Biological medicinal products contain an active substance that is derived from a biological source such as a bacterium or yeast. They can include molecules such as insulin, erythropoietins or monoclonal antibodies. These substances are larger and more complex than non-biological medicines and may have a degree of variability in the molecules with the same active substance (see EMA Q&A for further information).
On expiry of the data protection/patent for a new biological medicine, a biosimilar medicine may be developed. A biosimilar medicine is developed to be similar to an existing biological medicine that is already registered in the EU (the reference product). Biosimilars are not the same as generics, which have simpler chemical structures and are considered to be identical to their reference products. Since 2003, a new regulatory pathway for approving biosimilar medicines in the EU has been in place.
The regulatory framework for biosimilar medicinal products is established in Article 10(4) of Directive 2001/83/EC and in Article 6 of Regulation (EC) No 726/2004. These set out the requirements for the comparability studies that are required to generate evidence to demonstrate that the biosimilar medicine does not have any meaningful differences from the reference product in terms of quality, safety or efficacy.
The studies on quality will include a comparison of the structure and biological activities of their active substances, while the studies on safety and efficacy should show no significant differences in their benefits and risks, including the risk of immune reactions.
In the EU the Biosimilar Medicinal Products Working Party (BMWP) makes a recommendation to the Committee for Medicinal Products for Human Use (CHMP) on the regulatory assessment of biosimilar medicinal products. The EMA evaluations do not include recommendations on whether a biosimilar should be used interchangeably with a reference medicine, and for questions related to switching from one biological product to another, patients should consult their doctor.
In order to assist manufacturers that are developing biosimilar biological medicines, the EMA also provides regulatory guidance including an ‘Overarching guideline’, product specific and other guidelines (see EMA website for further information).
The EBE Biosimilars TF has been established to provide the manufacturers of originator biological products with a forum to raise relevant issues, to establish dialogue with the regulatory authorities and provide input on relevant guidelines.
The Biosimilars TF is currently addressing the following priorities:
Tenders are used where multiple suppliers bid to provide products that are deemed to be interchangeable. Due to their unique starting material and the complex manufacturing process, biological medicines, including biosimilars, should not be subject to automatic substitution. Procurement practices such as tendering should therefore be limited to pharmaceutical products that are interchangeable and always provide for a sufficiently broad choice of products. EBE is developing material to support:
- Ability to choose and maintain the right medicine for each patient
- A more complete assessment of value and choice, based on a wider variety of criteria to establish most economically advantageous bids
- Input on the criteria and selection process from qualified scientific and healthcare practitioners
- Longer term sustainability of supply for medicines that have lost their patent protection, as well as the pipeline for new medicines
As the legislation to strengthen pharmacovigilance in the EU is implemented, EBE has been in contact with the regulators to exchange perspectives on solutions to further enhance traceability of biopharmaceuticals. For patient safety it is necessary to establish an effective pharmacovigilance system across Europe, in which it should be possible to link any reported adverse event with the exact medicinal product that was administered. This is particularly important for biological medicinal products, which have the potential to cause unwanted immunological reactions.
The current legislation requires that Member States record the name and batch number of any medicinal product dispensed. In practice, however, the batch numbers of medicinal products are often not recorded and the recorded name is often the international non-proprietary name. The problem is further confounded in that in the EU a biosimilar product may be approved using the same INN as the reference product.
In late 2014, EBE gave an unrestricted grant to Escher, the then TI Pharma platform for regulatory innovation – now managed by Lygature – for a the project ‘Pharmacovigilance of biologics’. This project looked into the challenges of product and batch traceability in adverse drug reaction reporting. It resulted in a number of scientific publications by the investigators, and a public report on a workshop held by Escher in 2015 on their findings, highlighting the need to improve practices for tracing biological medicinal products in clinical practice in order to strengthen ADR reporting.
See here for further information.
The Summary of Product Characteristics (SmPC) and the Patient Information Leaflet (PIL) provide information to the prescriber on the use of the product. The current guidance on labelling groups biosimilar products with generic and hybrid products. The EBE believes that this is not appropriate as this does not take into account some of the unique considerations which apply for biosimilars and is proposing a specific guidance on the labelling of Biosimilars to enhance the understanding and acceptance of these products with all stakeholders.
Cross border prescription template
In 2011, the European Union adopted a Directive on Cross-Border Healthcare in the EU. The Directive clarified the possibilities for receiving healthcare in another EU Member State and also provided for the development of a cross-border prescription template which would include a non-exhaustive list of elements to appear on the prescriptions. For biologics, it requires that the brand name be included.
The EBE will undertake a mapping of the transposition process at national level and develop a slide deck for use by local industry associations.
A survey summarising the current status of policies relating to biological has been undertaken in previous years with the aim of providing a reference document that can be used to support advocacy at local level. The survey will be updated and extended to cover additional issues such as tendering, naming and HTAs.