Adverse Drug Reactions and Pharmacovigilance: A Narrative Mini-review of Relevant Literature

Background: Adverse drug reactions (ADRs) are known to cause significant morbidity and mortality around the world, and, therefore, need precise terminology and prevention strategies to reduce the global burden on public health and increase safety of patient population. Pharmacovigilance is a powerful tool that detects, assesses and analyses spontaneously reported Mini-review Article Bakhsh et al.; JAMPS, 11(1): 1-18, 2016; Article no.JAMPS.30653 2 suspected serious and non-serious ADRs by healthcare professionals and patients, and provides important insights for preventing ADRs in healthcare settings. Poor quality reports and underreporting of ADRs limit the efficiency of pharmacovigilance. Objective: The aim of this mini-review is to describe precisely definitions of ADRs, adverse drug events (ADEs) and other related terms, their underreporting, pharmacovigilance, and how to optimize ADRs reporting by professionals and patients to pharmacovigilance. Methods: Electronic searches of relevant databases were conducted using keywords for retrieving relevant articles for inclusion in this study. Results: Several studies and healthcare organizations have clearly defined ADRs and ADE. Underreporting and poor quality reporting of ADRs remains a global problem. Continuous training of professionals and patients in ADR reporting to PV is one of the best strategies to optimize the spontaneous reporting of ADRs to pharmacovigilance for early signal detection and prevention of ADRs. Conclusion: The standardized use of ADRs terminology tends to focus attention on efforts aimed at eliminating preventable harm from ADEs. ADRs associated with high economic costs need to be prevented by optimal, better quality reporting of ADRs to pharmacovigilance. The key role of healthcare professionals and patients to report ADR spontaneously need no overemphasis and all stakeholders need continuous training in ADRs and pharmacovigilance.


INTRODUCTION
Adverse drug reactions (ADRs) are unintended and obnoxious reactions of a drug that cause harm to the patient, and these are beyond its therapeutic effect. ADRs are significant cause of morbidity and mortality around the world, and also associated with high healthcare costs and burden on public health. These reactions are often recognized during clinical practice and post-marketing phase and spontaneously reported to pharmacovigilance for identifying causative factors and prevention of their recurrences [1][2][3]. Healthcare professionals tend to report the ADRs to several pharmacovigilance centers provided they have good knowledge, attitude and practice towards ADRs and pharmacovigilance or else underreporting of ADRs remains a major healthcare problem worldwide and limit the efficiency of pharmacovigilance [4,5]. The main aim of this mini review is to describe several given definitions of adverse drug reactions and other related terms, their underreporting, and how to optimize their reporting to pharmacovigilance. The significance of this narrative review is that ADRs need to be identified early and reported spontaneously by healthcare professionals to the PV in order to prevent the occurrence and recurrence of ADRs which are globally associated with high morbidity and mortality and great burden on public health. Furthermore, though there are well established databases on ADRs and pharmacovigilance system in high income countries, there is dearth of data on ADRs in low and middle income countries including Saudi Arabia [6-12].

Search Method
The relevant literature published in English (-2016) was searched in PubMed, OvidSP and Google Scholar databases. The Boolean operators and keywords used in multiple electronic searches were definitions of adverse drug reactions "AND" adverse drug events, adverse drug reactions in hospitals "AND" pharmacovigilance (PV), OR drug surveillance and monitoring "AND" objectives of pharmacovigilance OR advantages of PV "AND" prevention of ADRs by pharmacovigilance centers. The search strategy and the keywords were modified as appropriate according to the searched database. In addition, the studies listed in relevant articles were hand searched. More than 21,725 articles were retrieved, which were reviewed by two independent reviewers (NAQ & DSAD). Our main focus was on full articles describing ADRs and PV in healthcare organizations. After removal of duplications

