Biosimilars

Dr. Kunal Chitnis3rd Yr Resident

Dept of PharmacologyT.N.M.C.

2nd Feb 2013

Biotechnology is in some ways as old as human history

Our ancestors harnessed living organisms to make bread, curd, paneer & wine

It was just during the early 20th century when the term biotechnology came into use The term was coined in 1917 by Karl Ereky, a Hungarian engineer & professor who described a technology based on converting raw materials into a more useful product

At that time, the newly categorized field was focused on food production, addressing such issues as malnutrition & famine

History of Biotechnology

Field soon expanded its focus to medical uses, led by the 1940s introduction of penicillin made through a deep fermentation process→ Greatly impacted countless lives over a half-century ago

Today, Biologic medicines are making significant impact on the lives of patients with serious illnesses throughout the world

Hold promise to cure diseases like Cancers, Alzheimer’s, Multiple sclerosis, Arthritis & Cardiovascular disorders

A standard definition of biotechnology was not reached until the United Nations & World Health Organization accepted the “1992 Convention on Biological Diversity” & defined biotechnology as:

“Any technological application that uses biological systems, living organisms or derivatives thereof, to make or modify products & processes for specific use”

Biopharmaceutical

A drug created by means of biotechnology, especially genetic engineering:Primarily rDNA protein & Monoclonal antibody

Typically derived from living organisms (animal cells, bacteria, viruses & yeast)

Include:

• Therapeutic proteins (cytokines, hormones & clotting factors), Insulin, DNA vaccines, monoclonal antibodies

• New experimental modalities such as gene therapy, stem cell therapy & RNA viruses

Biologic medicines are currently prescribed to treat a wide variety of conditions, including:

• Blood conditions: leuko/neutro/pancytopenias• Cancers: Colon & Breast Ca or NHL• Immune system disorders: Rheumatoid arthritis, Psoriasis & Crohn’s disease• Neurological disorders: Multiple Sclerosis

More than 400 biologics are in clinical trials

These include therapies for cancers, Alzheimer’s disease, heart disease, diabetes, HIV/AIDS & Autoimmune disorders

Represent a fast-growing segment of the pharmaceutical market constituting:

• 32% of products in the development pipeline

• 7.5% of marketed products

• Expected to grow exponentially at more than 20% per year

• By 2016, seven of top ten pharma products worldwide will be biologics

• Potential to reach up to 50% share in global pharmaceutical market in the next few years

Develop host cell

Identify the human DNA sequence for the desired protein

Isolate the DNA sequence

Select a vector to carry the gene

Insert the gene into the genome of a host

Modification of cells→ “recombinant” technology

The exact DNA sequence & type of host cell used will significantly influence the characteristics of the product

Manufacturing of Biopharmaceuticals

Modifying the selected cell

Growing a cell line from the original modified cell

Growing a large number of cells from the cell line

Cultivating them to produce the desired protein

Separating the protein from the cells

Purifying the collected protein

Major steps involved

Differences in manufacture of Conventional drugs & Biologics

Small Molecule Drugs

Low molecular weight drugs→ Made by adding & mixing together known chemicals & reagents, in a series of controlled & predictable chemical reactions

Production techniques usually same as for Innovator Product

Production process is highly standardised

Contaminants are consistent & quantifiable

Biopharmaceuticals

Strong relationship between manufacturing processes of biopharmaceuticals & characteristics of the final product

Manufacturing biologics is more complex

A high level of precision is required → produce a consistent product time after time

Even small changes in production (Minor equipment/ Environmental variations)

Significant changes in behaviour of the cells & changes in the protein

Alterations in the three-dimensional structure of the Protein

Quantity of Acid–base variants & Glycosylation

Impact Safety & Effectiveness of biologic

To assure high quality & consistency in final product, production process requires a high level of monitoring & testing throughout the process

A biologic drug typically has around 250 in-process tests during manufacturing, compared to around 50 tests for small molecule drugs

Biosimilars

What are biosimilars?

Legally approved subsequent versions of innovator biopharmaceutical products made by a different sponsor following patent & exclusivity expiry of the innovator product

• Because of structural & manufacturing complexities, these biological products are considered as similar, but not generic equivalents of innovator biopharmaceuticals

Definitions & Interpretations of Biosimilar Products

Term By Definition

SBP (Similar Biologic Product)

WHO Similar to an already licensed reference biotherapeutic product in terms of quality, safety & efficacy

FOB (Follow-On Biologic)

US-FDA Highly similar to the reference product without clinically meaningful differences in safety, purity and potency

SEB (Subsequent Entry Biologic)

Canada Drug that enters the market subsequent to a version previously authorized in Canada with demonstrated similarity to a reference biologic drug

Based on these different definitions, there are three determinants in the definition of the biosimilar product:

• It should be a biologic product• the reference product should be an already licensed biologic product• the demonstration of high similarity in safety, quality &

efficacy is necessary

Similarity should be demonstrated using a set of comprehensive comparability exercises at the quality, non-clinical & clinical level

High unit cost of biologics has resulted in patients’ concerns about continued access to potentially effective therapies

Recently, the expiration of patents for a number of blockbuster biologics has ushered in an era of the subsequent production of biosimilar products

Contribute to ↑ access to these products at an affordable price

Global Scenario

In 2010, sales of biologics reached $100 billion worldwide with the top 12 biologics generating $30 billion

By 2015, biologics responsible for $20 billion in annual sales will go off patent

Global market for biosimilars was $311 million in 2010 & expected to increase to $2 billion-$2.5 billion in 2015

Indian Scenario

India is one of the leading contributors in the world biosimilar market

Over 50 biopharmaceutical brands have got marketing approval

Potential to replicate success of Indian Generic Industry

Imported Innovators market is estimated around US$ 220 million

India has inherited advantages of: • Cost effective manufacturing • Highly skilled, reasonably priced workforce • Huge market

Key benefit→ Reduce cost by 20-25%

For instance, European Generic Medicines Agency estimated that biosimilars generated annual savings of € ∼ 1.4 billion in EU in 2009

Owing to affordability and easy accessibility, established good reputation among healthcare professionals

Cost Effectiveness of Biosimilars

Active Substance

Trade Name Company Price (INR)

Insulin Glargine (100 IU x 1 mL x

10ml)

Lantus Sanofi Aventis 2530

Basalog Biocon 1475

Active substance

Product name Launch date in India

Company

Epoetin alfa Epofit/Erykine Aug 2005 Intas Biopharma-

ceuticals

Darbopoetin alfa

Cresp Aug 2010 Dr Reddy’s Laboratories

Insulin glargine

Basalog 2009 Biocon

Reteplase Mirel 2009 Reliance Life Scienes

Rituximab Reditux Apr 2007 Dr Reddy’s Laboratories

Few Biosimilars Approved in India

Problem Statement

Biosimilars are not biological generics

Unique molecules which are supported by only limited clinical data at the time of approval

Concerns regarding their efficacy, long-term safety & immunogenicity

Generic drugs

Chemically & therapeutically equivalent to the branded, original, low molecular weight chemical drugs whose patents have expired

Identical to the original product

Most countries already have well-established scientific standards & legal mechanisms for authorising generics

Approval of Generics

In 1984, the US FDA was authorized to approve generic drug products under the ‘Hatch-Waxman Act’

When an innovator product is going off patent, pharmaceutical companies file an abbreviated new drug application (ANDA) for approval of generic copies of Innovator Product (IP)

According to FDA’s definition, the generic drug products should be comparable to the reference drug product in: dosage form, strength, route of administration, quality, performance characteristics & intended use

Authorised on the basis of demonstrating that they are the same in structure & bioequivalent to approved product

Requires evidence of comparable bioavailability → Conduct of Bioequivalence studies

Non-clinical & Clinical data are not usually required

Recognised for some time that this paradigm will not work for biologically derived drugs

