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gust 22, 2007 Helping the people of Canada maintain and improve their health Aider les Canadiens et les Canadiennes à maintenir et à améliorer leur santé Regulatory approach and consideration for Subsequent Entry Biologics (SEBs) in Canada Agnes V. Klein, MD DPH Biologics and Genetic Therapies Directorate Health Canada April, 2010 Health Products and Food Branch Topics for Discussion 12345- Introduction Fundamental Concepts and Principles Data Requirements Reference product Conclusions 2 Health Products and Food Branch 1- Introductions Health Canada’s mission is to help Canadians maintain and improve their health The mandate of the Health Products and Food Branch is to take an integrated approach to the management of the risks and benefits to health-related products and food by: Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and Promoting conditions that enable Canadians to make health choices and providing information so that they can me informed decisions about their health 3 Health Products and Food Branch Drivers for SEBs Expiry of patents for biologics Public demand for affordable products Change in global market dynamcs for biologic drugs Submissions for SEBs and enquiries for filing of SEBs 4 Health Products and Food Branch Canadian Regulatory Context Changing regulatory environment Lifecycle approach (Progressive Licensing Framework/Project) Increase in “best practices” approach; Regulated Marketplace, but: Smaller in size than USA and Europe Not primary target for SEB development and submissions 5 Health Products and Food Branch Differences: Biologics vs Pharmaceuticals Biologic Drugs Derived from living organisms Relatively large in size Pharmaceutical Drugs Derived from chemical sources: mostly by synthesis Relatively small in size (called small molecules) Highly variable Regulatory oversight on process of product Minimally variable Regulatory oversight on finished product 6 Health Products and Food Branch Challenges for SEBs Unpredictable immunogenicity of biologics Most biologics induce antibodies Manufacturing changes can cause unexpected changes Analytical methods can not fully predict biological properties Immunogenicity can have serious consequences Hence need for enhanced post-market surveillance for all new biologics, including SEBs 7 Health Products and Food Branch 2- Fundamental Concepts and underlying Principles The information and submission requirements for authorization of SEBs outlined in the guidance document should permit a sponsor to satisfy the requirements of the Food and Drug Regulations A New Drug Submission shall contain sufficient information to assess the safety and effectiveness of a new drug including…C.08.002(2) The onus is on the sponsor to provide the necessary evidence to support all aspects of an application for market authorization 8 Health Products and Food Branch Fundamental Concepts and underlying Principles Regulatory decisions on SEBs will be based on scientific and regulatory principles that are in the Food and Drugs Act and Regulations The principles within the existing regulatory frameworks for biologics, pharmaceuticals and generic pharmaceutical drugs are used as the bases for the regulatory framework for SEBs The basis for a product being authorized as an SEB hinges on the ability to demonstrate similarity to a suitable reference biologic product 9 Health Products and Food Branch Fundamental Concepts and underlying Principles SEBs are not “generic biologics” and many characteristics associated with authorization process and marketed use for generic pharmaceutical drugs do not apply Authorization of an SEB is not a declaration of pharmaceutical and/or therapeutic equivalence to the reference biologic drug Once a Notice of Compliance (NOC) is granted, the SEB is a new biologic drugs and is regulated like any other new biologic drug. However, and SEB can not be used as a reference biologic product 10 Health Products and Food Branch Fundamental Concepts and underlying Principles An SEB will only be authorized based on a submission that makes either a direct comparison to an innovator product previously authorized for sale in Canada. All the laws, patent and intellectual property principles outlined in the Food and Drug Regulations (Data Protection) and Patented Medicines (Notice of Compliance) Regulations are applicable to SEBs Subsequent manufacturer approval on the basis of direct or indirect comparison with the “innovator drug” is prohibited until 8 years after authorization of the innovator drug 6 year “no-filing period” drug in which SEB sponsors are prohibited from filing a submission that compares directly or indirectly with the innovative drug 6 months paediatric exclusivity NOTE: In some circumstances a biologic product (must be named) that is not marketed in Canada may be used as a reference. The biologic must be named and it is preferred that it be used in the comparative studies. The guidance document should be consulted 11 Health Products and Food Branch 3- Data Requirements Chemistry/Manufacturing Drug Substance Manufacture Characterization Control Ref. standard Container Stability Facility Information Drug Product Description Development Manufacture Control Ref. standard Container Stability Facilty Information Non-clinical Pharmacology •Primary activity •Secondary activity •Safety pharmacology •Interactions Clinical Pharmacology Pharmacokinetics •Single dose •Repeat dose •Special populations Pharmacokinetics Efficacy and Safety •ADME •Interactions •Dose finding •Schedule finding •Pivotal Toxicology •Single dose •Repeat dose •Genotoxicity •Carcinogenicity •Reproduction •Local tolerance •Indication1 •Indication 2, etc Immunogenicity Post-market PvP, RMPs, etc. 12 Health Products and Food Branch Quality Full Chemistry and Manufacturing package Extensive data on the demonstration