Pharmacovigilance Follow Verify

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Pharmacovigilance
Industry	Pharmaceuticals Life Sciences
Related Certifications	Certificate in Current Pharmacovigilance Landscape
Cost	FREE for students $20 for professionals
Launched	January 2016
Level	Advanced/Professional

The etymological roots for the word "Pharmacovigilance" are: "Pharmakon" "Φάρμακο" (Greek for drug) and "Vigilare" (Latin for to keep watch). Pharmacovigilance (PV) is defined by the World Health Organisation (WHO) as the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem. Pharmacovigilance also referred to, as drug safety, is the science of understanding the adverse effects caused by a drug and assessing whether the benefit will outweigh the risk. Beside this, there are also other definitions of pharmacovigilance:

• Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications, biological products, herbal products and traditional medicines.

• "Pharmacovigilance (PV) is the pharmacological science related to the detection, assessment, understanding and prevention of adverse effects, particularly short-term side effects of medicines after marketing of the drug.

• Pharmacovigilance is a branch of pharmaceutical sciences which deals with detection, assessment, understanding and prevention of side effects or adverse effects (ADR’s) of the active moiety. In short, it deals with the safety of the drug. According to WHO guidelines Pharmacovigilance ultimate goal is to improve the safe and rational use of the drug which eventually improves the patients care and public care.
• Pharmacovigilance has also been referred to as Post-marketing Surveillance which is crucial to quantify previously recognized adverse drug reactions to identify unrecognized adverse drug events to evaluate the effectiveness of the drugs in real-world situations and to decrease mortality and morbidity associated with adverse events.

The Scope of the Pharmacovigilance

Concept of Pharmacovigilance and its significance enhances the impact of pharmacovigilance on patient welfare and public health and to know what is pharmacovigilance. Pharmacovigilance legislation gives an outlook on the rules and laws to follow in Pharmacovigilance practice. The role of pharmaceutical industries in the improvement of pharmacovigilance system is very crucial to maintain data safety. Detection and evaluation of drug safety signals through manual and medical devices reporting. Pharmacovigilance scope also deals as Ecopharmacovigilance (EPV), pharmacoenvironmentology and pharmacovigilance in herbal medicines. The entire scope of pharmacovigilance includes the following domains:

Pharmacovigilance activities

Before a medicine is authorized for use, evidence of its safety and efficacy is limited to the results from clinical trials, where patients are selected carefully and followed up very closely under controlled conditions. This means that at the time of a medicine's authorization, it has been tested in a relatively small number of selected patients for a limited length of time.

After authorization the medicine may be used in a large number of patients, for a long period of time and with other medicines. Certain side effects may emerge in such circumstances.

It is therefore essential that the safety of all medicines is monitored throughout their use in healthcare practice.

Pharmacovigilance activities include:

• Searching and managing data on the safety of drugs.
• Going through the data to detect 'signals' (any new or changing safety issue, changes in the frequency of reported events).
• Evaluating the data and making decisions with regard to safety issues.
• Pro-actively observing risk factors and managing the same to minimize any potential risks associated with the use of the medicine.
• Acting to protect public health (including regulatory action i.e antibiotic regulation to avoid antibiotic resistance).
• Communicating with and informing stakeholders and the public.
• Audit outcomes of the actions taken and the key processes involved.
• Monitoring social media for information. In order to realize the potential that social media have to offer, a number of challenges remain to be resolved. Some of these are technical in nature while others require careful consideration from regulatory and ethical perspectives to understand fully and yield the benefits that social media have to offer.

Those directly involved in pharmacovigilance include:

• Patients who are the users of medicines and medical products.
• Doctors, pharmacists, nurses, paramedics, and all other healthcare professionals working with medicines.
• Regulatory authorities, including the European Medicines Agency (EMA) and those in the Member States responsible for monitoring the safety of medicines.
• Pharmaceutical companies and other companies importing or distributing medicines.
• Pharmacologists who deal with adverse drug reactions of patients enrolled in clinical trials, from fundamental pharmacodynamic studies to studies of pharmacokinetics and drug metabolism, to pharmacogenetics.

The areas of pharmacovigilance include:

• Drug/Product quality.
• Adverse drug reaction.
• Medication error. ​

The Impact and Use of Social Media in Pharmacovigilance

Social media attracts much attention from the pharmaceutical industry through the websites such as Linkedin, Twiiter, Facebook, Youtube, Flipboard, Flickr, and Pinterest which providing value in establishing intra- and inter-company stakeholder collaborations and other communities. Pharmacovigilance (PV) has been evolving and growing more complex over the past 5 to 10 years due to increasing data volumes, evolving regulations, influences of the emerging markets as well as emerging social media and innovative technological advances. Digital media is now used by biopharmaceutical companies for communication with patients to raise awareness about the diseases and various treatments, clinical trial enrollments and patient support programs. It presents new channels and methods that can enable companies to move away from the traditional PV systems and safety reporting methods towards more patient centered models in terms of reporting, analyzing and monitoring of safety data. Text mining has been applied to various sources of pharmacovigilance data including biomedical literature, clinical narratives and web search logs.

Biopharmaceutical companies operating in the social media space have a responsibility to document and follow-up on any potential adverse event (AE) reports which must be communicated through these forums in compliance with the applicable regulatory guidance's. Most of the regulatory guidance's and hence PV activities involving social media and the internet are primarily focused around the screening of social media websites and follow-up of reported safety data. Additional specific guidance is required to confirm the validity of safety data obtained via social media (within the norms of data privacy), protocols to guide further retrieval, analysis and integration of such data with other standard safety data (obtained from standard PV sources) along with effective use of social media for risk management and communication.

Companies rely on multiple AE reporting channels such as email correspondences, company websites and physician hotline resources. There are now multiple sites and applications to capture patient and consumer AE reports on computers and smartphones. Companies are now actively engaged to identify and understand the value drivers for adopting a comprehensive PV social media strategy, which encompasses proactively creating social media platforms to solicit/capture AE data, rather than monitoring and reporting what comes in passively on existing company sites, and further examine the successes and challenges of the different types of social media platforms being used. Social media data offers some advantages over traditional AE reporting data or data mined from health and reimbursement records. Social reports are rapid, closer to real-time data (occurring in close proximity to the event) and potentially richer sources than reports filtered through HCPs. Social media is a promising source for new safety data and potential emergent safety signals. Yet, it is important to keep in mind that this data is essentially unstructured and obtained via uncontrolled and ungoverned processes in a non-regulated environment and is neither driven by data quality standards nor by specific business area orientation. At the same time, it is vital to carefully verify safety data obtained via social media for confirmation of the “identifiability” for the both, the reporter and the patient, address related data privacy issues and verify accuracy of reported safety data in lieu of potential bias introduced by the “reporter population”.

Pharmacovigilance Challenges and Solutions with Digital Media

Social media monitoring has become a standard practice in PV. Overcoming various social media hurdles for validation and consolidation of incoming data poses a great challenge, requiring the concerted efforts of PV teams. At the same time, careful evaluation and assessment of the use of social media as a PV tool need to be constantly revisited; both in terms of meaningfulness and impact on outcomes. Understanding regulatory guidelines, current state and future considerations for the use of social media in PV, possible areas of influence and expected challenges are critical, along with potential solutions and next steps. To learn more about the future impact and potential areas to leverage social media in PV.

Pharmacovigilance activities start with safety information coming from a variety of sources, including clinical trials data, safety call centres, patients medical records, spontaneous reports, literature searches, and social media data where each has the potential to create an individual case. Within the pharmacovigilance department, each case is processed, assessed as to its relationship (causality) to the investigational product, and reported to the regulatory authorities and to the other stakeholders, either as an expedited report or as part of an aggregate report, based upon pharmacovigilance policies, regulations, and guidance documents. In addition, each case becomes a part of the total safety data set for that medicinal product.

PHARMACOVIGILANCE INDICATORS

Definitions

Indicators are specific objective measures that allow the evaluation of the baseline situation and progress in systems and the assessment of services and interventions. Pharmacovigilance indicators are measures of inputs, processes, outputs, outcomes, and impacts of development projects, programmes or policies related to health systems and services. They provide information for measuring how well a pharmacovigilance programme is achieving its objectives. The pharmacovigilance indicators are classified into the following three groups:

• Structural indicators
• Process indicators
• Outcome or impact indicators.
• Pharmacovigilance (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.

They can be also classified based on their importance or how essential they are to a functional pharmacovigilance system. The most fundamental indicators are classified as Core, and others as Complementary.

Rationale and objectives of pharmacovigilance indicators

The indicators should measure the existence and performance of key pharmacovigilance structures and processes and be able to identify the strengths and weaknesses, as well as revealing the achievements, growth or lack of growth of the pharmacovigilance systems. They should also measure the degree of attainment of set strategic objectives. The main objective of the pharmacovigilance indicators is to provide measures that will enable the assessment of the status of pharmacovigilance, the activities and their impact, globally at all levels of the health-care system, with a view to ensuring patient safety. The availability of this set of pharmacovigilance indicators will also provide objective indices with which to measure performance in this area. In essence, a set of indicators addressing pharmacovigilance issues will:

• Provide objective measures to describe the pharmacovigilance situation in a country;
• Assess pharmacovigilance activities – at the global (national), regional and health-care facility levels;
• Assess the capacity of (and for) pharmacovigilance at these levels;
• Provide tools for supervision and monitoring of pharmacovigilance activities;
• Assess progress and enable the prioritization of efforts, based on this assessment;
• Enable comparison of pharmacovigilance activities between geographical regions and health facilities at a given time and at different times;
• Provide tools for measuring the impact of interventions; and
• Provide information for governments and other stakeholders to enable them to take appropriate action in ensuring drug safety.

Characteristics of ideal pharmacovigilance indicators

The characteristics of ideal pharmacovigilance indicators are:

1. Simple to understand
2. Easy to measure and interpret
3. Reproducible
4. Specific and sensitive to any pharmacovigilance facility

ADVERSE EVENT REPORTING TIMELINES

"Adverse Event (AE) is any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment." According to ICH E6, all SAEs should be reported to the sponsor immediately, except for those identified in the protocol or another document as not needing immediate reporting. Fatal or unexpected ADRs occurring in clinical investigations should be reported to the regulatory authorities as soon as possible, but no later than seven calendar days after knowledge of the event by the sponsor followed by as complete a report as possible within eight additional calendar days. Serious unexpected reactions (ADRs) which are not fatal or life-threatening must be filed as soon as possible but no later than 15 calendar days after first knowledge by the sponsor that the case meets the minimum criteria for expedited reporting. Adverse events that do not meet the requirements for expedited reporting are reported at the end of the clinical trial as part of the marketing application or in PSURs.

Adverse Drug Reactions Monitoring An international system for monitoring adverse reactions to drugs (ADRs) using information derived from the Member States was established in 1971. WHO Headquarters is responsible for policy issues while the operational responsibility for the programme rests with the WHO Collaborating Center for International Drug Monitoring, Uppsala Monitoring Center, (UMC), in Sweden. The system started with 10 countries that had already established national systems for spontaneous adverse reaction reporting and who agreed to contribute data. The ADRs database in Uppsala currently contains over three million reports of suspected ADRs.For an effective international system to become operative, a common reporting form was developed, agreed guidelines for entering information formulated, common terminologies and classifications prepared and compatible systems for transmitting, storing and retrieving and disseminating data were created.

IDENTIFYING ADVERSE DRUG EVENTS Since the FDA has limited options for addressing safety questions about drugs after pre-marketing research has occurred, identifying ADEs requires the participation of health-care providers, consumers, and others. MedWatch, the FDA’s program for post-market surveillance, collects clinical information involving drugs from health-care professionals and consumers through a variety of channels, including mail, Internet, and telephone. The largest source of post-market information on ADEs is drug companies themselves. Companies typically submit large numbers of reports at a time in the batch form to the FDA. Data on adverse events are placed in the AERS and are evaluated by FDA staff to detect safety signals and monitor drug safety.

Challenges associated with current systems for reporting ADEs were discussed by workshop participants. Under-reporting and incomplete reporting and poor quality of data are concerns about all reporting systems. There have been suggestions that streamlining these systems and ensuring anonymity may motivate health-care providers to file adverse event reports with greater frequency and accuracy. Participants discussed the need for incentives to encourage the development of long-term safety studies. Furthermore, it was suggested that informing consumers about known drug risks and benefits may encourage consumer reporting of ADEs and participation in follow-up studies.

Potential adverse events are also identified through case reports in the medical literature and through epidemiologic surveillance of electronic claims and other data. Surveillance systems screen claims data for adverse events and notifies health-care providers who then determine if follow-up reporting is required. The Centers for Medicare and Medicaid Services captures data on drug use and clinical services for individual subscribers. And institutional review boards of individual health systems capture many adverse events in clinical trials.

Importance of Pharmacovigilance in Clinical Trials

Clinical trials are an essential part of the drug development process. They are conducted in order to determine the safety and efficacy of a chemical or biological compound with respect to its actions on symptoms or a known disease process. Pharmacovigilance provides an extra level of security to ensure that safe and effective products reach patients. Trials are closely monitored by investigators, sponsors, and CROs. However, the process also involves review from ethics committees, review boards, and regulatory bodies. This is where Pharmacovigilance becomes significant. This process provides an extra level of security to ensure that only safe and effective products reach the patients. As a part of the global healthcare system, it is the responsibility of drug manufacturers/developers and investigators to provide only the best possible care for patients. The concept of pharmacovigilance or safety monitoring in clinical trials differs from country to country as many other aspects (e.g., accent, access to healthcare institutions, and the availability of advanced diagnostics and treatments. Safety monitoring during clinical trials is now recognized as one of the major concerns for new drug development with three main areas of concern:

1. the collection of adverse experience information
2. assessment/monitoring of clinical data
3. reporting/communication of clinical data.

Pharmacovigilance or drug safety is the science of understanding the adverse effects caused by a drug and assessing whether the benefits outweigh the risks. This includes identifying adverse effects during clinical trials conduct and post-marketing approval. It's the responsibility of all stakeholders to monitor and update the risk-benefit ratio based on relevant findings, prevent or minimize adverse effects and most importantly, harmonize communication of these findings to the affected global regulatory authorities in a timely manner. Concept of drug safety is also known as Medication Safety in the field of health. It is associated with adverse effects of Pharmaceutical products involving many other scientific aspects, such as the side effects of drugs, the quality of medications, medication error in the usage of drugs, lack of efficacy of drugs, and counterfeit drugs. Patient Safety, Drug Interaction (drug-drug and food-drug interaction) Drug Pharmacokinetic, and Adverse Drug Reaction are several terms involved with Drug Safety. Companies have to conduct complete drug safety and pharmacovigilance audit to gauge their compliance with international standards of laws, regulations, and guidance. Once research into new drugs is in the post-marketing stage (Phase IV studies) safety may be monitored to comply with the conditions of registration, particularly when there are unresolved concerns. This may lead to improved and more rapid changes in labelling or even withdrawal of a new drug from the market. Routine application of principles of good clinical practice that ensure patient safety and strict compliance with prescribed regulatory requirements would substantially improve standards of clinical trials. Clinical trials are used throughout the world to determine the safety and efficacy of a chemical or biological compound with respect to its actions on symptoms or a known disease process. Trials are closely monitored by an investigator and the pharmaceutical company involved in the research and development of a medicinal product. But, the process also benefits from autonomous review by Independent Review Boards, Ethics Committees and drug safety firms. This is where pharmacovigilance fits into this process; to provide an extra level of security to ensure that safe and effective products reach patients. As part of the global healthcare and pharmaceutical system, manufacturers, drug developers, and investigators all have the responsibility to provide the best possible care for the patients and consumers around the world.

Pharmacovigilance, also referred to as drug safety, is the science of understanding the adverse effects caused by a drug and assessing whether the benefit will outweigh the risk. This includes detection of adverse effects during the clinical trial and post marketed phases, monitoring and updating the risk-benefit ratio based on relevant findings, prevention or minimization of adverse effects and, most importantly, harmonized communication of these findings to the affected global regulatory authorities in a timely manner. The concept of Pharmacovigilance and its Significance enhances the impact of pharmacovigilance on patient welfare and public health and to know what is pharmacovigilance. This track gives a brief discussion on Pharmacovigilance role the n healthcare system. Pharmacovigilance legislation gives an outlook on the rules and laws to follow in Pharmacovigilance practice. The Role of Pharma industries in the improvement of the pharmacovigilance system is very crucial to maintain the safety data, Detection and Evaluation of drug safety signals through manual and medical devices reporting. Pharmacovigilance scope also deals as Ecopharmacovigilance (EPV), pharmacoenvironmentology and pharmacovigilance in herbal medicines.

During the past decade, increased use of various expedited review approaches and other improvements have led to a decrease in time taken to bring new drugs to market. While this acceleration has led to more rapid access for patients, it also increases the risk of adverse drug reactions being detected for the first time when the product is already in the market, leading to higher demand for post-approval safety surveillance studies and related activities.

