Drug Approval Process in Canada

Introduction

It is critical for a drug, biologic or genetic therapy, medical device, combination product, natural health product, or other health product company seeking approval of their product for sale in Canada to understand that the approval process is scrutinized by the governing regulatory body.

However, the review and preparation process do not have to be complicated, daunting, or irritating. The aim is to understand, follow, and/or clarify the process associated with the health product of interest, and to assure readiness with appropriate data and documentation.

How are drugs reviewed and authorized to be marketed and sold in Canada?

• Most health products, including drugs, that are to be marketed or sold in Canada are reviewed and authorized by Health Canada's Health Products and Food Branch (HPFB), specifically the Therapeutic Product Directorate (TPD) for drugs and the Biologic and Genetic Therapies Directorate (BGTD) for biologics. 
• Each of these Directorates has its own set of offices and bureaus. Drugs are only allowed to enter that market when they have successfully completed the appropriate Bureau evaluation procedure, which is responsible for analyzing their safety, effectiveness, and quality, and getting a positive verdict. Even if a health product achieves a positive ruling and may be sold in Canada, its effectiveness and safety are continually monitored.

What is the Health Products and Food Branch?

Health Canada’s HPFB is the national authority that is responsible for regulating, evaluating, and monitoring the safety, efficacy, and quality of drugs, biologics, genetic therapies, and other health products available for the Canadian marketplace. The HPFB’s mandate is to manage the health-related risks and benefits of health products and foods for Canadians.

THE PROCESS OF DRUG DEVELOPMENT

It divided the drug development process into five stages and included a visual to complement the text.

Stage-1: Initial Drug Research

• On their route to generating a medication, researchers first uncover and identify several chemical, biological, or other compounds. This can be accomplished by new knowledge about a disease process, numerous tests of chemical compounds to identify potential therapeutic effects, current treatments that have unexpected outcomes, and new technology. 
• Once a potential molecule has been found, the researchers examine it for activity, efficacy, and toxicity, and finally obtain preliminary information on its effectiveness and safety. This preliminary study might require several years of trial. If the results are encouraging, the researchers will go on to the next stage of development.

The image below depicts a depiction of the Drug Development Process:

Stage 2: Pre-Clinical Studies

• The next step in development is where researchers administer the drug to selected species of animals (in vivo) or cells (in vitro). The drug must be shown to cause no serious harm (toxicity) at the doses required to have an effect.
• If results from these initial studies are promising and further tests show acceptable safety levels and clear or potential efficacy, then the next step would be to submit a Clinical Trial Application to the TPD or BGTD for authorization to allow human participation in a Canadian clinical trial.

Stage 3: Clinical Trials

• All medications approved for marketing or sale in Canada must have undergone clinical trials. The information acquired from these studies is then placed in the applicable regulatory dossiers to be examined by the HPFB, through the relevant Directorate, for the medicine to be subsequently authorized for sale in Canada.
• The outcomes of human clinical trials are critical components of the HPFB's evaluation process. A trial's purpose is to collect clinical information about a drug's effectiveness, safety, and best dosing/usage in humans, evaluate any adverse drug reactions, and compare results to existing treatments for the same disease or condition, or to placebo when no treatment exists for the aimed pathology.

Clinical Development:

• If clinical trials have already been done in Canada and/or in other countries, that is, at the end of the clinical development plan, the sponsor may choose to file a New Drug Submission with the HPFB in order to gain authorization to market and sell the drug in Canada. 
• However, when a sponsor aims to conduct a clinical trial in Canada, during the clinical development program, then a Clinical Trial Application (CTA) must be submitted to be reviewed and approved by the HPFB’s relevant Directorate in order to proceed with the trial. The results of these studies will be part of the drug approval process.

Clinical Trial Application:

The Canadian CTA dossier is simple and consists of the following documents (exceptions are possible): 

1. Administrative form, 
2. Protocol, 
3. Protocol summary (Health Canada’s template), 
4. Informed Consent Form, 
5. Investigator’s Brochure and quality dossier summary (Health Canada’s template per study phase).

