Republic of Latvia Cabinet Regulation No. 289 Adopted 23 March 2010

Regulations Regarding the Procedures for Conduct of Clinical Trials and Non-interventional Trials of Medicinal Products, Labelling of Investigational Medicinal Products and the Procedures for Assessment of Conformity of Clinical Trial of Medicinal Products with the Requirements of Good Clinical Practice

Issued pursuant to Section 5, Clauses 3, 6 and 15
of the Pharmaceutical Law

I. General Provisions

1. This Regulation prescribes the procedures for the conduct of clinical trials (including multi-centre trials) of medicinal products (except veterinary medicinal products) in accordance with the requirements of good clinical practice and non-interventional trials, as well as the procedures for the labelling of investigational medicinal products and the procedures for assessment of conformity of clinical trials of medicinal products with the requirements of good clinical practice.

2. A trial subject is an individual who participates in a clinical trial, using the investigational medicinal products, or in a control group.

3. An investigational medicinal product is a pharmaceutical form with or without an active substance, which is tested or used as a reference in a clinical trial, including medicinal products already registered, the method of administration, form or packaging, or indications of which differ from the registered or which are used in order to obtain supplementary information regarding the registered type.

4. The investigator is a medical practitioner who in accordance with the regulatory enactments regulating medical treatment has the right to practise medical treatment independently and who has practical experience in the field of medical treatment, which is related to the particular field of a clinical trial.

5. The sponsor is a natural person or a legal person, which takes responsibility for the commencement, management or financing of a clinical trial.

6. The protocol (also amendments made to the protocol) is a document that describes the objective, design, methodology, statistical considerations and the procedures for organisation of a trial, specifies the conditions of inclusion and exclusion of the trial subjects, as well as the procedures for the monitoring of a trial and the publication of the results.

7. A multi-centre clinical trial shall be conducted by several investigators in several sites in accordance with a single trial protocol. Trial sites may be located in one or several Member States of the European Union (hereinafter - Member States), or in Member States and third countries.

8. Trials involving gene therapy and somatic cell therapy medicinal products may only be conducted in specialised medical treatment centres in clinical university hospitals.

9. Information obtained in pre-clinical and clinical trials regarding an investigational medicinal product shall be adequate to support the necessity of the planned clinical trial.

10. The rights, safety and well-being of a trial subject shall prevail over the interests of science and society.

11. The qualification (education, training and experience) of each individual involved in the conduct of a clinical trial shall comply with the tasks to be performed by such person.

12. A clinical trial shall be scientifically sound and guided by ethical principles in all aspects thereof.

13. A clinical trial, including bioavailability and bioequivalence studies, shall be planned, conducted and reported in accordance with the requirements of good clinical practice.

14. Good clinical practice is a set of internationally recognised ethical and scientific requirements of quality, which are complied with in designing, conducting and registering of a clinical trial involving people or in providing reports regarding such trial.

15. Information of a clinical trial shall be recorded, handled and stored in such a way as to ensure the accurate provision, interpretation and verification of the information, concurrently ensuring the protection of confidentiality of the data of the trial subjects.

II. Liability of the Sponsor and the Investigator

16. The investigator and the sponsor, in commencing and conducting a clinical trial, shall comply with this Regulation, as well as the regulatory enactments regulating medical treatment and protection of the data of natural persons.

17. Liability for the medical care of a trial subject and for all the medical decisions related to a clinical trial shall rest with the investigator. The investigator shall also be responsible for the conduct of a clinical trial at a trial site. If a group of individuals conducts a clinical trial, the investigator who is responsible for such a group shall be called the principal investigator.

18. The sponsor shall select the investigator, taking into account his or her qualification and experience. If necessary, the sponsor shall ensure additional training of the investigator.

19. The investigator may participate in trials of phase one if he or she has previous experience in clinical trials of medicinal products.

20. The sponsor may authorise another legal person or natural person for the complete or partial performance of the functions thereof (hereinafter - person authorised by the sponsor). Also in such case the sponsor shall remain fully responsible for the conduct of a clinical trial and the compliance of the data generated by the trial with the requirements of this Regulation.

21. The investigator and the sponsor may be the same person.

22. The sponsor shall insure the civil legal liability thereof and of the investigator, foreseeing the conditions of insurance and compensation. The sponsor shall not be liable for harm that the investigator or other persons involved in the clinical trials have inflicted upon the trial subject deliberately or due to neglect.

23. The sponsor or a legal representative of the sponsor shall be registered in a Member State. If the sponsor or a representative of the sponsor is a natural person, he or she shall have a place of residence declared in the European Union.

24. The sponsor shall ensure the supply of the investigational medicinal product necessary for a clinical trial. The medicinal product shall be manufactured and the quality thereof shall be controlled in accordance with the requirements of good manufacturing practice.

25. The sponsor shall be responsible for the quality of the investigational medicinal product, the supply thereof to the clinical trial site (research centre), the specification of conditions and duration of storage and, where necessary, the dilution liquids and medical devices for the infusion of the medicinal product. All individuals involved in the circulation of the investigational medicinal product shall be informed regarding the referred to conditions. Such persons have the duty to observe the storage conditions of the investigational medicinal product.

26. The investigator shall be responsible for the storage and accounting of the investigational medicinal product in a research centre.

27. The sponsor shall supply the investigational medicinal product, as well as the medical devices for the infusion thereof, if such are necessary, free of charge.

III. The Investigator's Brochure

28. The investigator's brochure is a compilation of the clinical and pre-clinical information on the investigational medicinal product regarding the study of the medicinal product, in which human subjects are involved. The information in the investigator's brochure shall be presented in a concise, simple, objective, balanced and non-promotional form so that a medical practitioner or potential investigator could understand it and make an unbiased assessment of the appropriateness of the proposed clinical trial, taking into account the prospective risks and benefits. These requirements shall also apply to any update of the investigator's brochure.

29. If an investigational medicinal product is registered in a Member State or state of the European Economic Area, the investigator's brochure may be substituted for the description of the medicinal product.

