Pharmacovigilance Compiled by-Shamon Ahmad, M.Pharma (Q.A) Chandigarh Group of Colleges, Landran, Mohali(Punjab

India)email-shmmon@gmail.com on Date-25/12/2012

“PHARMACOVIGILANCE” is derived from Greek “pharmakon” = drug Latin “vigilare” = to be awake or alert, to keep watch.

Pharmacovigilance (abbreviated PV or PhV), also known as Drug Safety, is the pharmacological science relating to the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products.

GOOD PHARMACOVIGILANCE PRACTICE (GPVP)

Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines with a view to:

•Identifying information about potential new hazards

•Preventing harm to patients.

Pharmacovigilance heavily focuses on adverse drug reactions, or ADRs, which are defined as any response to a drug which is noxious and un-intended, including lack of efficacy, which occurs at doses normally used for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function. Medication errors such as overdose, and misuse and abuse of a drug, are also of interest because they may result in an ADR.

Information received from patients and healthcare providers, as well as other sources such as the medical literature, plays a critical role in providing the data necessary for pharmacovigilance to take place. In fact, in order to market or to test a pharmaceutical product in most countries, adverse event data received by the license holder (usually a pharmaceutical company) must be submitted to the local drug regulatory authority. (See Adverse Event Reporting below.)

Ultimately, pharmacovigilance is concerned with identifying the hazards associated with pharmaceutical products and with minimising the risk of any harm that may come to patients.

TERMS COMMONLY USED IN DRUG SAFETY:

Pharmacovigilance has its own unique terminology that is important to understand. Most of the following terms are used within this article and are peculiar to drug safety, although some are used by other disciplines within the pharmaceutical sciences as well.

• Adverse drug reaction (ADR) is a side effect occurring with a drug where a positive causal relationship between the event and the drug is thought(soch), or has been proven, to exist.

• Adverse event (AE) is a side effect occurring with a drug. By definition, the causal relationship between the AE and the drug is unknown.

• Benefits are commonly expressed as the proven therapeutic good of a product but should also include the patient’s subjective assessment of its effects.

• Causal relationship is said to exist when a drug is thought to have caused or contributed to the occurrence of an adverse drug reaction.

• Clinical trial (or study) refers to an organised program to determine the safety and/or efficacy of a drug (or drugs) in patients. The design of a clinical trial will depend on the drug and the phase of its development.

• Control group is a group of individual patients that is used as a standard of comparison within a clinical trial. The control group may be taking a placebo (where no active drug is given) or where a different active drug is given as a comparator.

• Dechallenge and Rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive dechallenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive rechallenge has occurred when the adverse event re-occurs after the drug is restarted. Dechallenge and rechallenge play an important role in determining whether a causal relationship between an event and a drug exists. • Effectiveness is the extent to which a drug works under real world circumstances, i.e.,

clinical practice. • Efficacy is the extent to which a drug works under ideal circumstances, i.e., in clinical

trials. • Event refers an adverse event. • Harm is the nature and extent of the actual damage that could be caused. • Implied causality refers to spontaneously-reported AE cases where the causality is always

presumed to be positive unless the reporter states otherwise. • Individual Case Study Report (ICSR) is an adverse event report for an individual patient. • Life-threatening refers to an adverse event that places a patient at the immediate risk of

death. • Phase refers to the four phases of development: I - small safety trials early on in a drug's

development; II - medium-sized trials for both safety and efficacy; III - large trials, which includes key (or so-called "pivotal") trials; IV - large, post-marketing trials, typically for safety reasons. There are also intermediate phases designated by an "a" or "b", e.g. Phase 2b.

• Risk is the probability of harm being caused, usually expressed as a percent or ratio of the treated population.

• Risk factor is an attribute of a patient that may predispose, or increase the risk, of that patient developing an event that may or may not be drug-related. For instance, obesity is considered a risk factor for a number of different diseases and, potentially, ADRs.

• Signal is a new safety finding within safety data that requires further investigation. There are three categories of signals: confirmed signals where the data indicate that there is a causal relationship between the drug and the AE; refuted (or false) signals where after investigation the data indicate that no causal relationship exists; and unconfirmed signals which require further investigation (more data) such as the conducting of a postmarketing trial to study the issue.

