Biosimilars, it's development process, manufacturing and approval pathway.

1. BIOSIMILAR DRUGS
SUBMITTED BY,
Usha Khanal
1 18HMPA06
M.Pharm IInd Semester
Pharmaceutical Analysis&QualityAssurance
HimalayanPharmacyInstitute

2. TOPICS TO BE DISCUSS:
 BIOLOGICAL PRODUCTS
 BIOSIMILARS
 DEFINITION OF BIOSIMILARS BY DIFFERENT AUTHORITIES
 DERTREMINANTS OF A BIOSIMILAR
 BASIC PRINCIPLE
 CHOICE OF REFERENCE PRODUCT
 BIOSIMILARS VERSUS ORIGINATOR BIOLOGICS
 DIFFERENCE BETWEEN CHEMICAL GERERICS AND BIOSIMILARS
 SWITCHING, SUBSTITUTION, AND INTERCHANGEABILITY

3.  IMMUNOGENICITY
 NAMING BIOSIMILARS
 INCREASING COMPETITION AMONG BIOLOGICS AND BIOSIMILARS
 A SIMILAR STEP-BY-STEP DEVELOPMENT PROCESS FOR BIOSIMILARS
FOLLOWED ACROSS GEOGRAPHIES
 ISSUES RELATED TO BIOSIMILARS
 PRINCIPLES FOR DEVELOPMENT OF BIOSIMILARS
 BIOSIMILARS MANUFACTURING
 EVOLUTION OF BIOSIMILAR APPROVAL PATHWAY IN U.S.
 BENEFITS OF BIOSIMILARS

4. BIOLOGICAL PRODUCTS
 They are medicines typically derived from living systems and produced using biotechnology –
e.g. vaccines, blood and blood components and recombinant therapeutic proteins.
 They address areas of clinical need that are unmanageable with conventional therapeutics
(including many cancers and genetic diseases)
 They are also called as biotechnological products or biopharmaceuticals.
 Several terms are used in various countries for ‘‘intended copy” products to biopharmaceuticals
(such as, Biosimilars, follow-on biologicals, follow-on protein products, subsequent-entry
biologicals, similar biological medicinal products).

5. BIOSIMILAR
 A biosimilar is exactly what its name implies — it is a biologic that is “similar” to another
biologic medicine (known as a reference product) which is already licensed by the U.S. Food
and Drug Administration (FDA).
 Biosimilars are officially approved versions of original "innovator" products and can be
manufactured when the original product's patent expires.
 Similar in terms of quality, safety and efficacy to an already licensed, well-established reference
medicinal product.
 Because of structural & manufacturing complexities, these biological products are considered as
similar but not generic equivalents of innovator biopharmaceuticals.

6. DEFINITION OF BIOSIMILARS BY
DIFFERENT AUTHORITIES
 As per EMA: A similar biological or 'biosimilar' medicine is a biological medicine that is
similar to another biological medicine that has already been authorized for use. Biological
medicines are medicines that are made by or derived from a biological source, such as a
bacterium or yeast. They can consist of relatively small molecules such as human insulin or
erythropoietin, or complex molecules such as monoclonal antibodies.
 As per WHO: A biotherapeutic product which is similar in terms of quality, safety and
efficacy to an already licensed reference biotherapeutic product. They are termed as
“similar biologic product (SBP).

7.  US-FDA: A biopharmaceutical product highly similar to the reference product without
clinically meaningful differences in safety, purity and potency. They are described as
“Follow on Biologic (FOB)”.
 Health CANADA: Drug that enters the market subsequent to a version previously
authorized in Canada with demonstrated similarity to a reference biologic drug. They are
termed as “Subsequent entry biologic(SEB)”

8. BIOSIMILAR’S INCLUDE
 Blood and plasma products
 Non recombinant products
 Recombinant products
 Monoclonal antibodies
 Vaccines etc.

9. DERTREMINANTS OF A BIOSIMILAR
 It should be a biologic product.
 Reference product should be an already licensed biologic product.
 The biosimilar should demonstrate a high similarity of safety, quality and efficacy to that
of the reference product.
 Similarity should be determined by comparing the biosimilar product with the reference
product based on quality, non clinical and clinical studies.

