure.


29. If the investigational products are registered in a Member State or the European Economic Area, a Summary of Product Characteristics may be used instead of the investigator’s brochure.
30. The Investigator’s Brochure shall be reviewed and updated by the sponsor at least once a year.

IV. Protection of Trial Subjects

31. A clinical trial may only be undertaken if the following conditions are met:


31.1 The Ethics Committee’s conclusion and the State Agency of Medicines’ permission for commencement of the clinical trial state that they have assessed the foreseeable therapeutic benefit for the trial subject and other present or future patients, as well as for the society in general, and the said benefit justifies the anticipated risks, and the clinical trial may only be commenced on the condition of continuous monitoring of the compliance with this requirement;
31.2 The trial subject or, when the person is not able to give informed consent, his/her legal representative has given his/her voluntary consent for participation in the clinical trial in writing, dated and signed, after having been informed of the essence, significance, implications and risks of the trial (hereinafter: ‘person’s informed consent’). If the relevant individual is unable to write, an oral consent in the presence of at least one witness will suffice as an exception;
31.3 The trial subject or, when the person is unable to give an informed consent, his/her legal representative has had the opportunity, in a private interview with the investigator or any other person engaged in conducting of the trial, to understand the objectives, risks and inconveniences of the trial, and the conditions under which it is to be conducted; and the trial subject or, when the person is unable to give an informed consent, his/her legal representative has also been informed of the right to withdraw from participation in the trial at any time;
31.4 The trial subject’s personal details are safeguarded as required by the relevant normative regulations on individual’s personal data protection;
31.5 The informed consent document shall provide for the opportunity for the trial subject to terminate his/her participation in the clinical trial at any time by informing the sponsor or the investigator about his/her informed consent withdrawal without any resulting unfavourable impact on the quality of the medical care provided to the trial subject;
31.6 The informed consent document shall provide for insurance and indemnity terms and conditions related to the civil liability of the investigator and sponsor.
32. In addition to the provisions of Paragraph 31 above, a clinical trial on minors may only be undertaken if the following prerequisites are met:
32.1 The informed consent of at least one parent or a legal representative must be obtained. The informed consent must represent the minor’s opinion and may be revoked at any time without unfavourable consequences for the minor;
32.2 The competent staff with experience in working with minors must inform the relevant minor, according to his/her capacity of understanding, about the trial, its risks and benefits. One of the minor’s parent or legal representative shall certify in writing that the minor has been informed, to the best of his/her understanding, about the essence, risks and benefits of the given clinical trial;
32.3 The investigator or the principal investigator must consider the explicit wish of a minor, who is capable of forming an opinion and assessing the information given as provided for in Paragraph 31.3 above, to refuse participation or withdraw from the clinical trial at any time;
32.4 No incentives or financial inducements are given to a minor except compensation of any expenses related to the participation in the clinical trial (incl. travel), as well as compensation for any damage to health or death caused by the clinical trial;
32.5 Direct benefit can be expected for a group of patients after the clinical trial, and the given trial is essential to confirm the data obtained by clinical trials, which involved persons able of giving an informed consent, or by using other research methods. Such research must either relate directly to a clinical condition from which the minor concerned suffers or be of such nature that it can only be carried out on minors;
32.6 The applicable scientific guidelines of the European Agency of Medicines must be observed;
32.7 A clinical trial must be designed in such a way as to minimize pain, discomfort, fear and other foreseeable risk in relation to the disease and developmental stage of the child. Both the risk threshold and the degree of distress have to be identified and continuously monitored;
32.8 The protocol must be endorsed by the Ethics Committee with paediatric expertise or after consulting with an expert on clinical, ethical and psychosocial issues in the field of paediatrics;
32.9 The patient’s interests shall always prevail over those of science or society.