In addition, the move from paper to electronic formats, along with increased vigilance from various stakeholders, has increased the amount and velocity of safety information in the environment. Spontaneous reports from all sources need to be managed with a full understanding of the role even a single case can play in changing the perceived benefit-risk profile of a product. The evaluation of cases at the point of initial entry needs to be undertaken at the highest standard of both quality and timeliness—despite ever-increasing volumes

Pharmacovigilance Techniques

According to the International Conference on Harmonization Efficacy 2 (ICHE2E) guidelines, pharmacovigilance techniques can be classified as :

I. Passive surveillance

Passive surveillance often gathers data from all potential reporting health care workers or consumers. Health authorities do not stimulate reporting by reminding health care workers to report disease nor providing feedback to individual health workers. A passive surveillance system relies on the cooperation of health-care providers — laboratories, hospitals, health facilities and private practitioners to report the occurrence of an event. Once the data have been received, they must be compiled and then analysed to monitor disease patterns and identify possible outbreaks. Passive surveillance involves the regular collection and reporting of surveillance data and is the commonest method used to detect vaccine-preventable diseases. In most countries with a passive surveillance system, every health facility is required to send a monthly (sometimes weekly/daily) report of all cases of vaccine-preventable disease (and sometimes other diseases of interest) on a standard form.

Regular reporting of disease data by all institutions that see patients (or test specimens) and are part of a reporting network is called passive surveillance. There is no active search for cases. It involves passive notification by surveillance sites and reports are generated and sent by local staff. A passive surveillance system relies on the cooperation of health-care providers — laboratories, hospitals, health facilities and private practitioners — to report the occurrence of a vaccine-preventable disease to a higher administrative level. Once the data have been received, they must be compiled and then analysed to monitor disease patterns and identify possible outbreaks. Passive surveillance involves the regular collection and reporting of surveillance data and is the commonest method used to detect vaccine-preventable diseases. In most countries with a passive surveillance system, every health facility is required to send a monthly (sometimes weekly/daily) report of all cases of vaccine-preventable disease (and sometimes other diseases of interest) on a standard form. Passive surveillance is less expensive than other surveillance strategies and covers wide areas (whole countries or provinces); however, because it relies on an extensive network of health workers, it can be difficult to ensure completeness and timeliness of data. Some countries might not have the capacity or resources to identify all cases of a disease, either because the diagnosis of the disease requires specialized clinical skills or because laboratory resources are not available throughout the country. Under these circumstances, passive surveillance can be adapted in a number of ways, depending on the completeness and quality of data required, financial constraints and the availability of specialist skills and services.

Spontaneous reporting system (SRS)

When a physician suspects a serious clinical event to be an ADR, they are encouraged to complete a questionnaire and notify the country’s drug regulatory agency about the suspected ADR. An adverse event is serious when it results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect (3). In some countries, the spontaneous reporting scheme has been extended to reporting from pharmacists, nurses, and even patients.

Although the spontaneous reporting questionnaire differs from country to country, in general the information collected includes patient details (such as age, sex, weight), details on the suspected drug (such as dose, duration of treatment), details on the suspected reaction(s) (such as description of the event, seriousness, outcome), medical history of the patient, and other concomitant medication that the patient was taking. Examples of spontaneous reporting systems include the “Yellow card scheme” operated by the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and the Commission on Human Medicines, and the Adverse Event Reporting System (AERS) which is a database of spontaneous reports received by the US Food and Drug Administration (FDA) through the MedWatch form. In India, the suspected ADR reporting scheme is undertaken by the Central Drugs Standard Control Organization (CDSCO).

The pharmaceutical industry and regulatory bodies collect and analyze these reports and utilize them in identifying previously unknown adverse reactions and where appropriate take action to minimize the risk due to the drug. Action taken may be in the form of change(s) to the product label (e.g., change in dosage regime or addition of a contraindication) providing information to physicians through “health professional letters,” publication in the medical literature, changes in the patient information leaflet, restricted drug distribution, or drug withdrawal (4).

A study by Wysowski and Swartz (4) recorded a total of 24 drug withdrawals (between 1978 and 2003) where the identification/evidence of the safety issue had originated from spontaneous case reports to the US FDA. These include phenformin (indicated for diabetes mellitus and withdrawn due to lactic acidosis), fenfluramine (indicated for diet aid for obesity and withdrawn due to cardiac valvulopathy), troglitazone (indicated for diabetes mellitus and withdrawn due to hepatotoxicity), cisapride (indicated for nocturnal heartburn and withdrawn due to drug interaction/ventricular arrhythmias), and cerivastatin (indicated for hypercholesterolemia and withdrawn due to rhabdomyolysis) (4). Furthermore, two recent examples where spontaneous reports have identified new safety issues and lead to changes in the drug label include the following: rhabdomyolysis with rosuvastatin (lead to revised dosing instructions and improved warning) and hepatic disorders with atomoxetine (lead tthe o warning)

Case series

Series of case reports can provide evidence of an association between a drug and an adverse event, but they are generally more useful for generating hypotheses than for verifying an association between drug exposure and outcome. There are certain distinct adverse events known to be associated more frequently with drug therapy, such as anaphylaxis, aplastic anaemia, toxic epidermal necrolysis and Stevens-Johnson Syndrome. Therefore, when events such as these are spontaneously reported, sponsors should place more emphasis on these reports for detailed and rapid follow-up.

Case series are a commonly reported study design, but the label "case series" is used inconsistently and sometimes incorrectly. Mislabeling impairs the appropriate indexing and sorting of evidence. This article tries to clarify the concept of case series and proposes a way to distinguish them from cohort studies.

In the event that one or more cases suggest a safety signal warranting additional investigation, FDA recommends that a case series should be assembled and descriptive clinical information should be summarized to characterize the potential safety risk and, if possible, to identify risk factors.

A case series commonly includes an analysis of the following:

1. The clinical and laboratory manifestations and course of the event;
2. Demographic characteristics of patients with events (e.g., age, gender, race);
3. Exposure duration;
4. Time from initiation of product exposure to the adverse event;
5. Doses used in cases, including labelled doses, greater than labelled doses, and overdoses;
6. Use of concomitant medications;
7. The presence of co-morbid conditions, particularly those known to cause an adverse event, such as underlying hepatic or renal impairment;
8. The route of administration (e.g., oral vs. parenteral);
9. Lot numbers, if available, for products used in patients with events; and
10. Changes in event reporting rate over calendar time or product lifecycle.

Expedited reporting

Single Cases of Serious, Unexpected ADRs. All adverse drug reactions (ADRs) that are both serious and unexpected are subject to expedited reporting. This applies to reports from spontaneous sources and from any type of clinical or epidemiological investigation, independent of design or purpose.

II. Stimulated reporting

Several methods have been used to encourage and facilitate reporting by health professionals in specific situations (e.g., in-hospital settings) for new products or for limited time periods. Such methods include on-line reporting of adverse events and systematic stimulation of reporting of adverse events based on a pre-designed method. Although these methods have been shown to improve reporting, they are not devoid of the limitations of passive surveillance, especially selective reporting and incomplete information. During the early post-marketing phase, companies might actively provide health professionals with safety information, and at the same time encourage cautious use of new products and the submission of spontaneous reports when an adverse event is identified.

A plan can be developed before the product is launched (e.g., through site visits by company representatives, by direct mailings or faxes, etc.). Stimulated adverse event reporting in the early post-marketing phase can lead companies to notify healthcare professionals of new therapies and provide safety information early in use by the general population (e.g., Early Post-marketing Phase Vigilance, EPPV in Japan). This should be regarded as a form of spontaneous event reporting, and thus data obtained from stimulated reporting cannot be used to generate accurate incidence rates, but reporting rates can be estimated.

Reporting that occurs consequent to the “Direct Healthcare Professional Communication”, publication in the press, questioning of healthcare professionals by company representatives, communication from patient's organizations to their members or class action lawsuits, should be considered spontaneous reporting.

III. Active surveillance

Active surveillance, in contrast to passive surveillance, seeks to ascertain completely the number of adverse events via a continuous pre-organized process. An example of active surveillance is the follow-up of patients treated with a particular drug through a risk management program. Patients who fill a prescription for this drug may be asked to complete a brief survey form and give permission for later contact. In general, it is more feasible to get comprehensive data on individual adverse event reports through an active surveillance system than through a passive reporting system.

• Sentinel sites

Active surveillance can be achieved by reviewing medical records or interviewing patients and/or physicians in a sample of sentinel sites to ensure complete and accurate data on reported adverse events from these sites. The selected sites can provide information, such as data from specific patient subgroups, that would not be available in a passive spontaneous reporting system. Further information on the use of a drug, such as misuse, can be a point to selected sentinel sites. Some of the major weaknesses of sentinel sites are problems with selection bias, small numbers of patients, and increased costs. Often the chosen sites are high volume medical centres, tending to be in urban areas. Differences in population demographics, reasons for admission, hospital affluence, and available resources/technology can all skew data and prevent the sample population from accurately describing the geographical population. Active surveillance with sentinel sites is most efficient for those drugs used mainly in institutional settings such as hospitals, nursing homes, haemodialysis centres, etc. Institutional settings can have a greater frequency of use for certain drug products and can provide an infrastructure for dedicated reporting. Intensive monitoring of sentinel sites can also be helpful in identifying risks among patients taking orphan drugs.

• Drug event monitoring

Drug event monitoring is a method of active pharmacovigilance surveillance. In drug event monitoring, patients might be identified from electronic prescription data or automated health insurance claims. A follow-up questionnaire can then be sent to each prescribing physician or patient at pre-specified intervals to obtain outcome information. Information on patient demographics, indication for treatment, duration of therapy (including start dates), dosage, clinical events, and reasons for discontinuation can be included in the questionnaire. Limitations of drug event monitoring can include poor physician and patient response rates and the unfocused nature of data collection, which can obscure important signals. In addition, maintenance of patient confidentiality might be a concern. On the other hand, more detailed information on adverse events from a large number of physicians and patients might be collected. Drug event monitoring can be done for real-time data such as social media data (Facebook/Twitter/Pinterest/Blogs/News etc.). Patients post the adverse events in their social media profiles in the public manner or privet manner, those details can be monitor by pharmacovigilance analysts of drug safety authority to complete the causality assessment. Patients will post their experiences with drugs and the medical devices, then pharmacovigilance analysts will categorize the details into the correct category of the adverse event, product quality complaint or device quality complaint. With the use of this process drug or medical device, manufacturers can have the updated results of their product and drug safety authorities will have the updated information of the adverse event of the drugs and devisers in the market.

• Registries

A registry is a list of patients presenting with the same characteristic(s). This characteristic can be a disease (disease registry) or a specific exposure (drug registry). Both types of registries, which only differ by the type of patient data of interest, can collect a battery of information using standardized questionnaires in a prospective fashion. Disease registries, such as registries for blood dyscrasias, severe cutaneous reactions, or congenital malformations can help collect data on drug exposure and other factors associated with a clinical condition. A disease registry might also be used as a base for a case-control study comparing the drug exposure of cases identified from the registry and controls selected from either patient with another condition within the registry or patients outside the registry. Exposure (drug) registries address populations exposed to drugs of interest (e.g., a registry of rheumatoid arthritis patients exposed to biological therapies) to determine if a drug has a special impact on this group of patients. Some exposure (drug) registries address drug exposures in specific populations, such as pregnant women.

• Active surveillance is a way of monitoring prostate cancer that hasn't spread outside the prostate (localized prostate cancer), rather than treating it straight away. You might hear it called active monitoring

IV. Comparatives observational studies

Cross-sectional study

Data collected on a population of patients at a single point in time (or interval of time) regardless of exposure or disease status constitute a cross-sectional study. These types of studies are primarily used to gather data for surveys or for ecological analyses. The major drawback of cross-sectional studies is that the temporal relationship between exposure and outcome cannot be directly addressed.

A cross-sectional study is a research tool used to capture information based on data gathered for a specific point in time. The data gathered is from a pool of participants with varied characteristics and demographics known as variables. Age, gender, income, education, geographical locations, and ethnicity are all examples of variables. The variables, or demographics, used in a single study are based on the type of research being conducted and on what the study aims to prove or validate. The research findings help remove assumptions and replace them with actual data on the specific variables studied during the time period accounted for in the cross-sectional study.

This type of study is used across various industries. These industries include (but are not limited to) business, psychology, social science, retail, medicine, education, religion, and government. In each of these industries, cross-sectional research provides important data that informs all kinds of actions. For business marketing in particular, this tool is used to learn more about various demographics for the purpose of analyzing target markets to sell to or introduce products and services. Have you ever wondered how marketers know how to target you for products? How do they capture your interest? How do they know how to price products and especially where to market these products? How do businesses know which new features to add to the new smartphone, iPad, or the 2015 Lexus? Do you think everyone gets the same ads in their mailboxes?

Before you think that you've never been sampled in this type of study, think again! Many of the ways we use technology every day are contributing to data collection about our purchasing behaviours and preferences. For example, your grocery store purchases are tracked when you swipe your discount card or when you use a debit or credit card. This information is then stored and sold to marketing companies. These tracking programs offer ongoing cross-sectional study material for researchers and marketers. Businesses then hire marketing firms to help them determine where to market their products, based on this purchase history information collected about you and everyone else shopping at the same places! When you receive coupons in the mail, it is because of research done on data which includes your spending habits.

The advantages of cross-sectional study include:

1) Used to prove and/or disprove assumptions. 2) Not costly to perform and does not require a lot of time. 3) Captures a specific point in time. 4) Contains multiple variables at the time of the data snapshot. 5) The data can be used for various types of research. 6) Many findings and outcomes can be analyzed to create new theories/studies or in-depth research

The disadvantages of cross-sectional study include:

1) Cannot be used to analyzed behaviour over a period to time. 2)Does not help determine cause and effect. 3) The timing of the snapshot is not guaranteed to be representative. 4) Findings can be flawed or skewed if there is a conflict of interest with the funding source. 5) May face some challenges putting together the sampling pool based on the variables of the population being studied.

Case-control study

In a case-control study, cases of disease (or events) are identified. Controls, or patients without the disease or event of interest, are then selected from the source population that gave rise to the cases. The controls should be selected in such a way that the prevalence of exposure among the controls represents the prevalence of exposure in the source population. The exposure status of the two groups is then compared using the odds ratio, which is an estimate of the relative risk of disease in the two groups. Patients can be identified from an existing database or using data collected specifically for the purpose of the study of interest. For rare adverse events, existing large population-based databases are a useful and efficient means of providing needed drug exposure and medical outcome data in a relatively short period of time. Case-control studies are particularly useful when the goal is to investigate whether there is an association between a drug (or drugs) and one specific rare adverse event, as well as to identify risk factors for adverse events. Risk factors can include conditions such as renal and hepatic dysfunction, that might modify the relationship between drug exposure and the adverse event. Under specific conditions, a case-control study can provide the absolute incidence rate of the event. If all cases of interest (or a well-defined fraction of cases) in the catchment area are captured and the fraction of controls from the source population is known, an incidence rate can be calculated.

Selection of participants Cases

Incident cases of diabetes were defined as the earliest date of a diagnosis of or treatment for diabetes, occurring at least three months after the beginning of the study period. We define the date for diagnosis as the index date. To ensure that the patients with diabetes were incident cases, we checked the medical and prescription records for any diagnosis of or treatment for diabetes before the study began. Patients identified as cases should not have had a prescription for insulin or oral antidiabetic agents within three months of the index date. The use of a three month window avoided the exclusion of patients with diabetes who contributed no more than three months of data. However, 97% of the cases were free of diabetes for six months or more.

Controls

For each case, we matched six controls with study periods at least as long as that of the case by age at index date (SD 5 years), sex, and index date. Controls that met the matching criteria were selected at random with SAS software. Controls were selected from patients who had been diagnosed as having or treated for schizophrenia but not diagnosed as having or treated for diabetes at any time. Controls were assigned the same index date as the cases to which they were matched. Therefore the calendar time distributions of the index date were the same for both cases and controls.

Drug use We classified antipsychotics as conventionals (depot or non-depot), olanzapine, risperidone, and other newer drugs. Non-depot conventional antipsychotics included benperidol, chlorpromazine, droperidol, flupenthixol, fluphenazine, haloperidol, loxapine, methotrimeprazine, oxypertine, pericyazine, perphenazine, pimozide, prochlorperazine promazine, sulpiride, thioridazine, trifluoperazine, trifluperidol, and zuclopenthixol. Depot conventional antipsychotics included flupenthixol decanoate, fluphenazine decanoate, fluphenazine enanthate, fluspirilene, haloperidol decanoate, and pipothiazine palmitate. Other newer antipsychotics included amisulpiride, remoxipride, and sertindole.

Statistical analysis We conducted all analyses with SAS version 7.0. Our main study comprised a nested case-control analysis. To account for the matched study design, we modelled the effect of drug use on the risk of diabetes development using conditional logistic regression.20

We used different referent groups to compare the risk of diabetes developing among users of different antipsychotics. The first group included all patients except those receiving the drug of interest. The second group included patients taking conventional antipsychotics. The third group included patients with no prescription for an antipsychotic within three months of the index date. In addition to the matching variables, we adjusted the analysis for use of other drugs known to affect the risk of diabetes, such as α blockers, β blockers, thiazide diuretics, corticosteroids, phenytoin, oral contraceptives containing norgestrel, and valproate.

