concept of biosimilars

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CONCEPT OF BIOSIMILARS KIRANKAUR OBEROI, FIRST YEAR M.PHARM(QUALITY ASSURANCE)

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CONCEPT OF BIOSIMILARS

KIRANKAUR OBEROI,

FIRST YEAR M.PHARM(QUALITY ASSURANCE)

OVERVIEW

Introduction

Definition

Biologics vs. small molecules

Science behind biologics

Regulations

Approval pathways

Commercial aspects

Role of pharmacist

Conclusion

References

Introduction Biopharmaceuticals are well established in biomedicine and

have opened new therapy options particularly in disease areas

where previously no, or only insufficient, therapies were

available. Some 165 biopharmaceutical products have gained

approval.

“A protein or nucleic acid based pharmaceutical substance

used for therapeutic or in vivo diagnostic purposes, which is

produced by means other than direct extraction from a native

(non-engineered) biological source.”

A generic term for a biomolecule (e.g., proteins),including anti

bodies and nucleic acids and antisense oligonucleotides,which

are produced in a transgenic organism—

e.g., mice, livestock, fish, or plant—

and used as a therapeutic agent.

The first recombinant protein drugs, like Eli Lilly’s insulin

(developed by Genentech, Inc.), were launched in the

1980’s.

The patent and regulatory data protection periods for the

first and second waves of biopharmaceuticals based on

recombinant proteins have started to expire, opening the

way for other manufacturers to place follow-on products to

the market as this has occurred since many years for

conventional medicines containing small-molecule drug

substances.

There are fundamental differences between conventional

small-molecule based drugs and biopharmaceuticals. This

has led to the adoption of distinct legal and regulatory

frameworks for follow-on products to biopharmaceuticals

(‘‘biosimilars”) in various parts of the world.

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Definition Several terms are used in various countries for

‘‘intended copy” products to biopharmaceuticals

(e.g., Biosimilars, follow-on biologicals, follow-on

protein products, subsequent-entry biologicals,

similar biological medicinal products). In this review,

Biosimilars are defined as biological medicinal

products which are:

similar in terms of quality, safety and efficacy to an

already licensed, well-established reference

medicinal product, and

marketed by an independent applicant following

expiry of patent and regulatory data/market

exclusivity periods of the reference product.

There are many differences between

biopharmaceuticals and the small molecule drugs.

Definition1)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.

2)As per WHO: A biotherapeutic product which

is similar in terms of quality, safety and

efficacy to an already licensed reference

biotherapeutic product. 7

Definition3) ) As per US FDA: “Biological Product” in the

Public Health Service Act (PHS Act) now includes

“protein”: a virus, therapeutic serum, toxin, antitoxin,

vaccine, blood, blood component or derivative,

allergenic product, protein (except any chemically

synthesized polypeptide), or analogous product

applicable to the prevention, treatment, or cure of a

disease or condition of human beings

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Pharmaceuticals vs. Biologics

Pharmaceuticals Biologics

Size (MW) Small (<1000) Large (>10,000)

Source Chemical synthesis Cultures of living cells

Form Generally oral solids Often injected or infused

Dispensed byUsually retail

pharmaciesOften by doctors or hospitals

Example

Lipitor (anti-

cholesterol)

Herceptin (breast cancer)

HERCEPTIN

MW = 185,000LIPITOR

MW = 558.64

Science of biologics

COMPLEXITY OF

PROTEIN MOLECULE:

Size – Proteins have

molecular weights from

about 10,000 up to more

than 200,000 Daltons, so

typically they are 100- to

1000-fold larger molecules.

Structure-To possess

biological activity, proteins

have to adopt the correct

three-dimensionally folded

secondary, tertiary, and

quaternary structures.

Stability – Proteins are

inherently unstable molecules,

and may structurally be

damaged by heat, prolonged

storage, denaturants, organic

solvents, oxygen, pH changes,

and by other factors, leading to

reduction or complete loss of

biological activity.

Micro heterogeneity– No

protein product will leave the

producing cell and the

manufacturing process as

predicted theoretically based on

the encoding DNA sequence

alone. Proteins are modified

both biologically by the

producing cell as well as by the

process conditions.