30. The sponsor shall evaluate and update the investigator's brochure at least once a year.

IV. Protection of a Trial Subject

31. A clinical trial may be conducted only in case if:

31.1. it is indicated in the opinion of the Ethics Committee and the permit of the State Agency of Medicines for the commencement of the clinical trial that the anticipated therapeutic benefit for the trial subject and other present or future patients, as well as to the society at large, has been assessed and it justifies the anticipated risk and the clinical trial may be continued if the conformity with this requirement is permanently monitored;

31.2. the trial subject or, when the person is not able to give consent, his or her legal representative has given his or her written voluntary consent to participate in the clinical trial after being informed of the nature, significance, implications and risks of the trial, signing the document of consent of the trial subject drawn up by the sponsor and indicating the date (hereinafter - the informed consent). If the relevant individual is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases;

31.3. the trial subject or, when the person is not able to give the informed consent, his or her legal representative has had the opportunity, in a prior interview with the investigator or another person involved in the conduct of the clinical trial, to understand the objectives, risks and inconveniences of the clinical trial, as well as the conditions, according to which it will be conducted, and the trial subject or, when the person is not able to give the informed consent, his or her legal representative has been informed of the right to withdraw from the participation in the trial at any time;

31.4. the personal data of the trial subject are safeguarded in accordance with the regulatory enactments regarding the protection of the data of natural persons;

31.5. the document of informed consent provides the trial subject with the possibility to discontinue the participation in the clinical trial at any time by informing the sponsor or the investigator regarding revoking of his or her informed consent, and it shall not result in unfavourable impact on the quality of health care provided to the trial subject; and

31.6. the conditions of insurance and compensation are foreseen in the document of informed consent, which cover the civil legal liability of the investigator and the sponsor.

32. In addition to the conditions referred to in Paragraph 31 of this Regulation a clinical trial, in which minors are the trial subjects, may be conducted only in case if the following conditions are complied with:

32.1. the informed consent has been obtained, which has been provided by at least one of the parents or the legal representative. The informed consent shall represent the minor's presumed will, and it may be revoked at any time without detriment to the minor;

32.2. staff with experience in working with minors has informed the relevant minor in accordance with the capacity of understanding thereof regarding the clinical trial, the risks and benefits thereof. One of the parents or the legal representative shall confirm in writing that the minor has been informed in accordance with the capacity of understanding thereof regarding the nature of the particular clinical trial, the risks and benefits thereof;

32.3. the investigator or the principal investigator has considered the explicit wish of a minor to refuse the participation or to discontinue the participation in the clinical trial at any time, if the relevant minor is capable of forming and justifying his or her opinion and assessing the information referred to in Sub-paragraph 31.3 of this Regulation;

32.4. a minor is not incited or financially induced, except for the compensation of expenditure, which is related to the participation in the clinical trial (including transport expenditure), as well as the compensation for harm caused to health or death caused by the clinical trial;

32.5. direct benefit for the group of patients is expected after the clinical trial, and such trial is essential, in order to validate the data obtained in the clinical trial on persons who are able to give the informed consent or by using other research methods. Such research shall either relate directly to a disease, from which the minor concerned suffers, or be of such a nature that it can only be conducted on minors;

32.6. the scientific instructions of the European Medicines Agency have been followed;

32.7. the clinical trial has been designed so as to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the development stage of the child. Both the risk threshold and the degree of distress have to be specially defined and constantly monitored;

32.8. the Ethics Committee, with paediatric expertise or after taking advice of an expert in clinical, ethical and psychosocial problems in the field of paediatrics, has endorsed the protocol; and

32.9. the interests of the patient prevail over the interests of science and society.

33. To persons who are incapable of giving the informed consent all the requirements referred to in Paragraph 31 of this Regulation, which are applicable to persons who are capable to give such consent, shall apply. If persons who are incapable of giving the informed consent and who have not given such consent or have refused to give the informed consent prior to losing such capabilities, are included in a clinical trial, the trial is allowed if such conditions are complied with in addition to the referred to requirements:

33.1. the informed consent of the legal representative has been obtained. The informed consent shall represent the trial subject's presumed will, and it may be revoked at any time without detriment to the trial subject;

33.2. the person who is not able to give the informed consent has received information according to his or her capacity of understanding regarding the clinical trial, the risks and benefits thereof;

33.3. the investigator or the principal investigator has considered the explicit wish of a person, if this person is capable of expressing his or her opinion and assessing the information, to refuse the participation in or to discontinue the participation in the clinical trial at any time;

33.4. the person who is not able to give the informed consent is not incited or financially induced, except for the compensation for expenditure, which is related to the participation in the clinical trial (including transport expenditure), as well as the compensation for harm caused to health or death caused by the clinical trial;

33.5. such clinical trial is essential in order to validate the data obtained in the clinical trial on persons who are able to give the informed consent or by using other research methods and relates directly to a life-threatening or debilitating clinical condition, from which the person concerned suffers;

33.6. the clinical trial has been designed so as to minimise pain, discomfort, fear and any other foreseeable risk in relation to the disease and the capability of understanding. Both the risk threshold and the degree of distress have to be specially defined and constantly monitored;

33.7. the Ethics Committee, with expertise in matters related to the relevant disease and the group of patients concerned or after the receipt of advice of an expert in clinical, ethical and psychosocial problems in the field of the relevant disease and the group of patients concerned, has endorsed the protocol;

33.8. the interests of the patient prevail over the interests of science and society; and

33.9. there are grounds to believe that the participation in the clinical trial will be beneficial to the patient outweighing the risks or producing no risk at all.

34. In case of emergency, if it is not possible to receive the informed consent from a trial subject and the trial subject does not have a legal representative or the legal representative is not available, the trial subject shall be involved in a clinical trial only in such case if the protocol includes the procedure of inclusion of a trial subject in case of emergency.

35. In order for a trial subject to receive independent information regarding the relevant clinical trial, the investigator shall provide the trial subject with the contact information of the Ethics Committee (which has provided the opinion regarding the relevant clinical trial) and the State Agency of Medicines.