33. All the requirements listed in Paragraph 31 hereof related to persons, who are able of giving an informed consent, shall also apply to persons incapable of giving such consent. Inclusion of such persons in a clinical trial, who are unable to give informed consent and have not given the same or who had not refused to give their informed consent before they lost capacity, may only be allowed if the following provisions are met in addition to the abovementioned requirements:
33.1 The informed consent of the legal representative has been obtained. The informed consent must represent the trial subject’s expressed will and may be revoked at any time without detriment to the subject;
33.2 The person, who is incapable of giving an informed consent, has been informed about the trial, the risks and the benefits according to his/her capacity of understanding;
33.3 The investigator or the principal investigator must consider the explicit wish of a person to refuse from participation or withdraw from the clinical trial at any time if the said person is capable of forming an opinion and assessing information,
33.4 No incentives or financial inducements are given to a subject incapable of giving informed consent except compensation of any expenses related to the participation in the clinical trial (incl. travel), as well as compensation for any damage to health or death caused by the clinical trial;
33.5 Such research is essential to validate data obtained in clinical trials on persons able to give informed consent or by other research methods and relates directly to the life-threatening or debilitating clinical condition from which the incapacitated adult suffers;
33.6 A clinical trial must be designed in such a way as to minimize pain, discomfort, fear and other foreseeable risks in relation to the disease and the capacity of understanding. Both the risk threshold and the degree of distress have to be identified and constantly monitored;
33.7 The protocol must be endorsed by the Ethics Committee with expertise in the relevant disease and the patient population concerned or after taking expert’s advice on clinical, ethical and psychosocial issues in the field of the relevant disease and patient population concerned;
33.8 The patient’s interests shall always prevail over those of science and society;
33.9 There are grounds for expecting that participation in the clinical trial will be beneficial for the patient, the risks being either justifiable or none.
34. In exceptional cases, when it is impossible to receive the trial subject’s informed consent and the trial subject has no legal representative or the legal representative is not accessible, the trial subject may only be included in a clinical trial if the protocol provides for a procedure of involving of a trial subject in emergency situations.
35. For the trial subject to be able to receive independent information about the relevant clinical trial, the investigator shall provide the trial subject with the contact details of the Ethics Committee (the one that issues an opinion about the relevant clinical trial) and the State Agency of Medicines.
36. A clinical trial is forbidden in women during pregnancy and lactation, except cases when it is otherwise impossible to carry out a clinical trial, and when the risks of clinical investigation are proportional to the anticipated benefits to the embryo, foetus or infant.
37. Trial subjects in need for active disease treatment may only be included in the control group, where the subjects receive reference product without the active substance, in case the provisions of Paragraphs 31, 32 and 33 hereof have been met, and the protocol contains scientific and ethical substantiation of the reason for such inclusion.
38. To insure protection of the trial subject’s identification data, the investigator assigns a unique code number to each subject, which is used instead of the trial subject’s name and surname in reports to the sponsor, the State Agency of Medicines and the Ethics Committee. The investigator may only disclose the patient’s name and surname at the request of such authorities which are authorised to familiarize themselves with the patient’s data as provided by the Law on Medical Care.
39. In case information is obtained in the course of a clinical trial regarding any circumstances threatening the trial subject’s health or life, the investigator shall promptly inform the trial subject. Information submitted to the trial subject shall be documented. In such cases, as provided for in Paragraph 31 hereof, an additional voluntary consent in writing for further participation in the clinical trial shall be obtained from the trial subject.
40. Should the clinical trial be suspended or terminated prior to the date indicated in the protocol, the investigator must notify the trial subject accordingly and determine his/her further treatment and follow-up.

