19. Agnes Klein - Health Canada

Helping the people

of Canada maintain and

improve their health

Aider les Canadiens et

les Canadiennes à maintenir

et à améliorer leur santé

Draft

Diversity of Approaches to the Interchangeability

and Substitutability of Biosimilars

Agnes V Klein, MD DPH

Jian Wang, MD PhD Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics

Biologics and Genetic Therapies Directorate

Health Canada

November, 2013

•August 22, 2007

•8:45-11:45

•Banting Theatre

Health Products and Food Branch

Highlights

What are the differences?

Biologics vs pharmaceuticals

Biosimilars vs generics

Interchangeability for biosimilars

A diversity of approaches to interchangeability

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Health Products and Food Branch

Sensipar ® (chemical drug)

molecular size (weight = 393)

Enbrel ® (protein drug)

molecular size (weight = 150,000)

Biologics, unlike pharmaceuticals, are derived from a variety of expression

systems (e.g. human, animal, microorganism, cell culture) or produced using

recombinant DNA technology. Examples of biological products: hormones, blood products, cytokines, growth factors,

vaccines, gene/cellular therapies, fusion proteins, monoclonal antibodies, etc.

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Health Products and Food Branch

Pharmaceuticals vs Biologics

Pharmaceuticals Biologics

Method of synthesis Chemical Living organism or cells

Molecular Size Small Large

Structure Usually fully known Complex, frequently

partially unknown

Susceptibility to

contamination during

manufacturing

Low High

Sensitivity to physical

factors (e.g., heat, light) Low Higher

Manufacturing methods Relatively simple Complex

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.

Health Products and Food Branch

Biologics vs Pharmaceuticals

Biologics Pharmaceuticals

Molecular weight Large Small

Species* Specific Independent

Immunogenicity* Antigenic (MW>10kDa) Non antigenic (generally)

ADME

absorption* Slower (s.c., i.m.) Faster

distribution Low/Limited High

metabolism Catabolized to endogenous

amino acids

Metabolized to non-active and

active metabolites

disposition* Often target-mediated Rarely target-mediated

PK profile* Non-linear (often) Linear (frequently)

Half-life Long Short(er)

Safety Exaggerated pharmacology Toxicity (variable

mechanisms)

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Health Products and Food Branch

Regulatory Pathways for Biosimilars

• It is widely accepted by global regulatory agencies and the biotech

industry that biosimilars cannot be identical copies of the innovator

products

• Inherent differences require different regulatory considerations and

guidelines tailored to biosimilars

• Many countries as well as WHO have published guidance documents on

how to regulate biosimilars

• In Canada, biosimilars are regulated as New Drugs by comparison with a

reference product previously authorized and marketed in Canada

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Health Products and Food Branch

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Biosimilars Generics

Regulatory Pathway NDS ANDS

Drug Substance Similar to reference Identical to reference

(Pharmaceutical

equivalence)

Comparative non-Clinical Required Not required

Comparative PK/PD Similar PK/PD profile Pharmacokinetic (PK)

equivalence (formal

declaration)

Comparative Clinical Trial At least one Not required

Efficacy/Safety No meaningful difference Therapeutic equivalence

Indication extrapolation Case by case Automatic

Interchangeability Generally no Yes

Biosimilars vs Generics

Health Products and Food Branch

Post-market traceability: Biosimilars Made by Many

Companies

Sandoz, the generic drug division of Swiss drug giant Novartis AG, is determined to lead the biosimilar field

Amgen Inc, the world's largest biotechnology company, and generic drugmaker Watson Pharmaceuticals Inc will work together to develop and sell biosimilar versions of several biotech cancer drugs

Pfizer, the world‟s biggest pharmaceutical firm, will work with Biocon, India‟s largest biotech company, to bring “biosimilar” insulin treatments to market

Merck & Co is to develop its own version of Pfizer‟s ageing arthritis drug Enbrel with a South Korean manufacturer, Hanwha

Korean electronics giant Samsung had entered into a biosimilars joint venture with US biotechnology company Biogen Idec

