Decree of the Ministry of Health and the Ministry of Agriculture No. 230 / 1999 Coll.
Decree of the Ministry of Health and the Ministry of Agriculture, which provides for good clinical practice and closer conditions for clinical evaluation of pharmaceuticals
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Effective from 14.10.1999
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14.10.1999
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230
DECLARATION
Ministry of Health and Ministry of Agriculture
of 28 September 1999
laying down good clinical practice and detailed conditions for the clinical trial of medicinal products
The Ministry of Health and the Ministry of Agriculture, pursuant to § 34 (1), § 39 (1) and § 75 (2) (b) of Act No. 79 / 1997 Coll., on Medicines, and on amendments and additions to certain related laws, hereinafter referred to as "the Act":
Preliminary provisions
(1) For the purposes of this decree:
(a) the commencement of the clinical trial of medicinal products for human use at the moment when the first assessmentsubject (1) or his legal representative signs an informed consent to participate in the clinical trial;
(b) commencing the clinical trial of veterinary medicinal products at the moment when the clinical trial was authorised by the Institute for State Control of Veterinary Bioprafts and Medicines;
(c) the end of the clinical trial of the medicinal product when the last action provided for in the Protocol is carried out in relation to the subjects of the trial; However, follow-up of the evaluation body shall not be considered as such,
(d) the investigational medicinal products of such active substances, medicinal products or products obtained from the technological processing of excipients (placebo) which are evaluated or used as comparators in clinical trials; medicinal products may be already authorised,
(e) a set of information for the examiner's document summarising all non-clinical and clinical data on investigational medicinal products relevant to the clinical trial;
(f) residues of all active substances or their metabolites remaining in meat or other animal products to which the evaluated veterinary medicinal product has been administered.
(2) If radiopharmaceuticals are involved, all clinical trials shall be conducted in accordance with specific legislation.2)
CLINICAL EVALUATION OF HUMANS
Composition of the Ethics Commission
(1) The Ethics Committee is an independent committee. 3) Any costs associated with the activities of the Ethics Commission shall be borne by its founder. At least one of the members of the Ethics Committee must be a person without a medical education and at least one of the members of the Ethics Committee must be a person who is not in employment or in similar employment relationship to the medical institution in which the proposed clinical trial will take place. The participation of that person in the meetings of the Ethics Committee shall be regarded as an obstacle to work in the general interest under the special legislature.4)
(2) Only the person who agrees may be a member of the Ethics Committee
(a) with its membership of the Ethics Committee and with a delay in making any comments on requests for consent to carry out a clinical trial for which it has a personal interest, as well as carrying out expert supervision of such a clinical trial, and immediately notifying the emergence of a personal interest in the clinical trial under consideration to the Ethics Commission; the Ethics Committee, in such a case, looks upon the notifier as if he was not a member of the Ethics Committee in relation to this clinical trial,
(b) with the publication of its membership of the Ethics Commission and other facts arising from the activities and membership of the Ethics Commission,
(c) maintaining confidentiality of information and facts which they learn in connection with their membership of the Ethics Commission.
Supervision of the course of clinical trial
The Ethics Committee shall supervise the course of the clinical trial, in particular by examining at least once a year the conduct of the clinical trial for which it has given its consent.
Lessons and informed consent of the evaluation body
(1) The details of the training of the evaluation body and the written informed consent are set out in Annex 2.
(2) The evaluation body or its legal representative shall receive a copy of the signed and dated informed consent as well as a copy of the written information on the clinical trial for the subjects of the evaluation.
Records and reports
(1) The documents referred to in Section I of Annex 1 shall be available before the start of the clinical trial at the medical establishment where the clinical trial is conducted. This Annex also sets out in Sections II and III the documentation to be kept during the clinical trial. These documents must be available unless otherwise specified in the authorisation for clinical trial.
