Canada Gazette, Part I, Volume 153, Number 13: Regulations Amending the Food and Drug Regulations (Improving Access to Generics)

March 30, 2019

Statutory authorities
Financial Administration Act
Food and Drugs Act

Sponsoring department
Department of Health

REGULATORY IMPACT ANALYSIS STATEMENT

(This statement is not part of the Regulations.)

Issues

The Food and Drugs Act establishes approval processes and sets standards for the manufacture, testing, packaging and labelling of regulated products. Applications for approval to market drugs, medical devices and other health products in Canada are reviewed by Health Canada, and include a pre-market review of a product’s safety, efficacy and quality, as well as a determination of the risks associated with a product’s use relative to its benefits.

A manufacturer that seeks to market a generic version of a drug previously authorized by the Minister of Health (e.g. an innovator drug) may seek to establish that the generic drug product is safe and effective by submitting an abbreviated new drug submission (ANDS). The Food and Drug Regulations (FDR) allow a manufacturer to file an ANDS where, in comparison with a Canadian reference product (CRP), the following four criteria are met:

However, due to pharmaceutical development strategies and manufacturing technologies, the medicinal ingredient in generic drug products sometimes differ from their CRP (e.g. a different salt, hydrate, or solvate of the medicinal ingredient), leading to difficulties in determining whether drugs are pharmaceutically equivalent such that they may be approved via the ANDS pathway. In addition, in certain cases, in both generic and brand name drugs, it is possible that there is a change in the form of an active pharmaceutical ingredient (or the input ingredient) during the manufacturing of a drug. This type of change is referred to as an “in-situ change.” In such cases, the form of the medicinal ingredient in the dosage form footnote 1 is different from the form of the active pharmaceutical ingredient used in the manufacturing process. The ANDS regulatory pathway does not explicitly refer to generic drug products containing medicinal ingredients that are chemically different but contain the identical therapeutically active component in comparison with the CRP.

There is a need for the FDR to clearly address submissions for generic drug products with a different medicinal ingredient with the identical therapeutically active component in comparison with the CRP. The Regulations Amending the Food and Drug Regulations (Improving Access to Generics) [the proposed Regulations] are intended to provide predictability for manufacturers filing drug submissions under Part C, Division 8, of the FDR as to whether to file an ANDS or a new drug submission (NDS). The proposed Regulations would also streamline labelling practices with respect to the labelling of drugs approved under Part C, Division 8,footnote 2 of the FDR to provide better transparency for Canadians regarding the medicinal ingredient in drugs they are taking.

Background

Health Canada’s 2003 policy interpretation

Health Canada’s 2003 policy, Interpretation of “Identical Medicinal Ingredient,” sets out the principles used to determine if two medicinal ingredients were considered identical or non-identical for the purposes of determining the pharmaceutical equivalence of the generic drug product and the CRP.

As outlined in the 2003 policy, “the term identical medicinal ingredient could literally be interpreted to imply medicinal ingredients that are both physically and chemically identical.” However, according to the 2003 policy, only the “chemical identicality” of the medicinal ingredients is taken into account when determining pharmaceutical equivalence. Consequently, Health Canada’s position as described in the 2003 policy was that “different complexes, esters or salts of the same active moiety are considered non-identical” and that “different isomers or mixtures with different proportions of isomers are considered non-identical.”

The policy defined active moiety (or therapeutic moiety) as the molecule or ion, excluding those appended portions of the molecule that cause the drug substance to be an ester, salt (including a salt with hydrogen or coordination bonds), or other non-covalent derivative (such as a complex or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.

The 2003 policy did not discuss the occurrence of changes to the form of the active pharmaceutical ingredient that may occur during the manufacturing process of the dosage form.

Apotex Inc. v. Canada (Health) 2013 FC 1217

In 2010, Apotex Inc. submitted an ANDS to Health Canada. The ANDS, if approved, would result in a notice of compliance (NOC) with a declaration of equivalence for Apotex Inc.’s product Apo-Telmisartan to the CRP Micardis. Health Canada’s position was that Apotex Inc.’s product was not eligible for the ANDS pathway due to differences in the medicinal ingredient in comparison with the CRP and therefore Health Canada refused the submission at the screening stage. Apotex Inc. applied for judicial review of Health Canada’s decision.

