Possible Changes to the Food and Drug Regulations: Generic Drug Equivalence and Related Terminology

Notice to Interested Parties

Objective

This Notice of Intent serves to solicit comments on possible changes to the Food and Drug Regulations around establishing pharmaceutical equivalence between a proposed generic drug product and the Canadian Reference Product (CRP). Health Canada also proposes to define the meaning of “medicinal ingredient” and other key terms (e.g., therapeutic moiety and drug product). In doing so, Health Canada aims to create greater alignment and convergence with the practices of other major regulatory jurisdictions and to standardize their use with those applied internationally.

Further, Health Canada is proposing to introduce language in the Food and Drug Regulations that would recognize generic drug products which contain the same therapeutic moiety in the medicinal ingredient as the CRP, but for which the medicinal ingredient is in a different physicochemical form (e.g., salt form), as approvable under an Abbreviated New Drug Submission (ANDS). If the therapeutic moieties are the same, and the differences in the physicochemical form of the medicinal ingredient do not result in a difference in safety or effectiveness, then these generic drug products would be considered “pharmaceutical alternatives” to the CRP and approvable as ANDSs, such that the resulting Notice of Compliance (NOC) would constitute a declaration of “therapeutic equivalence” to the CRP. It is not expected that this aspect of the proposal, which is specific to ANDSs, would apply to biological or radiopharmaceutical products, or to medicinal ingredients which do not possess a unique chemical structure (e.g., polymers with varying molecular weights).

This consultation document is intended to provide stakeholders an opportunity to review the proposed changes to the Food and Drug Regulations and to consider possible impacts on drug development, drug accessibility and interchangeability practices.

Introduction

Sponsors seeking authorization to market a generic drug product for human or veterinary use may file an ANDS. In order to be approved under the ANDS pathway, the sponsor must demonstrate that the generic drug product, in comparison with the CRP, is pharmaceutically equivalent, is bioequivalent, has the same route of administration, and the conditions of use are within those for the CRP. If found to be satisfactory, Health Canada will issue a NOC stating that the ANDS complies with the requirements of Section C.08.002.1 of the Food and Drug Regulations, constituting a declaration of equivalence with the CRP. Based on Health Canada’s NOC, provincial and territorial governments’ drug programs determine interchangeability of the generic drug product with the specified reference product.

Increasingly, Health Canada is presented with drug submissions from generic drug manufacturers for products with differing forms of the medicinal ingredient, but which have the same therapeutic moiety as the CRP. Although these medicinal ingredients differ physicochemically from those in their respective CRPs, generic drug manufacturers file ANDSs (e.g., as supported by bioequivalence and other studies) in order to seek declarations of equivalence.

Over the years, policy approaches have provided interpretations of the term “identical medicinal ingredient”^{Note de bas de page 1} and have specified the point at which identicality should be determined between a generic drug product and its CRP ^{Note de bas de page 2}. Currently in Canada, there are no explicit regulatory requirements for the approval of different forms of medicinal ingredients under the ANDS pathway. Further, the Food and Drug Regulations do not define a number of terms associated with a drug product’s composition and characteristics.

Key Concepts

This proposal introduces a distinction within the generic drug framework whereby, consistent with current practices, generic drug products with the same medicinal ingredient in the same dosage form would be considered “pharmaceutical equivalents”. In contrast, generic drug products with different salts, esters or complexes of the medicinal ingredient, and/or generic drug products with different but comparable dosage forms to the CRP, would be considered “pharmaceutical alternatives”. Either of these generic drug products could be considered therapeutically equivalent, if the generic for which bioequivalence has been demonstrated has the same route of administration and the same safety and effectiveness as the CRP. Upon approval of the submission, a NOC would be issued in respect of the pharmaceutical equivalent or alternative and would constitute a declaration of therapeutic equivalence for that new drug. The submission requirements and evidence standards for pharmaceutical equivalents and alternatives would be addressed through a guidance document.

Additionally, rather than treating the input material (i.e., the starting active pharmaceutical ingredient (API) that goes into the manufacture of the drug product) as the medicinal ingredient, the proposal seeks to add a definition of medicinal ingredient as the active substance that contains the therapeutic moiety in the drug product that is administered to or consumed by Canadians. As a result, the point at which sameness would be determined between a generic drug product and its CRP would change. This definition complements the existing regulatory definition of the term “non-medicinal ingredient”. To further clarify the definition of medicinal ingredient and align Health Canada internationally, other terms such as “therapeutic moiety” and “drug product” may also be defined.

This proposal is intended to address some concerns arising from the comparison of generic drug products to the CRP and create greater alignment and convergence with the practices of other major regulatory jurisdictions for pharmaceuticals. Further policy work on how this may impact Schedule C and D drugs is ongoing and input is welcome.

Rationale to Justify Proposal

The proposal seeks to add and revise regulatory language to more closely align with the practices of other major regulatory authorities and to provide greater clarity to stakeholders.

Currently, as explained in the 2015 Notice: Interim Policy on Health Canada's Interpretation of Medicinal Ingredient, Health Canada evaluates pharmaceutical equivalence between two drug products at the input stage (understood to mean the pharmaceutical equivalence of the APIs) and considers the manufacturing processes which can lead to variations in the chemical form of the medicinal ingredients in the drug product. The interim policy was implemented in view of a Federal Court decision by Madam Justice Kane, 2013 FC 1217. However, Health Canada’s position is that the Food and Drug Regulations should be amended to establish that the comparison of the medicinal ingredient between the generic drug product and the CRP for the determination of equivalence is made at the stage where the drug products are ready to be administered to, or consumed by, Canadians. This proposal also takes into account the recommendations from the 2012 Scientific Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology, namely that different salts of the same active moiety may in some cases be approvable in an ANDS, if supported by satisfactory safety and effectiveness data.

Overall, the proposal supports transparency and predictability of regulatory requirements and addresses long-standing issues related to the demonstration of equivalence between generic drug products and CRPs.

Providing Your Input

Questions or comments related to the consultation, including cost and savings considerations, should be directed before October 27, 2017 to:

Health Canada
Health Products and Food Branch, Therapeutic Products Directorate
Bureau of Policy, Science and International Programs
Address Locator 3102C3
Holland Cross, Tower B
1600 Scott St.
Ottawa, Ontario
K1A 0K9

Telephone: 613-948-4623
Fax number: 613-941-1812
Email: policy_bureau_enquiries@hc-sc.gc.ca

Input received by October 27, 2017 will be considered as part of future regulatory development. Please be aware that this is the first in a series of consultations on the topic.