(2) Any amendment or correction to the records of the evaluation bodies shall be indicated by the date, the signature of the person who made the change and, where appropriate, by an explanation; the change or correction shall be added to the original entry. Changes or repairs shall be carried out by the examiner or contracting entity of the authorised person in accordance with the written working procedures of the contracting authority; such modification or repair is confirmed by the signature of the examiner.
(3) The clinical evaluation records shall be accessible to the contracting authorities, the members of the Ethics Commission and the delegates of the supervisory authorities.
(4) The investigator shall ensure that the documentation set out in Annex 1 is preserved after completion of the clinical trial for a period laid down by law.
(5) The progress report (5) contains the data in Annex 6.
Notification of serious unexpected events
The notification to the State Institute for Drug Control, the relevant Ethics Commission and the contracting entity in accordance with the relevant provision of the Act (6) contains an indication of the place of evaluation, the name or name of the sponsor, the name of the clinical trial and the protocol number, patient identification, a description of the reaction, the name of the drug causing the serious unexpected event, including the dose administered and the route of administration.
Discontinuation of clinical trial
(1) If the clinical trial is interrupted, (7) the investigator shall immediately inform the subjects and ensure that they are treated and monitored.
(2) If the clinical trial is interrupted
(a) the investigator, without prior consent of the contracting authority, the investigator shall immediately inform the relevant health care institution, the contracting authority and the relevant ethics committee; the contracting authority and the Ethics Commission provide a detailed written explanation,
(b) the contracting authority or the State Institute for Drug Control, the investigator shall immediately inform the relevant health care establishment and the relevant Ethics Commission, which shall provide a detailed written explanation.
(1) The contracting authority shall ensure the establishment and maintenance of quality assurance and management systems and the use of written standard working procedures ensuring that the clinical evaluation, including the conduct of laboratory tests related to it, is carried out and the data are obtained, documented, processed, evaluated and reported in accordance with the Protocol, the principles of good clinical practice and legislation, 8) in order to ensure their credibility and accuracy.
(2) The clinical trial protocol, the choice of dosage form, dosage and duration and route of administration of the investigational medicinal product should be supported by sufficient data on safety and efficacy from non-clinical trials or clinical trials.
Application for authorisation and notification of a clinical trial to the State Institute for Drug Control
(1) The notification of a clinical trial or the application for authorisation of a clinical trial shall be submitted by the contracting entity or by the authorised person to the State Institute for Drug Control in duplicate. Where a declaration or application is submitted by a person authorised by the contracting authority, it shall submit an officially certified mandate with each notification or application. The individual parts of the documentation shall be presented separately, with continuously numbered pages, bearing the contents.
(2) The following documentation shall be submitted in duplicate with the application or notification of the clinical trial:
(a) the clinical trial protocol and any additions thereto containing the particulars listed in Annex 3;
(b) written information to the investigator, either in the form of a set of information for the examiner containing the information provided for in Annex 4 or in the form of a summary of product characteristics, 9)
(c) written informed consent of the subject or his legal representative in the Czech language with any additions;
(d) written information addressed to the bodies of the evaluation, including the instruction of the subject or his legal representative in the Czech language;
(e) the records of the subjects of the evaluation;
(f) whether the clinical trial has already been given an unfavourable opinion by an ethics commission or a foreign supervisory authority;
(g) pharmaceutical data on investigational medicinal products as set out in Annex 5.
If clinical trials are not designed to obtain evidence for the marketing authorisation or development of a medicinal product, the submission of a complete dossier is not required.
(3) At the request of the State Institute for Drug Control, the sponsor shall provide the additional supporting documents necessary for the assessment of the clinical trial. The State Institute for Drug Control may notify the various parts of the required documentation as referred to in paragraph 2, the procedure characterising the different types of clinical trial and the relevant requirements and supporting documents by publication in its information medium. 10)
Clinical trial conduct
(1) In the course of a clinical trial, the contracting authority shall continuously evaluate the clinical trial procedure, the safety of the investigational medicinal product and, where appropriate, the critical efficacy parameters and, on the basis of the findings, shall take appropriate measures, including changes in or termination of the clinical trial conditions.
