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					                                                                                          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 – a verification, 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).
4.1.19. Sample labelling of the investigational medicinal product in Ukrainian or Russian
        (additional information may be given in other languages).
4.1.20. Additional information about the investigational medicinal product (as an exception). If
        necessary, submitted should be a certificate of analysis for investigational medicinal
          products; viral safety studies; relevant permissions to conduct studies or for medicinal
          products having specific properties (if any), for example, GMO products,
          radiopharmaceuticals;       TSE       certificate  (TSE      is    Transmissible      Spongiform
          Encephalopathies); a statement of GMP status of the manufacture of an active biological
          substance (certifying a compliance with GMP requirements).
4.1.21. Document certifying health and life insurance of patients (healthy volunteers) as per current
          legislation. If the clinical trials are conducted according to the international contract the
          international insurance rules shall be applied.
4.1.22. Document which defines arrangements for rewards or compensation to subjects for their
          participation in the clinical trial (if envisaged by the clinical trial protocol). Information on
          arrangements for rewarding and compensating for subjects’ participation in the clinical trial
          may be given in the cover letter with reference to the appropriate document which envisages
          this.
4.2. Materials of a clinical trial shall be submitted to the Center in three copies. An application
         shall be submitted as an electronic file (3.5” diskette, Windows, Word 6.0/95 or more
         advanced version).
4.3.     The submitted clinical study materials shall be subject to expert evaluation at the Center
         which includes the following stages:
- initial expert evaluation of materials to verify the compliance of an application and materials to the
set requirements with special reference to completeness and accuracy of juridical arrangement;
- specialized evaluation of materials submitted in order to give a substantiated conclusion about the
possibility to conduct a clinical trial according to the protocol.
4.4. The Center and the applicant shall sign a contract for conducting clinical trial. The expert
         evaluation of clinical trial according to the protocol (without considering the number of
         clinical bases and amendments to the protocol attached to the application) is to be paid for.
4.5. The Center shall perform initial expert evaluation of the submitted materials about clinical
         trial within 10 working days after receipt of the application. Based on results of the initial
         expert evaluation the Center shall respond the applicant in writing.
4.6. In case the conclusions of initial evaluation are positive the materials of clinical trial shall be
         subject to specialized evaluation at the Center.
4.7. In case the conclusions of initial evaluation are negative the Center shall inform the applicant
         in writing that materials of the clinical trial could not be accepted for evaluation indicating
         grounds, or the Center shall request the applicant to provide additional or missing data and/or
         information necessary to ensure compliance of the clinical trial materials with juridical and
         technical requirements.
     The applicant shall finish off the registration dossier in accordance with the Center’s remarks
     within 90 calendar days. The time necessary for finishing-off shall not be included in the time
     period for conducting expert evaluation.
     If the applicant fails to provide the Center with the finished-off materials or a letter with
     substantiated timeframe necessary for their finishing-off within the above period, or if the
     applicant presented additional or missing data and/or information, which do not ensure
     compliance of the clinical trial materials with juridical and technical requirements the clinical
     trials materials shall be withdrawn from consideration. The Center shall inform the applicant
     about the decision taken in writing.
4.8. During specialized assessment of the clinical trial materials aiming at drawing a conclusion
about possibility to conduct the clinical trial, the Center may request the applicant to provide
additional materials. The time necessary for their preparation shall not be included in the timeframe
for conducting specialized assessment.

In case the applicant fails to provide the requested additional materials or a letter with substantiated
timeframe necessary for their preparation within 60 days, the clinical trial materials shall be
withdrawn from consideration. The Center shall inform the applicant about the decision taken in
writing with no cost of expert work being reimbursed to the applicant. Further on, at applicant's
request, the materials shall be submitted in order to obtain the Center’s conclusion about the
conduct of the clinical trial in due course.
4.9. Based on the results of expert evaluation the Center shall prepare a positive conclusion about
     conducting a clinical trial or a reasoned rejection of the conduct of a clinical trial.
4.10. Time for conducting a specialized assessment and issuing a conclusion about conducting the
     clinical trial shall not exceed 60 days after the Center’s positive conclusion based on the results
     of initial expert evaluation.
If the use of medicinal products for gene therapy or medicinal products containing genetically
modified organisms is envisaged in clinical trials the timeframe of specialized assessment may be
90 days; if necessary this term may be extended for another 90 days. In case of therapy with
xenogenic cells the time shall be unlimited.
