biosimilars in canada: does the process differ from other...

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Biosimilars in Canada: does the process differ from other countries? Agnes V. Klein, MD Director, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Biologics and Genetic Therapies Directorate Health Canada Toronto, Sep 16, 2014

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Biosimilars in Canada: does the process differ from other countries?

Agnes V. Klein, MD Director,

Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics Biologics and Genetic Therapies Directorate

Health Canada

Toronto, Sep 16, 2014

Points for Consideration

• Regulations and related considerations

• General Data Requirements for SEB Marketing Authorization

• Extrapolation of Indications

• Interchangeability/substitutability

• Immunogenicity; Risk-Management Plans; Post-market considerations and relationship to the naming of SEBs/biosimilars

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Canada’s Regulatory Framework

Clear regulatory framework for drugs and biologics under the Food and Drugs Act

Act gives authority to make regulations – Food and Drug Regulations : clinical trials, pre-and post-market requirements, cGMPs, establishment licenses

Schedule D (for biologics) to the Food and Drugs Act (R.S.C., c.F-27, 1985) can be traced back to 1927: currently considered outdated as it is too specific and is based on “old science”

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Filing SEB (biosimilar) Submissions in Canada

A SEB/biosimilar can be filed in Canada when

Patent(s) for the chosen reference has/have expired

Data protection ended at 8 years (6 year no

filing period; a 6-month pediatric

extension to the 8-year term) or

Patent owner waives its rights

– SEBs are regulated as “New Drugs” by comparing to a reference product previously authorized and marketed in Canada with a reduced non-clinical and clinical package

– The basis for accepting a reduced non-clinical and clinical data package for an SEB hinges on demonstrated similarity between the SEB and the suitable Reference Biologic Drug (RBD) [the two active ingredients are highly similar]

– SEBs are not generics (because biologics are more complex, SEB manufacturers cannot guarantee that their version is exactly identical to the original innovator's version). Authorization of an SEB is not a declaration of pharmaceutical or therapeutic equivalence to the RBD

– Once a Notice of Compliance (NOC) is issued, the SEB is a new biologic drug and regulated accordingly. However, an SEB cannot be used as a RBD for another SEB submission

Key Policy Statements

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History of SEB Regulation in Canada

2005 Working group for SEBs was created

2006 Fact sheets published

2008 Draft Guidance document released

2009 Revised Guidance document released

2010 Finalized Guidance released

2014* Process in place to update the Guidance document based on lessons learned

2005 First biologic (G-CSF) developed with the SEB concept rejected

2009 First SEB growth hormone authorized

Since 2011 >10 pre-market consultations for SEBs

2012-13* 8 SEB submissions (including one that is regulated in Canada as a stand-alone product)

2014* First SEB mAb authorised

Current** >20 SEB clinical trial applications in Canada

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ISSUES AND CONSIDERATIONS • Unexpected approaches to RBD, requiring unique

solutions to the acceptability of a non-Canadian reference product

• Unique approach to extrapolation as will be seen later

• Using ICH guidelines and stepwise building on knowledge acquired by experience

• Approach to number of clinical trials, to their design and validity for extrapolation to other indications

• Head to head comparisons: using the same or different RBD

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Biologics SEBs Generics

Regulatory Pathway New Drug Submission (NDS)

NDS Abbreviated NDS

Drug Substance New API (reference) Similar to Canadian reference

Identical to reference (Pharmaceutical equivalence)

Non-Clinical Study As required by ICH S6 (R)

Reduced and comparative to reference

Not required

PK/PD Study Standard PK/PD studies

Similar PK/PD profile to reference

Equivalence PK profile to reference

Clinical Trial Required for all indications

Comparative for at least one indication

Not required

Efficacy/Safety Establishing evidence of safety and efficacy

No meaningful difference to reference

(Declared therapeutic equivalence)

Indication Extrapolation

Not allowed Case by case Automatic/required?