• Temporal relationship is said to exist when an adverse event occurs when a patient is taking a given drug. Although a temporal relationship is absolutely necessary in order to establish a causal relationship between the drug and the AE, a temporal relationship does not necessarily in and of itself prove that the event was caused by the drug.

• Triage refers to the process of placing a potential adverse event report into one of three categories: 1) non-serious case; 2) serious case; or 3) no case (minimum criteria for an AE case are not fulfilled)

• • Adverse Event Reporting

The activity that is most commonly associated with Pharmacovigilance, and which consumes a significant amount of resources for drug regulatory authorities (or similar government agencies) and drug safety departments in pharmaceutical companies, is that of adverse event reporting. Adverse event (AE) reporting involves the receipt, triage, data entering, assessment, distribution, reporting (if appropriate), and archiving of AE data and documentation.

The source of AE reports may include: spontaneous reports from healthcare professionals or patients (or other intermediaries); solicited reports from patient support programs; reports from clinical or postmarketing studies; reports from literature sources; reports from the media (including social media and websites); and reports reported to drug regulatory authorities themselves. For pharmaceutical companies, AE reporting is a regulatory requirement in most countries. AE reporting also provides data to these companies and drug regulatory authorities that play a key role in assessing the risk-benefit profile of a given drug. The following are several facets of AE reporting

The "4 Elements" of an AE case

One of the fundamental principles of adverse event reporting is the determination of what constitutes an adverse event case. During the triage phase of a potential adverse event report, the triager must determine if the "four elements" of an AE case are present:

1. an identifiable patient 2. an identifiable reporter 3. a suspect drug 4. an adverse event

If one or more of these four elements is missing, the case is not a valid AE report. Although there are no exceptions to this rule there may be circumstances that may require a judgment call. For example, the term "identifiable" may not always be clear-cut. If a physician reports that he/she has a patient X taking drug Y who experienced Z (an AE), but refuses to provide any specifics about patient X, the report is still a valid case even though the patient is not specifically identified. This is because the reporter has first-hand information about the patient and is identifiable (i.e. a real person) to the physician. Identifiability is important so as not only to prevent duplicate reporting of the same case, but also to permit follow-up for additional information.

Coding of Adverse Events

Adverse events is the process by which information from an AE reporter, called the "verbatim", is coded using standardized terminology from a medical coding dictionary, such as MedDRA (the most commonly used medical coding ditionary). The purpose of medical

coding is to convert adverse event information into terminology that can be readily identified and analyzed. For instance, Patient 1 may report that they had experienced "a very bad headache that felt like their head was being hit by a hammer" [Verbatim 1] when taking Drug X. Or, Patient 2 may report that they had experienced a "slight, throbbing headache that occurred daily at about two in the afternoon" [Verbatim 2] while taking Drug Y. Neither Verbatim 1 nor Verbatim 2 will exactly match a code in the MedDRA coding dictionary. However, both quotes describe different manifestations of a headache. As a result, in this example both quotes would be coded as PT Headache (PT = Preferred Term in MedDRA).

Seriousness Determination

Although somewhat intuitive, there are a set of criteria within Pharmacovigilance that are used to distinguish a serious adverse event from a non-serious one. An adverse event is considered serious if it meets one or more of the following criteria:

1. results in death; 2. is life-threatening; 3. requires inpatient hospitalization or prolongation of existing hospitalization (out-

patient treatment would not necessarily be serious); 4. results in persistent or significant disability or incapacity; 5. results in a congenital abnromalty (birth defect); or is 6. "medically significant" - does not meet any of the preceding criteria, but is considered

serious because treatment or intervention would be required to prevent one of the preceding criteria.[3]

Clinical Trial Reporting

Also known as SAE (Serious Adverse Event) Reporting from clinical trials, safety information from clinical studies is used to establish a drug's safety profile in humans and is a key component that drug regulatory authorities consider in the decision-making as to whether to grant or deny market authorization (market approval) for a drug. SAE reporting occurs as a result of study patients (subjects) who experience serious adverse events during the conducting of clinical trials. (Non-serious adverse events are also captured separately.)

