Decree No. 139 / 2018 Coll.
Ordinance on Good Clinical Practice and Closer Conditions for Clinical Evaluation of Veterinary Medicinal Products
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Effective from 01.02.2022
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139
DECLARATION
of 26 June 2018
on good clinical practice and closer conditions for the clinical evaluation of veterinary medicinal products
According to Article 114 (4) of Act No. 378 / 2007 Coll., on Medicines and on Amendments to Certain Related Acts (Act on Medicines), as amended by Act No. 66 / 2017 Coll., for the implementation of § 60 (2), (4), (5) and (9), § 61 (2) (a) and (b) (6), § 61 (2) (c) and § 61 (4) (e) of the Law on Medicines:
Subject matter
This decree provides
(a) rules on good veterinary clinical practice;
(b) the content of the protocol for the clinical trial of veterinary medicinal products (hereinafter referred to as the "clinical trial") and its management,
(c) the extent of the data provided in the application for authorisation of a clinical trial;
(d) for the sponsor, the examiner and the person supervising the clinical trial (the monitor), a detailed definition of the scope of the activity in carrying out the clinical trial;
(e) changes relating to the contact details of the contracting entity which may be made and communicated to the Veterinary Institute without delay;
(f) the extent of the data reported in the clinical trial termination report;
(g) the method of labelling veterinary medicinal products; and
(h) evidence of clinical trial to be kept.
Definition of terms
For the purposes of this decree:
(a) studies carried out in a target animal species for the purpose of scientific verification of at least one hypothesis concerning the proposed claim on the efficacy or safety of the evaluated veterinary medicinal product in the target animal species;
(b) the initiation of a clinical trial at the time when the examiner carries out the first act linked to the animal in the context of a clinical trial authorised under Section 60 (3) (a) of the Drug Act;
(c) by interrupting a clinical trial for reasons that allow the clinical trial to continue in accordance with the applicable clinical trial conditions,
(d) termination of clinical trial
1. the moment specified by the clinical trial protocol ("the protocol"),
2. the moment when the sponsor terminates the clinical trial before its conclusion in accordance with point 1; or
3. The date on which the decision to terminate a clinical trial issued by the Veterinary Institute under Section 60 (8) of the Medicines Act became final,
(e) residues of the veterinary medicinal product in food of all residues in the veterinary medicinal product containing pharmacologically active substances or their metabolites remaining in meat or other animal products of animals producing animal products intended for human consumption to which the evaluated veterinary medicinal product has been administered;
(f) the evaluated veterinary medicinal product administered to an animal whose therapeutic, preventive, or diagnostic effect or ability to affect physiological function is the subject of an evaluation in a study;
(g) a controlled product of a registered veterinary medicinal product used in accordance with the conditions of its marketing authorisation, placebo, or, on the basis of detailed justification, another product used in the study to compare its effects with the evaluated veterinary medicinal product;
(h) records of the animals under assessment of documents intended to record all information relating to the animals in the clinical trial;
(i) by a contractual research organisation, a natural or legal person in a contractual relationship with a contracting entity that ensures that one or more of the activities or functions of the contracting entity relating to the clinical trial are carried out;
(j) standard working procedures, in writing, processed methods of carrying out individual operations in the framework of a clinical trial to achieve a uniform implementation of those operations;
(k) a blinding procedure whereby the breeder, or, where appropriate, the examiner or other persons involved in the clinical trial, do not have access to information on the assignment of the evaluated veterinary medicinal product to individual animals under assessment;
(l) a significant change in the protocol which is likely to affect safety or alter the scientific hypothesis of the clinical trial.
Content of the Protocol
The content of the Protocol and the manner in which it is managed are set out in Annex 1 to this Decree.
Scope of data provided in the application for authorisation of a clinical trial
The application for authorisation of a clinical trial shall include, in addition to the data provided for in the Drug Act:
(a) the Protocol and its additions, if any, processed in accordance with the requirements set out in Annex 1 thereto;
(b) written information addressed to the investigator, either in the form of a summary of the veterinary medicinal product characteristics or a set of available information on the veterinary medicinal product, with the information set out in Annex 2 to this Regulation;
(c) written information for breeders containing the information referred to in Annex 3 to this Regulation;
(d) pharmaceutical information on investigational veterinary medicinal products as referred to in Annex 4 to this Regulation;
(e) proof of the insurance policy of the contracting authority and the investigator by which compensation is provided for the breeder of the animal in the clinical trial; and
(f) whether the opinion of the foreign supervisory authority has already been delivered on the clinical trial.
Activities of the contracting authority
(1) The activities of the contracting authority are:
(a) provide scientifically substantiated information on the efficacy and safety of the investigational veterinary medicinal product on the basis of which it can be established unequivocally that there are no relevant reasons for the non-clinical trial;
(b) to guarantee the competence of the designated investigator, to ensure his availability throughout the duration of the clinical trial and to ensure his consent to take responsibility for the clinical trial in accordance with the requirements of this Decree;
(c) appoint a monitor with qualifications appropriate to the subject of the clinical trial;
(d) negotiate the preparation of standard working procedures for carrying out the clinical trial;
(e) prepare, in consultation with the examiner and monitor, a protocol in accordance with the requirements of this Order and sign it with the examiner and monitor; agree with the examiner and monitor further and sign any amendments to the protocol;
(f) ensure, at the same time, that all investigators carry out the clinical trial in accordance with the protocol,
(g) inform the investigator of the chemical, pharmaceutical, toxicological, safety and other relevant information concerning the clinical trial that will become available during the clinical trial and ensure that the Veterinary Institute is informed thereof,
(h) record all adverse reactions observed;
(i) ensure the treatment of animals in clinical trials and of animal products derived therefrom in accordance with legislation (1);
(j) prepare and maintain records of consignments of the investigational and control veterinary medicinal product; in the event of interruption or termination of a clinical trial, ensure that the products, including medicated feed, which have been produced thereof are removed;
(k) keep the clinical trial dossier at least to the extent specified in Annex 5 to this Regulation and protect it from damage or destruction;
(l) ensure the quality and integrity of clinical trial data through a systematic and independent assessment of the activities and documents relating to the clinical trial (hereinafter referred to as "the audit"), which shall determine whether the activities related to the clinical trial have been carried out and whether data have been recorded, analysed and accurately reported in accordance with the protocol, the standard working practices of the sponsor, good veterinary clinical practice and related legislation1);
(m) identify, for the purpose of auditing, persons with qualifications corresponding to the subject of the clinical trial, who have the knowledge necessary to carry out the clinical trial audit and who are independent of the clinical trial carried out; evidence of their qualifications to archive;
(n) ensure that audits are carried out in accordance with written procedures drawn up by the contracting authority, specifying the subject matter of the audit, the manner in which it is carried out, the frequency, form and content of the audit reports, and that the observations and findings of the audit are documented; the audit plan and procedures shall be guided by the importance and purpose of the clinical trial, the number of animals evaluated, the type and complexity of the evaluation, the level of risk to the animals evaluated and the historical knowledge of the clinical trial,
(o) to take immediate corrective action when serious deficiencies are identified, or, where appropriate, to end the clinical trial; inform the Veterinary Institute, the Examiner and the monitor immediately of these measures,
(p) keep the certificates of audits carried out as part of the clinical trial documentation;
(q) keep until the clinical trial has been evaluated sufficient veterinary medicinal products used in the clinical trial;
(r) inform the investigator, monitor and Veterinary Institute of changes to the conditions of the clinical trial, such as changes in study participants and changes in places to conduct the clinical trial; and
(s) to prepare a clinical trial termination report, including a summary report indicating the conclusions of the clinical trial and their evaluation.
(2) On the basis of information from the investigator or monitor, the sponsor shall suspend or terminate the clinical trial if, in the light of new information obtained before or during the initiation of the clinical trial, there has been a change in the ratio of foreseeable risks and difficulties to the expected benefit of the clinical trial, or if the conduct of the clinical trial is seriously impaired. The contracting authority shall immediately inform the Veterinary Institute, the examiner and the monitor of such measures. In the event of interruption or termination of a clinical trial prior to any acts provided for by the protocol, the sponsor shall ensure further treatment and monitoring of the health status of the animals under assessment.
Changes in the contact details of the contracting entity
An amendment shall be deemed to be a change in the contact details of the contracting authority which may be made and to inform the Veterinary Institute without delay.
(a) contact persons of the contracting entity;
(b) telephone or fax numbers for communication with the contracting authority; or
(c) e-mail addresses for communication with the contracting authority.
Investigator activities
The investigator's activities are:
(a) submit to the sponsor an updated professional CV, where appropriate, a statement of conflicts of interest, a declaration of confidential treatment of information and other personal data necessary for the clinical trial to take place in accordance with its protocol;
(b) ensure that the clinical trial is conducted in accordance with the Protocol and complies with the requirements of this Decree;
(c) keep signed and dated copies of the protocol in the clinical trial documentation, including any additions; any amendment to the Protocol prepared by the contracting authority or by the examiner shall be signed by them, indicating the date and specifying exactly what has been changed, including the justification;
(d) notify the contracting authority without delay of any derogations from the Protocol;
(e) to provide sufficiently qualified persons working at a clinical trial or caring for animals and to provide them with materials and information received from the contracting authority;
(f) ensure, during the clinical trial, the use of adequate and well-maintained equipment and apparatus and compliance with standard working procedures;
(g) ensure that animals are included in the clinical trial from each animal breeder before they are included in the clinical trial, on the basis of information relating to participation in the clinical trial, and inform the breeder without delay of any interruption or termination of the clinical trial,
(h) supervise housing, feeding and care of animals at the clinical trial site and inform breeders of animals housed outside their permanent housing;
(i) document all procedures and procedures, animal health changes and significant changes to the environment caused by, or the consequences of, clinical evaluation;
(j) to ensure the requirements of the Protocol on the use of animal products derived from animals producing animal products intended for human consumption to which veterinary medicinal products have been evaluated or controlled and to comply with the Protocol on the proper treatment of animals included in the clinical trial;
(k) record all adverse events detected and notify them without delay to the Veterinary Institute and the contracting authority; in the notification, indicate the clinical trial site, the name or name or, where applicable, the name and surname of the contracting entity, the name of the clinical trial and the number of the protocol, the identification of the animal and the description of the reaction, the name of the investigational and control veterinary medicinal product including the dose and the method of administration,
(l) ensure that blindness is infringed only in accordance with the Protocol and with the consent of the contracting authority;
(m) in the case of blindness, ensure the rapid identification of veterinary medicinal products;
(n) ensure the reception, storage, distribution and any other handling of the veterinary medicinal product evaluated and controlled and keep records of the veterinary medicinal product, including any remaining stocks;
(o) ensure the administration of investigational and control veterinary medicinal products to animals only in accordance with the Protocol;
(p) compare, upon completion of the clinical trial, the records of intake, use and unused quantities of veterinary medicinal products evaluated and controlled and explain the differences found;
(q) ensure appropriate documentation on the removal of the investigational and control veterinary medicinal product, including residues of medicated feed, when the clinical trial is interrupted or terminated;
(r) document unforeseen events which may affect the conduct of the clinical trial and the measures taken;
(s) keep complete records of all contacts with the sponsor, the representatives of the Veterinary Institute and the Central Veterinary Administration as well as other persons related to the organisation, conduct and documentation of the clinical trial;
(t) to safely store, protect against damage or destruction any documentation of the clinical trial, including copies thereof, for the period provided for in Section 61 (4) (e) of the Drug Act;
(u) to provide the sponsor, at his request, with a signed clinical trial dossier or a certified copy thereof, with a copy retained and, where appropriate, to participate in the preparation of the summary report;
(v) allow monitoring and audits to control the quality of clinical trials and the Veterinary Institute to allow inspections, including inspection of facilities used by investigators and all documentation, including the provision of requested copies to verify compliance with the protocol;
(w) in the event of interruption or termination of a clinical trial prior to any acts provided for in the Protocol, inform the breeders and persons working at the clinical trial referred to in the Protocol;
(x) keep the clinical trial documentation set out in Annex 5 to this Regulation,
(y) indicate any modification or correction in the documentation, records of the animals under assessment, and, where appropriate, the date and signature of the reports, where appropriate, by explanation, the original record being retained;
(z) make documents, records and reports related to the clinical evaluation available to the contracting authority, the Veterinary Institute, the monitor and the audited persons;
(aa) prepare a report on the course of the clinical trial containing the information set out in Annex 6 to this Regulation; and
(bb) keep records of analyses and characteristics of samples of individual batches of veterinary medicinal products used in the clinical trial together with documentation of the clinical trial.
Monitoring activities
Monitor activities are
(a) to provide an opinion to the contracting authority on the determination of the examiner;
(b) provide the examiner with the necessary information concerning the clinical trial by personal or telephone consultation, or by other means agreed upon by the monitor with the investigator, whenever the circumstances of the clinical trial so require,
(c) verify that investigators and persons working in a clinical trial have sufficient time to carry out a clinical trial, that the clinical trial is adequately equipped with spatial, equipment, equipment and personnel and that the necessary number of animals will be available for the duration of the clinical trial;
(d) verify that persons working in a clinical trial are informed of all relevant information relating to the clinical trial;
(e) verify that the investigator understood the requirements of the clinical trial and assumed responsibility for its implementation;
(f) to work in accordance with the requirements of the contracting authority;
(g) verify that the consent of the breeder has been obtained before the animals are admitted to the clinical trial;
(h) verify that all data are accurately, correctly and completely recorded and illegible, missing or corrected documentation is fully explained;
(i) to verify that the storage, issuing and recording of stocks of the veterinary medicinal product under assessment and control are safe and appropriate and unused and the veterinary medicinal product under review is returned to the contracting authority or removed;
(j) examine the source data and other clinical trial documentation necessary for compliance with the protocol and verify that the information retained by the investigator is complete and accurate;
(k) prepare and maintain full records of all contacts with the investigator, the sponsor and representatives of all other participating organisations; the records contain a summary of the subject-matter in sufficient detail to enable the operations of the investigator and the contracting authority to be carried out; and
(l) confirm compliance with the requirements of this Order by the investigator through signed and dated contact reports and documented activities during the conduct of the clinical trial; submit them at the end of the clinical trial to the contracting authority.
Evaluation of veterinary medicinal products
Veterinary medicinal products used in a clinical trial must, in the context of good veterinary clinical practice:
(a) have an appropriate storage period, temperature and, where appropriate, other storage conditions,
(b) be stable throughout their use;
(c) be in a container which protects them from contamination and degradation during transport and storage; and
(d) be manufactured by manufacturers authorised to manufacture veterinary medicinal products and according to the principles of good manufacturing practice.
Method of labelling of veterinary medicinal products used in clinical trials
Veterinary medicinal products used in a clinical trial shall be labelled in accordance with the protocol and shall be labelled "For use in a clinical trial only 'and" For animal treatment only'.
End of clinical trial report
The clinical trial termination report submitted by the sponsor to the Veterinary Institute shall contain the information set out in Annex 7 to this Regulation.
Efficacy
This Decree shall take effect 6 months after the date of publication of the Commission notice in the Official Journal of the European Union pursuant to Article 82 (3) of Regulation (EU) No 536 / 2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use and repealing Directive 2001 / 20 / EC.
Minister:
Ing. Milek v. r.
Příloha č. 1
Annex No 1 to Decree No 139 / 2018 Coll.
Contents of the Protocol and its management
The Protocol shall contain:
1. Name of study.
2. Identification of the study, which includes the protocol number, the status of the study protocol, whether it is a proposal, final text or addendum, and the date of the protocol version.
3. Information on the sponsor, examiner, monitor and other persons responsible for conducting the study, including their qualifications, professional CVs, addresses and telephone numbers.
4. Identification of the places to carry out the clinical trial, if known at the time of preparation of the protocol.
5. Objective of the study.
6. Justification for the purpose and necessity of the study including any relevant preclinical or clinical data available.
7. A study plan setting out the schedule of the pivotal moments of the study as the starting date, the period during which veterinary medicinal products (assessed, control) are administered, the follow-up period after administration, the withdrawal period, if applicable, and the end date of the study.
