Semra Şardaş, Coordinator

Asuman Karakaya

Sinan Süzen

Benay Can Eke

Bensu Karahalil

Pharmacovigilance can be defined as “collecting clinical data on the safety of medicines in daily clinical practice, following the problems encountered in pharmaceutical applications, identification, investigation, recording and exposure of responsible causes and taking the necessary precautions”. Therefore, the interest of pharmacovigilance is closely related to that of toxicology, which defines the principles of finding solutions to the adverse/toxic reactions that may occur as a result of drug usage. The contribution of toxicologists to pharmacovigilance is extremely important. The increase in drug use has caused further discussion about problems related to drugs in recent years. Information and opinions about the effectiveness and safety of drugs change constantly, new drugs enter the market and experiences with existing drugs expand. New side effects of many drugs are added to the known ones. The latest determined adverse effects have sometimes been an unnecessary source of concern, or, on the contrary, there may be delays in notification of physicians and other health personnel.

New indications or routes occur for existing drugs. Drug companies, regulatory authorities and all persons and institutions connected with drugs are expected to keep abreast of all the latest developments and to fulfil their responsibilities. Side effects, especially serious adverse effects due to drugs, cause public health problems more often than expected. All the developments that have taken place in relation to drug safety worldwide are closely monitored by the Ministry of Health Risk Management Office and many drugs have been withdrawn from the market for safety reasons in the last decade. Databases and the results from a large number of comprehensive pharmacoepidemiological studies carried out in countries with advanced pharmacovigilance systems have revealed that drug-related mortality and morbidity rates are quite high.

Pharmacoeconomic researches also show that the economic problems related to drugs have grown and become more complex. Taking into consideration the large differences between countries and regions, and in accordance with the data of some countries with developed pharmacovigilance systems, mortality in relation to adverse drug reactions is estimated to reach the 4 ^th level. For instance, according to data from the United States, in one year 100,000 people die and 1.5–2 million people are admitted to hospital due to adverse drug reactions. In fact, about 20–70 % of these adverse events are considered preventable.

Although novel drug development researches provide useful information about drug safety, it is inadequate to completely eliminate concerns in this regard. Reasons for this include: the fact that the results of animal experiments from preclinical studies regarding drug safety do not always reflect the situation in humans; the limited numbers and the mostly selected patient groups that are used in clinical studies; and the fact that these studies are performed within limited time frames. These types of restrictions before marketing have further increased the importance of post-marketing monitoring in terms of the adverse effects of drugs. There is a need to establish pharmacovigilance systems to monitor and evaluate the safety of accepted drugs on an institutional base, to take the necessary precautions or to ensure that they are taken, and to supply enough national and international communication. These are the most important problems experienced in relation to drug utilization. There have been attempts to introduce pharmacovigilance systems aimed at achieving healthy communication with public and private sectors at international, national, local, institutional and/or individual levels. In parallel with the levels of development of countries and the capacities of drug industries, pharmacovigilance systems have been developed rapidly since 1950. In 1961, the importance of pharmacovigilance systems became better understood due to the tragic development of phocomelia syndrome following intake of “thalidomide”, which was experienced globally, and particularly in European countries. Nowadays, there are quite functional pharmacovigilance systems in developed countries, especially in the United States, Canada, Japan, Australia and European Union countries. The pharmacovigilance units of several international organizations, including in particular the World Health Organization, have important functions in the cooperation between these systems and their successful execution in developed countries.

In terms of membership of the European Union, one important pharmacovigilance system that is of particular interest to our country is the European Medicines Agency (EMEA). The EMEA is quite active in pharmacovigilance information exchange. The developing countries in terms of the establishment of pharmacovigilance systems and performing pharmacoepidemiological studies in this area are not involved in this process. Although at first glance it seems that the pharmacovigilance data of developed countries can be used in countries that have no pharmacovigilance system, the role of many local factors, including in particular cultural and genetic factors in drug usage, have revealed the inappropriateness of this opinion. For example, during drug usage many sociocultural and economic factors have affected pharmacovigilance, including: patient compliance; the perceptions of patients regarding drug effects/adverse effects; what can be done when drug-related adverse effects/events occur; poly-pharmacy habits; drug-drug interactions; the ratios and diversity of drug-nutrient interactions; the frequencies of visiting the physicians of patients in different stages of their diseases; diversities of the overview given to family members (according to factors such as their age, gender and social status) in terms of solving drug-related problems; their habits in terms of taking into consideration news/comments/ads about drugs; the habit of smoking; consumption alcohol, e.g. by persons from different areas and cultures and their interactions with drugs; different incidences of some diseases in different regions; the attention habits of the drug dealers/pharmacists for the expiration dates, storage rules and shipment rules of drugs; the economic status of the patients or the payment rates of the treatment costs by reimbursements in terms of drug-purchasing power; and the effects of infrastructure and economic reasons on the notification of drug-related problems to the health-care agencies. Pharmacogenetic differences, such as the large variability in the enzymes that affect the pharmacokinetics of drugs between individuals and populations, are another important reason for the need for national pharmacovigilance systems. Apart from the differences arising from patients, the infrastructure and operational differences among the regulatory authorities, the knowledge and attitudes of physicians and other health-care personnel in the declaration of adverse effects/events, and the differences particularly in the notifications of periodic safety update reports by the pharmaceutical industry and on good pharmacovigilance practices can be listed among the causes of diversity at the national level. All the factors mentioned above have clearly shown the need for a national pharmacovigilance system.

