30. dr. jaap venema - abbvie

Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars

Jaap Venema, Ph.D.

Senior Director Biotherapeutics, Global Medical Affairs

BIOTHERAPEUTIC MEDICINES. Regulatory challenges and current practices. Approaches for harmonization.

MOSCOW, 16 MAY 2013

Biologicals and Biosimilars

Interchangeability & Substitution:DefinitionsRegulatory PerspectiveClinical Perspective

Summary and Conclusions

Molecular Complexity of Biologicals

MW: 144.2Formula: C8H16O2


MW: 747.95Formula: C38H69NO13

Clarithromycin (BIAXIN™)Valproic Acid (Depakote™)

MW: 18,464.5Formula: C821H1331N233O238S5

Human Erythropoietin (EPOGEN™)

MW: 148,683.5Formula: C6,440H9,928N1,704O2,011S56

1IGT

Antibody Structure

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Antibody Structure

Molecular Weight: 148,683.5 [g/mol]Molecular Formula: C6,440H9,928N1,704O2,011S56

•Four light chain domains

•Eight heavy chain domains

•Four inter-chain disulfide bonds

•Twelve intra-chain disulfide bonds

Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 4

Antibody Glycosylation


•N-Linked Oligosaccharide

- Naturally occurring post-translational modification

- Stabilizes CH2 domain

- Important determinant of Fc effector function

- Can alter pK

NA2F/Gal 2

GlcNAcGalManFucNeuAc

GlcNAcGalManFucNeuAc


Antibody Heterogeneity


• Primary Sequence Variants

• N-terminal heterogeneity

• Splice variants

• Mutations and mistranslations

•Chemical Variants

• Met oxidation

• Asn deamidation

• Isomerization

• Thioether formation

• Free –SH

• Scrambled disulfides

• Pyroglutamate formation

• Post-translational modifications

• O-linked glycoforms

• Glycation

• C-terminal lysine cleavage

Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars6

Antibody Stability


• Physical Stability

• Aggregation

• Fragmentation

• High Concentration Stability

• Thermodynamic Stability

• Chemical Stability

• Turbidity

• Viscosity


6,440 Carbon Atoms Are a Lot to Track

• Few intact antibody structures have been solved

• Rarely is detailed structural information available to help guide process development

• Differences frequently occur ina subpopulation of molecules further complicating analytical studies

Molecular Weight: 148,683.5 [g/mol] Molecular Formula: C6,440 H9,928 N1,704 O2,011 S56 (Anti-canine lymphoma monoclonal antibody “MAb 231”)


Harris LJ, Larson SB, Hasel KW, McPherson A. Biochemistry. 1997 Feb 18;36(7):1581-97.

What is important functionally?What is important functionally?

We don’t know unless identified and clinically tested!

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Carbo-hydrates

Protein Function Is Highly Dependent on Final Configuration

Modified from Access Excellence of the National Health Museum (http://www.accessexcellence.org/)

Amino Acids

Alpha HelixPleaded Sheet

Pleaded Sheet

Alpha Helix

Protein Science of Biosimilars. Nephrol Dial Transplant (2006)[Suppl 5]: v4-v8Protein Science of Biosimilars. Nephrol Dial Transplant (2006)[Suppl 5]: v4-v8

Protein’s Higher Order Structure - Ideally the Same

Protein’s Higher Order Structure - Ideally the Same

Post-Translational Modifications - Will be DifferentPost-Translational Modifications - Will be Different

Mechanism(s) of Action?PK/PD?

Tissue Distribution?Efficacy?Safety?

Immunogenicity?

}

9Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars

Two Different Processes CreateTwo Non-identical Biologic Products

Typical Protein Production Process

EN

DE

ND

Different biophysical Different biophysical characteristics in final characteristics in final productproduct

Different downstream processing

STARTSTARTBoth may use Both may use

the same the same gene gene

sequencesequence

Different fermentation/ culture conditions


Knowledge of and Input in Biologic and Biosimilar Manufacturing


Innovator: In Process Testing Data From Every Process Step

Cell Bank Bioreactor Harvest Chromatography1, 2, 3

Virus Filter ConcentrationBottling

Biosimilar: Final

Product Data

PurificationCell Culture Final Dosage Form

For comparability, the innovator has a rich testing database from every in process step of every batch, the biosimilar only has access to the final product

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Biosimilars: Similar But Not the Same

• Biosimilars manufactured by different manufacturers will differ from the innovative product and from each other

• They are not generic biologics

• They use a different process to develop the biosimilar product

• The active ingredient of a biosimilar can at best only resemble that of theoriginal biologic

• This is recognized in regulatory guidances by EMA1 and FDA2


1, Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.2. Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues EMA/CHMP/BWP/49348/2005.