Definitions of ADR
The confusion looms large about the definition of ADRs, adverse drug events (ADEs), side effects, adverse effects, and other related terms [13]. An ADR is defined in different ways in the given literature; "a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function" [1] and prevention of disease, disorder or syndrome. There is a causal link between a drug and an ADR as indicated by several indicators such as temporal relation and rechallenge. Side-and excess-effects (lateral effects, parallel effects),also termed as type A(80%) or augmented ADR (predictable or anticipated) based on mechanisms of drug action on targeted or untargeted receptors, are also an undesirable effect of drug, lees severe and more frequent than type B(20%) and comes under ADEs. Furthermore, a side effect of a drug is an effect, whether therapeutic or adverse, and it is secondary to the one intended. Although side effect is used to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug [14,15] Another definition of ADR reflects an injury caused by taking a medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs [20]. Karch and Lasagna defined ADR as any response to a drug that is noxious and unintended, and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy, excluding failure to accomplish the intended purpose [21]. Food and Drug Administration (USA) defined a serious ADE relating to drugs or devices as one in which "the patient outcome is death, life-threatening, i.e., real risk of dying, initial or prolonged hospitalization, significant, persistent, or permanent disability, congenital anomaly, or required intervention to prevent permanent impairment or damage [22]. Edwards and Aronson [2] defined ADR as "an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product." This definition is relatively expanded and more meaningful than WHO description of ADR. ADRs are classified into six types: dose-related (Augmented), non-dose-related (Bizarre), doserelated and time-related (Chronic, continuous), time-related (Delayed), withdrawal (End of use), and failure of therapy (Failure) [2]. The latter three ADRs are not mechanisms but their own characteristics of manifestations, and are difficult to diagnose [13]. The capital letters in brackets form mnemonics (ABCDEF) for easy remembrance of ADR types. The management of these ADRs certainly includes withdrawal of the drug if possible and specific treatment of its effects. The suspected ADRs need to be reported to PV systems, one of the drug surveillance and monitoring methods, to help detect signal and mostly prove causal associations [2]. Furthermore, a variety of variables including timing, the pattern of illness, the results of investigations, smoking and rechallenge could help attribute causality to a suspected ADR [23].
Idiosyncratic adverse drug reactions, also known as type B reactions, pharmacologically unexpected, are rare severe ADRs that unpredictably occur in patients and affect different organs such as the liver, skin, kidney, heart and muscle and are life threatening causing death. Some drugs cause severe generalized hypersensitivity (allergic) reactions (type B). In idiopathic ADRs, the cause is not known. Some suspected unexpected serious adverse reaction (SUSAR) are reported during randomized clinical trials or clinical care in subjects given a drug. These SUSAR are not or may be dose related and not consistent with current information available on ADRs. Severe ADRs are characterized by prolonged hospitalization, being life threatening and requiring intervention to prevent permanent damage and death [1,14.15]. Hatwig and colleagues described seven severity levels of ADRs which are level 1&2 (mild category), level 3& 4 (moderate category) and level5, 6&7 (severe category) [24]. Karch and Lasanga classified severity into minor (no intervention), moderate requiring interventions such as change in drug with one day hospitalization, severe in terms of potentially life threatening requiring intensive care and lethal linked with causation of death directly or indirectly [21]. ADRs could be very common (>=1/10), common (frequent,> = 1/100 and < 1/10), uncommon (infrequent, >= 1/1000 and < 1/100), rare (>= 1/10000 and < 1/1000) and very rare (< 1/10000) [25].A summary of all forms of adverse drug event, ADR and related terms with definitions is shown in Table 1.

Adverse Drug Reactions
Modern medicines are developed in order to relieve people suffering globally, achieve better healthcare outcome, and quality of life but many of them are associated with the occurrence of unintended and obnoxious reactions, which are known as ADRs [2,3]. ADR are known to represent a serious threat to public health around the world since they are not recognized during pre-marketing phase when clinical trials are conducted in humans [1,26]. Adverse drug reactions are also associated globally with significant economic burden on healthcare system attributable to multiple factors including serious to fatal outcome, increased mortality rate, hospital admissions, bed occupancy, and longer length of stay, productivity loss and absenteeism [1,2,7,27]. The incidence rate of reported ADRs is low ranging from 0.1% to 5.5% in Saudi Arabia [12,28] which is four times lower than the rate reported from other countries [29,30].The low incidence of ADRs reporting was attributed to a number of factors including healthcare infrastructure, ADR reporting methods and ADR detection approaches. Drugs mostly involved in the causation of ADRs were anti-infective and anti-epileptic affecting skin with mild rash and urticaria [12].One study suggested that all ADRs (100%) need to be reported internally to medication safety Unit and Pharmacy and Therapeutics Committee established in hospitals in Saudi Arabia [31]. However, this ideal reporting of ADRs to ADR reporting centers within the healthcare settings or national pharmacovigilance centers is unlikely to be achieved. More generalized hypersensitivity (allergic) reactions and due to an immunologic mechanism.
Type B less frequent but very severe (idiosyncratic ADRs) Idiosyncrasy (primary toxicity) Idiosyncratic adverse drug reactions are serious ADRs that occur rarely and unpredictably possibly attributed to genetic or acquired enzyme abnormality related toxic metabolites. Overdose Overdose and interaction are risk factors of ADRs Side effect Same as above Secondary, indirect effect The indirect or secondary effect is a physiologic consequence. Interaction Overdose and interaction are risk factors of ADRs Intolerance (drug sensitivity) Drug intolerance, a lower threshold to the normal pharmacologic action of a drug is uncommon, idiopathic, and unpredictable, and may be due to genetic variants of drug metabolism.

Idiosyncrasy
Same as above and not dose dependent.
Receptor abnormality, abnormality of a biological system that is unmasked by the drug, immunological response, drug-drug interactions, or be multi-factorial.
Idiosyncratic ADRs are not related to the known pharmacology of the drug and resolve only when treatment is discontinued Allergy (hypersensitivity) Same as above Pseudoallergy (anaphylactoid) Pseudoallergy is an adverse, nonimmunologic, anaphylaxis-like reaction with similar presentation to a true allergy of sudden onset, and is associated with food ingestion, and may also be caused by an anaphylactoid reaction, intolerance (e.g., psychogenic response), metabolic defect (e.g., enzymatic deficiency, tyramine reaction) and toxicity (e.g., tetrodotoxin, a potent neurotoxin found in certain fishes) Idiopathic ADR Cause is not known ME A medication error is any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Harm Impairment of the physical, emotional, or psychological function or structure of the body and pain or injury resulting there from. ADE An injury resulting from medical intervention Commonly occur

Terms Definition
Types and remarks related to a drug.ADE reflects any harm associated with any dose of a drug, whether the dose is "normally used in man" or not. All ADEs are associated with patient harm, but not all ADEs are caused by a medication error.
during clinical practice and resolve when dose is reduced Preventable ADE Harm caused by the use of a drug as a result of an error, i.e., patient given a normal dose of drug but the drug was contraindicated in this patient. These events warrant examination by the provider to determine why it happened.
Increase cost of patients' care, and loss of confidence in physicians.
Non-Preventable ADE Drug-induced harm occurring with appropriate use of medication, i.e., anaphylaxis from penicillin in a patient and the patient had no previous history of an allergic reaction. While these are currently non-preventable, future studies may reveal ways in which they can be prevented.
Preclude use of drug in most patients as ASRs occur in few patients ADR Any response to a drug which is noxious and unintended which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function. ADR is a subtype of ADE and all ADRs are ADEs, but not vice versa.

Quality of patients' life is adversely affected. ADRs mimic disease and invites unnecessary investigation
MHRA definition of ADR An adverse reaction is a response to a medicinal product which is noxious and unintended. ADRs during preapproval (phase) clinical experience All noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions. Suspected unexpected serious adverse reaction (SUSAR) These reactions are reported during premarketing phase when randomized clinical trials are in progress.

Even during clinical practice
Acceptability of ADR Benefit/risk judgment concerning benefit and harm caused by a drug determines the acceptability of ADR. When ADR exceeds harm over benefit is referred as alarming and not accepted. Conversely, when benefit exceeds the harm, ADR is deemed acceptable.
Acceptability of ADR varies in clinical practice in the context of pre-and post-drug administration and the disease Signal Denotes possible causal relationship between adverse event and drug, previously unknown or incompletely documented, and more than one report is needed, in case poor quality of the information and seriousness of the event.
Signal is Identified by pharmacovigilance.

Underreporting of ADRs
Adverse drug reactions are underreported by health professionals worldwide. This trend is due to multiple reasons which include but not limited to their knowledge, awareness, practice, and attitude towards ADRs detection and reporting [4,5,32]. The rate of underreporting ranges from 6% to 18.5% [29,33] that is high and unacceptable, despite PV and other related centers are well established within the healthcare organizations and at national level [4,5,34].
Surprisingly, professionals with positive attitude towards ADRs were found to underreport serious ADEs [35], and some professionals tend to show several attitudinal facets including complacency, and insecurity and fear that result in underreporting of ADRs [36]. Furthermore, professionals mostly suspected ADRs (90%) but underreported (4% to 60%) them to PV centers [10,37] possibly due to time constraints, inability to recognize ADRs, unfamiliarity with the reporting process, causality relationship, unawareness about PV, well-known and mild reactions, immediate management of ADRs, legal liability, complicated ADR reporting form, and unavailability of ADR reporting template in the practice office [4,5 10]. The bottom line is that strategies should be developed for optimal and good quality reporting of ADRs by healthcare professionals around the world. Notably, National Quality Reporting System exists in Ministry of Health, Saudi Arabia that facilitates better reporting of ADRs [38].

Interventions to Improve ADR Reporting
Notably, most of A type ADRs (up to 80%) are preventable in hospitals provided cost-effective mechanisms are in place [6,39]. Underreporting of ADRs attributed to multiple reasons including lack of experience [4,5,40] is a great impediment in the prevention of ADRs in healthcare organizations [1-3].The high rate of underreporting can significantly delay signal detection, affects the performance of PV and consequently impact negatively on the public health [41,42]. Therefore, several strategies including motivational and training programs using the skilled-oriented models directed towards all health professionals were developed for optimizing ADRs reporting [43][44][45]. Other approaches for improving ADRs reporting were introduction of ADRs in undergraduate curriculum, accreditation of health settings with policies and procedures to report spontaneously ADRs, establishment of PV in healthcare settings, and publication of and free access to ADR bulletin and receiving a feedback (or a customized acknowledgement letter) from the PV

Awareness Program for ADRs
This program raises the awareness of health professionals regarding detection and reporting of ADRs to national PV system, regional centers in hospitals and competent health and regulatory authorities in Saudi healthcare settings. This program also informs professionals to be aware of the presence of ADR reporting policy in workplace and reminds them to read it thoroughly, and to know the process how to report ADRs. Besides, this program further informs them about the availability of forms used in ADRs reporting in workplace. In case forms are not available, the professionals should contact medication safety unit and quality assurance teams for their supply and in such scenario may report ADRs verbally to professionals such as head of the department. To avoid this problem, quality or drug monitoring teams should check regularly for the availability of ADR reporting forms in healthcare departments, all wards, pharmacy, nursing stations, and emergency and ambulatory care services.
Continuing medical education department in collaboration with ADR campaign program regularly organize seminars, workshops and lectures for updating professionals' information on ADRs in Saudi Arabia [4,5].In addition, this program provides guidance for searching important databases for relevant information on ADRs, and also evaluate that the professionals are satisfied with ADR information provided by the workplace. Finally, this program raises the awareness of professionals about internal ADR reporting and monitoring center and the external National Center of Pharmacovigilance at Saudi Food and Drug Authority (SFDA) and Ministry of Health. The Post-Marketing Surveillance PV is vital to the whole process used for monitoring and evaluating the ADRs [1,49], and it is effective in preventing ADRs when these are reported spontaneously by physicians and allied professionals [49,50]. ADRs monitoring requires a number of steps which are detection of ADR, causality assessment between drug and suspected ADR by using various algorithms, documentation of ADR in patient's medical file, and report of serious ADRs to pharmacovigilance or other related internal or external centers and drug regulatory authorities. For more detailed information of these steps, see this source [51].

Pharmacovigilance in General
Pharmacovigilance is a powerful tool to detect signals of ADRs. PV also helps in assessing, analyzing and preventing ADRs. PV is defined as the practice of monitoring the effects of medical drugs after they have been licensed for use, especially in order to identify and evaluate ADRs reported post-marketing of drug, and often these reactions do not appear during phase I-III clinical trials (pre-marketing period). Another definition of PV is defined as "the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem [1]. Pharmacovigilance, also known as drug safety, is the pharmacological science concerning the collection, detection, assessment, monitoring, and prevention of adverse effects of pharmaceutical products and devices. Pharmacovigilance is the process and science of monitoring the safety of medicines and taking action to reduce the risks and increase the benefits of medicines [1-3]. Overall, PV prevents ADR and consequently ADEs. PV assesses and analyzes the spontaneously reported ADR during phase IV of drug post-marketing period. There is a need for global collaboration and partnership among stakeholders to develop diagnostic tools to further improve pharmacovigilance system.
PV system is an essential component of healthcare organizations worldwide because of many reasons. The collected clinical information about a medicinal product during its development phase is usually incomplete on account of a limited number of participants and the duration of clinical trials [3]. Moreover, phase I, II and III studies are done to establish the safety, toxicity, efficacy and side effect of newly developed drugs [3,26].The most common dose-related adverse drug reactions are usually detected in the premarketing phase [1]. Since most clinical trials exclude the elderly, children, pregnant women, patients with multiple diseases, and those on medications suspected of developing interaction with the drug under study, the participants are not representative of the real world situations where the drug is eventually used [41]. The Phase IV clinical trial studies start when the drug is granted marketing license and its evaluation extends over many years. These post-marketing pharmacoepidemiological studies evaluate extensively the effectiveness, safety, and utilization of the drug in larger, diverse populations in real-life conditions [53]. PV practices consistently help in early detection of ADRs. PV also facilitates in identifying both risk factors and the mechanisms underlying the ADRs. At the same time, PV system helps the healthcare agencies in taking precautions against future risks of medicinal products and recurrence of ADRs that are linked with large costs to public [3,26,53]. Currently PV scope has grown to involve herbs, traditional and complementary medicine, blood products, biological and medical devices, vaccine, substandard and counterfeit medicines, medication errors and irrational use of medicine, and antimicrobial resistance [1].Overall, as suboptimal reporting of ADRs is a worldwide phenomenon [36], detecting and reporting ADR to PV system is the responsibility of individual healthcare professionals including healthcare users for safe use of medicines [1-3].

Objectives of the Pharmacovigilance Center
Pharmacovigilance has multiple goals including developing pharmacoepidemiological trends of ADRs, estimation of quantitative aspects of benefit/risk analysis, dissemination of information needed to improve rational drug prescribing and proper regulation, develop strategies for rational and safe use of drugs and establishes communications and collaborations with international institutions having state-of-the art experience in PV [41]. Kingdom of Saudi Arabia became an official member to participate in the WHO Program for International Drug Monitoring since 2009 [54]. In accordance with the legislation, SFDA established a PV system for the collection and evaluation of information related to the risk-benefit ratio of medicinal products available in KSA, and monitors their safety profile. It takes appropriate action when necessary and monitors the compliance of The Marketing Authorization Holders and other related organizations linked with PV system. The SFDA ensures that these organizations implement management plans to effectively monitor and manage risks associated with the safety of their medicinal products. The PV activities in KSA come within the scope of the criteria of quality, safety and efficacy, as new information is accumulated on the medicinal products under normal conditions of use in the market. PV obligations apply to all authorized medicinal products in KSA [55]. All frequent, minor to major serious ADRs occurring in all age groups including special populations, and are associated with old and new medications, vaccines, medical devices, withdrawal of drugs, drug-drug interactions, herbal products or cosmetics, need to be reported to PV system and drug safety centers [41].

Pharmacovigilance in KSA
In 1998, the Ministry of Health (MoH) in KSA established post-marketing program that aims at early detection of unexpected and serious ADRs, epidemiological trend in known ADRs, and quality defect of registered products. This program publishes ADRs reports to disseminate data among healthcare professionals. Prior to conducting the training program, its course and objectives were announced in the main hospitals and private community pharmacies. In addition, ADR reporting form was distributed to these institutions to collect important information about ADRs and reporting system. Training program was carried out with the cooperation of the US FDA in the main 13 regions of KSA. Consequently, database from received ADR forms was constructed, and an advisory committee was established to study and classify the ADR reports. Although the training program targeted all healthcare professionals to report the ADRs, the response rate was limited [43].
To further consolidate the post-marketing pharmacovigilance, the Saudi Food and Drug Authority (SFDA) was established under the Council of Ministers resolution no (1) dated 07/01/1424 H. The SFDA is an independent body that directly reports to The President of Council of Ministers. The objective was to ensure safety of foods and drugs, biological and chemical substances, and electronic medical products. Once the FDA was fully functioning, the pharmacovigilance system was integrated with it. The SFDA has 4 main sectors including the drug sector which in coordination with different departments is responsible for protecting the public health in KSA [Fig. 2]. The drug sector has a number of objectives [56]. It issues license for manufacturing, importing, and exporting, and the distribution, promotion and advertisement of medications. Drug sector assesses and monitors the safety, efficacy and quality of marketed medications, and gives marketing authorization certificate. It has a team of experts that inspects manufacturing units, importers, exporters, wholesalers and dispensers of medication products. It focuses on pharmacovigilance system. The drug sector is an independent information source on medications to healthcare professionals and the public, and also assures the safety of cosmetic products. It builds an effective relationship with the international drug authorities and scientific societies around the world. The drug sector organizes regularly short courses for health professionals and public for enhancing their health information and pharmaceutical care knowledge. It sets up the suitable rules, specifications and standards for drug's marketing authorization in the KSA. It monitors and follows the marketed drug in order to observe its ADRs and prevents illegal marketing methods of medications [56]. Overall, it is wise to know that the rational use of medicines and patient safety are, but not limited to, the ultima pharmacovigilance [57].  11 builds an effective relationship with the international drug authorities and scientific societies around the world. The drug sector ourses for health professionals and public for enhancing their health information and pharmaceutical care knowledge. It sets up the suitable rules, for drug's marketing authorization in the KSA. It monitors and follows eted drug in order to observe its and prevents illegal marketing methods of ]. Overall, it is wise to know that the rational use of medicines and patient safety are, but not limited to, the ultimate goal of Adverse drug reactions are important cause of morbidity and mortality around the world. Spontaneous reporting of these reactions is a fundamental part of successful 3]. Unfortunately, unfamiliarity or unawareness with ADRs and their reporting procedures are major factors that lead to non-reporting of ADRs by professional including pharmacists [4,5,47,58 suboptimal reporting was found to be a common phenomenon globally. In several studies that explored KAAP of hospital physicians found that ADRs was underreported by those with low levels of awareness of policy and procedures, knowledge, and practice [4,5, 59,60 showed favorable attitude and willingness t improve their practice of ADR reporting, the latter was influenced by the job position and the knowledge score [48]. The low level of acquaintance with the institute's ADR reporting system and PV center and ADR forms varies from 25% to 47% across several studies [5,6 and both factors are linked with ADR underreporting. The reporting of ADRs is a shared responsibility that need collaboration of all the team members [4,5,47], and similar findings were reported in a study [3] which suggested the contribution of all professionals including the nurses to the reporting of ADRs to pharmacovigilance.

