28. dr. jiang wang - health canada

Helping the people of Canada maintain and improve their health

Aider les Canadiens et les Canadiennes à mainteniret à améliorer leur santé

Draft

Biosimilars: Variable Approaches to Interchangeability and Substitutability

Jian Wang, MD PhDAgnes V Klein, MD

Centre for Evaluation of Radiopharmaceuticals and BiotherapeuticsBiologics and Genetic Therapies Directorate

Health Canada Moscow, May 15-16, 2013

•August 22,

2007•8:45-11:45•Bantin

g Theatre

Health Products and Food Branch

Highlights

Biologics are different from pharmaceuticals

Biosimilars are not generics

Health Canada does not declare interchangeability for biosimilars

Global regulators have different approaches to interchangeability

2


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.

3


Differences between Pharmaceuticals and 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

4

.


Differences between Biologics and PharmaceuticalsBiologics 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)

5


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 and 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

6


7

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

Differences between Biosimilars and Generics


Concerns with Automatic Substitution/ Interchaneability• Quality: Two biologics can not be exactly the same. Minor differences in

the process used to produce biosimilars can lead to profound differences in clinical activity and side effect profile that may not become apparent until the product is in widespread use

• Safety: As a consequence of their complexity and impurity profile, automatic interchangeability of biologics or biosimilars could give rise to different (and sometimes unexpected) clinical consequences

• Immunogenicity: The immunogenicity of biosimilars cannot be fully predicted using preclinical/clinical studies. Repeated switches between the biosimilar(s) and originator’s product may increase immunogenicity with potentially negative effects

• Clinical: A biosimilar may not receive all indications or uses• Lack of reliable post-market traceability: It is necessary for analyzing

the cause when an adverse drug reaction occurs (see next slide)

8


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)

9


No 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)

10


Health Canada’s Position towards Interchaneability

• In a 2010 letter to Provincial Drug Plans concerning its guidance on approval of SEBs, Health Canada stated as follows:

SEBs are not “generic” biologics, and authorization of an SEB is not 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 a SEB for its reference drug …”.

11


Interchangeability vs. Substitutability (Canada)

• 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 of 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 provincial law and each province has different definitions of “interchangeability”

12


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

13

Efficacy/Safety/ Immunogenicity

results

Biosimilar

Reference

• Reference Reference Reference

Reference

Biosimilar


14

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)


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.

15


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.”

16


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 laws

• In many countries, automatic substitution of biosimillars is not recommended

17

Helping the people of Canada maintain and improve their health

Aider les Canadiens et les Canadiennes à mainteniret à améliorer leur santé

Draft

Thank youMerci

спасибо

[email protected]

mailto:[email protected]

28. dr. jiang wang - health canada

Health & Medicine