Cohort study

Cohort studies compare a group of individuals with a particular drug exposure to a group without the same exposure in terms of adverse outcomes. A cohort study is also called looking forward to study. In this study design, a specific group is followed over time and subjects are classed according to their exposure status and followed to determine disease outcome. Basic steps of a cohort study are

• Selection of study subjects
• Obtaining data on exposure
• Selection of comparison group
• Follow up
• Analysis

The study can be either prospective or retrospective. Since the population exposure to a specific drug during follow-up is known, incidence rates can be calculated. For example, a cohort study compared 90,000 patients who had been exposed to co-amoxiclav with 360,000 patients who had been exposed to amoxicillin. The study found that the co-amoxiclav users were six times more likely to experience acute liver toxicity. In many cohort studies involving drug exposure, comparison cohorts of interest are selected on the basis of drug use and followed over time. Cohort studies are useful when there is a need to know the incidence rates of adverse events in addition to the relative risks of adverse events. Multiple adverse events can also be investigated using the same data source in a cohort study. However, it can be difficult to recruit sufficient numbers of patients who are exposed to a drug of interest (such as an orphan drug) or to study very rare outcomes, also if they are done prospectively, they may take years to complete. Like case-control studies, the identification of patients for cohort studies can come from large automated databases or from data collected specifically for the study at hand. In addition, cohort studies can be used to examine safety issues in special populations (the elderly, children, patients with co-morbid conditions, pregnant women) through over-sampling of these patients or by stratifying the cohort if sufficient numbers of patients exist. The cohort study design is the best available scientific method for measuring the effects of a suspected risk factor. While randomized controlled trials (RCT) are considered the best, most rigorous way of investigating interventional medicine, they are unethical for testing the causes of diseases.

A birth cohort study is a long-term follow-up of people born in the same year. One has followed 17,000 people all born in the same week in 1958. Cohort studies are observational - the researchers simply observe what happens, without applying any intervention themselves. Conversely, experimental studies, such as RCTs, involve intervention by the scientists - the introduction of a drug, for example. MNT has more information about randomized controlled trials.

When looking for the causes of disease, it would be unethical to deliberately expose participants to a suspected risk factor (such as would be the case in an RCT). Instead, the design of a prospective cohort study is observational rather than interventional.

Randomized controlled trials in humans are used to test the safety and potential benefit of a treatment. While the harms of treatment sometimes prove to outweigh the benefits, this form of testing is acceptable to the participants because the investigators are aiming at the outset to develop new treatment and usually have a reasonable expectation of safety at least, if not a positive effect of treatment. finding causes of disease - the best available method.

V. Targeted clinical investigations

When significant risks are identified from pre-approval clinical trials, further clinical studies might be called for to evaluate the mechanism of action for the adverse reaction. In some instances, pharmacodynamic and pharmacokinetic studies might be conducted to determine whether a particular dosing instruction can put patients at an increased risk of adverse events. Genetic testing can also provide clues about which group of patients might be at an increased risk of adverse reactions. Furthermore, based on the pharmacological properties and the expected use of the drug in general practice, conducting specific studies to investigate potential drug-drug interactions and food-drug interactions might be called for. These studies can include population pharmacokinetic studies and drug concentration monitoring in patients and normal volunteers. Sometimes, potential risks or unforeseen benefits in special populations might be identified from pre-approval clinical trials, but cannot be fully quantified due to small sample sizes or the exclusion of subpopulations of patients from these clinical studies. These populations might include the elderly, children, or patients with the renal or hepatic disorder. Children, the elderly, and patients with co-morbid conditions might metabolise drugs differently than patients typically enrolled in clinical trials. Further clinical trials might be used to determine and to quantify the magnitude of the risk (or benefit) in such populations. To elucidate the benefit-risk profile of a drug outside of the formal/traditional clinical trial setting and/or to fully quantify the risk of a critical but relatively rare adverse event, a large simplified trial might be conducted. Patients enrolled in a large simplified trial are usually randomized to avoid selection bias. In this type of trial, though, the event of interest will be focused to ensure a convenient and practical study. One limitation of this method is that the outcome measure might be too simplified and this might have an impact on the quality and ultimate usefulness of the trial. The Guidance on Good Clinical Practices (GCP), developed by the International Conference on Harmonization (ICH), requires that trial monitors have access to and can review source documents. This guidance, ICH E6, has been adopted by both the Food and Drug Administration (FDA) in the US Code of Federal Regulations (CFR) under Title 21 and by the European Union (EU) as part of the EU directive on clinical trials. Guidance ICH E6 and the regulatory authorities that have adopted it, refer to source documents (i.e., primary health records, in the sections on investigators, sponsors, trial protocols, and essential documents).

According to the E6 guidance, source documents must be kept in good order and investigators must make source documents available to the sponsor and monitors working on behalf of the sponsor. Investigators are responsible for ensuring that the data reported on CRFs is consistent with source documents, 1 and the sponsor is responsible for ensuring that each subject has provided written consent to direct access to his or her medical records. 2 Sponsors must also ensure that the trial protocol or other written agreement specifies that the investigator(s)/institution(s) will allow trial-related monitoring. 3 and that the monitors verify the source documents are accurate, complete, up-to-date, and maintained. 4 Source documents are used to achieve two explicit regulatory objectives: to document the existence of the subjects and to substantiate the integrity of trial data. 5 Both objectives depend on effective Source Data Verification (SDV) by monitors. The most effective strategies for SDV depend on the particulars of each clinical trial. While 100 per cent SDV is not required by law, industry standards maintain 100 per cent SDV as the most straightforward approach to regulatory compliance. However, the FDA guidelines for monitoring clinical trials states, "...the monitor should compare a representative number of subject records and other supporting documents to the investigator's report..."6

Abstract Overexpression of the epidermal growth factor receptor (EGFR) is a common characteristic of head and neck squamous cell carcinomas (HNSCC). Cetuximab is a chimeric anti-EGFR monoclonal antibody (mAb) with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease. There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions. In addition, a variety of other anti-EGFR agents (the multitargeted small-molecule tyrosine kinase inhibitors [TKIs] lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings. The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention. Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR antisense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents. Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC. (Reference: http://www.sciencedirect.com/science/article/pii/S0305737213002065)

VI. Descriptive studies

Natural history of disease

The science of epidemiology originally focused on the natural history of a disease, including the characteristics of diseased patients and the distribution of a disease in selected populations, as well as estimating the incidence and prevalence of potential outcomes of interest. These outcomes of interest now include a description of a disease treatment patterns and adverse events. Studies that examine specific aspects of adverse events, such as the background incidence rate of or risk factors for the adverse event of interest, can be used to assist in putting spontaneous reports into perspective. For example, an epidemiologic study can be conducted using a disease registry to understand the frequency at which the event of interest might occur in specific subgroups, such as patients with concomitant illnesses. The natural history of a disease is the course a disease takes in individual people from its pathological onset ("Inception") until its eventual resolution through complete recovery or death.[1] The inception of a disease is not a firmly defined concept.[1] The natural history of a disease is sometimes said to start at the moment of exposure to causal agents.[2] Knowledge of the natural history of disease ranks alongside causal understanding in importance for disease prevention and control. The natural history of the disease is one of the major elements of descriptive epidemiology.

Drug utilization study

Drug utilization studies (DUS) describe how a drug is marketed, prescribed, and used in a population, and how these factors influence outcomes, including clinical, social, and economic outcomes. These studies provide data on specific populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics. DUS can be used to determine if a product is being used in these populations. From these studies denominator, data can be developed for use in determining rates of adverse drug reactions. DUS has been used to describe the effect of regulatory actions and media attention on the use of drugs, as well as to develop estimates of the economic burden of the cost of drugs. DUS can be used to examine the relationship between recommended and actual clinical practice. These studies can help to determine whether a drug has the potential for drug abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing. Important limitations of these studies can include a lack of clinical outcome data or information of the indication for use of a product. To evaluate the quality of the consumption of medicines in Spain, its potential efficacy, and its evolution during the last years, an assessment of the 'intrinsic value' of the most sold pharmaceutical specialities (amounting to more than 50% of the total pharmaceutical market) was carried out. A panel of five clinical pharmacologist classified medicines, according to their intrinsic value, in four groups: (i) 'high value' (41% of analyzed medicines in 1980); (ii) 'relative value' (12% in 1980); (iii) 'doubtful value' (3%); (iv) 'no-value' (23%), and (v) 'unacceptable value' (21%). Drugs were also classified according to their expected potential of use; and three groups were formed: (i) 'high' (32%); (ii) 'relatively high' (14%), and (iii) 'reduced' (10%). A fourth group of 'not applicable' (44%) in this classification was formed with pharmaceuticals considered invaluable or unacceptable in the first classification. The results of this study suggest that this kind of analysis may be a useful tool to evaluate the efficacy of drugs in the community and to identify priorities and guidelines in the selection of drugs in each country.

Drug utilization studies and drug policy decisions

Many of the questions asked in drug utilization research and the answers obtained are important for initiating and modifying a rational drug policy at both national and local levels. Two successful examples of the use of such research are given below.

Drug use in Estonia

An important reason for undertaking studies of drug use in Estonia after its independence was the need to make decisions on drug policy. At the time, no information was available in the country on which drugs were used (sold), or on the quantities and there was, therefore, no rationale for regulating the drug market. Moreover, in the absence of any feedback system, it was impossible to gauge the impact of possible future interventions. A national drug classification system was therefore developed for Estonia, and a reporting system from wholesalers, based on this classification, was implemented, checked and validated from 1992-1994. Since then, annual reviews of drug utilization have been used to provide background information for decisions on regulatory and reimbursement policies in Estonia; two examples are described below.

If physicians have high rates of inappropriate prescribing, drug regulatory authorities can require educational intervention or impose restrictions on specific drugs or on practitioners. In Estonia, it was decided to stop the import and use of some hazardous products, such as phenacetine, older sulphonamides and pyrazolones, after clarifying and explaining the reasons for this in the national Drug information bulletin, which is distributed free by the drug regulatory authority to all prescribers in Estonia.

In planning the reimbursement policies, the total volume of drug use in Defined Daily Doses (DDDs) was monitored carefully. During the 1990s, the use of prescription-only medicines measured as the number of DDDs per capita was less than one-third of that report from the Nordic countries. This proved to be the result of under-treatment of certain chronic diseases (i.e. hypertension and schizophrenia), and therefore the decision was to increase the availability and use of cardiovascular and neuroleptic drugs. Thus, the national drug use surveys in Estonia have been used to monitor the impact of drug regulatory activities as well as to follow the increase in drug expenditure.

Because data on drug use are only part of the background material relevant to the discussions and decisions on therapeutic strategies - at both the local and national levels - it is difficult to evaluate the specific influence of drug utilization research on developments in drug policies. It is, however, reasonable to assume that such studies have contributed to the more rational use of drugs in Estonia.1

1 The information about DURG-LA was provided in personal communication by Dr Albert Figueras and Professor Joan-Ramon Laporte, Barcelona, Spain.

Drug use in Latin America

The second example is the successful work within the Latin American DURG, in association with the WHO Collaborating Centre of Pharmacoepidemiology in Barcelona, Spain.

In September 1991, health professionals from Spain and eight Latin American countries met in Barcelona for the «First Meeting of Latin American Groups for Drug Epidemiology». It was made clear that in most of the countries taking part, data on drug utilization were scarce and fragmentary. Some national drug regulatory authorities had no access to either quantitative or qualitative data on drug consumption and realized that information on patterns of drug utilization would be useful for designing drug policy and educational programmes about drugs.

It was agreed at this meeting to set up a Latin American network (later called DURG-LA), with the following aims:

- To promote drug utilization research in Latin American countries;

- To exchange experiences and information between the participating groups;

- To use the knowledge generated to give technical advice to drug regulatory authorities and to guide the teaching of pharmacology;

- To write and disseminate information aimed at improving drug use, and

- To participate in the training of health professionals in pharmacoepidemiology and therapeutics.

Seven further DURG-LA meetings have been held over the subsequent ten years to promote drug utilization research. Part of the initial core group participated in a first multicentre study in six Latin American countries to examine self-medication and self-prescription. The study was carried out in a sample of pharmacies from different social-class districts in the catchment areas of 11 health centres.1

1 The information about DURG-LA was provided in personal communication by Dr Albert Figueras and Professor Joan-Ramon Laporte, Barcelona, Spain.(http://apps.who.int/medicinedocs/en/d/Js4876e/2.3.html)

Pharmacovigilance techniques can be also classified as hypothesis generation techniques and hypothesis testing techniques as follows:

1. Hypothesis generating techniques
   1. Spontaneous ADR reporting
   2. Prescription event monitoring
2. Hypothesis testing techniques
   1. Case-control study
   2. Cohort studies
   3. Randomized controlled trials

Patient versus healthcare professional spontaneous adverse drug reaction reporting

Increasing numbers of national pharmacovigilance schemes are accepting adverse drug reaction (ADR) reports from patients. The extent to which patient ADR reports contribute to pharmacovigilance requires comparisons to be made with reports from healthcare professionals (HCPs). However, despite the large and increasing number of national pharmacovigilance schemes that accept ADR reports from patients, few comparative studies have been undertaken of patient and HCP reporting. Comparison across schemes is challenging because of differences in reporting processes, the inclusion criteria of schemes and different reporter types. The true value of patient ADR reports to pharmacovigilance will remain unknown unless more comparative evaluations are undertaken. A systematic review (which complied with the PRISMA statement) and a narrative synthesis of the results has highlighted both similarities and differences between reporter behaviour, the implications of which, in terms of signal generation, require further exploration.

Pharmacovigilance inspection procedures

European Union pharmacovigilance inspectors have developed Union procedures and guidance on pharmacovigilance inspections of marketing-authorisation holders of human and veterinary medicines.

The Union procedures support harmonisation for the mutual recognition of pharmacovigilance inspections and to facilitate administrative collaboration and the exchange of inspection-related information. They apply to inspections conducted following adoption by the Committee for Medicinal Products for Human Use (CHMP) or under the national inspection programmes of concerned Member States.

Pharmacovigilance procedures

Pharmacovigilance procedures and best practices differ depending on which pharmacovigilance phase a given biopharmaceutical product is in. While the safety and quality of a biopharmaceutical are constructed throughout its R&D process, these properties are also highly susceptible to marketing approval and manufacturing stages. Thus, pharmacovigilance is established and maintained throughout the biopharmaceutical’s entire life-cycle by keeping to the highest standards and best practices within its three main phases. These phases are:

1. The clinical phase This encompasses safety and quality issues within the R&D process and the manufacturing process of a biopharmaceutical;

2. The post-marketing phase This encompasses pharmacovigilance activities relating to the distribution and dispensation of medicines, the local and international monitoring of ADR’s, and the establishment of a national pharmacovigilance monitoring system; and

3. The post-exclusivity phase This encompasses the safety and quality issues arising from the entry of generic products. As in phase 2, pharmacovigilance in this the phase includes both the institutionalized procedures and regulatory framework in place as well as actual use and application of those procedures by DRAs, health care professionals, manufacturers, patients and other relevant stakeholders.

Pharmacovigilance Databases

The most widely used method of Pharmacovigilance relies on spontaneous reporting of suspected ADRs and many important safety signals have been picked up in this way. Drawbacks of spontaneous reporting include under-reporting, incomplete information, and sensitivity to known or unknown external factors. Furthermore, the vast number of spontaneous reports received makes case-by-case analysis and medical evaluation more and more challenging and specific tools have therefore been developed to help identify patterns in the data (e.g. disproportionality analysis). To facilitate aggregated analysis of the data, spontaneous ADR reports are collected in databases. However, these databases may have some limitations too (e.g. reporting practices of the countries that submit the data to the database may differ considerably or time difference between the occurrence of the event and the availability in the database). There is software used as main databases for various pharmacovigilance purposes, such as compilation of safety reports, expedited or electronic reporting, signal detection, sharing and accessing global safety information.

There is an advantage in centralizing all safety data, clinical data, analysis and reporting with one provider. The pharmacovigilance Software tool provides a comprehensive analysis of adverse events arising from the use of pharmaceutical products (Medicinal Product, Medical Device, Vaccines, Non-Drug Therapy and Veterinary Medicinal Product). The Drug Safety database allows the risk-benefit analysis of medicinal products taking into account new and emerging information, in the context of cumulative information. Pharmacovigilance since the beginning has been a compliance-driven activity, wherein your regulatory compliance determines company’s Risk Assessment scores. A Drug Safety Database offers scheduling of alerts for expedited cases, follow-up cases and PSUR/PADER reports submission to meet regulatory timeline compliance.

Spontaneous reports are collected at a regional, national and international level through different databases. Here are some examples:

• The Eudravigilance database (European Union Drug Regulating Authorities Pharmacovigilance) is held by the European Medicines Agency and collects/exchanges electronically ADRs coming from national regulatory authorities, marketing authorization holders and sponsors of interventional clinical trials and non-interventional studies in Europe.

• The Vigibase, according to WHO, is the unique WHO global database of individual case safety reports (ICSRs). It is the largest database of its kind in the world, with over 15 million reports of suspected adverse effects of medicines, submitted, since 1968, by member countries of the WHO Programme for International Drug Monitoring. It is continuously updated with incoming reports. Vigilance is UMC’s starting point for the journey from data to wisdom about safer use of medicines and wise therapeutic decisions in clinical practice. It is the driving force at the heart of the work of UMC and the WHO Programme. The purpose of the Vigibase is to ensure that early signs of previously unknown medicines-related safety problems are identified as rapidly as possible. Alongside its data management and quality assurance tools, the VigiBase system is linked to medical and drug classifications such as WHO-ART, MedDRA, WHO ICD, and WHODrug. These classifications enable structured data entry, retrieval and analysis at different levels of precision and aggregation, which are vital in order to enable effective and accurate analysis.