Spontaneous reporting

Spontaneous reporting is the core data-generating system of international pharmacovigilance, relying on healthcare professionals (and in some countries consumers) to identify and report any adverse events to their national pharmacovigilance center, health authority (such as EMA or FDA), or to the drug manufacturer itself.[5] Spontaneous reports are, by definition, submitted voluntarily although under certain circumstances these reports may be encouraged, or "stimulated", by media reports or articles published in medical or scientific publications, or by product lawsuits. In many parts of the world adverse event reports are submitted electronically using a defined message standard.[6][7]

As such, spontaneous reports are a crucial element in the worldwide enterprise of pharmacovigilance and form the core of the World Health Organization Database, which includes around 4.6 million reports (January 2009),[8] growing annually by about 250,000

Signal Detection

Signal detection (SD) involves data mining of PV databases. These databases may be owned by a pharmaceutical company, a drug regulatory authority, or a large healthcare provider. The

WHO defines a safety signal as: “Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously”. Usually more than a single report is required to generate a signal, depending upon the event and quality of the information available.

Risk Management Plans

A Risk Management Plan (RMP) is a document that describes the risks (adverse drug reactions and potential adverse reactions) associated with the use of a drug. The overall goal of an RMP is to assure a positive risk-benefit profile once the drug marketed. The document is required to be submitted, in a specified format, with all new market authorisation requests within the European Union. Although not necessarily required, RMPs may also be submitted in countries outside the EU. The risks described in an RMP fall into one of three categories: Identified Risks, Potential Risks, and Unknown Risks. Also described within an RMP are the measures that the Market Authorisation Holder, usually a pharmaceutical company, will undertake to minimise the risks associated with the use of the drug. These measures are usually focused on the product's labeling and healthcare professionals

International collaboration in Pharmacovigilance

Several organisations play a key collaborative role in the global oversight of Pharmacovigilance:

CIOMS:

The Council for International Organizations of Medical Sciences (CIOMS), through its Working Groups, is a globally-oriented think tank that provides guidance on drug safety related topics. CIOMS is part of WHO and prepares reports are used as a reference for developing future drug regulatory policy and procedures. Over the years, many of CIOMS' proposed policies have been adopted. Examples of topics these reports have covered include: Current Challenges in Pharmacovigilance: Pragmatic Approaches (CIOMS V); Management of Safety Information from Clinical Trials (CIOMS VI); the Development Safety Update Report (DSUR): Harmonizing the Format and Content for Periodic Safety Reporting During Clinical Trials (CIOMS VII); and Practical Aspects of Signal Detection in Pharmacovigilance: Report of CIOMS Working Group (CIOMS VIII).

THE INTERNATIONAL CONFERENCE ON HARMONISATION( ICH):

The goal of ICH is to recommend global standards to be followed by drug companies and drug regulatory authorities around the world. The ICH (the International Conference on Harmonisation) is a global organisation with members from the European Union, the United States and Japan. The ICH Steering Committee (SC) is the governing body that oversees the harmonisation activities. Since its establishment in 1990, each of its six co-sponsors—the European Union (EU), the European Federation of Pharmaceutical Industries and Associations (EFPIA), the Ministry of Health, Labour and Welfare (MHLW, Japan), the Japanese Pharmaceutical Manufacturers Association (JPMA), the US Food and Drug Administration (FDA), and the Pharmaceutical Research and Manufacturers of America (PhRMA)—has had two seats on the SC. Other parties have a significant interest in ICH and have been invited to nominate Observers to the SC. The three Observers are the World Health Organization (WHO), Health Canada and the European Free Trade Association (EFTA). The

International Federation of Pharmaceutical Manufacturers Association (IFPMA) participates as a non-voting member of the SC.[13]

WHO;

The principle of international collaboration in the field of pharmacovigilance is the principal basis for the WHO International Drug Monitoring Programme, through which over 100 member nations have systems in place that encourage healthcare personnel to record and report adverse effects of drugs in their patients. These reports are assessed locally and may lead to action within the country. Through membership of the WHO Programme one country can know if similar reports are being made elsewhere. Member countries send their reports to the Uppsala Monitoring Centre where they are processed, evaluated and entered into the WHO International Database. When there are several reports of adverse reactions to a particular drug, this process may lead to the detection of a signal – an alert about a possible hazard communicated to members countries. This happens only after detailed evaluation and expert review.

National and Regional Drug Regulatory Authorities

Drug regulatory authorities also play a key role in the national or regional oversight of Pharmacovigilance:

Canada

In Canada, pharmocovigilance is regulated by the Marketed Health Products Directorate of the Health Products and Food Branch (Health Canada).

Egypt:

In Egypt, Pharmacovigilance is regulated by the Egyptian Pharmacovigilance Center of the Egyptian Ministry of Health.

