successfully performed with epinephrine. significant disability and incapacity, as a concept, is also subject to debate. while permanent disability following a stroke would no doubt be serious, would "complete blindness for 30 seconds" be considered "significant disability"? for birth defects, the seriousness of the event is usually not in dispute so much as the attribution of the event to the drug. finally, "medically significant events" is a category that includes events that may be always serious, or sometimes serious, but will not fulfill any of the other criteria. events such as cancer might always be considered serious, whereas liver disease, depending on its ctcae (common terminology criteria for adverse events) grade—grades 1 or 2 are generally considered non-serious and grades 3-5 may be considered serious. expedited reporting this refers to individual case safety reports that involve a serious and unlisted event (an event not described in the drug's labeling) that is considered related to the use of the drug (us fda). (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.) in most countries, the time frame for reporting expedited cases is 7/15 calendar days from the time a drug company receives notification (referred to as "day 0") of such a case. within clinical trials such a case is referred to as a susar (a suspected unexpected serious adverse reaction). if the susar involves an event that is life-threatening or fatal, it may be subject to a 7-day "clock". cases that do not involve a serious, unlisted event may be subject to non-expedited or periodic reporting. clinical trial reporting also known as ae (adverse event) or sae (serious ae) 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. ae reporting occurs when study patients (subjects, participants) experience any kind of "untoward" event during the conducting of clinical trials. non-serious adverse events are typically captured separately at a level lower than pharmacovigilance. ae and sae information, which may also include relevant information from the patient's medical background, are reviewed and assessed for both causality and degree of seriousness by the study investigator. this information is forwarded to a sponsoring entity (typically a pharmaceutical company or academic medical center) that is responsible for the reporting of this information, as appropriate, to drug regulatory authorities. spontaneous reporting spontaneous reports are termed spontaneous as they take place during the clinician's normal diagnostic appraisal of a patient, when the clinician is drawing the conclusion that the drug may be implicated in the causality of the event. spontaneous reporting system (srs) relies on vigilant physicians and other healthcare professionals who not only generate a suspicion of an adverse drug reaction, but also report it. it is an important source of regulatory actions such as taking a drug off the market or a label change due to safety problems. 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 the european medicines agency or fda), or to the drug manufacturer itself. 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. one of the major weaknesses of spontaneous reporting is that of under-reporting, where, unlike in clinical trials, less than 100% of those adverse events occurring are reported. further complicating the assessment of adverse events, ae reporting behavior varies greatly between countries and in relation to the seriousness of the events, but in general probably less than 10% (some studies suggest less than 5%) of all adverse events that occur are actually reported. the rule-of-thumb is that on a scale of 0 to 10, with 0 being least likely to be reported and 10 being the most likely to be reported, an uncomplicated non-serious event such as a mild headache will be closer to a "0" on this scale, whereas a life-threatening or fatal event will be closer to a "10" in terms of its likelihood of being reported. in view of this, medical personnel may not always see ae reporting as a priority, especially if the symptoms are not serious. and even if the symptoms are serious, the symptoms may not be recognized as a possible side effect of a particular drug or combination thereof. in addition, medical personnel may not feel compelled to report events that are viewed as expected. this is why reports from patients themselves are of high value. the confirmation of these events by a healthcare professional is typically considered to increase the value of these reports. hence it is important not only for the patient to report the ae to his health care provider (who may neglect to report the ae), but also report the ae to both the biopharmaceutical company and the fda, european medicines agency, ... this is especially important when one has obtained one's pharmaceutical from a compounding pharmacy. 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), growing annually by about 250,000. aggregate reporting aggregate reporting, also known as 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. worldwide, the most important aggregate report is the periodic safety update report (psur) and development safety update report (dsur). this is a document that is submitted to drug regulatory agencies in europe, the us and japan (ich countries), as well as other countries around the world. the psur was updated in 2012 and is now referred to in many countries as the periodic benefit risk evaluation report (pbrer). as the title suggests, the pbrer's focus is on the benefit-risk profile of the drug, which includes a review of relevant safety data compiled for a drug product since its development. 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 programmes 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. a number of countries have reporting requirements or reporting systems specific to vaccine-related events. 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. while one may assume that a positive temporal relationship might "prove" a positive causal relationship, this is not always the case. indeed, a "bee sting" adverse event — where the ae can clearly be attributed to a specific cause — is by far the exception rather than the rule. this is due to the complexity of human physiology as well as that of disease and illnesses. by this reckoning, in order to determine causality between an adverse event and a drug, one must first exclude the possibility that there were other possible causes or contributing factors. if the patient is on a number of medications, it may be the combination of these drugs which causes the ae, and not any one individually. there have been a number of recent high-profile cases where the ae led to the death of an individual. the individuals were not overdosed with any one of the many medications they were taking, but the combination there appeared to cause the ae. hence it is important to include in your/one's ae report, not only the drug being reported, but also all other drugs the patient was also taking. for instance, if a patient were to start drug x and then three days later were to develop an ae, one might be tempted to attribute blame drug x. however, before that can be done, the patient's medical history would need to be reviewed to look for possible risk factors for the ae. in other words, did the ae occur with the drug or because of the drug? this is because a patient on any drug may develop or be diagnosed with a condition that could not have possibly been caused by the drug. this is especially true for diseases, such as cancer, which develop over an extended period of time, being diagnosed in a patient who has been taken a drug for a relatively short period of time. on the other hand, certain adverse events, such as blood clots (thrombosis), can occur with certain drugs with only short-term exposure. nevertheless, the determination of risk factors is an important step of confirming or ruling-out a causal relationship between an event and a drug. often the only way to confirm the existence of a causal relationship of an event to a drug is to conduct an observational study where the incidence of the event in a patient population taking the drug is compared to a control group. this may be necessary to determine if the background incidence of an event is less than that found in a group taking a drug. if the incidence of an event is statistically significantly higher in the "active" group versus the placebo group (or other control group), it is possible that a causal relationship may exist to a drug, unless other confounding factors may exist. signal detection signal detection 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. data mining pharmacovigilance databases is one approach that has become increasingly popular with the availability of extensive data sources and inexpensive computing resources. the data sources (databases) may be owned by a pharmaceutical company, a drug regulatory authority, or a large healthcare provider. individual case safety reports in these databases are retrieved and converted into structured format, and statistical methods (usually a smathematical algorithm) are applied to calculate statistical measures of association. if the statistical measure crosses an arbitrarily set threshold, a signal is declared for a given drug associated with a given adverse event. all signals deemed worthy of investigation, require further analysis using all available data in an attempt to confirm or refute the signal. if the analysis is inconclusive, additional data may be needed such as a post-marketing observational trial. signal detection is an essential part of drug use and safety surveillance. ideally, the goal of signal detection is to identify adverse drug reactions that were previously considered unexpected and to be able to provide guidance in the product's labeling as to how to minimize the risk of using the drug in a given patient population. risk management plans a risk