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  1. 1. PHARMACOVIGILANCE Gaurav Kumar M.Pharm (Q.A) 7-FEB-2014
  2. 2. CONTENTS  Introduction.  Definitions.  Adverse event reporting.  International collaboration in pharmacovigilance.  National and regional drug regulatory authorities.  Pharmacoenvironmentology.  Pharmacovigilance of Medical Devices.  Pharmacovigilance of Herbal Medicines. Krupanidhi College of Pharmacy (Q.A)
  3. 3. DEFINITIONS ? Krupanidhi College of Pharmacy (Q.A)
  4. 4.  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.  The etymological roots for the word "pharmacovigilance" are: pharmakon (Greek for drug) and vigilare (Latin for to keep watch).  As such, pharmacovigilance heavily focuses on adverse drug reactions.  ADR, is defined as any response to a drug which is noxious and unintended, including lack of efficacy. (The condition, that this definition only applies with the 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 as well as drug exposure during pregnancy and breastfeeding, are also of interest (even without adverse event itself), because they may result in an ADR. Krupanidhi College of Pharmacy (Q.A)
  5. 5.  Adverse Drug Reaction is a side effect (non intended reaction to the drug) occurring with a drug where a positive (direct) causal relationship between the event and the drug is thought, 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 organized 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 (or cohort) 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. Krupanidhi College of Pharmacy (Q.A)
  6. 6.  Dechallenge and Rechallenge refer to a drug being stopped and restarted in a patient, respectively. A positive de-challenge has occurred, for example, when an adverse event abates or resolves completely following the drug's discontinuation. A positive re-challenge has occurred when the adverse event re-occurs after the drug is restarted. De-challenge 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.  Harm is the nature and extent of the actual damage that could be or has been 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. Krupanidhi College of Pharmacy (Q.A)
  7. 7.  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 IIb.  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. Others would be high blood pressure, diabetes, possessing a specific mutated gene, for example, mutations in the BRCA1 and BRCA2 genes increase propensity to develop breast cancer.  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 post-marketing trial to study the issue. Krupanidhi College of Pharmacy (Q.A)
  8. 8.  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). Krupanidhi College of Pharmacy (Q.A)
  9. 9. ADVERSE EVENT REPORTING  What information should be reported ? 1) On ADRs occurring in the course of the use of a drug. from drug overdose whether accidental or intentional. from drug abuse / misuse / non-approved use. from drug withdrawal. in the infant or a nursing mother. possibly as a result of exposure of the mother or the fetus during pregnancy. 2) Even if no ADR has been observed from drug overdose whether accidental or intentional. from drug abuse / misuse / non-approved use. from drug administration during pregnancy. Krupanidhi College of Pharmacy (Q.A)
  10. 10. SERIOUS ADR (Adverse Drug Reactions). Any ADR occurring at any dose which fulfills one of the following criteria: 1. Results in death. 2. Is life threatening. 3. Requires inpatient hospitalization or prolongation of existing hospitalization. 4. Results in persistent or significant disability/incapacity. 5. Is a congenital anomaly or birth defect. 6. Is an important medical event. Krupanidhi College of Pharmacy (Q.A)
  11. 11. 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) 2) 3) 4) An identifiable patient. An identifiable reporter. A suspect drug. An adverse event. Identifiable” Patient/reporter does not need to be identified at time of report but is identifiable if some effort is taken. Krupanidhi College of Pharmacy (Q.A)
  12. 12.  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. Krupanidhi College of Pharmacy (Q.A)
  13. 13.  The concept of identifiability also applies to the other three elements.  Although uncommon, it is not unheard of for fictitious adverse event "cases" to be reported to a company by an anonymous individual (or on behalf of an anonymous patient, disgruntled employee, or former employee) trying to damage the company's reputation or a company's product. In these and all other situations, the source of the report should be ascertained (if possible).  But anonymous reporting is also important, as whistle blower protection is not granted in all countries. In general, the drug must also be specifically named.  Note that in different countries and regions of the world, drugs are sold under various trade names.  In addition, there are a large number of generics which may be mistaken for the trade product.  Finally, there is the problem of counterfeit drugs producing adverse events.  If at all possible, it is best to try to obtain the sample which induced the adverse event, and send it to either the EMA, FDA or other government agency responsible for investigating AE reports. Krupanidhi College of Pharmacy (Q.A)
  14. 14. Coding of Adverse Events  Adverse event coding 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 dictionary).  The purpose of medical coding is to convert adverse event information into terminology that can be readily identified and analyzed. Krupanidhi College of Pharmacy (Q.A)
  15. 15. Expedited Reporting. This refers to ICSRs that involve a serious and unlabelled event (an event not described in the drug's labeling) that is considered related to the use of the drug. (Spontaneous reports are typically considered to have a positive causality, whereas a clinical trial case will typically be assessed for causality by the clinical trial investigator and/or the license holder). Within clinical trials such a cases is referred to as a SUSAR (a Suspected Unexpected Serious Adverse Reaction). 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. 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. Krupanidhi College of Pharmacy (Q.A)
