Biosimilars

Tahir Nabi MirzaHead of Regulatory Affairs, Quality Assurance andSafety Health & Environment

Contents

• Biosimilars & their considerations

• Regulations

• Patent

• Messages & conclusions

What are Biopharmaceuticals?

• Biopharmaceuticals are protein in nature & derived from living cells

• They are large complex molecules

• The manufacturing processes required to produce them are complex and highly specialized

• Examples are Erythropoietin, Interferon, Growth hormone, Insulin etc.

Biopharmaceutical Vs. Chemical Pharmaceutical

4

Paracetamol

Insulin

Interferon

What are Biosimilars?

A biosimilar is a product that is physically, chemically, biologically and clinically similar to an approved reference biopharmaceutical product

What are Biosimilars?

Different names around the globe

• Biosimilar• Subsequent entry biologic (SEB)• Similar biotherapeutic product (SBP)• Known biological product (KBP)• Follow-on biologic (FOB)• Interchangeable biological product• ….

What are Biosimilars?

Biosimilars or Follow-on biologics are :

• Officially-approved subsequent versions of innovator biopharmaceutical products

• Made by a different sponsor following patent and exclusivity expiry on the innovator product

Considerations

• Biosimilar manufacturer does not have access to the

-originator's molecular clone -exact fermentation and purification process -nor to the active drug substance

• Biotech medicines cannot be fully identical

Considerations

• A small distinction in cell line can make a major difference in side effects

• No two cell lines, developed independently, can be considered identical

• Two similar biologics can trigger very different immunogenic response

• Can have clinical consequences and does create putative health concerns

Different processes make different products

• The manufacturing process cannot be duplicated – two biologics produced by different processes cannot be the same

• Analytical characterization is not sufficient to predict clinical safety & efficacy, immunogenicity is a key safety issue

• Biosimilars approval requires proof of similarity in terms of quality, efficacy and safety by direct comparison with a reference product

Size, Structure & ComplexitySmall molecule

drug

Size

Com

plex

ity

Large moleculedrug

Human growth hormone

(hGH)~ 3,000 atoms

Car~ 3,000 lbs

Large biologic

IgG antibody~ 25,000 atoms

Business jet~ 25,000 lbs (without fuel)Bike

~ 20 lbs

Aspirin21 atoms

14

Intended Copies/Biosimilars of Biotech Products

A different manufacturer uses...Human Gene Sequence

Maybe the same gene sequence

DNA Vector

DNA Vector

ATG

Stop

Probably a different DNA vector

Host Cell Expression

A different recombinant production cell

Fermen-tation

A different fermentation process

Purifica-tion

A different downstreaming protocol

Ultrafiltration

Bulk Filling

Depth Filtration

Column2Column1

Drug ProductManufacturing

Cell free supernatant

Column3

Down stream processing (Purification)(Includes cell removal-, removal of HCP and HCDNA, viruses, medium components, removal of related substances (oxidated-, aggregated-, deamidated- and other truncated forms), concentration-steps, buffer-exchange)

Biotech Products Manufacturing

Biosimilars | Biologics manufacturing

The proprietary process is the product

Relatively easy to reproduce exactly

Manufacturing based on unique cell lines Processes are very complex and difficult to reproduce Changes may lead to different clinical efficacy and safety

GenericsFollow-on products of traditionalchemical pharmaceuticals are exactchemical copies

BiosimilarsSimilarity has been shown in terms ofquality, safety and efficacy to theoriginatorThere are no ‘bio-generics’, there areonly similar products

Regulation of Biosimilars

• Biosimilars are subject to an approval process

• Requires substantial additional data to that required for chemical generics

• Sound clinical data on safety & efficacy

• Preclinical testing or human trials

• Introduction of biosimilars also requires a specifically designed pharmacovigilance plan

Regulation of Biosimilars

• Clear focus on quality, safety and efficacy of biological products

• Intended copy of a biological product deserves the qualification of biosimilar

• Manufacturer has to provide scientific similarity evidence (burden of proof)

• We have to duly consider the broad spectrum of molecular complexity

Regulation of Biosimilars

• In Europe companies having biosimilars need to have a system to regularly monitor efficacy & safety of the product on long term basis

• Safe application of biologics is also dependent on an informed and appropriate use by healthcare professionals and patients

Regulatory Pathway

Biosimilars of Insulin, Erythropoietin and Growth hormones are available in the Europe, but all have gone through the mandatory procedure to prove their efficacy, safety & compatibility.

Regulation of Biosimilars

In Europe the pathway is based on:• Thorough demonstration of "comparability" of the

"similar" product to an existing approved product In US:• President Obama signed into law health care reform

legislation entitled the “Patient Protection and Affordable Care Act” on March 23, 2010

• Legislation provides FDA with a framework for approving biosimilars based on similarity to a reference biologic product, but leaves it up to FDA to determine how much data are needed.

