Generic Drug Sector Study - Appendix 1: Federal Regulatory Framework for Pharmaceutical Products

Overview

All drugs that are marketed in Canada are subject to the Food and Drugs Act ¹⁰²and Food and Drug Regulations . ¹⁰³The Food and Drugs Act defines a drug as in part as ?any substance or mixture of substances manufactured, sold or represented for use in the diagnosis, treatment, mitigation or prevention of a disease, disorder, abnormal physical state, or its symptoms... , restoring, correcting, or modifying organic functions ... , or disinfection in premises in which food is manufactured, prepared or kept?. ¹⁰⁴

Whether a product is categorized as a "drug" depends on its composition (medicinal value leading to a pharmacological effect), and/or what claims are made for the product.

Part C of the Food and Drug Regulations requires a manufacturer to obtain a Drug Identification Number (DIN) prior to selling a drug in Canada. ¹⁰⁵ A manufacturer or distributor is defined as ?a person, including an association or partnership, who under their own name, or under a trade-design or word mark, trade name or other name, word or mark controlled by them, sells a food or drug?.

In regulatory terms, the ?manufacturer? of a drug is not necessarily the company that makes the product, but the company to which the product is registered at the time of approval. The manufacturer may be located outside Canada, but there must be someone in Canada who is responsible for the sale of the drug.

Health Canada is responsible for ensuring compliance with the regulations and non-compliant products are subject to action.

Pre-Market Drug Submission Requirements

New drugs can be sold in Canada once they have successfully passed a review process to assess their safety, efficacy and quality. Health Canada's Health Products and Food Branch (HPFB) is responsible for this review process. ¹⁰⁶

A drug may be regulated as a new drug when it has not been on the market in Canada for long enough or in sufficient quantity to have proven its safety and effectiveness under conditions of use. As well as a DIN, a new drug must have a Notice of Compliance (NOC) with Part C of the Food and Drug Regulations issued before it can be sold in Canada.

A New Drug Submission (NDS) typically involves between 100 and 800 binders of data, containing scientific information about the product's safety, efficacy and quality. It includes:

• The results of both the pre-clinical and clinical studies
• Details on the production of the drug and its packaging and labeling
• Information about its claimed therapeutic value
• Information about its conditions for use and side effects.

A clinical trial does not have to be performed in Canada for a New Drug Submission or a DIN Application.

When a generic drug enters the market, Part C of the Food and Drug Regulations allows the manufacturer to file an Abbreviated New Drug Submission (ANDS). The ANDS contains data that demonstrate the drug's bio-equivalence with a Canadian reference product. A Canadian reference product is defined as a drug which has been issued an NOC and which is marketed in Canada by the innovator of the drug. Where the innovative drug (?brand-name? drug) is no longer marketed in Canada, a drug acceptable to the Ministry of Health can be used to demonstrate bio-equivalence.

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The ANDS must meet the same quality standards as an NDS and the generic product must be shown to be as safe and effective as the brand-name product. An ANDS typically involves between 10 and 20 binders of data. It includes scientific information on the generic product's performance compared with the brand-name product, and provides details on the production of the generic drug, its packaging and labeling.

Generics do not have to replicate the extensive clinical trials that have already been done when the original, brand-name drug was developed. Those trials usually involve a few hundred to a few thousand patients. Since the safety and efficacy of the brand-name product has already been well established in clinical testing and often many years of patient use, it is not scientifically necessary, and would be unethical, to require that such extensive testing be repeated for each generic drug that a firm wishes to market. Instead, generic applicants must scientifically demonstrate that their product is bio-equivalent (i.e., performs in the same manner) as the pioneer drug, within an acceptable range.

One way scientists demonstrate bio-equivalence is to measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstreams of 24 to 36 healthy, normal volunteers. This gives them the rate and extent of absorption or bio-availability of the generic drug, which they then compare to that of the pioneer drug. The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the pioneer drug.

A Supplemental NDS (SNDS ) must be filed by a brand-name or generic manufacturer if certain changes are made to an already-authorized product. Such changes might include:

• The dosage form or strength of the drug
• The formulation
• The method of manufacture, labeling or recommended route of administration.
• An expansion of the claim or conditions of use for the drug.

A DIN application must be filed for those products that do not meet the definition of a 'new drug'. This happens when a substance has been sold in Canada for long enough and in sufficient quantities to have established its safety and effectiveness for use as a drug.

The Review Process

If, at the completion of a new drug review, HPFB concludes that the benefits outweigh the risks and that the risks can be mitigated and/or managed, the product is issued a Notice of Compliance (NOC) and a Drug Identification Number (DIN), as required in the Food and Drugs Act and Regulations. This allows the manufacturer to sell the product in Canada.

Filing an ANDS as opposed to an NDS is less demanding for a generic drug manufacturer because many of the safety and efficacy concerns were addressed when the reference product was approved. The generic product goes through a screening process, which HPFB tries to complete in 45 days. If anything is unclear in the file, the manufacturer has 15 days to clarify the issue. If it fails to clarify, a Notice of Non-Compliance (NON) is issued and the company has three months to reply. Also, if there are deficiencies in the file, a Notice of Deficiency (NOD) is issued, although this is not very common.