V. Ethics Committee

41. Prior to commencement of a clinical trial, the Ethics Committee must give its opinion on any trial-related issue the society is concerned about in order to ensure the trial subjects’ rights, safety and well-being, as well as to assure the society in such protection. The Ethics Committee is an independent organisation operating within or outside a medical institution.


42. The Ethics Committee must involve qualified and experienced individuals capable of evaluating the ethical and scientific aspects of the relevant clinical trial. A list of the members of the Ethics Committee shall be endorsed by the Minister of Healthcare for an indefinite period.
43. The Ethics Committee must consist of at least nine members. The Ethics Committee must include at least two individuals without medical education, as well as at least two independent individuals who are not related to the trial site (the place of conducting the activities related to the clinical trial). Both genders must be represented in the Ethics Committee.
44. The Ethics Committee is entitled to invite nonvoting experts.
45. The Ethics Committee’s proceedings are held in accordance with the provisions adopted by the Chairperson of the Ethics Committee. The said provisions are worked out in line with these regulations, the good clinical practice guidelines and the normative acts on protection of personal data of an individual.
46. The Ethics Committee shall have a quorum if more than half of its members are present at the meeting of the Committee.
47. The Ethics Committee shall pass a resolution by a simple majority voting by show of hands.
48. The meetings of the Ethics Committee shall be recorded in the minutes, which shall also include all resolutions passed at the meeting. Any member of the Committee, whose opinion differs from the Committee’s final resolution, is entitled to set forth his/her view in an appendix to the minutes.
49. Only such Members of the Committee are entitled to voice and vote on the issues related to a concrete clinical trial, who are independent of the investigator and the sponsor of the clinical trial.
50. The Ethics Committee shall store all relevant documents for five consecutive years from the end of a clinical trial except cases when a longer storage period is required by the normative acts regulating medical documentation handling procedures.
51. Information about the names and qualifications of the members of the Ethics Committee, as well as the Provisions of the Ethics Committee shall be available to the investigator, the sponsor, the State Agency of Medicines and the Ministry of Healthcare upon request.
52. The Ethics Committee shall provide the Ministry of Healthcare with information about the list of Members of the Ethics Committee, including the contact details and information about the field of expertise and the amount of a fee for reviewing of an application for conducting a clinical trial. The Ministry of Healthcare shall include the said information in its website.
53. Once a year (not later than 1 February) the Ethics Committee shall submit to the State Agency of Medicines the list of all the reviewed applications for clinical trials and the respective resolutions for the previous year.
54. To receive an opinion of the Ethics Committee, the sponsor or his authorised person shall submit the following documents and information to the Ethics Committee:
54.1 The number in the European Database of clinical trials (EUDRACT);
54.2 An application signed by the sponsor or its authorised person, which is made using the application form worked out by the European Commission (available on the website of the State Agency of Medicines);
54.3 The protocol and any amendments thereof signed by the sponsor and the investigator;
54.4 The Trial Subject’s Consent Form worked out by the sponsor in the state language. If any persons are to be involved in a clinical trial that have no sufficient command of the state language to understand the information included into the said Consent form, it must also be provided in the language which is understandable for the trial subjects involved in the clinical trial;
54.5 Other written information in the state language as related to the concrete clinical trial and meant for the trial subject. If any persons are to be involved in a clinical trial that have no sufficient command of the state language to understand the said information, it must also be provided in the language which is understandable for the subjects involved in the clinical trial;
54.6 Description of the participation activities of the trial subjects;
54.7 The investigator’s brochure or in cases provided for in Paragraph 29 hereof – Summary of Product Characteristics;
54.8 Description of the experience and qualification (Curriculum Vitae) of the investigator and other persons involved in the clinical investigation who are selected by the investigator at the trial site and who work under the supervision of the investigator (hereinafter: ‘the investigator’s assistant’);
54.9 Documents related to compensation to be paid to the trial subject for his participation in the clinical trial, if such compensation is provided for;
54.10 Documents certifying the insured civil liability of the investigator and the sponsor including the provisions for compensation to the trial subject payable in case of health damage or death of the trial subject caused by the clinical trial;
54.11 Consent from the administration of the relevant medical institution to conduct of the clinical trial;
54.12 Power of attorney issued by the sponsor if the documents are submitted by the sponsor’s authorised person.
55. When evaluating an application for commencement of a clinical trial and preparing its opinion, the Ethics Committee shall pay a special attention to:
55.1 The significance and objectives of the clinical trial;
55.2 Whether the evaluation of the anticipated benefits and risks as required by Paragraph 31.1 is satisfactory and whether the conclusions are justified;
55.3 The protocol;
55.4 The suitability of the investigator and the supporting staff;
55.5 The investigator’s brochure;
55.6 The quality of the facilities and equipment;
55.7 The adequacy and completeness of the written information to be given and the procedure to be followed for the purpose of obtaining informed consent and the justification for the clinical trial on persons incapable of giving informed consent as regards the specific restrictions laid down in Paragraphs 31, 32 and 33;
55.8 Provisions for indemnity or compensation in the event of injury or death attributable to a clinical trial;
55.9 Any insurance or indemnity to cover the liability of the investigator and sponsor;
55.10 The amounts and, where appropriate, the arrangements for rewarding or compensating investigators and trial subjects and the relevant aspects of any agreement between the sponsor and the trial site;
55.11 The arrangements for the recruitment of trial subjects.
56. Within 30 days after filing the aforesaid application with all information as required hereof, the Ethics Committee shall issue a substantiated opinion in writing to the applicant. A copy of the opinion is forwarded to the State Agency of Medicines.
57. During the period provided for verification of an application, the Ethics Committee may send the applicant one extra request for further information. In such cases the period provided for in Paragraph 56 shall be extended till receipt of the requested information.
58. The Ethics Committee shall extend the period mentioned in Paragraph 56 hereof if the planned clinical trial involves medicinal products for gene therapy or somatic cell (any cells of the body except gametes) therapy or medicinal products containing genetically modified organisms. In such cases the period mentioned in Paragraph 56 hereof shall be extended but shall not exceed 180 days of the day of filing the request for authorisation. In case of xenogenic cell (foreign cells to human body) therapy, the period of issuing an authorisation has no time limits.
59. In case of a multi-centre clinical trial where all trial sites are located within Latvia, the Ethics Committee shall give a single opinion regarding the clinical trial. If a multi-centre clinical trial is conducted simultaneously in more than one Member State, the Ethics Committee shall give a single opinion on the clinical trial conducted in Latvia.
60. The applicant is entitled to appeal the decision of the Ethics Committee in the Central Medical Ethics Committee. The decision of the Central Medical Ethics Committee shall be final.

