Health Canada released proposed Regulations Amending the Food and Drug Regulations (Improving Access to Generics) (“proposed Regulations”) on March 30, 2019. Comments may be submitted until June 8, 2019.
The proposed Regulations clarify and codify Health Canada’s expectations and policies regarding differences in the form of the medicinal ingredient in a generic drug product eligible for submission under the abbreviated new drug submission (“ANDS”) pathway by introducing a regulatory definition for “therapeutically active component”. Most significantly, a generic drug having a different salt form of the medicinal ingredient in the Canadian reference product is eligible for submission as an ANDS under the proposed Regulations. Further, the proposed Regulations streamline identifying and labelling practices of the medicinal ingredient content in drug products, and make amendments to the definition of “innovative drug” in the data protection provisions of the Food and Drug Regulations (“FDR”).
The proposed Regulations follow Health Canada’s 2017 consultations regarding generic equivalence. In 2017, Health Canada separately issued an Updated Notice: Interim Policy on Health Canada's Interpretation of Medicinal Ingredient and Assessment of Identical Medicinal Ingredient (as reported here).
We have prepared an unofficial consolidated version of the relevant FDR sections, incorporating the proposed amendments.
ANDS submission pathway
Under the current FDR, to be eligible for assessment under the ANDS pathway, a generic drug product must be the “pharmaceutical equivalent” of the Canadian reference product (“CRP”) which means “a new drug that, in comparison with another drug, contains identical amounts of the identical medicinal ingredients, in comparable dosage forms, but that does not necessarily contain the same non-medicinal ingredients”.
Under the proposed Regulations, generic drug products, excluding radiopharmaceuticals and biologics, may be the subject of an ANDS if the new drug has identical amounts of “identical therapeutically active components”—instead of “identical medicinal ingredients”—as the CRP. “Therapeutically active component” is defined as “a medicinal ingredient, excluding those appended portions, if any, that cause the medicinal ingredient to be a salt, hydrate or solvate”.
Generic drug products with the following differences in the medicinal ingredient are eligible to be filed through the ANDS pathway:
- different hydrated or solvated forms
- different polymorphic forms and
- different salt forms
Generic drug products with the following differences in the medicinal ingredient are not eligible to be filed through the ANDS pathway:
- different complexes
- different clathrates
- different esters and
- different isomers or mixtures with different proportions of isomers
According to the Regulatory Impact Analysis Statement (“RIAS”) accompanying the proposed Regulations, complexes, clathrates, and esters were excluded from the definition including because they do not dissociate to yield identical therapeutically active components in solution. Isomers were also excluded as they could have different pharmacological activities.
The proposed Regulations specify that a reference to the “medicinal ingredient” of a new drug is a reference to the form of the medicinal ingredient in the dosage form of the new drug as determined by the Minister, taking into account the method of manufacture and the controls to be used in the manufacture of the dosage form. In contrast to Health Canada’s prior policies, the medicinal ingredient may not be the form of the medicinal ingredient used as the raw material input to manufacture the dosage form.
If the Minister has reasonable grounds to believe that there is a difference between the medicinal ingredient in the generic drug and the CRP, the Minister will have the power to request that the generic drug manufacturer provide information that demonstrates that any differences are inconsequential to the safety and effectiveness of the new drug.
Further, where there is a difference between the medicinal ingredients of the generic drug and the CRP, the notice of compliance for the generic drug will state any differences from the CRP.
The proposed amendments specify that the ANDS pathway is not available to drugs included in Schedule D to the Food and Drugs Act, commonly known as biologics. However, the RIAS states that “the proposed amendments would not prevent a manufacturer from filing an ANDS for a drug that is not referred to in Schedule D (e.g. a chemically synthesized drug), where the CRP is a drug referred to in Schedule D.”
The existing definition of “pharmaceutical equivalent” would continue to apply to radiopharmaceuticals (Schedule C drugs).
Labelling of medicinal ingredients and therapeutically active components in drug products
As proposed, the labelling requirements will be updated to require a listing of both the name of the medicinal ingredient and a quantitative list of the therapeutically active components on labels of drugs where the medicinal ingredient in the drug product, as determined by the Minister, is not the same as the therapeutically active component.
The labelling requirements would apply to all new drugs authorized pursuant to Division 8 of the FDR, not just generic drug products. According to the RIAS, this will create a consistent practice for the expression of strength.
The definition of “innovative drug” is proposed to be amended to align the “variations” terminology (i.e. the kinds of variations of a previously approved medicinal ingredient that preclude the grant of data protection) with the new definition of “therapeutically active component”, while maintaining the “variations” referred to in the original 2006 definition of innovative drug.
The current and proposed amended text read as follows:
Proposed amended version
C.08.004.1 (1) The following definitions apply in this section.
C.08.004.1 (1) The following definitions apply in this section.
innovative drug means a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph. (drogue innovante)
innovative drug means a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient. (drogue innovante) … variation includes, for the purposes of the definition innovative drug, (a) an enantiomer or a mixture of enantiomers; (b) a polymorph; (c) a medicinal ingredient that, when compared to a previously approved medicinal ingredient, is identical, excluding those appended portions, if any, that cause either medicinal ingredient to be a salt, ester, hydrate, or solvate; or (d) any combination of the variations found in paragraphs (a) to (c). (variation)
The proposed amendments therefore additionally specify that variations include a “mixture of enantiomers” and “any combination of the variations found in paragraphs (a) to (c)”.
The proposed Regulations will only apply to drug submissions filed after the coming into force of the Regulations, which will be 90 days after the day on which they are registered.
Related Health Canada draft Guidance documents
Health Canada is also holding a consultation on two related draft guidance documents: Generic Drug Equivalence: Medicinal Ingredients and Identifying and Labelling Medicinal Ingredients in New Drug Products. The consultation period will be open until June 17, 2019.