If the applicant doesn’t agree with the Center’s rejection to conduct clinical trial, he may submit a
notice of appeal to the Center’s Appeal Committee within 30 calendar days of receipt of the
decision. The Applicant shall present to the Center relevant materials with grounds for appeal
within 30 calendar days after the receipt of that decision about rejection to conduct clinical trial.
The Center shall examine the materials presented by the applicant within 60 calendar days after
their receipt in order to take a final decision. The final decision with appropriate grounds in writing
shall be sent to the applicant.

                         5. Obtaining the approval of the Ethics Committee
5.1. Ethics Committee
5.1.1. Clinical trial may be approved by the Ethics Committee which is formed and acts within
health care settings where clinical trials are conducted (local Ethics Committee) or the Central
Ethics Committee assigned by MoH Ukraine.
5.1.2. Ethics Committee shall act in compliance with generally recognized international standards,
the Helsinki Declaration, requirements of good clinical practice, acting legislation of Ukraine,
including this Procedure.
5.1.3. Ethics Committees shall have equal power related to the approval of clinical trial. In the
absence of an operating Ethics Committee within a health care setting or its activity is not in
accordance with requirements in paragraph 5.1.2. of item 5.1 of this Procedure as well as during the
multi-center clinical trials the applicant shall apply to the Central Ethics Committee for an approval
of clinical trial.
5.1.4. If a clinical trial was approved by the Central Ethics Committee in the presence of an
operating local Ethics Committee the applicant shall submit the Central Ethics Committee’s
approval to the local Ethics Committee. The local Ethics Committee shall recognize the Central
Ethics Committee’s approval of a clinical trial.
5.1.5. If one Ethics Committee decides to refuse conducting clinical trial at a certain clinical base
giving reasoned grounds it is prohibited to apply to another Ethics Committee (except for the
Central Ethics Committee) for approval of the same trial at the same clinical base/site.
5.2. Approval of clinical trial by Ethics Committee
5.2.1. In order to obtain the approval of a clinical trial of the medicinal product the applicant shall
submit to the Ethics Committee documents according to paragraphs 4.1.1 – 4.1.4, 4.1.6, 4.1.9,
4.1.11- 4.1.15, 4.1.21, 4.1.22 of item 4.1. In addition, submitted to the Ethics Committee should be
as follows:
    - Copy of the Center’s conclusion about the clinical trial (if any);
    - Current versions of professional curriculum vitae of responsible investigators at each
        clinical base/site.
5.2.2. One copy of the materials about clinical trials shall be submitted to the Ethics Committee.
Also submitted should be an electronic version of an application (diskette 3,5”, Windows 6.0/95 or
more advanced versions).
5.2.3. The Ethics Committee shall examine the submitted materials and approve the clinical trial or
provide a reasoned rejection in conducting a clinical trial.
Also, the Ethics Committee may request the applicant to submit additional materials (information)
needed to take a decision or give proposals related to introduction of changes in the submitted
materials. The time necessary for submission of additional materials shall not be included to the
time period for examination of the clinical trial materials.
The Ethics Committee shall send the applicant and the Center a reasoned conclusion on the decision
taken.
5.2.4. Timeframe for examination and providing a conclusion to the applicant shall not exceed 60
days of the receipt of the clinical trial materials by the Ethics Committee.
If the use of medicinal products for gene therapy or medicinal products containing genetically
modified organisms is envisaged in clinical trials the timeframe of specialized assessment may be
90 days; if necessary this term may be extended for another 90 days. In case of therapy with
xenogenic cells the time shall be unlimited.
If the Ethics Committee requests an additional information or give propositions related to the
introduction of changes in the submitted materials the applicant shall present within 30 days all
necessary materials, introduce changes or send a letter with substantiated timeframe necessary for
their preparation.
In case the applicant fails to provide the necessary information within 30 days the clinical trial
materials shall be withdrawn from consideration. Further on, at applicant’s request, the materials
shall be submitted for expert evaluation in due course again.

                                     6. Conducting a clinical trial
6.1. Start of a clinical trial
6.1.1. Clinical trial may start if the Ethics Committee has issued a favorable opinion and the Center
has given a positive conclusion for conducting a trial. The applicant may apply to the Ethics
Committee and to the Center in parallel, depending on his wish.