Health Canada’s view was that under the definition of “pharmaceutical equivalent,” the medicinal ingredient found in the dosage form must be identical to that of the CRP. Apotex, however, argued that the pharmaceutical equivalence ought to be assessed by comparing the starting ingredients used in the manufacturing of the dosage form. As explained by the Court, a chemical reaction may take place in Micardis given the non-medicinal ingredient sodium hydroxide. Some portion of the telmisartan is converted to a salt form of telmisartan, which would be telmisartan-sodium in the finished tablet. In the Apotex product, potassium hydroxide is used as a non-medicinal ingredient. A chemical reaction may take place converting some of the telmisartan into a salt form of telmisartan, which would be telmisartan-potassium. Health Canada was therefore of the view that Apo-Telmisartan and Micardis did not contain identical medicinal ingredients.

In December 2013, the Federal Court issued a judgment in which the Court found that the Minister of Health was unreasonable in her decision to reject the ANDS filed by Apotex Inc. at the screening stage and sent it back to Health Canada for reconsideration.

The decision noted that Health Canada’s 2003 policy, Interpretation of “Identical Medicinal Ingredient, did not address the point in a drug’s manufacture at which identicality is to be determined nor did it provide a clear definition of “medicinal ingredient.” Further, the Court held that the reference to “medicinal ingredient” in the phrase “identical medicinal ingredient” was the input ingredient, which the Court found to be telmisartan for both Apotex Inc.’s product and the CRP. Apotex Inc.’s ANDS was ultimately approved.

2015 Interim Policy on Health Canada’s Interpretation of Medicinal Ingredient

In response to the 2013 Federal Court decision, Health Canada provided guidance to industry by publishing an interim policy regarding the assessment of medicinal ingredients in cases of in-situ changes (e.g. when the medicinal ingredient undergoes a change in form during the manufacturing process of the dosage form). Health Canada reassessed its interpretation of medicinal ingredient for the purposes of the labelling requirements in subparagraph C.01.004(1)(c)(iv) of the FDR to mean the active pharmaceutical ingredient used as the raw material in the manufacture of the dosage form. Drug labels were to refer to the active pharmaceutical ingredient as the medicinal ingredient. For dosage forms in which the medicinal ingredient undergoes a change in form during the manufacturing process (e.g. in situ-changes), the label was to further indicate the form in the dosage form in brackets after the active pharmaceutical ingredient.

Under the 2015 interim policy, input ingredients would be considered the point of comparison for determining pharmaceutical equivalence for an ANDS, but if the medicinal ingredient in the generic drug product diverged into a different form than the CRP in the dosage form, additional safety, effectiveness and quality data could be required. However, if the generic and CRP’s medicinal ingredients were different forms at the input stage, but nonetheless converged into the same form in the dosage form, the medicinal ingredients would be considered “identical” and additional safety or effectiveness data would not be required.

2017 Interim Policy on Health Canada’s Interpretation of Medicinal Ingredient and Assessment of Identical Medicinal Ingredient

Prior to 2017, Health Canada’s position had been that different complexes, esters or salts of the same active (or therapeutic) moiety were considered non-identical, while different hydrated, solvated and polymorphic forms could be considered identical. The development of further experience and knowledge on the comparison of medicinal ingredients has led to an evolution of Health Canada’s view on what may be considered “identical.”

In the 2017 interim policy, Health Canada expanded on what may be acceptable as an ANDS and for which an NOC, which constitutes a declaration of equivalence, may be issued. Specifically, different salt forms of the same therapeutic moiety may now be considered to be filed through the ANDS pathway and potentially be approved as an ANDS. The interpretation of “medicinal ingredient” as stated in the FDR remained the same in the 2017 interim policy (i.e. the medicinal ingredient is the active pharmaceutical ingredient used in the manufacture of the dosage form).

In some cases, the active pharmaceutical ingredient undergoes a change in form during the manufacturing process of the dosage form. Where the medicinal ingredient in a generic drug product and its CRP are the same at the input stage and in the dosage form, an ANDS is the appropriate route. According to the 2017 interim policy, Health Canada also considers the following scenarios in determining whether two medicinal ingredients are “identical,” such that an ANDS may be the appropriate route for assessment, and whether additional data is required to support the ANDS:

Objectives

The objectives of the proposed Regulations include the following:

Description

ANDS submission pathway

A manufacturer may receive an NOC to market a generic drug product by filing an ANDS and having it approved by Health Canada. In an ANDS, among other data requirements, information must be submitted to demonstrate that the generic drug product is the pharmaceutical equivalent of the CRP.

