Ministry of Health of Ukraine

ORDER

Kyiv

Registered in Ministry of Justice of Ukraine on Dec 26, 2000 under # 947/5168

On Approval of Instructions for surveillance
over adverse reactions/effects of
medicinal products

In accordance with the Law of Ukraine "On medicines", Procedures for State Registration (Re-registration) of Medicinal Product approved by the Decree of the Cabinet of Ministers of Ukraine dated 13.09.2000 № 1422, in order to achieve a harmonization with the standards used in international practice – Guidelines of International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and Directive of the Council of the European Economic Community on Pharmacovigilance 75/319 EEC as amended by Directives 83/570/EEC and 93/39/EEC,

I ORDER:

1. To approve Instructions for surveillance over adverse reactions/effects of medicinal products (attached herewith).

2. That the Minister of Health of the Autonomous Republic of Crimea, Chiefs of Health Departments of the Oblast and Kyiv and Sebastopol City State Administrations, Managers of health care institutions within MH Ukraine provide for execution of the present Order.

3. That O.V. Stefanov, Director of the State Pharmacological Center MH Ukraine, arranges for submission of the present Order to the Ministry of Justice of Ukraine for state registration.

4. I hereby authorize A.Sh. Korotko, Deputy Minister of Health of Ukraine, to supervise execution of this order.

V.F. Moskalenko
Minister

Instruction
for surveillance over adverse reactions/effects of medicinal products
of Materials Pertinent to State Registration (Re-registration)
of Medicinal Products

1. Background

1.1. The present Instructions have been developed according to the Law of Ukraine "On Medicinal Products", Procedure for state registration (re-registration of medicinal products, approved by the Decree of the Cabinet of Ministers of Ukraine dated 13.09.2000 № 1422, with due consideration of the standards used in the international practice – Guidelines of the International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use and Directive 75/319/EEC as amended, Directive 83/570/EEC and 93/39/EЕС/.

1.2. Instructions envisage key requirements to acquisition of data, which are necessary for surveillance over adverse reactions/effects of medicinal products, which occur during clinical trials and in medical use of medicinal products, as well as to scientific evaluation of this information.

1.3. Surveillance over adverse reactions/effects of medicinal products shall be made by the State Pharmacological Center MH Ukraine (hereinafter – the Center).

2. Definition of Terms

2.1. Safety of medicinal product – lack of serious and unexpected adverse reactions/effects during clinical trials or medical use of medicinal product, which comply with the criterion "benefit/risk".

2.2. Investigator – an expert, who directly conducts clinical trial of medicinal product in a health care setting and knows or underwent training pertinent to conduct of clinical trials.

2.3. Additional clinical trials – trials that are made in order to confirm and reveal any dangerous properties of medicinal products at its medical use, which increase the risk for human health and require making a decision according to acting legislation.

2.4. Еxpert evaluation of material for medicinal product – verification, analysis and specialized assessment of materials for medicinal product in order to prepare a motivated conclusions for making a decision about its state registration (re-registration) or refusal in the state registration (re-registration) of medicinal product.

2.5. Еxpert evaluation of materials of generalized report – verification and specialized assessment of materials of a investigator or pharmaco-epidemiological or other type of research for making a decision as to safety of medicinal product.

2.6. Еxpress report – description and preliminary analysis submitted in writing of any unexpected adverse reactions/effects, which occurred during clinical trials of medicinal product to be presented by the investigator of applicant to the Center, Ethics Committee and applicant following submission of Form №1.

2.7. Applicant of clinical trial (sponsor) – legal entity or private person, who initiates the beginning of clinical trial of medicinal product and is responsible for its organization, control and/or funding.

2.8. Dangerous properties of medicinal product (adverse reaction/effect) - combination of or separate manifestations of negative properties of medicinal product, which prevent its effective and safe use by the patient or cause negative effect upon quality of his life.

2.9. Unexpected adverse effect – adverse effect, which character or level of expressiveness do not correspond to an information available about medicinal product in package-insert and/or instructions for medical use of medicinal product (for a product approved for medical use).