6.1.2. If the conduct of a clinical trial needs importation of investigational medicinal products,
auxiliary consumables on the territory of Ukraine, exporting biological samples for laboratory
assays with auxiliary consumables and unused investigational medicinal products from the territory
of Ukraine these may be done in compliance with Ukraine's legislation.
6.1.3. After the start of clinical trial (inclusion of the first subject) according to the approved
protocol the sponsor or its authorized representative (authorized person shall confirm the power
granted to him/her) shall inform about this the Center and the Ethics Committee, which approved
the clinical trial, within 10 working days according to the form presented in Annex 9. In case of
multicenter clinical trials, if not all declared clinical bases are involved in the trial the sponsor or his
authorized representative shall inform the Center and the Ethics Committee about this.
6.1.4. If necessary, during clinical trial and after its termination the Center may request the
investigator/the sponsor to provide some materials related to clinical trial.
6.2. Making amendments during a clinical trial
During a clinical trial the changes and amendments may be made to its materials. These changes
and amendments shall be considered as amendments which may be significant or insignificant.
6.2.2. Amendments to the materials of clinical trial shall be considered as significant if they may
affect:
    - Patient’s safety or physical or psychic wellbeing;
    - Scientific value of trial;
    - Course of trial or its management;
    - Quality or safety of any investigational medicinal product used in a clinical trial or if it is
        proposed to change the responsible investigator at a clinical base or include in the trial
        additional new clinical base in Ukraine (examples of aspects of clinical trial which the
        sponsor may amend significantly are presented in Annex 10).
6.2.3. If the amendments are significant the sponsor shall inform the Center and Ethics Committee
which has approved the relevant protocol of a clinical trial about the reasons and content of the
proposed amendments. For this purpose the applicant shall submit to the Center and the Ethics
Committee:
     - Cover letter including the reasons for considering the amendments as significant;
     - Application according to Annex 11;
     - Excerpts from the changed documents containing previous and new versions of the text or
         new version of the changed documents which may be identified by its new number and date;
     - Additional information including summary of data (if possible), amended general
         risk/benefit assessment (if possible), possible sequela for subjects already included in a trial,
         possible consequences to an assessment of trial results.
6.2.4. If the significant amendment relates to more than one protocol for a given investigational
medicinal product the sponsor may issue an integrated notification to the Center and the Ethics
Committee provided the cover letter contains a list of all protocols which the amendment is related
to.
6.2.5. The sponsor shall proceed with conducting a clinical trial in compliance with the made
amendments only if he obtains the Center’s favorable opinion on the proposed amendments and
their approval by the Ethics Committee.
6.2.6. The Ethics Committee shall examine the proposed amendments within 35 days of the date of
receipt of relevant application. In case of the reasoned refusal to approve amendments the sponsor
shall revise the amendments in due course or reject them.
If the sponsor gets the reasoned refusal he may again submit the proposed amendments to the Ethics
Committee in a letter substantiating the necessity of these amendments.
6.2.7. The Center shall give a conclusion on significant amendments based on their expert
evaluation, which includes the following stages:
- Initial expert evaluation of materials to verify the compliance of application and materials
submitted to the set requirements with special reference to completeness and accuracy of juridical
arrangement;
- Specialized evaluation of materials submitted in order to give a reasoned conclusion on the
possibility to conduct a clinical trial according to the amendments.
6.2.7.1. The applicant shall submit to the Center an application and information according to
         requirements of paragraph 6.2.3., item 6.2 of this Procedure in order to conduct an expert
         evaluation of amendments.
The Center and the applicant shall sign a contract for conducting an expert evaluation of
amendments. The expert evaluation of amendments to the clinical trial materials accompanying the
application is to be paid for.
6.2.7.2. The Center shall perform the initial expert evaluation of materials submitted within 5
         working days after receipt of the application. Based on results of the initial expert evaluation
         the Center shall respond the applicant in writing.
6.2.7.3. In case the conclusions of initial evaluation are negative the Center shall inform the
         applicant in writing, giving grounds, that the submitted materials related to the amendments
         could not be taken for evaluation, or request the applicant to provide additional or missing
         data and/or information necessary to ensure compliance of the submitted materials with
         juridical and technical and/or administrative requirements.