• The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's post-marketing safety surveillance program for drug and therapeutic biologic products. The informatic structure of the FAERS database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation (ICH E2B). Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology.[2]

Two new Pharmacovigilance Databases were launched in 2013 for pharmacovigilance and pharmacoepidemiological studies in Europe- the Drug Consumption Database and the PROTECT ADR database.

• The Drug Consumption Database is a comprehensive and structured source of information on drug consumption in Europe. It comprises two documents. The master document contains a detailed report of the available information, methods to retrieve this information, a description of the validity of national drug consumption data and a discussion. The country profile document summarizes the main results by country. It draws on out-patient and in-patient healthcare information from 17 EU countries namely Belgium, Bulgaria, Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, Latvia, Norway, Poland, Portugal, Spain, Sweden, The Netherlands, and the UK.
• The PROTECT ADR database lists all of the ADRs that are included in the SPC for drugs that have the authorization to be marketed in the EU. It is a downloadable Excel file listing of all MedDRA PT or LLT adverse drug reactions (ADRs). It is a structured Excel database of all adverse drug reactions (ADRs) listed in section 4.8 of the Summary of Product Characteristics (SPC) of medicinal products authorized in the EU according to the centralized procedure. It is based exclusively on MedDRA terminology. In principle, MedDRA Preferred Terms (PT) is used to map terms of the SPC. When they are used in the SPC to add precision in the description of the ADR, Low-Level Terms (LLTs) are also coded. PTs and LLTs are linked to a primary System Organ Class (SOC). The database also includes information on gender, causality, frequency, class warning and source of information for ADRs for which additional information is provided in the SPC.

At the national level, several regional centres support the national Agency by publicly posting a list of potential signals. For instance, the Netherlands Pharmacovigilance Centre Lareb provides a quarterly newsletter service including new emerging signals.

Safety reporting databases can be classified into two major categories:

1. Commercial off the shell (COTS) e.g. ARISg and Argus.

1. Customized reporting database e.g. Sapphire and Aware.

The Global Drug Safety database (ARISg™) A 21CFR compliant, fully validated safety database is an essential part of Good Pharmacovigilance Practice. An accurate and accessible database allows rapid assessment of data for signal detection, aggregate report production and statutory electronic reporting of cases to the regulatory authorities. ARISg™ is designed to be user-friendly yet still correctly process all pharmacovigilance data. It is widely appreciated by many of the world’s top pharmaceutical companies but is also extensively used by smaller companies. With complete compliance with international regulations, it facilitates the management of all the processes associated with individual case safety reports, including:

• All workflow associated with the particular product
• Managing multiple variants of products, for example, medicines, vaccines, combination products, medical devices etc.
• Reception of new data as it arrives
• Data entry
• Data assessment with full multi-lingual support
• Coding & reporting
• Follow up
• Storage of adverse event reporting at any stage of the product lifecycle
• Key features include the ability to handle:
• Tracking all communication
• Generating automatic reminders & standard letters
• Automated duplicate case checks.

Pharmacovigilance: Standard Operating Procedures and Safety Plans

The standard operating procedures were jointly developed by the Department of Health and the Systems for Improved Access to Pharmaceuticals and Services (SIAPS) Program. This was made possible by the generous support of the American people through the US Agency for International Development (USAID), under the terms of cooperative agreement AID-OAA- A-11-00021. The contents are the responsibility of Management Sciences for Health and do not necessarily reflect the views of USAID or the United States Government.

Depending on the scope and complexity of activities undertaken by a company, the number of SOPs may vary from a few to an extensive list. Companies may follow a system of writing very generic SOPs and further develop study-specific procedures (SSPs) based on those SOPs in accordance with the scope of work. Such SSPs provide a robust framework weaved around a particular project or specific product under clinical development. Some companies may bundle together all the pharmacovigilance procedures into a single drug safety plan, or pharmacovigilance plan, which forms a summary of all of the processes to be followed by the pharmacovigilance department together with the clinical trial personnel. In Europe, a detailed draft of the pharmacovigilance system must be included in the marketing authorization application. For a general framework of the Pharmacovigilance department the following SOPs/SSPs should be made functional:

• Serious adverse event reporting

• Safety case handling (intake, process flow, assessment, documentation, archiving)

• Safety database

• Safety data conventions

• Review of patient (clinical/laboratory) data

• Aggregate data review and report writing

• Safety signal detection

• Un-blinding

• Regulatory reporting of safety information and 24/7 safety coverage (pharmacovigilance call centre support)

Unblinding – European Directive

The Volume 10 of the guidance document “The Rules Governing Medicinal Products in the European Union” provides guidelines on un-blinding of the treatment allocation in a clinical trial when suspected unexpected serious adverse reactions (SUSARs) occur. In the European Union (EU) suspected unexpected serious adverse reactions (SUSARs) must be un-blinded before submission to the regulatory authorities; this may not be mandatory for other regulatory authorities in Asia or the USA. Recently, the FDA has acknowledged the increasing need for un-blinding some expedited safety reports, but suggests alternatives to un-blinding be undertaken as far as possible; this rule came into effect on March 28, 2011. It is essential that access to un-blinded data be available to only the reviewers and all other personnel involved in a clinical trial remain blinded to the treatment allocation. This preserves the integrity of the clinical study.

'Steps in Serious Adverse Event Case Processing'

1. When an investigator, healthcare provider, or clinical site monitor identifies a potential SAE, the event is reported to the sponsor immediately.

2. Upon receipt of an SAE at the pharmacovigilance department, the report is assessed as to whether it fulfils the minimum requirements for reporting.

3. A valid case is checked for duplication, i.e. whether the same case w as previously reported, or whether this is follow-up information on a previously opened case.

4. If the case is identified as valid for initial data entry, it will undergo a triage step, being reviewed for expectedness, relatedness, and seriousness, with special attention as to whether the case is fatal or life-threatening. This determines the appropriate timeline for processing and reporting to the regulatory authorities.

5. The case then undergoes data entry, a case narrative is created and the case undergoes medical review. Any missing or unclear information is queried and added to the case.

6. Once all of these activities are completed and quality checked, the case is finalized within the allotted timeframe and if expedited reporting is required the information is sent to the appropriate recipients.

7. The process is repeated as additional information becomes available until the event is resolved or no further information can be obtained.

Pharmacovigilance Quality Management System (QMS)

The role of pharmacovigilance (PV) has changed from a regulatory and legal momentous for capturing and reporting adverse events, to a business important for risk assessment, risk management and risk mitigation. Regulatory oversight of companies’ safety activities for approved pharmaceutical products is now much more holistic than the previously limited objective of assuring that license holders establish adequate and complaint procedures to meet their legal obligations. Regulations are targeted towards strengthening companies’ PV systems and defining clear roles and responsibilities across both the regulatory agencies and the industry. The volume and complexity of drug safety data that is captured, processed, analyzed and reported have grown substantially. These developments have resulted in the need to optimize their PV systems and processes. Operational complexity increases with the inclusion of multiple groups. Being able to adapt fast with respect to proactive patient safety and regulatory compliance necessitates efficiency and scalability in operations and consistency in quality. With increased emphasis on quality and compliance, regulatory agencies have also made it clear that quality is integral to product safety and PV quality systems constitute the foundation of PV operations. The Quality Management System (QMS) is essential to and needs to drive, the biopharmaceutical PV operations.

With drug safety evolving into a key priority area for the biopharmaceutical industry, the emphasis on quality and compliance has increased substantially. Regulatory agencies have made it clear that quality is integral to drug safety, and pharmacovigilance (PV) quality systems constitute the foundation of PV operations.

The International Conference on Harmonization (ICH), European Medicines Agency (EMA) and US Food and Drug Administration (US FDA) have laid out their expectations with respect to quality management systems (QMS) for PV. The past few years have also seen a steep rise in outsourcing of safety operations, (case processing, call centre, aggregate report writing, signal evaluation amongst others etc.) and this has put the spotlight on how sponsor organizations provide oversight to outsourced operations with the ultimate goal of ensuring high quality and compliance with the deliverables. This paper will review the QMS-related requirements and specifications and will compare and contrast requirements by various organizations, primarily to elaborate on how these requirements can be implemented, what constitutes a robust QMS and how it can be built into PV operations. Means of ensuring quality and compliance through appropriate oversight will be discussed.

Signals in Pharmacovigilance

What is a signal?

The DSRU has defined signal as "Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously". The definition is not self-contained, being followed by a qualifier that stipulates that usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information. This qualifier is important because it implies that the information content of the signal must sufficiently reduce uncertainty to justify some action, and therefore partially mitigates the former limitation. This should be part of the definition. .

The Council for International Organizations of Medical Sciences Working group VIII Practical Aspects of Signal Detection in Pharmacovigilance (CIOMS, Geneva 2010) has defined signal as, "Information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action.”

Meyboom et al. stated that ‘‘A signal in pharmacovigilance is more than just a statistical association. It consists of a hypothesis together with data and arguments, arguments in favor and against the hypothesis. These relate to numbers of cases, statistics, clinical medicine, pharmacology (kinetics, actions, previous knowledge) and epidemiology, and may also refer to findings with an experimental character.’’ It is important to note that a single report or a few reports can sometimes constitute a signal of suspected causality. This is the case of well documented, high-quality reports with positive re-challenge. These so-called anecdotes provide definitive drug-related reactions, which do not necessarily need further formal verification.

In Pharmacovigilance, anecdotes have also been technically defined as “Designated Medical Event” (DME), which is a rare but serious reaction with high drug-attributable risk (i.e., a significant proportion of the occurrences of these events are drug-induced). Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) and Torsade de Pointes (TdP) are a typical example of DMEs, although a formal and universally accepted list of DMEs does not exist. The most balanced way to analyze DMEs is to use disproportionality in conjunction with a case-by-case evaluation, in order to capture all possible information from spontaneous reports.

In addition to contributing to the safety profiles of existing drugs, pharmacovigilance activities help to improve the knowledge set and contribute to the breadth of epidemiological data. Pharmacovigilance is, therefore, vital for the advancement of medical understanding, future research, drug development and epidemiological studies. Any improvements in drug safety or understanding will ultimately lead to improvements in patient care

Signal detection

Signal detection is the most important aim of Pharmacovigilance and it represents the identification of potential drug-event association that may be novel by virtue of their nature, severity, and/or frequency. Early identification of the hazards associated with drugs is the main goal of those involved in pharmacovigilance ‘Signal detection'. In the literature, the term signal has been subject to debate and discussion. Some authors attempted to provide a comprehensive overview of definitions that have been proposed and implemented over the years.

The presence of a safety signal does not mean that a medicine has caused the reported adverse event. The adverse event could be a symptom of another illness or caused by another medicine taken by the patient. The evaluation of safety signals is required to establish whether or not there is a causal relationship between the medicine and the reported adverse event.

Early identification of the hazards associated with drugs is the main goal of those involved in pharmacovigilance ‘Signal detection’, ‘signal generation’ or ‘signalling’ refers to a process that aims to find, as soon as possible, any indication of an unexpected drug safety problem which may be either new ADRs or a change of the frequency of ADRs that are already known to be associated with the drugs involved. The results of this surveillance exercise tend to arouse suspicions and should always be followed up by in-depth investigations. Spontaneous reporting systems for suspected adverse drug reactions (ADRs) remain a cornerstone of pharmacovigilance.

Signal processing

Once a signal has been identified, it is assessed further by a group of scientists and physicians for the likelihood of a causal relationship between the drug and reaction, and to identify possible risk factors contributing to the reaction, for example, age, underlying disease, and genetic susceptibility.

In most of the cases, information that arises from one or multiple sources (including observations and experiments) should be taken into account for causality assessment. In causality assessment, the extent of the relationship between a medicine and an adverse event is established in individual patients or in case reports.

The most commonly used scales used for causality assessment are "The WHO scale of assessment" and "The Naranjo's scale".

After a suspicion has been raised - Signal generation, it needs to be corroborated by the accumulation of additional data - Signal strengthening. The final step involves the confirmation and quantification of the relationship between drug and ADR by epidemiological methods - Signal quantification. Although both individual case reports and analytical techniques are involved in every phase of the process, the relative importance of these approaches differs per phase.

Once a signal is verified, a number of regulatory actions may be considered, depending on the level of priority assigned to the signal. This prioritization process is mainly based on the assessment of public health impact, the severity of the adverse event and the strength disproportionality. Regulatory measures may range from close monitoring of the signal over time (without practical interventions, the so-called watchful waiting) to drug withdrawal from the market due to a negative risk/benefit profile.

Sources of Possible Safety Signals

Signals may originate from different data sources:

• Routine pharmacovigilance.
  • Pharmacovigilance databases (FAERS, EUDRAVIGILANCE, VIGIBASE, Aris G, Argus,etc).
  • Data mining.
  • Periodic safety update reports from drug manufacturers
• Study results
• Observations or experiments
• Medical literature
• Social Media
• New drug application (NDA) safety database
• Outside inquiry
• Foreign regulatory agencies
• Others

Signal Detection

What is the signal?

A ‘signal’ consists of reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented before. Usually, more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information.

At the DSRU, monitoring for unexpected findings is a key research activity. Two methods are applied: Qualitative methods are based on the clinical evaluation by a Research Fellow who reviews data reported by the GP for a single case or series of cases. Quantitative (‘automated’ or ‘data mining’) techniques complement the medical review by making use of computational power to analyse the large volume of data. These statistical techniques provide estimates of the extent of how the number of observed cases differs from the number of expected cases. The underlying principle is to explore indicators of disproportionality that may then reveal associations of interest. Different measures include the ranking of incidence rates and risks within time periods, risk and/or rate ratios between time periods, and reasons for treatment withdrawal. The data may also compared with the expected frequencies (e.g. from prescribing information), or from external data sources. Through our extensive experience in this area, we are able to offer advice and collaborate with partners on all aspects of signal detection and incorporating these techniques into risk management studies. What Is A Signal? The term is most commonly associated with drugs during the post-marketing phase, although it may also be used during pre-marketing clinical trials. The definition of a signal as provided by the CIOMS Working Group 8 is:

“…information that arises from one or multiple sources (including observations and experiments), which suggests a new potentially causal association, or a new aspect of a known association, between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action”.

This could be a problem which has never previously been suspected to be associated with the product, or a known event which is now occurring within a patient group for whom it has not been documented before or perhaps occurring with greater frequency than anticipated. The signal may be generated from qualitative analysis of spontaneous reports or quantitative analysis through data mining and statistical activities.

What Is Signal Management in Pharmacovigilance? The process of signal management in pharmacovigilance is a set of activities which aim to determine:

whether there are new risks associated with a particular drug, or whether risks associated with a particular drug have changed Sources for the detection of signals can come from:

spontaneous reporting active monitoring systems interventional studies (clinical trials) non-interventional studies (pharmacoepidemiology studies) non-clinical studies (e.g. animal toxicology studies) systematic reviews (i.e. thorough review of the published literature) meta-analyses (i.e. mathematical pooling of all the clinical trial data) other relevant sources

Healthcare professionals are encouraged to report adverse reactions via national spontaneous reporting systems. Consumers and patients may also report adverse reactions in this way as well as via a wide variety of media, including the internet. Relevant information may also be made available from other sources, such as poisons centres.

Signals arising from spontaneous reports also could be detected via:

Monitoring large adverse drug reaction databases such as Eudravigilance and the FDA AERs system Published articles PSURs Ongoing benefit-risk monitoring

The process for managing signals within pharmaceutical companies and regulatory authorities/pharmacovigilance centres must systematically address the following steps:

Signal detection Validation and Confirmation Analysis Prioritisation Assessment Recommending action

All steps are taken and recommendations made must be accurately tracked and documented at every stage. There are resulting legal obligations which must be fulfilled in an accurate and timely manner but the ultimate goal is to confirm or refute whether there is some new issue with the safety of medicine so that action might then be taken to reduce the risk.

Please note that signal management in Pharmacovigilance is a complex area within pharmacovigilance and this page, therefore, cannot constitute any form of professional advice.

Pharmacovigilance Stakeholders

Maintaining the safety and quality of drugs was traditionally the sole responsibility of the pharmaceutical companies manufacturing the drugs and the drug regulation agencies authorizing and approving them for use. Today, there are many more key players required for successful pharmacovigilance.

The key stakeholders

As the world’s population increases and emerging markets in developing countries are also increasing the demand for medicine, the intrusion of counterfeit drugs has burgeoned as well. It is now recognized that the safety of medicines is the responsibility of all stakeholders - the pharmaceutical companies, the government drug regulation agencies, healthcare professionals (HCPs), and patients. As clinical research and development of drugs are becoming increasingly regulated, contract research organizations (CROs) and sites (that is, clinics, hospitals, and communities where clinical trials are conducted) and even customs administrations, are now also considered stakeholders.