DISCUSSION
food and drug authority, drug sector departments , 2016; Article no. JAMPS.30653 reporting procedures are major factors that lead reporting of ADRs by professionals 47,58]. Therefore, suboptimal reporting was found to be a common ly. In several studies that explored KAAP of hospital physicians found that ADRs was underreported by those with low levels of awareness of policy and procedures, 0], though they showed favorable attitude and willingness to improve their practice of ADR reporting, the latter was influenced by the job position and The low level of acquaintance with the institute's ADR reporting system and PV center and ADR forms varies across several studies [5,61], and both factors are linked with ADR underreporting. The reporting of ADRs is a shared responsibility that need collaboration of ], and similar findings were reported in a study [3] which the contribution of all professionals including the nurses to the reporting of ADRs to Physicians working in critical care units had the highest ADRs awareness and ADRs reporting compared to those in surgical departments attributed to the differences in the settings and alertness, the types of patients, and the increasing number of medications used [42,47,62]. The use of medications in surgical departments is often limited to antibiotics and pain killers, whereas in critical care or emergency departments a wide spectrum of medications is used [63]. Physicians with favorable attitudes, also influenced by place of work and culture of safety, fulfill their obligations to patient benefits by good quality reporting of ADRs to PV system [49,64]. Surprisingly, physicians' high awareness of ADRs reporting is found to have reverse relationship with their attitude in critical care including emergency departments [65,66] attributed to high frequency of ADRs in such settings [5,47] and absence of clinical services provided by clinical pharmacists [66]. Similarly, detecting ADRs and practice of their reporting by physicians did not show direct relationship [61,64] attributed to self image bias [68] together with inadequate and inappropriate reporting especially by verbal means [5]. The misconceptions related to the safety of drugs once in the market, and the confidentiality issues associated with ADRs reporting are some other factors underlying suboptimal reporting of ADRs to PV [4,5,47]. The underreporting and poor quality of ADR reporting are managed by using different strategies including decentralization of PV, educational interventions, lectures, development of alerts and monthly bulletins, scientific research, use of social networking, and extension projects [68]. Overall diverse factors underlie suboptimal reporting of ADRs to PV that negatively impact PV performance and patient safety.
Some studies suggested that the patients have a role in reporting ADRs and they need training in several areas including early detection and reporting of ADRs to PV and other reporting centers in hospitals [5,47]. The training of patients is essential because they are reported to have limited awareness and knowledge of ADRs and reporting system, and about half of those who experienced ADRs have reported to their family physicians [69]. The implication of this finding is that the family physicians have a definite role in ADRs monitoring and reporting. In another study, patients expressed that reporting of ADRs is not their responsibility, and they need training to increase their awareness of ADRs and their reporting perspectives [70]. A randomized clinical trial that used an interactive educational program demonstrated the effectiveness of improving patients' reporting of ADRs [71]. The role of patients in reporting ADRs remains controversial and possibly underestimated; nonetheless the reporting of ADRs by consumers tends to improve PV programs [72]. Other researchers stated that reporting of ADRs by consumers tends to increase the rate of ADR reporting to [8,73] and reliability of PV system [74]. In another study, Härmark and colleagues reported three key points concerning patientreported drug safety information that adds value to pharmacovigilance signal detection, and leads to better understanding of the patient's experiences of the ADR. Furthermore, pharmacovigilance needs to develop patientspecific form, development of a severity grading and evolution of the database in order to make use of patients reported ADR information [75]. In a nutshell, the reporting of ADRs by healthcare users is a true reflection of their real experiences.