VI. Obtaining Authorisation from the State Agency of Medicines

61. To obtain the State Agency of Medicines’ authorisation for commencement of a clinical trial, the sponsor or its authorised person shall submit the following data and information to the State Agency of Medicines:


61.1 Confirmation of receipt of the number in the European Database of clinical studies (EUDRACT);
61.2 An application signed by the sponsor or his authorised person, which is made using the application form worked out by the European Commission (available on the website of the European Commission http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/vol-10/11_an1_14-2005_en.pdf) (may also be submitted in the form of an XML file);
61.3 The protocol and protocol amendments, if any, signed by the sponsor and the investigator;
61.4 A review of all active investigations with the corresponding investigational medicines;
61.5 A file on the investigational medicinal product file, which is a compilation of data on the investigational product, including references to the quality of the preparation and placebo (inert medicinal form without an active substance, which objectively has no specific action with regard to a concrete therapy), the results of a preclinical investigation and any previous clinical trials, as well as a summarized risk-benefit assessment with a critical analysis of the preclinical and clinical data with regard to the risks and benefits of the proposed clinical trial, or a simplified abridged file on the investigational product in case of repeated assessment of the given investigational product on the part of the State Agency of Medicines;
61.6 A Summary of Product Characteristics for medical products registered in the Member States;
61.7 The list of Member States where the given application has been submitted, as well as information about the resolutions passed by the relevant authorities, if available;
61.8 A copy of the manufacturer’s licence if the investigational medicinal products were manufactured in an EU Member State or EEA (European Economic Area) Member State;
61.9 Certificate of the manufacture’s conformity to the requirements of good manufacturing practice, which are at least equivalent to the EU good manufacturing practice, and a copy of the importer’s licence if the investigational medicinal products were manufactured outside the European Union;
61.10 Certificate of compliance of the investigational medicine’s active substances manufacture with the requirements of good manufacturing practice;
61.11 The trial subject’s consent form worked out by the sponsor in the state language. If any persons are to be involved in a clinical trial who have no sufficient command of the state language to understand the written information in the document, it must also be provided in the language which is understandable for the subjects involved in the clinical trial;
61.12 Other written information in the state language as related to the concrete clinical trial and meant for the trial subject. If any persons are to be involved in a clinical trial that have no sufficient command of the state language to understand the said written information, it must also be provided in the language which is understandable for the subjects involved in the clinical trial;
61.13 A medical institution’s consent in writing for conducting of the clinical trial;
61.14 Documents, which certify that the civil liability of the investigator and the sponsor has been insured, and include the provisions regarding compensation to the trial subject in case of any harm to his/her health or in case of death of the trial subject caused by the clinical trial;
61.15 Documents related to compensation to be paid to the trial subject for his/her participation in the clinical trial if such compensation is provided for;
61.16 The investigator’s brochure or in cases provided for in Paragraph 29 hereof - Summary of Product Characteristics;
61.17 A specimen of labelling of the investigational product in the state language;
61.18 Description of the experience and qualification of the investigator and the investigator’s assistants;
61.19 The investigator’s written acknowledgment that the investor is aware of the good clinical practice requirements and the normative acts applicable to clinical trials of medicinal products;
61.20 The Power of Attorney issued by the sponsor if the aforesaid documents are submitted by the sponsor’s authorised person.
62. The applicant shall cover all costs related to reviewing of his submission for clinical trial authorization in accordance with the State Agency of Medicines’ prices for public services. In case of refusal of a clinical trial, the incurred expenses (fees) are not refunded.
63. The State Agency of Medicines shall review the submitted application (appended with all such information as required in Paragraph 61 hereof) within 60 days of receipt of the submission.
64. During the period provided for verification of an application, the State Agency of Medicines may send the applicant a request for further information, in which case the period provided for in Paragraph 63 shall be extended till receipt of the requested information.
65. The State Agency of Medicines shall extend the period mentioned in Paragraph 63 hereof if the planned clinical trial involves medicinal products for gene therapy or somatic cell (any cells of the body except gametes) therapy or medicinal products containing genetically modified organisms. In such cases the period mentioned in Paragraph 63 hereof shall be extended but shall not exceed 180 days of the day of filing the request for authorisation. In the case of xenogenic cell (foreign cells to human body) therapy, the period of issuing an authorisation has no time limits.
66. Within the period mentioned in Paragraphs 63 and 64 above, the State Agency of Medicines shall decide whether to authorize or reject the commencement of a clinical trial, in case of non-observance of such requirements as provided hereof, and notify the applicant of its well-grounded decision within five working days of the day of the decision. No authorisation shall be given before the payment mentioned in Paragraph 62 hereof has been effected. Authorisation shall be valid for the period of the clinical trial as stated in the protocol.
67. No authorisation shall be given for such a gene therapy trial, which may cause modification of genetic information identity in the trial subject’s gametes.
68. The State Agency of Medicines may only authorise the conduct of a clinical trial of products containing genetically modified organisms after the sponsor has received authorisation issued in compliance with the relevant regulations on restrictions of use and deliberate propagation of genetically modified organisms in the environment.
69. The applicant is entitled to appeal the decision of the State Agency of Medicines in the Healthcare Ministry. The Healthcare Ministry’s resolution may be re-appealed in a court.
70. In case of a multi-centre clinical trial where all trial sites are located within Latvia, the State Agency of Medicines shall give a single opinion regarding the clinical trial. If a multi-centre clinical trial is conducted simultaneously in more than one Member State, the State Agency of Medicines shall give a single opinion on the clinical trial conducted in Latvia.