Each of these key stakeholders has a fundamental role to play in pharmacovigilance. The pharmaceutical industries provide the financial capital for clinical research in discovering, developing, and trialling drugs. Contract research organizations are increasingly taking on research work for pharmaceutical companies. Traditionally, CROs merely conducted the different phases of clinical drug trials, but increasingly, CROs themselves also now conduct research to discover new drugs as pharmaceutical companies outsource more research jobs to CROs. Drug regulation agencies review the data from clinical trials and conduct investigations as to the safety and therapeutic claims of drugs developed by pharmaceutical companies. Healthcare professionals prescribe the drugs to their patients and report any adverse drug reactions (ADRs) they might observe in their practice. Patients participate in clinical trials when drugs are being developed; and after drugs have been approved and authorized for sale and use, patients provide feedback as to their experiences of taking the drugs. Healthcare sites provide the venue and the eased ability for the screening of patients as participants in drug trials, for the collection of data, and for the administration of the drugs during clinical trials. Customs administrations and law enforcement agencies protect the intellectual property of the pharmaceutical companies by ensuring that counterfeit drugs are taken off the market and don’t compete with legitimate drugs. By seizing counterfeit drugs, they are also protecting the general public from the health hazards posed by the counterfeit drugs to those who use them. Together, these stakeholders uphold the integrity and quality of the drugs that the public consumes. The question that arises now is, with so many stakeholders involved how can pharmacovigilance remain efficient in ensuring the safety of drugs? There are various types of stakeholders (regulators, MAHs, HCPs, patients and their caregivers and the wider public) with different responsibilities, which contribute to the Pharmacovigilance systems in both, industrialized and developing countries by providing information about the medicinal product and any possible effect on product safety.

I. Marketing Authorization Holders (MAHs)

Marketing Authorization Holders (MAHs) are owners of the medicinal product and their primary responsibility, which is under the legal framework, is to ensure that the goals set for Pharmacovigilance are achieved and to respond promptly when it is necessary.

MAHs have the responsibility to:

• Continuously monitor Pharmacovigilance data and scientifically evaluate all information on the risks of the medicinal product.
• Submit accurate and verifiable data on Adverse Drug Reactions (ADRs) to the relevant authority.
• Effectively communicate with the relevant authority concerning any information that may impact the benefit/risk balance.
• Update the product information to reflect all scientific knowledge and communication of relevant safety information with health professionals and patients.
• Implement risk management plan - Additional measures aimed at minimization of risks on a national level.

II. Regulators

Drug regulatory experts have to deal with the approval of new medicines, clinical trials, the safety of complementary and traditional medicines, vaccines, biological medicines, developing communication links between all parties involved in drug safety and ensuring that they are open and able to function efficiently, especially at times of crisis.

They have the responsibility to:

• Supervise the compliance of applicants with their Pharmacovigilance activities and facilitate Pharmacovigilance activities in their territory.
• Proactively review medicinal product safety and capture data related to cohort event monitoring which is linked to a particular healthcare investment or initiatives like health care programs initiated by WHO and other non-governmental organizations and charities.

Regulators are also responsible for organizing Pharmacovigilance inspections in order to:

• Ensure that the MAH has everything in order to meet the Pharmacovigilance requirements.
• Identify and address non-compliance and take enforcement action when necessary.

III. Healthcare Professionals (HCPs)

Healthcare Professionals include physicians, pharmacists or other healthcare workers who are the most involved in the drug prescription, delivery and use by a patient, and these stakeholders are the biggest contributors to spontaneous safety reporting, the most frequently used mechanism for safety reporting.

They have the responsibility to:

• Ensure that the patient is informed enough and stimulated to report any unexpected effect that they may experience.
• Ensure traceability of prescribed product by providing all the relevant information related to this product, and by making sure that this information is included in the patient file, which can be used for verification in the case of reported ADR.

IV. Patients and their Care givers

Patients themselves and their carers have the responsibility to thoroughly follow the treatment plan and recommendations from the product label and to be aware of potential benefits and risks.

V. Contract research organizations (CROs)

Contract research organizations(CROs) are outsourcing firms that perform specific R&D tasks for the biotech industry. They are specialized in parts of the developing process or certain fields and use their expertise and experience to fast-track drug development and commercialization. They can offer a full range of services for clinical trial activities.

Together, these stakeholders uphold the integrity and quality of the drugs that the public consumes.

Maintaining relationships: the key to more effective pharmacovigilance

During the 8th Conference on Pharmacovigilance, the issue of more effectual pharmacovigilance was explored. In a panel discussion facilitated by Dr Eszter Teleki, Group Director at Bristol-Myers Squibb Pharma EEIG, the importance of cooperation and collaboration was underscored - to make the relationships between stakeholders work and also to make pharmacovigilance more effective. The importance of involving patients more in pharmacovigilance efforts was also stressed

It was suggested that the level of collaboration and cooperation between stakeholders must start with “shared understandings” and “realistic expectations of communication,” especially in forming practical policies and in resolving problems.

Shared understandings and expectations of communication can be applied in practical terms in order to formulate policies and resolve problems;

1. Data pooling

Pharmaceutical companies and CROs need to effectively communicate regarding the data they collect. Even during the clinical trial phases, much data is available that serves as signals to risks of potential ADRs. The CROs can already use data from clinical trials to hypothesize likely ADRs that may develop and recommend ways in which the risks can be managed.

Data pooling can also benefit individual drug companies as it will drive research costs down. Researching a question which has been researched by someone else will not only prove a costly proposition, but it also wastes time. Data pooling and sharing can help re-focus research efforts and identify new areas of research.

In this regard, the views and descriptions of patients who participate in clinical trials are valuable as their descriptions include the impact of the effects of the drugs on their quality of life. In turn, patients’ views as to their experiences may determine new “off-label” uses for drugs.

A recent example of data pooling in practice is the collaboration of ten companies working to identify promising drug targets for Alzheimer’s disease, lupus and diabetes treatments. This initiative was led by the US National Institute of Health in Bethesda, Maryland, as part of wider efforts to help the pharma industry accelerate the development of new drugs.

2.Data sharing

Most research and development data is proprietary and is usually kept confidential. However, once a drug has been authorized, the information must be made available to patients, HCPs, and law enforcement agencies. In the first place, HCPs must understand how the newly authorized drug works and what benefits it can give to patients. This information can also help them recognize ADRs in their patients.

Furthermore, patients need to have access to information about the results of clinical trials, and they need to have access to the patient information provided pre-trial. This is to ensure that they are informed as to the potential risks that taking the drug might pose to them. When patients have access to data that is significant to them, they become active partners and not passive subjects in clinical trials.

Lastly, law enforcement agencies need access to drug information so that they can use it to evaluate if the drugs passing through their jurisdiction are counterfeit or legitimate. Law enforcement agencies aren’t experts in detecting counterfeit drugs. They need information that is readily available to use as a basis for evaluating the quality of the drugs they are inspecting. They also need information as to unique characteristics of packaging and labelling and pictures so that they can judge for themselves if the medicines in front of them are identical to the medicines that the legitimate manufacturers are selling.

3.Reporting of ADRs

Not all ADRs are reported by HCPs because they often don’thaveenough information about a drug to detect if a patient’s presenting symptoms are ADRs. They may also feel that treating an ADR is their job but not preventing ADRs, hence, they don’t see the value of reporting them. Therefore, there clearly needs to be some assistance provided to increase the self-efficacy of HCPs to report ADRs and to recognize their responsibility to do so.

A more patient-centred approach to clinical trials is also required. Patients can be an invaluable source of information and data about ADRs, especially if they are trained and educated not only to observe possible ADRs but also to self-measure and self-manage when ADRs do occur.

In 1991, it was estimated that the cost of developing drugs was $318 million USD. Today, the cost of developing a new drug has ballooned to $1.3 billion USD. It is in the interest of all stakeholders to cooperate and collaborate not only to reduce the cost of developing new drugs because this translates into the availability of more affordable drugs, but also because reducing the cost of legitimate drugs will lower the demand for counterfeit drugs, which are always sold at a fraction of the price of legitimate drugs.

The internet is a convenient way of increasing the accessibility of information, for pooling it and disseminating it to stakeholders who need the information in order to make decisions that can save lives. Better information translates into better education for all stakeholders which will make the surveillance of the safety of drugs in the market more efficient, less time-consuming, and less costly.

Protocols, policies, laws, contracts, and consent forms are full of words; but what makes pharmacovigilance effective and efficient, is the trust between the different parties and stakeholders. Thus, it is in everyone’s best interest to effectively communicate and collaborate.

Pharmacovigilance Regulations

In the major regions of the world where medicinal products are developed, pharmacovigilance is highly regulated. Structures, systems, and roles are determined by laws, regulations, guidances, and guidelines; it is within this context that the department’s organizational structure is established, the individual roles and the systems required are defined, the skill sets necessary are determined, and the tools to perform pharmacovigilance effectively are created.

Every country has its own regulatory authority which is responsible to enforce the rules and regulations and issue the guidelines to regulate drug development process, licensing, registration, manufacturing, marketing and labelling of pharmaceutical products. The major regulatory stakeholders driving the formation of global pharmacovigilance regulation are the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), UK Regional Health Authority (HA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA). In the USA, the Code of Federal Regulations is legally binding, as are the European national laws and ordinances. Directives reflect current thinking on a topic and bind member states to common objectives, which must be implemented into national law within a given time frame. Guidance documents, guidelines, and recommendations are not legally binding but should be respected and play an important role in actual practice.

Global principles are harmonized through the International Conference on Harmonization (ICH). ICH E1eE2F focus on clinical safety. The direction is provided in ICH E2AeC (Clinical Safety Data Management), E2D (Post-Approval Safety Data Management: Definitions and Standards for Expedited Reporting), E2E (Pharmacovigilance Planning), and E2F (Development Safety Update Report). ICH E6 (Good Clinical Practice) describes the responsibilities and expectations of all stakeholders in the conduct of clinical trials.

The European Union has introduced a method to label certain medicines which are expected to be monitored more diligently naming it as “additional monitoring”. These medicines are depicted by inverted black triangles which are shown in their package leaflet. This practice came into existence from Autumn, 2013. This black triangle on any medicine appears especially when the drug is new to the market and not much information is available for it, or in case of biological medicines such as vaccine or blood products.

However, even as efforts to harmonize pharmacovigilance processes continue, companies must still comply with national laws and local regulations. As in other areas of development, companies should have SOPs around pharmacovigilance processes in order to ensure consistency, compliance, and quality. Pharmacovigilance and Risk Management plays a major role in the Drug industry. The new turn in the Drug industry is to use Information technology in pharmacovigilance companies. Drug Industry need to promote companies in pharmacovigilance practice and the Review of software’s used in pharmacovigilance and clinical trials.

In the global pharmacovigilance market, the legislation requires the Marketing Authorisation Holder (MAH) of medicinal products to have a pharmacovigilance system where all aspects comply with the requirements of the appropriate regulatory authority. As more MAHs work globally it is increasingly important that they understand local differences in requirements for compliance around the world including inspection procedures and legal implications. The European Medicines Agency developed the good-pharmacovigilance-practice (GVP) guideline to facilitate the performance of pharmacovigilance activities in the European Union. GVP is a key deliverable of the 2010 pharmacovigilance legislation to replace earlier guidance drawn up by the European Commission.

Until July 2012, the European Commission drew up pharmacovigilance guidelines in accordance with Article 106 of Directive 2001/83/EC of the European Parliament and the CouncilExternal link icon, known as volume 9A. With the application of the new pharmacovigilance legislation as of July 2012, volume 9A has now been replaced by the good-pharmacovigilance-practice (GVP) guideline, published by the Agency.

Regulatory Affairs for clinical trials is the major part in the clinical trials approaches. Regulatory affairs help the healthcare industries to make safe and effective healthcare products available worldwide. Every clinical trial must be analysed according to the Regulatory Affairs Guidelines.

Legislation on Pharmacovigilance

Legislation on pharmacovigilance is based on two new legislative acts:

•Regulation (EU) 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products. [[3]]

•Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use. [[4]]

A new medicine must pass three hurdles before its approval by the national drug regulatory authority. Sufficient evidence is required to show the new drug to be:

• of good quality,
• effective, and
• safe for the purpose or purposes for which it is proposed.

Whereas the first two criteria must be met before any consideration can be given to approval, the issue of safety is less certain. Safety is not absolute, and it can be judged only in relation to efficacy, requiring judgement on the part of the regulators in deciding on acceptable limits of safety.

There is a possibility that rare yet serious adverse events (such as those occurring with a frequency of, say, one in five thousand) will not be detected in the pre-registration development of the drug. For example, fatal blood dyscrasia occurring in 1 in 5,000 patients treated with a new drug is only likely to be recognized after 15,000 patients have been treated and observed, provided that the background incidence of such a reaction is zero or a causal association with the drug is clear.a

a This arbitrary ‘rule of three’ is based on the experience that for any given adverse effect approximately threefold the number of patients need to be treated and observed for the side effect to become manifest and reliably linked with the drug assuming a background incidence of zero of the effect being observed.

Sound drug regulatory arrangements provide the foundation for a national ethos of drug safety, and for public confidence in medicines. The issues with which drug regulatory authorities have to contend besides the approval of new medicines, include:

• clinical trials
• safety of complementary and traditional medicines, vaccines and biological medicines
• developing lines of communication between all parties with an interest in drug safety and ensuring that they are open and able to function efficiently, particularly at times of crisis.

Guideline on GVP The guideline on GVP is divided into chapters that fall into two categories:

• GVP modules I to XVI which cover major pharmacovigilance processes and the development of this set of guidance is concluded;
• product- or population-specific considerations developed for vaccines and biological medicinal products.

Each chapter is developed by a team consisting of experts from the European Medicines Agency and the EU Member States. The guideline on GVP is a key deliverable of the 2010 pharmacovigilance legislation.

Modules covering major pharmacovigilance processes

• Guideline on good pharmacovigilance practices: Module I – Pharmacovigilance systems and their quality systems
• Guideline on good pharmacovigilance practices: Module II – Pharmacovigilance system master file
• Guideline on good pharmacovigilance practices: Module III – Pharmacovigilance inspections
• Guideline on good pharmacovigilance practices (GVP) - Module IV – Pharmacovigilance audits (Rev. 1)
• Guideline on good pharmacovigilance practices: Module V – Risk management systems
• Guideline on good pharmacovigilance practices: Module VI – Management and reporting of adverse reactions to medicinal products
• Guideline on good pharmacovigilance practices (GVP): Module VII – Periodic safety update report
• Guideline on good pharmacovigilance practices: Module VIII – Post-authorization safety studies
• Guideline on good pharmacovigilance practices: Module VIII addendum I – Member States' requirements for transmission of information on non-interventional post-authorization safety studies
• Guideline on good pharmacovigilance practices: Module IX – Signal management
• Guideline on good pharmacovigilance practices: Module X – Additional monitoring
• Guideline on good pharmacovigilance practices: Module XV – Safety communication
• Guideline on good pharmacovigilance practices: Module XVI– Risk minimization measures - Selection of tools and effectiveness indicators
• Guideline on good pharmacovigilance practices (GVP): Module XVI Addendum I – Educational materials

EMA has recently modified Module VIII – Post-Authorization Safety Studies and Module IV – Pharmacovigilance Audits.

Pharmacovigilance Regulatory Bodies Worldwide

Major pharmacovigilance regulatory bodies in the world are:

• CDSCO (India) - Central Drugs Standard Control Organization

• FDA (US) - Food and Drug Administration

• EMA (EU) - European Medicines Agency

The European Medicines Agency (EMA) coordinates the European Union (EU) pharmacovigilance system and operates services and processes to support pharmacovigilance in the EU.

• PMDA (Japan) - Pharmaceutical and Medical Device Agency

• ANSM (France) - the National Agency for the Safety of Medicines and Health Products -

• BfArM (Germany) - Federal Institute for Drugs and Medicinal Devices -

• MHRA (United Kingdom) -. Medicines & Healthcare products Regulatory Agency

• Health Canada (Canada) -

• TGA (Australia) - Therapeutic Good Administration

• SFDA (China) - State Food and Drug Administration

• Medsafe (New Zealand) - Medicines and Medical Devices Safety Authority

• ANVISA (Brazil) - Agencia Nacional de Vigiloncia Sanitaria

• MPA (Sweden) - Medical Products Agency
• EPVC (Egypt) - Egyptian Pharmaceutical Vigilance Center, part of Egyptian Drug Authority (EDA)

• MHI (Israel) - Ministry of health Israel

• ANMAT (Argentina) - Administración Nacional de Medicamentos, Alimentos y Toxicologia Medica

• INVIMA (Colombia) - Instituto Nacional de Vigilancia de Medicamentos y Alimentos

• ISP (Chile) - Instituto de Salud Publica

• COFEPRIS (Mexico) - Comision Federal para La Proteccion Contra Riesgos Sanitarios

• DIGEMID (Peru) - Direccion General de Medicamentos, Insumos y Drogas

• MSP (Uruguay) - Ministerio de Salud

• MSPBS (Paraguay) - Ministerio de Salud Publica y Bienestar Social

• KFDA (South Korea) - Korea Food Drug Administration

• MINSA (Panama) - Ministerio de Salud - Centro Nacional de Farmacovigilancia.

• CECMED (Cuba) - Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Medicos.

• FAMHP (Belgium) - Federal Agency for Medicines and Health Products.

• EOF (Greece) - National Organization for Medicines.

