. Regulatory Approach to Subsequent Entry Biologics in Canada Anthony Ridgway, Ph.D. Senior Regulatory Scientist Biologics & Genetic Therapies Directorate Health Canada IPIC 86th Annual Meeting Secondary Entry Biologics: The Future of Medicine – What About the Future of IP? Vancouver, October 11, 2012

Presentation Outline .. Origins & approaches to the Canadian guidance: biosimilarity based on concepts of comparability Considerations for development and approval Choice of Reference Biologic (RB) Generation and analysis of data Challenges, opportunities, issues

WHERE DO SEBs FIT? Chemical Drugs: Generics New Chemicals Identical Regulatory Pathway ANDS NDS Identical? Biological Drugs: New Biologics SEBs Adapted from Mary Hefford, 2008 3

Origins & Approaches to Guidance Science-based Practical Considerations “Copies” of innovator biologics are inevitable; need to decide on “sufficient evidence of quality, safety and efficacy” Many years of safe use and real-world experience for a similar product must have value There are multiple innovator versions of some biologics, all safe and effective, and none identical (therefore, some differences are not critical) Innovators often make manufacturing changes with minimal or no clinical data No scientific or regulatory grounds for refusing to evaluate SEBs/Biosimilars (clearly possible within current regulations). This was prime motivation. What does the science support? Project initiated within BGTD. Was not politically or financially motivated e.g. need to save healthcare $ (i.e. the process in the US). Others forced to adapt, e.g. changes to guidances for data protection regulations and P(NOC)C regulations. Interest from Legislative and Regulatory Modernization. In Canada: rhInsulin (27y), rhGH (24y), IFN (24y), EPO (20y), G-CSF (18y) (filgrastim).

Origins & Approaches to Guidance Science-based Practical Considerations Use as a model the comparability exercise undertaken by innovators after a manufacturing change Incorporate need for new clinical data generated with SEB (therefore, data bridged through similarity is considered supportive) Adapt international guidance, especially ICH (e.g., Q5E); and consider EMEA clinical guidance 1) Quality guidance is a bit more detailed than that of EMA (which is very high-level). High-level clinical guidance has many similarities to EMA guidance. 3) Elements of the US FDA perspective were previously recognized indirectly through their collaboration in contributing to the development of the WHO guidance document. Their recently released guidelines have much in common with the WHO and Canadian guidelines.

Canadian Guideline on Subsequent-Entry Biologics (March 8, 2010) General policy statements Concepts and definitions Scope of eligible products Cross referencing to regulations and guidances covering patented medicines and data protection Considerations for selecting “reference biologic” Information to be provided, and relevant guidance on conducting comparability studies, for: quality non-clinical clinical to support a potential determination of “similarity” Product labelling Post-Market Requirements Regulatory approach is guidance-based. No new regulations introduced. Guidance on information to be provided, and on conduct of comparability studies is fairly detailed but not product-class-specific. We may eventually develop product-class-specific clinical guidelines but currently we believe the EMA guidelines are of great value to sponsors. The prospect of eventual guidelines that might be harmonized for several regulatory jurisdictions is very appealing.

Significant lssues Most general scientific concepts are accepted / understood but there will probably be some product-class-specific issues. By the end of stakeholder consultations, most significant issues related to patent protection, period of market exclusivity, and market access (rules and/or choice regarding new or already treated patients). Canadian vs non-Canadian reference biologic Substitution and Therapeutic Interchange Product labelling

? Comparability The Question Product of Process X Product of Process Y Extent of studies will depend on: Stage/extent of changes Impact on the product Analytical capability Link between quality criteria and safety and efficacy

ICH Q5E - General Principles The demonstration of comparability does not necessarily mean that the quality attributes of the pre-change and post-change products are identical; but that they are highly similar and that the existing knowledge is sufficiently predictive to ensure that any differences in quality attributes have no adverse impact upon safety or efficacy of the drug product. i.e., previously derived clinical data is still relevant.