of similarity with the reference biologic drug including Characterization studies side by side Studies should be comprehensive and well rationalized to allow deduction of similarity Formulated drug product may be feasible to undertake comparability Comparison of drug substance may be beneficial or the only scientific option; additional studies should demonstrate that the drug substance is not changed Comparison of SEB drug product and SEB isolated drug substance may be helpful 13 Health Products and Food Branch Quality Comparability exercise: Considerations Same principle and approaches as in ICH Q5E are applicable Purpose to ascertain whether SEB and chose reference can be judged highly similar in terms of quality attributes allowing to support conclusions of similarity for safety and efficacy Extent of studies will depend on: Nature of the product Availability of suitable analytical techniques to detect differences Relationship between quality attributes and safety and efficacy, based on overall non-clinical and clinical experience The following should be evaluated, for ex: physicochemical and biological characterization, analyses from different stages of process, stability data, multiple batches to characterize variability 14 Health Products and Food Branch Quality Determine critical control points, adequacy of in-process controls, type and extent of data to be derived from non-clinical studies Analytical techniques Select carefully and optimize Depends on the reference biologic drug chosen Assays should be scientifically sound and provide reliable results Characterization Use appropriate techniques as per ICHQ6B including Characterization of physicochemical properties Biological Activity Immunochemical properties, purity, impurities, contaminants and quantity 15 Health Products and Food Branch Quality Complete side by side characterization Additional characterization may be needed Physicochemical properties According to ICHQ6B Biological Activity Limitations of biological assays should be considered (e.g. high variability) Can confirm that change in structure has not occurred When not adequate, data from non-clinical or clinical studies may be supportive If reliance is too high, the procudt may not be suitable as a SEB 16 Health Products and Food Branch Quality Immunochemical properties Specifications Stability (ICHQ5C and Q1A(R) Manufacturing process considerations Determination of similarity Signifies that the quality attributes of the two products are highly similar (not identical) Non-Clinical and clinical data previously generated with the reference product are relevant to the SEB 17 Health Products and Food Branch Quality Analytical procedures are not sufficient to discern relevant differences Relationship between specific quality attributes and safety and efficacy has not been established, and differences Between quality attributes of the SEB and the reference biologic drug are likely to be observed Data should be organized as per CTD Once grand an NOC, an SEB becomes a standalone product 18 Health Products and Food Branch Non-Clinical and Clinical Information Apply to SEBs that have demonstrated to be similar to the reference product chosen Only general guidance is provided One or more indications may be applied for, based on the product chosen for reference Proposals for additional indications of the reference product may be granted to the SEB; PK/PD may be sufficient for extrapolation; extrapolation may also be possible based on pathophysiological mechanisms; scientific rationale is required The reference biologic should the same for all studies 19 Health Products and Food Branch Non-Clinical and Clinical Information Non-clinical studies According to principles in ICH S6; comparative and designed to detect significant differences between the SEB and the reference biologic In vitro: receptor binding or cell-based assay, as/when appropriate In vivo: relevant PD studies; at least one repeat toxicity study; sufficient duration to detect differences in toxicity and/or immune responses; local tolerance. All studies can be concurrent, as part of one study Other toxicological studies, safety pharmacology, reproductive toxicity; mutagenicity and carcinogenicity – not required, unless warranted by the results of the repeat-dose toxicological studies 20 Health Products and Food Branch Clinical Studies Pharmacokinetic studies Comparative PK studies should consider the following: T/2 of the biologic Linearity of PK parameters Endogenous levels/diurnal variation where applicable Diseases/Conditions to be treated Route (s) of administration Indication (s) being applied for Use volunteers, but most likely patient population Use doses for studies, within the therapeutic range of the reference as specified in PM Use general principles of study design and statistical methods Clearance times should be compared Exclude data only if acceptable to Health Canada-BGTD 21 Health Products and Food Branch Clinical Studies Acceptable criteria should be defined in advance, for similarity taking into consideration known PK parameters and their variations, assay methodologies, all available safety and efficacy of the reference biologic Consider criteria used for bioavailability studies of generic pharmaceuticals; when not met, implications of findings should be discussed Pharmacodynamic studies Parameters should be clinically relevant Surrogates should be clinical validated PD studies may be combine with PK studies; PK/PD relationship should be characterized; PD studies should be comparative in nature 22 Health Products and Food Branch Clinical Studies Clinical efficacy and Safety Trials Conducted to demonstrate the similarity in safety and efficacy between SEB and the reference biologic with a few exceptions: e.g. Insulin for which only comparative safety is needed Equivalence trials are generally preferred Design