Data Protection for Innovative Drugs in Canada

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Canada, like many other countries, has a system of data protection for innovative drugs. The purpose of this article is to provide an overview of the data protection system in Canada and some of its nuances.

BACKGROUND

Canada is a signatory to two major treaties that require member states to provide data protection for innovative drugs.

Article 39(3) of the Agreement on Trade-Related Aspects of Intellectual Property Rights (“TRIPS”) provides as follows:

Members, when requiring, as a condition of approving the marketing of pharmaceutical or agricultural chemical products which utilize new chemical entities, the submission of undisclosed test or other data, the origination of which involves considerable effort, shall protect such data against unfair commercial use.

Article 1711 of the North American Free Trade Agreement Between the Government of Canada, the Government of Mexico and the Government of the United States (“NAFTA”) provides as follows:

(5) If a Party requires, as a condition for approving the marketing of pharmaceutical or agricultural chemical products that utilize new chemical entities, the submission of undisclosed test or other data necessary to determine whether the use of such products is safe and effective, the Party shall protect against disclosure of the data of persons making such submissions, where the origination of such data involves considerable effort, except where the disclosure is necessary to protect the public or unless steps are taken to ensure that the data is protected against unfair commercial use.

(6) Each Party shall provide that for data subject to paragraph 5 that are submitted to the Party … no person other than the person that submitted them may, without the latter’s permission, rely on such data in support of an application for product approval during a reasonable period of time after their submission. For this purpose, a reasonable period shall normally mean not less than five years from the date on which the Party granted approval to the person that produced the data for approval to market its product, taking account of the nature of the data and the person’s efforts and expenditures in producing them.

When Canada, the United States and Mexico recently renegotiated the terms of NAFTA, the parties originally agreed to mandate an increase in the length of data protection for biologic drugs. The final version of the text, however, did not include this requirement.

The first data protection regime that was implemented in Canada applied to drugs approved before June 17, 2006.  Under this regime, an innovative drug was entitled to five years of data exclusivity but only if Health Canada actually compared the content of the generic manufacturer’s Abbreviated New Drug Submission (“ANDS”) with the content of the innovator’s New Drug Submission (“NDS”).

As a result of complaints from innovative drug manufacturers, the Canadian government created a new data protection regime that applies to drugs approved on or after June 17, 2006.

Canada’s data protection system is contained within the Food and Drug Regulations (the “Regulations”), regulations that were implemented under the Food and Drugs Act. Subsection C.08.004.1(3) of the Regulations provides that if a manufacturer seeks a NOC 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 a NDS, a supplement to a NDS, an ANDS or a supplement to an ANDS in respect of the new drug before the end of six years after the day on which the first NOC was issued to the innovator in respect of the innovative drug; and
• the Minister of Health shall not approve that submission or supplement and shall not issue a NOC in respect of the new drug before eight years after the first NOC was issued to the innovator in respect of the innovative drug; and
• the eight-year limit is extended by six months in situations where the innovator provided the Minister with the description and results of clinical trials relating to the use of the innovative drug in relevant pediatric populations.

An “innovative drug” is defined in subsection C.08.004.1(1) of the Regulations 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”.

INTERPLAY BETWEEN DATA PROTECTION AND PATENT SYSTEMS

It can be seen from the above that the data protection regime provides important coverage that, in several respects, is independent from the patent system in that:

• data exclusivity is not dependent on the existence of a patent;
• data exclusivity is not dependent on the existence of a patent for the relevant drug on the Patent Register maintained by the Minister;
• even in the absence of a patent, data exclusivity can still delay market entry of a generic version of an innovative drug; and
• data protection is not subject to the same range of attacks as is a patent.

OPTIONS FOR GENERIC MANUFACTURERS

Faced with a no-file limit imposed by Canada’s data protection regime, a generic manufacturer has the following options:

• wait for the expiry of the six-year limit before filing an ANDS and wait for the expiry of the eight-year limit before obtaining a NOC; or
• challenge the data protection on the innovative drug.

Typically, a generic manufacturer will seek to challenge data protection on the basis that the drug listed on the register is not an “innovative drug” or is not being marketed in Canada. It is therefore necessary to examine several aspects of the definition of “innovative drug” contained in the Regulations in order to determine the limits of data protection.

NOT PREVIOUSLY APPROVED

If a generic manufacturer can establish that the drug in question contains a medicinal ingredient that was, in fact, previously approved by the Minister, then the drug would not be entitled to data protection. Canadian courts have therefore, on several occasions, explored what it means for a medicinal ingredient to have been “previously approved”.

SAP Authorizations

In Teva Canada v. Minister of Health 2011 FC 507 aff’d 2012 FCA 106, Teva sought to market a generic version of the drug ELOXATIN. In 1999, the Minister had authorized the use of ELOXATIN under the Special Access Programme (the “SAP”). The SAP is a programme that permits the Minister to authorize the sale of a new drug to a physician for the emergency treatment of a patient. The SAP is typically used as a last resort and does not subject a drug to the same level of scrutiny of safety and efficacy that a drug would typically receive when going through the usual NOC process. 