36. It is prohibited to perform a clinical trial on a pregnant woman and a nursing mother, except in cases when a clinical trial cannot be otherwise conducted, and the risk from conducting the clinical trial is reasonably balanced with the expected benefit for the embryo, foetus or the suckling infant.

37. A trial subject who needs active treatment of a disease shall be included in a control group, in which the trial subject receives a comparator preparation without the active substance, only in the case where the conditions referred to in Paragraphs 31, 32 and 33 of this Regulation are complied with and the protocol includes the scientific and ethical justification of involvement of the trial subjects.

38. In order to ensure the protection of the personal data of a trial subject, the investigator shall assign to each trial subject an identification code, which shall substitute the given name and surname of the trial subject when submitting reports to the sponsor, the State Agency of Medicines and the Ethics Committee. The investigator may decode the given name and surname of a patient only upon the request of such institutions, which in accordance with the Medical Treatment Law have the right to become acquainted with the information regarding the patient.

39. If, in the course of a clinical trial, information is acquired regarding such circumstances as may threaten the life or health of the trial subject, the investigator shall notify the trial subject without delay. Information provided to the trial subject shall be documented. In such cases additional voluntary written consent regarding the further participation in the clinical trial shall be obtained from the trial subject in accordance with Paragraph 31 of this Regulation.

40. If a clinical trial is discontinued or terminated prior to the time for completion specified in the protocol, the investigator shall notify the trial subject thereof and ensure his or her further treatment and observation.

V. The Ethics Committee

41. The Ethics Committee shall provide an opinion, before the commencement of a clinical trial, regarding any issue related to the trial and of concern to the society in order to ensure the rights, safety and well-being of a trial subject, as well as to provide the society with certainty of such protection. The Ethics Committee is an independent organisation, which operates in or outside a medical treatment institution.

42. The Ethics Committee shall consist of qualified and experienced individuals who may assess ethical and scientific aspects of the relevant clinical trial. The Minister for Health shall approve the personnel of the Ethics Committee for an indefinite period of time.

43. The Ethics Committee shall consist of not less than nine members. At least two persons who do not have medical education, as well as at least two independent persons who are not related to the research centre (the site where activities related to the clinical trial take place) shall be included in the Ethics Committee. The Ethics Committee shall comprise representatives of both genders.

44. The Ethics Committee has the right to invite experts without voting rights.

45. Activities of the Ethics Committee shall take place pursuant to the by-law approved by the Chairperson of the Ethics Committee. The by-law shall be developed in accordance with this Regulation, recommendations of good clinical practice and the regulatory enactments regarding the protection of the data of natural persons.

46. The Ethics Committee has the right to take a decision if more than a half of the members of the Ethics Committee participates in a meeting thereof.

47. An opinion of the Ethics Committee shall be taken with a simple majority by open voting of the members of the Ethics Committee.

48. Meetings of the Ethics Committee shall be recorded in minutes, and decisions of a meeting shall be recorded in the minutes. A member of the Committee whose opinion differs from the final decision of the Committee is entitled to express his or her opinion in an Annex to the minutes.

49. Only the members of the Committee independent from the investigator and the sponsor concerned shall vote and express an opinion regarding the issues related to a particular clinical trial.

50. The Ethics Committee shall store all documents for five years after the termination of the relevant clinical trial, except the cases where a longer period has been specified for the storage of documents in the regulatory enactments regarding the procedures for the record-keeping of medical documentation.

51. Information regarding the personnel of the Ethics Committee and qualification of the members, as well as the by-laws of the Ethics Committee, shall be available upon the request to the investigator, the sponsor, the State Agency of Medicines and the Ministry of Health.

52. The Ethics Committee shall submit to the Ministry of Health the contact information of the personnel of the Committee, as well as the information regarding the field of expert-examination and payment for the examination of a clinical trial submission. The Ministry of Health shall insert this information on the Internet home page thereof.

53. Once a year (until 1 February) the Ethics Committee shall submit to the State Agency of Medicines a list of all clinical trial submissions examined and decisions taken in the preceding year.

54. In order to obtain an opinion of the Ethics Committee, the sponsor or a person authorised by the sponsor shall submit to the Ethics Committee the following documents and information:

54.1. the number in the European Clinical Trials Database (EUDRACT);

54.2. a submission signed by the sponsor or a person authorised by the sponsor, which is drawn up on the basis of the sample of the submission developed by the European Commission (available on the Internet home page of the State Agency of Medicines);

54.3. the protocol and amendments to the protocol, if such have been made, signed by the sponsor and the investigator;

54.4. a document of the informed consent of the trial subject developed by the sponsor in the official language. If it is intended to involve in the clinical trial persons whose level of understanding of the official language is not sufficient in order to comprehend the information written in the document of informed consent, such document shall also be submitted in the language, which may be understood by the persons involved in the trial;

54.5. other written information in the official language, which is related to the particular clinical trial and which is provided for the trial subject. If it is intended to involve in the clinical trial persons whose level of understanding of the official language is not sufficient in order to comprehend the referred to information, such document shall also be submitted in the language, which may be understood by the persons involved in the trial;

54.6. the description of measures for involvement of the trial subject;

54.7. the investigator's brochure or in the case provided for in Paragraph 29 of this Regulation - the description of the medicinal product;

54.8. the description of the experience and qualifications of the investigators and other persons involved in the clinical trial (Curriculum vitae) whom the investigator selects at the research centre and who work under the supervision of the investigator (hereinafter - the investigator assistant);

54.9. the documents, which are related to the payment of the compensation, if such is provided, to the trial subject for the participation in the clinical trial;

54.10. the documents, which confirm the insurance of the civil legal liability of the investigator and the sponsor and which include the conditions regarding compensation to a trial subject in case of possible harm or death of the trial subject caused by the clinical trial;

54.11. the consent of the management of the medical treatment institution to the conduct of the clinical trial; and

54.12. the power of attorney of the sponsor, if the documents are submitted by a person authorised by the sponsor.

