DRW Monthly
July 2008
Issue No. 20

Health Canada's Progress in Regulating Subsequent Entry Biologics: Draft Guidance Issued in March

With Health Canada's recent publication of its draft guidance entitled, "Information and Submission Requirements for Subsequent Entry Biologics (SEBs)," the agency has initiated its plan to introduce a comprehensive regulatory, legal and scientific framework to approve biologic products that are similar to already approved biologics upon patent expiration. These products, also referred to as biosimilars by the agency, have posed a regulatory challenge for government agencies worldwide. The European Medicines Agency was the first to establish a regulatory plan in 2005 for biosimilars, or what is referred to as "similar biological medicinal products" in the EU. The US, on the other hand, is in the midst of debating the most appropriate legislative pathway for the abbreviated approval of biosimilars, or what this country refers to as "follow-on biologics" or "follow-on protein products."

The draft guidance specifically targets sponsors or manufacturers who will be seeking clearance for SEBs following innovator product patent expiration. An SEB is defined by Health Canada's Biologics and Genetic Therapies Directorate (BGTD) as "a biologic product that would enter the market subsequent to, and similar to, an approved innovator biologic, which would rely in part, on prior [publicly available] information regarding safety and efficacy that is deemed relevant due to the demonstration of "similarity" to a reference biologic product."(1) The determination of "similarity" will be based upon analytical testing, biological assays, clinical data and non-clinical data. As delineated in the guidance, biologics are drugs listed on Schedule D of the Food and Drugs Act, and as such, sponsors or manufacturers will be required to file a New Drug Submission (NDS) for BGTD review as a basis for applying for market authorization. The extent of the clinical data required may be different than that originally required for the innovator's product to be determined on a case-by-case basis depending on product class and demonstrated similarity between the SEB and the reference biologic product. However, "[w]hen the comparability of an SEB to the reference biologic product cannot be adequately established, the submission for such a product should be filed as a full NDS with complete non-clinical and clinical data."(2)

The agency plans to amend the Canadian Food and Drug Regulations to ensure that the SEB authorization process is transparent to applicants. However, the draft currently offers a flexible framework in which SEB submissions may be effectively reviewed in the interim. Some of the fundamental concepts and principles laid down in the guidance are as follows:

• SEBs should be eligible to apply for indications(s) within those granted to the reference biologic product, however, each indication must be supported by scientific data and the sponsor cannot assume that all indications will be automatically granted;
  
  
• Regulatory decision making pertaining to SEBs shall be based on scientific and regulatory principles existing within the Food and Drugs Act and Regulations;
  
  
• Once a Notice of Compliance is granted, an SEB is treated as a new biologic product and, as such, is regulated like any other new biologic product. However, an SEB cannot be used as a reference biologic product because it has not been authorized on the basis of a complete quality, safety and efficacy assessment, including clinical data, as is a reference product.(3) It will also have a different product monograph than that of the original reference product;
  
  
• A determination of interchangeability, which enables physicians to prescribe either an SEB or a reference product, is allowable if both products are approved for the same indication, and can be used for the said indication. A decision to use an interchangeable biologic product would be determined separately from any approval ruling covered by the draft guidelines.(4)

These elements have typically appeared in voluntary risk minimization action plans (RiskMAPs) that have been submitted by drug manufacturers to the agency since 2005. FDA's implementation of FDAAA's REM provisions has formalized the drug industry's practice of submitting these voluntary plans. In addition, under the FDAAA, a REMS may include a Medication Guide, a patient package insert, a communication plan for health care providers, an implementation system, restrictions on distribution or use, and a timetable for an assessment of the REMs(3). However, a drug or biological manufacturer who submitted only a Medication Guide prior to the approval of the FDAAA provisions, but provided no "elements to assure safe use", will no longer be "deemed to have a REMs" according to the act's provisions.

Health Canada intends to publish additional guidance documents in the coming months to provide information and data requirements for specific SEB product classes. It is the agency's ultimate goal to harmonize the approval process for SEBs with international organizations including the World Health Organization and the International Conference on Harmonisation. It will also be interesting to see what legislative developments unfold in the US as several biologic products will be coming off-patent worldwide in the next five years, and the biologics industry will be increasingly pressing for the regulation of follow-on biologic products.

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