     If the applicant fails to provide the Center with the finished-off amendments or a letter with
     substantiated timeframe necessary for their finishing-off within the above period, or if the
     applicant presents additional or missing data and/or information which do not ensure
     compliance with juridical and technical and/or administrative requirements the submitted
     materials shall be withdrawn from consideration. The Center shall inform the applicant about
     the decision taken in writing.
Further on, at applicant’s wish, the amendments may be submitted in due course to the Center for
approval.
6.2.7.4. In case the conclusions based on results of the initial expert evaluation are positive the
         amendments shall be subject to specialized evaluation at the Center.
6.2.7.5. During specialized assessment of the amendments aiming at drawing up a conclusion
related to the possibility of their introduction in the conduct of clinical trial, the Center may request
the applicant to provide additional materials. The time necessary for their preparation shall not be
included to the time period for conducting specialized assessment.
In case the applicant fails to provide the requested additional materials or a letter with substantiated
timeframe necessary for their preparation within 30 calendar days, the amendments shall be
withdrawn from consideration. The Center shall inform the applicant about the decision taken in
writing with no cost of expert work being reimbursed to the applicant. Further on, at applicant’s
wish, the amendments may be submitted in due course to the Center for its conclusion.
6.2.7.6. Based on the results of expert evaluation the Center shall prepare a positive conclusion
         about the amendments or a reasoned refusal of their approval.
6.2.7.7. If the applicant doesn’t agree with the Center’s refusal to approve amendments he may
submit a notice of appeal to the Center’s Appeal Committee according to item 4.10 of this
Procedure.
6.2.7.8. The timeframe for a specialized assessment of amendments and issuing a conclusion shall
not exceed 35 calendar days of the date of issuing the Center’s positive conclusion based on results
of the initial expert evaluation of compliance of the application and materials submitted with the
requirements with special reference to completeness and and accuracy of juridical arrangement.
6.2.8. If amendments are not significant (amendments are not significant (insignificant
         amendments), for example, in case of changing a contact number, a name of manufacturer, a
         monitor or investigator in any country except for Ukraine etc.) according to the criteria set
         forth in paragraph 6.2.2. of item 6.2, as well as if they are not related directly to a conduct of
         clinical trial in Ukraine they shall not be subject to expert evaluation at the Center. In this
         case the applicant shall only notify the Center and the Ethics Committee about insignificant
         amendments to the documentation.
6.2.9. If during a trial there occurs an event related to that trial or to the development of the
         investigational medicinal product capable of affecting the subject’s safety the sponsor and/or
         the investigator shall take measures to assure the subject’s safety. The sponsor shall
         immediately inform the Center and the Ethics Committee about the event occurred and
         measures to remove it.
6.3.     Termination of clinical trial
6.3.1. The Sponsor shall inform the Center and the Ethics Committee about termination of clinical
trial (date of last visit of the last subject) in Ukraine within 90 days of its end in accordance with the
form submitted in Annex 12.
6.3.2. In case of international multicenter clinical trials the sponsor shall additionally inform the
          Center and the Ethics Committee about complete termination of the trial in other countries.
6.3.3. In case of early termination of the trial the sponsor shall inform the Center and the Ethics
          Committee within 15 days indicating the reasons for early termination of the trial.
6.3.4. The investigator shall inform in writing (at the Center’s or the Ethics Committee’s request)
          about the status of the conduct of clinical trial.
6.3.5. The investigational medicinal products not used during the clinical trial shall be removed in
          due course or shall be given back to the sponsor.
6.3.6. The sponsor shall provide to the Center a final report within one year after complete
          termination of the clinical trial (in international clinical trials – the end of the trial in all
          countries). The format of the report on clinical trial is presented in Annex 13.
6.3.7. When submitting a report the applicant may submit an application of approved form for
          state registration of a medicinal product and obtain an invoice for payment of a state fee for
          the state registration.
6.3.8. The Center shall perform an expert evaluation of the report about the clinical trial
          conducted (except for international clinical trials).
Based on the results of expert evaluation the Center may:
- Recommend or not recommend to continue conducting a clinical trial of a medicinal product;
- Make comments or request additional materials and assign an inspection of the clinical trial;
- Recommend medicinal product for state registration after payment of the state fee for registration
of medicinal product, provided the results of the Center’s expert evaluation of the report of clinical
trial, results of expert evaluations conducted by the Center, materials of clinical trials indicated in
Part 4 of this Procedure, and other materials envisaged by the structure of registration dossier, are
positive.
