The proposed regulations clarify and codify Health Canada's expectations and policies regarding differences in the form of medicinal ingredients in generic drug products that are eligible for submission under the abbreviated new drug submission (ANDS) pathway by introducing a regulatory definition for 'therapeutically active component'. Most significantly, generic drugs which have a different salt form from the medicinal ingredient in the Canadian reference product are eligible for submission as an ANDS under the proposed regulations. Further, the proposed regulations streamline identifying and labelling practices relating to the medicinal ingredient content in drug products and amend the definition of 'innovative drug' in the data protection provisions of the Food and Drug Regulations.
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 (for further details please see "Updates from Health Canada").(1)
ANDS submission pathway
Under the current Food and Drugs Regulations, to be eligible for assessment under the ANDS pathway, a generic drug product must be the pharmaceutical equivalent of the Canadian reference product (CRP). 'Pharmaceutical equivalent' is defined as follows:
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.
Non-biologics 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 like 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 can 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 cannot be filed through the ANDS pathway:
different esters; and
different isomers or mixtures with different proportions of isomers.
According to the Regulatory Impact Analysis Statement accompanying the proposed regulations, complexes, clathrates and esters were excluded from the definition because they do not dissociate to yield identical therapeutically active components in solution. Isomers were also excluded as they can have different pharmacological activities.
The proposed regulations specify that a reference to a new drug's 'medicinal ingredient' is a reference to the form of the medicinal ingredient in the dosage form of the new drug as determined by the minister, considering the manufacturing method and the controls 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 there are reasonable grounds to believe that there is a difference between the medicinal ingredient in the generic drug and the CRP, the minister can request the generic drug manufacturer to 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.
Biologics The proposed amendments specify that the ANDS pathway is unavailable to drugs included in Schedule D to the Food and Drugs Act, commonly known as 'biologics'. However, the Regulatory Impact Analysis Statement 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.
Radiopharmaceuticals The existing definition of 'pharmaceutical equivalent' will continue to apply to radiopharmaceuticals (Schedule C drugs).
Labelling medicinal ingredients and therapeutically active components
As proposed, the labelling requirements will be updated to require a list of both the medicinal ingredient's name and a quantitative list of the therapeutically active components on drug labels where the drug product's medicinal ingredient, as determined by the minister, is different from the therapeutically active component.
The labelling requirements would apply to all new drugs authorised pursuant to Division 8 of the Food and Drug Regulations, not just generic drug products. According to the Regulatory Impact Analysis Statement, this will create a consistent practice for the expression of strength.
It has been proposed that the definition of 'innovative drug' be amended to align the variations terminology (ie, the kinds of variation of a previously approved medicinal ingredient that precludes 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 version of Section C.08.004.1(1) defines 'innovative drug' as:
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.
The proposed version of Section C.08.004.1(1) defines 'innovative drug' as follows:
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...
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).
Therefore, the proposed amendments specify that variations include a "mixture of enantiomers" and "any combination of the variations found in paragraphs (a) to (c)".
The proposed regulations will apply only to drug submissions filed after the regulations come into force (ie, 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: