Notice: Application of the definition of Canadian Reference Product
January 26, 2024
Our file number: 23-111326-154
Generic drugs are generally approved by Health Canada through the Abbreviated New Drug Submission (ANDS) or Abbreviated Extraordinary Use New Drug Submission (AEUNDS) pathways. In order for drug submissions to be filed through these pathways, specific criteria must be met by a generic drug in relation to the Canadian Reference Product (CRP) as outlined in subsection C.08.002.1(1) of the Food and Drug Regulations (FDR).
The purpose of this Notice is to advise stakeholders of the Department's application of the definition of CRP in section C.08.001.1 of the FDR. Following the recent Spring 2023 consultation, Health Canada confirms that a drug listed as 'Dormant' in the Drug Product Database (DPD) can be considered to be evidence that the drug is "no longer marketed", as used for the purpose of paragraph C.08.001.1(b) of the FDR. Further details are provided in the Application section below.
Definition of CRP
Section C.08.001.1 of the FDR states the following:
Canadian reference product means
- a drug in respect of which a notice of compliance is issued under section C.08.004 or C.08.004.01 and which is marketed in Canada by the innovator of the drug,
- a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, where a drug in respect of which a notice of compliance has been issued under section C.08.004 or C.08.004.01 cannot be used for that purpose because it is no longer marketed in Canada, or
- a drug, acceptable to the Minister, that can be used for the purpose of demonstrating bioequivalence on the basis of pharmaceutical and, where applicable, bioavailability characteristics, in comparison to a drug referred to in paragraph (a);
As outlined in the Guidance Document: Regulatory requirements for Drug Identification Numbers (DINs), after a drug has been marketed, it is possible that there may be periods where the manufacturer has not sold the drug.
Manufacturers of the following drug types for human use are required under section C.01.014.71 of the FDR to submit a notification to Health Canada within 30 calendar days after a period of 12 consecutive months that a drug has not been sold on the Canadian market by the manufacturer:
- Drugs included in Schedules I, II, III, IV or V to the Controlled Drugs and Substances Act
- Prescription drugs
- Drugs listed in Schedules C and D to the Food and Drugs Act
- Drugs that may be sold without a prescription, but are administered only under a practitioner's supervision (e.g., hemodialysis solutions, pre-filled syringes with epinephrine for severe allergic reactions, magnetic resonance imaging (MRI) contrast agents, insulins and vaccines).
After a complete notification is received and processed, Health Canada updates the status of the drug in the DPD to 'Dormant'. A drug that is deemed 'Dormant' is still authorized for sale in Canada.
Manufacturers of all other drugs are still encouraged to report 12 months without sale within 30 days as this will allow Health Canada as well as patients, health care practitioners, and other health care stakeholders to have a clear and up to date picture of which drugs are available on the Canadian market.
For all marketed drugs, which have been issued a DIN under subsection C.01.014.2(1) of the FDR, the manufacturer must indicate, on the Annual Drug Notification Form (ADNF), whether the drug is 'Dormant' at the time of filing the ADNF (pursuant to subparagraph C.01.014.5(1)(a)(ii) of the FDR).
Pursuant to section C.01.014.72 of the FDR, if the manufacturer restarts the sale of a drug that was previously reported as 'Dormant', the manufacturer must return, within 30 days after re-starting sale of the drug, a signed and dated Drug Notification Form (DNF).
If a decision is made to permanently cease the sale of a given drug, drug manufacturers must notify the Minister pursuant to section C.01.014.7 of the FDR. The Minister would then cancel the DIN and update the DPD to reflect the drug's 'Cancelled Post-Market' rather than 'Dormant' status.
For a variety of reasons, drugs that would otherwise meet the definition of CRP in paragraph C.08.001.1(a) of the FDR may cease being marketed. In cases where a drug that would otherwise have been identified as the CRP in accordance with paragraph C.08.001.1(a) is listed as 'Dormant' in the DPD, Health Canada confirms that this 'Dormant' status can be considered to be evidence that the drug is "no longer marketed", as used in paragraph C.08.001.1(b) of the FDR. In such situations, a manufacturer may file an ANDS or AEUNDS using an alternate CRP (e.g., a generic drug) in accordance with paragraph C.08.001.1(b), provided the alternate CRP is otherwise acceptable to the Minister. Preferably, the CRP identified in accordance with paragraph C.08.001.1(b) would have been approved through the issuance of a Notice of Compliance under the ANDS or AEUNDS pathway by demonstrating bioequivalence on the basis of pharmaceutical and where applicable bioavailability characteristics with the 'Dormant' drug that would otherwise have been identified as the CRP in accordance with paragraph C.08.001.1(a).