In 2007, the Minister placed ELOXATIN on the register of innovative drugs. Teva argued that the SAP authorization meant that the drug had been “previously approved” by the Minister in 1999. Teva further argued that by 2007 the Minister had evidence of safety that was based on thousands of people having used the drug under the SAP.

The Minister took the position that authorizations under the SAP do not constitute a previous approval for the purpose of the definition of an “innovative drug”.

When the case reached the Federal Court of Appeal, it noted that the Regulations were not a compromise between innovators and generic manufacturers but, rather, were concerned with the safety and efficacy of drugs as evidenced by approvals based on data and studies. These approvals were signified by the issuance of a NOC and a drug identification number (“DIN”).

The Court of Appeal further noted that the SAP is different than the NOC process in that the SAP allows for the use of drugs despite the absence of data and studies showing safety and efficacy. As such, a SAP authorization constitutes “compassionate permissions” rather than an approval of the drug in question.

The Court of Appeal noted that C.08.004.1(1) of the Regulations was designed to implement Canada’s obligations under NAFTA and TRIPS and that these treaty provisions aimed to protect an innovator who submitted undisclosed data in support of an application to market a drug containing a new chemical entity. Further, given that the definition of “innovative drug” in the Regulations was intended to implement these treaty provisions, “previously approved” must mean a previous marketing approval.

In the case of ELOXATIN, although it had received many authorizations under the SAP, it had not previously received a NOC or a DIN. Therefore, the Court of Appeal ruled, the Minister was correct in deciding that ELOXATIN was an innovative drug.

Natural Health Approvals

In Epicept v. Minister of Health 2010 FC 956, the courts again had an opportunity to consider what it meant for a drug to have been “previously approved”. Epicept had, in filing a NDS for CEPLENE histamine dihydrochloride, submitted substantial clinical data. The evidence established that histamine dihydrochloride had been previously approved in “drugs’ under the DIN process of the Natural Health Products Regulations (“NHPR”). The Minister held that CEPLENE was not an “innovative drug” because it had been previously approved and it was irrelevant that such prior approval was not by way of a NOC.

The Federal Court applications judge agreed with the Minister, holding that NAFTA and TRIPS do not protect all drugs, only new chemical entities. A drug that had been approved by a DIN or under the NHPR was not a “new chemical entity” that had not been previously approved.

The Federal Court of Appeal dismissed Epicept’s appeal for mootness (2011 FCA 209).

Withdrawn Approvals

In Celgene v. Minister 2012 FC 154 rev’d 2013 FCA 43, the Federal Court was again called upon to determine what it meant for a drug to have been “previously approved”. This case involved the drug thalidomide. Thalidomide was initially launched in 1957 for use in treating sleeplessness and morning sickness. In 1960-61, thalidomide was approved in Canada for two manufacturers. In 1962, given a link that had been established between thalidomide and birth defects, the drug was ordered withdrawn from sale in Canada. In 1994, Celgene focused on the use of thalidomide to treat leprosy, cancer and other illnesses. In 1995, thalidomide was first made available through the SAP.

In 2009, Celgene filed a NDS for THALOMID thalidomide. The following year, the Minister issued a NOC to Celgene but also advised Celgene that thalidomide was not eligible for data protection because of the prior approvals in 1960 and 1961.

Celgene challenged the Minister’s decision, arguing that the prior approvals were based only on safety considerations (and not efficacy) and became null and void when the Minister withdrew the approval for safety reasons in 1962.

The Federal Court applications judge held that the requirement that a drug not be previously approved is to ensure that a manufacturer is not granted data protection for:

• something in previous use; and
• for which no innovation is required.

The applications judge held that Celgene’s innovation was in taking something banned as dangerous and, without relying on old data, showing the drug to be a useful, lifesaving drug. The Court also interpreted the purpose of the Regulations to be to encourage and reward innovation by protecting data an innovator must generate to obtain approval.

The Court further held that thalidomide was returned to the status of a new drug when marketing approval was revoked in 1992 and therefore THALOMID was entitled to data protection.

On appeal, however, the Federal Court of Appeal took a much stricter reading of the Regulations, holding that meaningful distinctions could not be made between, for example, a scenario in which a previously approved drug was removed from the market because of errors in the manufacturer’s data versus a scenario in which a NOC was cancelled due to regulatory error. The Court of Appeal therefore reversed the applications judge and restored the Minister’s decision to deny data protection.

Variations of a Previously Approved Drug

In Takeda Canada v. Minister of Health 2011 FC 1444 aff’d 2013 FCA 13, Takeda sought data protection for DEXILANT dexlansoprazole. Dexlansoprazole had not been previously approved. It was, however, an enantiomer of lansoprazole which was a previously approved drug. Takeda argued that it was nevertheless entitled to data protection because it had to conduct extensive clinical programs in order to establish safety and efficacy.