10. BASIC PRINCIPLE
 The concept of a “similar biological medicinal product” is applicable to any biological medicinal
product.
 Biological medicinal products are usually more difficult to characterize than chemically derived
medicinal products
 Therefore: –
 The standard generic approach is normally applied to chemically derived medicinal products.
Due to the complexity of biological/biotechnology-derived products the generic approach is
scientifically not appropriate for these products. The “similar biological medicinal products”
approach, based on a comparability exercise, will then have to be followed.

11.  Comparability exercises to demonstrate similarity are more likely to be applied to highly
purified products, which can be thoroughly characterized (such as some biotechnology
derived medicinal products).
 The ‘similar biological medicinal product’ approach is more difficult to apply to other
types of biological medicinal products, which by their nature are more difficult to
characterize, such as biological substances arising from extraction from biological sources
and/or those for which little clinical and regulatory experience has been gained.
 Whether a medicinal product would be acceptable using the ‘similar biological medicinal
product’ approach depends on the state of the art of analytical procedures, the
manufacturing processes employed, as well as clinical and regulatory experiences.

12.  It should be recognized that, by definition, similar biological medicinal products are not
generic medicinal products, since it could be expected that there may be subtle differences
between similar biological medicinal products from different manufacturers or compared
with reference products, which may not be fully apparent until greater experience in their
use has been established. Therefore, in order to support pharmacovigilance monitoring, the
specific medicinal product given to the patient should be clearly identified

13. CHOICE OF REFERENCE PRODUCT
 The reference drug should be already approved on the basis of a complete dossier package.
 The reference drug should be used throughout the studies supporting the quality, safety and
efficacy of the product.
 The dosage form, strength, and route of administration of the biosimilar product should be
the same as that of the reference product.
 The biosimilar product should not be used as a reference drug.

14. BIOSIMILARS VERSUS ORIGINATOR
BIOLOGICS
 Biosimilars are not exact copies of originator biologic and neither these are expected to be the exact replicas
of the innovator biologics as the manufacturing process through which a biologic is made cannot be exactly
duplicated by another manufacturer.
 They are similar to their innovator products but there being some minor difference in the structure due to
different manufacturing processes involved they are not the same; however, these differences are not
clinically significant and so the clinical outcome with innovator biologics and biosimilars is identical.
 Though both innovator biologics and biosimilars being protein in nature have immunogenic potential,
biosimilars tend to produce more adverse drug reactions than reference products, immunogenicity being the
most common among them; as biosimilars do not have to go through the same regulatory approval process as
innovator product.

15. DIFFERENCE BETWEEN CHEMICAL
GERERICS AND BIOSIMILARS
 BIOSIMILARS
 Produced by living cell cultures.
 High molecular weight compounds.
 Complex dimensional structure.
 Unstable and sensitive
to external conditions.
 Immunogenic
 Clinically identical to their reference products but not
the same (Active product likely to have variation)
GENERICS
 Produced by chemical synthesis.
 Low molecular weight compounds.
 Well defined structure.
 Stable
 Mostly non-immunogenic.
 Therapeutically equivalent with their reference products
(Active product always the same)

16. DIFFERENCE BETWEEN GENERICS
AND BIOSIMILARS

19. BIOSIMILARS
 manufacturing complex & variable
 Cost of developing is around $75-250 million
 For Approval regulators require clinical trials,
manufacturing and post-approval safety
monitoring programs similar to that of the
original innovator companies. They do not accept
equivalence.
 Substitution of biosimilars is not permitted, as
the substituted product may not be comparable to
prescribed product in terms of safety and
efficacy.
GENERICS
 Manufacturing simple and consistent
 Cost of developing is around $2-3 million.
 For Approval regulators require bioavailability
& bioequivalence studies
 Substitution is permitted for generics

20. Comparison of biologic, biosimilar, and
generic

21. SWITCHING, SUBSTITUTION, AND
INTERCHANGEABILITY
 Typically, if a patient has a prescription for a small molecule medication, a pharmacist may substitute a
generic version without consulting with the patient’s physician. This is called interchangeability.
 However, biosimilars are not interchangeable with their originator biologic.
 A physician may choose to switch their patient from an originator biologic to the biosimilar product if they
think it will be beneficial, but a pharmacist may not change the patient to a biosimilar.
 Switching refers to a one-time change made by a physician, and should only be made if it is in the patient’s
best interest and if the patient agrees.
 Little is known about switching between biosimilar products at this time.

