The European Medicines Agency (“EMA”) has adopted a new chapter to its guidelines on good pharmacovigilance practices (“GVP”). The new chapter addresses the specific challenges of pharmacovigilance relating to biological medicinal products. The chapter entitled “Product- or population-specific considerations II: Biological medicinal products” (“the Chapter”) came into effect on 16 August 2016.

The Chapter applies to all biological medicinal products (reference products, biosimilars and related products) except for vaccines and advanced therapy medicinal products. The Chapter is intended to be read alongside process-related GVP Modules that apply to all medicinal products, and highlights specific issues to be taken into account when monitoring and managing the safety of biological medicinal products post-authorisation. The Chapter outlines the roles and responsibilities of marketing authorisation holders, competent authorities and the EMA on how to better monitor and manage the safety of biological medicinal products.

Risks specific to biological medicinal products identified in the Chapter

The particular risk areas identified in the Chapter that relate to biological medicinal products are immunogenicity, manufacturing variability, non-adherence to good distribution practices and product traceability. This is due to the complexity of biological active substance molecules, and complexity of manufacturing processes with many steps that can each have an effect on product quality and safety. Immunogenicity refers to an unwanted immune response, which can arise from:

  • Product-related factors (e.g. choice of cell line, impurities, choice of product containers);
  • treatment-related factors (e.g. route of administration, dosing frequency); or
  • patient or disease-related factors (e.g. genetic background, concomitant medications, nature of the underlying disease and immune status).

While all medicinal products have the potential to cause immunogenicity, the risk is greater for biological medicinal products and requires specific consideration. The Chapter provides that pre-marketing authorisation studies on biological medicinal products cannot usually adequately assess the risk of immunogenicity arising from all of these factors. A company’s risk management plan should therefore provide for continued surveillance of immunogenicity post-authorisation, and revaluations of benefit-risk assessments. This is especially important following any changes to the manufacturing process of such products.

The manufacturing variability risks relates to the fact that minor variations at various stages of the manufacturing process of biological medicinal products (such as changes in choice of cell line, starting materials, fermentation, purification) can have a significant effect on product quality, safety and efficacy. The Chapter provides that changes to the manufacturing process should be submitted as variations or extensions to existing marketing authorisations by marketing authorisation holders, and supported by adequate comparability assessments, as well as additional non-clinical and/or clinical studies if necessary.

The safety of biological medicinal products may change over time for the same product, and the quality assessment of reference products may differ from that of biosimilars and related products. Quality of biological medicinal products may also differ between specific batches as a consequence of standards specified at later stages of the supply chain not being properly complied with such as storage and handing conditions, cold chain and good distribution practices.

The Chapter further provides that non-adherence to appropriate storage and handling conditions, cold chain and good distribution practices may affect the stability and quality of biological medicinal products, which in turn may introduce or alter immunogenicity or contamination. Life-cycle pharmacovigilance is therefore an important aspect for biological medicinal products.

Another key requirement for pharmacovigilance of biological medicinal products identified in the Chapter is the need to ensure continuous product and batch traceability in clinical use. The greater variability between products means that pharmacovigilance of biologicals should be carried out at both product and batch level. Different products with the same INN should be easily distinguishable and supply should be traced through to batches and patients if necessary.

Structure and processes in the risk management system (“RMP”) of biological medicinal products

The Chapter recommends biologicals-specific content that should be included in the RMP that is submitted with the marketing authorisation application. In particular, RMPs should include an evaluation of the potential risks of immunogenicity and the significant clinical effects that may result from the immunogenicity or any changes in manufacturing processes. The RMP should also include a description of additional pharmacovigilance activities to assess and address these risks. For example, companies should take into account the specific clinical settings in which the products are to be used, as this may impact on how product names and batch numbers are recorded (e.g. primary or tertiary care). The Chapter also recommends that SmPCs for biologicals should include a prominent statement that the product name and batch number be recorded in the patient file, as well as in promotional material and any direct communication with healthcare professionals.

Where an application for a variation to the marketing authorisation of a biological medicinal product is made following changes to the manufacturing process, an updated RMP should also be submitted if the comparability assessment concludes that the change have a significant impact on the quality or safety of the product. The updated RMP should describe how pre- and post-change products can be distinguished. Any changes to the RMP of a reference product should also be applied to the RMP of any biosimilar or related product, unless otherwise justified.

Reporting of adverse reactions and signal management

The Chapter also provides specific recommendations for marketing authorisation holders and competent authorities for reporting of adverse reactions and signal management. Marketing authorisation holders and competent authorities should take measures to ensure that reporting of adverse reactions includes the product name and batch number. They should encourage healthcare professionals to record and provide this information to patients when administering/prescribing the product, especially if different versions of the same product are used interchangeably by the same patient. Competent authorities, in collaboration with marketing authorisation holders, should also provide the appropriate infrastructure to ensure product and batch traceability at all stages of the supply chain from manufacture release to patient administration (such as through bar coding).

With support from competent authorities and the EMA, companies should implement signal management processes that are particularly sensitive to new risks that may arise from changes to the manufacturing process, differences between batches and differences between reference products and biosimilars. Signal detection for biological medicinal products should therefore be specific to the product, as well as the active substance.

Safety communication

Additionally, the Chapter recommends that the specific risks associated to biological medicinal products be communicated to patients and healthcare professionals. In particular, such persons should be informed of the different factors that may affect safety of biological products, and therefore result in an adverse reaction where the product had previously been well tolerated.

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