2.10. Non-serious adverse reaction or non-serious adverse event – any adverse reaction or adverse event, any adverse effect that does not meet the criteria defined as serious adverse reaction or serious adverse event.

2.11. Adverse effect – any undesirable reaction conditioned by pharmacological properties of medicinal product and occurs exclusively when used in doses recommended for medical use of medicinal product.

2.12. Adverse reaction – dangerous reaction, undesirable to patient's health provided cause-effect relationship between this reaction and use of medicinal product cannot be excluded.

2.13. Adverse event – any unfavorable medical manifestation in the patient at the use of medicinal product, which do not necessarily has a causal relationship with the use of medicinal product (change of laboratory data; symptom or disease, which retain in time with the use of medicinal product, etc.).

2.14. Information of the State Pharmacological Center MH Ukraine – quality printed information (in medical literature or separate editions) for physicians and health workers about cases of adverse reactions/effect, etc. in Ukraine and abroad.

2.15. Registration certificate (trade license) – document, issued to an applicant, which is a permit for medical use, import and sale of medicinal product in Ukraine.

2.16. Serious adverse reaction or serious adverse event – any dangerous to life adverse events at the use of medicinal product (irrespective of dosage), which lead to hospitalization or extension of the hospitalization time, disability, death of patient, cause malformations in the growth of fetus and congenital anomalies.

2.17. Spontaneous reports – notifications about all kinds of adverse effect of medicinal products at their medical use.

2.18. Generalized report – submitted in writing qualitative descriptions and analysis of all adverse reactions, which occurred at clinical trials or as a result of pharmacoepidemiological (or other forms of) investigation of adverse effect of medicinal products at their medical use.

2.19. Pharmacological surveillance – state system of acquisition, scientific evaluation and control of information about adverse reaction/effect of medicinal product in order to make respective decisions at the stage of clinical trials and its medical use according to acting legislation.

2.20. Form 1 – notification card about any suspected adverse events, serious or unexpected adverse reactions/events, which occur during clinical trials. The card should necessarily be submitted by an investigator to sponsor and the Center within the timeframe, specified by the present Instructions (it should necessarily be attached to final report, express-report about adverse reactions/events of medicinal products).

2.21. Form 2 – notification card about all spontaneous cases of adverse effect of medicinal products in Ukraine, which are filled in by doctors of the state and communal health facilities, all health care settings irrespective of their departmental subordination and sent to the Center within the timeframe, specified by the present Instructions.

2.22. Form 3 – notification card about any suspected serious or unexpected adverse effects of medicinal product, which occur during medical use of medicinal product in Ukraine and abroad. The card should necessarily be submitted by a Ukrainian or foreign manufacturer/owner of registration certificate or their authorized representative to the Center within the timeframe, specified by the present Instructions.

3. Sources of acquisition and exchange of information about adverse reactions/effects of medicinal products

3.1. Information about adverse reactions/effects of medicinal products shall come to the Center from:

• doctors, state and communal health facilities irrespective of their departmental subordination and forms of ownership;
• manufacturers/ registration certificate holders or their authorized representatives;
• authorized international organizations (World Health Organization – hereinafter WHO, European Community – hereinafter EC, etc.);
• medical information sources and scientific publications;
• public organizations, which represent the interests of consumers of medicinal products, as well as citizens;
• Ethics Committees (during clinical trials of medicinal products).

3.2. The Center shall get information about adverse reactions/effects of medicinal products, makes it systematic, analyze it according to timeframes listed in Annex 1 to the present Instructions, and prepares information bulletins, analytical overviews, express information, methodical recommendations for doctors, investigators, manufacturers/registration certificate holders, as well as proposals to MH Ukraine for taking appropriate measures and decisions.

3.3. The Center shall send the reports about suspected serious adverse reactions to MH Ukraine, WHO (through WHO Liaison Office in Ukraine) with copy to EC Agency.

4. Procedure for submission of information about adverse reactions/events at clinical trials

4.1. During conduct of clinical trial of medicinal product the information about adverse reaction/event shall be necessarily submitted by the investigator to the Center and applicant. In addition, information about all serious and/or unexpected reactions/events shall also be submitted to the Ethics Committee.

