Following a consultation process that commenced early in 2008, on March 8, 2010, Health Canada released to the public its Guidance Document entitled “Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics (SEBs)”. The Guidance Document is intended to assist sponsors of SEBs in satisfying the requirements under the Food and Drug Act and the Food and Drug Regulations concerning authorization of SEBs in Canada.
This paper provides an overview of key principles outlined in the Guidance Document and its implications for aspects of the drug approval process relating to intellectual property protection in Canada.
It should be noted at the outset that the Guidance Document does not follow from any amendments to Canadian law concerning approval of drugs or intellectual property. Rather, the Guidance Document explains Health Canada’s policies within the existing regulatory framework. Indeed, even prior to issuance of the Guidance Document, Health Canada had approved Sandoz Canada’s OMNITROPE (somatropin) product as an SEB.
Overview of the SEB Approval Process
The Guidance Document explains that the SEB approval process applies to all biologic drug submissions where the sponsor seeks authorization for sale based on demonstrated similarity to a previously approved biologic drug and where the sponsor relies, in part, on prior information regarding the previously approved biologic drug so that a reduced clinical and non-clinical data package may be submitted.
A number of policy statements are set forth, outlining fundamental concepts and principles of the SEB regulatory framework. Amongst these, perhaps the most notable are the following:
- The basis for accepting a reduced non-clinical and clinical data package for an SEB hinges on demonstrated similarity between the SEB and a suitable reference biologic drug.
- SEBs are not considered to be “generic biologics” and authorization of an SEB is not a declaration by Health Canada of pharmaceutical or therapeutic equivalence to the reference biologic drug.
- An SEB submission involves a comparison to another product and thus SEBs are subject to the data protection provisions of the Food and Drug Regulations, the provisions of the Patented Medicines (Notice of Compliance) Regulations, and the Patent Act. These issues are discussed in greater detail herein.
- An SEB is not to be used as a reference biologic drug for another SEB submission.
Biologic drugs are described in the Guidance Document as being those drugs listed in Schedule D to the Food and Drug Act and the Guidance Document explains that biologic drugs are derived through the metabolic activity of living organisms and tend to be significantly more variable and structurally complex than chemically synthesized drugs. An SEB is a biologic drug that enters the market subsequent to a version previously authorized in Canada and which has demonstrated similarity to a reference biological drug. An SEB is a biologic drug, the approval of which relies in part on prior information regarding safety and efficacy deemed relevant to the demonstration of similarity to a reference biologic drug and which influences the amount and type of new data required. A reference biologic drug is one authorized on the basis of a complete quality, non-clinical and clinical data package to which an SEB is compared in studies to demonstrate similarity.
In the Guidance Document, Health Canada makes clear that SEBs are subject to the data protection provisions of C.08.004.1 of the Food and Drug Regulations and to the requirements of the Patented Medicines (Notice of Compliance) Regulations. In particular, in the New Drug Submission (NDS) for the SEB, the SEB sponsor must clearly identify the product to which it is subsequent and to which it is considered to be making a direct or indirect comparison according to the Patented Medicines (Notice of Compliance) Regulations and C.08.004.1 of the Food and Drug Regulations. In this regard, published concurrently with the Guidance Documents were updates to Health Canada’s Guidance Document concerning administration of the Patented Medicines (Notice of Compliance) Regulations and its Guidance Document concerning data protection under C.08.004.1 of the Food and Drug Regulations, both of which are discussed in greater detail below.
The Guidance Document explains that the reference biologic drug to which similarity of the SEB is to be demonstrated should be a drug authorized for sale and that should be marketed in Canada. Importantly, although a sponsor must name the biologic drug authorized in Canada to which the SEB will be subsequent, and while a Canadian reference biological drug is preferred, in some instances a non-Canadian reference biologic drug may be used. Considerations are outlined for the use of non-Canadian reference biologic drugs. For instance, the SEB sponsor is responsible for showing that the non-Canadian reference biologic drug used for the purposes of demonstrating similarity is a “suitable proxy” for the version of the product approved in Canada. This requires explaining the link between the two products and confirming that the non-Canadian reference biologic drug is marketed by the same innovator company that has approval to market the medicinal ingredient in the same dosage form in Canada. It is notable that the approval of OMNITROPE was based on a comparison to Pfizer’s GENOTROPIN product which is not marketed in Canada.
The Guidance Document explains the information required for a new drug submission seeking approval of an SEB. Quality information is required, including a full chemistry and manufacturing data package and extensive data on the demonstration of similarity with the reference biologic drug, including characterization studies conducted in a side-by-side format.
