How the Safety of Medicinal Products Is Monitored – an Introduction

How the Safety of Medicinal Products Is Monitored – an Introduction

Comprehensive Testing Prior to Marketing Authorisation

Before a medicinal product is authorised and put into use after authorisation, its quality, safety and efficacy must be demonstrated. Data is collected for this purpose by the developer during manufacturing and in extensive non-clinical studies and controlled clinical trials.

An active substance is initially tested in laboratory tests and animal tests that are subject to authorisation before it is administered to a few people for the first time in phase I clinical trials. These individuals are usually healthy subjects. The phase I study examines the tolerability of the medicinal product, i.e. whether it is suitable for use on humans in general. This is followed by phase II studies – often involving 100 to 300 people – to collect and evaluate initial data on the efficacy of a medicinal product against the disease for which it is intended. The focus in a phase II study is on the optimal dosage. Phase III trials are then usually conducted on a large number of people to gather information about the efficacy and safety, i.e. the common, occasional or even rare (1:1,000) side effects of a medicine. These randomised, controlled clinical trials, in which people in the control group are generally treated with either standard therapy or a placebo, provide reliable results from high levels of evidence and form the basis for the initial benefit-risk assessment by the medicines authorities during the authorisation process.

All clinical trials in Germany and the European Union (EU) must be authorised by the competent national medicines authority, which also requires the approval of the competent ethics committee. The Paul-Ehrlich-Institut is responsible for the authorisation of clinical trials held in Germany involving vaccines and biomedicines (immunological drugs such as sera, monoclonal antibodies and antibody derivatives, fusion proteins with antibody moiety and immunotherapeutics, allergens, blood stem cells, coagulation factor preparations, tissue preparations and advanced therapy medicinal products).

Benefit-Risk Assessment for Marketing Authorisation

The data collected in the non-clinical and clinical trials is submitted with the application for marketing authorisation and analysed and evaluated by the experts of the competent medicines authority. In an EU-wide centralised authorisation procedure, the experts of the national medicines authorities on the Committee for Medicinal Products for Human Use (CHMP) at the European Medicines Agency (EMA) evaluate the application for authorisation.

The CHMP recommends authorisation in the presence of a favourable benefit-risk ratio. The Paul-Ehrlich-Institut is represented on the CHMP by a co-opted member, i.e. an expert chosen on the basis of their special expertise. Among the other CHMP members are one expert from each national medicines authority of the EU Member States and one expert from each of the medicines authorities of the European Economic Area (EEA) member states Iceland, Liechtenstein and Norway. The European Commission may grant authorisation on the basis of the CHMP recommendation.

A medicinal product shall only be authorised if the evaluation of the data submitted with an application for authorisation shows that the benefit-risk profile of the medicinal product is favourable.

Post-Authorisation Pharmacovigilance

Even after authorisation a medicinal product must maintain a favourable benefit-risk ratio. It is therefore important to continuously and systematically monitor the safety of a medicinal product, even after authorisation. Rare and very rare side effects can still be detected after authorisation and market launch once a very large number of people have been vaccinated or treated.

All activities related to the observation, detection, evaluation, understanding and prevention of side effects or other medicine-related problems are referred to as pharmacovigilance. The data and findings from national, European and other international clinical trials and studies form an important basis for assessing the benefit and safety of a medicinal product. Pharmacovigilance is carried out in close European and international cooperation between the medicines authorities.

Other important components of pharmacovigilance are:

• The spontaneous reporting system for the recording of suspected adverse events by the competent medicines authority: There may be valuable indications (signals) for rare, hitherto unknown side effects. Reports of adverse drug reactions (ADRs), commonly referred to as side effects, are recorded in the spontaneous reporting system. The reports are "spontaneously" documented and reported outside of systematic examinations. The reporting of a suspected adverse event, adverse vaccination reaction, or vaccination complication can be submitted by those affected or their relatives as well as healthcare professionals. In accordance with their professional code, doctors and pharmacists are obliged to report suspected adverse events. Doctors and heads of pharmacies that carry out vaccinations are also obliged under the Infection Protection Act to report the suspicion of vaccination complications, i.e. symptoms that go beyond a typical vaccination reaction.
• Periodic Safety Update Reports (PSURs) that are completed by the marketing authorisation holders and must be submitted to the medicines authorities at specified intervals: A PSUR is subject to an assessment by the competent medicines authority, which in turn reviews the content of the data submitted and evaluates the conclusions of the pharmaceutical company. Additional evaluations are initiated when necessary and any appropriate actions are taken, such as modifying the product information text as needed.
• The implementation of risk-minimising measures, that are set out in risk management plans during the authorisation process: A risk management plan ensures that there is already a structured plan in place with potential risk minimisation measures and additional safety investigations when the medicinal product is authorised.
• Post-authorisation studies, such as phase IV clinical trials or observational studies.

By taking on the pharmacovigilance regulatory tasks for vaccines and biomedicines in Germany, the Paul-Ehrlich-Institut makes an important contribution to protecting individuals receiving a vaccine or undergoing treatment from risks associated with medicinal products.