VII. Commencement of a Clinical Trial

71. The sponsor may only start a clinical trial after the Ethics Committee has issued a favourable opinion and inasmuch as the State Agency of Medicines has issued authorisation for commencement of the clinical trial. The Sponsor is entitled to file applications both to the Ethics Committee and the State Agency of Medicines at the same time. Prior to commencement of a clinical trial, the sponsor shall conclude a contract with each medical institution, where the clinical trial is planned to be conducted, providing for the contracting parties’ duties and responsibilities with regard to the conduct of the clinical trial (including intellectual property provisions and a confidentiality clause), as well as financial terms (including the amount of remuneration to the medical institution for the use of its human resources and material base in the clinical trial and a payment schedule).


72. If the State Agency of Medicines notifies the sponsor of the decision to reject the application for a clinical trial, the sponsor may amend, just once, the contents of the application, which is mentioned in Paragraph 61.2 hereof, to take due account of the reasons of the rejection. If the sponsor fails to amend the application in accordance with the reasoning given in the decision, the application shall be deemed as rejected and the clinical trial may not commence.

VIII. Conduct of a Clinical Trial

73. Upon commencement of a clinical trial, the sponsor is entitled to make amendments to the protocol. If such amendments may significantly affect the trial subject’s safety, physical or mental integrity, the scientific value of the investigation, the course or management of the investigation, the quality or safety of the investigational product, the sponsor shall submit a notice to the State Agency of Medicines using the form of essential amendments, which was validated by the European Commission (available on the website of the European Commission http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/vol-10/11_an2_14-2005_en.pdf), as well as notify the competent Ethics Committee in writing.


74. The Ethics Committee issues an opinion and the State Agency of Medicines makes a decision not later than within 30 days of receipt of the amendments mentioned in Paragraph 73 above.
75. If the Ethics Committee issues a favourable opinion and the State Agency of Medicines accepts the amendments, the sponsor shall be entitled to proceed with the clinical trial observing the amendments to the protocol.
76. If the opinion of the Ethics Committee or the decision of the State Agency of Medicines is unfavourable in view of non-observance of these regulations, the sponsor shall not be entitled to make amendments to the protocol until he has taken account of the grounds mentioned in the opinion and the decision. If the sponsor fails to take account of the grounds mentioned in the opinion and the decision, the sponsor’s proposed amendments to the protocol shall be deemed as rejected.
77. In the light of any such circumstances in the course of the clinical trial as relate to the conduct of the trial or the study or development of the investigational product, which may affect the safety of the trial subject, the sponsor and the investigator shall take appropriate urgent safety measures to protect the trial subject. The sponsor shall forthwith inform the State Agency of Medicines of such circumstances and the measures taken and ensure that the Ethics Committee is informed at the same time.
78. If amendments are to be made to the protocol as regards administrative issues, the sponsor shall notify accordingly the Ethics Committee and the State Agency of Medicines in writing. In such case no authorisation from the Ethics Committee or the State Agency of Medicines is necessary.
79. Within 90 days of the end of a clinical trial, the sponsor shall notify the State Agency of Medicines and the Ethics Committee that the clinical trial has ended in the Republic of Latvia. The sponsor submits a notice to the State Agency of Medicines using the form of a notice of the end of a clinical trial worked out by the European Commission (available on the website of the European Commission http://ec.europa.eu/enterprise/sectors/pharmaceuticals/files/eudralex/vol-10/11_an3_14-2005_en.pdf). The sponsor shall notify the State Agency of Medicines about the number of patients involved in the clinical trial conducted in Latvia. In case the trial is terminated before the planned date, the sponsor shall notify the State Agency of Medicines and the Ethics Committee in writing about the trial termination within 15 days of the termination clearly explaining the reasons for such early termination.

IX. Exchange of Information

80. The State Agency of Medicines shall enter information in the European clinical trials database on each application for a clinical trial submitted in the territory of Latvia, including:


80.1 The sponsor’s request to the State Agency of Medicines for authorisation for commencement of a clinical trial;
80.2 Any amendments made to the application and the enclosed documents in line with the State Agency of Medicines’ recommendations and Paragraph 72 hereof;
80.3 Any amendments made to the protocol after commencement of the clinical trial as provided for in Paragraphs 73, 74 and 75 hereof;
80.4 The opinion of the Ethics Committee;
80.5 Notice of the completion of the clinical trial in the Republic of Latvia;
80.6 Information about surveillance of the clinical trial and assessment of its compliance to the good clinical practice.
81. At the motivated request of any Member State, the European Medicines Agency or the European Commission, the State Agency of Medicines shall submit the requested information in addition to the abovementioned (Paragraph 78 hereof).

X. Clinical Trial Termination and Violations

82. Where the State Agency of Medicines has a substantiated reason to believe that the provisions of the application mentioned in Subparagraph 61.2 above or the requirements provided hereof are no longer met or has information raising doubts about the safety or scientific validity of the clinical trial, the State Agency of Medicines is entitled to suspend or prohibit the clinical trial and shall notify the investigator and the sponsor accordingly.


