APPROVED
Order of Ministry of Health of Ukraine
of 13.02.2006 № 66
PROCEDURE
for Conducting Clinical Trials of Medicinal Products
and Expert Evaluation of Materials of Clinical Trials
1. General
1.1. Procedure for conducting clinical trials of medicinal products and expert evaluation of materials of clinical trials (hereinafter – Procedure) has been developed in accordance with Articles 7 and 8 of the Law of Ukraine "On Medicines" and with consideration of requirements of Directive 2001/20/EC of the European Parliament and European Council, ICH GCP, Helsinki Declaration: ethical principles for medical research involving human subjects (1964).
1.2. Procedure specifies main requirements to conducting clinical trials of medicinal products, which may be conducted on patients (volunteers) along full and shortened programs including bioavailability/bioequivalence studies, as well as multicenter trials.
International standards may be applied while arranging and conducting the clinical trials.
1.3. Procedure shall cover all types of clinical trials of medicinal products except for non-interventional studies and clinical trials of medicinal products which were registered in Ukraine in due order in compliance with their indications and dosages which are conducted without pharmaceutical companies’ participation.
Procedure shall not cover clinical trials of immunological products, human blood and human plasma products, food supplements.
1.4. The State Pharmacological Center MoH Ukraine (hereinafter – the Center) shall be responsible for an expert evaluation of materials of clinical trials of medicinal products.
2. Definition of Terms
The terms used in this Procedure have the following definitions:
2.1. Multi-center clinical trial – the trial of a medicinal product which is conducted according to a standard protocol at more than one health care setting (by more than one investigator).
2.2.Bioavailability – the rate and extent to which an active substance or its active moiety is absorbed from a pharmaceutical form and becomes available at the site of action.
2.3.Bioequivalence – two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutically alternative and if their bioavailability after administration in the same molar dose is similar to a degree that their effects, with respect to both efficacy and safety, will be essentially the same.
2.4.Investigator’s brochure – a condensation of the clinical and pre-clinical data about medicinal product under study which are relevant to its investigation in human beings.
2.5. Manufacturer of medicinal product – a legal entity that performs at least one stage of manufacture of a medicinal product, including packaging.
2.6. Subject (study subject) – a patient (healthy volunteer) who participates in a clinical trial or is a group member, who takes a medicinal product under investigation or a control group member, who takes a comparable medicinal product.
2.7. Investigational medicinal product - a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including products already with a registration certificate but used or assembled (formulated or packaged) in a way different from the registered form, or when used for an unregistered indication, or when used to gain further information about the registered form of the medicinal product.
Investigational medicinal product’s dossier – an information about the quality of any investigational medicinal product including a control product and a placebo as well as data of the clinical trials and an information about previous clinical trials or clinical use of the investigational medicinal product.
2.8. Investigator – a doctor with scientific background and the experience in patient care. The investigator is responsible for the conduct of a clinical trial at a health care setting. If a trial is conducted by a team of individuals at a health care setting, the investigator is the leader responsible for the team and may be called the principal investigator.
2.9. Expert evaluation of materials of clinical trial – averification, an expert evaluation and a specialized assessment of materials of clinical trial of a medicinal product in order to prepare motivated conclusions for taking a decision as to the conduct of a clinical trial, or refusal of its conduct.
2.10. Ethics Committee – an independent body in a region, country or community of countries within health care settings in which clinical trials are conducted and which include medical and scientific professionals and non-medical members, whose responsibility is to protect the rights, safety and well-being of study subjects and to provide public assurance of that protection, through, among other things, expressing an opinion on the trial protocol, assessment of investigators' skills, the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent.
2.11. Legal representatives– parents, adoptive parents, parent tutors, tutors, trustees, representatives of tutorial and custodial authorities.
2.12. Applicant for clinical trial – a natural person or a legal entity (e.g., sponsor, contract research organization), which submits an application for conducting a clinical trial to MoH or its authorized organization. An applicant may submit the application for conducting a clinical trial only if sponsor's power of attorney with clearly defined granted powers is available.
2.13. Clinical study report – results of a clinical study and their analysis in writing.
2.14.Case Report Form (hereinafter - CRF) – a printed, electronic or optical document designed to record all of the trial protocol required information on trial subject.
2.15.Inspection of clinical trial of medicinal product – a procedure of formal verification by the Center of documentation, facilities, equipment and instruments, records, quality assurance arrangements, and any other resources that are deemed by the competent authority to be related to the clinical trial and that may be located at health care setting, sponsor’s or contract research organization’s facilities, or at other establishments which the Center may consider necessary to inspect.
2.16. Informed consent – a decision, which must be in writing, dated and signed, to take part in a clinical trial, taken freely after being duly informed of its nature, significance, implications and risks and appropriately documented, by any person capable of giving consent or, by his or her legal representative; if the person concerned is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases.
2.17. Clinical trial (clinical study) of medicinal product - any investigation in human beings intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of one or more investigational medicinal product(s), and/or to identify any adverse reactions to one or more investigational medicinal product(s) and/or to study absorption, distribution, metabolism and excretion of one or more investigational medicinal product(s) to confirm its (their) safety and/or efficacy.