Importantly, the Guidance Document concludes that the “demonstration of similarity” does not signify that the quality attributes of the SEB and the reference product are identical, but that they are highly similar such that: (1) the existing knowledge of both products is sufficient to predict that any differences in quality attributes should have no adverse effect on safety or efficacy of the SEB; and (2) non-clinical and clinical data previously generated with the reference biologic drug are relevant to the SEB.
The Guidance Document explains that an SEB product sponsor is eligible to apply for one or more clinical indications granted to the reference biologic drug in Canada. It appears that this typically should be supported by safety and efficacy data generated with the SEB in clinical trials. In some situations, additional indications held by the reference biologic drug may be granted for the SEB absent such clinical data, where other types of data are deemed to be sufficient. However, where a clinical indication sought for the SEB is not held by the reference biologic drug, full clinical trial data shall be provided in support of that indication.
The Guidance Document stresses that comparative clinical trials are of critical importance for demonstrating the similarity and efficacy and safety profiles between the SEB and the reference biologic drug. However, there may be exceptions, and the example is given of recombinant human soluble insulin products for which the Guidance Document states that only a comparative clinical safety study is required.
Risk management plans are discussed, as are post-market requirements.
The labeling requirements for the SEB are notable. It will not be possible to use the product monograph of the reference biologic drug in its entirety, in contrast to the approach taken for generic small molecule drugs. The product monograph for an SEB must include:
- a statement indicating that the product is an SEB;
- key data on which the decision for market authorization was made;
- tables showing results of the comparisons between the SEB and reference biologic drug; and
- information concerning the indications approved for use.
Moreover, the product monograph for the SEB should not make claims for bioequivalence nor clinical equivalence with the reference biologic drug.
The Patented Medicines (Notice of Compliance Regulations)
The Patented Medicines (Notice of Compliance) Regulations (hereinafter the “PM(NOC) Regulations”) link the drug approval process to the Canadian patent system.
Very briefly, the PM(NOC) Regulations permit a first person, generally an innovative pharmaceutical company, to list a patent relating to a drug on a Patent Register maintained by Health Canada in certain circumstances. If a second person, usually a generic drug manufacturer, then seeks regulatory approval of a drug, and in doing so directly or indirectly compares the drug with, or makes reference to the innovator’s drug marketed in Canada, the generic manufacturer must address the innovator’s patent on the Patent Register. This involves either the generic manufacturer accepting that they will not receive a Notice of Compliance (i.e. regulatory approval) from Health Canada until expiry of the patent, or alleging, among other things, that the patent has expired, is invalid, or would not be infringed.
In the latter case, the innovator may commence a court proceeding, asserting that the generic’s allegations are unjustified and seeking an order prohibiting the Minister of Health from issuing a notice of compliance to the generic until after the expiration of the patent.
Under section 5 of the PM(NOC) Regulations, a requirement to address a patent on the Patent Register is triggered when a second person files a submission for a Notice of Compliance in respect of a drug and the submission “directly or indirectly compares the drug with, or makes reference to, another drug marketed in Canada under a notice of compliance issued to a first person and in respect of which a patent list has been submitted”.
Importantly, in the above-mentioned updates to its Guidance Document: Patented Medicines (Notice of Compliance) Regulations, published together with the SEB Guidance Document, Health Canada confirms that the language of section 5 of the PM(NOC) Regulations is not exclusive to abbreviated new drug submissions but is instead meant to capture submissions approved on the basis of a direct or indirect comparison with, or reference to, another drug. New drug submissions submitted in accordance with the SEB Guidance that demonstrate similarity with a biologic drug marketed in Canada, and in respect of which there are patents listed on the Patent Register are considered by Health Canada to make a comparison or reference within the meaning of section 5 of the PM(NOC) Regulations. Accordingly, sponsors of such submissions will be required to fulfill the requirements for second persons under the PM(NOC) Regulations. Health Canada also indicates that supplemental submissions for a change in formulation, change in dosage form or change in use of the medicinal ingredient that relies on a demonstration of similarity to the reference biologic drug in order to justify reduced clinical and non-clinical data will also be captured by section 5 of the PM(NOC) Regulations.
Health Canada also confirms that, if an SEB submission contains a demonstration of similarity with a non-Canadian reference biologic drug, such a submission is considered to contain a comparison with, or reference to, the Canadian drug as contemplated by section 5 of the PM(NOC) Regulations.