Manufacturing process

Desired gene isolation

Insertion into vector

Host cell expression

Cell cultureCell bank

establishment

characterization

Protein production

Protein purification

Analysis

Formulation

Typical steps in manufacturing of a biologic

product.

Regulation

• The regulatory pathway for approval of Biosimilars is

more complex than for the generic innovator product

because the design of a scientifically valid study to

demonstrate the similarity of a highly process-

dependent product is not easy.

• Modest differences may have clinical implications and

pose a significant risk to patient safety.

• Therefore, it is considered necessary that Biosimilars

must be assessed for clinical efficacy and safety by

valid preclinical and clinical studies before marketing

approval.

Regulation:

European Union• The European Union became the first region globally

to introduce a particular regulatory framework for

Biosimilars developed by EMEA’s Committee for

Medicinal Products for Human Use (CHMP).

• It consists of an overarching guideline , a guideline

on quality issues, a guideline on non-clinical and

clinical issues , as well as class-specific guideline

annexes describing the non-clinical and clinical

requirements for specific classes of new products. In

addition to these guidelines, product-class-specific

guidelines have been issued for the development of

Biosimilars based on recombinant erythropoietin,

somatotropin, human granulocyte colony-stimulating

factor, human insulin, recombinant IFN-a, and low

molecular weight heparins.

Regulation:

United States• In the US, after the approval of Biosimilars

Omnitropein 2006, the FDA stated that no other

Biosimilars will be approved until a specific

regulation has been issued.

• The Pathway for Biosimilars Act of 2009 and the

Patient Protection and Affordable Care Act of 2010

have provided greater clarity, and a reasonably clear

mandate from the US.

Regulation:

India• The “Guidelines on Similar Biologics” prepared by

Central Drugs Standard Control Organization

(CDSCO) and the Department of Biotechnology

(DBT) lay down the regulatory pathway for a similar

biologic claiming to be similar to an already

authorized reference biologic.

• The guidelines address the regulatory pathway

regarding manufacturing process and quality aspects

for similar biologics.

• These guidelines also address the pre-market

regulatory requirements including comparability

exercise for quality, preclinical and clinical studies

and post market regulatory requirements for similar

biologics. This was decided in the year 2012.

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Approval pathway for biosimilars

In the US, the Biologics Price Competition and Innovation Act (BPCI Act, 2009) provided the pathway to create an abbreviated licensure procedure for biologic products that are demonstrated to be biosimilar to or interchangeable with a Food and Drug Administration (FDA) licensed biologic product.

In February 2012, the FDA issued three guidelines that list the requirements for biosimilar registration. The topics covered include scientific and quality considerations to demonstrate biosimilarity to a reference product and a guidance that clarifies the BPCI Act implementation.

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Approval pathway for biosimilars

According to these guidelines, the FDA will consider

different aspects when evaluating biosimilarity, such

as product formulation, complexity, and stability

which will have a risk-based approach and will

depend on the degree of knowledge of the product

characteristics, as well as clinical experience with the

reference one.

The FDA intends to use a risk-based and facts-

focused approach for review of applications of

biosimilars, although it faces several challenges.

Once a biologic medicine has been demonstrated to

be biosimilar to the reference product, an abridged

development program for the biosimilar medicine

can be carried out. 22

Approval pathway in IndiaIn India, similar biologics are regulated by the:

1. Drugs and Cosmetics Act, 1940 (Drugs and Cosmetics Act);

2. Drugs and Cosmetics Rules, 1945 (as amended from time to

time);

3. Rules for the Manufacture, Use, Import, Export and Storage

of Hazardous Microorganisms and Genetically Engineered

Organisms or Cells, 1989 (Rules 1989) notified under the

Environment (Protection) Act, 1986;

4. Recombinant DNA Safety Guidelines, 1990;

5. Guidelines for Generating Preclinical and Clinical Data for

rDNA Vaccines, Diagnostics and other Biologicals, 1999;

6. The Central Drugs Standard Control Organization

(CDSCO) Guidance for Industry, 2008 {including: (a)

Submission of Clinical Trial Application for Evaluating Safety

and Efficacy

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Approval pathway in India

; (b) Requirements for Permission of New Drugs Approval; (c)

Post Approval Changes in Biological Products: Quality,

Safety and Efficacy Documents; and (d) Preparation of the

Quality Information for Drug Submission for New Drug

Approval: Biotechnological/Biological Products}; and

7. Guidelines and Handbook for Institutional Biosafety

Committees (IBSCs), 2011.