2.18. Contract research organization – a natural person or a natural entity which according to the contract concluded with the sponsor performs one or more of its functions (powers) in the clinical trial and acts on the basis of the power of attorney with clearly defined granted powers issued by the sponsor.
2.19. Health care setting for conducting clinical trial of medicinal product – a specialized health care setting assigned by MoH Ukraine at the Center’s presentation as such which may conduct clinical trials of a medicinal product.
2.20. Site of trial (hereinafter - clinical trial site) – a site for conducting a clinical trial.
2.21. Monitor – a person assigned by the sponsor or contract research organization who controls the performance of a clinical trial in compliance with the protocol.
2.22. Non-interventional trial - a study where the medicinal products are prescribed in the usual manner in accordance with terms of the registration certificate. The assignment of the patient to a particular therapeutic group is not decided in advance by a trial protocol, but the prescription of the medicine falls within current practice and is clearly separated from the decision to include the patient in the study. No additional diagnostic or monitoring procedures shall be applied to the patients and epidemiological methods shall be used for the analysis of collected data.
2.23. Unexpected Adverse Reaction - an adverse reaction, the nature or severity of which is not consistent with the applicable product information, presented in Investigator's Brochure for a non-approved product or package insert/summary of product characteristics for an approved product).
2.24.Patient (healthy volunteer) - an individual who directly contacts health care setting and offers himself at his own will to participate in a clinical trial of medicinal product.
2.25.Source Documents – outgoing documents, data and records (e.g., case histories, hospital records, laboratory notes, memos, subjects’ diaries or evaluation checklists, medicines dispensing records, recorded data from automated instruments and transcripts of sound track, microfiches, photographic negatives, microfilms or magnetic carriers, x-rays, administrative materials, data of pharmacy, laboratory and instrumental diagnostics department involved in a trial).
2.26. Adverse reaction – within a pre-registration clinical trial of an investigational medicinal product or study of its new indications, particularly if therapeutic doses of the medicinal product are not defined, any negative or unexpected adverse reactions associated with an administration of any dose of the medicinal product shall be considered as adverse reactions of the medicinal product. The term “associated with an administration of any dose of the medicinal product” means the presence of at least minimal possibility of causality between the medicinal product and adverse reaction, i.e. the relationship should not be ruled out.
As regards the registered medicinal products this term means any negative or unexpected reactions associated with the use of medicinal product in normal doses for the prevention, diagnosis or therapy of disease, restoration, correction and modification of physiological function.
2.27. Adverse event - any untoward medical event in a subject which does not necessarily have a causal relationship with the use of medicinal product (changes in laboratory findings; symptom or diseases temporally associated with the use of an investigational medicinal product, etc.).
2.28. Protocol amendment - a written description of changes to or formal clarification of a protocol of a clinical trial.
2.29. Protocol of clinical trial – a document that describes the objectives, methodology, procedures, statistical considerations and organization of a clinical trial, as well as data obtained previously on the investigational medicinal product and the verification of a trial.
2.30. Serious adverse reaction or serious adverse event – any untoward medical occurrence that at any dose of the medicinal product results in death is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect.
2.31. Sponsor – a natural person or a legal entity which takes responsibility for the initiation, management and/or financing of a clinical trial of the medicinal product.
3. General principles of conducting clinical trials
3.1. As specified by a sponsor clinical trials shall be conducted in specialized health care settings (clinical bases/sites) assigned in due order by MoH Ukraine at the Center’s presentation. If a clinical trial is to be conducted in a health care setting not included in the list defined by MoH the clinical trial shall be conducted in such health care setting only in case of the Center’s positive conclusions based on the results of expert evaluations of the materials submitted to the Center as per paragraph 4.1.6, item 4.1 of this Procedure.
3.2. All clinical trials shall be conducted according to ethical principles of the Helsinki Declaration with an assurance of the compliance with relevant requirements to the protection of subjects (patients or healthy volunteers) as stated in Annex 1. A trial should be conducted only if the anticipated benefits justify the risk.
3.3. All clinical trials shall be conducted after obligatory evaluation of trial materials by Ethics Committees which are set up to protect rights, safety and well-being of subjects as well as assure such protection to the public.
3.4. Planning, conduct of and reporting about all phases of clinical trials including bioavailability and bioequivalence studies shall be made in compliance with Good Clinical Practice requirements approved by MoH Ukraine.
3.5. Organization, conduct, data collection, documentation and check-up of the clinical trial results shall be fulfilled according to this Procedure as well as in compliance with standard operating procedures.
3.6. Clinical trial information should be recorded, processed, and stored in a way that allows its accurate reporting, interpretation and verification. The list of clinical trial principal documents which are to be stored at the clinical site/base and in еру sponsor for at least 15 years after the termination of a clinical trial is presented in Annex 2.