Primary Responsibilities of National Pharmacovigilance System

A national pharmacovigilance system has the following primary responsibilities in relation to identifying drug-related problems with a view to resolving emerging problems with the most appropriate option available: to open channels for detecting the adverse effects of all drugs, especially newly licensed drugs or drugs that have serious adverse effects that are the subject of current debate; to collect data and carry out original scientific research, or arrange for such research to be performed, on this topic if needed; to determine the relationship between adverse drug reactions and the related drug use and to determine the community at risk; to evaluate, or to arrange the evaluation of, data related to the notification of adverse effects and the performance of feedback; to take the necessary precautions in trying to prevent the emergence of serious adverse effects or to minimize the extent of possible problems; to restrict the use of a drug, and give patients, physicians and other health personnel notice, and if necessary to get these precautions carried out by pharmaceutical companies, and get the necessary precautions written on the drug package or prospectus, and to recall the drug from the market or to suspend the licence permission of the drug; to provide exchange of information with relevant persons and organizations at national and international levels; to monitor the operability, compliance and results of the regulations and warnings related to drug safety and to identify and apply new strategies if necessary. Particularly by encouraging the performance of observational studies about the drugs concerned, especially in regard to the side effects currently being discussed or recently approved, and by doing so, to facilitate noticing and detecting problems regarding drugs; and in order to be used in drug safety studies, to create databases related to drug use at local, regional and national levels. As a result, the ultimate aim of a pharmacovigilance system is to ensure optimization of the risk/benefit ratios of the drugs in clinical use at national and international levels after marketing. “Regulation on the Monitoring and Evaluation of the Safety of Human Medicinal Products”, published in Official Gazette No. 25763, dated 22 March, 2005, entered into force on 30 June, 2005 along with “Pharmacovigilance Guideline for Licence Holders of Human Medicinal Products” and was published in the Official Gazette in 2014. “Pharmacovigilance Guideline” was also renewed in April 2015. The chronology of the pharmacovigilance system in the country is shown in Table 1. Nowadays, many of our colleagues in charge are involved in performing pharmacovigilance activities with national and international pharmaceutical companies or the health authority. The adverse effect notification form, the details of the responsibilities of the members (licence owners and health professionals) regarding pharmacovigilance, and the regulations and guidelines can be accessed from the TİTCK website ( http://www.titck.gov.tr).

Furthermore, many pharmacist colleagues in health-care organizations have provided health-care services on the website of theTurkish Drug and Medical Device Association (TİTCK) such as Pharmacovigilance Contact Points (FINs).

These persons are responsible for encouraging the reporting of adverse effects, collecting and communicating pharmacovigilance data, and conducting efforts in relation to education and information when necessary. The names and surnames of (FINs) who are responsible in different provinces of Turkey, and the names of the hospital in which they work, are available as a list on the TITCK website (http://www.titck.gov.tr).

Adverse effect notification is mostly accessible to the public as well as to health professionals. Such notifications may be delivered by e-mail. In adverse effect assessment, when asking about the drugs that patients use, it also needs to be taken into consideration that the patients may use herbal products and/or food supplements as well as the prescribed medications without physician control. It is important to inform TFM in cases where the suspected adverse reaction resulted from the products that used without physicians advice.

In conclusion, the primary objectives of our working group are as follows: to enlighten society about pharmacovigilance; to engage in educational and research activities; to contribute to collaboration between interested people, institutions and organizations; to accelerate the training activities related to drug safety; to advise the Board of the Turkish Society of Toxicology on sustaining and improving the scientific studies on drug safety and organizing events for the purpose of knowledge sharing; and to present opinion/evaluation about subjects related to drug issues in our country and the world. In summary, our working group aims to enhance the studies and collaborations in this field and to provide scientific and technical/technological contributions to the studies in our country.