55. In assessing a submission for the commencement of a clinical trial and in preparing an opinion, the Ethics Committee shall pay particular attention to:

55.1. the significance and purpose of the clinical trial;

55.2. the assessment of the anticipated benefits and risks in accordance with Sub-paragraph 31.1 of this Regulation and the justification of conclusions;

55.3. the protocol;

55.4. the suitability of the investigator and personnel;

55.5. the investigator's brochure;

55.6. the quality of the premises and equipment;

55.7. the adequacy of the written information to be given to the particular clinical trial, the procedures for obtaining the informed consent, as well as the justification for the clinical trial on persons incapable of giving the informed consent, taking into account the restrictions specified in Paragraphs 31, 32 and 33 of this Regulation;

55.8. provisions regarding the indemnity or compensation if harm or death has been caused due to the clinical trial;

55.9. any insurance or indemnity, which covers the liability of the investigator and the sponsor;

55.10. the amounts and, where appropriate, the conditions for the indemnity or compensation provided for the investigator and the trial subject, as well as the contract entered into by the sponsor and the research centre specifying the relevant aspects; and

55.11. the measures for the recruitment of the trial subjects.

56. The Ethics Committee, within 30 days after the registration of such submission, which includes all the information referred to in this Regulation, shall provide a written opinion to the applicant, indicating the justification of the position provided in the opinion. A copy of the opinion shall be submitted to the State Agency of Medicines.

57. Within the period of the examination of a submission regarding the provision of an opinion, the Ethics Committee may send to the applicant a single request for supplementary information. The time period that is specified in Paragraph 56 of this Regulation shall be prolonged until the receipt of the supplementary information.

58. The Ethics Committee shall prolong the time period referred to in Paragraph 56 of this Regulation, if a clinical trial involving a medicinal product provided for gene therapy or somatic cell (any cells of an organism, which are not germ cells) therapy or a medicinal product containing genetically modified organisms is planned. In such case the time period referred to in Paragraph 56 of this Regulation shall be prolonged, but it shall not be longer than 180 days from the day of the registration of the submission. In the case of xenogenic cell (cells that are strange to a human body) therapy, there shall be no time limit to the issuance of the opinion.

59. If a multi-centre clinical trial is conducted and all research centres are located in Latvia, the Ethics Committee shall issue a single opinion regarding such clinical trial. If a multi-centre clinical trial is conducted in more than one Member State simultaneously, the Ethics Committee shall provide a single opinion regarding the clinical trial in Latvia.

60. An applicant has the right to contest a decision of the Ethics Committee in the Central Medical Ethics Committee. The decision of the Central Medical Ethics Committee shall not be subject to appeal.

VI. Receipt of the Permit of the State Agency of Medicines

61. In order to obtain the permit for the commencement of a clinical trial from the State Agency of Medicines, the sponsor or a person authorised by the sponsor shall submit to the State Agency of Medicines the following documents and information:

61.1. the confirmation of the receipt of the number in the European Clinical Trials Database (EUDRACT);

61.2. a submission signed by the sponsor or a person authorised by the sponsor, which is drawn up using the sample of the submission developed by the European Commission (the link is 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) (to be submitted also as an XML file);

61.3. the protocol and amendments to the protocol, if such have been made, signed by the sponsor and the investigator;

61.4. a report regarding all active trials involving the relevant investigational medicinal product;

61.5. the file of the investigational medicinal product, in which the data regarding the investigational medicinal product are compiled, including the references regarding the quality of the preparation and placebo (inert pharmaceutical form without the active substance, which objectively does not have any specific activity in relation to particular medical treatment), the results of the pre-clinical and previously conducted clinical trials, as well as the summary of the benefit and risks assessment, in which the pre-clinical and clinical data are critically analysed in relation to the risks and benefit of the planned clinical trial, is included, or an abridged file of the investigational medicinal product, if the State Agency of Medicines assesses the investigational medicinal product repeatedly;

61.6. the description of the medicinal product for medicinal products registered in the Member States;

61.7. the list of such Member States, in which the submission has been submitted, as well as the information regarding the decisions of such institutions, if such information is available;

61.8. a copy of the manufacturer's licence if the investigational medicinal product is manufactured in a Member State or a State of the European Economic Area;

61.9. a statement that the production unit complies with the requirements of good manufacturing practice, which are equivalent at least to the requirements of good manufacturing practice of the European Union, as well as a copy of the importer's licence if the investigational medicinal product is manufactured outside the European Union;

61.10. the certification regarding the compliance of the manufacturing of the active substance of the investigational medicinal product with the requirements of good manufacturing practice;

61.11. a document of the informed consent of the trial subject developed by the sponsor in the official language. If it is intended to involve in the clinical trial persons whose level of understanding of the official language is not sufficient in order to comprehend the information written in the document, information shall also be submitted in the language, which may be understood by the persons involved in the trial;

61.12. other written information in the official language, which is related to the clinical trial and which is provided for the trial subject. If it is intended to involve in the clinical trial persons whose level of understanding of the official language is not sufficient in order to comprehend the information written, information shall also be submitted in the language, which may be understood by the persons involved in the trial;

61.13. the written consent of the management of the medical treatment institution to the conduct of the clinical trial;

61.14. the documents, which confirm the insurance of the civil legal liability of the investigator and the sponsor and which include the conditions regarding compensation to a trial subject in case of possible harm or death of the trial subject caused by the clinical trial;

61.15. the documents, which are related to the payment of the compensation, if such is provided, to the trial subject for the participation in the clinical trial;

61.16. the investigator's brochure or in the case provided for in Paragraph 29 of this Regulation - the description of the medicinal product;

61.17. the sample of labelling of the packaging of the investigational medicinal product in the official language;

61.18. the description of the experience and qualifications of the investigator and investigator assistants;

61.19. the written certification that the investigator has acquired the requirements of good clinical practice and the regulatory enactments regarding the conduct of the clinical trial; and

61.20. the power of attorney of the sponsor, if the documents are submitted by a person authorised by the sponsor.