• AIFA (Italy) - Agencia Italiana del Farmaco

• INFARMED (Portugal) - Autoridade Nacional do Medicamento e Produtos de Saúde, I.P.

• RZN (Russia) - Roszdravnadzor.

• EOF (Greece) - National Organization for Medicines

• Fimea (Finland) - Finish Medicines Agency

Big data in Pharmacovigilance

Big Data can be a foundation for integrating and analyzing the vast variety of data in pharmacovigilance. Safety concerns can have serious implications on patient health and a company’s financial health and reputation. Different types of data from multiple sources need to be integrated:

1. Adverse Event (AE) cases reported directly to companies and their partners,
2. Health agency databases such as FDA Adverse Event Reporting System (FAERS) and Uppsala Monitoring Center (VigiBase),
3. Real world data from cohort studies can be provided as both structured and unstructured data,
4. Published literature on safety and efficacy,
5. Data from social media (Twitter, Facebook, blogs), while this data is not as reliable as others, it is becoming the earliest warning signal and it is creating a definite and special need to seek, store, and analyze to spot safety concerns.

The surge in data availability, in terms of volume and variety, provides several alternatives to gain insights:

• Integrating data from multiple sources: There is significant value in looking at data integrated from several sources. A sequential view/analysis of data does not provide the synergy that comes from integrated data.

• New techniques in analyzing data: There are several new techniques available to analyze. For example, research publications can be analyzed using text mining methods to summarize the findings. Therapy or drug-based ontologies (taxonomy combined with interrelationships among entities) can be developed to refine searches. The ontologies can, in turn, be developed through machine learning.

Techniques for analyzing Big data in Pharmacovigilance

Data mining

Data mining has gained an important role during all stages of drug development, from drug discovery to post-marketing surveillance. Data mining may allow identification of unusual or unexpected product-event combinations warranting further investigation. Data mining can be used to augment existing signal detection strategies and is especially useful for assessing patterns, time trends, and events associated with drug-drug interactions. Data mining is not a tool for establishing causal attributions between products and adverse events.

Statistical techniques used for data mining include cluster analysis, link analysis, deviation detection, and disproportionality assessment, which can be used to detect the presence and strength of adverse drug event signals. The use of data mining techniques in clinical pharmacology can be broadly grouped into two main areas, each with specific aims:

• Identification of new effects of drugs (mostly adverse reactions, but sometimes also new therapeutic effects, and effects in special populations);

• Appropriateness in drug use (e.g., frequency of use in patients with contraindications, concomitant prescriptions of drugs known for the risk of clinically relevant interactions).

Both aims can be addressed using each of the three conventional sources of data listed below, although the inherent purpose for which they are created should be kept in mind when interpreting results: any secondary analysis of data collected for other purposes carries intrinsic biases.

• Spontaneous reporting systems (SRS)
• Electronic medical records
• Claim databases

After identification of the most appropriate source of data to address the research question, the appropriate methodology to approach data analysis should be identified. From data cleaning to statistical methodologies (e.g., multiple regression analysis), all steps of data management are considered parts of data mining techniques. Usually, each source of data is analyzed by the own natural data mining approach (e.g., disproportion calculation for SRSs, multiple regression analysis for electronic medical records), but there are also emergent strategies for better exploitation of more accessible sources, such as self-controlled time series.

Text-mining and information mining are also frequently used in searching possible associations between drugs and adverse events, although this is virtually ignored by regulatory agencies. Especially, in this case, the source of data is a key step for a reliable result of the analysis: both free-text searches into electronic patient records and text analysis of any document freely published online represent possible sources of data for these strategies. Because of the huge variety of information processed by this approach, a more strict plausibility of the associations found between drug and effect should be claimed, because of, for instance, the high risk of inverse causality.

In general terms, data mining can be considered an activity related to “knowledge discovery in databases”, i.e., the process of extracting information form a large database. In this context, data mining is referred to as the computer-assisted procedures, starting from the processing of dataset by data “cleaning” and culminating into the application of statistical techniques, often known as data mining algorithms (DMAs). DMAs are currently and routinely used by pharmacovigilance experts for quantitative signal detection. The purposes of quantitative signal detection are many-fold and may vary depending on the local habit of Pharmacovigilance experts. For instance, DMAs can be used as an aid to the traditional case-by-case assessment; as a screening tool to periodically generate a list of signals requiring in depth investigation (i.e., to prioritize signals); on ad hoc basis to detect complex data dependencies, which are difficult to be manually detected (e.g., drug-drug interactions or drug-related syndromes).

Two Tiered Approach to Analysis

There is a need for a tiered approach to analyze the data from low and high reliability, to mine text versus data, and to understand the speed versus the reliability of insights. The data from social media is available faster than data from published journals, but may be from a patient who may not be a qualified physician, while the other is from a qualified physician who has spent hours thinking, collecting evidence, analyzing, and putting the concept in a structured format. The real world data and physician-reported adverse events are available faster than those from published journals, but the level of research is less reliable than the information from journals.

Big data tools and technologies are ideally suited for this tiered analysis approach. The Big Data layer is enabled by cost-effective technologies, newer analytics and visualization, and quicker implementation timelines.

1.A first tier (big data) that emphasizes the following:

a. Speed to Insight through faster data ingestion

b. A consolidated view of the data

c. A company and therapeutic specific ontology automated through machine learning

d. Business friendly analysis through:

• Data exploration
• Text mining
• Ontology-based searches
• Quick data visualization
• Testing ad hoc hypothesis

2. A second tier (traditional) can leverage the information and insight gained from the output of first-tier and continue with the traditional analysis of case processing and signalling:

a. Focused analysis of insights from Tier 1

b. Expanded scope to text-based insights from detailed case analysis and summary reports

c. Harmonized findings from the first tier and the traditional approach

In the last 10 years, the term "big data" has become a keyword in many different contexts. Despite being a widespread term, though, it is not always clear what it refers to. The most appropriate definition is the one that breaks it down to the so-called "4 Vs": Volume, Variety, Velocity and Veracity, i.e. a big amount of heterogeneous data that are rapidly analysable and undergo quality checks systematically. "Big data" has become a more and more cited term in health care, for the potential use of the huge amount of data collected from digital medical records or administrative data (e.g. drug prescriptions, hospital dismissal forms, healthcare services etc.) and also as a support for regulatory decisions, pharmacovigilance included. Since the Nineties, the use of health databases has become widespread especially in Europe and America, and more recently in Asia, and health databases are used to evaluate the post-marketing phase of pharmacological treatments, in particular for the analysis of their prescription appropriateness, comparative effectiveness and safety. Post-marketing safety analysis uses wide data sources, among which the informative systems for suspect adverse reactions spontaneous reporting. The Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) is available for public consultation. In 2006, FAERS received almost half a million reports, reaching 1.2 million in 2014. Other reporting systems that collect information in their databases are Vigibase, the World Health Organisation (WHO) informative system that so far has received almost 15 million adverse reaction reports,8 and EudraVigilance by the European Agency for Medicines (EMA), that has collected almost 11 million reports. Besides databases for spontaneous reporting, other types of databases are used in pharmacovigilance, for example, the databases that collect administrative data and electronic medical records (EMR). Administrative databases are very common in Italy, such as those concerning services and products reimbursed by the National Health Service. Administrative data include drug prescriptions and hospital discharge letters, which record diagnosis and medical procedures for every hospitalisation. By combining this data with the data collected by the National Health Service, it is possible to recover the medical history of any patient. In many Italian regions, health administrative data are managed by the Local Health Authorities, which use them for pharmacovigilance activities and drug safety evaluations. The EMR databases, on the other hand, contain patients' demographic and medical information, such as diagnoses and prescriptions, that is recorded by the general practitioner every time he visits the patient. The simultaneous use of several databases to evaluate the effectiveness and safety of drugs, also by integrating databases of different typologies (for example, administrative and EMR databases), has become more and more frequent. Multi-database initiatives have shown a tendency to create wide data infrastructures for the post-marketing evaluation of effectiveness and safety of drugs, but also to increase the power of studies on rare diseases that, because of the scarce number of cases, can hardly become the object of randomised clinical studies (RCT). The increasing use of health database networks has allowed the development of new analytical methodologies through the elaboration of big volumes of heterogeneous data, for example, Observational Health Data Sciences and Informatics (OHDSI) has developed methods and instruments for the construction of database network infrastructures. Similarly, the initiative called PROTECT (http://www.imi-protect.eu/) has shown that it is possible to conduct analysis on more than one database, by adopting common protocols instead of a centralised data analysis. In order to foster cooperative research by creating health database networks, EMA has been coordinating for almost a decade a network of Pharmacoepidemiology and Pharmacovigilance (ENCePP) that includes around 200 Public Institutions and Contract Research Organization (CRO) involved in activities related to pharmacoepidemiology and pharmacovigilance. In regard to the database networks used for pharmacovigilance, two relevant initiatives have been implemented internationally: Sentinel and EU-ADR. Sentinel is a post-marketing surveillance system developed in 2008 by FDA, based principally on the medical data of 193 million people in the United States.15 All data are collected and uniformed according to a common data model, thanks to which it has been possible to manage and elaborate the data with a single coordinating centre, guarantying the privacy of each patient. EU-ADR, on the other hand, is an initiative funded by the European Union in 2008, with the goal of early identifying drug safety signals by means of data-mining techniques applied on eight medical databases of four European countries (Denmark, Italy, Netherland and United Kingdom)16 for a total of around 30 million subjects. Other international networks have been developed in the last years, in order to increase the power of post-marketing studies on medicines and vaccines, among which ARITMO (http://www.aritmo-project.org), SAFEGUARD (http://www.safeguard-diabetes.org/), ADVANCE (http://www.advance-vaccines.eu/), SOS (https://www.sosnsaids-project.org/), EUROmediCAT in Europe (http://www.euromedicat.eu/), CNODES in Canada (https://www.cnodes.ca/) and Asian Pharmacoepidemiology Network (AsPEN) in Asia and Australia (http://aspennet.asia/index.html). In databases, most part of the information is usually coded: for example, medical diagnosis is usually coded with the International Classification of Diseases (ICD) or the International Classification of Primary Care (ICPC), whilst information on drugs are often coded with the Anatomical Therapeutic Chemical (ATC) classification system. The data of interest can be selected by identifying the relevant codes, ideally in accordance with validation studies on the identification of diseases available in the literature to ensure the accurateness and reproducibility of the results. However, clinical information in these databases can also be entered as free text, as from specialists or general practitioners who record the details of their clinical practices with text notes in their digital medical records. Artificial intelligence could be used to analyse data collected as free text, and, specifically, "machine learning". This methodology can be supervised or unsupervised and both approached have been used in pharmacovigilance for the automatic identification of safety signals. The unsupervised machine learning (UML) is an automatic learning system whose aim is to identify links among the provided inputs, without labelling them either correct or incorrect. This approach has been used to identify drug safety signals and usage pattern. On the other hand, possible inputs and their desired outputs are given to supervised machine learning (SML), with the goal of identifying patterns that associate the input to the output. An example of SML is the correct decoding of free text. The identification of adverse reactions in databases is carried out by a particular type of learning machine called Natural Language Processing (NLP). In order to identify potential adverse events, NPL has been applied not just to health databases, but to social media as well, such as Twitter, that mostly contains strings of data in text format. In particular, free text data from social network forums where users share their clinical experience and data from case reports that described potential adverse events have been aggregated. In health care, the importance of social media is acknowledged because of the huge amount of users registered on social networks like Facebook (almost 2 billion users) and Twitter (more than 300 million users). Increasing interest has been given to research in pharmacovigilance employing analysis of data from social media. Although social media can play a role in the post marketing evaluation of drug safety, to date it seems that these instruments do not specifically improve the identification of the drug safety signals. With more and more devices collecting data, such as apps or electronic devices for monitoring clinical parameters or life style ones (known as wearables), it will be interesting to see if and how rapidly these technologies will have an impact on pharmacovigilance. Despite the several advantages associated with using medical databases, there are also some limits that must be taken into consideration. One of the principal criticalities concerns the quality of the contents: if poor (for example because of erroneous data registration or high frequency of missing data), the value of the results will have limited. Therefore, it is essential to thoroughly understand the limits of the employed data sources and to choose the most appropriate study design for the analysis that needs to be carried out, accurately evaluating whether the data source is fit to assess the clinical question correctly instead of adapting the clinical question at the core of the study to the data source. In general, the availability of different data sources and the increase of analysis instruments represent an opportunity for carrying out studies on the use and safety of drugs, on a wider and wider scale and with more and more details. However, it is important to remember that the results obtained from the analysis of big data from different sources must be supported by a robust and critical clinical interpretation. The process that leads to the identification of a drug safety signal cannot be completely automatic and careful evaluations from experts in the field remain essential. All the data present in administrative databases, in disease registers, in the EMRs from general practitioners and in the adverse event spontaneous reporting systems should not be evaluated separately but should be considered parts of a wider context. In general, these data have a very limited value in itself, but when correctly analysed and interpreted they can represent a very useful instrument that can support and guide regulatory decisions on drugs.

Pharmacovigilance in Commercialization and Marketing

Once approved by the FDA, a drug manufacturer is free to introduce the medication to a mass market. This approval includes the requirement to engage in the fourth stage of clinical testing, known as post-marketing surveillance. The manufacturer must continue to collect data regarding the efficacy and safety of the drug and consider further developments to the product. The broad-scale introduction allows the company to include in its annual reports to the FDA data such as incorrect usage by consumers and doctors, interactions with other drugs and counterfeiting activity. It also allows for investigation by interested parties outside of the drug manufacturer, including medical associations, the media and academic researchers.

Using Social Media in Pharmacovigilance

Pharmaceutical companies used digital Media to communicate with patients to create awareness about diseases and treatment, clinical trial enrollments and patient support programs. Recently social media has become the power source for news updates, marketing, entertainment, etc. Pharma companies have to document and follow up on any reportable safety information communicated through social media forums. Today EMA and FDA have focused on company-owned social media channels to ensure maximal safety reporting. Traditional disease surveillance has been a key ingredient in any public health portfolio for many decades. Disease surveillance is widely recognized as one of the most important tools to assess, predict, and mitigate infectious disease outbreaks. Traditional disease surveillance is based on data collected by health institutions, and the data typically consists of information such as morbidity and mortality data, laboratory reports, individual case reports, field investigations, surveys, and demographic data. They are generally collected by physicians, public health laboratories, hospitals, and other health providers and institutions. The computer revolution that began in the 1970s has affected traditional disease surveillance systems by improving the accessibility of data and by increasing the speed at which data are transmitted between institutions. However, the ongoing Internet and mobile phone revolution have a qualitatively distinct effect: in addition to making epidemiologic data available faster and more broadly, new data are generated directly by the public, often on platforms not primarily designed for health purposes. The widespread use of the Internet and of social media, in particular, has had a dramatic effect not only on infectious disease surveillance but also on the surveillance of drug use and related events. Perhaps even more so than traditional infectious disease surveillance, traditional surveillance of adverse drug reactions (ADRs) after drug use is slow and patchy. When reported by patients or healthcare professionals, ADRs are typically assessed by drug experts and pharmaceutical companies, and the results are then passed on to government agencies. This leads to substantial data loss and delays. In recent years, user-posted data on social media, primarily due to its sheer volume, has become a useful resource for ADR monitoring. Social media (SM) presents new channels and methods that can enable companies to move away from traditional pharmacovigilance systems and safety reporting methods towards more patient-centric models for reporting, analyzing and monitoring of safety data. These channels have the capability to allow swift and open communication between companies and the consumers/patients and healthcare providers using medicinal products, thereby helping foster transparency and build public trust. GVP Module VI states that marketing authorization holders (MAH) should regularly screen the internet and/or digital media under their management and responsibility, for potential reports of suspected adverse reactions.

Pharmacovigilance practice has evolved and grown more complex over the past 5 to 10 years due to higher data volumes, evolving regulations, increased influence of emerging markets and the emergence of social media and innovative technological advances.

The phenomenal reach of the internet and social media over the last few years has led to a revolutionary shift in how people are communicating with one another today. Social media platforms and applications are fast becoming the go-to form of communication in the era of Web 2.0. Digital media is used by biopharmaceutical companies for communication with patients to create awareness about diseases and treatments, clinical trial enrollments and patient support programs. However, unlike other areas of healthcare, the use of the internet and social media has progressed slower in Product safety/Product Vigilance (PV). This presents the life science and service provider industry with multiple exciting, yet overwhelming, opportunities for appropriate and effective use of social media to drive innovative and meaningful changes in PV and how we communicate with patients and healthcare practitioners around the world.

ABPI (Association of the British Pharmaceutical Industry) had introduced guidance for the pharmaceutical industry for using social media compliantly in 2013 and in 2016 ENCEPP (European Network of Centres for Pharmacoepidemiology and Pharmacovigilance) published guidelines which will mandate monitoring social media for adverse events. The benefits of using social media for Adverse Drug Reaction (ADR) reporting are slowly becoming recognized, not just among regulatory authorities but also the pharmaceutical industry stakeholders and Healthcare Professionals (HCPs). If utilized correctly, ADR reporting and monitoring via social media could potentially prove to be an efficient and expeditious means of Post-Market safety surveillance and overcome limitations of traditional ADR reporting systems such as under-reporting.

