The international arena

In 1968, the WHO established its Programme for International Drug Monitoring in response to the notorious thalidomide catastrophe, which was detected in 1961. The program provides a forum for WHO member states to collaborate in the monitoring of drug safety, and notably, the identification and analysis of new adverse reaction signals from data submitted to the WHO global individual case safety report (ICSR) database by member countries [2]. WHO’s definition of signal is “Notice of an early concern or hypothesis about a possible medicines safety problem, with evidence and arguments to support it” [3]. The WHO promotes PV at an international level as well as on a country level. Globally, the WHO’s Collaborating Centre for International Drug Monitoring, located in Sweden, collects information from over 140 countries throughout Africa, the Americas, Asia, Australia, and Europe. The WHO’s global ICSRs database is called VigiBase. This database includes a web-based reporting and retrieval tool (VigiLyze) and an automated signal detection process. In April 2015, the WHO launched VigiAccess. VigiAccess is a new web application that will allow anyone to access information and encourage the reporting of adverse effects from medicinal products [1].

Europe

Pharmacovigilance activities in Europe are overseen by the European Medicines Agency (EMA) as well as at states level. Each of the 28 member states in the EMA, operates a national PV system which collects and analyzes its findings locally and reports them centrally. The EMA also supports and coordinates the European PV system and consults on the safe and effective use of drugs. Pharmacovigilance information is gathered from various sources and stakeholders, including regulatory agencies, industry, healthcare professionals, as well as from consumers. At the EMA, the reports are assessed by the PV Risk Assessment Committee. This committee is responsible for evaluating and monitoring safety issues for human medicinal products and is composed of experts from regulatory authorities in member states, experts in medicine safety, healthcare professionals, and patient representatives [4].

The EMA’s reporting system for suspected cases of adverse reactions is the EudraVigilance. The EudraVigilance database includes reports of suspected adverse reactions to medicines from medical practice and from clinical trials. This system is not fully accessible by the general public and has different levels of access for different stakeholders [5].

United States

The US Food and Drug Administration (FDA) Division of Pharmacovigilance assesses safety issues and detects signals for all marketed medicinal products in US. The FDA uses a variety of PV tools including post-marketing reports of adverse events, published scientific literature, and preclinical/clinical data to provide a comprehensive evaluation that leads to regulatory actions as well as safety communications concerning marketed products. The reports are maintained in the FDA Adverse Event Reporting System (FAERS). This database is designed to support the FDA’s post-marketing safety surveillance program for drug and therapeutic biologic products [6].

Pharmacovigilance in Israel

Israel established a Pharmacovigilance and Drug Information Department within the Pharmaceutical Division of the MOH in 2012. Prior to this, reports on safety issues related to the use of medications were dealt with by various departments within the Pharmaceutical Division and not managed centrally. The Department was created in response to a series of multiple adverse events reported to the Ministry, highlighted by intense media and social media coverage; this was commonly referred to as the “levothyroxine (Eltroxin) event”. Upon establishment of the Department its manager underwent extensive training at the WHO’s center in Uppsala, Sweden. The Department also adopted the main principles of PV as practiced by the FDA and EMA.

The Pharmacovigilance and Drug Information Department is composed of pharmacists and clinical pharmacists who work in collaboration with the Clinical Pharmacology Department at Asaf Harofeh Medical Center in Israel. The department’s main functions include ADR and signal management, submission of safety evaluations of medicinal products to other departments within the MOH, implementation of risk minimization plans and communicating drug safety issues to healthcare professionals and to the public.

Background: the levothyroxine event

In February 2011, the composition of the levothyroxine product, Eltroxin, which has been registered and marketed in Israel since 1981, was changed. Upon introduction of the new formulation in Israel, health care professionals began receiving reports of adverse events which were mostly related to hormonal imbalance (underactive thyroid, overactive thyroid) and a few involving allergic reactions. Since, the health care professionals were not aware of the change in the formulation, the adverse events were not attributed to the formulation of the medication. At the time, there was no requirement for medical institutions/health care providers to report suspected ADR to the MOH, therefore only some of the events were reported to the MOH. After additional investigation the ministry decided to take measures and instructed the MAH to raise awareness of health care providers and patients about the change and the need of close monitoring.

In the aftermath of the event, an investigation revealed that a similar change in formulation took place in Denmark in 2006 and in New Zealand in 2007. These changes also resulted in hundreds of reports of adverse events. Gaps in transferring this important PV information by the MAH to the Israeli Ministry of Health prevented preemptive measures that should have been taken by the Ministry.

In January 2012 an inquiry committee appointed by the Ministry’s Director General, published its report [7]. By then, 800 reports were received by the Pharmaceutical Division of the Ministry of Health. The committee emphasized that Israel had no requirement for medical institutions/health care providers to report ADRs to the Ministry of Health, as was the standard practice in other mature agencies worldwide, and noted the situation to be problematic. As such, it stressed the need to establish an infrastructure within the Pharmaceutical Division for collecting and analyzing adverse drug reactions reports and other safety data. The final report of the committee included recommendations to publish a procedure for reporting adverse events and safety information, to establish a PV and drug management department, to expand the collaboration with health authorities worldwide in the area of safety of medicinal products, to improve ways of communicating safety data to health care professionals and patients, and to increase the awareness among health care professionals of the importance of reporting adverse drug events. In light of the committee’s recommendations, the MOH established the Pharmacovigilance and Drug Information Department.

Legislation and procedures for pharmacovigilance

Prior to establishing legislation on PV, the Ministry of Health followed procedures that were published in 2012 and were updated in February 2013. However these procedures were only aimed at the MAHs and excluded the obligation of health institutions to report the Ministry. In June 2013, the Israeli Parliament (“Knesset”) amended the Pharmacists Regulations (Medical Products) 1986, and anchored the obligations of all MAHs, health maintenance organizations (HMOs), and hospitals in Israel to report ADRs, or any new safety information relating to medications used in Israel to the MOH. This also included a requirement for the reporting to be done by a designated appointed person, also known as Qualified Person Responsible for Pharmacovigilance (QPPV), and for the organization to operate a drug safety monitoring system. As per the regulation, the QPPV has to be a pharmacist or a physician holding an Israeli license to practice, with practical experience of at least 2 years in his/her profession. This individual needs to be appointed by the organization and approved by the MOH. For situations involving medical gases, a practical engineer may also be appointed to this position.

Subsequently, In October 2013, the Pharmacovigilance and Drug Information Department published an updated version of the procedure for reporting adverse events and new safety information [8]. The updated version sets out PV requirements for the MAHs. It clarifies the work processes relating to ADR and other safety data reporting as well as the types of information which must be reported by the MAHs. In 2014, the Medical Affairs Administration of the MOH published a directive to medical directors of hospitals and HMOs regarding the importance of ADR reporting and guidance for establishing an ADR reporting system in their institutions.

In accordance with the aforementioned legislation, each of the 4 Israeli HMOs appointed a QPPV whose responsibility is to receive and collect reports from health care professionals within the institution and submit them to the MOH’s Pharmacovigilance and Drug Information Department. Clalit health services (“Clalit”), which serves more than 4 million citizens [9], is the largest HMO in Israel. Clalit is responsible for community care as well as secondary care and it operates a network of 14 hospitals in Israel. Clalit’s QPPV is also responsible for the collection and the reporting of ADRs from these hospitals. QPPVs at other HMOs are responsible for reports arising only at the primary care (community) settings. Currently, some of the hospitals have already appointed an in-house QPPV while, in others, the process of appointing a QPPV is ongoing.

ADR reporting system and ICSRs

Individual case safety reports are received by the Department from health care professionals, patients, and from the MAH. Between September 2014 and August 2016, 16,500 reports were entered into the PV central database. Of these reports, 94.3%were submitted by pharmaceutical companies (MAH and importers), 5.5% were submitted by health care professionals from medical institutions, and only 0.2% of the reports have been submitted by patients and the general public. In addition to the electronic reports received in the database, health care professionals also reported adverse events via mail or by phone and patients reported them as complaints or questions via the drug information call center or ADRs patients’ Forum, a web-based service offered by the PV department to the public (more than 130 per year). 40% of the ADR reports in the database, were defined as serious, 59% defined as non-serious, and for the other 1% seriousness was not specified.

Individual case safety reports can be submitted to the Pharmacovigilance and Drug Information Department by sending a standard International Conference on Harmonization (ICH) E2B format, an electronic format facilitated by the ICH for transmission of ADR reports. This method of transmission is currently used mainly by the industry (mostly MAH but also by some importers of unlicensed drugs which may be used in Israel due to drug shortages). Additionally the Department developed a designated electronic form allowing for an online reporting of ADRs by the general public, health care professionals as well as from QPPVs at various MAH/importers who do not have ICH E2B reporting system [10]. The form enables a structured method for reporting and filing an adverse event. The form is based on the WHO guidelines for effective and valid report. The minimum information for a valid report includes at least one patient identifier (initials, age, or gender), an identifiable reporter, at least one reaction, and at least one suspect drug. Individual case safety reports in both formats are received and displayed in the PV system described above.

