Informative Notice
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Clinical testing of medicinal products
Before a medicinal product is placed on the market, it must be analysed, non-clinically pharmacologically and toxicologically and clinically tested in order to assess its quality, safety and effectiveness. A medicinal product is also tested analytically, non-clinically pharmacologically and toxicologically and clinically when it has already obtained a permit for placement on the market or when it is already placed on the market if the test is in order to acquire additional data about the product or because of quality control of the product.
Clinical testing of a medicinal product for human use is research on healthy individuals and patients for the purpose of discovering or confirming the clinical and pharmacological effects of the tested medicinal product, discover undesired effects of the product or examine the absorption, distribution, metabolism and excretion of the product in order to prove its safety or effectiveness in human use.
Clinical testing of medicinal products for the use in veterinary medicine is an organised examination of the effects of medicinal products on the animal organism for the purpose of discovering or confirming the clinical and pharmacological effects of the product for the use in veterinary medicine, to discover the undesired effects of the product or examine the absorption, distribution, metabolism and excretion of the tested product and its residues in order to prove its safety or effectiveness in targeted animal species.
A non-routinely prepared medicinal product for advanced therapy must not be clinically tested.
Clinical testing of medicinal products is carried out by the health-care service or veterinary service providers which dispose of staff authorised to prescribe medicinal products in accordance with the regulations and principles of good clinical practice.
The manner and procedure of analytical and pharmacological and toxicological testing of medicinal products for human use and the content of documentation on their quality, safety and effectiveness are determine in the Annex to Commission Directive 2003/63/EC of 25 June 2003 amending directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (L No 159 of 27 June 2003, page 46) and in the Annex to Directive 2009/120/EC.
Detailed guidelines and the content of the documentation referred to in the previous paragraph are published in the guidelines adopted by the European Commission: The Rules Governing Medicinal Products in the European Union, Volume 3 – Medicinal Products for Human Use: Guidelines.
Applies for SKD:
- Hospital activities P86.100
Conditions
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Medicinal products are clinically tested by providers of medical or veterinary activities.
Registration and an appropriate status form are required in order to pursue the activity.
Evidence
Extract from the Business Register (AJPES) the competent authority acquires it ex officio
Legal basis
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Clinical trials of medicinal products must comply with modern scientific achievements and principles and the guidelines of good clinical practice.
The principles of clinical trials of medicinal products include:
- a clinical trial must be scientifically justified and conducted according to ethical principles as per the Declaration of Helsinki of the World Health Organisation on biomedical research involving human subjects;
- the rights, safety and well-being of the trial subject take priority over the interests of science and society;
- a clinical trial may only be implemented if the expected benefits in the treatment of the trial subject or patients were compared with the foreseeable risk and the established relationship was recognised as beneficial;
- all data on clinical trials are recorded, processed and stored in a way that ensures their credibility, whereby the confidentiality of data of trial subjects remains guaranteed;
- all available non-clinical and clinical data on the medicinal product in a clinical trial must be ensured;
- all persons executing the clinical trial of a medicinal product must have suitable education, experience and professional qualifications.
Legal basis
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The examiner insures their liability for possible damage which may be caused to trial subjects.
Legal basis
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The examiner of a medicinal product consents to the appointment of the principal researcher and other researchers and to the use of premises, staff and equipment during the implementation of a clinical trial of the medicinal product.
Legal basis
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The examiner provides the principal researcher with the conditions for implementing a clinical trial of a medicinal product.
Legal basis
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The examiner of the medicinal product ensures the undisturbed work of the assessor, monitor and pharmaceutical supervisor in a clinical trial of a medicinal product.
Legal basis
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Clinical trials may also be conducted by business entities employing staff authorised to prescribe medicinal products in accordance with the regulations and principles of good clinical practice.