8. Organisation of a study involving the overall organisation of a study (e.g. clinical field efficacy study with placebo controls or random block versus positive control arrangements, blinded study), a random selection method including accepted procedures for the division of animals into groups including justification, scope and method of blindness and other techniques to reduce the inobjectivity of the procedures used.
9. Selection and identification of animals, specifying their source, identification number, closer data as species, age, sex, breeding category, weight, physiological status and prognostic factors.
10. Criteria for the inclusion or non-inclusion of the animal in the study and criteria for the removal of the animal after inclusion in the study.
11. Animal treatment and housing in the study, animal spatial conditions, microclimatic conditions (heating, cooling, ventilation), permissible and unacceptable veterinary care and treatment, feeding and drinking methods including feed preparation and storage, supplies and availability and water quality.
12. Feed for animals indicating the nutritional need for the animals to be monitored and the preparation of feed according to these requirements, its composition (feed, mineral and vitamin supplements, other additives) with the calculation of the nutritional value for all feed used in the study, the procedures for sampling of feed and subsequent analyses, with the determination of the criteria for determining whether the feed complies with the requirements, feed programme and records of the quantity of feed submitted and rejected.
13. The investigational and control veterinary medicinal product with its precise identification in order to clearly identify its composition, indicating the instructions for handling it, the specification of the packaging and the storage conditions. If the veterinary medicinal product is administered in feed or water, describe the procedure for determining the concentration including the sampling method used and the test methods.
Method of labelling the veterinary medicinal products used in the clinical trial and, if blinded, encoding data.
The assessment veterinary medicinal product shall bear at least the words "For use in clinical trials only 'and" For animal treatment only' and, if not a blinded study, identify the evaluated veterinary medicinal product by the batch number and the shelf life.
Identify the veterinary medicinal product by its name, pharmaceutical form, composition, batch number and expiry date and store it and use it in accordance with the package leaflet.
Description of the method of removal of residues of veterinary medicinal products after completion of the study including residues of medicated feed.
14. Method of administration of the investigational and control veterinary medicinal product, with a justification for the dose used, a description of the dose regimen (route of administration, site of administration, dose and frequency of administration), a specification of objective criteria for the potential use of the accompanying treatment, a description of the measures taken to ensure the safety of those medicinal products, an indication of the measures taken to ensure the administration of these products in accordance with the protocol or their package leaflet.
15. Treatment of animals included in the clinical trial and care of animals excluded from the study according to predetermined criteria. Determination of the conditions for the use of animal products derived from the animals under surveillance.
16. Evaluation of effectiveness, describing the effects to be achieved, how they are to be monitored and recorded, specification of timing and frequency of observation, presentation of analyses and tests including the time and intervals of sampling and storage of samples, the definition of the evaluation system necessary for the objective capture of the target response in the animals to be monitored and for the evaluation of the clinical response and the method of evaluation and calculation of the effect of the evaluated veterinary medicinal product.
17. Statistics with detailed description of the statistical methods used in assessing the effectiveness of the veterinary medicinal product including the test hypothesis, the parameters set, the materiality levels and the statistical model.
18. Records indicating the procedures for recording, processing, handling and storing source data and other required documents.
19. Possible adverse reactions, describing procedures for monitoring animals with sufficient frequency to detect adverse reactions, indicating appropriate measures for their occurrence, including possible blinding violations for appropriate treatment, documentation entry and notification to the contracting authority.
20. Protocol Appendices specifying all standard working procedures used in the study concerning management, monitoring and records, copies of all forms and records used in the study, and including all relevant additions.
21. Amendments to the Protocol, providing instructions for the preparation of amendments and records of derogations from the Protocol.
22. Links with citations of relevant literature.
Method of running the Protocol:
1. The study identification is placed on the front page of the protocol.
2. The protocol is provided with the content and the pages of the protocol are numbered.
3. If some of the information given in the protocol is contained in other clinical trial documents, a reference to the relevant document shall be made in the protocol.
4. The contracting authority, the examiner and the monitor, which date and confirm the final version of the protocol, shall co-participate.
5. All amendments to the protocol are numbered and dated.
Příloha č. 2
Annex No 2 to Decree No 139 / 2018 Coll.
