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Fact Sheet: Subsequent Entry Biologics in Canada

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What is a biologic?

Biologics are drugs listed on Schedule D to the Food and Drugs Act. Schedule D includes names of individual products (such as "insulin"), product classes (such as "immunizing agents"), references to particular sources (such as "drugs, other than antibiotics, prepared from microorganisms") and methodology (such as "drugs obtained by recombinant DNA procedures"). It is generally accurate to say that biologics are manufactured from animals, or microorganisms, or through the use of, animals, or microorganisms. Other examples of biologics include blood and blood components, monoclonal antibodies, cytokines, protein hormones and gene therapy products.

Biologics are derived through the metabolic activity of living organisms and tend to be more variable and structurally complex than chemically synthesized drugs. Biologics are typically labile and sensitive to changes in manufacturing processes and conditions. Biological source materials, production cells or their fermentation media could present risks such as the initial presence of pathogens or the growth of adventitious agents such as viruses. Because of this, careful attention is paid to raw material controls, viral/bacterial inactivation or clearance during product purification and product testing. Changes to source materials, manufacturing processes, equipment or facilities may result in significant unexpected changes to the intermediate and/or final product, so the phrase "the process is the product" is often used in reference to biologics, and much effort is focussed on manufacturing control and quality assurance.

How are biologics regulated?

The Biologics and Genetic Therapies Directorate (BGTD) regulates biologics under Divisions 1, 1A, 2, 4, 5, and 8 of Part C of the Food and Drug Regulations. Information provided by manufacturers is evaluated to verify that the biologic meets quality, safety and efficacy requirements, and that the benefits of the biologic outweigh the risks for its intended use. BGTD tests intermediates and/or final products of some biologics in its laboratories to confirm their quality and consistency of manufacture prior to granting market authorization, and performs on-site evaluations of manufacturing facilities. A Notice of Compliance (NOC) and Drug Identification Number (DIN) are issued to sponsors when their products are authorized for sale (distribution) in Canada. After a biologic has received an NOC, the manufacturer must adhere to BGTD's Lot Release Program, which sets out risk-based criteria for testing of the product prior to its release onto the Canadian market. The level of regulatory oversight for biologics in Canada is consistent with that of other competent regulatory authorities.

What is a generic drug?

A generic drug is a term used for drugs that contain the same medicinal ingredient(s) as an innovator drug. In most cases, the innovator product must have an NOC and be marketed in Canada and is called the Canadian Reference Product. A Canadian generic drug must be the pharmaceutical equivalent and bioequivalent of the innovator drug, have the same route of administration, and its use must fall within the conditions of marketing approval for the innovator drug.

Generic drugs are assessed according to an abbreviated process which is intended to demonstrate that the generic drug is bioequivalent to (ie. acts in the same way in vivo as) the innovator drug and, as such, is interchangeable. A generic drug sponsor submits the required information as an Abbreviated New Drug Submission (A/NDS). The clinical data requirements for an A/NDS are purposely limited, based on the assumption that the safety and efficacy of the innovator product, demonstrated in the original submission and confirmed during the extensive period of marketing, can be extrapolated to the generic drug. Generic drugs may be substituted for branded drugs by pharmacists in the absence of specific requests to the contrary. They are traditionally more affordable to bring to market and provide an economical alternative to users.

What is a Subsequent Entry Biologic?

The term "subsequent entry biologic" (SEB) is used by BGTD to describe a biologic product that would be similar to and would enter the market subsequent to an approved innovator biologic. This term was chosen as an alternative to "biogeneric"so as to clearly indicate a distinction between the provisional, but evolving, regulatory process for SEBs and that currently used for generic drugs. Other terms used include "similar biological medicinal products" in the Europen Union and "follow-on protein products" in the United States.

What are the challenges associated with producing SEBs?

The development of a process whereby regulatory decisions on SEBs would be based on the evaluation of reduced/limited clinical data presents challenges to manufacturers and regulators alike. The assurance of safety, quality and efficacy for a biologic is closely tied to a carefully controlled and highly reproducible manufacturing process. Following a manufacturing change, an innovator must demonstrate the comparability of the product obtained from a revised process to the product obtained from the earlier process. The extent of the testing depends on the nature of the proposed manufacturing change, and at times, the design of a scientifically sound study is challenging. An SEB manufacturer faces an even greater challenge, having to develop their product and demonstrate comparability to the innovator product, all without having access to the innovator's unformulated drug substance for testing purposes. Such challenges often increase with the molecular size and complexity of the product, and are further complicated if the product exhibits multiple biological activities, since each such activity and the biological and physicochemical factors influencing them, would need to be evaluated.

What is planned for the future regarding SEBs?

A number of biologics will come off-patent worldwide in the next five years, and the patents for others such as insulin, human growth hormones, some interferons have already expired. BGTD is working on developing a comprehensive regulatory framework for SEBs, addressing the regulatory, legal, and scientific issues related to SEBs.

How will SEBs be regulated in the interim?

In the interim, SEBs are subject to all of the current regulatory requirements for biologics. Manufacturers are required to file a New Drug Submission (NDS) for review as a basis for seeking market authorization, although the extent of the clinical data required may be different than that required for the innovator's product. Key factors to be considered in regulatory decision-making will include the choice of the innovator product used to demonstrate comparability, the design of comparability studies, and details of the clinical data generated.

The extent of the comparability studies and the assessment criteria will be influenced by the complexity of the product and the capability of the methods used to demonstrate comparability. The nature and extent of the clinical data to be provided will be influenced by the extent to which a demonstration of comparability brings clinical data in the public domain into relevance, but also by the number and type of clinical indications, and additional factors such as whether the product has a narrow therapeutic index. The SEB manufacturer must rigorously demonstrate that their active ingredient is sufficiently similar to the innovator's active ingredient, in order to justify less clinical data.

What type of information should be provided in an NDS for an SEB?

BGTD encourages sponsors who are interested in filing a submission for an SEB to participate in pre-submission meetings. Submission requirements for SEBs will be determined on a case by case basis, and may include, but not be limited to:

  • A complete chemistry and manufacturing data package for the SEB.
  • A rationale for the choice of the innovator biologic as the comparator and extensive published information on its safety and efficacy.
  • Sufficient characterization information to demonstrate both chemical and biological comparability of the SEB to the innovator product chosen as the comparator.
  • Sufficient comparative animal toxicity and toxicological data, where appropriate.
  • Pharmacodynamic data to demonstrate comparable bioactivity based on parameters or surrogate markers that are clinically relevant and validated.
  • Pharmacokinetic data to demonstrate comparable bioavailability of the SEB to the innovator product based on suitable validated pharmacokinetic parameters.
  • Data characterizing the immunogenic profile of the SEB in humans and its potential impact on safety and efficacy.
  • A clinical package which demonstrates the safety and efficacy of the SEB including comparative studies between the SEB and innovator products, and data for the innovator product in the public domain. The study design and clinical comparability margins are important and should be given careful consideration and justification.

Further questions?

For further information, please contact:

Policy and Promotion Division,
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Health Canada.

Sponsors interested in filing a submission for an SEB should contact:

Manager, Regulatory Affairs Division,
Centre for Policy and Regulatory Affairs
Biologics and Genetic Therapies Directorate
Health Canada.