Biosimilars A biosimilar is a biological medicine highly similar to another already approved  biological medicine  (the 'reference medicine'). (A medicine whose active substance is made by a living organism.) Biologicals Biological medicines contain active substances from a biological source, such as living cells or organisms and are often produced by cutting-edge technology. Biological medicinal product Biological Medicinal Products, also known as biologics or biologicals, are medicinal products that are manufactured using biotechnology processes and derived from living organisms or their products. They can include vaccines, blood products, gene therapies, monoclonal antibodies, recombinant proteins, and other complex biological substances. Biological Investigational Medicinal Product Refer to biological products that are being investigated in clinical trials or research studies to evaluate their safety, efficacy, or pharmacokinetic properties. These products have not yet received marketing authorization and are still in the experimental phase. In the European Union, A biological substance is referred as the active ingredient in biological products. A "biological substance" is defined as "a substance that is produced by or extracted from a biological source That requires a combination of physico-chemical-biological testing, along with the production process and its control, for its characterization and the determination of its quality.“ Examples: Immunologic medicines Medicines derived from human blood and plasma Medicines developed by means of recombinant DNA technology Hybridoma and mAb methods Advanced therapy medicinal products The requirements of the EU centralized procedure. The approval standards for biotechnology products are the same as for chemically synthesized medicines. Both types of products must be safe and effective and have appropriate quality. MAA for a biotechnology product must meet the standard dossier submission requirements MAA must generally comply with the CTD format, including with respect to Module I (administrative information, including labelling) Module 2 (various summaries) Module 3 (chemical, pharmaceutical, and biological information) Module 4 (nonclinical reports) Module 5 (clinical study reports) The EU has approved the highest number of biosimilars worldwide, and consequently has the most extensive experience of their use and safety. EMA has issued scientific guidelines to help developers conform to the strict regulatory requirements for approving biosimilars. The guidelines have evolved to keep pace with rapid advances in biotechnology and analytical sciences, and they take on board increasing experience of clinical use. All medicines produced using biotechnology and those for specific indications must be approved in the EU through EMA Some biosimilars may be approved at national level, such as some low-molecular weight heparins derived from porcine intestinal mucosa.

1. Development and Regulatory
Approval of Biologics in European
Union
1
Presented by:
Vanshika Gupta
RAHB (MRA202T)
2nd sem M.Pharm
(RA)

2. 2
Development and Regulatory Approval of
Biologics in European Union
Contents
• Abbreviations
• Definitions
• IMP Development
and Approval in EU
• Biosimilar
development and
approval in the
EU
• References

3. Development and Regulatory Approval of Biologics in European Union 3
• Investigational medicinal product
IMP
• Committee for medicinal products for human use
CHMP
• European Union
EU
• Marketing authorisation applications
MAA
• Embryo–fetal development
EFD
• Pharmacokinetic and Dynamic
PK–PD
• Pre- and postnatal development
PPND
• Nonhuman primates
NHPs
• Good Clinical Practice
GCP
• Investigational medicinal product
IMPD
• Common Technical Document
CTD
• European Medicine Agency
EMA
Abbreviations

4. Definitions
Biosimilars
• A biosimilar is a biological medicine highly similar to
another already approved biological medicine (the
'reference medicine'). (A medicine whose active
substance is made by a living organism.)
Biologicals
• Biological medicines contain active substances from a
biological source, such as living cells or organisms and
are often produced by cutting-edge technology.
4
Development and Regulatory Approval of Biologics in European Union

5. Definitions
Biological medicinal product
• Biological Medicinal Products, also known as biologics or biologicals, are medicinal
products that are manufactured using biotechnology processes and derived from
living organisms or their products. They can include vaccines, blood products, gene
therapies, monoclonal antibodies, recombinant proteins, and other complex
biological substances.
Biological Investigational Medicinal Product
• Refer to biological products that are being investigated in clinical trials or research
studies to evaluate their safety, efficacy, or pharmacokinetic properties. These
products have not yet received marketing authorization and are still in the
experimental phase.
Development and Regulatory Approval of Biologics in European Union 5

6. Biological Medicinal Products
are authorized and approved for marketing
Biological Investigational Medicinal
Products are still undergoing investigation
and have not yet received regulatory
approval.
----------x-----------
Biological medicines also called
“biopharmaceuticals” in EU
Development and Regulatory Approval of Biologics in European Union 6
Major difference