62. An applicant shall cover expenditure that is related to the examination of a submission for a clinical trial on the medicinal product in accordance with the price list of public paid services of the State Agency of Medicines. If a clinical trial is refused, the paid expenditure shall not be repaid.

63. The State Agency of Medicines shall examine a submission (to which all the information referred to in Paragraph 61 of this Regulation has been appended) within 60 days after the receipt thereof.

64. In a time period, during which the examination of a submission takes place, the State Agency of Medicines may send a request for supplementary information to the applicant. The time period specified in Paragraph 63 of this Regulation shall be prolonged until the receipt of the supplementary information.

65. The State Agency of Medicines shall prolong the time period referred to in Paragraph 63 of this Regulation, if a clinical trial involving a medicinal product provided for gene therapy or somatic cell (any cells of an organism, which are not germ cells) therapy or a medicinal product containing genetically modified organisms is planned. In such case the time period referred to in Paragraph 63 of this Regulation shall be prolonged, but not more than by 180 days from the day of the registration of the submission. In the case of xenogenic cell therapy there shall be no time limit to the issuance of the opinion.

66. The State Agency of Medicines shall take a decision in the time period referred to in Paragraphs 63 and 64 of this Regulation regarding the commencement of a clinical trial or regarding the prohibition to commence a clinical trial if the requirements referred to in this Regulation have not been observed and shall inform the submitter regarding the decision within 5 working days after taking thereof in writing, indicating the justification of the decision. The permit shall not be issued until the payment referred to in Paragraph 62 of this Regulation has been made. The permit shall be issued for the time period of the clinical trial specified in the protocol.

67. The permit shall not be issued to such gene therapy trial, which causes modifications in identity of genetic information of the clinical subject's germ cells.

68. The State Agency of Medicines shall issue the permit for a clinical trial on a medicinal product containing genetically modified organisms after the sponsor has received a permit in accordance with the regulatory enactments regarding the limited use of genetically modified organisms and intentional distribution thereof in the environment.

69. An applicant has the right to contest the decision of the State Agency of Medicines to the Ministry of Health. A decision of the Ministry of Health may be appealed to a court.

70. If a multi-centre clinical trial is conducted and all research centres are located in Latvia, the State Agency of Medicines shall take a single decision regarding such clinical trial. If a multi-centre clinical trial is conducted in more than one Member State simultaneously, the State Agency of Medicines shall take a single decision regarding the clinical trial in Latvia.

VII. Commencement of a Clinical Trial

71. The sponsor shall initiate a clinical trial only after the Ethics Committee has issued a favourable opinion and the State Agency of Medicines has issued the permit for the commencement of the clinical trial. The sponsor has the right to submit a submission to the Ethics Committee and to the State Agency of Medicines simultaneously. Prior to the commencement of a clinical trial the sponsor shall enter into a contract with each medical treatment institution, in which the conduct of the particular clinical trial is planned, providing for the duties and responsibility of the contracting parties in relation to the conduct of the clinical trial (including the observation of the intellectual property rights and confidentiality), as well as the financial conditions (including the amount of indemnity to the medical treatment institution for the use of the human resources and material resources thereof in the clinical trial and the payment schedule).

72. If the State Agency of Medicines has informed the sponsor regarding a decision to prohibit the commencement of the clinical trial because the requirements referred to in this Regulation have not been observed, the sponsor shall amend the content of the submission referred to in Paragraph 61.2 of this Regulation only once in order to take into account the arguments referred to in the justification of the decision. If the sponsor has not taken into account the arguments referred to in the justification of the decision, the submission shall be regarded rejected and it is not allowed to commence the clinical trial.

VIII. Conduct of a Clinical Trial

73. After the commencement of a clinical trial, the sponsor has the right to make amendments to the application and the documents appended thereto. If such amendments may have a substantial impact on the safety of the trial subject, the physical or mental integrity of the subject, the scientific value of the trial, the process or management of the trial, the quality or safety of the investigational medicinal product, the sponsor shall submit to the State Agency of Medicines a submission on the basis of the submission for an essential amendment approved by the European Commission (the link is 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 inform the relevant Ethics Committee in writing.

74. The Ethics Committee shall provide an opinion and the State Agency of Medicines shall take a decision within 30 days after receipt of the amendments referred to in Paragraph 73 of this Regulation.

75. If the opinion of the Ethics Committee is favourable and the State Agency of Medicines has taken the favourable decision, the sponsor shall proceed to conduct the clinical trial following the amendments to the protocol.

76. If the opinion of the Ethics Committee or the decision of the State Agency of Medicines is unfavourable because the requirements referred to in this Regulation have not been observed, the sponsor shall not introduce the amendments to the protocol before the arguments indicated in the opinion and the justification of the decision have been taken into account. If the sponsor has not taken into account the arguments indicated in the opinion and the justification of the decision, the amendments to the protocol submitted by the sponsor shall be regarded as rejected.

77. If, during a clinical trial, the conditions related to the conduct of the trial or trial or development of the investigational medicinal product occur, which may affect the safety of the trial subject, the sponsor and the investigator shall take appropriate urgent safety measures in order to protect the trial subject. The sponsor shall inform without delay the State Agency of Medicines regarding such conditions and the measures taken and ensure that the Ethics Committee is also informed at the same time.

78. If amendments to the protocol are related to administrative issues, the sponsor shall inform the Ethics Committee and the State Agency of Medicines thereof in writing. In such case the opinion of the Ethics Committee and the permit of the State Agency of Medicines shall not be necessary.

79. The sponsor shall, within 90 days after the end of a clinical trial, inform the State Agency of Medicines and the Ethics Committee that the clinical trial in the Republic of Latvia has ended. The sponsor shall submit to the State Agency of Medicines a submission on the basis of the sample of the submission for the end of a clinical trial approved by the European Commission (the link is 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 inform the State Agency of Medicines regarding the number of patients involved in the clinical trial in Latvia. If a clinical trial is terminated prior to the planned end of the trial, the sponsor shall inform the State Agency of Medicines and the Ethics Committee regarding the termination of the trial within 15 days after the termination of the clinical trial of the medicinal product, explaining the reasons for the termination of the clinical trial.