Over the course of the assessment period, 50% of the reports were submitted via the online government form and 50% were submitted via E2B format. We performed an analysis of the ICSRs in our database according to Anatomical Therapeutic Chemical (ATC) classification – a classification of the suspected drug or active substance, according to the organ or system on which they act and their therapeutic, pharmacological and chemical properties [11]. The most frequently reported medication group was the immunosuppressant drugs (categorized by ATC -3). This is also the most frequent reported group in the WHO ICSRs database (VigiLyze).

During the assessment period, the top 10 ATC-3 medication groups, which account for 68% of all ADRs reported to the department were immunosuppressant drugs (L04A), antineoplastic agents (L01X), parathyroid hormones and analogues (H05A), antithrombotic agents (B01A), blood glucose lowering drugs (excluding insulin; A10B), hypothalamic hormones (H01C), direct acting antivirals (J05A), hormonal contraceptives for systemic use (G03A), immunostimulant drugs (L03A), and all other therapeutic products (V03A). The latter medication group consists of antidotes, iron chelating agents, drugs for hypercalcemia, hyperkalemia and hyperphosphatemia, detoxifying agents, tissue adhesives, drugs for embolization, medical gases, nalfurafine, diazoxide, cobicistat and ethanol. Figure 1 presents the 10 most common ATC-3 medication groups as percentage, of the total number of reports received in database from September 2014 through August 2016.

Signal management and regulatory actions

Signal detection is often based on a review of ICSRs. In the Pharmacovigilance and Drug Information Department, pharmacists and clinical pharmacists, specializing in PV, perform a case by case assessment to detect signals.

Additional sources for signals are reports of medication misuse and/or quality concerns arising from medical staff, industry-operated patient support programs, observational studies, clinical trials, ADRs patients’ forum, scientific literature, periodic safety reports/periodic benefit risk evaluation reports (a document submitted by the MAH to regulatory agencies), and safety communications from other health authorities (whose websites are monitored on daily basis). In order to confirm a signal, it is cross referenced with various sources of data. This process of signal detection, evaluation and prioritization takes into consideration factors such as frequency of the ADR, its severity, impact on public health, and the feasibility of counteract measures.

Additional factors taken into consideration include signals that involve serious, unexpected ADR, with reasonable causal association to the suspected drug, or a new aspect of a known association involving new product or new formulation. Moreover, the Department prioritizes signals derived from ADR reports that can indicate national safety issues such as a local quality concern and unusual frequency of a known ADR. Another important resource used by the Department to evaluate ADRs, signals, and other safety issues is an independent experts advisory committee appointed by the MOH for this purpose. Comparable committees exist at other regulatory agencies such as the FDA and EMA. The advisory committee consists of representatives from a variety of health disciplines, including clinical pharmacologists, pharmacists, and other specialists.

In addition, Israel has signed agreements with several leading medicines agencies, such as Swissmedic and the FDA. These memorandums of understanding include PV data sharing. Overall, when needed, the Department communicates safety dilemmas with other regulatory agencies, mainly the EMA, FDA and Swissmedic. Following an internal assessment process and additional consultation with other regulatory agencies (if needed), the Department concludes whether the evidence is sufficient to support a safety concern to the public and determines what steps should be taken to manage and minimize this potential risk.

Since 2014 until the end of 2016, 850 signals have been identified from all sources. Following evaluations that took into account the impact on public health and the feasibility of counteract measures, it was determined that 430 signals required inquiry or follow-up and 420 of the signals required additional regulatory actions. Forty percent of the signals originated from ADR reports.

Among the PV activities initiated following the signal detection were: initiating leaflets and label updates, informing health care providers and the public regarding safety concerns, and in special cases –withdrawing a drug from the market, recalls or inventory holds of specific products or batches. Figure 2 represents the distribution of PV activities initiated in response to signals (n = 850).

In addition to the described activities, as of 2015 the Pharmacovigilance and Drug Information Department takes proactive risk management process to minimize potential risks associated with the use of medications by implementing risk minimization plans (RMPs) with the MAHs. RMPs are key regulatory tool for characterization, assessment, mitigation, and minimization of risks associated with use of a medicinal products. A procedure that sets the guidelines for submitting RMPs to the Pharmaceutical Division was published in March 2016. Since 2015 to date, 30 RMPs were implemented in Israel.

Examples of PV activities based on signal detection from ADR reports and/or other sources