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• Within 30 calendar days of the application being deemed complete, Health Canada evaluates the CTA and notifies the sponsor. During the review, questions may be posed, and the sponsor will have two calendar days to respond (exceptions may apply). CTAs are essential for clinical studies in stages I through III. Prior to starting the experiment and importing the investigational product(s) into Canada, authorization (No Objection Letter) is required.
• If the HPFB grants permission, the research can begin with human participants who have been informed and have given their agreement to be administered the medicine in exchange for their participation. It should be noted that the study materials (protocol, Investigator's Brochure, and Informed Consent Form) must also be approved by a Canadian Ethics Committee.
• Tests are conducted in a controlled environment where drug administration procedures and results are closely tracked, monitored, and analyzed.

Clinical Trial Phases

There are, in summary, four (4) phases in the clinical trial process. Each clinical trial phase for drugs has a different purpose.

1. Safety phase

This phase often involves testing an experimental medicine on a small sample of healthy people for the first time (unless it is not morally appropriate to do so). The goal is to assess the medications' pharmacokinetics/pharmacological activity, define a safe dose range, and identify adverse drug responses. 

2. Effectiveness phase

During this stage, the medicine is administered to a larger number of people with the pathology to be treated (typically several hundred). The goal is to collect data on the drug's effectiveness, to further examine the drug's safety, and to find the appropriate dose.

3. Confirmation phase

If the Phase 2 findings are positive, the medication maker will move on to Phase 3 studies. During this stage, the medicine is administered to even bigger groups of patients (typically thousands). The goal of this phase is to validate the medicine's efficacy, monitor adverse effects, compare the drug to other regularly used therapies, and collect other data that will allow the drug to be used and sold safely.

4. Monitoring phase

Phase 4 studies are conducted after the medicine has been licensed and is on the market. The goal of this phase is to acquire additional information about the optimal methods to utilize a medicine, as well as the population's long-term advantages and hazards.

• Unless agreed to with Health Canada, these studies do not need to be submitted under a Clinical Trial Application, when used according to the terms of the market approval.

Stage 4: Drug Approval Process

New Drug Submission (NDS)

• If the results of all the preclinical studies and the clinical trials show that a drug’s potential therapeutic benefit outweighs its risks (side effects, toxicity, etc.), and the chemistry and manufacturing dossier is complete, then the sponsor may decide to file an NDS with the appropriate HPFB Directorate in order to be granted authorization to sell the drug in Canada.
• A sponsor can submit an NDS whether the clinical trials were conducted in Canada or elsewhere. The NDS must incorporate the findings of quality (chemistry and manufacturing), preclinical, and clinical research, whether conducted in Canada or elsewhere. Before making a choice, the drug's effectiveness and safety data are assessed, and a Risk/Benefit analysis is undertaken.
• The information needed as part of an NDS application must be thorough enough for Health Canada to assess the new drug's safety and efficacy. All contributions must be submitted to Health Canada in the form of an electronic Common Technical Document (eCTD).

The CTD format is presented below.

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Module 1 (regional) includes the following, amongst other information:

1. Administrative form
2. Product Monograph
3. Mock-up of Inner and Outer labels
4. Certified Product Information Document
5. Brand Name Analysis
6. Risk Management Plan

Abbreviated New Drug Submission (ANDS)

• The ANDS regulation was created to make the approval process for generic drugs simpler and more cost-effective. Under an ANDS, the manufacturer of a drug has to prove that its product is pharmaceutically equivalent and/or bioequivalent with the innovator’s drug.
• For the purpose of an ANDS, the sponsor may need to perform a bioequivalence study or a physicochemical comparison (parenteral drugs or drugs for which it is not ethical to conduct the study on healthy volunteers). 

Review Process

• The HPFB reviews the NDS and all the information about the drug captured during the development process (quality, preclinical and clinical) and evaluates the risks of the drug versus its benefits to the Canadian population.
• More specifically, HPFB reviews information regarding the drug’s manufacturing, packaging, and labeling, as well as, information about the drug’s therapeutic claims and side effects.
• The medicine's monographs and information sheets will also be assessed to see what doctors and patients will be taught about the drug. All pharmaceuticals supplied in Canada are subjected to a review to verify that they fulfill the standards of the Food and Pharmaceuticals Act and its Regulations.
• Once these conditions have been completed, the sponsor (often the Marketing Authorization Holder) will get a Notice of conformity certifying the dossier's conformity with the Food and Drugs Act and its Regulations.

How long does the drug review process take?

• The target review timeline ranges from 7 months (accelerated review and ANDS) to 1 year (standard NDS). The exact time for Health Canada to review drug safety and efficacy information from an NDS depends on the type of drug, the quality of the dossier, the number of questions that Health Canada raises during the review process, the answers provided by the sponsor and if the targeted timelines for the responses are respected. 
• Once the review is complete, the Regulatory Agency decides to approve (or reject) the use of a new medication. In some instances, it can take longer than the targeted review timelines.
• HPFB review timelines are based on internationally competitive performance targets that are usually respected. By experience, the review can take anywhere from 6 months to 2 years, rarely more. The average time of the full drug development and approval process from initial research, preclinical studies, through the 3 phases of clinical trials to drug approval is 12 years (between 8 & 15 years).

The Notice of Compliance

Once the review is complete, if the conclusion is that the benefits of the drug outweigh the risks, that the risks can be managed, and confirming the dossier compliance with the Food and Drugs Act and its Regulations, then the sponsor in Canada receives a Notice of Compliance (NOC), as well as a Drug Identification Number (DIN), which is specific to a drug product to be sold on the Canadian market. 

What happens if a Drug receives a Notice of Non-Compliance?

Upon the completion of the review process, if the HPFB finds that there is insufficient evidence to support the safety, efficacy or quality claims of the drug, HPFB will not grant a marketing authorization for that drug. At this point, the sponsor typically has 3 options: 

1. To supply additional information to the HPFB, 
2. To re-submit a submission at a later date with additional supporting data (without prejudice), 
3. To ask that HPFB reconsider its decision.

Accelerated Review Process

For health conditions that are serious, life-threatening or severely debilitating diseases (such as Alzheimer’s disease, cancer, AIDS, or Parkinson’s Disease), the HPFB can provide faster authorization of a drug as follows:

1. Priority Review (PR): This applies to drugs that show substantial evidence of clinical effectiveness at the end of the clinical trial phases.
2. Notice of Compliance with Conditions (NOC/c): This applies to drugs with promising evidence of clinical effectiveness throughout the clinical trial phases. Approval would be granted to a manufacturer to market and sell that drug in Canada with the condition that the manufacturer executes additional studies to confirm the drug’s benefit and safety.

To be considered for PR or NOC/c, the drug must meet the following standards as described by Health Canada; the drug must provide:

• effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or
• a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for a disease or condition that is not adequately managed by a drug marketed in Canada.

Related to the NOC/c, some of the conditions of the Notice of Compliance include a requirement to closely monitor the drug for safety and to provide HPFB with regular updates. Once the conditions are met, the designation of “with a condition” is removed from the NOC.

Stage 5: After-Approval

• Getting a Notice of Compliance from Health Canada isn’t the last step in the process of selling and marketing the drug in Canada. Once a health product is approved and, on the market, the HPFB requires a sponsor to ensure that the use of its drug is done under the terms of its market authorization.
• Furthermore, Life Cycle Management efforts (post-approval filings to Health Canada for new indications, new dosage forms, new strengths, manufacturing modifications, etc.) are necessary to guarantee the product License and its associated enhancements are maintained. In summary, sponsors must guarantee that their products remain in accordance with the Food and Drug Regulations while they are on the market.
• On the other hand, Health Canada monitors drug information & adverse drug reactions reporting, conducts market surveillance, investigates complaints, and manages recalls if necessary, amongst other things. There are also more processes and regulations to follow and consider, either before, during, or after the review process, and before that drug is officially marketed, distributed, and sold in Canada.
• Topics such as licensing, warehousing, wholesale distribution rules and the Drug Establishment Licence (DEL), regulations around distribution to consumers, regulations around the marketing and advertising activities, provincial requirements, and health insurance funding rules, among others.

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