Medicinal product safety refers to the overarching concept of all measures, systems, and regulations that ensure that authorised medicinal products have an acceptable benefit–risk balance under routine conditions. It encompasses both the preclinical and clinical safety assessment prior to authorisation and the ongoing monitoring after market launch through the pharmacovigilance system. The objective is to protect patients from preventable medicinal product-related harm while ensuring therapeutic benefit.
Regulatory framework in the EU
In the European Union, medicinal product safety is safeguarded by a dense regulatory framework. The key legal bases are Directive 2001/83/EC (Community code relating to medicinal products for human use) as well as the Pharmacovigilance Regulation (EU) No 1235/2010 and the associated Directive 2010/84/EU. The EMA coordinates pharmacovigilance at European level through its Pharmacovigilance Risk Assessment Committee (PRAC), which assesses safety signals, recommends risk minimisation measures, and decides on variations to, or withdrawals of, marketing authorisations. In Germany, the BfArM is responsible for national pharmacovigilance for most medicinal products, and the Paul-Ehrlich-Institut (PEI) for biologics and vaccines. Both authorities are part of the EudraVigilance network, in which adverse events are reported and analysed.
Clinical safety assessment prior to authorisation
Safety assessment begins in the preclinical phase with toxicity studies in animal models—single-dose toxicity, repeated-dose toxicity, genotoxicity, reproductive toxicity, and carcinogenicity. In Phase I to III clinical trials, the safety profile and tolerability are systematically investigated in increasingly large patient populations. Phase I trials focus on first-in-human safety and pharmacokinetics, Phase II on dose finding and early safety signals, and Phase III on the safety profile in the target population. All adverse events are recorded in the Case Report Form (CRF); serious adverse events (SAEs) must be reported to the sponsor within 24 hours and, in accordance with ICH E2A, submitted to the authorities as Suspected Unexpected Serious Adverse Reactions (SUSARs).
Particular attention is paid to medicinal product safety in vulnerable populations: children, pregnant women, older patients, and immunosuppressed individuals are often excluded from, or underrepresented in, Phase III trials. Post-marketing data from registries and observational studies are therefore often the only source of insight for these groups regarding the actual safety profile in routine care. To address these gaps, patient registries and structured real-world evidence programmes are now indispensable complements to controlled trial evidence and are explicitly encouraged by authorities.
Post-marketing safety monitoring
After marketing authorisation, the post-marketing surveillance system begins. Its cornerstone is spontaneous reporting: physicians, pharmacists, and patients can submit adverse events via national reporting centres or directly into EudraVigilance. Sponsors are required to submit regular Periodic Safety Update Reports (PSURs) or Development Safety Update Reports (DSURs) to the authorities, in which the cumulative safety profile is assessed. The Risk Management Plan (RMP) accompanies the medicinal product throughout its entire life cycle and is updated when relevant safety signals arise. Post-Authorisation Safety Studies (PASS) may be conducted by the sponsor voluntarily or as conditions imposed by authorities after authorisation to address specific safety questions.
Medicinal product safety for medical devices
For medical devices, EU MDR 2017/745 sets out specific post-market surveillance (PMS) requirements that are conceptually similar to pharmacovigilance but tailored to the product. Manufacturers must report serious incidents within defined timelines to the authorities and the European Database on Medical Devices (EUDAMED). Periodic Safety Update Reports (PSURs) and post-market clinical follow-up (PMCF) activities ensure continuous benefit–risk assessment throughout the product life cycle. Notified Bodies review manufacturers’ PMS systems as part of their conformity assessment and may impose corresponding requirements in the event of deficiencies.
A key instrument of modern medicinal product safety is the Risk Management System (RMS), which sponsors must maintain for each authorised medicinal product. It includes the safety specification, the pharmacovigilance plan, and the plan for risk minimisation measures. These can range from simple warnings in the Summary of Product Characteristics to controlled distribution programmes, physician training, or pregnancy prevention programmes. The more complex the risk profile, the more extensive the required measures—an elaborate RMS can delay market launch and requires early regulatory planning.
Digitalisation is also profoundly transforming medicinal product safety. Automated signal-detection algorithms in EudraVigilance analyse thousands of reports every day and identify statistical anomalies significantly earlier than manual reviews. Social media and patient platforms are increasingly being incorporated as supplementary sources of safety signals. For sponsors, this means that modern pharmacovigilance systems must be data-driven in order to remain competitive in this accelerated environment.
Frequently Asked Questions
What is the exact difference between an SAE and a SUSAR in clinical trials?
A Serious Adverse Event (SAE) is any adverse event in a clinical trial that results in death, a life-threatening situation, hospitalisation, persistent disability, or a congenital anomaly. A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an SAE that is causally related to the investigational medicinal product and is not described in the Investigator’s Brochure. SUSARs must be reported without delay to authorities and ethics committees.
How are safety signals detected after authorisation?
Safety signals arise from statistical analyses in EudraVigilance, spontaneous reports, published literature, PASS study results, or findings from other markets. The EMA’s PRAC conducts regular signal-detection analyses and can initiate an accelerated assessment if required. Signals from social media or non-traditional data sources are also increasingly incorporated into signal management.
What happens if a safety signal is confirmed?
If a safety signal is confirmed, the EMA and national authorities have various measures at their disposal: updating the Summary of Product Characteristics and package leaflet, introducing or strengthening risk minimisation measures (e.g., training programmes, pregnancy prevention programmes), restricting the indication, or, in extreme cases, withdrawing the medicinal product from the market. The sponsor is informed of the planned measures and may provide comments.