SubscribeData Requirements for the registration of a traditional herbal medicine in the EU
Any herbal product that makes a medicinal claim and is on the market in the EU from April 2011 onwards will be required to be registered in accordance with the Directive on Traditional Herbal Medicinal Products 2004/24/EC as an established medicines in accordance with Directive 2001/83/EC as amended. All new herbal medicines throughout the EU must now be registered as traditional herbal medicines.
Traditional Herbal Medicines Registration
This article examines the basic data requirements for traditional herbal medicines registration in the EU.
For any medicine, including herbal medicines, there are a number of legislative requirements to conform to in order to be allowed to market the medicine. The Directive provides the legislative basis, and further guidance documents are available providing more explanation about the data requirements. There are four basic types of data required and these are discussed below.
Product Information Data Requirements
There are a number of product information data requirements, and the information contained in the key documents are built up from the entire data package available for a product. A medicine requires a Summary of Product Characteristics (SmPC), which is a summary of the clinical and pharmaceutical data for the product. It includes the name of the product, the strength, pharmaceutical form, quantity of the active ingredients, list of excipients and shelf life, posology, method of administration, indications, contraindications and any special warnings and precautions for use. Any statement in the SmPC must be supported by data that has been assessed and approved by the health authority in the European Member State where the medicine is to be placed on the market.
The SmPC is a key document. It is used as the basis to write the package insert (often known as the Patient Information Leaflet, the “PIL”) and the packaging. The content of the SmPC is also used as the basis for any advertising for the product.
The package insert must undergo a process called readability (or “user”) testing to ensure that it can be clearly understood by potential users of the medicine, so that the medicine will be used safely and effectively.
Pharmaceutical Good Manufacturing Practice
Quality Data Requirements
Quality data requirements apply to both the drug substance, (the starting materials), and also the drug product, (the finished product available for supply).
A medicine must be made in a manufacturing facility that is compliant with Good Manufacturing Practice (GMP). The medicine will need to be manufactured using a declared formulation and the manufacturing process must be validated to be able to prove the medicine can be reliably and reproducibly manufactured. A finished product specification will be required. The product must be manufactured at least at pilot scale and three batches used for stability studies carried out under ICH conditions of differing temperature and humidity. Stability studies should be carried out on the product packaged in the container proposed for marketing. A summary of the stability studies undertaken, including the batch analytical data at different time points, and at different storage conditions, throughout the studies is required. From the stability data shelf life and storage precautions should be proposed.
Whilst the manufacture of the medicine, the drug product, is important, a quality dossier must also be provided relating to the starting ingredients, the herbal drug substance. It must be produced from herbs that have been cultivated and harvested if possible in accordance with Good Agricultural and Collection Practice (GACP). Other information must also be provided such as a specification and stability data. The starting material must be evaluated for risk of any environmental contamination.
There are many guidance documents that provide more detailed information about the data requirements for the quality data, and these are available from the European Medicines Agency (EMEA). If there are any European monographs, available in the European Pharmacopoeia, applicable to the product then the monographs are legally binding and the product must be fully compliant with them.
Safety Data Requirements
Data must be provided on the non-clinical and clinical safety of the product to meet the safety data requirements. The data may be assembled from published literature and a bibliographic review prepared. The safety review must include any known or potential interactions with other conventional medicines or other herbal substances, side effects, and data that support the proposed contraindications or precautions and warnings in the SmPC. Use in special patient groups such as children, the elderly or pregnant women should also be considered.
If there is an HMPC (Committee on Herbal Medicinal Products) monograph issued or in draft for a herbal drug substance, or an entry for the substance on the EU Community List then this should be referred to in the safety review.
Traditional Use Evidence
There is no requirement to prove efficacy. Instead data must show either bibliographic or expert evidence that the medicine, or a corresponding product, has been in use as a medicine for a 30 year period, of which at least the last 15 years must be in the EU.
All data must be provided and assembled into a particular format called Common Technical Document (CTD) format before it can be submitted as an application for registration as a Traditional Herbal Medicine.