  16. 16. Aggregate Reporting. Aggregate, or periodic, reporting plays a key role in the safety assessment of drugs. Aggregate reporting involves the compilation of safety data for a drug over a prolonged period of time (months or years), as opposed to single-case reporting which, by definition, involves only individual AE reports. The advantage of aggregate reporting is that it provides a broader view of the safety profile of a drug. Other reporting methods. Some countries legally oblige spontaneous reporting by physicians. In most countries, manufacturers are required to submit, through its Qualified Person for Pharmacovigilance (QPPV), all of the reports they receive from healthcare providers to the national authority. Others have intensive, focused programs concentrating on new drugs, or on controversial drugs, or on the prescribing habits of groups of doctors, or involving pharmacists in reporting. All of these generate potentially useful information. Such intensive schemes, however, tend to be the exception Krupanidhi College of Pharmacy (Q.A)
  17. 17. RISK MANAGEMENT Risk Management is the discipline within Pharmacovigilance that is responsible for signal detection and the monitoring of the risk-benefit profile of drugs. Other key activities within the area of Risk Management are that of the compilation of Risk Management Plans (RMPs) and aggregate reports such as the Periodic Safety Update Report (PSUR), Periodic Benefit Risk Evaluation Report (PBRER), and the Development Safety Update Report (DSUR). Causality Assessment One of the most important, and challenging, problems in pharmacovigilance is that of the determination of causality. Causality refers to the relationship of a given adverse event to a specific drug. Causality determination (or assessment) is often difficult because of the lack of clear-cut or reliable data. Signal Detection Signal detection (SD) involves a range of techniques (CIOMS VIII). 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. Krupanidhi College of Pharmacy (Q.A)
  18. 18. Risk Management Plans  A Risk Management Plan (RMP) is a documented plan that describes the risks (adverse drug reactions and potential adverse reactions) associated with the use of a drug and how they are being handled (warning on drug label or on packet inserts of possible side effects which if observed should cause the patient to inform/see his physician and/or pharmacist and/or the manufacturer of the drug and/or the FDA, EMA)).  The overall goal of an RMP is to assure a positive risk-benefit profile once the drug is (has been) marketed. Krupanidhi College of Pharmacy (Q.A)
  19. 19. INTERNATIONAL COLLABORATION IN 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 that are used as a reference for developing future drug regulatory policy and procedures. 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 Harmonization) is a global organization with members from the European Union, the United States and Japan. ISoP The International Society of Pharmacovigilance (ISoP) is an international non-profit scientific organisation, which aims to foster Pharmacovigilance both scientifically and educationally, and enhance all aspects of the safe and proper use of medicines, in all countries. Krupanidhi College of Pharmacy (Q.A)
  20. 20. 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. Member countries send their reports to the Uppsala Monitoring Centre where they are processed, evaluated and entered into the WHO International Database. Krupanidhi College of Pharmacy (Q.A)
  21. 21. NATIONAL AND REGIONAL DRUG REGULATORY AUTHORITIES CANADA In Canada, pharmacovigilance is regulated by the Marketed Health Products Directorate of the Health Products and Food Branch (Health Canada). 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. INDIA Indian Pharmacopoeia Commission as National coordination Centre under Pharmacovigilance Program of India, Ministry of Health and Family Welfare, Government of India, is the Pharmacovigilance regulatory authority in India. Krupanidhi College of Pharmacy (Q.A)
  22. 22. JAPAN In Japan, pharmacovigilance is regulated by the PMDA and MHLW. 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) Krupanidhi College of Pharmacy (Q.A)
  23. 23. 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. Krupanidhi College of Pharmacy (Q.A)
  24. 24. 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. Given the inherent difference between medicinal products and medical products, the pharmacovigilance 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. Krupanidhi College of Pharmacy (Q.A)
  25. 25. PHARMACOVIGILANCE OF HERBAL MEDICINES The safety of herbal medicines has become a major concern to both national health authorities and the general public. The use of herbs in Traditional medicines continues to expand rapidly across the world. Many people now take herbal medicines or herbal products for their health care in different national health-care settings. However, mass media reports of adverse events with herbal medicines can be incomplete and, therefore, misleading regarding the use of herbal medicines. Nevertheless, it can be difficult to identify the causes of adverse events since the amount of data is generally less than with more traditional medicines since the requirements for adverse event reporting is far less stringent with herbal medications than it is with more traditional medicines Krupanidhi College of Pharmacy (Q.A)
  26. 26. CONCLUSION  Responsibility for the holistic approach to drug safety that is encompassed in the science and practice of pharmacovigilance.  The scientists, clinicians, pharmaceutical manufacturers, drug developers, regulators, public policy makers, patients and the general public all have their own complementary roles in achieving what is envisaged.  Among the important issues are information, information sharing and broader communication.  What we need is a continuing and dynamic development of modern professional practice. We must recognize that solutions to the challenges will come from those inspired and committed individuals and institutions round the world with a vision of improved public health and patient safety. Krupanidhi College of Pharmacy (Q.A)