Policy Statement: Clarifying the appropriate regulatory pathway for subsequent entry low molecular weight heparins

Draft Date: 2013/08/16

1.0 Purpose

Health Canada's Biologics and Genetic Therapies Directorate (BGTD) is the Canadian federal authority that regulates biological drugs (products derived from living sources) for human use in Canada, whether manufactured in Canada or elsewhere.

This Policy Statement describes BGTD's approach to regulating low molecular weight heparins (LMWHs) containing medicinal products claiming to be similar to another heparin which is already marketed. It is intended to help guide sponsors by clarifying the appropriate regulatory pathway for these subsequent entry LMWHs.

2.0 Background

LMWHs are derived from a biological source (typically porcine intestine) and are a complex mixture of polysaccharide polymers, whose components are not fully characterised. In 2008, recognising the importance of their biological origin and to better support heparin new drug submissions, particularly the proposed subsequent entry submissions, Health Canada transferred the review of these products, from the Therapeutic Products Directorate (TPD), to the BGTD.

Since the transfer, BGTD has attended a number of pre-NDS meetings with sponsors seeking to market subsequent entry LMWHs using the abbreviated new drug submission (ANDS) pathway, which is intended primarily for generic versions of small molecule pharmaceuticals. In these meetings, BGTD has consistently advised sponsors that the ANDS pathway is inappropriate for subsequent entry LMWHs and that the subsequent entry biologics (SEB) regulatory framework should be used instead.

3.0 Scope

This document applies to manufacturers seeking to market subsequent entry versions of LMWHs in Canada.

4.0 Policy statement

According to section C.08.002.1 (1) of the Food and Drug Regulations (Regulations), a sponsor may file an ANDS for a new drug where, in comparison with a Canadian reference product, the new drug is the pharmaceutical equivalent of the Canadian reference product.

Section C.08.001.1 defines pharmaceutical equivalence as, "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."

The 2003 Health Canada policy Interpretation of "Identical Medicinal Ingredient" clarifies the term "identical medicinal ingredient", stating that, in the context of the Regulations, only the "chemical identicality" of the medicinal ingredients is taken into account while determining pharmaceutical equivalence.

Given the complex and heterogeneous nature of LMWH, it is the position of BGTD that it is not currently possible to demonstrate that two LMWH products contain identical amounts of the identical medicinal ingredients. As such, the ANDS regulatory pathway, which relies on this demonstration, is inappropriate for LMWH.

Although LMWHs are not currently listed on Schedule D of the Food and Drugs Act, because of their biological origin, they are in effect considered biologics and have been regulated as such for several years.Footnote 1

In order to accommodate manufacturers interested in pursuing subsequent entry versions of previously marketed biologic drugs, as a first step, Health Canada introduced in 2006 a Fact Sheet on SEBs in Canada and then, in 2010, the Guidance Document Information and Submission Requirements for Subsequent Entry Biologics (SEB Guidance), which clarifies the appropriate regulatory pathway for SEB submissions and outlines the quality, clinical and non-clinical data BGTD would expect in an SEB submission.

The SEB regulatory framework allows for a drug submission where the sponsor seeks authorisation for sale based on demonstrated similarity to a previously approved biologic drug and relies, in part, on prior information regarding that biologic drug in order to present a reduced clinical and non-clinical package as part of the submission.

5.0 Application

Sponsors seeking to market a subsequent entry version of a LMWH should follow the SEB Guidance and are encouraged to engage with BGTD well ahead of filing a submission.

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