Legal basis
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The duties of the lead investigator in the clinical trial procedure are:
- to select a sufficient number of tested persons in accordance with inclusive and exclusive criteria of the clinical trial protocol;
- to verbally or in written form explain to test persons in an understandable way the basic data on the medicinal product in the clinical trial, the purpose and progress of the clinical trial, hazards and benefits for participants in the clinical trial, on the rights and responsibilities of tested persons;
- to explain to the tested persons the method of selection and an approximate number of participating tested persons in the clinical trial and other possible forms of treatment, their advantages or deficiencies;
- to acquire from the tested persons or their legal representatives a written statement prior to the start of the clinical trial declaring that they understand the data on the clinical trial and that they participate voluntarily;
- to guarantee the tested person appropriate treatment during the clinical trial and after it, if the treatment continues or is the consequence of complications during the clinical trial;
- to guarantee the tested person that their personal data is available only to persons authorised for the clinical trial and that they will be notified on any important information in connection with the clinical trial;
- to ensure accuracy, completion, legibility and the appropriate timing of data in connection with the clinical trial;
- to provide for the confidentiality of the secret code of the tested person and the medicinal product in the clinical trial;
- they can only disclose the secret code according to their judgement in emergency cases;
- to ensure appropriate storage, registration, issue, use of samples and the storage of unused samples of medicinal products for clinical trials and for their destruction in agreement with the sponsor;
- to notify the sponsor without delay on any serious adverse events in the clinical trial, except on those for which the testing protocol or the investigator brochure do not determine immediate reporting.
Such immediate reports shall be followed by detailed, written reports. To notify the sponsor in due time determined in the testing protocol on any adverse events and laboratory results which the testing protocol determines as critical in terms of the safety assessment.
In the case of death of tested persons, send the sponsor all additionally required data; in case of immediate danger for the tested person, terminate the clinical trial and notify the sponsor and, if necessary, submit an incentive for changing the testing protocol. In this case, the researcher is obliged to notify all tested persons and guarantee them appropriate therapy and monitoring of their health. The lead investigator in a clinical trial must have appropriate education and experience.
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The researcher in clinical trials of medicinal products must have appropriate education and a licence.
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The trial subject has the right to physical and mental integrity, privacy and the protection of personal data as per the provisions on human rights and freedoms under the Constitution of the Republic of Slovenia and regulations in the field of personal data protection.
The trial subject is entitled to the reimbursement of direct costs incurred relating to their participation in clinical trials of medicinal products.
People from certain population groups (healthy women in a fertile period, particularly pregnant women and nursing mothers, older people, seriously ill people) and people who are not able to give their free and informed consent do not usually participate in clinical trials of medicinal products if these products can be tested with less risk and on persons able to give such consent.
If women in a fertile period are included in clinical trials of medicinal products, they must be enabled a suitable form of contraception and their pregnancy must be excluded before the implementation of the trial. Individual age groups are included only in special clinical trials of medicinal products.
Clinical trials on minors may only be implemented if:
- their parents or a legal representative agree to the clinical trial, which expresses the minor’s alleged will;
- the minor is acquainted with the clinical trial and its risks and benefits as per their ability to understand;
- the wishes of the minor are observed when they are able to express their opinion that they refuse to participate in the clinical trial of a medicinal product and may withdraw from the clinical trial of the medicinal product at any time;
- a minor receives no reward or financial support for their participation in the clinical trial of a medicinal product except compensation for direct costs (transport costs and similar);
- a clinical trial of a medicinal product has a direct benefit for the minor and it is necessary for the assessment of data obtained through clinical trials of medicinal products on people able to voluntarily consent. Furthermore, a clinical trial of a medicinal product must refer to the disease of the minor or a clinical trial of a medicinal product which can only be conducted on minors;
- a clinical trial of a medicinal product is prepared in a way that, as far as possible, reduces pain, fear or any other foreseeable risk relating to the disease;
- the National Medical Ethics Committee supports the protocol of a trial after consulting an expert in the field of paediatrics;
- the interests of the patient must prevail over the interests of science and society.
A clinical trial of a medicinal product on adults who are not able to understand information may, while observing all requirements which apply to trial subjects able to voluntarily consent, be implemented only if:
- the voluntary consent of their legal representative is obtained which expresses the alleged will of the trial subject;
- if the trial subject as per their ability to understand is acquainted with the clinical trial of the product and its risks and benefits;
- the wish of the trial subject is observed when they are able to express their opinion that they refuse to participate in the clinical trial of a product and may withdraw from the clinical trial of the product at any time;
- the trial subject receives no reward or financial support for their participation in the clinical trial of a product except compensation for direct costs (transport costs and similar);
- a clinical trial of a product is necessary for the assessment of data obtained through clinical trials of medicinal products on people able to voluntarily consent and refer directly to the disease of the trial subject;
- a clinical trial of a medicinal product is prepared in a way that, as far as possible, reduces pain, fear or any other foreseeable risk relating to the disease;
- the National Medical Ethics Committee supports the protocol of a trial after consulting an expert in the field of paediatrics;
- the interests of the patient must prevail over the interests of science and society;
- it is expected that the medicinal product in the clinical trial will be beneficial for the trial subject, so that the benefit will outweigh the risk or that no risk will occur at all.