22. Immunogenicity
 Because biologics are proteins, the body can develop antibodies to them over time, which
might affect how they work.
 This immune response, also called immunogenicity, might increase when switching from
one biologic to another or back again, and is a strong reason for a discussion with health
care provider before switching among biologic products.
 Whether immunogenicity increases with switching is still unknown and requires further
study.

23. NAMING BIOSIMILARS
 Currently, biosimilars use the same international non-proprietary name (INN) as the originator biologic, even though they are
not the exact same product. Health Canada and other similar groups internationally are looking into options for distinguishing
between biologics and their biosimilars.
 The World Health Organization has been considering adding what they term a Biological Qualifier to all biologic products, but
opinions on this are mixed, and there is no definite timeline of when they would implement this in Canada.
 Patient safety is paramount and there is a strong regulatory need in Canada for distinguishable INNs between innovator
biologics and their biosimilar medications.
 A biosimilar is not the same as the biologic it is similar to, and giving the products the same INN might cause further
confusion.
 For now, the words ‘biosimilar’ or ‘originator’ often precedes the INN, and each drug has a unique Drug Identification
Number (DIN) The DIN is the 8-digit number located on the label of prescription and over-the-counter drug products that
have been evaluated by the Therapeutic Products Directorate branch of Health Canada and approved for sale in Canada.

24. PRINCIPLES FOR DEVELOPMENT OF
BIOSIMILARS
 Developed through sequential process.
 Extensive comparative studies between reference drug and drug under development.
 Extent of testing of biosimilar is less than that of reference product.
 Product should meet acceptable levels of safety, efficacy and quality with the reference drug.
 Should be authorized using complete dossier.
 Rationale for the choice of reference biologic provided by the manufacturer.
 The reference biologic selected should be used in all comparative studies during the development of biosimilar.
 Licensed and should be an innovator product.
 An existing similar biologic cannot be used as a reference biologic.

25. Increasing Competition Among Biologics and
Biosimilars
 In 2010, Congress approved the Biologics Price Competition and Innovation Act (BPCIA), creating an abbreviated
approval pathway for biosimilars, while maintaining incentives for continued medical advances.
 To support innovation and competition in the marketplace, Congress provided 12 years of data protection for
innovative biologic medicines.
 This framework provides a balance between providing incentives for development of innovator biologics and spurring
the introduction of and access to biosimilars.
 To date, the FDA has issued several draft and final guidance documents to assist biosimilar sponsors in generating
data to support biosimilar applications.
 The FDA approved the first biosimilar product for marketing in the United States in March 2015.

26.  The FDA is working to provide additional guidance on how biosimilar products could be
designated “interchangeable” to reference products.
 In 2018, FDA Commissioner Gottlieb introduced the Biosimilars Action Plan to help spur
competition and innovation for biosimilars. As of March 2019, 18 biosimilars have been
approved in the U.S.
 As the market and experience with biosimilars increases, we expect usage to play an
expanded role in options for patients and decrease prescription drug spending.

27. Step-by-step development process for
biosimilars followed across geographies
 The development of a biosimilar involves stepwise comparability exercise(s) beginning with an evaluation of the
quality characteristics of biosimilar and reference biological product. Establishing similarity between biosimilar and
reference biological requires comparison of quality characteristics that will lead to the reduction of non-clinical and
clinical data needed for the approval process.
 If relevant differences are found in the quality, non-clinical or clinical studies, the product will not likely qualify as a
biosimilar, and a more extensive non-clinical and clinical data set will likely be required to support its application for
licensure.
 The extent and nature of the non-clinical and clinical studies to be performed depend on the level of evidence
obtained including the robustness of the physicochemical, biological and nonclinical In vitro data.
 The goal is to exclude differences between the biosimilar and the reference medicinal product. Therefore, studies
should be sensitive enough with regard to design, population, endpoints, and conduct to detect such differences.