In response, the Minister took the position that the definition of “innovative drug” in the Regulations expressly excluded enantiomers of previously approved medicinal ingredients and therefore the Minister could not recognize DEXILANT as an innovative drug.

Takeda, in challenging the Minister’s decision before the Federal Court and Federal Court of Appeal, argued that the Minister took too literal a reading of the Regulations and failed to consider the nature and extent of Takeda’s data.

A majority of the Federal Court of Appeal agreed with the Minister’s decision, holding that the definition of “innovative drug” was clear and that it excluded enantiomers of previously approved drugs. The majority held that if the Minister found that a medicinal ingredient was an ester, salt, enantiomer, solvate or polymorph of a previously approved medicinal ingredient, then the Regulations clearly provided that the new medicinal ingredient could not qualify as an “innovative drug”. If, on the other hand, it was arguable that a medicinal ingredient was a “variation” of a previously approved medicinal ingredient but it did not fall within any of the categories of an ester, salt, enantiomer, solvate or polymorph of a previously approved medicinal ingredient, then the Minister should go on to consider the clinical data that was gathered.

The dissenting judge was of the view that whether an enantiomer is a “variation” of a previously approved drug depended on the circumstances surrounding the data that had to be submitted and that if regulatory approval required the submission of data that was generated through considerable effort and the medicinal ingredient has qualities of safety and efficacy materially different than a previously approved medicinal ingredient, then it is not a “variation”.

In Photocure ASA v. Minister of Health 2015 FC 959, the applicant sought data protection for CYSVIEW hexaminolevulinate hydrochloride [HAL HCl]. The Minister, however, refused to grant data protection for CYSVIEW on the basis that its medicinal ingredient is an ester variation of a previously approved medicinal ingredient, aminolevulinic acid hydrochloride [ALA HCl]. The Minister held that because HAL HCl has the identical chemical structure as ALA HCl but with the additional of an ester group that it is therefore an ester of ALA HCl.

In seeking judicial review of the Minister’s decision, Photocure advanced a number of factual and legal arguments. One of its technical arguments was that HAL HCl is a salt of HAL which, in turn, is an ester of ALA and so HAL HCl cannot be said to be an ester of ALA HCl. The Federal Court applications judge found that the Minister’s decision in this regard was reasonable and so could not be overturned on judicial review.

Photocure also argued that if HAL HCl could be said to be an ester of ALA HCl then it was also a salt of ALA HCl and so it did not fall within the exceptions to an “innovative drug” contained in the Regulations.  For this purpose, Photocure argued that the definition of “innovative drug” only excluded medicinal ingredients that were a salt, ester, enantiomer, solvate or polymorph of a previously approved medicinal ingredient and not, for example, a medicinal ingredient that was both a salt and an ester of a previously approved ingredient. The Court did not agree with Photocure’s interpretation.

As a result of the Takeda and Photocure decisions, the law is well established that:

• if a medicinal ingredient is a salt, ester, enantiomer, solvate or polymorph of a previously approved medicinal ingredient, then it cannot qualify as an “innovative drug” regardless of the extent of clinical data that the applicant performed in its research regarding the medicinal ingredient; and
• if a medicinal ingredient is a arguable variation of a previously approved medicinal ingredient but is not a salt, ester, enantiomer, solvate or polymorph of the previously approved medicinal ingredient, then one would need to consider the nature and extent of clinical data in order to determine whether the medicinal ingredient qualifies as an “innovative drug”.

REQUIREMENT FOR DRUG TO BE MARKETED

Subsection C.08.004.1(5) of the Regulations contains an important exception to data protection coverage. It provides that the data-protection bars contained in subsection (3) do not apply if the innovative drug is not being marketed in Canada. Subsection (5) raises the question of when a drug will be considered not to be “marketed” in Canada.

In AstraZeneca Canada v. Minister 2004 FC 1277, aff’d on other grounds 2006 SCC 49, the Federal Court held:

“marketing” means something more than “sales” or “sold”. It means the action or business of promoting and selling products including market research and advertising.

PRIOR APPROVAL FOR DIFFERENT TYPE OF USE

In 2011, the Minister issued a Guidance Document in which it was noted that prior approval of a medicinal ingredient in a drug for veterinary use does not preclude the granting of data protection to a drug for human use containing the identical medicinal ingredient or a variation. The same analysis also applies in the reverse situation (i.e., prior approval of a medicinal ingredient for human use does not affect data protection for the identical medicinal ingredient for veterinary use).

As can be seen from the above summary, Canada’s data protection regime can provide valuable rights to the manufacturers of innovative drugs. There are, however, important nuances to this protection and so it is vital that any manufacturer carefully consider the relevant facts in order to assess whether data protection is available in a particular situation.

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