Legal basis
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The approval for clinical trials of a medicinal product must be acquired when testing will be implemented with:
- medicinal products for genetic treatment;
- with medicinal products for treatment with somatic and xenogeneic cells;
- with medicinal products that contain genetically modified organisms.
The approval for clinical trials is not required for non-intervention clinical trials.
The applicant sends the application for the approval of a clinical trial to the competent authority.
The application is prepared based on the recommendations of the European Commission; EudraLex - Volume 10 Clinical trials guidelines.
The application for approval or notification must contain:
- an accompanying letter; when the application is lodged in the name of the sponsor by a proxy, they have to submit the authorisation letter of the sponsor;
- complete and signed uniform European form for the approval or notification of a clinical trial for a medicinal product;
- the trial protocol signed by the sponsor and main researcher or researcher coordinator in the case of multi centric clinical trials;
- brochure for the researcher;
- investigational medical product dossier (IMPD):
- the entire investigational medical product dossier is submitted by the applicant when the data on the medicinal product in clinical trial is sent to the authority responsible for medicinal products for the first time;
- a short version of the dossier is submitted by the applicant when the medicinal product in clinical trial has obtained the authorisation for trading in any EU Member State or the authority responsible for medicinal products acquired data on the medicinal product from another clinical trial;
- summary of main features of the medicinal product, when the clinical trial does not exceed the frames of the summary;
- the summary of the clinical trial protocol in five copies in Slovenian;
- the list of countries where the sponsor has provided an application for the same clinical trial;
- the opinion of the National Medical Ethics Committee; when the approval or notification procedure for the clinical trial is conducted simultaneously, the applicant must submit the opinion of the National Medical Ethics Committee immediately when it is available;
- the authorisation for manufacturing the medicinal product when the medicinal product in clinical trial has been manufactured in the European Union; the authorisation for import into the European Union and the statement of the responsible person that the manufacture runs in accordance with good manufacturing practice when the medicinal product in clinical trial was manufactured in third world countries;
- a short CV of the main researcher responsible for the clinical trial at an individual trial location;
- evidence on the damage liability insurance of the sponsor in case of potential damage to the tested person which emerges as the consequence of a clinical trial of a medicinal product;
- the form with written approval of the tested person and the text informing the tested person preliminarily on the purpose of the clinical trial and potential health risks (in Slovenian and English);
- completed KLPR-A form with data on the clinical trial which the applicant must submit in electronic form, i.e. Word file;
- he statement of the main researcher on the KLPR-B form that is available on the website of the authority competent for medicinal products;
- the consent of the responsible person of the examiner (director, chief) to the appointment of the main researcher and the use of premises, staff and equipment at the implementation of clinical trial on the KLPR-C form which is available on the website of the authority responsible for medicinal products;
- draft of the label of the medicinal product in clinical trial in Slovenian language;
- other documents in accordance with the recommendations of the European Union;
- evidence on the payment of procedure costs;
- prescribed administrative fee.
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The approval for clinical trials of a medicinal product must be acquired when testing will be implemented with:
- medicinal products for genetic treatment;
- with medicinal products for treatment with somatic and xenogeneic cells;
- with medicinal products that contain genetically modified organisms.
The notification of clinical trials of a medicinal product is required in all other cases that are not indicated in the previous paragraph.
The notification of the clinical trial of a medicinal product is not necessary for non-intervention clinical trials.
The applicant sends the application for the approval of a clinical trial to the competent authority.
The application is prepared based on the recommendations of the European Commission; EudraLex - Volume 10 Clinical trials guidelines.