28. Step-wise approach
A. Analytical, quality comparison/characterization
 Manufacturing process
 Product characterization
 Structural and physicochemical properties
 Biological activity
 Immunological properties
 Purity and impurities
 Stability
 Quality comparability study

29. B. Non-clinical studies (Comparative)
 In vitro studies
 In vivo studies
C. Clinical studies (Comparative)
 Pharmacokinetic (PK) studies
 Pharmacodynamics (PD) studies
 Confirmatory safety and efficacy studies
 Safety and immunogenicity data

30. D. Data requirement (including local clinical data)
 Biosimilars need to establish similarity to the reference product in terms of quality, non-clinical and clinical studies.
 Analytical and non-clinical data requirement are similar across countries.
 Local subject participation is required in local or global phase I and phase III study.
 Since local participation is required in all countries, so Phase III trial should be global and multi-centric.
 There is a need to develop a robust post-marketing surveillance plan to allay safety/immunogenicity concerns.
E. Reference product requirement
 Reference product should be registered in a country where the approval for a biosimilar is sought.
 Reference product registered in a different country may be used with bridging data comparing biosimilar, country
registered reference product and out-site country registered reference product used in comparability exercise.

31. F. Clinical trials initiation and filing of biosimilar application
 Clinical trials can be initiated at any time irrespective of patent expiry.
 Biosimilar application can be filed only after the expiry of regulatory/data exclusivity.
 In Europe, the application can be filed after eight years of data exclusivity; however, approval can happen
after ten years of exclusivity (8+2 exclusivity).
 There is no data exclusivity in India and Brazil.
 However, a biosimilar can only be approved or launched after the expiry of patent and regulatory exclusivity.
 To be among the early entrants in the main markets, clinical development of biosimilars should be completed
at least two years before the expiry of the patent, taking into consideration time for dossier preparation and
regulatory review.

32. G. Indication extrapolation
 Extrapolation to other indications is acceptable based on scientific justification. By submitting
data for one lead indication, approval for other approved indications (extrapolation) of reference
product is possible if scientific justification is provided.
H. Interchangeability
 No provision of interchangeability in guidelines of most geographies

33. I. India-biosimilar regulatory requirement
Guidelines
 Regulatory requirements for marketing authorization of similar biologic in India were released in 2012 and require extensive
quality/analytical comparative data in addition to abridged clinical/non-clinical studies are required for biosimilar approval.
 DATA REQUIREMENT
Analytical and quality characterization data
Comparability according to critical quality attributes of product including physicochemical properties, biological activity,
immunological properties, functional assays, purity (process and product-related impurities, etc.), contamination, strength, and
content.
Non-clinical studies
• In vitro studies: e. g. cell-based bioassay (e. g., cell proliferation assays or receptor binding assays)
• In vivo studies: PD activity, immunogenicity, at least one repeat dose toxicity study, local tolerance (may be part of repeat dose
toxicity study); safety pharmacology, reproductive toxicity, mutagenicity, and carcinogenicity studies are not required unless
warranted by repeat dose toxicity studies.

34. Clinical studies •
 Phase I: Comparative PK (Pharmacokinetics) and PD (Pharmacodynamics) studies;
PK/PD relationship may be evaluated. PD evaluation can also be done as part of Phase III
study (usually 1 or 2 Clinical Trails (CTs) depending on indications)
 Phase III: Comparative efficacy and safety/immunogenicity study are essential (usually 1
or 2 CTs, depending on a number of indications and safety profile).
 Equivalence design study is preferred.
 Non-inferiority design needs to be justified.
 Safety and efficacy CT can be waived off if comparable quality, non-clinical and clinical
PK-PD data with post-marketing risk management plan is provided (cannot be waived if
there is no reliable and validated PD marker).