European Union

The pharmacovigilance effort in the European Union is coordinated by the European Medicines Agency (EMA) and conducted by the national competent authorities (NCAs). The main responsibility of the EMA is to maintain and develop the pharmacovigilance database consisting of all suspected serious adverse reactions to medicines observed in the European Community. The system is called EudraVigilance and contains separate but similar databases of human and veterinary reactions. EMA requires the individual marketing authorisation holders (drug companies), to submit all received adverse reactions in electronic form (save in exceptional circumstances). The reporting obligations of the various stakeholders are defined in the Community legislation, namely Regulation (EC) No 726/2004, and for human medicines,European Union Directive 2001/83/EC as amended and Directive 2001/20/EC. In 2002 Heads of Medicines Agencies[14] agreed on a mandate for an ad hoc Working Group on establishing a European risk management strategy. The Working Group considered the conduct of a high level survey of EU pharmacovigilance resources to promote the utilisation of expertise and encourage collaborative working.

India

National Pharmacovigilance protocol, Ministry of Health and Family Welfare, Government of India, is the pharmacovigilance regulatory authority in India.[15][16]

Japan

In Japan, pharmacovigilance is regulated by the PMDA and MHLW.

]United States

See also: Regulation of therapeutic goods in the United States

In the U.S., the drug industry is regulated by the FDA, which is the largest national drug regulatory authority in the world. The FDA authority is exercised through the enforcement of regulations published in the U.S.Code of Federal Regulations (CFR). The principal drug safety regulations are found in 21 CFR Part 312 (IND regulations) and 21 CFR Part 314 (NDA regulations). Pharmaceutical manufacturers, and the academic/non-profit organizations (such as RADAR and Public Citizen) also play a role in pharmacovigilance in the US. The rule-making process within the US federal government also permits significant input from the legislative and executive branches of the US government, which also play a role in determining FDA policy.

Pharmacoenvironmentology

Despite receiving attention and necessary action by regulatory agencies like FDA and the European Union, there is a lack of substantial procedures regarding impending monitoring of drug concentrations in the environment and the palpable adverse effects. In 2006 a new concept of pharmacovigilance in environmental pharmacology, entitled as 'Pharmacoenvironmentology' was suggested by Syed Ziaur Rahman. It is a form of pharmacovigilance which deals specifically with those pharmacological agents that have impact on the environment via elimination through living organisms subsequent to pharmacotherapy

Pharmacovigilance of 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.

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.[22] This is in contrast to the voluntary reporting of AEs with medicinal products

pharmacovigilance (PV) has never been more important. To ensure patient safety, minimize costs and ease regulatory compliance, pharmaceutical firms must aggressively detect and manage emerging safety risks. Yet early risk detection can be undercut by manual processes and a lack of integration across information sources.

What is ISoP

The International Society of Pharmacovigilance (ISoP) is an international non-profit scientific organisation, which aims to foster(devlop) Pharmacovigilance both scientifically and educationally, and enhance all aspects of the safe and proper use of medicines, in all countries.

These objectives will be met by:

• Encouraging and extending research in the field of pharmacovigilance

• Promoting a regular exchange of information bearing on Pharmacovigilance by means

of meetings, symposia, workshops, and bulletins, and specifically organising ISOP

congresses, including an Annual Meeting

• Encouraging pharmacovigilance education at all levels. Cooperating with other

organizations and societies concerned with pharmacovigilance

• Publishing scientific and other relevant aspects of Pharmacovigilance

• Engaging in other activities which are pertinent to pharmacovigilance

• Seeking funds, and awarding grants, fellowships, subventions and other contracts to

promote pharmacovigilance. (statutes art 1 & 2)

• ISoP should provide an authoritative view of the clinical application of

pharmacoepidemiological results.

• Overall, ISoP is committed to the view that:

the Society should be both professional and convivial

• younger practitioners should have the opportunity to benefit from engagement with

experienced scientists and enjoy training through personal contact

• ISoP's constituency is those engaged in the practical and clinical aspects of

pharmacovigilance, the doers, and that the Society is committed to person to person

communications

• ISoP may be able to provide assistance to individual countries to improve the

coherence of their national systems

• ISoP must be aware of cultural, linguistic, organisational and regulatory diversity, and

make provision for responding to differing needs and aspirations