7. Development and Regulatory Approval of
Biologics in European Union
7

8. Development of Biologics in EU
• In the European Union, A biological substance is referred as the active
ingredient in biological products.
• A "biological substance" is defined as "a substance that is produced by or
extracted from a biological source
• That requires a combination of physico-chemical-biological testing, along with
the production process and its control, for its characterization and the
determination of its quality.“
• Examples: Immunologic medicines
1. Medicines derived from human blood and plasma
2. Medicines developed by means of recombinant DNA technology
3. Hybridoma and mAb methods
4. Advanced therapy medicinal products
Development and Regulatory Approval of Biologics in European Union 8

9. Development Stages
Nonclinical Studies
Clinical studies
MAA
Development and Regulatory Approval of Biologics in European Union 9

10. Nonclinical Studies
• CHMP has adopted ICH S6 as a guideline governing preclinical testing
of biologics. “Preclinical safety evaluation of biotechnology-derived
pharmaceuticals - Scientific guideline”
• The CHMP adopted the addendum to this guideline The addendum
complements, clarifies, and updates ICH S6 and is intended to further
harmonize the standards for nonclinical studies.
• The addendum covers the following five topics: species selection, study
design, immunogenicity, reproductive and developmental toxicity, and
carcinogenicity
Development and Regulatory Approval of Biologics in European Union 10

11. Nonclinical Studies Contents
Species selection
Study design
Immunogenicity
Reproductive and developmental toxicity
Carcinogenicity
Development and Regulatory Approval of Biologics in European Union 11

12. Conti...
1. Species Selection:
• Discusses the factors that sponsors should consider in selecting relevant
species for nonclinical testing
• This testing should permit identification of a species model that can
demonstrate potentially adverse consequences of target modulation.
2. Study Design:
• Sponsors should consider PK–PD approaches
• When no PD endpoint is available, the sponsor should select the high dose
based on PK data
• The sponsor may need to assess subject recovery from the medicine’s
pharmacologic and toxicologic effects when these effects occur at clinically
relevant exposures.
Development and Regulatory Approval of Biologics in European Union 12

13. Conti...
3. Immunogenicity:
• Nonclinical studies are not useful in predicting potential immunogenicity of
human or humanized proteins in humans.
• The addendum provides more detail than ICH S6 regarding situations when the
sponsor should measure antidrug antibodies
4. Reproductive and Developmental Toxicity:
• The addendum first provides general advice on reproductive and
developmental testing and then discusses more specific recommendations for
fertility studies, embryo–fetal development (EFD) studies and pre- and
postnatal development (PPND) studies, and the timing of studies in nonhuman
primates (NHPs).
Development and Regulatory Approval of Biologics in European Union 13

14. Conti...
5. Carcinogenicity:
• The sponsor may design a strategy addressing
potential carcinogenicity based on a weight of
evidence approach, including a review of
relevant information, such as literature
information on class effects, target biology, and
mechanisms of action; in vitro data clinical data
and data from chronic toxicity studies.
Development and Regulatory Approval of Biologics in European Union 14

15. Clinical studies
Biologics need to undergo clinical trials before a marketing authorization
application. The Clinical Trials Directive sets forth the general requirements for
clinical trials of medicinal products, including biologics.
Development and Regulatory Approval of Biologics in European Union 15
Clinical Trial Authorisation
GCP and other Consideration for Clinical Trials
Study Design Consideration
Consultation with European medicinal agency

16. Conti...
1. Clinical Trial Authorization
A clinical trial may commence only if-
• The trial subjects understand the objectives and risks of the trial and give informed,
written consent to participate.
• The trial safeguards the physical and mental integrity of the subjects
• Insurance covers the liability of the sponsor and investigator
2. GCP and Other Considerations for Clinical Trials
• Clinical trials of biologics must comply with GCP, as described in Directive 2005
/28 /EC on Good Clinical Practice.
• Investigators must obtain freely given informed consent from every trial subject
before each subject is enrolled.
• Clinical trial information must be handled, recorded, and stored with respect for
relevant confidentiality and privacy rules. Trials must comply with the ethical
principles of the World Medical Association’s Declaration of Helsinki.
Development and Regulatory Approval of Biologics in European Union 16

17. Conti...
3. Study Design Considerations
• General guidance on study design applies to biologics as well as small molecule
medicines.
• Phase I usually involves the initial safety and PK studies
• phase II study is a therapeutic exploratory study that explores efficacy.
• Phase III typically involves therapeutic confirmatory studies
4. Consultation with the European Medicines Agency
• A sponsor may obtain, scientific advice regarding clinical trial protocols from the
EMA.
• The agency’s remarks will only address scientific issues and will generally focus on
matters such as the selection of endpoints and comparator, the duration of treatment
or follow-up, and the design of pivotal studies.
Development and Regulatory Approval of Biologics in European Union 17