The Center shall inform in writing the applicant about the decision taken.
6.3.9. If necessary the applicant may finish-off the report within 30 calendar days. The time
necessary for the applicant to finish-off shall not be included in the time period for conducting
specialized assessment.
In case the applicant fails to provide the finished-off report or a letter with substantiated timeframe
necessary for its finishing-off within 30 calendar days, the report shall be withdrawn from
consideration. The Center shall inform the applicant about decision taken with no cost of expert
work reimbursed to the applicant.
Further on, at applicant's wish, the clinical trial materials may be submitted again in due course.


                         7.       Notification of adverse events and reactions
7.1. Notifications which are to be made by the investigator
7.1.1. While conducting clinical trial the investigator shall report all serious adverse events to the
sponsor except for those that the protocol or investigator’s brochure identifies as such not requiring
immediate reporting. The immediate/initial and follow-up reports shall identify subjects by unique
codes assigned to them for the study.
7.1.2. The investigator shall also report the sponsor any adverse events and/or laboratory
abnormalities identified in the protocol as critical to safety evaluations according to the reporting
requirements and within the time periods specified by the sponsor in the protocol.
7.1.3. If the revealed negative medical condition may be identified as a serious adverse reaction
(except for international clinical trials) the investigator shall inform the Center and the Ethics
Committee of this within 2 working days after their detection using the form given in Annex 14 to
this Procedure. Reports on sequela of the reactions or all additional information on this event the
investigator may provide using the same form.
7.1.4. In case of subject’s death the investigator shall provide the sponsor, the Center and the
         Ethics Committee any additional information requested by them.
7.2.     Notifications which are to be made by the sponsor
7.2.1. The sponsor shall:
     a) Record immediately and within seven calendar days after learning about such case report all
         suspected unexpected serious adverse reactions which resulted in death or were life-
         threatening, to the Center and the Ethics Committee. Follow-up relevant information shall
         be given within an additional eight days. Requirements to the notification are listed in
         Annex 15.
     b) Report to the Center and the Ethics Committee all other serious unexpected adverse
         reactions which become known to him within fifteen days;
     c) Inform all investigators who take part in clinical trial of the given medicinal product of all
         detected events capable of affecting subjects' safety. The information may be collected as a
         listing of suspected serious unexpected adverse reactions and submitted regularly depending
         on peculiarities the clinical trial and the number of suspected unexpected serious reactions
         which become known to the sponsor;
     d) Store documentation related to all adverse events the investigators report to him.
     7.2.2. During long-term clinical trials the sponsor shall provide the Center and the Ethics
     Committee a listing of all unexpected serious adverse reactions and a report on the safety of
     investigational medicinal product at least once a year in compliance with requirements stated in
     Annex 16 to this Procedure. Reporting period shall begin from the date of receipt of the
     Center’s positive conclusion on the conduct of clinical trial.
7.2.3. In case of conducting several clinical trials of the same investigational medicinal product, the
sponsor shall provide in a cover letter attached to the report a listing of all clinical trials conducted
in Ukraine or with Ukraine’s participation which are associated with this report. In this case the
term of annual reporting begins from the date of receipt of the Center’s positive conclusion on the
conduct of the first listed clinical trial.
7.3.     Recording and analysis of notifications about suspected unexpected serious adverse
         reactions by the Center
7.3.1. The Center shall record all cases of unexpected serious adverse reactions which become
known to it and study them.
7.3.2. If there is a suspicion of an increased risk to subjects the Center may request the sponsor an
          additional information on the safety of investigational medicinal product which shall be
          provided within 7 days.
If during this period the sponsor does not provide an additional information or a letter with
substantiated timeframe necessary for their preparation, the Center may take a decision on
temporary suspension or stoppage of the given clinical trial, informing the applicant about this in
writing.

8.      Inspection of clinical trials of medicinal products

8.1. Subject to the inspection shall be documents, facilities, equipment and instruments, records,
quality assurance system and other resources related to a clinical trial, which can be kept in the
health care setting, in the offices of sponsor and/or contract research organization or in other
institutions the Center may consider necessary to inspect.