Regulatory and Clinical Approaches for SEBs

Quality: How Similar is Similar Enough

Comparative Analytical Characterization (FDA draft PK/PD guideline) • Not similar • Similar

• Needs additional information to determine if highly similar (e.g., additional analytical data, or other studies to determine if observed differences are within an acceptable range to consider the proposed biosimilar product to be highly similar to the reference product)

• Highly similar • Permits the sponsor to conduct targeted and selective animal and/or

clinical studies to resolve residual uncertainty and support a demonstration of biosimilarity

• Highly similar with fingerprint-like similarity • Permits a more selective and targeted approach to demonstrate

biosimilary

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Clinical Trials: Canadian approach

• Equivalence trial is preferred over non-inferiority trial (Suggested superiority in a non-inferiority setting would raise questions about the comparability of the two products)

• ICH defines an equivalence trial as a trial designed to show that two interventions do not differ in either direction by more than a pre-specified insignificant margin (i.e., a two-sided test)

• This equivalence margin is the largest difference that can be judged as clinically acceptable for the SEB and should be smaller than differences observed in superiority trials of the reference

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SensitiSensitive Population and Sensitive Study Endpoint

• The sensitive population is the population in whom potential differences between a SEB and a reference product can be most easily detected and study outcomes can be used to support extrapolation of indications

• The study should be conducted using a clinically relevant and sensitive endpoint to detect potential differences which could be different from the innovator's original study endpoint(s), e.g., a well established surrogate or a more sensitive endpoint

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First Canadian Authorized SEB: Omnitrope

Same Indications as Canadian

reference product Adult

Authorized: Treatment of adults with either adult onset or childhood onset GHD based on extrapolation

Pediatric

Authorized: Treatment of children with growth failure due to growth hormone deficiency (GHD) based on clinical data,

Not authorized (Non-Canadian indications:

Prader-Willi Syndrome, Small for Gestational

Age, Turner Syndrome, and Idiopathic Short

Stature)

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Extrapolation of Indications: Other Factors

Study population: age, sex, and race • Should be similar between studied indications and indications for

which extrapolation is necessary (e.g. direct extrapolation from adult to pediatric is unlikely to be acceptable)

Pivotal trial duration, route of administration and dosage range • Should be similar: very unlikely that extrapolation to a different

route or dosage would be permissible/acceptable if there is no PK/PD bridging study

Safety/Immunogenicity profile • Differences in immunogenicity between indications/uses should be

considered • Extrapolation between two indications with very different

immunogenic profiles would not be likely (e.g. infliximab monotherapy vs. infliximab combination therapy).

Monotherapy/combination therapy • monotherapy should be used to support extrapolation if it is

feasible

First monoclonal antibody authorised:

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Indications for Canadian

Reference Product

rheumatoid arthritis (RA) ankylosing spondylitis (AS)

psoriatic arthritis (PsA) plaque psoriasis (Ps) Crohn’s disease (CD) ulcerative colitis (UC) pediatric CD and UC

Indications for SEB based on Clinical

Data

rheumatoid arthritis (RA) ankylosing spondylitis

(AS)

Indications for SEB based on

Extrapolation

psoriatic arthritis (PsA) plaque psoriasis (Ps)

Extrapolation of Indications: Allowed

• The indications for psoriatic arthritis and plaque psoriasis were extrapolated on the basis of similarity and the absence of meaningful differences, between the SEB Mab and the reference product, in: • product quality, • mechanism of action, • disease pathophysiology, • safety profile, • dosage regimen and • on clinical experience with the reference product

• Scientific rationales submitted by the sponsor were found to be adequate to support extrapolation to the indications and uses pertaining to the arthritic diseases: psoriatic arthritis and plaque psoriasis;

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Extrapolation of Indications: not authorised

• Extrapolation to indications and uses pertaining to Crohn's disease and ulcerative colitis could not be recommended because the comparability between the reference and the SEB Mab indicated insufficient similarity between the two products

• This arose from the observed differences in the level of afucosylation, FcγRIIIa receptor binding, and some in vitro Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) assays

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Extrapolation of Indications: Why Not Allowed

Quality Concerns Comparability to the reference was considered adequate for those situations where the

mechanism of action depends exclusively on its binding to TNFα receptors Where the mechanism of action is not yet clearly defined and because comparability

was not considered to be sufficient and where the mechanism included a role for ADCC it could not be clearly or conclusively determined that extrapolation was warranted

Clinical Concerns Differences in ADCC were observed between the two products Because ADCC could be considered to be an active mechanism of action for this Mab

in the setting of IBD but not in the setting of rheumatic disease (the directly studied populations), extrapolation from the settings of RA and AS to IBD could not be recommended due to the absence of clinical studies in the IBDs.