WEB-RADR

Recognising Adverse Drug Reactions

Summary

Detecting the adverse effects of medicines – as well as their misuse – poses a big challenge for health authorities. Under-reporting is an issue, with individuals sometimes more likely to express their frustration via social media channels than consult their doctor. By bringing together industry and academic experts, regulators, patients and small and medium-sized enterprises (SMEs), IMI’s WEB-RADR project developed a mobile application which allows patients to directly report potential medicine side effects and also receive reliable information on their drugs. The work done in this project is already helping medicine manufacturers and regulators to detect new safety signals and intervene earlier in case of adverse drug reactions, thus improving medicine monitoring and patient safety.

Pharmacovigilance is the monitoring of the safety of medicines to identify new or changing risks to support the safe and effective use of medicines. This includes the monitoring and reporting of adverse drug reactions (ADRs), i.e. side effects that can be experienced during treatment. Patients experiencing ADRs and their healthcare professionals are requested to report these side effects to their national pharmacovigilance centre. However, paper-based report forms are not always available and are often perceived as inconvenient and complex. If more reports were submitted, this could facilitate the faster identification of risks.

To address this, IMI’s WEB-RADR project has developed a mobile app that allows users of pharmaceutical products to directly report ADRs to relevant health authorities, find out about reported side effects and opt to receive alerts on specific medicines. During the project, the app was rolled out across three EU countries – Croatia, the Netherlands, and the UK – and had about 10 000 downloads in those countries alone.

Thanks to collaboration with the World Health Organization, the app was also rolled out to support malaria programmes in two African countries: Burkina Faso and Zambia. The implementation of the app in those countries had a substantial impact, with Burkina Faso receiving more ADR reports in the first six months after the roll out than they had in all the time previously.

A dozen additional countries around the world have also expressed interest in the app and some have already adopted it. For example, in early 2018 the United Arab Emirates also launched the app.

The reports received via the app have already contributed to the identification of new safety issues with various medicines, enabling regulatory authorities in relevant countries to take appropriate action.

Social media data mining

The WEB-RADR project team also explored the value of social media data for pharmacovigilance. They found that in certain circumstances it could be hugely valuable and that people are far more likely to discuss issues like medicine misuse on social media than with their doctor. To mine this wealth of data, the team developed methods to detect, extract, standardise and analyse medicine-related information reported in unstructured free text by social media users.

This has already led to concrete insights. For example, thanks to social media mining, the team uncovered patterns of misuse of a particular medicine by communities of students who want to improve their performance around examination time. This has provided additional information to the traditional sources, because students would normally not share this information with their doctors and pharmacists.

WEB-RADR policy recommendations on the collection and use of data – both through the app and social media mining – have been passed on to the European Medicines Agency (EMA) for implementation in future guidance on how the pharmacovigilance legislation in the EU should be operated.

Ethical and data protection issues

A consistent area of concern for the project was potential conflicts over data gathering and privacy regulations, as well as ethical considerations about harvesting social media data. To address this, the researchers engaged leading medical ethicists and data protection experts to assist them. That set a sound and robust framework for the analysis that they were doing, ensuring that they were both operating within the law and conducting the work in accordance with the highest ethical standards.

Benefits for industry, academia and SMEs

The industry is already benefitting from the tools and resources developed within this project, especially from the guidelines on how they can use social media to monitor drug safety issues and improve their interaction with patients and carers.

The academic community has benefitted from the exchange of ideas and viewpoints with different stakeholders in the project, as well as from innovative research ideas and identification of new research areas. SMEs have also benefitted from the network formed within the project, and have expanded their businesses.

Finally, patients and healthcare providers benefitted from gaining a new, user-friendly way to report adverse drug reactions and receive official, reliable and regulator-approved information on their treatments via the mobile app.

Current Status of Social Media in PV

Social media activities for PV by companies fall into three broad categories, listening (safety data reporting), engaging (follow-up) and broadcasting (risk communication), each with varying degrees of complexity, associated issues, and requirements.

Today, most of the regulatory guidance and hence PV activities involving social media and internet are primarily focused around the screening of social media sites and follow-up of reported safety data, as detailed further in this section. However, their impact and use in other areas of PV like retrieval, integration, and analysis of safety data and as potential tools for risk communication and management, is either minimal or absent.

There are now multiple sites and applications for the patient and consumer reports on computers and smartphones. One such tool is the MedWatcher, a free tool that allows patients and physicians to submit adverse event reports to the FDA via smartphone or tablet (MedWatcher.org). The primary purpose of such tools is to give patients or healthcare professionals (HCPs) information on drugs, devices, interactions and other pharmaceutical information while some also allow reporting of AEs. It is likely that these tools will proliferate and will further become smarter (user-interactive) and sophisticated and help both sponsors and regulators to listen to the voice of patients and consumers directly.

Today, more and more medical and consumer health companies are realizing the importance of having appropriate and sufficient controls over social media sites to avoid potential gaps/risks in the areas of reporting, identification and monitoring of AE data.

Companies are now actively engaged to identify and understand the value drivers for adopting a comprehensive PV social media strategy, which encompasses proactively creating social media platforms to solicit/capture AE data to enable an organization’s social media monitoring and reporting activities as they relate to AE compliance (rather than monitoring and reporting what comes in passively on existing company sites) and further examine the successes and challenges of the different types of social media platforms being used. Companies are now also providing their employees with social media guidance and best practices to facilitate effective safety reporting via social media. Employees are encouraged to be a scout for reporting safety issues/adverse events that they come across on social media sites, wherein side-effects are mentioned after having taken one of the client products drugs in a credible and identifiable way12.

Companies rely on multiple AE reporting channels such as email correspondences, company websites and physician hotline resources. Further to the regulatory guidance from EMA and FDA1-10, today many companies in both EU and US, already show responsibility for their own online content. This is evident, based on data from several surveyed companies, wherein social media serves as one of the adverse event-reporting channel (32%) in these companies11. The internet represents an excellent means of collecting drug and device AEs primarily from healthcare providers. Adverse events can be directly reported to the FDA MedWatch in the US, to Health Canada MedEffect in Canada as well as to the “Yellow Card Scheme” in the UK and in Australia. Social media has already impacted the community of medical practitioners (www.sermo.com), the community of patients (www.patientslikeme.com), the community of medical education and community of medical care facilities (Mayo Clinic). These sites have proven that appropriate messages posted on social media platforms and channels can have a meaningful and rapid impact.

Today, most guidance from EMA and FDA is focused on the screening of company owned/monitored websites, forums and other social media channels to enable and ensure maximal safety reporting. Additional specific guidance is required in terms of confirmation of validity of safety data, obtained via social media (within the norms of data privacy), protocols to guide further retrieval, analysis and integration of such data with other standard safety data (obtained from standard PV sources) and also effective use of social media for risk management and communication

Challenges in AE data mining in social media

There are many challenges in actual AE detection in the data received from SM. One is the high volume of comments from SM channels that potentially makes screening and tracking of AEs difficult. Secondly, the detected AEs from such unstructured data sources are not always obvious. Identifying these AEs and a lack of clarity in those cases where you cannot identify the consumer/Patient can cause problems.

Key challenges in identifying adverse drug events from social media

1) Drugs may be described by their brand names, active ingredients, colloquialisms or generic drug terms (e.g. ‘antibiotic’) or it could be with spelling mistakes, abbreviations

2) ADRs may be referred to using creative idiomatic expressions or terms not found within existing medical lexicons.

3) The informal nature of social media results in a prevalence of poor grammar, spelling mistakes, abbreviations and slang.

4) The existence of a side effect may be clear while the specific side effect experienced remains unclear

5) Discussion of a drug could involve indications, beneficial effects or concerns of an adverse event or even one's opinion on the drug.

6) Edits made in old comments after posting

7) Supervised machine learning, while powerful, need training data which requires the time-consuming and expensive generation of human-annotated data.

Future Impact and Potential Areas to Leverage Social Media in PV

Users in an online community often share a wide variety of personal medical experiences. For many reasons, patients often share health experiences with each other rather than in a clinical research study or with their physician13. One study, led by Knezevic et al in 2011, describes how a Facebook group was created as an Adverse Event (AE) channel and its effectiveness was tracked. The group found that it was able to connect with 1,000 Facebook users and received 21 adverse reactions within the course of seven months14. Social data offers some advantages over traditional AE reporting data or data mined from health and reimbursement records. Social reports are rapid, closer to real-time data (occurring in close proximity to the event) and potentially richer sources than reports filtered through HCPs (coming directly from the patients).

Consumers can communicate the same thing in different ways using variations in their language, slang and accents which is one of the biggest challenges in AE mining in the social media. Most of them don’t always mention brand names of the drug, instead, they also specify generic names, the active ingredient, through colloquialisms or even by the shape and size of a drug which is unique to a brand, for instance, there was a recent comment in social media related to a blue rhomboid shaped pill which is a unique shape of a pill produced by a famous pharmaceutical company. In which case the product is identified and hence it qualifies for an ADR if an AE is also mentioned.

Edits made in old comments after posting is another challenge in AE data mining, sometimes content with less information might not have been qualified to be an AE in the initial mining, but the next time it becomes a clear adverse event with the additional information given during their edits. In such cases, AE mining task is complicated as the company needs to spend more time and money in analyzing their old data. More AE's mined from social media means more time and money needs to be invested in doing the causality assessment by the MAH's as the data may not be 100% accurate due to the informal nature of the social media content which is another big challenge to the pharmaceutical companies.

SM activities for pharmacovigilance by companies fall into three broad categories, social listening (safety data reporting), engaging (follow-up) and broadcasting (risk communication), each with varying degrees of complexity, associated issues, and requirements. Social media listening will likely become a standard practice in pharmacovigilance in the future. However, before that, careful evaluation and assessment of the use of SM as a pharmacovigilance tool need to be done; both in terms of meaningfulness and impact on outcomes. Further, evaluation of regulations and laws required for effective use, the practicality of the use of big data obtained via social media channels, cost of use and overall cost-benefit analysis needs to be done.

Social data offers some advantages over traditional AE reporting data or data mined from health and reimbursement records. Social reports are rapid, closer to real-time data (occurring in close proximity to the event) and potentially richer sources than reports filtered through HCPs (coming directly from the patients). The conversation about products and brands are taking place in unstructured data from the social media which is diverse and located in multiple sites. The ability of companies to leverage social media can transform these platforms into strategic PV tools to bring structure to unstructured web conversations into an actionable, smart format. One of the key areas of influence is, therefore, to establish SM as an AE reporting channel by expanding its existing use and unlocking its potential as a value-add for companies' PV strategies.

Several researchers have tried to analyze qualitative and quantitative correlations between AE mentions in social media and spontaneous reports from other sources. Nabarun Dasgupta et al; has analyzed AE mentions in twitter and has seen a similar pattern (by system organ class) of AEs reported to FAERS within the same time period.

The role of social media in pharmacovigilance has been gaining in interest with various social media sources used for detecting ADRs, including general purpose social networking sites such as Twitter, and health and support networks including PatientsLikeMe, DailyStrength and MedHelp. Previous reviews in this area have focused on the approaches that have been taken to analyze social media, and the analysis of various pharmacovigilance text sources including biomedical literature, clinical narratives, and social media.

Today, more and more medical and consumer health companies are realizing the importance of having appropriate and sufficient controls over social media sites to avoid potential gaps/risks in the areas of reporting, identification and monitoring of AE data.

The volume and velocity of data generated from social media sources potentially provide exciting opportunities for advances in pharmacovigilance. However, in order to realize the potential that social media has to offer, a number of challenges remain to be resolved. Some of these are technical in nature while others require careful consideration from regulatory and ethical perspectives to understand fully and yield the benefits that social media have to offer. Indeed, the critical question that needs to be answered is what value social media adds to the current processes of pharmacovigilance, where that value lies, and what processes and regulatory aspects need to be put into place to realize that value. Recent years have seen an explosion in the use of social media. While in the past there were no clear guidelines on monitoring pharmacovigilance activities on social media websites, the U.S. Food and Drug Administration recently issued proposed guidelines for the pharmaceutical and medical device industries for posting information on social media networks and correcting misinformation posted by others. The proposal would require companies to post both the benefits and the main risks associated with a product, potentially with a hyperlink taking the reader directly to a more detailed list of risks. Definite challenges exist in reporting on social media discussion, however, it’s both exciting and reassuring to know that regulatory advances are being made in an area with such opportunity for drug safety and risk monitoring.

Why pharmacovigilance is needed in every country

There are differences among countries (and even regions within countries) in the occurrence of ADRs and other drug-related problems. This may be due to differences in e.g.:

• Diseases and prescribing practices;

• Genetics, diet, traditions of the people;

• Drug manufacturing processes used which influence pharmaceutical quality and composition;

• Drug distribution and use including indications, dose, and availability;

• The use of traditional and complementary drugs (e.g. herbal remedies) which may pose specific toxicological problems, when used alone or in combination with other drugs.

Data derived from within the country or region may have greater relevance and educational value and may encourage national regulatory decision-making. Information obtained in one country (e.g. the country of origin of the drug) may not be relevant to other parts of the world, where circumstances may differ.

Therefore, drug monitoring is of tremendous value as a tool for detecting ADRs and specifically in relation to counterfeit and substandard quality products. ADR monitoring is to help ensure that patients obtain safe and efficacious products. The results of ADR monitoring also have a very important educational value.

Also, Pharmacy Practices and its Challenges track principally targeted on Pharmacy observe and its pointers and Challenges in the change of integrity and dispensing observe. Indefinite quantity program, drug toxicity and drug safety measures place vital position in clinical analysis.

pharmacovigilance is a dynamic clinical and scientific discipline. It provides reliable, balanced information for the effective assessment of the risk/benefit profile of medicines. However, under-reporting remains the corner stone that hinders pharmacovigilance activities

(PDF) Why do we need Pharmacovigilance?. Available from: https://www.researchgate.net/publication/265906758_Why_do_we_need_Pharmacovigilance [accessed Dec 13 2018].

The National Pharmacovigilance Centers

At present, post-marketing surveillance of medicines is mainly co-ordinated by national pharmacovigilance centres. In collaboration with the Uppsala Monitoring Centre (UMC) and the program for internationa Drug Monitoring (PIDM), the National Centres have achieved a great deal in:

• Collecting and analysing case reports of ADRs
• Distinguishing signals from background "noise"
• Making regulatory decisions based on strengthened signals
• Alerting prescribers, manufacturers and the public to new risks of adverse reactions.

The number of National Centres participating in the WHO International Drug Monitoring Programme has increased from 10 in 1968 when the Programme started, to 127 member countries and 29 associate countries preparing for full membership. The centres vary considerably in size, resources, support structure, and scope of activities. Collecting spontaneous reports of suspected ADRs remains their core activity.

National Pharmacovigilance Centres are responsible for:

• Promoting the reporting of adverse reactions.
• Collecting case reports of adverse reactions.
• Clinically evaluating case reports.
• Collating, analyzing and evaluating patterns of adverse reactions.
• Distinguishing signals of adverse reactions from “noise”.
• Recommending or taking regulatory action in response to findings supported by good evidence.
• Initiating studies to investigate significant suspect reactions.
• Alerting prescribers, manufacturers and the public to new risks of adverse reactions.
• Sharing their reports with the WHO Program for International Drug Monitoring.

The scope of activities of national centers has expanded to include communication of information about the benefits, harm and effectiveness of medicines to practitioners, patients, and the public.

In recent years the UMC has expanded its role as a communications and training center and clearing-house for information on drug safety. Through the following

• mail discussion groups

• website development

• newsletters

• annual National Center meetings

The UMC team, in collaboration with the WHO, facilitates and encourages the international collaboration, which was identified in 1972 as being vital for the success of Pharmacovigilance.

Controversies

The safety of medicines in the development stage is increasingly affected by the constraints placed by sponsors on the study plan, laboratory program and the open sharing of information as the research agenda is negotiated with clinical collaborators. There is growing public concerns that close collaboration between academia and the pharmaceutical industry may adversely affect medical practice and clinical research.

A worrying development for drug safety is ‘direct to consumer’ advertising by pharmaceutical manufacturers, other sellers of medicines and parties with a vested interest. Spending on this activity has doubled in the USA over the past four years. While it may improve patients’ understanding and is in keeping with the need to improve access to drug information, lack of reliability and accuracy may compromise patient care and safety.

Even where direct advertising of prescription medicines to consumers is illegal, the Internet provides a medium that makes communication possible across borders. This may make national regulations about advertising ineffective. Websites now make it possible to buy and sell prescription drugs such as benzodiazepines without controls. These developments in communication all have an impact on the safety of medicine.

All these issues suggest the need for more thorough monitoring of drug safety and scrutiny of advertising. Resources and expertise are necessary to ensure that promotional materials contain accurate and balanced information and that practices are ethical. Self-regulation by industry is unlikely to be sufficient in many countries. Regional or international collaboration in the implementation of a regulatory code of practice for advertising medicinal products, overseen by an impartial advisory body, would help in this regard.

Misrepresentation and lack of full disclosure may have equally important and potentially serious safety implications. Certain international medical journals have developed a uniform policy that reserves the right to refuse to publish drug company-sponsored studies unless the researchers are guaranteed scientific independence. A joint editorial, which outlines the rationale for this policy, states that this action is a response to the industry’s increasingly tight control over research, results and, in many cases, whether and how results are made public. More collaboration with journalists and the media needs to be fostered to ensure the objectivity and reliability of published medical information.