Several studies have reported a number of motivating and hindering factors underlying ADRs reporting to PV centers [5,47,67].The low awareness of ADRs reporting system is another reason for ADRs underreporting [67], and this finding is inconsistent with the results of other study in which more than 80% of the physicians were aware of the system, and yet underreported ADRs [5]. The literature provides strong evidence of improvement in attitudes towards ADR reporting by various types of interventions such as skill-based training [45], self-training aided by educational tools [64], and on job educational programs supported by handouts [76]. The physicians' awareness of ADR detection and reporting influenced by the feeling of being adequately trained underscore the importance of CME in improving their knowledge, awareness, attitude, practice towards ADR and PV [36,47,64,76,77]. Similarly, the undergraduate training in PV needs to be sufficiently delivered to physicians who are involved in ADR monitoring and reporting in their future career [8]. Arguably, continuous training of professionals including community pharmacists in ADRs reporting to PV needs to be mandatory in all general hospitals around the world [67,78]. Community pharmacists tend to report ADRs to physicians rather than to PV center [58] and, therefore, a strong link need to be developed between health professionals and community pharmacists. Overall continuing training of health professionals in ADR need to be a global agenda as it is linked to optimal, quality reporting of ADRs to pharmacovigilance that ensures patient safety.
Pharmacovigilance, an essential tool for patient and public safety [79] detects adverse effects of pharmaceutical products not identified during clinical trials conducted pre-marketing period. These ADRs are rare but potentially important from the perspective of patient safety. In other words, post-marketing drug surveillance is complementary to the pre-marketing identification of most frequent ADRs of newer drugs. However, most ADRs need to be reported spontaneously to the PV by professionals in health settings, drug industries and patients. Most importantly pharmacovigilance needs to be patient focused [75]. As underreporting of ADRs adversely affects the functioning of pharmacovigilance [80], and, hence, optimal reporting of ADRs needs to be achieved. This is important because PV analyses these reactions and provide immediate solutions to prevent ADRs and ensures patient safety. Roux et al. [80] developed a practical approach for evaluating automatic signal generation methods implicitly involved the human, material, and time resources available for interpreting and exploiting retrieved information. Moreover, this approach should be adopted not only for evaluating measures of association, but also for developing new measures [80]. Validated data collected in pharmacovigilance system on ADRs using mining techniques such as Multi-item Gamma Poisson Shrinker [81] have other clinical applications including identification of higherthan-expected reporting relationships between drugs and events [82], detection of delayed toxicity of concomitant drug such as antipsychotics induced pancreatitis and diabetes mellitus [81], and assisting drug regulatory functions in terms of safety warnings, changes of product information, suspension or withdrawal of drug license [57]. Pharmacovigilance centers also alert prescribers, manufacturers and the public to new risks of ADRs. Pharmacovigilance is now considered a medical science. Furthermore, pharmacovigilance archived data from International Pharmacovigilance Agency (WHO database, VigiBase™) could be used to study the rare syndromes such as Kounis Syndrome in which symptoms of cardiovascular system (acute coronary syndrome and myocardial infarction) and allergy occur concurrently and often patient dies of acute cardiovascular disease [83]. Pharmacovigilance system may also help in identification of ADRs globally and risks of self-medications provided related ADRs are reported spontaneously to PV [84]. Overall, pharmacovigilance fairly contributes to the safe use of medicinal products and devices globally; however there remain many challenges including priority to pharmacovigilance development and good pharmacovigilance practice in the Eastern world [85,86].

CONCLUSION
Adverse drug events including adverse drug reactions cause significant mortality and morbidity around the world. Although several reports have clarified the confusion concerning the terminology of ADRs and related terms, a large number of factors underlying poor quality reporting of ADRs and their underreporting are perceived to be the major challenges that pharmacovigilance faces in current circumstances.
The role of healthcare professionals and patients is to report all serious ADRs spontaneously and qualitatively to pharmacovigilance that helps early signal detection leading to safe use of drugs and, thus, ensures patient safety and reduction in public health burden.

CONSENT
It is not applicable.

ETHICAL CONSIDERATION
It is not applicable.