In 2012, CDSCO, in collaboration with the DBT, issued

the Guidelines on Similar Biologics: Regulatory Requirements

for Marketing Authorization in India (Guidelines). The

Guidelines detail the regulatory requirements, such as data

requirements for the manufacturing, characterization,

preclinical studies and clinical trials, for receiving marketing

authorization of similar biologics. The Guidelines are

applicable for similar biologics developed in or imported into

India.24

Approval pathway in India According to the Guidelines, similar biologics are developed

through a sequential process designed to demonstrate the

similarity, by extensive characterization studies, of the

molecular and quality attributes of the similar biologic with a

reference biologic.

It is essential that the testing of the similar biologic be

sufficient to ensure that the product meet acceptable levels of

safety, efficacy and quality to ensure public health.

Generally, a reduction in data requirements is possible for

preclinical and or clinical components of the development

program by demonstrating comparability of the product (to

the reference biologic) and consistency in the production

process.

If any significant differences in safety, efficacy and quality

between the similar biologic and the reference biologic are

identified, more extensive preclinical and clinical evaluation

will be necessary. It is quite likely in this instance that the

product may not qualify as a similar biologic. 25

Quality, efficacy and safety

• The quality, safety, and efficacy of a Biosimilars

product must be approved by the relevant regulatory

body before marketing approval can be gained.

• . The quality comparison between the Biosimilars

and the innovator product is crucial, because the

quality of a protein product affects its safety and

efficacy.

• Towards the particular manufacturing process used,

biopharmaceuticals exhibited great sensitivity, and

variation in product quality was commonly observed,

even when the exact same process of manufacturing

was used.

• Variability of source material has also been known to

affect product quality. Thus the product is affected

both by the host cell and the processing steps that

follow.

Quality, efficacy and safety

• The recent guidelines of the International Conference

on HarmonizationQ8 on pharmaceutical

development,47 and the roll-out of the Quality by

Design48 and Process Analytical Technology

initiatives from the FDA have improved

understanding of the impact of manufacturing

processes and their starting materials, on product

quality.

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Methods for QSE assessment of Biosimilars

Attributes Methods

Primary sequence (peptide map

and amino acid

sequence analysis),

immunogenicity (immunoassay)

other identity indicators

IE, HPLC, gel electrophoresis

Potency Cell-based bioassay, gene

expression bioassay, ADCC, CDC

Conformation Near/far UV circular dichroism

spectroscopy, Fourier transform

infrared

spectroscopy, X ray

crystallography and differential

scanning calorimetry

Methods for QSE assessment of Biosimilars

Attributes Methods

Host cell proteins ELISA, DNA,

endotoxin (Limulus

amebocyte lysate

assay)

Binding Cell assays,

spectroscopy, ELISA

Biological activity Cell assays, animal

models

Pharmacovigilance

• Pharmacovigilance is particularly concerned with adverse

drug reactions.

• The most critical safety concern relating to

biopharmaceuticals (including Biosimilars) is

immunogenicity.

• Minimization of immunogenicity has to begin at the

molecule design stage by reducing or eliminating antigenic

epitopes and building in favorable physical and chemical

properties.

• Pharmacovigilance is important in the Biosimilars market

because of the limited ability to predict clinical

consequences of seemingly innocuous changes in the

manufacturing process and the scientific information gap.

Pharmacovigilance• Pharmacovigilance systems should differentiate

between innovator product and Biosimilars products, so

that effects of Biosimilars are not lost in the back–

ground of reports on innovator products.

• Further, the risk management plan for Biosimilars

should focus on increasing pharmacovigilance

measures, identify immunogenicity risk, and implement

special post-marketing surveillance.

• Although International Nonproprietary Names (INNs)

served as a useful tool in worldwide

pharmacovigilance, for biological products, they should

not be relied upon as the only means of product

identification.