Differences between chemical generics & biosimilars

I. Heavier

Unlike structurally well-defined, low molecular weight chemical drugs, biopharmaceuticals are: High molecular weight compounds with complex three- dimensional structure

For example, the molecular weight of Aspirin is 180 Da whereas Interferon-β is 19,000 Da

II. Larger

Typical biologic drug is 100 to 1000 times larger than small molecule chemical drugs

Possesses fragile three-dimensional structure as compared to well-characterized one-dimensional structure of chemical drug

III. Difficult to define structure

Small Molecule drugs → easy to reproduce & specify by mass spectroscopy & other techniques

Lack of appropriate investigative tools to define composite structure of large proteins

IV. Complex manufacturing processes

Manufacturers of biosimilar products will not have access to manufacturing process of innovator products→ Proprietary knowledge

Impossible to accurately duplicate any protein product

Different manufacturing processes use different cell lines, protein sources & extraction & purification techniques → heterogeneity of biopharmaceuticals

Versatile cell lines used to produce the proteins have an impact on the gross structure of the protein

Such alterations may significantly impact: Receptor binding, Stability, Pharmacokinetics & Safety

Immunogenic potential of therapeutic proteins→ Unique safety issue→ Not observed with chemical generics

Issues of concern with use of biosimilars

I. Efficacy issues

Differences between the bioactivity of the biosimilars & their innovator products

Example 1:

• 11 epoetin alfa products from 4 different countries (Korea, Argentina, China, India)

• Significant diversions from specification for in vivo bioactivity

• Ranged from 71-226%

• 5 products failed to fulfill their own specification

• Adequate hemoglobin monitoring→ variance in potency may not be a critical issue

• Monoclonal antibody therapy for treating a transplant rejection/cancer patient→ variability not acceptable

Example 2:

Study compared quality parameters (purity, content & efficacy) of several biosimilar brands taken from the Indian market & with those of the innovator drug products

Carried out on 16 commercial brands covering 3 different biopharmaceuticals: pegylated G-CSF, G-CSF & erythropoietin Marked lack of comparability between biosimilars & innovator products Significant difference in the level of purity was observed among various brands of biosimilars as per European & Indian Pharmacopoeia standards

II. Safety issues

Concerns regarding immunogenicity

Example

• ↑ in no. of cases of Pure Red Cell Aplasia associated with specific formulation of epoetin α

• Caused by the production of neutralizing antibodies against endogenous epoetin

• Most of the cases in patients treated with Eprex→ biosimilar of epoetin α produced outside of the US

• Cause→ subtle changes in manufacturing process Eprex, human albumin stabilizer was replaced by polysorbate 80→ ↑ immunogenicity → formation of epoetin-containing micelles by interacting with leachates released by the uncoated rubber stoppers of prefilled syringes

III. Pharmacovigilance

Due to limited clinical database at the time of approval→ Vigorous pharmacovigilance required

Immunogenicity is a unique safety issue

Adverse drugs reactions monitoring data should be exhaustive

Type of adverse event & data about drug such as: Proprietary name, International nonproprietary name (INN) & dosage

IV.Substitution

Allows dispensing of generic drugs in place of prescribed IP

Rationale for generics→ Original drugs & their generics are identical & have the same therapeutic effect

Produce cost savings

Same substitution rules should not be applied:

Decrease the safety of therapy or cause therapeutic failure

Uncontrolled substitution → confounds accurate pharmacovigilance

Adverse event emerges after switching from IP to its biosimilar without documentation → event will not be associated to a specific product or it will be ascribed to a wrong product

V. Naming and labeling

Generic adaptation of chemical medicines is assigned the same name→ identical copies of the reference products

Biosimilars require unique INNs, as this would facilitate:

• Prescribing & dispensing of biopharmaceuticals • Precise pharmacovigilance

Need for Comprehensive labeling of biosimilars including deviations from IP & unique safety & efficacy data

Assist the physician & pharmacist in making informed decisions

Status of Regulations for Biosimilars Globally

Strong need for regulations governing biosimilars

Implementation of an abbreviated licensure pathway for biological products presents challenges, given the associated scientific & technical complexities