Pharmaceutical equivalent

The proposed Regulations would make the following amendments to the definition of “pharmaceutical equivalent” in section C.08.001.1 of the FDR:

Amendments to the definition of “pharmaceutical equivalent” in section C.08.001.1 of the FDR would codify Health Canada’s policies and expectations towards different forms of the medicinal ingredient with the identical therapeutically active component (e.g. different salt forms) in a generic drug product in comparison to the CRP.

Therapeutically active component

Under the proposed Regulations, ANDS eligibility for drugs not referred to in Schedule C (radiopharmaceuticals) or Schedule D (biologicals) to the Food and Drugs Act would no longer be determined by a criterion of “identical medicinal ingredient.” Instead, ANDS eligibility would be determined by a test of “identical therapeutically active component.” In the proposed Regulations, “therapeutically active component” is defined as the following:

It is possible that the therapeutically active component is the same as the medicinal ingredient, if there are no appended portions that cause the medicinal ingredient to be a salt, hydrate or solvate. Under the proposed Regulations, the therapeutically active component in a generic drug product would be required to be chemically identical in comparison to that in the CRP.

Schedule C and Schedule D drugs

Schedule C drugs (radiopharmaceuticals) will continue to be able to use the ANDS pathway. Under the proposed Regulations, the scope of the ANDS pathway for radiopharmaceutical drugs under the FDR is not being changed. The existing definition of “pharmaceutical equivalent” will continue to apply to radiopharmaceutical drugs.

However, under the proposal, the Regulations would explicitly exclude an ANDS for a drug referred to in Schedule D of the Food and Drugs Act, commonly known as biologic drugs. Biosimilars (i.e. biologic drugs with demonstrated similarity to a previously approved reference biologic drug) must be approved through the existing NDS pathway under the FDR. However, these 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.

Safety and effectiveness

The proposed Regulations would also give the Minister specific authority to request information from a manufacturer in cases where the Minister has reasonable grounds to believe that there is a difference between the medicinal ingredient with the identical therapeutically active component in the dosage form of a generic drug product and the CRP. The Minister may request information that demonstrates that the difference, if any, between the medicinal ingredient in the generic drug product and the CRP is inconsequential with respect to the safety or effectiveness of the generic drug product.

Identification of the medicinal ingredient, labelling and strength of the dosage form

For new drugs regulated under Division 8 footnote 3 where the NDS, Extraordinary Use New Drug Submission (EUNDS), ANDS or Abbreviated Extraordinary Use New Drug Submission (AEUNDS) is filed after the coming into force of the proposed amendments, a reference to the medicinal ingredient of a new drug would be a reference to the form of the medicinal ingredient in the dosage form of the new drug.

The form of the medicinal ingredient would be 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. If the Minister is unable to make this determination because of uncertainty as to what constitutes the form of the medicinal ingredient in the dosage form, the Minister may request that the manufacturer provide information and materials on the medicinal ingredient. These requests may be made in the context of an NDS, EUNDS, ANDS, AEUNDS, or a supplement to any of those submissions, for a new drug regulated under Division 8 of the FDR.

In the case of a supplement, the Minister may request information to ensure the form of the medicinal ingredient in the dosage form has not changed due to any changes in the method of manufacture made in the supplement. Further, changes that result in a different medicinal ingredient with the identical therapeutically active component should continue to be filed by way of an NDS, EUNDS, ANDS or AEUNDS, rather than a supplement.

The proposed Regulations also clarify that the requirements in paragraphs C.08.002(2)(c) and C.08.003(2)(c) to submit specifications for the ingredients of a new drug are with respect to the ingredients used in the manufacture of the drug, and not the medicinal ingredient in the dosage form.

The proposed Regulations would require that the labels express the strength of the medicinal ingredient in the dosage form. Where the medicinal ingredient and the therapeutically active component (i.e. the medicinal ingredient, excluding those appended portions, if any, that cause the medicinal ingredient to be a salt, hydrate or solvate) are different, the label would be required to indicate the strength of the dosage form in terms of the therapeutically active component and the name of the medicinal ingredient in the dosage form [e.g. “Each tablet contains X mg of new drug (as new drug hydrochloride)”].