83. Before the State Agency of Medicines makes a decision on such cases as mentioned in Paragraph 82 above, it shall request the sponsor and the investigator to submit information within one week about the reasons of such non-observance of the aforesaid provisions, except cases posing a serious risk for the trial subject.
84. Where the State Agency of Medicines has a substantiated reason to believe that the sponsor or the investigator or any other person involved in the conduct of the trial no longer meets the applicable obligations, it shall notify the relevant person accordingly, indicating the course of action which he/she must take to remedy the given state of affairs. The State Agency of Medicines shall inform the Ethics Committee, other competent authorities and the European Commission about the measures taken.
85. The State Agency of Medicines is entitled to prohibit a clinical trial if it poses a serious risk to the trial subject, and the sponsor and the investigator fail to take necessary steps to ensure the safety of the trial subject.
86. The State Agency of Medicines shall notify the other competent authorities, the corresponding Ethics Committee, the European Medicines Agency and the European Commission about its decision to suspend or prohibit the clinical trial in case of non-observance of the provisions hereof and of the reasons for such decision.

XI. Investigational Medicinal Product Manufacturing, Importing and Labelling

87. Manufacture and importation of investigational medicinal products are subject to the regulations (normative acts) on production and control of medicinal products and importation and distribution of the same.


88. The outer packaging of an investigational medicinal product or, where there is no outer packaging, the immediate packaging must bear the product particulars in the state language in accordance with the European Commission’s recommendations (guidelines) as provided by the Pharmacy Law, Clause 25.2, which are published in the European Community’s legal regulations on medicinal products (Eudralex).

XII. Clinical Trial Master File and Its Storage Requirements

89. The clinical trial master file consists of essential documents, which enable evaluation of both the conduct of a clinical trial and the quality of the obtained data. Those documents show whether the investigator and the sponsor have complied with the principles and guidelines of good clinical practice and with the applicable requirements regarding marketing authorisation of medicinal products.


90. The trial master file provides the basis for the audit by an independent auditor appointed by the sponsor and for the inspection and assessment that are performed by the State Agency of Medicines.
91. The content of essential documents shall conform to the phase of the clinical trial.
92. The sponsor and the investigator shall retain the essential documents relating to the clinical trial for at least five years after its completion, except for such documents as mentioned in Paragraphs 93 and 94 below.
93. The investigator is responsible for retention of the trial subjects’ identification code numbers register for at least 15 years.
94. The sponsor is responsible for retention of the protocol, standard operating procedures, the investigator’s brochure, case report form for each trial subject, clinical trial report, written opinions on the protocol and procedures of the trial for at least five years after the marketing authorisation of the investigational product.
95. Essential documents may be retained for a longer period, where so required by other applicable regulations regarding medical documentation or by an agreement between the sponsor and the investigator.
96. Essential documents are stored in such a way as to ensure their immediate availability, upon request of the State Agency of Medicines or the Health Inspection in accordance to the relevant persons’ competence and the normative acts regarding physical persons’ personal data protection. The identification codes are only available to such authorities that, according to the Medical Care Law, are entitled to access to patients’ personal data.
97. Medical files on trial subjects are retained in accordance with the regulations on medical documentation handling procedures.
98. Any transfer of ownership for the data or the documents shall be documented. The new owner must assume responsibility for data storage and archiving in accordance with Paragraphs 92, 93, 94, 95, 96 and 97.
99. The sponsor appoints an individual responsible for the archives (responsible persons).
100. Access to archives shall only be allowed to such responsible persons as mentioned in Paragraph 99 above.
101. Essential documents are stored in such a way as to ensure that those documents remain complete and legible throughout the required storage period and are available to the authorities mentioned in Paragraph 96 above upon request.
102. Any alterations to documents must be easily traceable; the amended text is also retained.

XIII. Procedure for Surveillance and Assessment of Clinical Trial Compliance with Good Clinical Practice

103. Assessment is an official verification conducted by the State Agency of Medicines by reviewing documents, facilities, records, quality assurance arrangements, and any other resources that are deemed by the State Agency of Medicines to be related to the clinical trial and that are located at the trial site, at the sponsor’s or sponsor’s authorized person’s facilities, or at any other establishment which the State Agency of Medicines may find assessable.