European Union has regulations in place for quite some time for approving biosimilars

US & India have recently covered these under their respective Acts by bringing in applicable guidelines for their evaluation & overall regulation

WHO Guidelines

Scientific basis for the evaluation & regulation of biosimilars was discussed & agreement for developing WHO Guidelines was reached at the first ‘WHO informal consultation on Regulatory evaluation of Therapeutic Biological Medicinal Products’ held in Geneva, 2007

Published guidelines on Evaluation of Similar Biological Products with detailed recommendations on clinical development in October 2009

Regulatory framework in EU

Guidelines on similar biological products containing biotechnology-derived proteins as active substance were adopted by European Medicines Agency (EMEA) in June 2006

Issued product specific biosimilar guidelines

In European Union, the first patent on biopharmaceuticals expired in 2001 & first biosimilar medicine was approved by EMEA in 2006

In 2010, the European biosimilars market generated revenues of approximately $172 million

Regulatory framework in US

US FDA issued three draft guidance documents as recent as 9th Feb 2012 on biosimilar product development under Biologics Price Competition & Innovation Act of 2009 (BPCI Act)

Based on sponsors proving structural, composition & clinical similarities with an approved Biologic

Includes importance of extensive analytical, physico- chemical & biological characterization in demonstrating that proposed biosimilar product is highly similar to the reference product not withstanding minor differences in clinically inactive components

Regulatory framework in India

Similar biologics are regulated as per:

• The Drugs and Cosmetics Act, 1940

• The Drugs Cosmetics Rules, 1945

• Rules for the manufacture, use, import, export & storage of hazardous microorganisms/genetically engineered organisms or cells, 1989. Notified under the Environment Protection Act

Apart from Central Drugs Standard Control Organization (CDSCO), the office of Drug Controller General of India (DCGI) two other competent authorities are involved in the approval process 1. Review Committee on Genetic Manipulation(RCGM) Works under Department of Biotechnology (DBT)

Regulates import, export, carrying out research, preclinical permission, No objection certificate for clinical trial (CT)

2. Genetic Engineering Approval Committee (GEAC) Functions under the Department of Environment (DoE)

Statutory body for review & approval of activities involving large scale use of genetically engineered organisms & their products

Department of Biotechnology (DBT) definition

“Biologics”Substances produced by living cells used in the treatment, diagnosis or prevention of diseases “Similar Biological Product”Biological product produced by genetic engineering techniques & claimed to be similar in terms of quality, safety & efficacy to a reference innovator product, which has been granted a marketing authorization in India

Principles for development of Similar Biologics

Developed through sequential process

To demonstrate the similarity by extensive characterization studies revealing molecular & quality attributes with regard to Reference Biologic (RB)

The extent of testing of the Similar Biologic (SB) is less than RB

Ensure that the product meets acceptable levels of safety, efficacy & quality to ensure public health

In case Reference biologic used for more than one indication→ efficacy & safety of similar biologic has to be justified or if necessary demonstrated separately for each of the claimed indications

Justification will depend on:

• Clinical experience

• Available literature data

• Whether or not the same mechanism of action is involved in specific indication

Selection of Reference Biologic (RB)

RB→ Authorized using complete dossier

Rationale for the choice of RB provided by the manufacturer in the submissions to the DBT & CDSCO

Used in all the comparability exercise with respect to quality, preclinical & clinical considerations.

