Pharmacovigilance and Drug Safety

A major change in the approach to drug safety surveillance after marketing has been introduced in the last 5 years in the EU in the form of risk management planning. This has been incorporated into EU law and is extensively covered by guidelines in Volume 9A. There has been a similar initiative by the US FDA.

For the EU, it is mandatory for companies to submit a Risk Management Plan in accordance with a detailed template and guideline at the time of application for a Marketing Authorisation for most products. Plans also have to be submitted if new safety concerns are identified for a marketed product and all plans must be updated as circumstances change.

Thus companies are required to specify at the time of first marketing areas of safety about which they are currently uncertain and how they will resolve this uncertainty. They must also indicate what measures they will take to reduce known risks and how they will test whether these measures work.

The EU Risk Management Plan (EU-RMP) has 3 main elements. First, a detailed consideration of what is known about the safety of the product, based on pre-clinical and clinical studies. This “safety specification” considers identified risks and potential risks – the latter being areas of uncertainty regarding safety. It also specifies what the limitations of the clinical research program are and what important information about safety is currently missing. In the second component, the “pharmacovigilance plan”, the company must indicate how it proposes to resolve the uncertainties – what extra studies it will carry out after marketing to fill the important gaps in knowledge. The third component is the “risk minimization plan”. This states how the company proposes to reduce the severity or frequency of known adverse reactions. This may involve special communication programs, or educational exercises, or perhaps registration programs for patients, doctors or pharmacists, or other measures. The pharmacovigilance plan and risk minimization plan must include timelines for setting up the programs and milestones for their evaluation.

There are two broad types of post-authorisation or ‘Phase IV’ study: clinical trials and pharmacoepidemiological studies. In general, clinical trials involve interventions in the management of the patients’ disease and pharmacoepidemiology studies are non-interventional. ‘Interventional’ means that there is some systematic allocation of patients to specific treatment which may not be what they would have received normally, or there might be investigations or procedures carried out that, again, are not part of routine practice. ‘Non-interventional’ studies involve the patient receiving a medicine as routine treatment, in accordance with the SPC and without any special investigations: in other words, the study is completely observational.

The company marketing a product may set up post-authorisation clinical trials for purposes of obtaining information on use in particular patient populations (e.g. the elderly, or liver-impaired) or for obtaining other data on the way that the product is used.

Post-authorisation studies that are set up specifically to evaluate product safety are referred to in as “post-authorisation safety studies” or PASS. These studies are described in the risk management plan at the time of application for marketing authorisation and become post-marketing commitments for the company. They may also be required to be set up, if regulatory authorities consider that there is a need for additional safety information after marketing.