4.2. All serious and/or unexpected reactions/events should be reported by the investigator to the Center, applicant and Ethics Committee within 48 hours after occurrence of serious adverse reaction/event according to the Form, given in Annex 2 to the present Instructions. In case a medicinal product is investigated in several centers, the applicant shall report all cases of serious adverse reactions/events of other investigators of the same medicinal product.

4.3. After submission of information according to item 4.2 of the present Instructions a investigator within 15 days shall submit a detailed written report to the Center, applicant and Ethics Committee according to requirements, set up by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use in the EEC Countries (ICH), with definitions and standards of express reports (ICH Guideline for Clinical Safety Data Management Definition and Standards to Expedited Reporting).

4.4. According to requirements of protocol for clinical trials of medicinal products an investigator shall submit to the Center, applicant and Ethics Committee an information about any negative reactions/events and/or pathological changes of laboratory indicators, specified in the protocol in order to assess safety of medicinal product as per Form 1, given in Annex 2 to the present Instructions.

4.5. In case of serious or unexpected adverse reaction/event (item 4.2 of Instructions), if necessary, a investigator shall submit, on request of the Center, applicant and Ethics Committee, a related additional information (case history, postmortem epicrisis).

4.6. In case of multicenter clinical trials, the applicant is requested to permanently inform investigators, the Center and Ethics Committee about all serious or unexpected adverse reactions/events in accordance with international requirements.

4.7. In case of long-term clinical trials, the applicant shall submit to the Center new data regarding danger of an investigational medicinal product at least every year.

4.8. After completion of clinical trial the data about safety of an investigational medicinal product shall be submitted in a report about clinical trial according to Instructions for conduct of clinical trials of medicinal products and expert evaluation of materials of clinical trials, approved by the Order of MH Ukraine in due course.

4.9. In case of serious or unexpected adverse reactions/events, the manager of clinical trials is requested to stop clinical trials or its separate stages if the situation threatens patient’s life due to their manifestations and report to the Center and applicant.

4.10. Based on the information received the Center shall take a decision about stoppage of clinical trials of medicinal product or its separate stages. The Center shall inform the applicants about decision taken.

4.11. In case of serious or unexpected adverse reactions/events during clinical trials the Center may request additional materials about clinical trial of medicinal product, with the time necessary for its preparation being not included to the time period for conduct of their specialized assessment.

If a applicant fails to submit the requested materials or a letter with motivated terms, necessary for their preparation, within 90 calendar days, the Center shall make a decision about non-renewal of clinical trial.

4.12. The Center shall inform the applicant of clinical trial about decision taken in writing.

4.13. All disputes that occur during conduct of clinical trial of medicinal product, shall be settled by MH Ukraine or court.

5. Procedure for submission of information about adverse effect of medicinal product, approved for medical use

5.1. Doctors and health workers of the state and communal health facilities, irrespective of their departmental subordination, are requested to submit to the Center an information about any adverse effects of medicinal product, approved for medical use, according to special form, given in Annex 3 of the present Instructions.

5.2. Information about adverse effects of medicinal product should be included by the doctor to primary documentation, hospital records, case history, and patient’s discharge card.

5.3. Manufacturers/owners of registration certificate (or their authorized representatives) of medicinal product, approved for medical use, should submit to the Center an information about adverse effects of medicinal product according to special form, given in Annex 4 of the present Instructions.

5.4. Manufacturers/registration certificate holders (or their authorized representatives) of medicinal product should submit to the Center a generalized report about adverse effect of medicinal product:

• every 6 months – during first 2 years after getting a registration certificate;
• every year – during subsequent 3 years;
• further on – every 5 years (provided the medicinal product is re-registered).

5.5. Expert evaluation of materials submitted for an assessment of safety of medicinal product is made by the Center free.

5.6. In case of adverse reaction/effect (unsafe properties unknown previously) of medicinal product the Center shall propose the MH Ukraine to make a decision about permanent or temporary ban of medical use of this medicinal product until the results of additional clinical trial and specialized assessment are received in order to confirm or disprove unsafe properties of medicinal product.