Apotex Inc., the largest Canadian-owned generic pharmaceutical company and Intas Biopharmaceuticals Limited of India have extended their business agreement to develop a biosimilar version of pegfilgrastim (PegG-CSF)

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Health Products and Food Branch

Interchangeability declaration by HC

• Regulations: Health Canada doesn‟t declare interchangeability neither for

generics nor for biosimilars (Called Subsequent Entry Biologics, SEBs in

Canada))

• Health care: Interchangeability remains a provincial decision in Canada

• Clinical Practice: The decision to treat a patient with an originator‟s

product or a biosimilar is within the authority of a qualified healthcare

professional, and in the best interest of his/her patient/s

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Health Products and Food Branch

Health Canada’s Position re Interchageability

• In a 2010 letter to Provincial Drug Plans concerning its guidance

on the market autorisation of SEBs, Health Canada stated:

SEBs are not “generic” biologics, and authorization of an SEB is not

a declaration of pharmaceutical or therapeutic equivalence to the

reference biologic drug.

Reminding plans that, as a result of manufacturing drift, Health

Canada “… does not support automatic substitution of an SEB for its

reference drug …”.

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Health Products and Food Branch

Interchangeability vs. Substitutability (Canada)

• Not all regulators define the two terms ad distinct: in Canada, terms

are defined under various provincial laws, for example:

“Interchangeability” generally refers to the requirement to “interchange” a

lower cost generic version of a name brand drug (a „cost-driven‟

decision)

(A condition for designation is that the drugs must be bioequivalent)

“Substitutability” or “therapeutic substitution” generally refers to

substituting an altogether different drug as „functionally‟ equivalent to a

prescribed drug for treating the same condition (a medical decision)

• The situation is highly dependent on the specifics of the law, and

each province has different definitions of “interchangeability”

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Health Products and Food Branch

Therapeutic Interchangeability or Substitution

“Therapeutic interchangeability or substitution” could be supported by

specifically designed clinical trials for each indication, for example

Switch over Follow-up

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Efficacy/Safety/

Immunogenicity

results

Biosimilar

Reference

•Reference Reference Reference

Reference

Biosimilar

Health Products and Food Branch

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In the EU, decisions

on the

interchangeability or

substitution of

biosimilars and

originator biologics

are not made by

EMA but at each

national level

(Fifteen nations

have prohibited

automatic

substitution)

While the FDA can

designate a

biosimilar as

interchangeable

with its reference

originator product ,

the individual states

govern the practice

of pharmacy

including drug

substitution laws

Health Canada

doesn‟t declare

interchangeability

neither for generics

nor for biosimilars.

Interchangeability

remains a provincial

decision in Canada.

Interchangeability vs. Substitutability (Global)

Health Products and Food Branch

Interchangeability under U.S. Legislation (FDA)

• Under U.S. legislation, Interchangeable or Interchangeability

means:

The biological product is biosimilar to the reference product;

It can be expected to product the same clinical result as the

reference product in any given patient; and

For a biological product that is administered more than once to an

individual, the risk in terms of safety or diminished efficacy of

alternating or switching between use of the product and its

reference product is not greater than the risk of using the reference

product without such alternation or switch.

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Health Products and Food Branch

Interchangeability under U.S. Legislation (States)

• Some states are proposing or moving to vote on amendments to

their generic-equivalent laws to include guidance on biosimilars

• These amendments intend to establish that pharmacies can only

substitute if the FDA licenses a biosimilar as interchangeable and

then only if the physician does not specify “brand medically

necessary.”

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Health Products and Food Branch

Conclusions

• A Biosimilar is not identical to the reference biologic

• Each country has its own approach to interchangeability of

biosimilars based on the national or local law

• In contrast to a regulatory decision process on interchangeability,

substitution (or interchangeability) of biosimilars is an

administrative process (different in every country), which allows

pharmacies to substitute a prescribed product with another

“equivalent product”

• In many countries, automatic substitution of biosimillars is not

recommended

16

Helping the people

of Canada maintain and

improve their health

Aider les Canadiens et

les Canadiennes à maintenir

et à améliorer leur santé

Draft

Thank you Merci

[email protected]

613-954-5706