Biological & Biosimilar Medicines – Pharmacovigilance Particularities from a Safety Physician’s Perspective in the EU (Part Two)

In Part One, we looked at GVP particularities for biologicals/biosimilars. In Part Two we will look at pharmacovigilance specifics to biological/biosimilar medicines and Quality, Non-clinical and Clinical issues and their interconnection with safety.


Pharmacovigilance specifics to biological/biosimilar medicines2

Unlike chemically synthesised medicines which can be easily characterised and reproduced across different manufacturers, biological active substances are complex molecules produced usually using complex manufacturing processes with many upstream or downstream steps that shape the overall safety, quality and efficacy profile. The manufacturing process is as much a determinant of the product’s quality as the active substance itself, and any minor changes in these steps can affect the product’s quality, and subsequently its safety and efficacy. This molecular fundamental complexity is what makes the pharmacovigilance of biological/biosimilars challenging and deserving of a different approach.

Extra considerations when assessing biological/biosimilars safety:

A) Immunogenicity

A common thread across all safety related topics concerning biological and biosimilars is immunogenicity. As with any medicinal product, the safety profile of a biological is determined partly by the direct or indirect pharmacological properties of the active substance (e.g. exaggerated immunomodulation or immunosuppression), of the excipients and process-related impurities (e.g. host cell proteins), or by host or disease-related susceptibility (e.g. medicine-induced allergic reactions, auto-immunity, inflammatory events).

For all medicines, the basic principles of benefit-risk assessment apply to potential or identified risks. In this instance, due to their extremely complex nature, biologicals/biosimilars pose a greater potential risk of immunogenicity compared to non-biologicals and require specific safety considerations.

Moving forward, we will use the term ‘immunogenicity’ to refer to any unwanted immune response that is considered potentially clinically relevant and that may require product-specific pharmacovigilance and risk management activities. The sources triggering this reaction are multi-factorial and involve one or more product-related factors (e.g. choice of cell line, post-translational changes and alterations to the 3D structure during downstream processing, impurities, choice of product containers), treatment-related factors (e.g. route of administration, dosing frequency) and patient or disease-related factors (e.g. genetic background, concomitant medications, nature of the underlying disease and immune status). The clinical consequences may include partial or complete loss of efficacy of the product due to induction of neutralising antibodies, altered pharmacokinetics due to antibody binding, general immune effects such as anaphylaxis, formation of immune complexes and potential induction of cross-reactivity with endogenous proteins or other auto-antibodies.

The potential risk of immunogenicity should be reflected in the RMP and requires specific aRMMs and/or aPVs in the post-authorisation phase as deemed appropriate. Similarly, despite biosimilars initial marketing authorisation being based on studies (physico-chemical/analytical and biological assays) that demonstrate their biosimilarity to the reference product, it is stated clearly that “data from pre-authorisation clinical studies are usually insufficient to identify rare adverse effects. Therefore, clinical safety of biosimilars must be monitored closely on an ongoing basis during the post approval phase including continued benefit-risk assessment”. This leads us to being aware that both biologicals and biosimilars have a dynamic quality profile, with the potential for serious new risks to emerge at any point in the product’s life-cycle due to changes in their quality or characteristics (which may also be related to product handling and patient characteristics). These potential changes are relevant not only within a product (e.g. change in quality specifications over time), but also across products with the same INN. In the long-term post-authorisation period, the reference product and biosimilars may potentially exhibit different safety profiles as these evolve through their life-cycles (e.g. if they change their manufacturing process).

B) Stability and cold chain

Beyond the point of manufacture and release, overall product stability is maintained by adherence to appropriate storage and handling conditions, cold chain and good distribution practices. Non-adherence to these processes and standards may affect the stability and quality of biologicals, which in turn may introduce or alter immunogenicity or contamination affecting in turn the product’s safety. Although this may only occur infrequently, when it occurs it is usually circumscribed to specific batches. Life-cycle pharmacovigilance at the levels of products and batches is therefore an important issue for biologicals.

C) Product traceability

It is essential that different products with the same INN can be readily distinguishable so newly emerging and product-specific safety concerns and immunogenicity can be rapidly detected and evaluated throughout a product’s life-cycle, and that supply can be traced to locations and patients if necessary. Batch traceability is an important aspect to be considered in any associated updates to RMPs. Since product name and batch information is included in the packaging, this information is available to be recorded and reported at all levels in the supply chain from manufacturer release to prescription, dispensing and patient administration.


Quality, Non-clinical and Clinical issues and their interconnection with safety.

