Signal detection based on spontaneous reporting involves looking for any new patterns or seemingly significant new findings in the safety database. It may be one or more reports showing particularly strong evidence of a previously unknown adverse reaction for that drug, or involving adverse events that are usually caused by drugs, such as aplastic anaemia or toxic epidermal necrolysis. More often, it is a matter of looking for patterns or clusters of reports that stand out from the background. These clusters may be identified by looking at data tables, or – for large databases, such as those held by regulatory authorities or by a company with product with many cases reported – using computerised methods involving statistical disproportion. Examples include the Proportional Reporting Ratio, Bayesian Combination Propagation Neural Network used by the WHO Uppsala Monitoring Centre and the Modified Gamma Poisson Shrinker method used by FDA and MHRA.
Having identified potential tentative signals it is necessary to evaluate them and to consider whether they are real or not. Often, an apparent signal can result just from the disease that the drug is treating – so if a drug is used in patients for the treatment of high blood pressure, it would not be surprising to find reports of high blood pressure itself, and also kidney disease, stroke and heart failure, because these are either contributory or complications of high blood pressure. This is often a difficult process: evaluating signals involves looking at the individual case reports and assessing the strength of causation of the drug in each case. Other sources of safety data are usually also checked at this time – for example, the data from clinical trials and toxicology studies.
It may then be appropriate and necessary to set up a study specifically investigating a particular signal or safety concern. Other possible actions could be to institute a review of the benefits and risks of the product; to suspend or revoke the marketing authorisation; to propose a change to the product information (SPC, labelling); to issue a warning to health professionals in the form of a Dear Health Professional communication; or perhaps just to keep the issue under review. At some point, it may become apparent that the signal was not real, and the issue can be shelved.
This is the reporting by healthcare professionals (and in some countries, patients, relatives and others) “spontaneously” of their suspicion of an adverse reaction having occurred. The reporting might be directly to the company marketing the product, or it could be made to the regulatory authority. If there has been spontaneous reporting of a suspected ADR to a pharmaceutical company (including reporting to any employee, such as sales representatives or to contractors) there are legal obligations on the company to report serious reactions within a specified time frame to the regulatory authority (“expedited reporting). This takes place to the authorities in that country where the report was received and possibly to other regulatory authorities also. For non-serious reactions, reports usually have to be included in periodic safety update reports (see below).
In addition, the pharmaceutical company has to identify reports of adverse reactions published in the medical and scientific literature (by a process of weekly “literature screening”) and cases must be reported by the company in a similar way to the regulatory authorities.
The authorities in turn are required to report to each company anonymised information on the serious adverse reactions that they have received in relation to that company’s marketed products. There are also requirements for companies to report spontaneous cases of serious adverse reactions that they have received from certain regulatory authorities to their own authorities. There are mechanisms in place to identify and remove duplicate reports.
All these cases – ‘Individual Case Safety Reports’ (ICSRs) – are entered on the company’s safety database and on the regulatory authority’s safety database. They are examined individually and in the aggregate for a product in order to identify clusters of reports that could represent a signal of a previously unknown adverse reaction or drug interaction or some change in the character of a known adverse reaction. It may also be possible to recognise a new risk factor for a reaction to a product, such as a sub-group of patients at particular risk.
The main limitation of spontaneous reporting schemes is that there is under-reporting of adverse reactions, as in most countries the process for the initial reporter (i.e. the healthcare professional) is voluntary and unpaid. However, their main purpose is not the quantification of the frequency of adverse reactions, but the identification of signals.
In addition to the national regulatory agency databases of spontaneous reports and the company databases, there are two over-arching international databases. The EMEA maintains the EUDRAVIGILANCE safety database, including ICSRs received from all companies with products marketed in the European Economic Area, reports received by the national regulatory agencies in the EEA, and serious cases from clinical trials. This database is linked electronically to the national regulatory agency databases and exchanges data with them and with the company databases electronically.
In addition, the World Health Organization operates a global scheme involving national collaborating centres (most of the national regulatory agencies worldwide) and a coordinating centre in Sweden – the Uppsala Monitoring Centre (UMC). The regulatory authorities send the UMC all serious adverse reaction reports that they have received. The UMC database (“Vigibase”) is the only database in the world that includes all the regulatory authority and company ADR reports. The UMC has a panel of independent experts who review the data for signals of new adverse reactions. Aggregate data from Vigibase are made available to pharmaceutical companies for purchase.