Objectives of pharmacovigilance Pharmacovigilance has been defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other medicine-related problem. In line with this general definition, underlying objectives of the applicable EU legislation for pharmacovigilance are: • Preventing harm from adverse reactions in humans arising from the use of authorized medicinal products within or outside the terms of marketing authorisation or from occupational exposure; and • Promoting the safe and effective use of medicinal products, in particular through providing timely information about the safety of medicinal products to patients, healthcare professionals and the public. Pharmacovigilance is therefore an activity contributing to the protection of patients’ and public health.

History

• 150 years ago, on Jan 29, 1848, 15-year-old Hannah Greener from Winlaton, northeast England, had a routine general anesthetic before treatment of an ingrowing toenail. The anesthetic agent, chloroform, had only been introduced into clinical practice a year earlier by James Simpson, professor of midwifery at Edinburgh since it produced less nausea and vomiting than ether. Unfortunately, Hannah Greener died during the anesthetic from what was possibly an episode of ventricular fibrillation. Because of the continuing concerns of the public and profession about the safety of anesthesia, The Lancet set up a commission, which invited doctors in Britain and its colonies to report anesthesia-related deaths. These findings were subsequently published in the journal in 1893. Thus, the forerunner of a spontaneous reporting system for suspected ADRs was established, at least for a time. Since that episode, advances in drug regulation often seem to be provoked by misfortune, or even disaster. In 1906, the US Federal Food and Drugs Act was passed; this act required drugs to be pure and free from contamination, but there was no requirement for them to be efficacious. Nonetheless, there were 107 deaths in the USA in 1937 from the use of diethylene glycol as a solvent for sulfanilamide. Although the toxicity of diethylene glycol was known at the time, it was not known to the manufacturer, and an amendment to the original act was passed in 1938 to outlaw misbranding of ingredients or false advertising claims.

• However, the most pivotal event in pharmacovigilance occurred in 1961 when an Australian obstetrician, William McBride reported a 20% increase in fetal malformation and the appearance of a hitherto rare malformation, phocomelia (literally “seal limbs”), in association with the use of the hypnotic thalidomide in pregnancy. This drug had not been adequately screened for teratogenic effects, but similar malformations were subsequently shown in the rabbit and (at high dose) in the rat. The impact was especially devastating in West Germany (4000 affected individuals), where the drug had been sold over the counter. Licensing of the drug had been delayed in the USA because of concerns over hypothyroidism and peripheral neuropathy, although there were a few cases of phocomelia in the children of mothers who had taken part in clinical trials. In the USA, the Kefauver-Harris amendment to the US Federal Food and Drugs Act, requiring pre-marketing submission of both efficacy and safety data to the Food and Drug Administration (FDA), was passed in 1962. The thalidomide disaster also stimulated the development of spontaneous reporting pharmacovigilance systems and legislation in Europe, such as the UK’s “yellow card” system (1964) and legislation to regulate medicines in the UK (Medicines Act 1968) and Europe (EC Directive 65/65). Before the Medicines Act came into force in 1971, the Dunlop Committee, the forerunner of the UK Committee on Safety of Medicines, provided independent advice on the safety of medicines.

• As a means of pooling existing data on ADRs, WHO’s Programme for International Drug Monitoring was started in 1968. Initially a pilot project in 10 countries with established national reporting systems for ADRs, the network has since expanded significantly as more countries worldwide developed national pharmacovigilance centers for the recording of ADRs. Currently, 86 countries participate in the programme, which is coordinated by WHO together with its collaborating center in Uppsala, Sweden. The collaborating center is responsible for maintaining the global ADR database, Vigibase. At present, the database contains more than four million ADR reports.

• In 1974, 4 years after the cardio-selective beta-adrenoreceptor blocking drug practolol was first marketed in the UK, reports of an unusual oculomucocutaneous syndrome and sclerosing peritonitis were reported in association with the drug, and a warning was issued a year later. In 1976, the manufacturers withdrew the drug from chronic oral use. Skegg and Doll reported minor eye complaints in 14 (14%) of 71 patients in clinical trials of practolol compared with 4 (6%) during an equal period before the drug was prescribed. They argued that early recognition of the mild and relatively common effects of practolol would have led to earlier diagnosis of the more severely affected patients, some of whom lost their sight. They also suggested that recording of all adverse events rather than just suspected ADRs during clinical trials might prevent investigators from overlooking drug toxicity.

• The non-steroidal anti-inflammatory drug benoxaprofen was marketed in 1980. A year later, photosensitivity and serious hepatotoxicity were reported in association with the drug, and it was withdrawn in 1982. The UK Committee on Safety of Medicines set up the Grahame-Smith Working Party, which made 29 recommendations in 1983, most of them to address the problem of under-reporting of suspected ADRs. They concluded that increased publicity should be given to the spontaneous suspected ADR (yellow card) reporting system and that yellow cards should be made more easily available to potential reporters.

• In 1982, the biguanide oral hypoglycemic agent phenformin hydrochloride was also withdrawn from the UK market after 50 deaths from lactic acidosis were reported in association with this drug. In fact, a significant (around 10%) incidence of reduction of alkali reserve and one death from metabolic acidosis had been reported in association with this drug in 1959, 10 years before it was even marketed. The Grahame-Smith Working Group was reconvened and recommended that pre-marketing drug-safety studies should be of adequate size and that companies should be encouraged to undertake post-marketing surveillance studies on issues identified in the premarketing stage on all new medicines intended for widespread, long-term use. It also recommended that patients should be given more information about the drugs they use, including possible ADRs.

• In 1993, almost 20 years after Skegg and Doll’s comments on the importance of scrutinizing all adverse events, the nucleoside analog fialuridine was associated, in the USA, with worsening liver function, severe lactic acidosis, and the deaths of several patients with hepatitis B in clinical trials of the drug. An FDA task force subsequently commented that in all instances in which drug toxicity might have been suspected, none was attributed by the sponsors to a toxic effect of the drug, and worsening liver function seemed always to have been attributed to worsening of hepatitis.

• WHO established its Programme for International Drug Monitoring in response to the thalidomide disaster detected in 1961. Together with the WHO Collaborating Centre for International Drug Monitoring, Uppsala, WHO promotes PV at the country level. At the end of 2010, 134 countries were part of the WHO PV Programme.
• The rapid growth of pharmaceutical industries has resulted in innovations and increase in the number of drugs into the market, which has also resulted in the rise of adverse drug events. These events have led to a rise in public safety concerns, stringent regulatory policies, expectations and tough inspection regimes, providing the much-needed stimulation for the growth of pharmacovigilance market. The field of drug safety reporting has been extended to medical devices, traditional medicines and biologics.

Pharmacoenvironmentology; (Ecopharmacovigilance [EPV]

Despite attention from the FDA and regulatory agencies of the European Union, procedures for monitoring drug concentrations and adverse effects in the environment are lacking. Pharmaceuticals, their metabolites, and related substances may enter the environment after patient excretion, after direct release to waste streams during manufacturing or administration, or via terrestrial deposits (e.g., from waste sludges or leachates). A concept combining pharmacovigilance and environmental pharmacology, intended to focus attention on this area, was introduced first as pharmacoenvironmentology in 2006 by Syed Ziaur Rahman and later as ecopharmacology with further concurrent and later terms for the same concept (ecopharmacovigilance [EPV], environmental pharmacology, ecopharmacostewardship).

The first of these routes to the environment, elimination through living organisms subsequent to pharmacotherapy, is suggested as the principal source of environmental contamination (apart from cases where norms for treatment of manufacturing and other wastes are violated), and EPV is intended to deal specifically with this impact of pharmacological agents on the environment.

Activities of EPV have been suggested to include:

• Increasing, generally, the availability of environmental data on medicinal products;
• Tracking emerging data on environmental exposure, effects and risks after product launch;
• Using Environmental Risk Management Plans (ERMPs) to manage risk throughout a drug's life cycle;
• Following risk identification, promoting further research and environmental monitoring, and
• In general, promoting a global perspective on EPV issues.

Medical devices

A medical device is an instrument, apparatus, implant, in vitro reagent, or similar or related article that is used to diagnose, prevent, or treat disease or other conditions, and does not achieve its purposes through chemical action within or on the body (which would make it a drug). Whereas medicinal products (also called pharmaceuticals) achieve their principal action by pharmacological, metabolic or immunological means, medical devices act by physical, mechanical, or thermal means. Medical devices vary greatly in complexity and application. Examples range from simple devices such as tongue depressors, medical thermometers, and disposable gloves to advanced devices such as medical robots, cardiac pacemakers, and neuroprosthetics.

Given the inherent difference between medicinal products and medical products, the vigilance of medical devices is also different from that of medicinal products. To reflect this difference, a classification system has been adopted in some countries to stratify the risk of failure with the different classes of devices. The classes of devices typically run on a 1-3 or 1-4 scale, with Class 1 being the least likely to cause significant harm with device failure versus Classes 3 or 4 being the most likely to cause significant harm with device failure. An example of a device in the "low risk" category would be contact lenses. An example of a device in the "high risk" category would be cardiac pacemakers.

Medical device reporting (MDR), which is the reporting of adverse events with medical devices, is similar to that with medicinal products, although there are differences. For instance, in the US user-facilities such as hospitals and nursing homes are legally required to report suspected medical device-related deaths to both FDA and the manufacturer, if known, and serious injuries to the manufacturer or to FDA, if the manufacturer is unknown.^[39] This is in contrast to the voluntary reporting of AEs with medicinal products.

Clinical Evaluation Report

A Clinical Evaluation Report (CER) documents the conclusions of a clinical evaluation of your medical device. A CER consists of analyzed clinical data that was collected either from a clinical investigation of your device, or the results of other studies on substantially equivalent devices. The CER demonstrates that your device achieves its intended purpose without exposing users and patients to further risk. Medical devices range from simple tongue depressors and bedpans to complex programmable pacemakers with micro-chip technology and laser surgical devices. In addition, medical devices include in vitro diagnostic products, such as general purpose lab equipment, reagents, and test kits, which may include monoclonal antibody technology. Certain electronic radiation emitting products with medical application and claims meet the definition of medical device. Examples include diagnostic ultrasound products, x-ray machines and medical lasers. The Medical Product Safety Network (MedSun) is an adverse event reporting program launched in 2002 by the U.S. Food and Drug Administration’s Center for Devices and Radiological Health (CDRH). The primary goal for MedSun is to work collaboratively with the clinical community to identify, understand, and solve problems with the use of medical devices. MedSun fosters an important partnership between clinical sites and FDA. MedSun also serves as a powerful two-way channel of communication between CDRH and the clinical community. Once a problem is identified, MedSun researchers work with each facility’s representatives to clarify and understand the problem. Reports and lessons learned are shared with the clinical community and the public, without facility and patient identification, so that clinicians nationwide may take necessary preventive actions. The Safe Medical Devices Act (SMDA) defines ‘user facilities’ as hospitals, nursing homes, and outpatient treatment and diagnostic centers. They are required to report medical device problems that result in serious illness, injury, or death. MedSun participants are also highly encouraged to voluntarily report problems with devices, such as ‘close-calls,’ potential for harm, and other safety concerns. By monitoring reports about problems and concerns before a more serious event occurs, FDA, manufacturers, and clinicians work together proactively to prevent serious injuries and death. Participants use an Internet-based system that is designed to be an easy and secure way to report adverse medical device events. Each facility has online access to the reports they submit to MedSun so that they can be tracked and reviewed at any time.

Clinical Evaluation Reports are required for all medical devices in Europe. You must submit your CER to your Notified Body as an attachment to your European CE Technical File. The Technical File is an essential step to obtaining CE Marking for your device, which is required to sell or distribute medical devices in Europe.

How to prepare a Clinical Evaluation Report for medical devices

A clinical evaluation takes place in three steps. In step one, manufacturers identify clinical data from existing literature, clinical experience, clinical trials, or any combination of the three. Stage two involves appraising the data's relevance, applicability, quality, and significance. The third step requires you to articulate your conclusions in the CER, based on the data you collected. Approach the CER as a standalone document even though you will include it with your technical file or design dossier. A list of possible elements to include in your CER is as follows:

• • General information: device and manufacturer name
  • Concise physical and technical device description and intended application
  • Outline of intended therapeutic or diagnostic claims
  • Clinical evaluation and data types
  • Summary of clinical data and review
  • Describe analyses used to assess performance, safety, and relevance/accuracy of product literature
  • Conclusions about safety, performance, and conformity

Top 5 Recent Tweets

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September 3rd,2019	@CarrotPharma	https://twitter.com/carrotpharma/status/1168935469821902848?s=20
September 3rd, 2019	@SafeMedicines	https://twitter.com/SafeMedicines/status/1168917051160899586?s=20
September 3rd, 2019	@Virtue_Insight	https://twitter.com/virtue_insight/status/1168912760652128258?s=20
September 3rd, 2019	@Praconsultancy	https://twitter.com/praconsultancy/status/1168889747223318530?s=20
September 3rd, 2019	@Farm_Hosp	https://twitter.com/farm_hosp/status/1168887032883634178?s=20

Top 5 Recent News Headlines

1. May 1, 2017 - UK Pharmacovigilance Post-Brexit: Lots of questions few answers - No one knows what UK pharmacovigilance will look like after the UK leaves the EU, and that uncertainty puts the many Qualified Persons Responsible for Pharmacovigilance (QPPVs) residing in the UK in a precarious position.

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Date	Author	Tweet
Oct 24, 2016	Wall Street Journal	Merck drug gets FDA approval as a first-line lung cancer treatment http://on.wsj.com/2fakoyH
Jul 20, 2015	Chris Cestaro	FDA looking to Google & real world data for pharmacovigilance! Another step toward next generation clinical trials? https://lnkd.in/e6z5yTU
Oct 21, 2016	Daily Express	Kidney cancer treatment FINALLY approved: Revolutionary drug given green light on NHS bit.ly/2epqUPY

Pharmacovigilance IT Systems The new EudraVigilance system was launched on 22 November 2017 Major achievements in 2017 The fieldwork of the independent audit of the EudraVigilance (EV) functionalities agreed by Pharmacovigilance Risk Assessment Committee (PRAC) and the EMA Management Board (MB) took place in February and April 2017.  Based on the independent audit report and on a favourable recommendation from the PRAC, on 22 May 2017 the EMA MB confirmed that the EudraVigilance system had achieved full functionality and the system meets the functional specifications that were adopted by PRAC and Board in December 2013 (announcement of the EMA Management Board).  Testing with national competent authorities (NCAs) and stakeholders was initiated on 26 June 2017 following the release of the new EudraVigilance test environment (XCOMP). This allowed organisations to become familiar with the new system and to test their local pharmacovigilance IT system and their interoperability with the enhanced EV system.

 The registration process for marketing authorisation holders (MAHs) to access the EudraVigilance data analysis system (EVDAS) was launched on 1 June 2017. By 6 December 2017, access to EVDAS had been granted to 6266 EV users. In total, 8831 new EV users and 560 new organisations were registered in EudraVigilance by 6 December 2017.  Based on the agreed EudraVigilance training plan, EMA published e-learning modules and technical documentation including user manuals, a revised change management plan and a Question and Answer document. In addition, EMA organised 41 stakeholder webinars including national competent authorities (NCAs), MAHs and sponsors of clinical trials. Pharmacovigilance (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. WHO established its Programme for International Drug Monitoring in response to the thalidomide disaster detected in 1961. Together with the WHO Collaborating Centre for International Drug Monitoring, Uppsala, WHO promotes PV at the country level. At the end of 2010, 134 countries were part of the WHO PV Programme. The aims of PV are to enhance patient care and patient safety in relation to the use of medicines; and to support public health programmes by providing reliable, balanced information for the effective assessment of the risk-benefit profile of medicines.

References

Medication error reporting and learning systems The most important knowledge in the field of patient safety is how to prevent harm to patients during treatment and care. The fundamental role of a patient safety reporting system is to enhance patient safety by learning from failures of the health-care system. Health-care errors are often provoked by weak systems and often have common root causes which can be generalized and corrected. Although each event is unique, there are likely to be similarities and patterns in sources of risk which may otherwise go unnoticed if incidents are not reported and analysed. The WHO draft guidelines for adverse event reporting and learning systems were published by the World Alliance for Patient Safety in 2005 to help countries develop or advance reporting and learning systems in order to improve the The safety of patient care. Reporting is fundamental to detecting patient safety problems. However, on its own, it can never give a complete picture of all sources of risk and patient harm. The guidelines also suggest other sources of patient safety information that can be used both by health services and nationally. Figures from the United Kingdom, one of the countries that is active in implementing ME reporting and learning systems may illustrate the level and type of reporting performance that can be achieved. Between January 2005 and December 2010, 517 415 medication incident reports were received from England and Wales, constituting about 10% of all patient safety incidents. Of the medication incidents 75% came from acute general hospitals, while smaller numbers, 8.5%, came from primary care. Some 16% of the medication incidents reported actual patient harm and 0.9% of these incidents resulted in death or severe harm. The process steps involved in the largest number of error reports were • medicine administration, 50%; • prescribing, 18%; • omitted and delayed medicine, 16%; and • wrong dose, 15% (Cousins et al., 2012).

144. https://www.imi.europa.eu/projects-results/project-factsheets/web-radr

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