of studies and comparability margins as well as primary endpoints should be given careful consideration Non-inferiority trials are considered but must be justified as they could suggest superiority of the SEB, and this needs to be assessed for relevance, including impact on safety. If confirmed, the product can no longer be considered as an SEB Extrapolation from non-inferiority studies to other indications might not provide support for extrapolation 23 Health Products and Food Branch Clinical Studies Nature, severity and frequency of AEs should be compared: numbers should be sufficient and study of sufficient duration, to allow this to happen Immunogenicity should be evaluated in the clinical trials or specific studies with state of the art methods: rationale for strategy should be provided Clinical Safety and Efficacy Impact of neutralizing and cross-reacting antibodies, when detected, on PK/PD parameters should be analyzed and their impact assesses Duration of studies may have to be extended in such event Detailed PvP and RMP may need to be implemented 24 Health Products and Food Branch Clinical Studies Post-market activities SEBs reach market base on reduced non-clinical and clinical package: therefore, RMP is important Include methods to distinguish AEs from those for other products, including the reference product The RMP may be implemented and maintained throughout the lifecycle of the product PvP: should be provided with PSURs to include a discussion the benefit-risk balance of the SEB post-market 25 Health Products and Food Branch Clinical Studies Other Post-Market Requirements Adverse Drug Reaction (ADR) reporting: as per C01.016; should be reported as per the regulations within 15 days of receipt Analyses may be conducted on request, with additional analyses as needed PSUR’s: should be submitted as discussed in the PvP, following ICH E2E as noted at time of NOC C.08.006 defines the authority for suspend the NOC (marketing of a drug) 26 Health Products and Food Branch Labelling requirements Canadian Label is the Product Monograph (PM) Unlike generics, the pm of the reference product can only be used practically Requirements: Indicating that product is and SEB Key data on which decision to allow marketing has been mad Information on the indications approved for use No claims of bioequivalence can be made No claims for clinical equivalence can be made 27 Health Products and Food Branch Role of reference product Additional non-clinical and clinical data are obtained from publicly available information the Reference Product to support the authorization of the SEB Reference biologic product is therefore critical to the authorization of SEBs The Reference Product is not the sole source of no-clinical and clinical information For generics, the reference product or national comparator determines the use and/or of the generic as a substitute; extrapolation to available supportive clinical data in order to reduce unnecessary patient enrolment The choice/use of RBP is not to precisely indicate the marketed product for which the SEB can be substituted 28 Health Products and Food Branch Role of reference product Authorization of an SEB will be based on a less extensive clinicl data package (i.e. reduced number and/or size of clinical trials) Data from Reference Product must be of high quality SEB must be demonstrated to be similar to the reference product Comparability Exercise (quality component) does not provide complete information required for the decision to authorize The reference biologic product should be authorized and marketed in Canada The active substance of reference product should have significant safety and efficacy data accumulated such that the demonstration of similarity will bring into relevance a substantial body of reliable data Where a non-Canadian Reference Product is contemplated, the sponsor should contact Health Canada early in the development process. 29 Health Products and Food Branch Role of reference product Use of non-Canadian reference product Non-Canadian reference product From jurisdictions with an established relationship with HPFB is preferred Widely marketed in a jurisdiction that adopts ICH guidelines and with regulations and principles of evaluation, post-market surveillance, and approach to comparability similar to Canada The submission includes sufficient information to explain explicitly the link between the Reference Product and the same innovative product approved in Canada 30 Health Products and Food Branch Indications and Substitutability Indications granted shall be based on data provided by the sponsor If the SEB sponsor does not provide data to support all the indications of the reference product, the SEB will not automatically be granted all the indications of the RBP Indications not held by the reference biologic product will require supportive clinical trial data SEBs should be eligible to apply for indication (s) within those granted to the reference biologic product Interchangeability (Substitutability) remains a Provincial decision in Canada 31 Health Products and Food Branch Conclusions SEBs will be part of the high quality, safe and effective biologic drugs available to Canadians SEBs are “stand alone” and not “generic” versions of the RBP SEBs can be equated to innovator biologic drugs SEBs are not automatically substitutable and may not have all indications of reference products Health Canada intends to harmonize as much as possible with other competent regulators and international organizations such as the WHO, as much as possible 32 Health Products and Food Branch Conclusions HC may adapt definitions, terminology and applicable guidance, in the future HC recommends that sponsors refer to class-specific guidance of the EMEA, as the scientific principles are consistent with those in Canada 33 Health Products and Food Branch Thank you ? 34