Health Canada does not comment on the circumstances in which the new drug submission for an SEB is based on a demonstration of similarity with a non-Canadian reference biologic drug in instances where no reference biologic drug has been marketed in Canada. It appears this circumstance could arise where an innovator has obtained a Notice of Compliance to market a biologic drug in Canada but has only yet marketed a comparable product in another jurisdiction.
Data Protection Under C.08.004.1 of the Food and Drug Regulations
Part C.08.004.01 of the Food and Drug Regulations provides a term of data protection for innovative drugs that receive a Notice of Compliance on or after June 17, 2006. These provisions implement aspects of the North American Free Trade Agreement (NAFTA) and the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) concerning the requirement for data protection.
An “innovative drug” is defined as “... a drug that contains a medicinal ingredient not previously approved in a drug by the Minister and that is not a variation of a previously approved medicinal ingredient such as a salt, ester, enantiomer, solvate or polymorph”. If a manufacturer seeks a Notice of Compliance for a new drug on the basis of a direct or indirect comparison between the new drug and an innovative drug, the manufacturer may not file its drug submission before the expiry of six years from the date on which the first Notice of Compliance was issued to the innovator in respect of the new drug. The Minister of Health shall not approve the submission and shall not issue a Notice of Compliance in respect of the new drug before the expiry of eight years from the issuance of the first Notice of Compliance to the innovator in respect of the innovative drug. This eight-year period is lengthened by six months in instances where clinical trials in relevant pediatric populations are involved in the approval of the innovative drug.
These provisions restricting the filing of a drug submission making a comparison to an innovative drug and the restriction on granting a Notice of Compliance do not apply if the innovative drug is not being marketed in Canada.
Health Canada has updated its Guidance Document: Data Protection under C.08.004.1 of the Food and Drug Regulations to explain the application of the data protection provisions to SEBs.
Health Canada explains that approval of an SEB is sought by filing a new drug submission in which the sponsor seeks to reduce the clinical and non-clinical study requirements by demonstrating similarity to a previously approved reference biologic drug. The demonstration of similarity is based on comparative data which may include analytical testing, biological assays and non-clinical and clinical data. Health Canada confirms that such a submission, containing a demonstration of similarity to a reference biologic drug is considered to make a comparison to an innovative drug as described above. Accordingly, such submissions will not be accepted for filing within the six-year period from the issuance of the Notice of Compliance for the reference biologic drug.
Health Canada further notes that where the SEB sponsor uses a non-Canadian reference biologic drug as a proxy for a Canadian reference biologic drug, this will nevertheless be considered to constitute a comparison between the SEB and the Canadian drug as contemplated in the data protection provisions of the Food and Drug Regulations described above. Accordingly, an SEB submission made based on comparison to a non-Canadian reference drug will not be accepted for filing within the six-year period from the date of issuance of the Notice of Compliance for the Canadian reference of biologic drugs.
In either case described above, a Notice of Compliance will not be issued to the SEB sponsor before the end of the period of eight years after the day on which the first Notice of Compliance was issued for the innovative drug, or eight years and six months where the innovative drug qualifies for the pediatric extension.
An area of possible uncertainty concerns the very definition of “innovative drug” in the Food and Drug Regulations, as set forth above. This definition does not appear well-suited to describing the differences between complex biomolecules. For instance, the same protein expressed in two different host cells may have different patterns of glycosylation (carbohydrate chains attached to the protein after its synthesis). Whether one such protein is a “variation” of another such that the second would not quality for data protection is not readily determined based on the examples of variations provided in the definition of innovative drug, wherein salts, esters, enantiomers, solvates or polymorphs of existing drugs are given as examples of variations that do not qualify for data protection. Such terminology is perhaps better suited to traditional small molecule pharmaceuticals.
In any event, Health Canada explains that because approval for an SEB is sought by filing a new drug submission in which the sponsor seeks to reduce the clinical and non-clinical study requirements by demonstrating similarity to a previously approved reference biologic drug, an SEB will not be considered to be an “innovative drug”.
Conclusions
As acknowledged by Health Canada, its various Guidance Documents are administrative instruments and do not have the force of law. Ultimately, there must be compliance with the relevant provisions of the Food and Drug Regulations, the PM(NOC) Regulations and the Patent Act. While there is an extensive body of law concerning the application of many aspects of these provisions to traditional small-molecule pharmaceuticals, the application of these statutory instruments to biologics has not yet been explored to any significant degree.