104. To oversee and assess the compliance with the good clinical practice requirements, the State Agency of Medicines is entitled to visit the sites related to the conduct of any clinical trial, particularly trial sites (research centres) and any laboratory used for making tests for the clinical trial.
105. The State Agency of Medicines shall observe the data safeguarding requirements with respect to information obtained during surveillance and assessment of the compliance with good clinical practice.
106. Surveillance and assessment may only be carried out by a qualified person of the State Agency of Medicines who has:
106.1 Higher education or equivalent experience in medicine, pharmacy, pharmacology, toxicology or another relevant field;
106.2 Knowledge of the principles and processes that apply to the development and clinical research of medicinal products, and awareness of the applicable European Union’s guidelines and the Republic of Latvia regulations relating to clinical trials and marketing authorisation;
106.3 Expertise in the procedures and systems for recording clinical trial data, and the organisation and legal regulation of the healthcare system.
107. The State Agency of Medicines regularly updates records of the qualifications, training and experience of the persons entitled to inspect and assess compliance with good clinical practice, and submits the relevant information upon request to the European Medicines Agency. The State Agency of Medicines ensure training of those persons, regularly assessing their training needs and taking adequate steps for maintenance and improvement of the said persons’ skills.
108. The State Agency of Medicines provides the persons mentioned in Paragraph 107 above with standard operating procedures and detailed descriptions of responsibilities, liability and training requirements. The State Agency of Medicines regularly updates the description of standard operating procedures and other information meant for the persons mentioned in Paragraph 107 hereof.
109. The State Agency of Medicines provides the persons mentioned in Paragraph 107 hereof with a document (identification card) that certifies that the holder is authorised to inspect and assess compliance of a clinical trial with good clinical practice.
110. When proceeding to work, the persons mentioned in Paragraph 107 must give a written statement of any financial or other kind of connection with the person or the site to be inspected and certify the said information. The State Agency of Medicines must take this certification into account when appointing them to carry out surveillance and assessment as inspectors of concrete clinical trials.
111. Assessment of compliance with good clinical practice compliance may take place on the following occasions:
111.1 Before, during or after the conduct of clinical trials;
111.2 As part of the verification of applications for marketing authorisations.
112. If assessment of compliance with good clinical practice as provided for in Subparagraph 111.2 entails travel expenses, the applicant shall cover all travel (transport) expenses incurred by the officials of the State Agency of Medicines travelling to the trial site or any trial-related institution and backwards, as well as their accommodation (hotel) costs, visas, health insurance and per diem allowance as provided for in the normative acts regulating the procedure of reimbursement of expenses related to employees’ official journeys and business trips.
113. The State Agency of Medicines shall inform the European Medicines Agency about the inspections conducted. Surveillance and assessment (inspections) may be carried out on behalf of the European Union and the results shall be recognised by all other Member States. The State Agency of Medicines may request assistance from another Member State in surveillance and assessment.
114. Following an inspection, the State Agency of Medicines prepares an inspection report. It must be made available to the sponsor while ensuring the necessary data protection. It may also be made available to the other Member States, the Ethics Committee and the European Medicines Agency, at their reasoned request.
115. A foreign competent authority is entitled to inspect a clinical trial at 30-days’ notice to the State Agency of Medicines in writing. A representative from the State Agency of Medicines is entitled to take part in such an inspection.
116. To ensure surveillance and assessment, all persons involved in the conduct of a clinical trial are obliged to provide the State Agency of Medicines and foreign inspectors with direct access to the documents at all sites related to the clinical trial.
117. The Health Inspection is entitled to inspect a clinical trial within the limits of its competency. The Health Inspection shall report to the State Agency of Medicines about the results of such inspections.
118. The State Agency of Medicines may, if necessary, invite experts with appropriate qualification and experience for inspecting a concrete clinical trial.

XIV. Notification of Adverse Events

119. The investigator shall report all serious adverse events immediately to the sponsor in writing about any untoward medical occurrence in trial subjects during the period of administration of the investigational product irrespective of the causal relationship with this treatment and that at any dose results in death, is life-threatening, requires or extends hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect (hereinafter — serious adverse event), except for those adverse events that the protocol or the investigator’s brochure identifies as not requiring immediate reporting. After the immediate report the investigator shall send the sponsor a detailed report in writing. The immediate and follow-up reports shall identify the trial subjects by the unique code numbers assigned to them.


120. Serious adverse events and laboratory deviations identified in the protocol as critical to safety evaluations shall be reported to the sponsor in accordance to such reporting requirements and within such time periods as provided for in the protocol.
121. In case of death of a trial subject, the investigator shall supply the sponsor and the Ethics Committee with all additional information requested.
122. The sponsor shall keep detailed records of all the adverse events which are reported to him by the investigators, assess the gravity, reasons and predictability of such events, and submit the records upon request to the competent authorities of the Member States in whose territory the clinical trial is being conducted.

XV. Notification of Serious Adverse Effects

123. The sponsor shall ensure that all serious adverse and unexpected reactions to the investigational product observed at all trial sites related to a concrete clinical trial, irrespective of the dosage, whose essence and gravity differ from the available information about the investigational product (hereinafter - unexpected adverse effects), and which result in the subject’s death or are life-threatening, are recorded. The sponsor must enter information about such adverse effects into the Database Clinical Trial Module (EVCTM) of the European Adverse Effects Surveillance System (Eudravigilance) of the European Medicines Agency as soon as possible but not later than within seven days of receipt of the relevant information. Any serious unexpected adverse reactions to the investigational product observed at trial sites in Latvia, which result in the subject’s death or are life-threatening, shall be reported by the sponsor to the State Agency of Medicines, indicating the EVCTM address of the State Agency of Medicines, and to the Ethics Committee, and submit a further report within eight days of the initial report.