(2) The contracting authority shall use the unique identifier of the assessment bodies to identify all the data monitored by each evaluation body.
(3) Where data or observations obtained during a clinical trial are further processed, comparison of original data and observations with processed data shall be possible.
Other information about the drug and clinical trial
The clinical trial sponsor shall inform the State Institute for Drug Control in writing without undue delay:
(a) the change of registered office or address;
(b) new knowledge of the investigational medicinal product;
(c) measures by authorities of foreign States or Ethics Commissions which relate to the clinical trial concerned and may affect the safety of the subjects of the trial;
(d) interruption of the clinical trial in the Czech Republic; in this case, it shall provide information within 15 days at the latest;
(e) stopping drug development.
Information on termination of clinical trial and summary report
(1) Information on the termination of the clinical trial is submitted by the sponsor to the State Institute for Drug Control within 90 days of the end of the clinical trial in the Czech Republic.
(2) Information on the termination of the clinical trial as well as information on the discontinuation of the clinical trial shall include the data set out in Annex 7.
(3) Upon completion of the clinical trial, the contracting authority shall draw up a summary report without delay setting out the conclusions of the clinical trial and its interpretation. The summary report shall contain the elements set out in Annex 8.
CLINICAL EVALUATION OF VETERINARY INVESTMENTS
Supervision of the course of clinical trial
The Institute for State Control of Veterinary Bioprafts and Medicines shall supervise the course of the clinical trial for which it has given its consent. The degree of surveillance is dependent on the extent and focus of the clinical trial.
Records and reports
(1) The documentation set out in Annex 9 is kept for the course of the clinical trial.
(2) The documents listed in Annex 9 shall be available at the site prior to commencing the clinical trial.
(3) Any modification or correction in the records of the animals under assessment shall be marked with a date, signature, and, where appropriate, an explanation, the original entry being retained. Amendments or corrections shall be made in accordance with the written working procedures of the contracting authority.
(4) The clinical evaluation records shall be accessible to both the contracting authorities and the Institute for State Control of Veterinary Bioprafts and Medicines.
(5) The investigator shall ensure that the documentation set out in Annex 9 is preserved after completion of the clinical trial for the period laid down by law.
(6) The clinical trial course report contains the data set out in Annex 13.
Notification of serious adverse reactions
The notification of the Institute for State Control of Veterinary Bioprafts and Medicines and the contracting entities shall contain an indication of the place of evaluation, the name or name of the sponsor, the name of the clinical trial and the number of the protocol, the identification of the animal, the description of the reaction, the name of the drug causing the serious adverse event, including the dose administered and the route of administration. The notification of the Institute for State Control of Veterinary Bioprafts and Medicines shall be deemed to be immediate if it is received not later than 15 days after the event has been captured; in the event of an event which has resulted in death or has endangered the animal in life, the information shall be delivered no later than 7 days after the event.
Interruption and early termination of clinical trial
If the clinical trial is interrupted or terminated prematurely, the investigator shall immediately inform the contracting authorities, breeders, the Institute of State Control of Veterinary Bioprafts and Medicines and the relevant district veterinary administration and ensure further treatment and monitoring of animal health.
(1) The contracting authority is responsible for the establishment and maintenance of quality assurance and management systems and for the use of written standard working procedures ensuring that clinical trials, including the conduct of laboratory tests related to it, are carried out and data are collected, documented, processed, evaluated and reported in accordance with the Protocol, the principles of good clinical practice, good laboratory practice and other legislation, 5) in order to ensure their reliability and accuracy.
(2) The clinical trial protocol, the choice of dosage form, duration and route of administration of the investigational medicinal product should be supported by sufficient data on general safety and efficacy from non-clinical trials or clinical trials.
