Pharmacovigilance and materiovigilance

Pharmaco/materio vigilance is a very important factor in protecting public health. Reports of adverse reactions which have arrived in the Agency mostly contain all necessary information, but there is a small number of reports. The system of spontaneous reporting does not provide enough information about safe administration of medicinal products and medical devices in B-H. For these reasons one of the main goals of the Agency is to make possible for the health workers to be continuously informed about the importance of their involvement in the system of spontaneous reporting. Likewise, the activities of the Agency will be directed toward more significant involvement of marketing authorisation holders and distributors in the system of pharmacovigilance/materiovigilance.

Adverse drug reaction reaction is any undesirable harmful effect of a medicinal product in its usual dosage for prophylactic, diagnostic or therapeutic purposes, or for modification of physiological functions, under the condition that there is causality or that the connection cannot be excluded. In the period of clinical trials, adverse reaction represents any undesirable harmful sign, symptom or illness connected with any dosage of consumed medicinal product while the therapeutic dosage of medicinal product is not determined and before issuing marketing authorisation for medicinal product.

Adverse event is any negative or undesirable reaction of a patient or a healthy volunteer who participates in clinical trial of a medicinal product. That reaction may not necessarily imply causality with the treatment.
SA signal is published information about possible causality between an adverse event and a drug, whereas that causality is previously unknown or incompletely documented. Usually, more than one report is required for a signal to be shown, which depends on the gravity of event or the quality of information.

Pharmacovigilance is a set of knowledge and activities used for discovering, assessment, understanding and prevention of adverse drug reactions and problems caused by medicinal products.
Objectives of pharmacovigilance are:

• assessment of risks and benefits from a medicinal product in therapy thorough its life cycle;
• preparing a signal of suspicion of adverse reaction and development of hypothesis;
• analysis of signal and everything that consists and surrounds that signal, especially confirmation or rejection of the hypothesis, risk assessment, identifying potentially exposed populations;
• circulation of information among health workers and patients in suitable manner and possible regulatory measures;
• evaluation of consequences of undertaken measures.

Phamracovigilance includes monitoring of medicinal products not just in its post-marketing phase but also during preclinical and clinical trials. Some authors consider monitoring of medicinal products in the post-marketing phase as the fourth phase of clinical trials.

This area has been regulated in Bosnia and Herzegovina by the Regulation on principles of registering, collecting and monitoring adverse drug reactions (“Official Gazette of Bosnia and Herzegovina”, no.58/12).
On Picture 1, displayed below, it is possible to see the information flow from patients to the collecting centre, or to the Drug Regulatory Authorities where experts conduct evaluation, analysis and assessment of collected data and where decisions are made about further activities in assuring quality protection of population/patients’ health.

If necessary, appropriate regulatory measures are taken:

I warning level:

• revision of instructions for use of medicinal product,
• revision of proposed indications
• revision of adverse drug reactions

II warning level:

• withdrawal of medicinal product from the market

Deadlines for reporting adverse drug reactions:

• the marketing authorisation holder shall be required to provide complete information about every serious adverse drug reaction or suspicion which are received from medical staff on the territory of Bosnia and Herzegovina, and to report to the Agency using the report form for adverse drug reaction, within 15 days after being informed of an adverse reaction or a suspicion;
• the marketing authorisation holder shall be required to provide complete information about every unexpected serious adverse drug reaction or suspicion which is received from medical staff on the territory of Bosnia and Herzegovina, and to report to the Agency using the report form for adverse drug reaction, within 1 day after being informed of an adverse reaction or a suspicion;
• the marketing authorisation holder shall be required to provide complete written information about every serious adverse and unexpected drug reaction, which is received from outside of the territory of Bosnia and Herzegovina, within 15 days after receipt of the report, using the form in which the information is originally received;
• the marketing authorisation holder shall be required to inform the Agency in writing about any other adverse drug reaction or events that are connected with consummation of or suspicion on medicinal product, regardless of its geographic origin or source of data in form of periodic reports of medicinal product safety.

Materiovigilance
Undesirable occurrence from the medical device is every malfunction (loss of attribute values, absence or decrease of the effectiveness of medical devices in medical or technical sense or some other adverse reaction of medical devices), as well as every inaccuracy in labeling or instructions for use which could cause or has already caused death, serious deterioration of patients’, users’ or third persons’ health condition.
Materiovigilance is a system of identifying, collecting, reporting and estimating undesirable occurrences and reacting to them, or safety corrective actions related to medical devices. Materiovigilance includes activities of collecting, estimating, understanding and reacting to new findings of risks arising from the use or application of medical devices, particularly of harmful effects on patients/users or health care professionals, interaction with other substances or products, contraindications, falsifications, reduced efficiency, malfunctions or technical defects.

This area is regulated by the Regulation for monitoring adverse effects of medical devices in Bosnia and Herzegovina (materiovigilance) - “Official Gazette of Bosnia and Herzegovina”, no.58/12, 30 July 2012.
This Regulation devises the system for identifying, collecting, informing and estimating adverse effects and responses to them, namely safety corrective actions related to medical devices and other responsibilities of participants in the system of materiovigilance.
The system of materiovigilance includes:

• manufacturers of medical devices authorized for the territory of Bosnia and Herzegovina;
• representatives of manufacturers of medical devices;
• legal entities responsible for wholesale and retail marketing of medical devices (importers, doctors, pharmacists, dentists and other medical workers/health professionals);
• the Agency for medicinal products and medical devices of B-H (hereinafter referred to as: the Agency), including the Committee for medical devices,
• conformity assessment bodies;
• users and others interested in the permanent safety of medical devices.

When adverse effects occur, criteria for their registration are the following:

• That there is suspicion of its connection to medical device;
• That adverse effect has caused or could cause patient’s death or deterioration of patient’s, user’s or any other person’s health conditions

If there is suspicion of adverse effect, participants of the system of materiovigilance are required to report the adverse effect to the Agency by mail, fax or e-mail. In circumstances when application or report are submitted verbally or electronically, it is always necessary to deliver it in written form as soon as possible.
The activities of the Agency in the procedure of materiovigilance are:

• filing users’ reports or those from other sources and forwarding the said reports to manufacturers without delay or translation, while assuring the confidentiality of the patient’s data
• monitoring investigation of adverse effect undertaken by a manufacturer, undertaking additional actions, if necessary, beside those carried out by manufacturer;
• depending on the result of the investigation, spreading of any information that can contribute to the future prevention of adverse effects (or to limit their consequences);
• encouragement for reporting of adverse events by users and other persons involved in distribution, delivery, releasing for use or marketing of a medical device, including organisations and individuals responsible for calibration insurance and for maintenance of the medical device
• assessment of reports along with consultation with manufacturer or its representative, if possible; advising, if necessary, and intervention, when it is necessary;

The deadlines for reporting of the adverse reactions related to medical devices are:

• for serious threat to public health: IMMEDIATELY, no later than two days after the manufacturer has become aware of the threat
• for patient’s death or unexpected serious deterioration of patient’s health condition: IMMEDIATELY, no later than ten days after the manufacturer of the medical device has detected connection between medical device and adverse event;
• for other adverse reactions: IMMEDIATELY, no later than thirty days after manufacturer of the medical device has established connection between medical device and adverse event

In case that a report of adverse reaction has been filed to the Agency by a user or a health care professional, the report should be forwarded to the manufacturer which is required to verify the report according to the criteria of registering and to reply to the Agency with a report of adverse event or with an explanation why it is not necessary to register that event.