management plan 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, european medicines agency. the overall goal of a risk management plan is to assure a positive risk-benefit profile once the drug is (has been) marketed. the document is required to be submitted, in a specified format, with all new market authorization requests within the european union (eu). although not necessarily required, risk management plans may also be submitted in countries outside the eu. the risks described in a risk management plan fall into one of three categories: identified risks, potential risks, and unknown risks. also described within a risk management plan are the measures that the market authorization holder, usually a pharmaceutical company, will undertake to minimize the risks associated with the use of the drug. these measures are usually focused on the product's labeling and healthcare professionals. indeed, the risks that are documented in a pre-authorization risk management plan will inevitably become part of the product's post-marketing labeling. since a drug, once authorized, may be used in ways not originally studied in clinical trials, this potential "off-label use", and its associated risks, is also described within the risk management plan. risk management plans can be very lengthy documents, running in some cases hundreds of pages and, in rare instances, up to a thousand pages long. in the us, under certain circumstances, the fda may require a company to submit a document called a risk evaluation and mitigation strategy (rems) for a drug that has a specific risk that fda believes requires mitigation. while not as comprehensive as a risk management plan, a risk evaluation and mitigation strategy can require a sponsor to perform certain activities or to follow a protocol, referred to as elements to assure safe use, to assure that a positive risk-benefit profile for the drug is maintained for the circumstances under which the product is marketed. risk/benefit profile of drugs pharmaceutical companies are required by law in most countries to perform clinical trials, testing new drugs on people before they are made generally available. this occurs after a drug has been pre-screened for toxicity, sometimes using animals for testing. the manufacturers or their agents usually select a representative sample of patients for whom the drug is designed – at most a few thousand – along with a comparable control group. the control group may receive a placebo and/or another drug, often a so-called "gold standard" that is "best" drug marketed for the disease. the purpose of clinical trials is to determine: if a drug works and how well it works if it has any harmful effects, and if it does more good than harm, and how much more? if it has a potential for harm, how probable and how serious is the harm? clinical trials do, in general, tell a good deal about how well a drug works. they provide information that should be reliable for larger populations with the same characteristics as the trial group – age, gender, state of health, ethnic origin, and so on though target clinical populations are typically very different from trial populations with respect to such characteristics. the variables in a clinical trial are specified and controlled, but a clinical trial can never tell you the whole story of the effects of a drug in all situations. in fact, nothing could tell you the whole story, but a clinical trial must tell you enough; "enough" being determined by legislation and by contemporary judgements about the acceptable balance of benefit and harm. ultimately, when a drug is marketed it may be used in patient populations that were not studied during clinical trials (children, the elderly, pregnant women, patients with co-morbidities not found in the clinical trial population, etc.) and a different set of warnings, precautions or contraindications (where the drug should not be used at all) for the product's labeling may be necessary in order to maintain a positive risk/benefit profile in all known populations using the drug. pharmacoepidemiology pharmacoepidemiology is the study of the incidence of adverse drug reactions in patient populations using drug agents. pharmacogenetics and pharmacogenomics although often used interchangeably, there are subtle differences between the two disciplines. pharmacogenetics is generally regarded as the study or clinical testing of genetic variation that gives rise to differing responses to drugs, including adverse drug reactions. it is hoped that pharmacogenetics will eventually provide information as to which genetic profiles in patients will place those patients at greatest risk, or provide the greatest benefit, for using a particular drug or drugs. pharmacogenomics, on the other hand, is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. international collaboration the following organizations play a key collaborative role in the global oversight of pharmacovigilance. the world health organization (who) the principle of international collaboration in the field of pharmacovigilance is the basis for the who programme for international drug monitoring, through which over 150 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. since 1978, the programme has been managed by the uppsala monitoring centre to which member countries send their reports to be processed, evaluated and entered into an international database called vigibase. membership in the who programme enables a country to know if similar reports are being made elsewhere. when there are several reports of adverse reactions to a particular drug, this process may lead to the detection of a signal, and an alert about a possible hazard communicated to members countries after detailed evaluation and expert review on the biological stasis and homeostasis of the body. clb12/2020001 the international council for harmonisation (ich) the international council for harmonisation is a global organization with members from the european union, the united states and japan; its goal is to recommend global standards for drug companies and drug regulatory authorities around the world, with its activities overseen by the steering committee overseeing harmonization activities. established in 1990, each of its six co-sponsors—the eu, the european federation of pharmaceutical industries and associations, japan's ministry of health, labor and welfare, the japanese pharmaceutical manufacturers association, the u.s. food and drug administration (fda), and the pharmaceutical research and manufacturers of america (phrma)—have two seats on the sc. other parties have a significant interest in the international council for harmonisation and have been invited to nominate observers to the sc; three current observers are the who, health canada, and the european free trade association, with the international federation of pharmaceutical manufacturers association participating as a non-voting member of the sc. the council for international organizations of medical science (cioms) the cioms, a part of the who, is globally oriented think tank that provides guidance on drug safety related topics through its working groups. the cioms prepares reports that are used as a reference for developing future drug regulatory policy and procedures, and 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 society of pharmacovigilance the international society of pharmacovigilance is an international non-profit scientific organization, which aims to foster pharmacovigilance both scientifically and educationally, and enhance all aspects of the safe and proper use of medicines, in all countries. it was established in 1992 as the european society of pharmacovigilance. society of pharmacovigilance, india, also established in 1992, is partner member of the international society of pharmacovigilance. other local societies include the boston society of pharmacovigilance physicians. regulatory authorities drug regulatory authorities play a key role in national or regional oversight of pharmacovigilance. some of the agencies involved are listed below (in order of 2011 spending on pharmaceuticals, from the ims institute for healthcare informatics). united states