The application for approval or notification must contain:
- an accompanying letter - when the application is lodged in the name of the sponsor by a proxy, they have to submit the authorisation letter of the sponsor;
- complete and signed uniform European form for the approval or notification of a clinical trial for a medicinal product;
- the trial protocol signed by the sponsor and main researcher or researcher coordinator in the case of multi centric clinical trials;
- brochure for the researcher;
- investigational medical product dossier (IMPD):
- the entire investigational medical product dossier is submitted by the applicant when the data on the medicinal product in clinical trial is sent to the authority responsible for medicinal products for the first time;
- short version of the dossier is submitted by the applicant when the medicinal product in clinical trial has obtained the authorisation for trading in any EU Member State or the authority competent for medicinal products acquired data on the medicinal product from another clinical trial;
- summary of main features of the medicinal product, when the clinical trial does not exceed the frames of the summary;
- the summary of the clinical trial protocol in five copies in Slovenian;
- the list of countries where the sponsor has provided an application for the same clinical trial;
- the opinion of the National Medical Ethics Committee; when the approval or notification procedure for the clinical trial is conducted simultaneously, the applicant must immediately submit the opinion of the National Medical Ethics Committee when it is available;
- the authorisation for manufacturing the medicinal product when the medicinal product in clinical trial has been manufactured in the European Union; the authorisation for import in the European Union and the statement of the responsible person that the manufacture runs in accordance with good manufacturing practice when the medicinal product in clinical trial was manufactured in third world countries;
- a short CV of the main researcher responsible for the clinical trial at an individual trial location;
- evidence on the damage liability insurance of the sponsor in case of potential damage to the tested person which emerges as the consequence of a clinical trial of a medicinal product;
- the form with written approval of the tested person and the text informing the tested person preliminarily on the purpose of the clinical trial and potential health risks (in Slovenian and English);
- completed KLPR-A form with data on the clinical trial which the applicant must submit in electronic form, i.e. Word file;
- the statement of the main researcher on the KLPR-B form that is available on the website of the authority responsible for medicinal products;
- the consent of the responsible person of the examiner (director, chief) to the appointment of the main researcher and the use of premises, staff and equipment at the implementation of the clinical trial on the KLPR-C form which is available on the website of the authority responsible for medicinal products;
- draft of the label of the medicinal product in clinical trial in Slovenian language;
- other documents in accordance with the recommendations of the European Union;
- evidence on the payment of procedure costs;
- prescribed administrative fee.
Fees in connection with the notification and clinical trial approval procedures for children and orphan designation amount to half of the value of an individual fee.
There are no fees in connection to the notification or clinical trial of a medicinal product approval within the compassionate use programme.
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In the case of relevant changes or additions to a clinical trial for a medicinal product, the proposer of a clinical trial must submit an application for the notification of changes.
Relevant changes under the previous paragraph are provided, when they impact the:
- safety and integrity of tested persons,
- scientific value of the clinical trial,
- the implementation of management of the clinical trial,
- the quality and safety of medicinal products in the clinical trial.
The application should be drafted based on the European Commission recommendations; EudraLex - Volume 10 Clinical trials guidelines.
The application must contain:
- an application letter with reasoning behind the change of the clinical trial;
- filled out and signed uniform European form for the notification of the change of clinical trial;
- explanations signed by the main researcher or researcher - coordinator, which must entail: the assessment of the:
- impact of the changes on tested persons who are included in the clinical trial;
- impact of changes on the assessment of results of the clinical trial;
- the benefits and risks, when necessary;
- the opinion of the National Medical Ethics Committee when the change impacts the ethical aspect of the clinical trial; if the procedure for the notification of the relevant change of the clinical trial is implemented simultaneously, the applicant must submit the opinion of the National Medical Ethics Committee immediately when it is available;
- evidence on the payment of procedure costs;
- the prescribed administrative fee.
Fees in connection with the notification and clinical trial approval procedures for children and orphan designation amount to half of the value of an individual fee.
There are no fees in connection to the notification or clinical trial of a medicinal product approval within the compassionate use programme.
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The applicant informs the authority responsible for medicinal products within 90 days after the completed clinical trial of a product that the clinical trial of the medicinal product in the Republic of Slovenia has been concluded. In the case of an early termination of a clinical trial of a medicinal product, the applicant informs the authority responsible for medicinal products within 15 days after the completed clinical trial of the product and provides reasons for the termination.
The notification on the completion of a clinical trial is submitted by the applicant in accordance with the Rules on clinical trials of medicinal products and recommendations of the European Commission, 'Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human use to the competent authorities, notification of substantial amendments and declaration of the end of the trial', as per its respective and valid text.