• In addition, biological products should always be

commercialized with a brand name or the INN plus the

manufacturer’s name.

Commercial opportunities

• Biosimilars development is a landmine of

complexities with respect to regulatory,

manufacturing, and marketing aspects, making it one

of the most expensive development propositions in

the pharmaceutical industry.

• Like generic pharmaceuticals, Biosimilars enter the

market with the aim of reducing healthcare cost, but

entry to the Biosimilars market carries higher costs,

greater risks, and more time and expertise in relation

to the clinical development of these products.

• The considerable costs to obtain FDA approval, and

the substantial costs to develop manufacturing

capacity, will limit the number of Biosimilars

competitors.

Commercial opportunities

• The type and amount of resources required for biosimilar

development can create high barriers of entry, not just for small to

mid-sized companies, but even for the larger, well-established

generics players and global biopharmaceutical companies.

• Gaining market share for a biosimilar could be challenging when

there is no added benefit over the innovator and insignificant cost

savings. The price decrease can be achieved when multiple

biosimilars are introduced to the market.

• On the other hand, if a substantial price decrease is not viable for a

biosimilar, a better strategy seems to be to develop a biosimilar as a

new product.

• It would benefit the sponsor to use a scientific rationale and its own

nonclinical and clinical testing, most of which will be required

anyway, to develop its product as a unique innovator product, and

gain the benefit of extended market exclusivity.

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Development of next-generation products

• Competition in biopharmaceuticals is dynamic and

many biologicals have next generation products in

development

• Roche is developing subcutaneous injection

presentations for its Rituxan and Herceptin products

• Biogen is developing a PEGylated version of its

interferon beta 1-a product for multiple sclerosis

• Next generation products may be in the planning

stages for Avastin and Remicade

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Market advantages Biopharmaceutical drugs have outperformed the

pharmaceutical market as a whole largely due to two factors:

1)They address areas of clinical need that are unmanageable with conventional therapeutics (including many cancers and genetic diseases)

2) They are able to command a premium price.

Datamonitor, for example, forecast growth in biopharmaceuticals of 11% a year between 2004 and 2010 compared to 3.4% annually for the total market. Currently, the USA accounts for 55% of the biopharmaceuticals market.

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Market advantages

Usually, the imminent expiry of a drug’s

patent leads to companies developing cheaper,

bioequivalent versions of the original brand

(generics), followed by intense price

competition. This approach to the

biopharmaceuticals market can yield

significant reward.

Biopharmaceuticals’ commercial value derives

from their ability to address otherwise unmet

need.

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Market advantages Genzyme’s Cerezyme (imiglucerase) offers a case in

point. Cerezyme treats Gaucher’s Disease, which

occurs because of an inherited deficiency in an

enzyme called glucocerebrosidase. As a result, levels

of a fat called glucosylceramide rise excessively,

which grossly enlarges the liver, spleen, bone

marrow and other organs leading to numerous

potentially fatal complications and considerable

morbidity among those who survive. Before

imiglucerase, there were no effective treatments.

Cerezyme markedly improves the prognosis of

people affected by Gaucher’s Disease. Cerezyme,

which addresses this previously unmet need, is priced

at around $200 000 per patient per year.40

Market challenges

Many commercially important biopharmaceuticals, including monoclonal antibodies (MAbs) such as Herceptin (trastuzumab), Rituxan (rituximab) and Humira (adalimumab), were launched fairly recently and will not be open to generic competition for many years.

They are protected by a complex series of patents that even the biggest, most experienced generics companies find impenetrable.

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Market challenges

The commercial and scientific hurdles facing biopharmaceuticals hinder the entry of generic biopharmaceuticals and mean that companies that want to develop biosimilars will need to rethink some fundamental assumptions about the generics market and work according to new business models.

The innate variation and the lack of established methods to determine bioequivalence mean that regulators are likely to be much stricter when considering an application for marketing approval of biosimilars than they are with conventional generics.

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Market challenges

As a result, regulators will require more extensive clinical testing for biosimilars than for conventional generics.