Notice of compliance

An NOC is issued to a manufacturer following the satisfactory review of a submission for a new drug and signifies compliance with the FDR. An ANDS- or AEUNDS-based NOC issued pursuant to subsection C.08.004(4) or C.08.004.01(4) of the FDR constitutes a declaration of equivalence to the CRP. The proposed Regulations would require that an ANDS- or AEUNDS-based NOC for a generic drug product make note of any difference between the medicinal ingredient in the generic drug product in comparison to the medicinal ingredient in the CRP.

Data protection

The FDR provide a period of market exclusivity for certain innovators. “Innovative drugs,” as defined in the FDR, are protected from competition for a period of eight years through the protection of innovator data (i.e. a six-year no filing period and a two-year no marketing period for a drug submission making a direct or indirect comparison to an innovative drug). The North American Free Trade Agreement (NAFTA), Canada-European Union Comprehensive Economic and Trade Agreement (CETA) and World Trade Organization/Trade-Related Aspects of Intellectual Property Rights (TRIPS) include an obligation to protect undisclosed test data submitted to regulatory authorities by companies for the purpose of proving that a drug that uses a new chemical entity is safe and effective.

In the FDR, “innovative drug” is defined as a drug that contains a medicinal ingredient not previously approved in a drug by the Minister that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph. The proposed Regulations would amend the definition of “innovative drug” in section C.08.004.1 of the FDR so that the description of a “variation” of a medicinal ingredient is consistent with the terminology used to describe medicinal ingredients in relation to a “therapeutically active component.”

At the same time, the variations referred to in the 2006 definition of “innovative drug” are maintained in the proposed amendment, and the list of variations that prevent a drug from being an “innovative drug” is broader than the list of differences eligible to be assessed through the ANDS pathway under the proposed Regulations. The proposed Regulations that provide for the medicinal ingredient to be considered the form in the dosage form also apply to the medicinal ingredient as used in the “innovative drug” definition.

Under the proposed amendment, “innovative drug” would be defined 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. A “variation” would include

The appended portions of a medicinal ingredient that make it a salt, ester, hydrate or solvate are first determined by considering chemical structure. In some cases, it may still be unclear which part of a medicinal ingredient is an appended portion for the purposes of section C.08.004.1. For example, where a medicinal ingredient is an ester, an ester linkage connects two parts of the medicinal ingredient. In cases where it remains unclear after considering the chemical structure, the appended portion would also be determined for the purposes of section C.08.004.1 by identifying the non-principal part of the medicinal ingredient that is not primarily responsible for the mechanism of action of the medicinal ingredient.

Coming into force and transitional provisions

The proposed Regulations would come into force 90 days after being registered. The proposed amendments would not apply to drugs where the NDS, EUNDS, ANDS or AEUNDS was filed before the coming-into-force date. For greater certainty, the proposed Regulations specify that the version of the “innovative drug” definition that was in effect at the time an NDS or an EUNDS was filed by the innovator is the version that applies for that “innovative drug.”

Consequential amendments to the Fees in Respect of Drugs and Medical Devices Regulations

Currently, the definition of “new active substance” in Schedule 1 of the Fees in Respect of Drugs and Medical Devices Regulations is aligned with the definition of “innovative drug” in the Food and Drug Regulations. The proposed amendments would ensure the terms “new active substance” and “innovative drug” remain in alignment.

Regulatory development

Consultation

A notice to interested parties was published in June 2017 seeking stakeholder feedback on potential changes to the FDR relating to the requirements and terminology for establishing equivalence between a proposed generic drug product and the CRP.

The respondents included veterinary and human drug manufacturers from the innovative and generic industries, as well as pharmacy and hospital regulatory and professional associations. In general, respondents supported the idea of harmonizing Health Canada’s generic drug review practices with those of international regulators. Federal, provincial and territorial drug plan managers have responded positively to approaches that may increase the availability of generic drugs and lower drug costs. However, common concerns emerged about terminology, proposed concepts and data requirements.