35.  Post-marketing: Safety and immunogenicity data must be submitted
Extrapolation to other indication
May be possible if the same Mechanism of Action (MOA)/receptors for indications (with
similar safety, efficacy, preclinical and quality data)

36. Reference product requirements
 Reference biologic should be licensed in India and should be innovator product.
 If reference biologic is not marketed in India, then it should be licensed and widely
marketed for four years post approval in innovator jurisdiction in a country with the well-
established regulatory framework.
 In case no medicine or only palliative therapy is available or in the case of national
healthcare emergency, this period of 4 years may be reduced or waived.
Interchangeability
Not mentioned in the guideline.

37. II. Europe-biosimilar regulatory requirement
Guidelines
 EU Guideline on similar biological medicinal products containing biotechnology-derived proteins as active
substance.
 Similar Biological Medicinal product is a biological medicinal product that is similar to the active substance
of an already authorized biological medicinal product (reference medicinal product) in European Economic
Area (EEA).
 The similarity to reference medicinal product in terms of quality characteristics, biological activity, safety and
efficacy based on a comprehensive comparability exercise must be established. Comparative analytical data
along with the clinical and non-clinical data is required to establish the similarity

38.  DATA REQUIREMENT
Analytical, quality characterization data
Comprehensive analyses of biosimilar and reference product. Any differences detected in quality attributes will
have to be appropriately justified concerning their potential impact on safety and efficacy.
Non-clinical data
 Phase 1: Comparative PK/PD studies
 Usually 1 or 2 CTs depending on indications
 Phase 3: Confirmatory Safety and Efficacy Studies
 Usually 1 or 2 CTs, depending on a number of indications and safety profile.
 In general, an equivalence design should be used.
 Post-marketing: Safety and immunogenicity data.

39. Extrapolation to other indication
 Extrapolation to other indications needs to be scientifically justified
 Additional data required , if the drug acts on multiple active sites/receptors in different indications
The infliximab biosimilar (Remsima) was approved by EMA (European Medicines Agency) for all
indications for reference biologic on the basis of submitted clinical data for rheumatoid arthritis and
ankylosing spondylitis.
Reference product requirement
 Must be authorized in European Economic Area (EEA)
 In the case of non-EEA authorized comparator, bridging data comparing all three products including
analytical studies with clinical and non-clinical data should be submitted (proposed biosimilar, EEA-
authorized reference product and not EEA authorized comparator).

40. Interchangeability
 In EU countries, treatment decisions to treat patients is left to the physicians and patients
to avoid “automatic substitution.”
 France Law (2014) states that a biosimilar may be dispensed only as an initial treatment to
a new, or “naive” patient.
 In the case of substitution, records are maintained by the pharmacists.

41. ISSUES RELATED TO BIOSIMILARS
 EFFICACY ISSUES
 Issues arising from differences between the bioactivity of biosimilars and their innovator
products.
 Example: Epoetin alpha products
 11 epoetin from 4 different countries(Korea,Argentina, China, India) were analysed and
significant diversions from specifications for in vivo activity were observed.
 Deviation varied in the range from 71 to 226%

42.  SAFETY ISSUES
 These are concerns regarding immunogenicity.
 Example : Eprex
 Eprex is a biosimilar of epoetin alpha produced outside the US.
 Change in manufacturing process by replacing human albumin stabilizer by polysorbate
80 resulted in increased immunogenicity.

43.  SUBSTITUTION
 Prescribed chemical entity can be substituted by generic chemical.
 Same rule of substitution cannot be applied in case of biosimilar due to the issues related
to safety and efficacy.
 Uncontrolled substitution of biologics can lead to severe consequences.