If the submission is complete, it enters the formal review process, which HPFB attempts to complete in 180 days (it may take much longer). Three reviews are performed to determine if the drug complies with the Food and Drugs Act :

• Chemistry and manufacturing
• Safety and efficacy
• Product information.

If, on completing its review, HPFB finds that the submission does not comply with the requirements of the Food and Drugs Act and Regulations , it will issue a Notice of Non-Compliance (NON). This notice outlines HPFB's concerns and generally asks for more information. The manufacturer must respond by a specified date. If the submission does comply, a NOC is issued.

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The Patented Medicines (Notice of Compliance) Regulations

The Patented Medicines (Notice of Compliance) Regulations (NOC Regulations) ¹⁰⁷ are the link between the Patent Act ¹⁰⁸and the review process under the Food and Drugs Act and Regulations . The dual purpose of the NOC Regulations is to ensure that, on the one hand, the timely access to Canadians of lower cost medicines and, on the other hand, the ?early working? exception to patent infringement is not abused by second entry manufacturers.

The Therapeutic Products Directorate of Health Canada maintains a patent register consisting of patent lists submitted by first persons (innovators). The Patent Register ¹⁰⁹ is an alphabetical listing of medicines and the associated patents, patent expiry dates and other related information, established in accordance with the NOC Regulations. When a generic or second entry manufacturer seeks approval of a drug in Canada based on a previously approved drug, it must address all patents listed on this register concerning that drug.

After a generic manufacturer files an ANDS on a drug covered by a patent on the Patent Register, and while the safety and efficacy are being reviewed, the applicant must either:

• Advise HPFB that it will accept that the NOC will not be issued until the patent expires or
• File a statement claiming that the person who filed the patent list is not the patent owner (or acting with the owner's consent) or
• File a statement that the patent has either expired, is not valid, or is not infringed (a Notice of Allegation, or NOA). ¹¹⁰

The NOA must be served on the person who submitted the patent list (generally the holder of the original NOC). That person then may, within 45 days, apply for a court order prohibiting HPFB from issuing an NOC for the second-entry (generic) product.

If it receives notice of such a court application, HPFB cannot issue a NOC for 24 months, or until the court makes a determination regarding the allegations in the NOA, whichever comes first. The court may shorten the 24-month period or extend it if the parties consent, or if the court finds that one or both of the parties has failed to reasonably co-operate in expediting the application.

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The generic manufacturer must address all patents on the patent list given by the patentee to Health Canada. Prior to October 2006, a patentee was able to re-start the 24 month automatic stay by listing new patents for formulations or uses after a generic company filed its ANDS. This practice would extend market exclusivity long after the initial patent or patents on it had expired.

The new patents could be added at any time, and in some cases, new patents were added days before the original patent on the active ingredient expired. Under the October 2006 amendments to the NOC Regulations , a generic manufacturer who files a submission or supplement for an NOC for a generic version of an innovative drug need address only the patents on the Register as of that filing date. Patents added to the register after that filing date would not have to be addressed. The register is "frozen" for the generic manufacturer. ¹¹¹

If the person who submitted a patent list applies for a court order, an NOC cannot be issued for the generic product until either:

• The 24 month stay expires or
• The patent expires or
• The court declares there would be no patent infringement or
• The court application is withdrawn, discontinued or dismissed. ¹¹²

If the patentee wins the case, the NOC cannot be issued until the final patent expires. If the generic wins, an NOC can be issued as soon as Health Canada has completed its review for safety and efficacy.

Filing and Management of Drug Submissions

All drug submissions must be accompanied by:

• A completed drug submission application form
• A submission evaluation fee form
• A copy of the proposed label(s)
• The appropriate drug submission certification form.

New drugs must have a copy of the product monograph. Drug submissions are processed according to the Management of Drug Submissions Policy , which also identifies the performance targets for review time frames for different types of submissions.

The Submission Evaluation Fees Guide identifies the evaluation fee and the timing of payment for different types of pre-market drug submissions. Fees are charged for the following services linked to the regulation of drugs:

• Drug Submission Evaluation
• Drug Master File Registration
• Issuance of Export Certificates (for non-controlled drugs).

In addition to the fee for evaluating the safety, efficacy and quality of a product, HPFB levies other user fees ¹¹³ for drug therapeutic product regulatory activities:

• Fees for maintaining the right to market a product (an annual fee must be paid for each Drug Identification Number (DIN) that pertains to a drug)
• A fee for an establishment license that certifies the type of operations and category of products that the establishment is authorized to handle.

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Product Labelling

Once a drug is approved for the Canadian market, it must be packaged and distributed with information that will help consumers make an informed choice about its use. The general labeling requirements are outlined in Part C of the Food and Drug Regulations .