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Interchangeability, Substitution and Switching• Interchangeability - Health Regulatory Authority Designation

• Expected to produce the same clinical result as the reference product in any given patient

• Repeated switching between biosimilar and reference product presents no greater safety or efficacy risk than continued use of the reference product

• Substitution – Pharmacist Action

• When a pharmacist substitutes a certain prescribed product by another equivalent product

• If without the prescribing physician’s permission or knowledge, it is considered “automatic” or “involuntary” substitution

• Switching - Treating Physician Decision

• When a prescribing physician changes medication


Interchangeability and Substitution for Generics

• For generics, pharmaceutical equivalence = therapeutic equivalence

• Regulators designate the two as interchangeable

• Depending on local or institutional rules, pharmacists may be authorized or even required to substitute a generic for the original without informing the prescribing physician (automatic substitution)


• For biosimilars pharmaceutical equivalence ≠ therapeutic equivalence

• Therefore, granting biosimilar status by a regulator does not imply interchangeability, and therefore automatic substitution is not allowed

• Depending on the regulatory agency, interchangeability has to be shown by the BS sponsor

Interchangeability and Substitution for Biosimilars


US1

FDA requirements to meet interchangeability threshold still unclear, automatic substitution of interchangeable drugs to be determined at state level.

US1

FDA requirements to meet interchangeability threshold still unclear, automatic substitution of interchangeable drugs to be determined at state level.

Japan3

Interchangeability and automatic substitution highly discouraged

Japan3

Interchangeability and automatic substitution highly discouraged

EMA2

Decision on automatic substitution left to member states - no country has explicitly authorized it

EMA2

Decision on automatic substitution left to member states - no country has explicitly authorized it

Brazil4

Developed guidelines for biosimilars, but has not yet

addressed interchangeability or automatic substitution

Brazil4

Developed guidelines for biosimilars, but has not yet

addressed interchangeability or automatic substitution

Australia5

Not applying substitution at this time, but may consider in the future

Australia5

Not applying substitution at this time, but may consider in the future

1: FDA Biosimilar Guidance Webinar, February 15, 2012; 2: EMA, Questions and Answers on biosimilar medicines; European Biopharmaceutical Enterprises (EBE) Survey on Biosimilars, May 2011; 3: MHLW Guideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products, March 2009 ; 4: FDLI Update, July 2012; 5: Discussion paper on Similar Biological Medicinal Products (SBMPs), Australia PBS; 6: Health Canada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010

Interchangeability and Automatic Substitution Worldwide


Canada6

Health Canada does not support automatic substitution, but allows provinces to determine interchangeability

Canada6

Health Canada does not support automatic substitution, but allows provinces to determine interchangeability

Following passage in 2009 of the Biologics Price Competition and Innovation Act (BPCIA), FDA allows automatic substitution of “interchangeable” biosimilars

Under U.S. law, interchangeable means:

--FDA Biosimilar Guidance Webinar, February 15, 2012


US FDA

FDA Biosimilar Webinar

• the biological product is biosimilar to the reference product

• it can be expected to produce the same clinical result as the reference product in any given patient

• for a product administered more than once, the safety and reduced efficacy risks of alternating or switching are not greater than with repeated use of the reference product without alternating or switching


EU EMA

The EMA’s evaluations do not include recommendations on whether a biosimilar should be used interchangeably with its reference medicine:

• the MA dossier does not contain evidence to substantiate an interchangeability determination, thus;

• the granting of an MA for a biosimilar does not imply that the biosimilar is interchangeable or substitutable with its reference (or other biologics)

• “For questions related to switching from one biological medicine to another, patients should speak to their doctor and pharmacist.”

However, the legal decision on interchangeability is left to member states

--EMA Questions and answers on biosimilar medicines, Sept 2012

EMA Q&A on Biosimilars


European Commission Consensus Information Paper 2013

“It is important to note that biosimilar market uptake has been possible despite the fact that substitution between the biosimilar and its reference medicinal product is not practiced at the pharmacy level.

The decision on whether to substitute a biological medicinal product lies outside the remit of the EMA/CHMP and is the responsibility of the relevant competent authorities within each EU Member State. Since October 2011, pharmacists in Germany may substitute, within the framework of the aut idem substitution, biotechnologically manufactured products among each other which (a) have been approved with reference to the same reference product and which (b) have been produced by the same manufacturer with the same manufacturing process. The only difference between such substitutable products is their trade name.

At the point in time of publication of this consensus information paper, no country has explicitly authorized the substitution of biological products from different manufacturers, and a number of EU Member States have put legal, regulatory, and political provisions in place that prevent this practice.”

Consensus Information Paper 2013. What you need to know about Biosimilar Medicinal Products. http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf

FDA – Scientific Principles of Biosimilar Interchangeability

• The possible adoption of scientific standards for biosimilar interchangeability is unique to the US FDA

• The biosimilar applicant must demonstrate through comparable switching studies that:

• their product is biosimilar to the reference product (the foundation)

• it can be expected to produce the same clinical result as the reference product in any given patient

• (in case of multiple dosing) the risk in terms of safety or diminished efficacy of alternating or switching between use of the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch

*Biologics Price Competition and Innovation Act of 2009 (BPCIA) – U.S. Law


Interchangeability – Key Considerations


Factors to consider in support of substitution in “Any Given Patient”:

•Safety signals during biosimilar development•Known safety issues with reference product•Immunogenicity risk (frequency, severity, anti-drug antibodies)•Safety and efficacy in different indications, especially when indication extrapolation has occurred•Subpopulations with distinct efficacy or safety issues (e.g. pediatric)•Statistical power to demonstrate equivalent safety and efficacy•Sensitivity of the population or drug to minor changes (e.g. narrow therapeutic index drugs)

Clinical evidence should contribute to totality of the evidence and be based on a rigorous risk assessment

Interchangeability - Switching Study Design 1

• Switching studies should follow a cross-over design:

• For chronic diseases, both naïve patients and patients on stable treatment should be studied

BiosimilarBiosimilar

Reference ProductReference Product


Interchangeability - Switching Study Design 2

• Switching studies should also address alternating (i.e. switching more than once)

• Issues with Switching Study Designs:• Carry-over effect due to long half lives of most biologics

• Ethical and clinical feasibility of long wash-out period

• Change in clinical status of the patient over time

• Absence of benefit/deterioration of disease state generated by investigational treatment regimen

• Recruitment issues

BiosimilarBiosimilar

Reference ProductReference Product


Interchangeability - Switching Study Considerations

• Study duration should be sufficient to capture:

• Equivalent efficacy

• Time course of pre-defined safety events

• Study size and statistical power should ensure:

• demonstration of equivalent efficacy

• detection of critical safety events including loss of efficacy

• Immunogenicity should always be assessed

• Drug neutralization or loss of efficacy is one of the major risks associated with switching

• The choice of biologic treatments is often limited for many diseases/patients – lost ground is lost forever

• Detection of rare events should be justified by a risk-based approach, including extended “post-interchangeability designation” studies


Interchangeability and Extrapolation

• Interchangeability/Substitution cannot be extrapolated from one tested indication or, if pertinent, a specific patient population to another non-tested one• Clinical data from controlled switching studies should be required for

each labeled indication

• A biosimilar may be designated interchangeable in one indication when interchangeability has been demonstrated for all routes of administration of the reference product for that particular indication• However, this may create confusion if products are deemed

interchangeable in one indication, but not in the other


Interchangeability – Post Designation and Pharmacovigilance

• Accurate tracking and tracing of adverse events• Substitution between biopharmaceuticals with similar substances may

further complicate the linking of an adverse event to a specific drug

• Post-marketing surveillance plans should distinguish between treatment emergent events (including loss of efficacy) due to the biosimilar or to the reference product

• Distinct non-proprietary name for biosimilars could help tracking of adverse events, but would not solve the tracing issue


Interchangeability and Substitution of Biosimilars

• Current science does not justify interchangeability and substitution for any biologic, including biosimilars

• Approval of a biosimilar product should not be intended to allow for interchangeability and/or (automatic) substitution with their reference product

• Demonstration of interchangeability requires higher standards and additional clinical data in all indications, and if pertinent, patient populations for which biosimilar approval is sought

• Switching studies are complex for technical and ethical reasons and very little data is available on this topic

• No studies with switching as the primary endpoint have been performed to date comparing a biosimilar to its reference product

• Only a treating physician who has carefully evaluated the consequences of a patient’s response to approved biotherapeutics should make the decision to alter a treatment regime


Thank you!Большое спасибо!


30. dr. jaap venema - abbvie

Health & Medicine

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