EU Guidelines EMA/CHMP

• Similar biological medicinal products are not generic medicinal products

• Expected that there may be differences between similar biological medicinal products from different manufacturers or compared with reference products

EU Guidelines EMA/CHMP

• Similar biological medicinal products are manufactured and controlled according to their own development

• An appropriate comparability exercise will be required to demonstrate that the similar biological and reference medicinal products have similar profiles in terms of quality, safety and efficacy

Biosimilars rejected or withdrawn

Alpheon biosimilar of Roferon-A (IFN-alpha-2A):

Rejected by EMA in 2006 for following reasons • Quality and clinical difference with reference product• Inadequate data on stability of active substance• Inadequate validation of process for finished product• Insufficient validation of immunogenicity testing

Biosimilars rejected or withdrawn

Marvel insulin biosimilar of Humilin withdrawn Withdrawn by Marvel for following CHMP concerns: • Comparability with reference product (Humilin, Eli Lilly)• Insufficient information on active substance• Inadequate validation of process for finished product

Biosimilars rejected or withdrawn

Comparability not alone but other issues such as validation of analytical tools may also be required

for approving Biosimilar products

EU Data Requirements for the Approval of Biosimilars

• “It is important to note that biotherapeutics which are not shown to be similar to a RBP as indicated in this guideline should not be described as “similar”, nor called a “SBP”. Such products could be licensed through the usual processes using a more extensive non-clinical and clinical data set or full licensing application.”

The WHO Guidelines on Biosimilars

EMA Draft Guideline on mAbsLanguage on extrapolation

• Extrapolation of Indications Section:– “If a reference mAb is licensed both as an immunomodulator and

as an anticancer (cytotoxic) antibody, the scientific justification as regards extrapolation between the two (or more) indications is more challenging.”

– “For the mechanism of action, e.g. the depletion of immune cells, several mechanisms may play a role, and at present stage of knowledge it cannot be assumed that the same mechanisms of cell depletion are of the same importance in different disease states.”

• Executive Summary Section:– “Extrapolation of clinical efficacy and safety data to other

indications of the reference mAb, is possible based on the results of the overall evidence provided from the biosimilarity exercise and with adequate justification.”

FDA View on Extrapolation of Indications

(Draft Guidance, February 2012)Scientific Justifcation Should Address:• The MOA (s) in each condition of use for which licensure is sought; this may

include the following– The target/receptor(s) for each relevant activity/function of the product– The binding, dose/concentration response, and pattern of molecular signaling

upon engagement of target/receptor(s)– The relationship between product structure and target/receptor interactions– The location and expression of the target/receptor(s)

• The PK and bio-distribution of the product in different patient populations; PD measures may provide important information on the MOA

• Differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to the pharmacological activity of the product or to off-target activities

• Any other factor that may affect the safety or effectiveness of the product in each condition of use and patient population for which licensure is sought

EMA View on Interchangeability

• Advice from EMA (Doc. Ref. EMEA/74562/2006, June 2007):– Biosimilars cannot be considered identical to their

biological reference products– Decision to treat a patient with either should be made

by a qualified healthcare professional• Fifteen countries across Europe have brought in new rules

to prevent automatic substitution of biological medicines by biosimilars (Source: APM Health Europe, 21 February 2008).

FDA View on Interchangeability fromDraft Guidance on Biosimilars (Feb 2012)

• An interchangeable product must be shown to be biosimilar to the reference product and meet the other standards described in section 351(k)(4) of the PHS Act.

• At this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment.

• FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product

Patent

A patent is a set of exclusive rights granted to an

inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention

Pharmaceutical Patent

• A pharmaceutical patent is a patent for an invention in the chemical or pharmaceuticals industry

• Patents are particularly important to protect the large investments that are necessary to develop drugs

Pharmaceutical Patent

• The "originator" companies are active in research, development, manufacturing, marketing and supply of innovative medicines

• These are usually subject to patent protection, needed to provide a reward for innovation and incentives for future research

The Purpose of the Patent System

Society’s View:• To promote progress of science and useful arts by

incentivizing the disclosure of inventions• It encourages Innovation that is beneficial to the economy

Corporate View:• Protect investments into research and development of new

products

Importance of Intellectual Property Rights

• With our discovery, development and delivery of new medicines and diagnostics we help to treat serious and life-threatening diseases

• With its business model, Roche is dependent on intellectual property rights and their efficient protection

No unfair claims

• No unsubstantiated comparisons

• No claims of efficacy beyond an approved label

• No claims of safety beyond an approved label or the balance of scientific evidence

• No claim of similarity if a manufacturer can not provide the required scientific similarity evidence

Cheap price :Expensive for the patient

• It is more important to look in to the efficacy & safety of the product than only price.

• Any biosimilar without established clinical efficacy & safety data can prove to be EXPENSIVE for patients as immunogenic response of biological products is unpredictable.

Messages/Conclusions

• There is a need for a consistent and efficient approach to regulation of biosimilars

• There is no compromise on quality and safety of biosimilars

• There is a need for knowledge and experience sharing between regulators (coordinated by WHO)

• Stakeholders should aim for global consistency and harmonization

• Transparency, open dialogue and education are key to a robust regulatory framework

Q & A

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