Good Manufacturing Practices (GMP)

All drugs marketed in Canada are subject to good manufacturing practices (GMP) as outlined in Part C of the Food and Drug Regulations . The GMP and establishment licensing requirements apply to drugs in dosage form and to most bulk intermediates. The Food and Drug Regulations make it mandatory for fabricators, packagers/labelers, importers and distributors to have detailed information available about drug products for sale in Canada. All facilities involved in these activities are licensed and inspected by Health Canada to ensure that the GMP standards are met.

Environmental Assessment

All products regulated under the Food and Drugs Act are subject to the Canadian Environmental Protection Act , 1999 ¹¹⁴ and the New Substances Notification Regulations . ¹¹⁵ Pharmaceuticals, cosmetics, veterinary drugs, food additives, novel foods, biologicals (including genetic therapies), radio-pharmaceuticals, medical devices, and natural health products are all included. Before importing or manufacturing a new substance in Canada, importers or manufacturers must provide additional data to Health Canada so that an environmental assessment can be conducted.

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Establishment Licenses

Establishment licenses ensure that manufacturers comply with good manufacturing practices (GMP) or equivalent standards for drugs and natural health products. All establishments that fabricate, package, label, import, distribute or wholesale these products, or operate a testing laboratory for them, must have an establishment license, unless they are expressly exempted under the Food and Drugs Act and Regulations .

HPFB also inspects manufacturing plants and other sites where products covered under the Food and Drugs Act are handled to verify compliance with regulatory requirements. Establishment licenses, issued by Health Canada, are renewed on a yearly basis. Establishment license holders are inspected every three years. Traditional medicines, homeopathic preparations, and vitamin and mineral supplements, when in dosage form and intended for self-medication, are currently exempt from this requirement.

Imported Products

It is mandatory that a person in Canada be responsible for imported drug products. Importers usually must hold an establishment license and have evidence available that the imported products meet Canadian GMP or equivalent standards.

Where a drug is registered in the name of a company not located in Canada, the name of the importer and the business address of the person in Canada responsible for its sale must appear on the inner and outer labels of the drug. Importers must provide evidence that their products meet the same standards as those manufactured domestically, before they can become available in Canada. This may involve inspection of specific incoming shipments and close cooperation with the Canada Border Services Agency.

An establishment license is not required if:

• The importer is a practitioner, pharmacist or a person under the supervision of a practitioner
• The drug is imported for a prescription
• The drug is not commercially available in Canada.

To determine whether imported drugs meet Canada's GMP regulatory requirements, Health Canada uses reports from its own inspectors or from recognized partner countries under the terms of Mutual Recognition Agreements (MRA) ¹¹⁶ and the Pharmaceutical Inspection Cooperation Scheme (PIC/S). It also uses inspection reports from the United States Food and Drug Administration.

The use of inspection reports from recognized partner countries is based on a rigorous process that has established equivalency of both GMP standards and compliance inspection procedures and reports between the two countries.

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Distribution

Schedule F to the Food and Drug Regulations identifies those drugs that are authorized for sale on condition that they are prescribed by a physician. The distribution of drug products for human use is governed by the Provinces.

Compliance and Enforcement

HPFB has inspectors who verify compliance with the Food and Drugs Act and Regulations . Where necessary, they take steps to enforce the prohibitions outlined in these laws. Under the authority of the Food and Drugs Act , inspectors can enter and inspect places where drugs are manufactured, prepared, preserved, packaged or stored. If any non-compliance is found, appropriate actions are taken.

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¹⁰² R.S.C. 1985, c. F-27, available at laws.justice.gc.ca/en/F-27/.

¹⁰³ C.R.C., c. 870, available at laws.justice.gc.ca/en/F-27/.

¹⁰⁴Food and Drugs Act , s. 2.

¹⁰⁵ The DIN is an eight-digit number located on the label of prescription and non-prescription drug products n authorized for sale in Canada.

¹⁰⁶ See www.hc-sc.gc.ca/hpfb-dgpsa/.

¹⁰⁷SOR/93-133, available at laws.justice.gc.ca/en/p-4/sor-93-133/164296.html.

¹⁰⁸ R.S.C. 1985, c. P-4.

¹⁰⁹The Therapeutic Products Directorate has developed a web-accessible version of the Patent Register available at: www.patentregister.ca/.

¹¹⁰NOC Regulations , s. 5.

¹¹¹Ibid. , s. 5(4).

¹¹²Ibid. , s. 7.

¹¹³More information available at www.hc-sc.gc.ca/dhp-mps/prodpharma/fees-frais/index_e.html.

¹¹⁴ S.C. 1999,c. 33.

¹¹⁵ SOR 2005/247 and SOR 2005/248.

¹¹⁶ Canada has established MRA with Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Liechtenstein, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, and the United Kingdom. An MRA is also being finalized with Australia. The Pharmaceutical Inspection Cooperation Scheme members include the MRA countries listed above, as well as: Czech Republic, Hungary, Malaysia, Romania, Singapore, Slovak Republic and Latvia.