Following factors should be considered for selection of the reference biologic:

• Licensed in India & should be Innovator Product

• Licensed based on a full safety, efficacy & quality data

• Another SB cannot be considered as RB

• In case RB not marketed in India: Licensed & marketed for 4 years post approval in innovator jurisdiction→ Country with well established regulatory framework

• Period of 4 years may be reduced or waived→ - No medicine/ palliative therapy is available - In national healthcare emergency

• Active substance, dosage form, strength & route of administration of the SB→ same as that of RB

Manufacturing Process

Should be highly consistent & robust

If host cell line used for production of RB is disclosed, use the same cell line

Alternatively any cell line that is adequately characterized & appropriate for intended use

Applicant should submit a full quality dossier

Prerequisites before Conducting Preclinical Studies

At preclinical submission stage include a complete description of:

1. Molecular Biology Considerations

• Details regarding host cell cultures, vectors, gene sequences, promoters etc. used in the production

• Details of post translational modifications: ‐ Glycosylation, oxidation, deamidation, phosphorylation

2. Fermentation Process Development & Protein Purification details should be provided

• A well-defined manufacturing process with its associated process controls in accordance with Good Manufacturing Practice (GMP)

3. Product Characterization

• Physicochemical properties, biological activity,immunochemical properties, purity (process & productrelated impurities), contamination, strength & content

i. Structural and Physicochemical Properties:

Includes determination of primary & higher order structure of the product

ii. Biological Activity:

Appropriate biological assays to characterize the activity & establish the product’s mechanism of action

iii. Purity & Impurities:

Differences observed in the purity & impurity profiles → Assess potential impact on safety & efficacy by conduct of Preclinical & Clinical studies

Apply more than one analytical procedure to evaluate the same quality attribute

Reference to acceptance limits for each test parameter should be provided & justified based on the data from sufficient lots of similar biologics.

Differences between SBP & RBP evaluated for their potential impact on safety & efficacy→ Additional characterization studies may be necessary

Submit the data generated along with the following to RCGM for obtaining permission

Preclinical Studies

Comparative in nature & designed to detect differences

Study design depends on: Therapeutic index, type & number of indications applied

Conducted with the final formulation

Dosage form, strength & route of administration should be same as that of RB Approval:• Prior to conduct of the studies statutory approvals from respective Institutional Biosafety Committee (IBSC) & Institutional Animal Ethics Committee (IAEC) be submitted

The following studies are required for preclinical evaluation:

1. Pharmacodynamic Studies

i. In vitro studies:

Comparability established by in vitro cell based bioassay (e.g. cell proliferation assays or receptor binding assays)

ii. In vivo studies:

Cases where in-vitro assays do not reflect the pharmacodynamics, In vivo studies should be performed

2. Toxicological Studies

At least one repeat dose toxicity study in a relevant species is required to be conducted

Other toxicological (mutagenicity, carcinogenicity) studies not generally required

Animal models to be used:

Scientific justification for the choice of animal model

Relevant animal species is not available→ undertaken in two species i.e. one rodent & other non rodent species

Route of administration→ include only intended route

Dose→ Calculated based on the therapeutic dose RB

Three levels of doses (low, medium and high) → Corresponding to 1X, 2X & 5X of human equivalent dose

Schedule of administration→ therapeutic schedules

3. Immune Responses in Animals

Test serum samples tested for reaction to host cell proteins

Immune complexes in targeted tissues by histopathology→ evaluating immune toxicity

Clearance:

• Study reports cleared by respective IBSC before being presented & cleared by RCGM for conducting appropriate phase of clinical trial

Clinical Studies

Data Requirements for Clinical Trial Application

Applicant has to submit application for conduct of clinical trial as per the CDSCO guidance for industry, 2008

I. Pharmacokinetic Studies

Design should take following factors into consideration:

Half life, Linearity of PK parameters, Endogenous levels & diurnal variations of SB, Conditions & diseases to be treated, Route(s) of administration & Indications

Standards to demonstrate bioequivalence should meet the CDSCO Guideline for Bioavailability and Bioequivalence studies

Comparative pharmacokinetic (PK) studies → Healthy volunteers or patients to demonstrate similarities in pharmacokinetic characteristics

If patient population is used for PK studies, Phase III / PD study can be coupled in one study design

Appropriate design considerations can be combined with adequate justification:

A. Single Dose Comparative PK Studies

Dosage within the therapeutic dose range of RB

Appropriate rationale for dose selection

Parallel arm design→ • Biologics with a long half life or • Proteins for which formation of antibodies is likely or • Study is done in patients