5.7. Based on results of review of the proposals submitted by the Center, the MH Ukraine shall make a decision about permanent or temporary ban of medical use of this medicinal product.

The Center shall inform a manufacturer/owner of registration certificate (or his authorized representative) about decision taken by MH Ukraine.

5.8. Based on results of specialized assessment the Center may propose restriction related to the medical use of medicinal product, namely: change of indications and contraindications, more precise definitions that are being introduced to the instructions for medical use of medicinal product.

The Center shall inform a manufacturer/registration certificate holder (or his authorized representative) about proposed changes.

5.9. Any disputes pertinent to permanent or temporary ban of medical use of this medicinal product in case of adverse reactions/effects are revealed during its use, shall be settled by the MH Ukraine or court.

O.V. Stefanov
Director,
State Pharmacological Center MH Ukraine

Annex 1 to item 3.2 of
Instructions for surveillance over
adverse reactions/effects of
medicinal products

Definition of terms related to adverse reaction/effect of medicinal products

Potential adverse reaction – clinical signs, which include changes of laboratory parameters and occur during use of medicinal product, but are unlikely to have association with concurrent diseases or other factors, worsen after withdrawal of medicinal product, and the fact of their recurrence after rechallenge of the medicinal product is unknown

Proved adverse reaction – clinical events that include changes in laboratory measurements and occur during use of medicinal product, but could not be explained by presence of existing diseases and influence of other factors and chemicals, and to become worse after the withdrawal of medicinal product and recur on its readministration.

Local reactions – reactions, which occur at the site of application of medicinal product.

Possible adverse reaction – clinical signs, which include changes of laboratory indicators and occur during use of a medicinal product, are explained by concurrent diseases or by use of other medicinal products or chemicals, and for which reaction on withdrawal of the medicinal product is unknown.

Unexpected adverse reaction/event – adverse reaction/event, nature or severity of which is not consistent with the available product information in investigator’s brochure (for an investigational product).

Non-serious adverse effect – any adverse effect that does not meet the criteria defined as serious adverse effect.

Expected adverse effect – adverse effect, nature or severity of which is consistent with the available product information in package-insert and/or instructions for medical use of medicinal product (for a product approved for medical use).

Expected adverse reaction/event – adverse reaction/event, nature or severity of which is not consistent with the available product information in investigator’s brochure (for an investigational product).

Adverse reaction, which is beyond classification – report on adverse reaction, which occurrence is suspected, but could not be evaluated for lack of information and for its inconsistency.

Adverse effect – unsafe property of medicinal product under its medical use, which is not associated with dosage regimen.

Reactions on withdrawal of medicinal product – adverse reaction occurred on abrupt suspension of medicinal product use.

Interactions reaction – reactions, which occur during use of several medicinal products and result from their interaction at pharmacodynamic and/or pharmacokinetic stages.

Serious adverse effect – any untoward life-threatening adverse effect that occurs during medical use of medicinal product and results in patient hospitalisation or prolongation of existing hospitalisation, disability/incapacity, patient’s death, birth defect and congenital anomaly.

Signal – information on possible causal association between adverse event and use of medicinal product, which has been unknown before or there were insufficient data (in case there is one and more signals, the information is valuable and an event is serious), which shall be reported to the Center and to the applicant in accordance with the form set by the Instructions.

Questionable adverse reaction – clinical signs including changes of laboratory indicators that occur for lack of clear association with a time period of medicinal product use. This reaction may be caused by other factors (use of other medicinal products, concurrent diseases, chemicals, etc.).

Conditional adverse reaction – clinical events including changes of laboratory indicators, which pertain to adverse reactions, but require additional data for accurate assessment.

Annex 2 to item 4.2 of
Instructions for surveillance over
adverse reactions/effects of
medicinal products

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Annex 3 to item 5.1of
Instructions for surveillance over
adverse reactions/effects of
medicinal products

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Annex 4 to item 5.3 of
Instructions for surveillance over
adverse reactions/effects of
medicinal products

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