Information set for the examiner
The information file for the examiner shall contain:
1. The name of the sponsor and the name of the investigational veterinary medicinal product, the date of issue and, where applicable, the number of the version of the information package for the examiner.
2. The chemical name of the active substances contained in the evaluated veterinary medicinal product and, if any, their international non-proprietary or commercial name, the content of the active substances and the pharmacotherapeutic group.
3. Physical, chemical and pharmaceutical properties and composition, indicating the description of the active substance contained in the evaluated veterinary medicinal product, including its rational and structural chemical formula; the formulation and composition of the excipients and the instructions for the proper storage and handling of the evaluated veterinary medicinal product shall be provided.
4. Non-clinical tests on the results of pharmacodynamic, pharmacokinetic, and toxicological and residue tests, including used assessment methodologies and interpretation of findings in relation to the evaluated veterinary medicinal product and possible adverse effects on the evaluated animal, human health and the environment, including a comparison of the identified effective and non-toxic dose for the proposed dose.
5. Information on the therapeutic potential of the veterinary medicinal product and the hazards associated with its use.
6. Information that the active substance used in the pharmaceutical medicinal product is first treated as an active substance.
7. Basic pharmacological mechanisms by which the evaluated veterinary medicinal product exercises its therapeutic effects, the overall pharmacological evaluation of the active substance, with particular reference to the potential for side effects including the effect of the route of administration, the pharmaceutical form of the product. For a product containing more than one active substance, the potential interactions between components shall be indicated. Data on pharmacokinetics (including metabolism, absorption, protein binding, distribution and elimination), bioavailability with the formulation (absolute or relative), data in different animal groups (e. g. gender, age, organ dysfunction), interactions (e. g. interactions with other medicinal products or the effect of food) shall be provided.
8. Toxicological indicators such as single dose toxicity, repeated dose toxicity, tolerability of the animal species evaluated, effect on reproduction including teratogenic effects, mutagenicity and carcinogenicity, immunotoxicity, microbiological properties of residues, effect on human health and the environment.
9. Residue tests demonstrating the extent and duration of residues of the evaluated veterinary medicinal product or its metabolites in the tissues of the treated animal or in the foodstuffs obtained from that animal. On their basis, real withdrawal periods shall be established. The metabolism and kinetics of residues (pharmacokinetics and depletion) shall be summarised. In addition, analytical methods shall be provided for the detection of residues which have a sensitivity such that they allow for a positive demonstration of a breach of the officially established MRLs.
10. Effects of the evaluated veterinary medicinal product on the animal in the form of all completed clinical trials and any other experience of the use of the evaluated veterinary medicinal product in practice.
11. Information on the safety and dependency of the dose of the evaluated veterinary medicinal product or its metabolites obtained in previous clinical trials in healthy or sick animals and an overview of adverse reactions from all clinical trials, possible risks and adverse reactions that can be expected from previous experience with the evaluated veterinary medicinal product or medicinal products related and data on the occurrence of resistance to organisms. Information on warnings or the need for special supervision when using an investigational veterinary medicinal product.
12. Experience from the use of the investigational veterinary medicinal product in practice in countries where the evaluated veterinary medicinal product is authorised or where the marketing authorisation has been refused or revoked. Summary of information obtained from practical use (including pharmaceutical form, dosage, route of administration and adverse reactions used).
13. Overall assessment of non-clinical and clinical data on the evaluated veterinary medicinal product from various sources and interpretation of available data, including consequences for future clinical trials. Evaluation of published reports on related medicinal products, which will enable the adverse effects of the evaluated veterinary medicinal product to be predicted or other problems in the clinical trial.
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Regulation Information
| Citation | Decree No. 139 / 2018 Coll., on Good Clinical Practice and Closer Conditions of the Clinical Evaluation of Veterinary Medicinal Products |
|---|---|
| Regulation Type | - |
| Author | - |
| Collection | Code of Laws |
| Date of Promulgation | 12.07.2018 |
|---|---|
| Effective from | 01.02.2022 |
| Effective until | - |
| Status | Valid |
The regulation text is for informational purposes only.
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