8.2. Inspection of a clinical trial may be conducted as planned, purposeful (if necessary) or
retrospective after its termination. Planning and conducting an inspection shall be performed in
compliance with preliminary developed standard operating procedures which shall be revised and
approved annually by the Center’s director.
8.3.     The inspection shall be conducted within 14 calendar days after submission of preliminary
notification and agreement with the responsible investigator and/or sponsor of the clinical trial on
the start date and duration of the inspection, its purpose, listing of documents and premises to be
inspected.
8.4.     The inspection of the clinical trial shall be carried out in compliance with the protocol by the
Center’s specialists being familiarized with main principles of development of medicinal product,
having experience in arranging and conducting clinical trials and not taking part in their conduct as
well as being independent from the sponsor and investigators.
8.5. The representatives of the State Agency for Pharmaceuticals and Medical Devices may be
involved in conducting an inspection (if it is necessary to inspect the conditions of manufacture of
the investigational medicinal product).
8.6. Persons who conduct the inspection shall not disclose confidential data they obtain during
     inspection of the clinical trial materials in compliance with current legislation and international
     requirements.
8.7. During the inspection of a clinical trial the responsible investigator should be present at the
clinical base. Also present may be sponsor’s representatives.
8.8. Based on inspection's results a statement shall be prepared, indicating all remarks/shortcomings
(if any) and the deadlines for their elimination. The Center shall send a statement about the
inspection to the sponsor and the responsible investigator of the clinical trial.
8.9. If during the inspection some shortcomings which cannot affect the results of the clinical trial
and do not require temporary suspension or stoppage of the clinical trial are revealed the
investigator and/or sponsor must eliminate them. The schedule for shortcomings elimination shall
be defined and the date shall be indicated when the sponsor informs the Center about its fulfillment
and completion.
If the shortcomings revealed have not been eliminated and no substantiated clarification were given
the Center may stop conducting clinical trial.
8.10. The Center may assign a repeated inspection of clinical trial of the medicinal product in due
course to verify the elimination of shortcomings revealed during the preliminary inspection.
8.11. If during the inspection some violations were revealed in the conduct of clinical trial which
affect its results, the trial may be temporarily suspended (e.g., failure to fulfill the conditions
specified in the application for conducting clinical trial; violations of ethical nature; adulteration of
clinical trial data). If the above violations are confirmed during the retrospective inspection the
results of the clinical trial shall not be recognized.
The Center shall inform the sponsor in writing about the decision taken and grounds for taking a
decision about temporary suspension of the clinical trial.
8.12. The sponsor shall respond in writing to the Center within one week. If the sponsor does not
give a substantiated answer about the revealed violations, possibility and schedule for their
elimination, the clinical trial may be stopped.

                    9. Suspension of a clinical trial and elimination of violations
9.1. A clinical trial may be suspended by the sponsor, investigator or the Center.
9.2. If the sponsor suspends or stops ahead of schedule the trial in case of the increased risk to
subjects’ health or life, or in case of substantial violations in conducting clinical trial, or for other
reasons, he shall inform investigators, the Ethics Committee and the Center in compliance with
paragraph 6.3.3, item 6.3. of this Procedure.
9.3. In case of the increased risk to subjects’ health or life the investigator shall suspend clinical
trial and inform the Center, sponsor and the Ethics Committee accordingly.
9.4. If the Center has the objective grounds to suggest that the conditions declared in the application
for getting the Center’s conclusion are not met, or the Center has got data prejudicing the subjects’
safety or the scientific substantiation of the clinical trial, it may temporarily suspend or stop the
clinical trial. The Center shall inform the sponsor, investigators and the Ethics Committee about its
decision and grounds for it.
Prior to taking a decision the Center shall request sponsor’s and/or investigator’s opinion except for
cases of inevitable risk to subjects. The response to the requested opinion shall be provided within
one week.
In case the Center has got objective reasons to consider that the sponsor, investigator or other
person involved in the trial fail to observe the set obligations, the Center may determine actions the
sponsor must take to correct the situation. The schedule for taking actions shall be defined and the
date shall be indicated when the sponsor should inform the Center about its fulfillment and
completion. In addition, the Center shall inform the relevant Ethics Committee about this
immediately.




(Signature)
V.T. Chumak

Director
State Pharmacological Center MoH Ukraine

				
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