IX. Exchange of Information

80. The State Agency of Medicines shall enter the information into the European Clinical Trials Database regarding each clinical trial announced in the territory of Latvia, including:

80.1. the submission of the sponsor to the State Agency of Medicines regarding the request of the permit for the commencement of a clinical trial;

80.2. any amendments that have been made to the submission or the documents appended thereto in accordance with the instructions of the State Agency of Medicines and Paragraph 72 of this Regulation;

80.3. any amendments that have been made to the protocol after the commencement of the clinical trial in accordance with Paragraphs 73, 74 and 75 of this Regulation;

80.4. the opinion of the Ethics Committee;

80.5. the notification regarding the end of the clinical trial in the Republic of Latvia; and

80.6. the information regarding the supervision of the clinical trial and the assessment of the conformity thereof with the requirements of good clinical practice.

81. Upon the justified request of any Member State, the European Medicines Agency or the European Commission, the State Agency of Medicines, in addition to the information referred to in Paragraph 80 of this Regulation, shall provide the necessary information.

X. Suspension of a Clinical Trial and Infringements

82. If the State Agency of Medicines has a justified reason to consider that the conditions of the submission referred to in Paragraph 61.2 of this Regulation are not complied with, as well as the requirements referred to in this Regulation have not been observed or it possesses information, which raises doubts regarding the safety or scientific validity of the clinical trial, the State Agency of Medicines has the right to suspend the clinical trial, informing the investigator and the sponsor thereof.

83. Before the State Agency of Medicines takes a decision in the case referred to in Paragraph 82 of this Regulation, it shall ask the sponsor and the investigator to provide information regarding the reasons of non-compliance with the conditions within one week, except the cases where a serious risk to the trial subject exists.

84. If the State Agency of Medicines has a justified reason to consider that the sponsor or the investigator or any other person involved in the conduct of the clinical trial does not fulfil the specified liabilities, it shall inform the relevant person thereof and indicate the activities that such person must perform in order to remedy such situation. The State Agency of Medicines shall inform the Ethics Committee, other competent authorities and the European Commission about the activities performed.

85. The State Agency of Medicines has the right to prohibit a clinical trial, if the clinical trial causes serious risk to the trial subject, but the sponsor and the investigator does not take the necessary measures in order to ensure the safety of the trial subject.

86. The State Agency of Medicines shall inform other competent authorities, the relevant Ethics Committee, the European Medicines Agency and the European Commission regarding the decision to suspend or to prohibit a clinical trial if the requirements referred to in this Regulation have not been observed, as well as the reasons of such decision.

XI. Manufacture, Import and Labelling of Investigational Medicinal Products

87. The requirements for the manufacture and import of investigational medicinal products shall be determined by the regulatory enactments regarding the manufacture and control of medicinal products and regarding import and distribution of medicinal products.

88. Information shall be indicated on the outer packaging or, if such does not exist, on the immediate packaging of investigational medicinal products in the official language in accordance with the recommendations (guidelines) of the European Commission specified in Section 25.² of the Pharmaceutical Law, which have been published in the volumes of the Rules Governing Medicinal Products in the European Union (Eudralex).

XII. Clinical Trial Master Files and the Requirements for the Storage Thereof

89. The clinical trial master files are the essential documents of a trial, which ensure the conduct of the clinical trial and evaluation of the quality of the data obtained in the trial. Such documents shall testify whether the investigator and the sponsor act in accordance with the principles and guidelines of good clinical practice, as well as the regulatory enactments regarding the registration of medicinal products.

90. The clinical trial master files shall provide the basis for the audit, which is performed by an independent auditor appointed by the sponsor, as well as for the supervision and assessment performed by the State Agency of Medicines.

91. The content of the essential documents shall comply with the phase of the clinical trial.

92. The sponsor and the investigator shall store the essential documents for at least 5 years after the end of the relevant trial, except the documents referred to in Paragraphs 93 and 94 of this Regulation.

93. The investigator shall be responsible for the storage of the list of identification codes of the trial subjects for at least 15 years.

94. The sponsor shall be responsible for storage of the protocol, standard operating procedures, researcher's brochure, data registration document of each trial subject, report on the clinical trials, written opinion regarding the clinical trials protocol and the course of its implementation, for at least five years after the registration of the investigational preparation.

95. The essential documents shall be stored for a longer period of time if it has been specified in the regulatory enactments regarding the procedures for the record-keeping of medical documentation or in the contract entered into by the sponsor and the investigator.

96. The essential documents shall be stored in a way that ensures that, upon the request of the State Agency of Medicines or the Health Inspectorate, they are readily available in accordance with the competence of the relevant persons and the regulatory enactments regarding the protection of the data of natural persons. Identification codes shall be available only to such institutions, which, in accordance with the Medical Treatment Law, have the right to get acquainted with information regarding patients.

97. Medical records regarding trial subjects shall be stored in accordance with the regulatory enactments regarding the procedures for the record-keeping of medical documentation.

98. Any change in ownership rights of the data or of the essential documents shall be documented. The new owner shall assume responsibility for the storage and archiving of the data in accordance with Paragraphs 92, 93, 94, 95, 96 and 97 of this Regulation.

99. The sponsor shall appoint a person responsible for the archive (responsible persons).

100. Access to the archive shall be granted only to the persons referred to in Paragraph 99 of this Regulation.

101. The essential documents shall be stored in such conditions which ensure that they are complete and legible throughout the specified storage period and are available upon the request of the institutions referred to in Paragraph 96 of this Regulation.

