Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA
Abstract
:1. Introduction
2. Overview of Biosimilar Medicines
2.1. Biological Medicines
2.2. Biosimilar Medicines
2.3. Intended Copies, Biobetters and Stand-Alone Biologics
2.4. Biosimilars vs. Generics
3. Biosimilar Medicines Regulatory Framework
4. Development of Biosimilar Medicines
4.1. Selection and Characterization of the Reference Product
4.2. Cell Line Creation
4.3. Cultivation and Production
4.4. Isolation and Purification
4.5. Formulation, Filling and Finishing
5. Demonstration of Biosimilarity
5.1. Quality Comparability Studies
Statistical Approaches to Evaluate Analytical Similarity
5.2. Non-Clinical Comparability Studies
5.3. Clinical Comparability Studies
5.3.1. Clinical Pharmacology Studies (PK/PD)
5.3.2. Efficacy Studies
5.3.3. Safety Evaluation
5.3.4. Immunogenicity Concerns
5.4. Other Relevant Aspects
5.4.1. Extrapolation of Indication
5.4.2. Nomenclature
5.4.3. Interchangeability
5.4.4. Patent Protection and Market Exclusivity
6. Biosimilar Medicines: Marketing Authorization
6.1. Data Requirements
6.2. European Medicines Agency and Food and Drug Administration Pathways
6.2.1. European Medicines Agency
6.2.2. Food and Drug Administration
7. Market Evaluation
8. Conclusions and Future Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Regulatory Authority | Biosimilar Medicine Definition |
---|---|
EMA | “Biological medicine highly similar to another biological medicine already approved in the EU” [2]. |
FDA | “Biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product” [12]. |
Topic | Title |
---|---|
Tailored clinical approach for biosimilars | Concept paper for the development of a reflection paper on a tailored clinical approach in biosimilar development. |
Overarching biosimilar guidelines | Similar biological medicinal products. Similar biological medicinal products containing biotecnology-derived proteins as active substance: non-clinical and clinical issues. Similar biological medicinal products containing biotecnology-derived proteins as active substance: quality issues. |
Product-specific biosimilar guidelines | Biosimilar medicinal products containing recombinant granulocyte-colony stimulating factor. Non-clinical and clinical development of similar biological medicinal products containing low-molecular-weight heparins. Non-clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues. Similar biological medicinal products containing interferon beta. Similar biological medicinal products containing monoclonal antibodies: non-clinical and clinical issues. Similar biological medicinal products containing recombinant erythropoietins. Similar biological medicinal products containing recombinant follicle-stimulating hormone. Similar medicinal products containing somatropin. Reflection paper: Non-clinical and clinical development of similar medicinal products containing recombinant Interferon Alfa. |
Other guidelines relevant for biosimilars | Comparability of biotechnology-derived medicinal products after a change in the manufacturing process—non-clinical and clinical issues. Immunogenicity assessment of biotechnology-derived therapeutic proteins. Immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use. Biosimilars—What are the key pharmacokinetic considerations in the assessment of biosimilarity? |
Year | Title |
---|---|
2014 | Reference Product Exclusivity for Biological Products Filed Under; Draft Guidance for Industry. |
2015 | Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product; Guidance for Industry. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; Guidance for Industry. |
2016 | Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product; Guidance for Industry. |
2018 | Labelling for Biosimilar Products; Guidance for Industry. |
2019 | Considerations in Demonstrating Interchangeability with a Reference Product; Guidance for Industry. Development of Therapeutic Protein Biosimilars: Comparative Analytical Assessment and Other Quality-Related Considerations; Draft Guidance for Industry. |
2020 | Biosimilars and Interchangeable Biosimilars: Licensure for Fewer Than All Conditions of Use for Which the Reference Product Has Been Licensed; Draft Guidance for Industry. Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act; Draft Guidance for Industry. |
2021 | New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 3); Draft Guidance for Industry. Questions and Answers on Biosimilar Development and the BPCI Act; Guidance for Industry. |
2022 | Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics; Guidance for Industry. |
2023 | Classification Categories for Certain Supplements Under BsUFA III; Draft Guidance for Industry. Labeling for Biosimilar and Interchangeable Biosimilar Products; Draft Guidance for Industry. Biosimilarity and Interchangeability: Additional Draft Q&As on Biosimilar Development and the BPCI Act (Revision 1); Draft Guidance for Industry. |
2024 | Considerations in Demonstrating Interchangeability with a Reference Product: Update; Draft Guidance for Industry. Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers; Draft Guidance for Industry. |
Attribute | Methods |
---|---|
Primary structure | Peptide mapping: liquid chromatography (LC) and mass spectrometry (MS). Peptide mass fingerprint: matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS). |
Higher order structure | Nuclear magnetic resonance (NMR). Surface plasmon resonance (SPR). |
Post-translational modifications | Normal-phase high-performance liquid chromatography coupled with mass spectrometry (NP-HPLC–MS). Gas chromatography–mass spectrometry (GC–MS). |
Size, detection of aggregates | Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE). High-performance size exclusion chromatography (HP-SEC). |
Binding | Surface plasmon resonance (SPR). Enzyme-linked immunosorbent assay (ELISA). |
Biological activity | Cell assays. In vivo assays. |
Module 3 Quality | Module 4 Non-Clinical | Module 5 Clinical |
---|---|---|
Drug Substance:
Drug Product:
| Pharmacology:
Pharmacokinetics:
Toxicology:
| Pharmacology Pharmacokinetics:
Pharmacodynamics:
Efficacy and safety:
Post-marketing:
|
Mandatory Scope | Medicinal products developed by means of one of the following biotechnological processes:
|
Optional Scope | Similar biological medicinal products of a centrally authorized product have automatic access to the CP. |
Similar biological medicinal products of a National/MRP/DCP product could, at the request of the applicant, be accepted for consideration under the CP, when the applicant shows that the medicinal product constitutes:
|
EMA | FDA | |
---|---|---|
Approval Process | Centralized procedure | Section 351(k) of the PHSA |
Scope | Valid at regional level, covering all 27 Member States of the EU and the countries of the EEA, Norway and Iceland. | Valid nationally, only within the US. |
Teams Involved | BMWP, CHMP and PRAC. | CBER, CDER and OTBB. |
Main Steps of the Evaluation | Pre-submission; assessment; Preparation of responses; Assessment of responses; Preparation of responses; Final CHMP opinion; Final EC decision. | Pre-submission activities; Process submission; Plan the review of the application; Conduct scientific/regulatory review; Official action on the application; Post-decision feedback. |
Steps After the Evaluation | Transmission of Opinion and Annexes in all EU languages to Applicant, Commission, members of the Standing Committee, Norway and Iceland; EMA issues press releases and updates its official website to inform about the approval. | The final decision is communicated to all team members and to the applicant; The biosimilar is included in the Purple Book. |
Time | 210 “active” days + periods when the clock is stopped. | About 10 months (~300 days). |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Amaral, C.; Rodrigues, A.R.; Veiga, F.; Bell, V. Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA. Appl. Sci. 2024, 14, 7529. https://doi.org/10.3390/app14177529
Amaral C, Rodrigues AR, Veiga F, Bell V. Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA. Applied Sciences. 2024; 14(17):7529. https://doi.org/10.3390/app14177529
Chicago/Turabian StyleAmaral, Carolina, Ana Rita Rodrigues, Francisco Veiga, and Victoria Bell. 2024. "Biosimilar Medicines: From Development Process to Marketing Authorization by the EMA and the FDA" Applied Sciences 14, no. 17: 7529. https://doi.org/10.3390/app14177529