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Canadian Reference Product

Drugs Directorate
Tunney's Pasture
Postal Locator # 0702A
OTTAWA, Ontario
K1A 0L2

December 5, 1995

Subject: Canadian Reference Product

Please find attached the Drugs Directorate Policy regarding the use of a non-Canadian Reference Product under the provisions of Section C.08.002.1(c) of the Food and Drug Regulations.

The comments received in response to my letter of March 15, 1995, have been reviewed and a number of the suggestions incorporated into the current policy. For your information, a summary of the other comments received, together with our analysis of them, is attached (Appendix I). I hope that this information is helpful to you.

This policy is effective immediately. If you have any questions or comments, please do not hesitate to contact Dr. Norman Pound, Chief, Division of Biopharmaceutics Evaluation, Drugs Directorate at (613) 941-9522.

Original Signed by/

Dann M. Michols
Director General

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Appendix I - Consultation

Comments concerning the draft policy were solicited from the stakeholders. Thirteen responses were received (7 from provincial governments, 1 from health professionals and 5 from pharmaceutical manufacturers). Three of the respondents agreed with the proposal as it is. Several others had specific comments which have been incorporated in the revised policy. In addition, a number of concerns identified in this policy have been considered and addressed as follows:

1. Some respondents had a concern that the innovator product marketed in Canada and in another country may differ therapeutically.
   
   Response:
   
   The policy calls for a full pharmaceutical equivalence between the Canadian and non-Canadian reference products as well as other criteria. It is our position that any remaining difference is not likely to be therapeutically significant for the classes of drugs covered by this policy.
   
   
2. The policy is not consistent with the Drugs Directorate's unwillingness to accept foreign reviews for innovative products. Policy is beneficial only to the generic sector.
   
   Response:
   
   The policy is not intended to benefit one sector of the industry over another. It will also apply to changes in innovative formulations involving a bioequivalence study.
   
   
3. Some respondents disagreed with points b) and c) under Purpose as they imply that demonstration of bioequivalence against the innovator's product marketed in Canada is the exception rather than the rule. It was also pointed out that under "Purpose", paragraph (c) includes the possibility to compare a second entry product to another generic or to a similar dosage form.
   
   Response:
   
   Points b) and c) under Purpose are quotes from Section C.08.002.1 of the Regulations to the Food and Drugs Act. This policy establishes the acceptance criteria for the use of a non-Canadian reference product, pursuant to paragraph (c) of this Regulation. It is restricted to products marketed in other countries by the Canadian innovator.
   
   
4. Criteria 2 is likely to be used to refute bioequivalence of any drug.
   
   Response:
   
   Criterion 2 is to make provision for the exclusion of dosage forms or ingredients with demonstrated bioavailability problems. Criteria 6 a), b) and c) further elaborate on the condition outlined in criteria 2.
   
   
5. Criteria 6c) i) should also consider simple combination products.
   
   Response:
   
   Definition of simple combinations can be controversial. All combinations drug products are currently classified as "complicated" as defined by the Expert Advisory Committee on Bioavailability Report C. As outlined under 6b), this policy is restricted to "uncomplicated drugs" at this time.
   
   
6. Criteria 6c) ii) - "same" contradicts the preamble.
   
   Response:
   
   Full pharmaceutical equivalence with regard to the quantity of medicinal ingredients is intended under this criterion.
   
   
7. The same clinical data for the reference is used to register worldwide, therefore, it does not matter where the reference was purchased.
   
   Response: This is a complex issue, i.e., clinical judgement and experience as well as regulatory evaluation of the clinical data in one country may be different from others. The issue at hand is the bioequivalence of the subsequent entry products with the innovator's formulation marketed in Canada.
   
   
8. Rationale of the policy is sound and need not be restricted only to drugs which are "uncomplicated" and conventional release. Criterion 1 should be expanded beyond immediate release solid oral dosage forms.
   
   Response:
   
   The potential for problems arising from differences in formulation is greater for complicated drugs and/or modified release dosage formulations. For this reason the policy has been restricted to uncomplicated drugs and immediate release products at this time.
   
   
9. Exclusion of liquid oral and injectables is not justified. Expand criteria to include these as well as suspensions, solutions or topicals formulations.
   
   Response:
   
   Extension of the policy to encompass these products will be considered in future.
   
   
10. The Drugs Directorate should require manufacturing documents ensuring that Canadian and foreign reference products were manufactured by the same process.
    
    Response:
    
    In general, this documentation is not available to the submission sponsors. It is our position that, for drugs which meet the criteria in this policy, differences, if any, in the manufacturing process between the samples of the innovator's product which is used as a reference product and that which is sold in Canada are unlikely to be significant.
    
    
11. Do the rules of proportionality apply or must each strength be tested in vitro?
    
    Response:
    
    The proportionality policy applies within a product line and is not relevant to comparison between the strengths of the same innovator product marketed in two different countries.
    
    
12. Criterion 6c) iii) - the innovator can adjust colour, shape or size to thwart a generic.
    
    Response:
    
    If the colour is different, it increases the likelihood that other ingredients in the formulations may be significantly different. Shape and size differences can result in a biopharmaceutical problems and hence the restriction has been retained in the policy.
    
    
13. Criteria 4 and 6c)i) - it should be clear that the products must contain the same salt form and (when important) the same polymorphic form of the medicinal ingredient for acceptance as reference.
    