102. Any alteration to documents shall be easily traceable, preserving also the text, to which alteration was made.

XIII. Procedures for the Supervision and Assessment of Conformity of a Clinical Trial with the Requirements of Good Clinical Practice

103. Assessment is an official examination performed by the State Agency of Medicines, during which it examines the documents, equipment, records, quality assurance measures, as well as any other resources, which the State Agency of Medicines considers to be related to the clinical trial and which are located in the trial site, in the premises of the sponsor or a person authorised by the sponsor, as well as in any other institution, which the State Agency of Medicines regards as suitable for assessment.

104. In order to supervise and assess the compliance with the requirements of good clinical practice, a qualified person of the State Agency of Medicines has the right to visit the sites, which are related to the conduct of a clinical trial, especially the trial site and any laboratory that is used for conducting the tests in the clinical trial.

105. The State Agency of Medicines shall meet the data protection requirements in relation to the information obtained during the supervision and assessment of good clinical practice.

106. The supervision and assessment shall be performed by a qualified person of the State Agency of Medicines who has:

106.1. higher education or appropriate experience in medicine, pharmacy, pharmacology, toxicology or another appropriate field;

106.2. knowledge of the principles and activities, which are related to the development and clinical trial on the medicinal products, as well as knowledge of the regulatory enactments of the European Union and the Republic of Latvia regarding the conduct of a clinical trial and the registration of medicinal products; and

106.3. knowledge of the registration system of the clinical trial data and the activities related to registration, as well as of the organisation and legislation of the health care system.

107. The State Agency of Medicines shall maintain information regarding the qualified persons who are entitled to supervise and assess the compliance of a clinical trial with good clinical practice, their qualification, training and experience and provide the relevant information to the European Medicines Agency upon the request thereof. The State Agency of Medicines shall ensure the training of such persons, assess the study needs on a regular basis, as well as take appropriate measures for the maintenance and improvement of skills of the relevant persons.

108. The State Agency of Medicines shall ensure the persons referred to in Paragraph 107 of this Regulation with the description of the standard procedure of work, as well as the detailed description of responsibilities, liability and requirements for training. The State Agency of Medicines shall update the description of the standard procedure of work, as well as other information provided for the persons referred to in Paragraph 107 of this Regulation on a regular basis.

109. The State Agency of Medicines shall ensure the persons referred to in Paragraph 107 of this Regulation with a document (identification card) that confirms their right to supervise and assess the compliance of a clinical trial with the requirements of good clinical practice.

110. Upon commencing work, the person referred to in Paragraph 107 of this Regulation shall certify any financial relation or relation of another type with the supervised person or site where the clinical trial is conducted in writing. The State Agency of Medicines shall take into account such certification in appointing the relevant person for the conduct of the supervision and assessment of the relevant clinical trial.

111. Assessment of good clinical practice may be performed in the following cases:

111.1. before the commencement of a clinical trial, during a clinical trial or after the end thereof; or

111.2. in relation to the examination of a submission for the registration of a medicinal product.

112. If the assessment of the compliance of good clinical practice provided for in Sub-paragraph 111.2 of this Regulation is related to a travel, a submitter shall cover the travelling (transport) expenditure of officials of the State Agency of Medicines to the research centre or the institution related to the research and back, hotel (accommodation) expenditure, visa expenditure, health insurance expenditure and daily subsistence allowance in accordance with the regulatory enactments regarding the procedures for reimbursement of expenditure in relation to official travel and working trips of employees.

113. The State Agency of Medicines shall inform the European Medicines Agency regarding the assessment performed. The supervision and assessment may be performed on behalf of the European Union, and the results thereof shall be recognised by other Member States. The State Agency of Medicines has the right to request the assistance of another Member State in relation to the supervision and assessment.

114. After assessment the State Agency of Medicines shall prepare an assessment report. The report shall be available to the sponsor, ensuring the necessary data protection. It shall be available to other Member States, the Ethics Committee and the European Medicines Agency if a justified request has been received.

115. A foreign competent authority is also entitled to participate in the inspection of a clinical trial. In such case the relevant foreign institution shall inform the State Agency of Medicines regarding the intended inspection within 30 days prior to its commencement. A representative of the State Agency of Medicines shall be allowed to participate in the inspection.

116. In order to ensure the supervision and assessment, all persons involved in a clinical trial have the duty to ensure the State Agency of Medicines, as well as foreign assessors with direct access to the documents in all the sites related to the clinical trial.

117. The Health Inspectorate is entitled to conduct the examination of a clinical trial according to the competence thereof. The State Agency of Medicines shall be notified regarding the results of the examination referred to in this Paragraph.

118. Where necessary, the State Agency of Medicines shall involve experts whose qualification and experience complies with the particular clinical trial in the assessment of the clinical trial of a medicinal product.

XIV. Notification of Adverse Events

119. The investigator shall inform without delay the sponsor in writing regarding all medical cases unfavourable to the trial subject, which take place during the usage of the investigational medicinal product regardless of the causal link with the usage of the investigational medicinal product and which, regardless of the dosage, cause death, threaten life, cause the need of hospitalisation or prolong the existing hospitalisation, cause incessant or heavy disability or incapacity for work or which is an inherited anomaly or birth malformation (hereinafter - a serious adverse event), except such serious adverse events that are not referred to in the protocol or investigator's brochure among those, regarding which immediate reporting is required. The investigator shall send to the sponsor the detailed written report after the immediate report. The unique identification code assigned to the trial subject shall be used for the identification of the trial subject in the immediate and further reports.

120. The investigator shall notify the sponsor in writing regarding serious adverse events and laboratory deviations, which are specified in the protocol as substantial for the assessment of safety of the investigational medicinal product, in accordance with the requirements and terms for submission of the reports indicated in the trial protocol.

121. In the event of death of a trial subject the investigator shall provide the sponsor and the Ethics Committee with all the requested supplementary information.

122. The sponsor shall keep a detailed record of all adverse events reported by the investigators and assess the severity, cause and predictability thereof, as well as issue, upon the request, such data to the competent authorities of such Member States where the particular clinical trial is conducted.