Cross over design→ Drugs with short half life

B. Multiple Dose Comparative PK Studies

Biologic used in a multiple dose regimen

Markedly higher or lower concentrations are expected at steady state than that expected from single dose data PK measurements

Time-dependence & dose-dependence of PK parameters cannot be ruled out

II. Pharmacodynamic (PD) Studies

Done in patients or healthy volunteers

If PD marker is available in healthy volunteers→ PD in healthy volunteers can be done

At least one PD marker→ linked to efficacy of molecule

Surrogate markers should be clinically validated

PD studies combined with PK studies→ PK/PD relationship have to be characterized

PD study can also be a part of Phase III clinical trial wherever applicable

III. Confirmatory Safety & Efficacy Study

Based on the comparability established during preclinical & PK / PD studies

Clinical trials

Comparative, parallel arm or cross-over

Sample sizes should have statistical rational

To demonstrate the similarity in safety & efficacy profiles, Equivalence trials with equivalence designs → Require lower & upper comparability margins

In the case of a non-inferiority trial, only the lower margin is defined

Nature, severity & frequency of Adverse events should be compared

Confirmatory clinical safety & efficacy study can be waived if all the below mentioned conditions are met:

i. Structural & functional comparability characterized to a high degree by physicochemical & in vitro techniques

ii. The SB is comparable to RB in all preclinical evaluations

iii. PK / PD study has demonstrated comparability & done in: • in-patient setting • safety measurement (including immunogenicity) • for adequate period & • with efficacy measurements

iv. Comprehensive post-marketing risk management plan→ Gather additional safety data →

Specific emphasis on gathering immunogenicity data

Cannot be waived if there is no reliable & validated PD marker

IV. Safety & Immunogenicity Data

Comparative safety data based on adequate patient exposure (numbers & time) with published data on RB

Both pre-approval & post-approval assessment of safety is desired

Pre-approval safety assessment → Intended to provide assurance of absence of any unexpected safety concerns

V. Extrapolation of Efficacy & Safety Data to Other Indications

If following conditions are met:

• Similarity with respect to quality has been proven to RB

• Similarity with respect to preclinical assessment

• Clinical safety & efficacy is proven in one indication

• Mechanism of action is same for other clinical indications

• Involved receptors are same for other clinical indications

New indication not mentioned by innovator will be covered by a separate application

VI. Market Authorization Application

Submit application for market authorization as per CDSCO guidance document for industry

Post-Market Data for Similar Biologics

The risk management plan should consist of the following:

A. Pharmacovigilance Plan

Clinical studies done on SB prior to market authorization are limited in nature→ Rare adverse events are unlikely to be encountered

Comprehensive Pharmacovigilance plan should be prepared by manufacturer

Periodic safety update reports (PSURs) submitted every six months for the first two years after approval

For subsequent two years the PSURs to be submitted annually to DCGI office

B. Adverse Drug Reaction (ADR) Reporting

All serious unexpected adverse reactions must be reported to the licensing authority within 15 days of initial receipt of the information by the applicant

C. Post Marketing Studies (PMS)

Plan of PMS should be captured in Pharmacovigilance plan & update on the studies should be submitted to the CDSCO

At least one non-comparative post-marketing clinical study with focus on safety & immunogenicity should be performed

If immunogenicity is evaluated in clinical studies→ Not mandatory to carry out additional non-comparative immunogenicity studies in PMS

Assay methods should be validated & be able to characterize antibody content & type (neutralizing/ cross reactivity) of antibodies formed

Neutralizing antibodies→ their impact on the PK/PD parameters, safety & efficacy assessed

D. Archiving of Data

Applicant should archive all the data for a period of at least five years after marketing approval

Site & Material of archiving should be indicated

Conclusion

Biotechnological medicines shall become an important part of future healthcare landscape

With patent expiration of innovator products, biosimilars will increasingly become available

Awareness of the deviations between biosimilars & innovator products in terms of efficacy, safety & immunogenicity is essential for proper prescription & safety of the patients

How similar is similar enough?