The cost of manufacturing a biopharmaceutical is much higher than that of a conventional generic. The estimated cost to develop a biosimilar is estimated to be in the range $10-40 million, largely because of the need for extensive safety and efficacy testing. This compares with $1-2 million for a traditional generic.

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Market challenges

Physicians will be cautious about the

relative safety and efficacy of biosimilars

in the short term at least. Therefore, the

market may develop slowly, which is one

reason why the commercial rewards are

likely to be limited in the short term.

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The role of hospital pharmacists• It is of utmost importance that the hospital pharmacist is aware that

the innovator products and biosimilars are not interchangeable,

because patients must be carefully monitored if their treatment is

changed between products.

• Moreover, patient welfare is foremost and for pharmacists, the

knowledge that biosimilars are not generics, and the possible

implications for clinical outcomes when products are switched, will

help ensure patient safety.

• Systematic checklists have been proposed for the evaluation of

biopharmaceuticals coming on to the market, which have provided

additional reassurance for the pharmacist.

• For example, the Pharmacy Checklist for Retacrit (epoetin zeta)

provides information on manufacturing, protein and product

formulation, batch consistency, supply reliability, good handling

practice, clinical efficacy, and clinical safety and tolerability.

Summary and conclusions

• Biologics represent a major structural change in terms of

innovation, new indications, costs, and competition

• Biosimilars have large potential commercial

opportunities but they also face high regulatory and

other hurdles compared to generic drugs for chemically

derived drugs

• Biosimilar cost savings are expected to be modest, but

scientific advances eventually could lead to easier entry

and more robust price competition.

References

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pharmacological classification. Nat Reviews Drug Discovery.

2. Genentech Inc. Corporate Chronology. 1982. http://www.gene.com/

gene/about/corporate/history/timeline.html.

3. Global Biopharmaceutical Market Report (2010–2015) IMARC

October 29, 2010:234 Pages. Pub ID: IMRC2849563.

4. http://www.icis.com/Articles/2010/02/15/9333235/follobw-on-

biologicspresent-opportunity-to-big-pharma.html.

5. Roger SD, Goldsmith D. Biosimilars: it’s not as simple as cost

alone.J Clin Pharm Ther. 2008;33:459–464.

6. Avidor Y, Mabjeesh NJ, Matzkin H. Biotechnology and drug

discovery: from bench to bedside. South Med J. 2003;96:1174–1186.

References7. IMS Health. IMS Webinar: Biologics. 2009.

http://www.imshealth.com/portal/site/imshealth/menuitem.a67578132

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2010

11. Shaldon S. Biosimilars and biopharmaceuticals: what the

nephrologist needs to know – a position paper by the ERA-EDTA

Council. Nephrol Dial Transplant. 2009

References

13. De Groot AS, Scott DW. Immunogenicity of protein therapeutics.

Trends Immunol. 2007;28:482–490.

14. Marshall SA, Lazar GA, Chirino AJ, Desjarlais JR. Rational

design and engineering of therapeutic proteins. Drug Discovery

today

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Pharmacists J (CPJ/RPC). 2010;143:184–191.

16. Crommelin DJA, Storm G, Verrijk R, Leede L, Jiskoot W, Hennink

WE.Shifting paradigms: biopharmaceuticals versus low molecular

weight drugs.

17. Biosimilars: an overview, Bhupinder Singh Sekhon Vikrant

Saluja,Institute of Pharmacy, PCTE Group of Institutes, Near

Baddowal Cantt,(Ludhiana), India

References

18. Biosimilars – Science, status, and strategic

perspective, Georg-Burkhard Kresse ,European

Journal of Pharmaceutics and

Biopharmaceutics,2009.

19. Biosimilars by Sandoz: Capturing the future

opportunity,Ameet Mallik,Global Head, Sandoz

Biopharmaceuticals and Oncology Injectables.

20.Biosimilar Biological Products, Rachel E. Sherman,

MD, MPH,Associate Director for Medical Policy

Center for Drug Evaluation and Research.

21. www.fda.gov

22.WHO. Guidelines on Evaluation of Similar

Biotherapeutic Products (SBPs) WHO; Geneva,

Switzerland: 2009.

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