18. Marketing Authorization Application
1. The requirements of the EU centralized procedure.
• The approval standards for biotechnology products are the same as for chemically
synthesized medicines.
• Both types of products must be safe and effective and have appropriate quality.
2. MAA for a biotechnology product must meet the standard dossier submission
requirements
• MAA must generally comply with the CTD format, including with respect to
• Module I (administrative information, including labelling)
• Module 2 (various summaries)
• Module 3 (chemical, pharmaceutical, and biological information)
• Module 4 (nonclinical reports)
• Module 5 (clinical study reports)
Development and Regulatory Approval of Biologics in European Union 18

19. Development and Regulatory Approval of
Biologics in European Union
19
Regulatory Pathway
for
Biological
Investigational
Medicinal Products

21. Clinical Trial Application (CTA)
Overview of Contents of Clinical Trial Application (CTA):
1. Covering Letter
2. Application Form
• Module 1 – Contains information on the administration of the trial, trial site(s) with
principal investigator(s), the trial design and on the investigational medicinal
products (IMP).
• Module 2 – Represents national or local Ethics Committee application form
3. Clinical Trial Protocol
4. Information on Investigational Medicinal Products (IMP)
5. Recruitment Arrangements
6. Subject information and the informed consent procedure
7. Suitability of the investigator and quality of the facilities
8. Insurance and indemnity
9. Financial Arrangements
Development and Regulatory Approval of Biologics in European Union 21

22. Development and Regulatory Approval of
Biologics in European Union
22

23. Biosimilar development
• EMA evaluates biosimilars according to the same standards of pharmaceutical
quality, safety and efficacy that apply to all biological medicines approved in the
EU.
Development and Regulatory Approval of Biologics in European Union 23
Developers of biosimilars are required to
demonstrate
comparability studies
with the 'reference' biological
medicine that: There are no clinically
differences between
the biosimilar and the
reference medicine in
terms of safety, quality
and efficacy
Their biological
medicine is
highly similar
to the reference
medicine

24. Development and Regulatory Approval of Biologics in European Union 24
Biosimilar development

25. Development and Regulatory Approval of Biologics in European Union 25
Regulatory framework for biosimilars
Process For approval of biosimilars
in EU
Data Required for approval
Immunogenicity
Extrapolation

26. Regulatory Framework for biosimilars
• The EU has approved the highest number of biosimilars
worldwide, and consequently has the most extensive
experience of their use and safety.
• EMA has issued scientific guidelines to help developers
conform to the strict regulatory requirements for
approving biosimilars.
• The guidelines have evolved to keep pace with rapid
advances in biotechnology and analytical sciences, and
they take on board increasing experience of clinical use.
Development and Regulatory Approval of Biologics in European Union 26

27. Process For Approval of biosimilars in EU
• All medicines produced using biotechnology and those for specific indications must
be approved in the EU through EMA
• Some biosimilars may be approved at national level, such as some low-molecular
weight heparins derived from porcine intestinal mucosa.
• When a company applies for marketing authorisation at EMA, data are evaluated by
EMA’s scientific committees on human medicines and on safety, as well as by EU
experts on biological medicines and specialists in biosimilars.
• The review by EMA results in a scientific opinion, which is then sent to the
European Commission, which ultimately grants an EU-wide marketing
authorisation.
Development and Regulatory Approval of Biologics in European Union 27

28. Data requirements for approval:
• For any biological medicine with a new active
substance, a positive benefit-risk balance is determined
mainly from evidence of safety and efficacy in pivotal
trials in humans.
• A positive benefit-risk balance is based on
demonstrating biosimilarity, i.e. that the active
substance is highly similar to the reference medicine.
• This is achieved via comprehensive comparability
studies with the reference medicine
Development and Regulatory Approval of Biologics in European Union 28

29. Comparative Data requirements
Development and Regulatory Approval of Biologics in European Union 29
Same Pharmaceutical
Quality Standards for
all medicines
Comparability Studies:
the key to the
development of
biosimilars
Comparability: a
scientific principle
routinely used after
manufacturing changes
to medicines on the
market
Comparative trials are
designed to conform
biosimilarity and clinical
performance

30. Development and Regulatory Approval of Biologics in European Union 30
Requirements for the MAA

31. Immunogenicity
• Immunogenicity is always studied for biological medicines.
• This is because of the intrinsic ability of proteins and other biological
medicines to cause an unwanted immune response which, in rare cases,
could cause a serious adverse reaction.
Development and Regulatory Approval of Biologics in European Union 31