Manufacturers of generic drugs should be aware that a drug may be listed as 'Dormant' in the DPD despite sales of that drug having since restarted for up to 6 weeks. This 6-week period reflects the 30 days that a manufacturer has to notify Health Canada that it has restarted the sale of its drug (pursuant to section C.01.014.72 of the FDR) and also accounts for the time necessary for Health Canada to process the manufacturer's DNF and update the DPD.
If a generic manufacturer files a submission under the ANDS or AEUNDS pathway using a CRP identified in accordance with paragraph C.08.001.1(b) and it is determined (after receipt of the submission) that the drug listed as 'Dormant' in the DPD, which would otherwise have been identified as the CRP in accordance with paragraph C.08.001.1(a), had restarted sales and was therefore 'marketed' on the date of submission filing, the ANDS or AEUNDS may be requested to be withdrawn and/or may be subject to a negative decision. This withdrawal and/or negative decision would be based on the ANDS' or AEUNDS' being ineligible to rely on an alternate CRP under paragraph (b) of the CRP definition due to the marketed status of the CRP identified in accordance with paragraph C.08.001.1(a) at the time of ANDS or AEUNDS filing. The manufacturer would then be requested to file a new submission using the CRP identified in accordance with paragraph C.08.001.1(a) (and would be subject to any applicable fees).
While the approach described above remains the same as the proposal described in the consultation, based on stakeholder feedback received, the information below is provided for greater clarity.
- The approach described above only applies to submissions filed under the ANDS and AEUNDS pathways, and not to biosimilar drugs subject to new drug submissions.
- It is acknowledged that the approach described above (i.e., cases involving 'Dormant' status) may only represent a small fraction of all potential scenarios that may be faced by a generic drug manufacturer seeking to file an ANDS or AEUNDS. For scenarios not covered by the above approach, manufacturers are welcome to seek additional input from the Department through the usual communication channels respecting the application of the CRP definition.
Assessment of Canadian Reference Product
- Based on the existing legal framework under the FDR, the assessment of whether a proposed alternate reference product in accordance with paragraph C.08.001.1(b), can be relied on by an ANDS or AEUNDS manufacturer will be made based on the marketing status of the CRP identified in accordance with paragraph C.08.001.1(a) at the time of ANDS or AEUNDS filing.
- For greater clarity, any changes to the marketing status of drugs that occur after the date of the ANDS filing will not impact the assessment nor require re-assessment of the appropriateness of the CRP (which is determined as of the time of ANDS filing).
Potential for submission withdrawal and/or a negative decision
- There is a potential for submission withdrawal and/or a negative decision in cases where an ANDS or AEUNDS seeks to rely on a CRP in accordance with paragraph C.08.001.1(b) but at the time of ANDS or AEUNDS filing the drug identified as the CRP in accordance with paragraph C.08.001.1(a) was in fact marketed.
- The approach described above relies on updates to the DPD to assess the 'Dormant' or 'Marketed' status of CRPs identified in accordance with paragraph C.08.001.1(a) at the time of ANDS or AEUNDS filing. These updates to the DPD are based on notifications that drug manufacturers are required to make to the Minister under the FDR.
- However, in cases where an ANDS or AEUNDS seeks to rely on a CRP identified in accordance with paragraph C.08.001.1(a), but at the time of filing the CRP identified in accordance with paragraph C.08.001.1(a) is no longer marketed, the ANDS or AEUNDS may continue to rely on that CRP pursuant to paragraph (b) of the CRP definition.
- While it is understood that the above approach is unlikely to resolve all challenges associated with generic drug development, it should nevertheless provide a degree of clarity and predictability when contending with the specific scenario outlined.
Any questions related to this Notice may be directed to:
Bureau of Policy, Science and International Programs
Pharmaceutical Drugs Directorate
Health Products and Food Branch
- Date modified: