DDReg Pharma

DDReg Pharma
Regulatory Approval

Biologics development & regulatory approval – EMA perspective

Biologic medicinal products, particularly biosimilars, have revolutionized the treatment of chronic conditions. As biologic products lose patent protection, biosimilars emerge as more readily accessible treatment alternatives. In the European Union (EU), the European Medicines Agency (EMA) is responsible for product approval.
The EMA was the first regulatory authority to establish a regulatory framework for biosimilars [1]. It approved the very first biosimilar of the EU in 2006 and has since approved the largest number of biosimilars worldwide [2]. The EMA has issued guidelines to help follow strict regulatory requirements regarding biosimilar development and approval, which have been adopted as a reference framework for multiple countries worldwide.
Medicines that are developed in EU organizations, including biosimilars, must demonstrate, using sufficient data, that the medicine is manufactured to agreed standards and that it is suitable for its intended clinical use.

Head-to-head comparisons

Regulations for biosimilars are dependent on the biosimilar product being able to demonstrate its biosimilarity to the reference product, which is achieved through rigorous comparability studies involving comprehensive and head-to-head comparisons. Comparability consists of 3 steps and is unique for each product:
Regulations for biosimilars are dependent on the biosimilar product being able to demonstrate its biosimilarity to the reference product, which is achieved through rigorous comparability studies involving comprehensive and head-to-head comparisons. Comparability consists of 3 steps and is unique for each product:

Comparative Quality Studies determine physical & chemical properties, and biological/pharmacological activity (in-vitro)

Comparative Non-Clinical Studies determine pharmacodynamics and toxicology (in-vitro, and in-vivo if there is no suitable in-vitro model that exists)

Comparative Clinical Studies determine pharmacokinetics/pharmacodynamics, efficacy, safety, and immunogenicity

In order for a drug to be approve, it must demonstrate a positive benefit-risk balance using data from efficacy, quality and safety studies. If a drug contains a new active substance, the positive benefit-risk balance is determined by the efficacy and safety evidence in pivotal human trials supported by robust non-clinical and quality data. For a biosimilar drug, the similarity of the active substance in the reference medicine determines the positive benefit-risk balance. By demonstrating biosimilarity, a biosimilar drug can rely on the safety and efficacy experience gained with the reference medicine
The table below provides outlines the development process for a biologic/references medicine vs. a biosimilar medicine [2]:

Biological/reference medicine

Biosimilar medicine

No knowledge on efficacy and safety

Uses information on clinical use of reference medicine over many years to build on safety and efficacy data

Demonstrates safety and efficacy in patients

Demonstrates comparable safety and efficacy, by establishing biosimilarity

Comparability studies only for manufacturing changes during development

Comprehensive comparability studies with the reference medicine

Full non-clinical data (pharmacology and toxicology)

Amount of non-clinical data is determined by the outcome of quality studies

Conventional clinical trials demonstrate efficacy and safety in all claimed therapeutic indications

Comparative clinical trials to exclude clinically meaningful differences

Trials designed to compare with placebo or current standard therapy using relevant patient population and endpoints such as long-term outcome, mortality, structural damage, to demonstrate benefit

Trials designed mainly to show clinical equivalence with reference medicine using more sensitive endpoints in populations where product-related differences in clinical performance can be detected

Positive benefit-risk mainly established based on safety and efficacy studies in the intended population

Positive benefit-risk based on demonstrating Biosimilarity, using comparability studies


As with any drug, biosimilars can also instigate immune responses that could negatively impact efficacy and safety. Manufacturing processes may undergo minor differences which could also alter the immunogenicity profile. Though this is rare, it is still crucial to conduct head-to-head assessment of biosimilar drugs to their reference drugs. A validated, tiered approach for the detection of anti-drug antibodies (ADA) s is recommended that consists of 4 main stages: 1) ADA screening; 2) ADA confirmation assays; 3) ADA characterization & titration; 4) analysis of neutralizing capacity. The assay’s results should be considered integral in pharmacology, safety and efficacy analysis [3].


If there is high similarity between a biosimilar and reference drug and demonstrates comparable efficacy and safety in a particular therapeutic indication, the efficacy and safety data can be extrapolated to different indications that are approved for the reference product. As a result, few clinical trials (or even no trials) will need to be conducted. Robust comparability quality, clinical and non-clinical studies provide the data for extrapolation to other indications [4].

Drug Safety

Majority of the adverse drug reactions (ADRs) can be predicted and can occur with the reference and biosimilar drugs. The EMA has a well-established system that monitors, reports, assesses and prevents ADRs. The safety monitoring is the same for biologic medicines- there are no specific guidelines for biosimilars.
A Risk Management Plan (RMP) is a requirement for all new medicinal products and must be submitted as per the EU guidelines. This is unique to each product and includes a pharmacovigilance plan and risk minimization measures that identifies, characterizes, and minimizes the important risks for a medicine. A biosimilar’s RMP is based on knowledge and information that is provided by the reference drug data. A post-authorization safety study (PASS) may be required at the time of approval for the reference and biosimilar drug.

EMA Governance mechanism for biologicals

The EMA has many scientific committees, working parties and other groups that overlook the scientific and technical work. Medicines are authorized in Europe after the committees have evaluated the market authorization (MA) applications that are submitted through centralized procedures [5]. The working parties and committees also contribute to drug development and regulation by:

The main committees consist of European experts made available by national competent authorities of the EU and EEA Member States. More information about the committees and working parties can be found here: How the committees work | European Medicines Agency (europa.eu)

For biologic product development, the working parties prepare guidelines which is adopted by the Committee for Medicinal Products for Human Use (CHMP) or Committee for Advanced Therapies (CAT).
CHMP’s Biologics Working Party (BWP) develops quality aspects and cover areas including comparability, process development, validation among others. The other working parties, such as Vaccines Working Party (VWP) and Biosimilars Working Parties (BPWP), maintain discipline-specific guidelines regarding safety and efficacy aspects of vaccines and blood products.
Biosimilars fall under the responsibility of the BMWP and BWP. The EMA has established guidance and provides advice to support international regulators, applicants, and other stakeholders.


Biosimilar development is a stepwise procedure that entails comparative studies between the reference product and the biosimilar product to determine biosimilarity. The regulatory approval uses the “totality of evidence” that is provided by head-to-head, comprehensive comparisons of data elements. Every step of the biologic development allows regulators to identify potential differences between the biosimilar and reference product. Therefore, the data must demonstrate concrete similarities between the reference and biosimilar product, to ensure that regulatory approval can be granted.


[1] (PDF) Biosimilars: A Multidisciplinary Perspective (researchgate.net)

[2] Biosimilars in the EU – Information guide for healthcare professionals (europa.eu)

[3] Comparative immunogenicity assessment of biosimilars – PubMed (nih.gov)

[4] EMA: Extrapolation Across Indications for Biosimilars a Possibility (biopharminternational.com)

[5] biological-medicinal-products_en.pdf (europa.eu)

[6] How the committees work | European Medicines Agency (europa.eu)