    Response:
    
    The products must contain the same ingredient, including the same salt form. It is unlikely that the two samples of the innovator's product would contain different polymorphs. However, if polymorphism were considered to be a concern, this would be addressed under criteria 2.

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POLICY Issue
from the Drugs Directorate

Canadian Reference Product

Purpose

Revisions to Section C.08.002.1 of the Food and Drug Regulations provide a definition for the Canadian Reference Product, in connection with the filing of an Abbreviated New Drug Submission. Under the regulations, "Canadian Reference Product" means:

1. "a drug in respect of which a notice of compliance is issued pursuant to section C.08.004 and which is marketed in Canada by the innovator of the drug,
   
   
2. 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 pursuant to section C.08.004 cannot be used for that purpose because it is no longer marketed in Canada, or
   
   
3. 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)".

This policy establishes acceptance criteria for the use of a non-Canadian reference product, pursuant to paragraph (c) of this regulation.

Background

The purpose of demonstrating equivalence against the Canadian innovator's product is to provide evidence that the safety and efficacy profiles of the subsequent-entry (generic) product will be comparable to that of the innovative product which is marketed in Canada and for which safety and efficacy has been demonstrated clinically.

However, with the increasing globalization of the drug industry, many products are manufactured with the same formulations and under the same conditions to benefit from economies of scale and to facilitate registration with various regulatory agencies. On occasion, products are manufactured in only one location for world wide distribution.

In such instances, to reduce costs and to avoid unnecessary exposure of subjects to drugs, the Drugs Directorate will consider comparative bioavailability data which has been generated using a sample of the innovative product purchased outside Canada. It is recognized that it can not be established unequivocally that the product marketed in Canada and the "foreign" reference standard are identical, but it is our opinion that, even if slight differences should exist between products which meet the following criteria, the differences would be of no therapeutic consequence.

Criteria

In order for a drug product purchased in another country to be considered acceptable for use as Canadian Reference Product, it must comply with the following criteria:

1. The drug product must be a conventional, immediate-release solid oral dosage form, i.e. tablets or capsules.
   
   
2. There is no documented evidence of bioavailability problems related to the medicinal ingredient or the drug product, or ingredients or products of similar chemical structure or formulations.
   
   
3. It must be documented that the drug product is authorized for marketing by the health authority of a country with drug assessment criteria documented to be comparable to those in Canada as required by Division 8 of the Food and Drugs Act and interpreted in Drugs Directorate guidelines and policies.
   
   
4. It must be documented that the drug product is marketed in the country of origin by the same innovator company or corporate entity which currently markets the same medicinal ingredient in the same dosage form in Canada, or that it is marketed in the country of origin through a licensing arrangement with the innovator company or corporate entity which currently markets the product in Canada.
   
   
5. Copies of the labelling for the drug product and the innovator product marketed in Canada, together with Certificates of Analysis for both products, analyzed using the specifications proposed in the submission for the second-entry product, must be provided.
   
   
6. The medicinal ingredient and the drug product must satisfy the following criteria:
   
   
   1. the medicinal ingredient exhibits an aqueous solubility of more than 1%.
      
      
   2. the medicinal ingredient is "uncomplicated" as defined in the Drugs Directorate Guideline: Conduct and Analysis of Bioavailability and Bioequivalence Studies; Part A: Oral Dosage Formulations Used for Systemic Purposes, e.g, it does not exhibit:
      
      
      1. a narrow therapeutic range or safety margin, e.g., does not require careful dosage titration or patient monitoring;
         
         
      2. a steep dose/response relationship;
         
         
      3. a risk of serious undesired effects;
         
         
      4. complicated or variable pharmacokinetics; for example:
         
         
         • nonlinear pharmacokinetics;
           
           
         • variable or incomplete absorption;
           
           
         • an absorption window, i.e., site-specific absorption;
           
           
         • substantial first-pass metabolism (>40%);
           
           
         • an effective half-life of more than 24 hours;
           
           
   3. the drug product:
      
      
      1. contains a single medicinal ingredient;
         
         
      2. contains the same quantity of medicinal ingredient as the innovator product marketed in Canada;
         
         
      3. is the same as the drug product marketed in Canada with respect to colour, shape, size, weight, type of coating (e.g., uncoated, film-coated or sugar-coated);
         
         
      4. must demonstrate individual and mean values of the dissolution profiles comparable to the product marketed in Canada.
         
         The dissolution profiles should be determined in at least three (3) media within the physiological range (pH 1 - 7.5 ), e.g. water, 0.1N HCl, and
         
         pharmacopoeial buffer media at pH 4.5, 6.5, and 7.5. One dissolution medium should be that described in the USP or BP monograph, if one exists. Media should be selected to emphasize possible differences between the products, e.g., a medium in which the dissolution rate is relatively slower (e.g. pH of the medium close to the pKa value of the drug) may offer some advantages.
         
         The percentage of drug content released should be measured at a number of suitably spaced time points, e.g. at 10, 20 and 30 minutes, and continued to achieve virtually complete dissolution. At least six dosage units of each batch should be tested using the same apparatus and, if possible, on the same day.

If any of the above conditions are not met, the manufacturer must demonstrate the equivalence of the second-entry product to the innovator's product marketed in Canada by the appropriate comparative in-vivo study or studies.