Labelling comprises the prescribed information on the immediate and outer packaging of a medicinal product. It serves clear identification, safe use, traceability and – for investigational medicinal products – also the protection of blinding and reliable trial conduct. Which details are required essentially depends on whether it is an investigational medicinal product in a clinical trial or an authorized medicinal product.
Labelling of investigational medicinal products in clinical trials
For unauthorized investigational medicinal products and unauthorized auxiliary medicinal products, Regulation (EU) No 536/2014 regulates labelling in Articles 66 to 69 as well as in Annex VI. The information on immediate and outer packaging must be clearly legible. It should identify contact persons or stakeholders, the clinical trial, the medicinal product and its use. Annex VI specifies the required information, including main contact, trial code, investigational medicinal product, pharmaceutical form, route of administration, quantity, batch or code number, directions for use, storage conditions and period of use.
In a blinded study, the label must simultaneously allow for unblinding in an emergency and maintain the blinding. It therefore contains the identification or treatment numbers specified in the protocol, without disclosing the allocation. The Member State concerned determines the language and multilingualism. For authorized investigational medicinal products, labelling according to Article 67 can either follow the study requirements or be carried out in accordance with Title V of Directive 2001/83/EC. The detailed Commission guidelines C(2017) 8179 final on good manufacturing practice for investigational medicinal products in turn refer to Articles 66 to 69 and Annex VI for labelling; they require that the labelling operation is carried out in an authorized manufacturing site, and that in case of an altered period of use, an additional label is affixed with the new expiry date, repeated batch number and clinical trial reference number.
Labelling of authorized medicinal products
For medicinal products placed on the market in the European Union, Title V of Directive 2001/83/EC contains requirements for labelling and package leaflet. Article 54 names for the outer packaging or, where there is no outer packaging, on the immediate packaging, for example, name, strength and pharmaceutical form, qualitative and quantitative particulars of the active substances, contents, method and, if necessary, route of administration, warnings, expiry date, storage conditions as well as information on the marketing authorization holder. The specific legal requirements depend on the respective product and its pharmaceutical form.
The package leaflet accompanies the medicinal product and is aimed at users. According to Article 59, it must be drawn up in accordance with the summary of the product characteristics. The Directive generally requires a package leaflet, unless all the required information is directly conveyed on the outer packaging or on the immediate packaging. Labelling, packaging and package leaflet thus form different but coordinated information carriers. Changes to safety-relevant product information must be implemented in a controlled manner into the approved texts and the affected packaging materials.
Differentiation from Summary of Product Characteristics/SmPC and the US meaning of “Labeling”
The Summary of Product Characteristics, SmPC, is an independent authorization document in the European Union directed at healthcare professionals. It describes the professional characteristics and conditions of use. It is not to be equated with the label affixed to the container or outer carton. The package leaflet is derived from the SmPC according to the Directive, while the labelling contains the legally required information on the packaging. The term labelling is therefore narrower in the EU context than the entirety of all product information.
In US regulatory usage, “labeling” is defined more broadly. According to the FDA, the labeling of prescription drugs includes the Prescribing Information for healthcare professionals, the labeling of container and carton and, if applicable, patient or caregiver information. The Prescribing Information is functionally similar to the Summary of Product Characteristics, but not identical to the European SmPC. In international projects, it must therefore be clearly stated whether “labeling” means the packaging label, the approved product information or, in the US sense, the entire information package.
Relevance for clinical trials
Errors in labelling can cause the administration of the wrong investigational medicinal product, incorrect storage, the loss of blinding or inadequate traceability. The text must therefore match the protocol, randomization, packaging configuration and release status. For multiple countries, the respective language requirements, approved text versions and label versions must be controlled. Changes to expiry date, storage conditions or dose strengths require a controlled procedure so that only correctly labelled units are supplied to study centers.
Full-service CROs such as Mediconomics support the coordination of labelling texts with the protocol and medicinal product logistics, the coordination of country-specific versions as well as the management of label versions and releases. They connect regulatory affairs, project management, supply chain, monitoring and quality management so that labels are available on time, blinding remains protected and documentation is comprehensible for depots, study centers, audits and inspections.
Frequently Asked Questions (FAQ)
Which regulation is decisive for the labelling of an unauthorized investigational medicinal product?
In the European Union, Article 66 and Annex VI of Regulation (EU) No 536/2014 regulate the information on immediate and outer packaging. The specific layout must also match the approved protocol.
May an authorized medicinal product be used in a study with the normal market labelling?
Article 67 of Regulation (EU) No 536/2014 provides for authorized investigational medicinal products and authorized auxiliary medicinal products, under certain conditions, to be labelled according to the study requirements or according to Title V of Directive 2001/83/EC.
Is the Summary of Product Characteristics the same as the US Prescribing Information?
Both are directed at healthcare professionals and contain essential information for safe use. However, they are created in different legal frameworks; designation, format and regulatory embedding must not be equated.
Regulatory references
- Regulation (EU) No 536/2014, Articles 66 to 69 and Annex VI – determines the labelling of investigational medicinal products and auxiliary medicinal products in clinical trials.
- Directive 2001/83/EC, Title V, Labelling and Package Leaflet – regulates packaging information and package leaflet of authorized medicinal products for human use.
- Detailed Commission guidelines C(2017) 8179 final, Good Manufacturing Practice for Investigational Medicinal Products – regulate labelling operation, re-labelling and additional labels.
- FDA, Frequently Asked Questions about Labeling for Prescription Medicines – explains the US-wide meaning of “labeling” including Prescribing Information and container labeling.