3.7. Manufacture, storage and handling of the investigational medicinal product shall be fulfilled in due course in compliance with Good Manufacturing Practice (GMP). Main requirements to labeling of the investigational medicinal product are described in Annex 3. The investigational medicinal product shall be used only in accordance with the approved protocol of a trial.
3.8. Sponsor may grant some or all his powers to a natural person or legal entity (company, institution or organization). Even so the sponsor remains to be responsible for conducting a clinical trial and data obtained from a trial.
3.9. If necessary the Center may conduct an inspection as per Section 8 of this Procedure “Conducting inspection of clinical trial of medicinal products” in accordance with preliminary developed standard operating procedures at any stage of clinical trial or after its termination.
4. Obtaining the Center’s conclusion about conducting clinical trial of medicinal product(s)
4.1.The Center shall issue a conclusion about conducting a clinical trial. In order to obtain the conclusion about conducting a clinical trial of medicinal product the applicant shall submit to the Center the following documents (materials of clinical trial):
4.1.1.Cover letter in optional form (a cover letter should include the following information: identification number and protocol's coded number assigned by the sponsor with a title of clinical trial). Special attention in the text should be paid to all special issues pertinent to application, such as special groups of those to be investigated, first administration of a new active substance to humans, unusual investigational medicinal products, unusual design of clinical trial, provision for indemnity or compensation for participation in a clinical trial etc. Also specified should be the sections of application materials in which the related information could be found.
4.1.2.Application of the due form (Annex 4).
4.1.3.Protocol of clinical trial of the medicinal product with all amendments. The protocol format is given in Annex 5.
4.1.4.Brief description of the protocol content in Ukrainian or in Russian (for international clinical trials).
4.1.5.Individual registration form (except for international clinical trials).
4.1.6.Investigator’s brochure or equivalent document (Annex 6).
4.1.7.Dossier of the investigational medicinal product or simplified dossier of the medicinal product, or a summary of main product characteristics (SmPC) (full dossier shall be submitted, when the investigational product is to be studied in Ukraine for the first time. Full dossier shall contain information about the quality of investigational medicinal product including controls and placebo, as well as data of pre-clinical studies and information of previous clinical trials or clinical use of the investigational medicinal product (if any). The applicant may submit an independent dossier of the investigational medicinal product or cross referencing to investigator’s brochure. The information included in the full dossier of the investigational medicinal product is indicated in Annex 7. The simplified dossier may be submitted if the related information about investigational medicinal product was evaluated by the Center previously as part of the registration dossier or part of the application for obtaining the conclusion about conducting clinical trial of the medicinal product concerned. In the latter case it may be necessary a confirmation in writing, allowing cross-referencing to the data which had been submitted by another applicant. Information about placebo may be submitted as a simplified dossier. Still the relevant chemical, biological and pharmaceutical data should be presented. The sponsor may submit the current version of summary of main product characteristics as a dossier of the investigational medicinal product if the medicinal product has already been registered in Ukraine.
4.1.8.Results of the Center’s previous expert evaluations and/or decisions related to pre-clinical study and clinical trial of the medicinal product (if any).
4.1.9.List of authorized competent bodies of other countries to which applications for this clinical trial had also been submitted, and detailed information about decisions taken (if any).
4.1.10.Copy of conclusion of the Ethics Committee’s (if any).
4.1.11.If the applicant of a clinical trial is not the sponsor, the power of attorney issued by the sponsor with clearly defined granted powers.
4.1.12.Form of a written informed consent and other information in writing which are to be presented to subjects.
4.1.13.List of activities related to the recruitment of subject (e.g., information and advertising materials to be used to involve subjects in a clinical trial, if pertinent).
4.1.14.Brief information about all current trials which are conducted with the use of the given investigational medicinal product (if any).
4.1.15.Expert evaluation of trial (if any).
4.1.16.If the clinical site/base is not on the MoH Ukraine approved list of health care settings which may conduct clinical trials it may be involved in conducting clinical trial on a one-time basis; for this purpose the principal investigator shall submit a letter of application in optional form for inclusion of the clinical base/site in conducting clinical trial, card of certification of the clinical base (Annex 8), signed and dated current versions of curriculum vitae of investigators (written information about investigator signed and dated by the him which allows to evaluate his professional skills and suitability to conduct clinical trial).
4.1.17.If the investigational medicinal product is manufactured outside Ukraine, a confirmation in writing shall be submitted indicating that the work performed at the manufacturing site is in compliance with Good Manufacturing Practice (GMP) or its equivalents.
4.1.18.If the investigational medicinal product is manufactured in Ukraine it is necessary to submit: a copy of manufacturing license (for batch production) or an information about the manufacturing site of the medicinal product submitted for clinical trial as well as a certificate of origin of the medicinal product; information about technological process (manufacture) of the medicinal product and documentation related to the production and quality control of the medicinal product (also attached should be a certificate of methods for analysis of the Center’s Laboratory for Pharmaceutical Analysis). In order to approve/validate analytical methods it is necessary to provide the laboratory with the medicinal product’s samples in quantity sufficient for the analysis, as well as reference substances with batch certificate indicating production date, shelf-life and storage conditions).