Application for authorisation of a clinical trial
(1) The application for authorisation of a clinical trial shall be submitted by the contracting authority or by the person authorised by it in duplicate by the Institute for State Control of Veterinary Bioprafts and Medicines. Where an application is submitted by a person authorised by the contracting authority, he shall submit with each part an officially certified mandate. Individual parts of the documentation shall be presented separately, with continuously numbered pages and content.
(2) The application shall be submitted in duplicate with the following documentation:
(a) authorisation for the use of experimental animals issued by the competent State authority under specific legislation, 11)
(b) the clinical trial protocol and any additions thereto containing the particulars listed in Annex 10;
(c) written information to the investigator, either in the form of a set of information for the examiner, containing the information set out in Annex 11, or in the form of a summary of product characteristics, 9)
(d) written information for breeders in the Czech language;
(e) the records of the animals under assessment,
(f) information as to whether a dissent opinion has already been given by the foreign supervisory authority on the clinical trial;
(g) pharmaceutical data on investigational medicinal products as set out in Annex 12;
(h) proof of payment of the costs in advance in accordance with the relevant provisions of the law. 12)
(3) Upon request of the Institute for State Control of Veterinary Bioprafts and Medicines, the contracting authority shall provide the additional supporting documents necessary for the assessment of the clinical trial concerned. The Institute for the State Control of Veterinary Bioprafts and Drugs may notify the various parts of the required documentation referred to in paragraph 2, the procedure laid down for each type of clinical trial and the relevant requirements and supporting documents by publication in its information medium. 13)
Clinical trial conduct
(1) In the course of a clinical trial, the contracting authority shall continuously evaluate the clinical trial procedure, the safety of the investigational medicinal product and, where appropriate, the critical efficacy parameters and, on the basis of the findings, shall take appropriate measures, including changes in or termination of the clinical trial conditions.
(2) The contracting authority shall use the unique identifier of the animals to be evaluated to identify all data monitored by each of the animals to be evaluated.
(3) Where data or observations obtained during a clinical trial are further processed, comparison of original data and observations with processed data shall be possible.
Other information about the drug and clinical trial
The clinical trial sponsor shall immediately inform the Institute for State Control of Veterinary Bioprafts and Drugs in writing of:
(a) the change of registered office or address;
(b) new knowledge of the investigational medicinal product;
(c) measures taken by authorities of foreign States relating to the clinical trial concerned and which may affect the safety of the animals under assessment;
(d) temporary or permanent termination of the clinical trial in the Czech Republic,
(e) stopping drug development.
Information on termination and summary report
(1) Information on the termination of a clinical trial is submitted by the sponsor of the Institute for State Control of Veterinary Bioprafts and Medicines within 60 days of the end of the clinical trial in the Czech Republic.
(2) Information on the termination of the clinical trial contains the data set out in Annex 14.
(3) Upon completion of a clinical trial, the contracting authority shall draw up a summary report without delay setting out the conclusions of the clinical trial and its interpretation. The summary report shall contain the elements set out in Annex 15.
Clinical evaluation of immunobiological products
The provisions of Part Three shall apply mutatis mutandis to the clinical evaluation of veterinary immunological products. Immunobiological products shall meet specific requirements concerning analytical, safety and efficacy tests. The tests shall be indicated so that they can be reproduced. In the case of tests referred to in pharmacopoeia 14, the description may be replaced by an appropriate reference. Where the proposals for quality, safety and efficacy tests deviate from the pharmacopoeia procedures, those derogations should be duly justified by the contracting authority.
Qualitative and quantitative details of ingredients
In the clinical trial, the contracting authority verifies qualitative details and expresses itself on
(a) the active ingredients of the immunobiological product;
(b) adjuvants,
(c) vehicles, preservatives, stabilisers, emulsifiers, dyes, aromatic substances, markers, etc., if they are contained in an immunobiological preparation.