Purity/Impurity Profile Characterization Purity/Impurity Profile Drug substance = Multiple entities Desired product (microheterogeneity) Product-related substances Product-related impurities Process-related impurities Contaminants

Clinical Considerations bridging study vs larger trial Comparability Clinical Considerations bridging study vs larger trial Indication mode of action outcome measures Dosing and Patient Response units of activity route of administration narrow therapeutic index Safety Versus Efficacy immunogenicity active ingredient vs impurities

Presentation Outline .. Origins & approaches to the Canadian guidance: biosimilarity based on concepts of comparability Considerations for development and approval Choice of Reference Biologic (RB) Generation and analysis of data Challenges, opportunities, issues

Choice of Reference Biologic General Scientific Considerations (I) The SEB/Biosimilar must be “subsequent” to a product approved for the Canadian Market Capable of meeting criteria for similar / comparable Similar manufacturing process = logical advantage Suitable analytical capability available & used Weight of evidence provided by “quality” studies Similarity brings suitable data on safety and effectiveness for Reference Biologic into relevance as supportive data (so choosing RB to access larger data set may be an advantage) 1) Does not need to be still marketed in Canada. 2) a) Will obviously have many differences since process for RB is proprietary - but e.g., no transgenics! b) Analytics should be capable of revealing potentially meaningful differences. c) Can’t fill significant “quality” gaps with non-clinical or clinical studies. 3) So choose RB to leverage best supportive data. If not Cdn RB, consider inter-batch comparability issue (adherence to ICH Q5E) and pharmacovigilance in country/region.

Choice of Reference Biologic General Scientific Considerations (II) Only clinical indications approved in Canada for the RB are available, supported by original data (or possibly extrapolated) One/the clinical indication should be the most sensitive for detecting any differences from the RB 1) So after best potential fit for “quality”, consider national comparator with the most indications (for possible extrapolation).

Choice of Reference Biologic Scientific basis for requiring a Canadian Reference Biologic (CRB) is not convincing NOC for CRB was likely many years earlier and original submission and review report may be of limited value due to evolving standards and approaches. Recent review experience may be limited (no recent manufacturing changes or product no longer marketed). SEB is not for automatic substitution therefore physician experience with RB is not critical to SEB use. (Also, possible legal issues around use of files associated with innovator product).

Generation and Analysis of Data Is comparison at level of Drug Product (DP) or Drug Substance (DS)? ….. De-formulation issues. Assess all biological activities and associated CQAs of molecule. SEB clinical material should be from the commercial process (and same as used for quality and non-clinical studies) so avoid process changes and associated internal comparability. Acquire/use DP representing different manufacturing campaigns of RB (e.g., multiple different expiry dates) for comparability studies. Documentation of purchase locations reflects RB manufacturing site Inter-batch differences may help support assessment of “similar”.

Pre-Clinical Elements (I) General guidance is provided (specific requirements for drug classes may differ) Appropriate non-clinical studies should be conducted prior to the initiation of any clinical studies, following principles recommended by ICH S6 Studies should be comparative and designed to detect significant differences between the SEB and the RB

Important Clinical Elements General guidance is provided (specific requirements for drug classes may differ) Comparative studies are required Trials designed to show equivalence are preferred Trials to show non-inferiority are possible but must be justified; if clinically meaningful superiority is identified, cannot be approved as a SEB. As a SEB, clinical indications are limited to those: held by reference biologic in Canada supported by data (some possible via rationale) New indications are possible through full clinical studies

Product Labelling for SEB Product Monograph (PM) for SEB should be developed according to PM guidance. Cannot use PM of reference biologic in its entirety (like a generic drug). PM information contents: Statement indicating product is a SEB Key data supporting authorization Tables with results of comparisons to named reference biologic Approved clinical indications No claims for clinical equivalence or bioequivalence Although not clearly stated in the guidance, each SEB requires a distinct name to allow implementation of: Risk Management Plan, Pharmacovigilance Plan, ADR Reporting, Periodic Safety Update Reports (PSURs)

Substitution / Interchange Therapeutic interchangeability can be supported by specifically designed clinical studies (but such studies are unlikely in most situations). Data used in the demonstration of “similarity” or “therapeutic interchangeability” are only truly valid at the time generated due to possible “manufacturing drift.” Once approved, a SEB is a “stand-alone” product like any innovator product and the sponsor may gain approval for additional strengths, presentations and indications. Therefore, Health Canada’s position is that any change in brand of medication should involve the physician and should be carefully considered. “Automatic substitution” → required by payer “Substitution” → at discretion of pharmacist “Therapeutic interchange” → switch by physician Manufacturing drift → biologics are sensitive to manufacturing changes so, as the innovator and SEB sponsor make multiple independent manufacturing changes, over time the products become less similar Legal prohibition of automatic substitution in most of EU. Therapeutic interchange may be permitted by pharmacists in some jurisdictions

Conclusions Health Canada has adopted a regulatory approach to SEBs (Biosimilars) that is science-based Where possible, principles and guidance from ICH documents are applied Opportunities for collaborative regulatory approaches are being actively pursued and relevant guidance from regulatory partners will be referenced or adopted C