In response to the feedback, Health Canada drafted the regulatory proposal to focus on addressing generic drug products with different forms of the medicinal ingredient by introducing a regulatory definition of “therapeutically active component.” This will form the basis for comparing a generic drug product to its CRP and help ensure that innovator and generic drug manufacturers label their products appropriately and also enhance the transparency and predictability of regulatory requirements. The revised proposal also clarifies the different forms eligible for assessment under the ANDS pathway. Further, the proposed amendments provide that the requirement to submit specifications for the ingredients of the new drug is limited to the ingredients used in the manufacture of the drug.

Modern treaty obligations and Indigenous engagement and consultations

Indigenous peoples would not be specifically impacted by this proposal.

Instrument choice

Health Canada considered regulatory and non-regulatory options, including

  1. Status quo: Under this option, Health Canada would continue to follow the 2017 Interim Policy on Health Canada’s Interpretation of Medicinal Ingredient and Assessment of Identical Medicinal Ingredient. As outlined in this policy, the medicinal ingredient would continue to be interpreted as the active pharmaceutical ingredient used as the raw material (input stage) in the manufacture of the dosage form. Under this policy, labels would not always reflect the form of the medicinal ingredient in the dosage form, or the strength of the therapeutically active component. Health Canada is of the view that to create greater consistency and transparency with respect to the labelling of new drugs approved under Division 8 of the FDR, the product labelling should indicate the strength of the therapeutically active component, as well as the form of the medicinal ingredient in the dosage form. In addition, the 2017 interim policy does not explicitly outline the types of differences in the medicinal ingredient of a generic drug that would be acceptable as an ANDS.
  2. Non-regulatory: Under this option, Health Canada would maintain the existing regulatory framework and expand on the 2017 interim policy through a guidance document. The guidance document would outline the acceptable differences in the medicinal ingredient in a generic drug in comparison with a CRP. However, without further clarification of the term “identical medicinal ingredient” in the FDR, there would still be uncertainty on its interpretation. Further, as in the first option, the medicinal ingredient would continue to be interpreted as the active pharmaceutical ingredient used as the raw material (input stage) in the manufacture of the dosage form, as outlined in the 2017 interim policy, and product labelling would not reflect the medicinal ingredient and the strength in the final dosage form.
  3. Regulatory: The regulatory option was chosen as the preferred option. There is a need for the FDR to clearly address submissions for generic drugs with different forms of the medicinal ingredient in comparison to the CRP. Providing this solution would improve clarity and predictability for manufacturers filing drug submissions under Division 8 of the FDR. In addition, regulatory amendments are necessary to ensure the labelling of a new drug under Division 8 includes the medicinal ingredient in the dosage form, as well as the strength expressed as the therapeutically active component, to provide consistency and transparency with respect to labelling.

Regulatory analysis

Benefits and costs

The regulatory proposal could result in health and safety benefits for Canadians. The regulatory proposal would provide greater certainty to industry by clarifying the different medicinal ingredients with the identical therapeutically active component that would be eligible to go through the ANDS pathway. Given this greater certainty, Health Canada estimates that four to five submissions per year would go through the ANDS pathway, rather than the NDS pathway.

When Health Canada approves an ANDS, the NOC issued constitutes a declaration of equivalence. The declaration of equivalence received for a drug approved by the ANDS pathway facilitates processes by provincial and territorial jurisdictions for interchangeability decisions. Increased availability of generic drug products could result in broader drug coverage or health system improvements through cost savings for provinces and territories, or it could lead to drug insurance providers providing coverage for generic versions of drugs that are cost prohibitive. Health and safety would be improved under these scenarios.

The regulatory proposal is not expected to result in increased costs to Government, industry, consumers or Canadians. Drug review fees for pre-market submissions are not set by the type of submission, but by the information contained in the submission. A sponsor that submits the same data for an NDS or an ANDS will be charged the same fee. NDSs and ANDSs are reviewed under the current regulatory framework. The technical requirements for these submissions would also essentially be the same whether an NDS or an ANDS was filed. It is Health Canada’s intent to only use the proposed authorities to request information from a manufacturer in keeping with the expectations currently set out in the Health Canada Guidance Document: Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs).

Small business lens

The generic drug industry is a mix of Canadian-based and foreign multinational enterprises and smaller companies. It is anticipated that small businesses would benefit from the greater certainty provided by the proposal in the same way as the rest of the industry.

“One-for-One” Rule

The “One-for-One” Rule does not apply to this proposal, as there is no incremental change in administrative burden on business.