The development of a biosimilar relies in part on the scientific knowledge gained from the reference biological medicine, provided that the active substance of the biosimilar has been shown to be similar to the active substance of the reference product approved in the community.5 The reference product must be authorised in the EEA and in the event of non-EEA authorised products it must be shown that they were authorised by a regulatory authority with similar scientific and regulatory standards as the EMA (e.g. ICH countries). In addition, it will be the applicant's responsibility to demonstrate that the comparator authorised outside the EEA is representative of the reference product authorised in the EEA.6 In principle, the concept of biosimilarity is applicable to any biological medicinal product. However, in practice, the success of developing a biosimilar will depend on the ability to produce a medicinal product which can convincingly demonstrate its similar nature to the reference. This should be achieved through comprehensive physicochemical and biological characterisation and comparison and requires knowledge on how to interpret any differences between a biosimilar and its reference medicinal product.7


Non-clinical studies

To support biosimilarity, relevant non-clinical studies should be performed before initiating clinical trials:

Step 1: In vitro studies

In order to assess any potential difference in biological activity between the biosimilar and the reference medicinal product.

Step 2: Determination of the need for in vivo studies

If the biosimilar comparability exercise for the physicochemical and biological characteristics and the non-clinical in vitro studies (step 1) are considered satisfactory and no issues are identified in step 2 which would block direct entrance into humans, an in vivo animal study is usually not considered necessary.

Step 3: In vivo studies

If an in vivo evaluation is deemed necessary, the focus of the study/studies (PK and/or PD and/or safety) depend on the need for additional information. Animal studies should be designed to maximise the information obtained.


Clinical studies

The clinical biosimilar comparability should start with pharmacokinetic and, if feasible, pharmacodynamic studies followed by clinical efficacy and safety trial(s) or confirmatory PK / PD studies for demonstrating clinical biosimilar comparability.8


Biological activity

The assessment of the biological properties constitutes an essential step in establishing a complete characterisation profile of a biological/biosimilar medicine. Biological activity describes the specific ability or capacity of a product to achieve a defined biological effect; potency constitutes the quantitative measure of said biological activity.

Examples of valid biological assays that should be provided by the biological/biosimilar manufacturer:

  • Animal-based biological assays, which measure an organism's biological response to the product.
  • Cell culture-based biological assays, which measure biochemical or physiological response at the cellular level.
  • Biochemical assays, which measure biological activities such as enzymatic reaction rates or biological responses induced by immunological interactions. Other procedures such as ligand and receptor binding assays, may be acceptable as well.9



Data from pre-authorisation clinical studies are usually insufficient to identify rare adverse effects. Therefore, clinical safety of biological and biosimilars must be monitored closely on an ongoing basis during the post approval phase including continued benefit-risk assessment. Within the authorisation procedure the applicant should present a description of the pharmacovigilance system and a risk management plan in accordance with current EU legislation and pharmacovigilance guidelines.

The risk management plan should consider identified and potential risks associated with the use of the reference biological and should detail how these issues will be addressed in post marketing follow-up. Immunogenicity should specifically be addressed in this context. Any specific safety monitoring imposed on the reference biological should be adequately addressed in the pharmacovigilance plan of the biosimilar as well. Biosimilar applicants are also encouraged to participate in already existing pharmacoepidemiological studies in place for the reference product. Risk minimisation activities in place for the reference product should also be included into the risk management programme of the biosimilar. Any deviation should be justified.8



aRMM: Additional Risk Minimization Measures.

aPV: Additional Pharmacovigilance Activities.

EU: European Union.

HA: Health Authority.

HCP: Healthcare professionals.

ICSR: Individual Case Safety Report.

INN: International non-proprietary name.

MAH: Marketing authorisation holder.

NCA: National competent authorities

PSUR: Periodic Safety Update Report.

PV: Pharmacovigilance.

RMP: Risk Management Plan.

SmPC: Summary of Product Characteristics.




  1. Biological medicine | European Medicines Agency. Accessed June 3, 2021.
  2. Corr. Guideline on Good Pharmacovigilance Practices (GVP) - Product- or Population-Specific Considerations II: Biological Medicinal Products.; 2016.
  3. Biologic medicines - EUPATI Toolbox. Accessed June 3, 2021.
  4. Biosimilar medicines: Overview | European Medicines Agency. Accessed June 3, 2021.
  5. Medicines Agency E. Committee for Medicinal Products for Human Use (CHMP) Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Quality Issues (Revision 1).; 2012.
  6. CHMP. Committee for Medicinal Products for Human Use (CHMP) Guideline on Similar Biological Medicinal Products.; 2014.
  7. Multidisciplinary: biosimilar | European Medicines Agency. Accessed June 2, 2021.
  8. Medicines Agency E. Committee for Medicinal Products for Human Use (CHMP) Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active Substance: Non-Clinical and Clinical Issues.; 2014.
  9. ICH Topic Q 6 B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products.; 1999.