pharmacovigilance pharmacovigilance pharmacovigilance (pv, or phv), also known as drug safety, is the pharmaceutical science relating to the "collection, detection, assessment, monitoring, and prevention" of adverse effects with pharmaceutical products.: 7 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), which are 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 disorder function was excluded with the latest amendment of the applicable legislation). 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 an adverse event, because they may result in an adverse drug reaction. information received from patients and healthcare providers via pharmacovigilance agreements, 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 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 minimizing the risk of any harm that may come to patients. companies must conduct a comprehensive drug safety and pharmacovigilance audit to assess their compliance with worldwide laws, regulations, and guidance. 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. the european medicines agency defines terms in its guideline on good pharmacovigilance practices (gvp): adverse drug reaction is effects arising when drug given even in therapeutic dose either immunologically mediated reaction or pharmacologically mediated adverse response or idiosyncratic reaction due to the peculiarities of individual. 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 (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. 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 to an adverse event. 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 safety report 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 clinical research and 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, adverse drug reactions. 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. 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 (pv), and which consumes a significant number 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 entry, 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 post-marketing 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: individual case safety report one of the fundamental principles of adverse event reporting is the determination of what constitutes an individual case safety report. during the triage phase of a potential adverse event report, it is important to determine if the "four elements" of a valid individual case safety report are present: (1) an identifiable patient, (2) an identifiable reporter, (3) a suspect drug, and (4) an adverse event. if one or more of these four elements is missing, the case is not a valid individual case safety 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. 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 tradenames. 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 european medicines agency, fda or other government agency responsible for investigating ae reports. if a reporter can't recall the name of the drug they were taking when they experienced an adverse event, this would not be a valid case. this concept also applies to adverse events. if a patient states that they experienced "symptoms", but cannot be more specific, such a report might technically be considered valid, but will be of very limited value to the pharmacovigilance department of the company or to drug regulatory authorities. activities involved in pharmacovigilance 1- case-control study (retrospective study). 2- prospective study (cohort study). 3- population statistics. 4- intensive event report. 5- the spontaneous report in the case is the population of the single case report. 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. 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" 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" 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: results in death, or is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital anomaly (birth defect); or is otherwise "medically significant" (i.e., that it does not meet preceding criteria, but is considered serious because treatment/intervention would be required to prevent one of the preceding criteria.) aside from death, each of these categories is subject to some interpretation. life-threatening, as it used in the drug safety world, specifically refers to an adverse event that places the patient at an immediate risk of death, such as cardiac or respiratory arrest. by this definition, events such as myocardial infarction, which would be hypothetically life-threatening, would not be considered life-threatening unless the patient went into cardiac arrest following the mi. defining what constitutes hospitalization can be problematic as well. although typically straightforward, it's possible for a hospitalization to occur even if the events being treated are not serious. by the same token, serious events may be treated without hospitalization, such as the treatment of anaphylaxis may be