Pharmacovigilance and Drug Safety

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.

PSURs are a regulatory requirement for authorised medicines in the EU and some other countries. They are generated by companies for each of their products at specified intervals – in the EU every 6 months for the first 2 years of marketing, then annually until the first renewal (at 4.5 years) and then every 3 years.

The PSUR provides an overview of the safety of the product, and includes all ADRs reported in the period since the last PSUR, together with a summary of the registration status of the product worldwide, actions taken for safety reasons, the worldwide usage of the product and an analysis of safety. The PSUR gives an opportunity for review of benefits and risks at intervals. Their preparation involves significant work by companies and the timing of their submission and content is subject to the regulations. Analogous documents are required for clinical trials –Annual Safety Reports covering every study on each investigational product.

Organization of safety monitoring

After approval in the EU, the company holding the marketing authorisation is required by regulation to continue monitoring safety. It must enter reports of suspected ADRs on a validated safety database and review the data for signals of possible new adverse reactions or other concerns. Any change to the balance of benefits and risks must be reported to the regulatory authorities, in addition to the reporting of individual cases and periodic safety update reports.

For products with national marketing authorisation in the EU, the regulatory authority in the Member State where the product is marketed has responsibility for reviewing safety by examining the safety reports that it receives from the company and directly from health professionals working in that country. The national regulatory authority also reviews PSURs from companies. It enters the case reports it receives onto the Eudravigilance database, held by EMEA.

For mutual recognition and centrally authorised products, the responsibility for monitoring safety rests with the EU regulatory authority that acted as Rapporteur or Reference Member State. However, each national regulatory authority will still receive local reports of adverse reactions from companies and health professionals and must enter these onto the Eudravigilance database. The EMEA acts as a coordinating body for the safety activities for centrally authorised and mutual recognition products, but the safety reviews are performed by assessors in the Member State regulatory authorities.

The Committee on Medicinal Products for Human use (CHMP) – comprised of representatives of each of the EU regulatory authorities – is involved at intervals with review of the PSURs for centrally authorised products and with safety issues arising post-marketing. These are channelled through its Pharmacovigilance Working Party (PhVWP), which comprises pharmacovigilance representatives from each Member State.

Legislation provides mechanisms for referral of important safety issues potentially affecting public health throughout Europe to the CHMP by the PhVWP. There are complex procedures for examining the benefit-risk balance of products if there are major safety concerns, and for making recommendations to the European Commission for suspending or revoking marketing authorisation.

There are two main strands to the assessment of safety of marketed medicines: spontaneous reporting and post-authorisation studies. However, it should be pointed out that company-sponsored research may be continuing in countries  where the product is not yet marketed, in order to obtain marketing authorisation there. Safety information from those studies is required by regulation to be reported to the competent authorities where the drug is marketed. In the same way, studies may be set up looking at new indications for the marketed drug, or use in new populations, or with different dosage forms. All of these may generate data on adverse reactions that is relevant to the marketed product and which is legally required to be forwarded by the sponsor company to the competent regulatory authorities.