Regulatory cooperation and alignment

Provincial-territorial

Health Canada must issue an NOC for a new drug before a generic drug product can be sold in Canada. Each province and territory manages a drug insurance plan that covers a unique inclusive list of drugs (i.e. a formulary), which the drug insurance plan will cover with or without eligibility requirements. Provinces and territories also have mandatory drug interchangeability requirements (i.e. the substitution of a generic drug for a brand name drug), and provide a list of eligible generic drugs for substitution. The interchangeability listing process is often facilitated by the declaration of equivalence provided by an ANDS-based NOC.

Certain provinces and territories are independently assessing the interchangeability of drug products for inclusion in their formularies (e.g. including differences in the form of the medicinal ingredients). Provincial and territorial drug plans that accept drug products with different salt forms of the medicinal ingredient as being interchangeable include Alberta, Ontario and Nova Scotia. The regulatory proposal would facilitate processes for generic drug products with different medicinal ingredients (e.g. different salts) as being interchangeable.

International

This regulatory proposal could reduce regulatory differences with other jurisdictions such as the United States Food and Drug Administration (U.S. FDA) and the European Union (EU) European Medicines Agency (EMA).

Both the U.S. FDA and EMA address generic drug products with different forms of the medicinal ingredient within their regulatory frameworks. The U.S. FDA has a separate regulatory pathway for differences in the form of the medicinal ingredient called a “505(b)(2) Application,” whereas the EMA allows these differences to be filed under the same pathway as identical generics (Directive 2001/83/EC).

According to the U.S. FDA and EMA guidelines, bioequivalence can be established between two drugs. The EMA, however, will authorize generic drug products that contain a different salt than the reference product as long as therapeutic equivalence is based on bioequivalence studies and the generic drug products containing the different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of a medicinal ingredient do not differ significantly in properties with regard to safety and/or efficacy.

The regulatory proposal is aligned with the practices of both the EMA and the U.S. FDA. One minor difference between this proposal and what is in place at the U.S. FDA is that Health Canada is proposing to use the existing ANDS regulatory pathway under the FDR, rather than proposing an alternative regulatory pathway (as is in place with the U.S. FDA). A specific regulatory pathway for pharmaceutical alternatives was not considered necessary as generic drug products can be regulated within the existing ANDS provisions of the FDR.

Health Canada and other regulatory authorities are engaged in international collaborative initiatives to facilitate information sharing among regulators and address increasing challenges associated with the regulation of pharmaceuticals. Internationally harmonized standards (where they exist) and the practices of other major regulatory authorities (e.g. the U.S. FDA, EMA) have been taken into consideration to leverage the work of these initiatives to facilitate access to safe, effective, and high-quality drugs for Canadians.

Strategic environmental assessment

In accordance with the Cabinet Directive on the Environmental Assessment of Policy, Plan and Program Proposals, a preliminary scan concluded that a strategic environmental assessment is not required.

Gender-based analysis plus

No gender-based analysis plus (GBA+) impacts have been identified for this proposal.

Rationale

ANDS submission pathway

The proposed Regulations are intended to codify Health Canada’s expectations and policies towards differences in the form of the medicinal ingredient in a generic drug product in comparison to the CRP.

Generic drug products with the following differences in the medicinal ingredient (with the identical therapeutically active component) in comparison to CRP would be eligible to be assessed through the ANDS pathway:

Different salts, similar to different solvates and hydrates, will dissociate upon dissolution of the dosage form to yield the identical therapeutically active component or, in the case of liquid dosage forms, will already be dissociated in the dosage form to yield the identical therapeutically active component. Different salts, solvates and hydrates can therefore be submitted for assessment under the ANDS pathway.

The following differences, however, would not be eligible to be assessed through the ANDS pathway:

There is inherent complexity and uncertainty in the behaviour of complexes and clathrates in delivering their therapeutic effect, and they typically do not dissociate to yield the identical therapeutically active component in solution. Further, esters do not dissociate to yield the identical therapeutically active component in solution. Finally, different isomers have different spatial arrangement of the compounds and could therefore have different pharmacological activities (e.g. the two enantiomers of thalidomide).

The term “therapeutically active component” differs from the scientific term “active moiety,” which was used in Health Canada’s 2003 policy. The term “active moiety” is widely used in the pharmaceutical field and means the molecule or ion, excluding those appended portions of the molecule that cause the drug substance to be an ester, salt (including a salt with hydrogen or coordination bonds), or other non-covalent derivative (such as a complex or clathrate) of the molecule, responsible for the physiological or pharmacological action of the medicinal ingredient.

However, different esters, complexes and clathrates when compared to the CRP are not considered eligible to be assessed under the ANDS pathway. Therefore, the term “therapeutically active component” is being used to describe the portion of the molecule that is required to be identical, and which differences would be eligible to be assessed under the ANDS pathway.

Schedule C and Schedule D drugs

Unlike for pharmaceutical drugs, for Schedule C (i.e. radiopharmaceutical) drugs there is no clearly established scientific data demonstrating that differences in forms of a generic and a CRP will always lead to indistinguishable clinical outcomes (nor is such scientific data likely to arise). The differences in forms of a generic and a CRP for Schedule C drugs lead to clinical ramifications (because it results in different amounts of radiation absorbed by the body due to differences in tissue uptake, overall distribution in the body, etc.).

Due to the size, complexity and natural variability of Schedule D (i.e. biologic) drugs, and because biologic drugs are made in living cells rather than with chemicals, a biosimilar and its reference biologic drug can be shown to be highly similar, but not identical. Therefore, the ANDS pathway is not considered appropriate for approval of biologic drugs. However, 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.

Medicinal ingredient and labelling

The proposed Regulations are intended to streamline labelling practices and create greater consistency and transparency with respect to the identification of the medicinal ingredient and the labelling for drugs approved under Part C, Division 8, of the FDR. Following the 2013 Federal Court decision and the subsequent 2015 and 2017 interim policies, the medicinal ingredient is the input ingredient used in the manufacturing process. However, under the proposed Regulations, the medicinal ingredient would be considered the form of the medicinal ingredient in the dosage form, as determined by the Minister.

Further, to support transparency, Health Canada’s position is that the labelling should include the name of the form of the medicinal ingredient in the dosage form, and not the input ingredient. Health care professionals rely on labelling of pharmaceutical products to know what is to be administered or prescribed to patients.

In addition, deviations in the expression of strength between a generic and its CRP may create confusion and possible medication errors when the strengths are expressed differently. This may lead to inaccurate dosing, especially in cases that require additional preparation instructions, where calculations are based on what the health care practitioner understands as the strength of the therapeutically active component in the formulation.

The proposed Regulations would create a consistent practice for the expression of strength (e.g. in terms of the therapeutically active component where it is different from the medicinal ingredient).

Data protection

Amendments to the data protection provisions under the FDR ensure that the integrity of the data protection framework is maintained by aligning the terminology in the definition of “innovative drug” with respect to variations with that used in the new definition of “therapeutically active component” under the ANDS pathway, but at the same time maintaining the variations referred to in the 2006 definition of “innovative drug.” As a result, the list of variations that prevent a drug from being an “innovative drug” is broader than the list of differences eligible to be assessed through the ANDS pathway under the proposed Regulations. A variation would also be described in terms of a medicinal ingredient, excluding those appended portions that cause the medicinal ingredient to be a salt, an ester, a hydrate or a solvate.

The proposed amendment to the definition of “innovative drug” in the regulatory proposal would more clearly articulate the original regulatory intent behind excluding certain variations from the scope of data protection and would facilitate the assessment of drugs with respect to “innovative drug” status.

Implementation, compliance and enforcement, service standards

Guidance on the implementation of this regulatory proposal would be outlined in Health Canada’s guidance documents Generic Drug Equivalence: Medicinal Ingredients and Identifying and Labelling Medicinal Ingredients in New Drug Products. Service standards are outlined in Health Canada’s Guidance for Industry: Management of Drug Submissions.

Contact

Bruno Rodrigue
Director
Office of Legislative and Regulatory Modernization
Health Products and Food Branch
Health Canada
Holland Cross, Suite 14
11 Holland Avenue
Ottawa, Ontario
K1A 0K9
Address locator: 3000A
Email: hc.lrm.consultations-mlr.sc@canada.ca

PROPOSED REGULATORY TEXT

Notice is given that the Governor in Council makes the annexed Regulations Amending the Food and Drug Regulations (Improving Access to Generics) pursuant to

(a) subsection 19(1) footnote a of the Financial Administration Act footnote b; and

(b) section 30 footnote c of the Food and Drugs Act footnote d.