XV. Notification of Serious Adverse Reactions

123. The sponsor shall ensure that serious adverse and unexpected response reactions to the usage of an investigational medicinal product observed in all trial sites involved in a clinical trial, regardless of the used dosage, the nature or level of seriousness of which does not comply with the information available regarding the investigational medicinal product (hereinafter - unexpected adverse reactions), which causes death of the trial subject or threatens the life thereof and which, possibly, has been caused by the investigational medicinal product, are registered. The sponsor shall enter the information into the Clinical Trial Module (EVCTM) of the European Adverse Effect Monitoring System (Eudravigilance) of the European Medicines Agency regarding them as soon as possible, but not later than within 7 days after receipt of the relevant information. The sponsor shall notify of serious unexpected adverse reactions that cause death of the trial subject or threaten the life thereof and that probably have been caused by the investigational medicinal product and that are observed in the clinical trial centres in Latvia to the State Agency of Medicines, indicating the address of the State Agency of Medicines in EVCTM, and to the Ethics Committee, submitting the supplementary report within 8 days after the first report.

124. The sponsor shall enter serious unexpected adverse reactions, which do not cause death of the trial subject or threaten the life thereof and which have probably been caused by the investigational medicinal product, in the Clinical Trial Module (EVCTM) of the European Adverse Effect Monitoring System (Eudravigilance) of the European Medicines Agency. The sponsor shall notify of serious unexpected adverse reactions that do not cause death of the trial subject or threaten the life thereof and that probably have been caused by the investigational medicinal product and that are observed in the clinical trial centres in Latvia to the State Agency of Medicines, indicating the address of the State Agency of Medicines in EVCTM, as well as to the Ethics Committee as soon as possible, but not later than within 15 days after receipt of the relevant information.

125. The State Agency of Medicines shall register information regarding all possible serious unexpected adverse reactions of investigational medicinal products notified thereto.

126. The sponsor shall inform all the investigators involved in a clinical trial regarding all serious unexpected adverse reactions, which have probably been caused by the investigational medicinal product (the periodicity shall be determined by the specificity of the research and the number of adverse reactions).

127. Once a year during a clinical trial not later than within 60 days after the end of the reporting period specified in the protocol, the sponsor shall provide the State Agency of Medicines and the Ethics Committee with the safety report regarding all serious unexpected adverse reactions observed in the relevant year, which have probably been caused by the investigational medicinal product, as well as the summary regarding the safety of the trial subject during the clinical trial. If a clinical trial lasts less than a year, the safety report may be submitted together with the report on the termination of the clinical trial.

XVI. Non-interventional Trials

128. Non-interventional trials shall comprise only such data as are obtained by the performer of the observation (physician) during his or her professional activities, on the basis of the opinion regarding the state of health and the treatment of the patient. Additional diagnostic and monitoring procedures shall not be performed to patients and epidemiological methods shall be used for the analysis of collected data.

129. Before the commencement of a non-interventional trial, the physician or a representative of the manufacturer of the medicinal product, who is responsible for the co-ordination of the observation, shall submit the following documents to the State Agency of Medicines and the Ethics Committee:

129.1. a submission in which the following information is indicated:

129.1.1. the name, common name, pharmaceutical form and strength of the medicinal product used in the observation;

129.1.2. the description of the observation project (also the criteria for the involvement of patients in the observation and methods used for the data analysis);

129.1.3. the physicians who participate in the observation, indicating their given name, surname and speciality;

129.1.4. the medical treatment institutions, which participate in the observation;

129.1.5. the planned number of patients to be involved;

129.1.6. the information whether the disease, for medical treatment of which it is intended to use the medicinal product to be observed, is included in the system for reimbursement of medicinal products;

129.1.7. the information whether the medicinal product to be observed is included in the list of reimbursable medicinal products; and

129.1.8. the time of the conduct of the observation, indicating the commencement and termination date;

129.2. a sample of the document, by which the patient confirms his or her consent to the collection and compilation of the data related to medical treatment; and

129.3. a sample of the document for registration of observation data.

130. A submitter shall cover the expenditure that is related to the examination of the submission for a non-interventional trial in accordance with the price list of public paid services of the State Agency of Medicines.

131. A non-interventional trial shall be commenced, if the Ethics Committee has provided a favourable opinion and the State Agency of Medicines, within 30 days after registration of the submission, has not informed the submitter regarding the reasons, due to which the non-interventional trial may not be commenced.

132. A physician shall notify the State Agency of Medicines regarding adverse reactions caused by the medicinal product, which were detected during the non-interventional trial, in accordance with the regulatory enactments regarding the supervision of adverse reactions caused by the use of medicinal products.

133. The physician or the responsible person referred to in Paragraph 129 of this Regulation shall, within 90 days after completion of observations, notify in writing the State Agency of Medicines of the completion of observations, providing the summary regarding the number of patients involved in the observations and the detected adverse reactions caused by the medicinal product.

134. The State Agency of Medicines shall supervise and the Health Inspectorate shall verify the compliance of the non-interventional trials with this Regulation according to the competence thereof.

135. Persons involved in non-interventional trials have the duty not to disclose the personal and clinical data of the patients, except the cases when the relevant data are requested by the institutions, which have the right to get acquainted with the data regarding a patient in accordance with the Medical Treatment Law.

XVII. Closing Provisions

136. Cabinet Regulation No. 172 of 28 February 2006, Regulations Regarding the Conduct of Clinical Trials and Non-interventional Trials, the Procedures for the Labelling of Investigational Medicinal Products and the Procedures for Inspection of Conformity with the Requirements of Good Clinical Practice, (Latvijas Vēstnesis, 2006, No. 45; 2008, No. 10) is repealed.

137. This Regulation shall come into force on 1 April 2010.

Informative Reference to European Union Directives

This Regulation contains legal norms arising from:

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

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 authorisation of the manufacturing or importation of such products.

Prime Minister V. Dombrovskis

Minister for the Interior
Acting for the Minister for Health L. Mūrniece

 

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Translation © 2010 Valsts valodas centrs (State Language Centre)