The notification on the completion of a clinical trial must include:
- a completed and signed uniform European form of the notification on the completion of a clinical trial of a medicinal product;
- report on the course of the clinical trial of a medicinal product in the Republic of Slovenia, and data on the number of trial subjects included and excluded. The report must be signed by the principal researcher or researcher/coordinator.
Legal basis
Competent Authority
Agency for Medicinal Products and Medical Devices of the Republic of Slovenia
Slovenčeva ulica 22
1000 Ljubljana -
One year after the completion of a clinical trial, the applicant must submit a summary report on the clinical trial of a medicinal product to the authority responsible for medicinal products.
Legal basis
Competent Authority
Agency for Medicinal Products and Medical Devices of the Republic of Slovenia
Slovenčeva ulica 22
1000 Ljubljana -
The sponsor is responsible for reporting on serious adverse reactions (SARs) to medicinal products being tested. The sponsor informs thereof the authority responsible for medicinal products.
Informing must be conducted in accordance with the recommendations of the European Commission as per its respective and valid text:
Informing
The sponsor reports on all severe adverse reactions or suspected unexpected serious adverse reactions (SUSARs) which refer to the same medicinal product in different clinical trials of medicinal products and result in death or a threat to life no later than in seven days after becoming aware of the reaction. Additional important information is submitted in the following eight days.
The sponsor reports on other severe adverse reactions or suspected unexpected serious adverse reactions (SUSARs) referring to the same medicinal product in different clinical trials of medicinal products no later than in 15 days after becoming aware of the reaction. Additional important information is submitted as soon as possible.
In the case of a blind clinical trial of a medicinal product, the sponsor usually informs about severe unexpected adverse reactions together with data on the disclosure of a secret label for the product being tested if this is necessary for the safety of trial subjects.
The sponsor reports on all severe unexpected adverse reactions or suspected unexpected serious adverse reactions, while the authority responsible for medicinal products submits these data electronically to the European database, 'EudraVigilance – Clinical Trial Module', in accordance with the recommendations of the European Commission, 'Detailed guidance on the European database of Suspected Unexpected Serious Adverse Reactions', European Commission, Enterprise Directorate – General – Pharmaceuticals, as per its respective and valid text.
Irrespective of the provisions under the preceding paragraph, the sponsor may, exceptionally, following the approval of the authority responsible for medicinal products, report on severe unexpected adverse reactions which occur in the Republic of Slovenia on form CIOMS I.
Periodical reports
The sponsor reports on severe unexpected adverse reactions to a medicinal product being tested also by means of periodical reports, i.e. every six months in the form of a list containing a short report.
Annual safety reports
During the course of a clinical trial of a medicinal product, the sponsor prepares an annual safety report which must be drawn up in compliance with recommendations of the European Commission, 'Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials of medicinal products for human use'.
Legal basis
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The medicinal product in a clinical trial must be marked on the external packaging; if no such packaging exists, then it must be labelled on primary packaging. The label must include data in Slovenian as per the requirements of the recommendations of the European Commission: 'Volume 4 – Good manufacturing practices, Annex 13', European Commission, Enterprise Directorate – General – Pharmaceuticals. When a medicinal product in a clinical trial has already obtained a marketing authorisation and special production or packaging of the medicinal product is not necessary for clinical trials of the product, the original packaging must be additionally furnished with a label containing data in Slovenian as per the requirements of recommendations of the European Commission under the preceding paragraph.
Legal basis
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Essential documents on a clinical trial (Trial Master File) include documents which enable the implementation of a clinical trial of a medicinal product and an assessment of the quality of the trial’s implementation. These documents serve as the basis for the implementation of supervision by the authority responsible for medicinal products and the independent assessor of the sponsor.
The Trial Master File must be stored in a way that enables immediate access at the request of the authority responsible for medicinal products. If the Trial Master File is stored on electronic media, their readability must be ensured for the entire duration of their storage.
The sponsor or the examiner appoint persons responsible for archiving the documentation. Only persons appointed in this way may have access to archived documentation.
The sponsor and the researcher or the examiner must store the Trial Master File for at least five years after the completion of the clinical trial or more if so required.
The medical documentation of trial subjects is kept in accordance with the act governing medical activities.
All transfers of the ownership of data on the clinical trial of the medicinal product must be recorded in the documentation on the clinical trial and implemented in a way that ensures traceability of the ownership and content of the documentation and that preserves its integrity.
Legal basis