32. Key considerations on potential immunogenicity
of biological medicines
Development and Regulatory Approval of Biologics in European Union 32
• Immunogenicity is not a safety concern in itself
1
• The nature of immune reactions depends on many
factors
2
• Harmful immunogenicity is unlikely after manufacturing
changes or after switching
3
• Immunogenicity is always monitored post-marketing
4

33. Conti...
1. Immunogenicity is not a safety concern in itself
• In most cases, an immune reaction against a biological
treatment is not responsible for serious problems that result
from a higher immune response, Connected to clinical
outcomes
2. The nature of immune reactions depends on many
factors
• Changes to the structure of the protein may occur during
improper storage or transport, or proteins could form
aggregates
3.Harmful immunogenicity is unlikely after manufacturing
changes or after switching
• A harmful immune response is unlikely after a change to
the manufacturing process of a biological medicine
Development and Regulatory Approval of Biologics in European Union 33

34. Conti...
4. Immunogenicity is always monitored post marketing
• Particularly important to learn of rare immune reactions
that can only be detected after a long follow-up period
in larger numbers of patients.
Immunogenicity data needed for approval of a
biosimilar
• The type of biological medicine and its intended use
• Product characteristics
• Previous knowledge of immunogenicity
Development and Regulatory Approval of Biologics in European Union 34

35. Extrapolation
• If a biosimilar is highly similar to a reference
medicine and has comparable safety and efficacy in
one therapeutic indication, safety and efficacy data
may be extrapolated to other indications approved for
the reference medicine.
• No trials at all need to be carried out with the
biosimilar in certain indications.
Criteria for extrapolation
• Before an indication for a biosimilar may be
approved based on extrapolated safety and
effectiveness, several factors need to be taken into
account.
Development and Regulatory Approval of Biologics in European Union 35

36. Criteria for extrapolation
Development and Regulatory Approval of Biologics in European Union 36
1 • Mechanism of action
2 • Relevant study population
3 • Extrapolation across different clinical settings
4 • Extrapolation of safety data
5 • Extrapolation of immunogenicity data

37. References
1. Guideline on the requirements for quality documentation concerning biological
investigational medicinal products in clinical trials [Internet]. Europa.eu. 2022 [cited
2023 May 20]. Available from: https://www.ema.europa.eu/en/documents/scientific-
guideline/guideline-requirements-quality-documentation-concerning-biological-
investigational-medicinal_en-2.pdf
2. No title [Internet]. Nclinnovations.org. [cited 2023 May 20]. Available from:
http://www.msk.nclinnovations.org/medregulations/v1/html/Biologics_EMA.htm
3. Europa.eu. [cited 2023 May 20]. Available from:
https://www.ema.europa.eu/en/documents/leaflet/biological-medicinal
products_en.pdf
37
Development and Regulatory Approval of Biologics in European Union

38. References
4. EMA. Biosimilar medicines: marketing authorisation [Internet]. European
Medicines Agency. 2018 [cited 2023 May 20]. Available from:
https://www.ema.europa.eu/en/human-regulatory/marketing-
authorisation/biosimilar-medicines-marketing-authorisation
5. Europa.eu. [cited 2023 May 20]. Available from:
https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-
healthcare-professionals_en.pdf.
6. EMA. Biosimilar medicines: Overview [Internet]. European Medicines Agency.
2018 [cited 2023 May 20]. Available from: https://www.ema.europa.eu/en/human-
regulatory/overview/biosimilar-medicines-overview
7. Nclinnovations.org. [cited 2023 May 20]. Available from:
http://www.msk.nclinnovations.org/medregulations/v1/html/Biologics_EMA.html
Development and Regulatory Approval of Biologics in European Union 38

39. References
8. Europa.eu. [cited 2023 May 20]. Available from:
https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-
healthcare-professionals_en.pdf
9. Medicinesforeurope.com. [cited 2023 May 20]. Available from:
https://www.medicinesforeurope.com/wp-
content/uploads/2016/03/biosimilars_report_en.pdf
10.Researchgate.net. [cited 2023 May 20]. Available from:
https://www.researchgate.net/publication/330901294_Regulatory_overview_of_biosi
milars_in_Europe
11.Kingham R, Klasa G, Carver KH. 4 key regulatory guidelines for the development
of biologics in the United States and Europe 1 [Internet]. Cov.com. [cited 2023 May
20]. Available from: https://shorturl.at/fsCEW
Development and Regulatory Approval of Biologics in European Union 39

40. Development and Regulatory Approval of
Biologics in European Union
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