124. Information on any unexpected adverse effects not resulting in death of the trial subject or not life-threatening, which were probably caused by the investigation product, shall be entered by the sponsor into the Clinical Trial Module (EVCTM) of the European Adverse Reactions Surveillance System Database (Eudravigilance) of the European Medicines Agency. Any other unexpected serious adverse effects not resulting in death of the trial subject or not life-threatening, which were probably caused by the investigation product and observed at clinical trial sites in Latvia, shall be reported by the sponsor to the State Agency of Medicines, indicating the EVCTM address of the State Agency of Medicines, and the Ethics Committee as soon as possible, but not later than within 15 days of receipt of the relevant information.
125. The State Agency of Medicines shall keep record of all reported cases of probable serious adverse unexpected reactions to investigational medicinal products.
126. The sponsor shall regularly (the frequency depends on the trial specifics and number of adverse effects) inform all the investigators involved in the clinical trial about all the serious adverse effects that were possibly caused by administration of the investigational product.
127. Once a year throughout the clinical trial, but not later than within 60 days of the end of the accounting period as provided for in the protocol, the sponsor shall provide the State Agency of Medicines and the Ethics Committee with a safety report on all serious unexpected adverse effects, which were possibly caused by the investigation products, and which occurred over the given period, as well as a consolidated report on the trial subjects’ safety during the clinical trial period. If a clinical trial lasts less than a year, the safety report may be submitted together with the notice of completion of the clinical trial.

XVI. Observational Studies of Administration of Medicinal Products

128. Only data obtained by the observer (physician) in his/her professional practice based on the opinion of the health condition and treatment of the patient shall be compiled in observational studies. The patient does not undergo any extra diagnostic or monitoring procedures, and epidemiological methods are used to analyse the obtained data.


129. Prior to commencement of observational studies, a physician or a representative of the medicinal product manufacturer, who is responsible for coordination of the observational study, shall submit the below listed documents to the State Agency of Medicines and the Ethics Committee:
129.1 An application containing the following details:
129.1.1 Name of the observed medicinal product, its generalized name, form and strength;
129.1.2 Description of the observational study project (as well as criteria for inclusion of patients in the observational study and data analysis methods to be used);
129.1.3 Physicians participating in the conduct of the observational study, stating the name, surname and speciality);
129.1.4 Medical institutions participating in the conduct of the observational study;
129.1.5 The planned number of patients to be involved;
129.1.6 Whether the disease, which is supposed to be treated using the observed medicinal product, is included into the medicine refund system;
129.1.7 Whether the observed medicinal product is included into the list of refunded medicines;
129.1.8 Period of the observational study, stating the days of commencement and completion;
129.2 A specimen of a document whereby a patient shall certify his/her consent to the treatment data collection and processing;
129.3 A specimen of an observational data recording document.
130. The applicant shall cover all costs related to reviewing of his/her request for authorization of an observational study in accordance with the State Agency of Medicines’ pricelist for public services.
131. An observational study may be commenced if the Ethics Committee has issued a favourable opinion and the State Agency of Medicines has not informed the applicant of its grounds for non-acceptance within 30 days of the day the request was filed.
132. The physician shall report any adverse drug-related reactions stated during the observational study to the State Agency of Medicines in compliance with the regulation on adverse reaction surveillance.
133. Within 90 days of completion of an observational study, the physician or the person referred to in Paragraph 129 of these Regulations, shall notify the State Agency of Medicines in writing about the completion of the observational study and submit a consolidated report on the number of patients involved and any adverse drug-related reactions stated.
134. The compliance of observational studies with these Regulations shall be supervised by the State Agency of Medicines and inspected by the Health Inspection within the limits of their competency.
135. Persons involved in observational studies shall not disclose the personal and clinical data of the patients except in cases the said data are requested by the institutions, which are entitled to familiarize themselves with patient’s data as provided by the Law on Medical Care.

XVII. Final Provisions

136. The declare null and void Cabinet Regulations No.172 of 28 February 2006 ‘Procedures for clinical trials and observational studies of administration of medicinal products, marking of investigational medicines and assessment of conformity to good clinical practice’ (Latvijas Vēstnesis, 2006, No 45; 2008, No 10).


137. These Regulations come into effect as of 1 April 2010.
Informative Reference to EU Directives

These Regulations contain legal rules following from:

1) Directive 2001/20/EC of the European Parliament and Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member-States relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use;

2) Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorization and importation of such products.



Prime Minister V. Dombrovskis

Minister of the Interior, Acting Minister of Healthcare L. Murniece


Verilənlər bazası müəlliflik hüququ ilə müdafiə olunur ©azrefs.org 2016
rəhbərliyinə müraciət

    Ana səhifə