Interested persons may make representations concerning the proposed Regulations within 70 days after the date of publication of this notice. All such representations must cite the Canada Gazette, Part I, and the date of publication of this notice and be addressed to Bruno Rodrigue, Director, Office of Legislative and Regulatory Modernization, Health Products and Food Branch, Department of Health, Address Locator: 3000A, 11 Holland Avenue, Suite 14, Ottawa, Ontario K1A 0K9 (email: hc.lrm.consultations-mlr.sc@canada.ca).

Ottawa, March 22, 2019

Jurica Čapkun
Assistant Clerk of the Privy Council

Regulations Amending the Food and Drug Regulations (Improving Access to Generics)

Amendments

1 Paragraph C.01.004(1)(c) of the Food and Drug Regulations footnote 4 is amended by adding the following after subparagraph (iv):

2 Subsection C.01.004.02(1) of the Regulations is amended by adding the following after paragraph (b):

3 Section C.01.004.03 of the Regulations is amended by striking out “and” at the end of paragraph (b) and by adding the following after paragraph (b):

4 The Regulations are amended by adding the following after section C.08.001:

C.08.001.01 (1) For the purposes of this Division, 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.

(2) If the Minister is unable to make this determination because of uncertainty as to what constitutes the form of the medicinal ingredient in the dosage form of the new drug, the manufacturer who has filed a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission, an abbreviated extraordinary use new drug submission or a supplement to any of those submissions, shall, at the request of the Minister, provide information and materials on the medicinal ingredient.

5 (1) The definition pharmaceutical equivalent in section C.08.001.1 of the Regulations is replaced by the following:

pharmaceutical equivalent means

(2) Section C.08.001.1 of the Regulations is amended by adding the following in alphabetical order:

therapeutically active component means a medicinal ingredient, excluding those appended portions, if any, that cause the medicinal ingredient to be a salt, hydrate or solvate. (composant thérapeutique actif)

6 Paragraph C.08.002(2)(c) of the Regulations is replaced by the following:

7 (1) The portion of subsection C.08.002.1(1) of the Regulations before paragraph (a) is replaced by the following:

(1) A manufacturer of a new drug, other than a new drug listed in Schedule D of the Act, may file an abbreviated new drug submission or an abbreviated extraordinary use new drug submission for the new drug where, in comparison with a Canadian reference product,

(2) Section C.08.002.1 of the Regulations is amended by adding the following after subsection (3):

8 Paragraph C.08.003(2)(c) of the Regulations is replaced by the following:

9 Section C.08.004 of the Regulations is amended by adding the following after subsection (4):

(5) If there is a difference between the medicinal ingredient in the new drug and the medicinal ingredient in the Canadian reference product, the difference shall be stated in the notice of compliance referred to in subsection (4).

10 Section C.08.004.01 of the Regulations is amended by adding the following after subsection (4):

(5) If there is a difference between the medicinal ingredient in the new drug and the medicinal ingredient in the Canadian reference product, this difference shall be stated in the notice of compliance referred to in subsection (4).

11 (1) The definition innovative drug in subsection C.08.004.1(1) of the Regulations is replaced by the following:

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)

(2) Subsection C.08.004.1(1) of the Regulations is amended by adding the following definition in alphabetical order:

variation includes, for the purposes of the definition innovative drug,

Consequential Amendment to the Fees in Respect of Drugs and Medical Devices Regulations

12 The portion of item 1 of Schedule 1 to the Fees in Respect of Drugs and Medical Devices Regulations footnote 5 in column 2 is replaced by the following:

Item

Column 2

Description

1

Submissions in support of a drug, excluding a disinfectant, 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, which includes

  • (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).

Transitional Provision

13 (1) The amendments set out in these Regulations do not apply in respect of a new drug that, before the coming into force of these Regulations, is the subject of a new drug submission, an extraordinary use new drug submission, an abbreviated new drug submission or an abbreviated extraordinary use new drug submission.

(2) For greater certainty, the version of the definition innovative drug in subsection C.08.004.1(1) of the Food and Drug Regulations that applies is the version of that definition that was in effect at the time the new drug submission or extraordinary use new drug submission was filed by the innovator in respect of the innovative drug in question.

Coming into Force

14 These Regulations come into force 90 days after the day on which they are registered.