Consequences: The sponsor could file a Supplementary New Drug Submission (SNDS) for a SEB that relies on the previously demonstrated similarity provided in the New Drug Submission (NDS) to support a label change (if the supplement contains sufficient information and material to enable the Minister to assess the safety and effectiveness of the new drug in relation to any change in labelling as specified in Section C.08.003(2) of the Regulations) Extrapolation to non-studies uses may be considered, based on clinical data provided in the SNDS, provided the information package filed is scientifically supportive and the rationale provided is persuasive

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Immunogenicity Assessments - Fundamentals

• Immunogenicity: Most biologics induce some level of anti-drug antibodies (ADAs) and these ADAs may have an undesirable clinical effect on pharmacokinetics, efficacy and/or safety

• From the safety perspective, ADAs can cause allergic or anaphylactic reactions, reduction of efficacy, induction of autoimmunity and/or neutralization of an endogenous counterpart. Example, the clinically significant immunogenicity problems (e.g. PRCA) widely acknowledged for erythropoietins (EPOs)

• Unwanted immunogenicity is currently difficult to predict from

the analytical and non-clinical data in terms of incidence, characteristics, clinical consequences and significance

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Immunogenicity Assessments - Strategy

Risk based immunogenicity evaluation strategy: •Immune system is sensitive and may provide additional assurance that the reference and the SEB are indeed similar •The SEB has to show similarity in safety and immunogenicity compared with the reference from a sufficient number of patients and a study duration of sufficient duration. •Immunogenicity data should be correlated with clinical parameters to assess impact

• It is usually necessary to continue assessment of unwanted immunogenicity and its clinical significance post-approval

• Post-marketing Risk Management Plan (RMP) is required • A strategy for testing immunogenicity should be provided with a rationale for the

choices • Assay methods should be validated and be able to characterize antibody content

(concentration or titre), as well as the type of antibodies formed • Of most concern are those antibodies that potentially have a serious impact on safety

and efficacy (such as neutralising antibodies and antibodies with cross-reactivity)

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Canadian Label and Naming for SEBs

The SEBs have their own brand name as for all new medicinal products in Canada

SEBs use the same International Non-proprietary Name (INN) as its reference product. HC currently follows WHO naming policy, which is being further discussed as to what triggers a unique INN

Brand name, INN, Drug Identification Number, lot/batch number and manufacturer of biological products are included in the Canadian product label

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WHO INN Policy for SEBs/Biosimilars

• The global INN system is overseen by the WHO

• WHO has recently suggested that the current system for choosing INNs remain intact, but that a four-letter code be attached at the end of every drug name

• At this time the WHO is proposing a random code added at the end of the INN with voluntary implementation. The document is on the WHO website for consultation: due date Sept 19th.

• HC will provide comments consolidated from our SEB/biosimilar working group members

• This approach may be useful as it avoids the confusion resulting from multiple INNs while taking into account the unique properties of biological products and the limits within which they can be reproduced from batch to batch. It would be in line with “generic” prescribing in Canada and increase post-market safety monitoring

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Drug Interchangeability

Interchangeable drug means a drug that:

• contains the same amount of the same active ingredients (pharmaceutical equivalence)

• demonstrates equivalent pharmacokinetic properties (bioequivalence)

• is to be administered in the same way as the drug prescribed Therapeutic equivalence (benefit and risk) can be assured when the

drug is both pharmaceutically equivalent and bioequivalent

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• While generics are freely interchangeable • Biologics can not be interchanged as the molecules

can not be reproduced identically between batches In a 2010 letter to Provincial Drug Plans, concerning its

guidance on the authorization of SEBs, Health Canada stated as follows: – SEBs are not “generic” biologics, and authorization of an SEB is not

declaration of a pharmaceutical or therapeutic equivalence to the reference biologic drug

– Because of concerns over manufacturing drift, Health Canada “… does not support automatic substitution of an SEB for its reference drug …”

Concerns with Automatic Substitution/Interchangeability

Pharmaceutics: Two biologics are not exactly the same

PK/PD: The SEB is not “bioequivalent” to the reference

Safety: As a consequence of their complexity, automatic interchangeability of biologics or SEBs could give rise to diverse and perhaps unforeseen clinical consequences

Immunogenicity: Repeated switches between SEBs and originator products may increase immunogenicity with potentially negative effects

Clinical use: An SEB may not receive all indications and/or uses of the reference

Post-market: Data used in the demonstration of “similarity” are only valid at the time of market authorization due to possible significant post-market changes and “manufacturing drift”

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Conclusions

• The clinical development for SEBs consists of complex processes that are associated with many regulatory and scientific issues

• Equivalence trials are highly recommended to be used for detecting potential differences between the reference and the SEB

• Extrapolation of indications is possible when the appropriate data and rationales are provided, but will not be granted automatically

• The consequences of an immune reaction to a therapeutic protein can be severe and should be carefully tested and monitored

• Naming and interchangeability issues remain to be resolved