44. BIOSIMILARS MANUFACTURING
Several major steps included in development-
 Modifying the selected gene of interest
 Inserting the desired gene into a specific host cell
 Replicating cell line and increased protein expression
 Harvesting protein products from the cell
 Purifying the selected protein

45. BIOSIMILARS MANUFACTURING

46. Evolution of Biosimilar Approval Pathway
in U.S.
Two federal laws for the approval of pharmaceuticals
 Food, Drug, and Cosmetic Act (FDCA)
 New drug application (NDA)
 Abbreviated NDA (ANDA)
 Public Health Service Act (PHSA)
 Biologics license application (BLA)
 Most biologics approved under PHSA
 Biologics Price Competition and Innovation Act (BPCI) of created an abbreviated FDA approval pathway for biosimilars
 Full interpretation and implementation still pending
 According to the FDA, “drugs” are different from “biologics”

47. FDAAPPROVAL PATHWAY

48. Implementation Committees
 FDA established three committees to ensure consistency in FDA’s regulatory approach and
guidance to sponsors regarding development programs for – proposed biosimilar biological
products intended for submission under section 351(k) of the PHS Act, and – related issues.
 The committees are charged with developing policy and coordinating activities related to
biosimilars: –
 CDER/CBER Biosimilar Implementation Committee
 CDER Biosimilar Review Committee
 CBER Biosimilar Review Committee

49. Why do we need an abbreviated approval
pathway for biological products?
 Biological products are the fastest-growing class of therapeutic products in the United States and account for
a substantial and increasing portion of health care costs. Congress, through the Biologics Price Competition
and Innovation Act, created an abbreviated approval pathway to provide the public with greater access to safe
and effective biological products. This pathway provides more treatment options, potentially lowering health
care costs through competition and increasing access to lifesaving medications.
 The abbreviated licensure pathway does not mean that a lower approval standard is applied to biosimilar or
interchangeable products. In fact, as described above, the data package required for approval of a biosimilar
or interchangeable product is extensive. If a biosimilar manufacturer can demonstrate that its product is
biosimilar to the reference product, then it is scientifically justified to rely on certain existing scientific
knowledge about the safety and effectiveness of the reference product to support approval. This allows for a
potentially shorter and less costly drug development program for a biosimilar.

50. Benefits of Biosimilars
 The cost of pharmaceuticals, particularly biologics, is an important consideration as experts
look at ways to make pharmaceutical care sustainable. Because they are complex and have
revolutionized the treatment for many diseases, biologic medicines are costly and consume
a large portion of public and private drug spending.
 In most cases, biosimilars are less costly than the innovator biologic, given that fewer
clinical trials are required for biosimilars. Biosimilar manufacturers can extrapolate
scientific evidence from one indication to another, which leads to fewer development costs

51.  Biosimilar manufacturers focus on manufacturing processes that result in a similar product
as well as studies demonstrating clinical similarity to the innovator biologic. These
approaches are less expensive than the clinical trials required for initial drug approval for
the innovator biologics.

52. CONCLUSION
 Biosimilars are not generic versions of originator biologics, but they are affordable
alternatives that work similarly. For patients who have not begun an original biologic,
biosimilars may be a useful alternative for physicians to prescribe. However,
only qualified health care professionals should be allowed to switch a patient from an
innovator biologic to a biosimilar, and only if it is best for the patients’ health.

53. REFERENCES
1. World Health Organization. Expert committee on biological standardization. Geneva,
Guidelines on evaluation of similar biotherapeutic products (SBPs). 2009, 8-12
2. Alamchandani RR et al. International Journal of Research in Medical
Sciences.2(2),2014,382-386
3. U.S. Food and Drug Administration. Draft Guidance for Industry on Biosimilars: the
Biologics Price Competition and Innovation Act of 2009. Rockville, Md. February 2012.
4. Soo-Kyoung Suh. Regulatory consideration for biosimilar products. 14th ICDRA
conference. 2010,2-16.

54. 5. Quality considerations in demonstrating biosimilarity to a reference protein product, FDA
draft guidance, Feb 2012
6. EMEA guideline on immunogenicity assessment of biotechnology-derived therapeutic
proteins London, 2007
7. CDSCO. Guidance for Industry on Submission of Clinical Trial Application for Evaluating
Safety and Efficacy (General considerations for conducting Clinical Trial as per Drugs and
Cosmetics Act 1940 and Rules 1945). Version – 1.1,6-180