In order to provide quantitative details of "active 'components, the contracting authority shall verify and express:
(a) the number of organisms in the immunobiological preparation;
(b) the specific protein content;
(c) the number of international units (IU) or units of biological activity per dose or volume;
(d) meat or volume of adjuvants or vehicles,
(e) the effectiveness of each preservative system;
(f) biological activity defined by an international unit.
Production and control of source materials
The contracting authority shall ensure that the source materials listed in the pharmacopoeia are applied to all substances in the immunobiological product. For non-pharmacopoeia material, the text of the set of requirements shall be the responsibility of the contracting authority.
The contracting authority shall ensure that:
(a) the production of vaccines is based on the stucco system and on the creation of cell banks;
(b) the origin, health and immunological condition of the producing animals are indicated for serum;
(c) the origin and history of the source materials are documented. If this material has been obtained by genetic engineering, all steps, including a proof of genetic stability, are indicated,
(d) stucco materials including cell banks and raw serum for antiserum production are tested for identity and foreign agents;
(e) cells of cell banks have retained unchanged properties,
(f) live attenuated vaccines are stable.
The contracting authority shall ensure, for control tests during manufacture:
(a) conformity of the manufacturing process and the final immunobiological product;
(b) testing for inactivation or detoxification in inactivated or detoxified vaccines or immediately after the inactivation or detoxification process for each production cycle.
The contracting authority shall ensure that in the control tests of the final immunobiological product:
(a) its general characteristics and, for example, physical and chemical characteristics are indicated;
(b) identification and analysis of active ingredients is carried out;
(c) identification and testing of essential parts of vehicle is carried out;
(d) safety tests are carried out on one of the most sensitive target species, the recommended route of application which creates the greatest risk;
(e) tests for sterility and purity shall be carried out to demonstrate the absence of contamination;
(f) the inactivation test is carried out on the final packaging;
(g) each batch of lyophilised immunobiological product is tested for residual moisture,
(h) compliance with consecutive batches is demonstrated.
The contracting authority shall examine the stability test and demonstrate:
(a) the period of application considered under the proposed conditions,
(b) for reconstituted immunobiological products, the shelf life after reconstitution;
(c) conducting studies in at least 3 batches.
Safety testing
The contracting authority shall ensure from the general test requirements:
(a) the target species;
(b) the dose recommended for use and containing a maximum titre or efficacy,
(c) a sample taken from the lot prepared in accordance with the procedure described.
The contracting authority shall verify in laboratory tests:
(a) the safety of administration of a single dose. The dose must be administered by each recommended route, each species and category for which it is intended, including animals of the lowest age category for application. The observation time of total and local reactions is at least 14 days after application,
(b) the safety of one administration of an excessive dose. This excess dose containing 10 doses of live vaccine or 2 doses of inactivated immunobiological product must be administered by each recommended route of administration, the most sensitive category of target animal. The observation time of total and local reactions is at least 14 days after application,
(c) the safety of repeated administration of a single dose. Application by the recommended route must be made to the most sensitive category of the target species. The observation period shall be at least 14 days after the last application;
(d) reproduction after administration of the recommended dose, for each of the recommended routes of application, in particular for materials with a potential risk factor (effects on offspring, teratogenic effects, etc.),
(e) immunological functions where the immunobiological product may adversely affect the immune response,
(f) live vaccines
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Regulation Information
| Citation | Decree of the Ministry of Health and the Ministry of Agriculture No. 230 / 1999 Coll., laying down good clinical practice and detailed conditions for clinical evaluation of pharmaceuticals |
|---|---|
| Regulation Type | Order |
| Author | - |
| Collection | Code of Laws |
| Date of Promulgation | 14.10.1999 |
|---|---|
| Effective from | 14.10.1999 |
| Effective until | - |
| Status | Valid |
The regulation text is for informational purposes only.
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