INTRODUCTION:

In the regulatory drug approval process a person, sponsor, an innovator, or an organization obtains permission to initiate a new drug in the market. Health Canada is a standard regulatory body to implement guidelines and regulations for registration for the marketing of drugs in Canada. They also implement certain guidelines. Canada has a unique healthcare system which is made up of 13 provisional and territorial programs and 6 additional federal plans. Making healthcare in Canada, share the responsibility between federal, provisional and territorial governments. A drug can take a decade to develop and the regulatory review body may take 5 more years to conduct the reviews¹.

The drug approval process includes two different stages i.e. clinical trial phase and marketing authorization period.

The clinical trials stage include 4 phases and after completing these studies the applicant can ensure the safety, efficacy and dose optimization in human beings. The drug application is submitted to the competent authorities by the sponsor, after completing the clinical trials for marketing a new drug. They review the application before approval of a drug for ensuring its safety and efficacy in human beings, the activity of the drug should be more comparable to its adverse effects. After approval, the drug is monitored by the government due to the side effects produced by the drug when it is used in a larger population. The drug-drug interaction should not be assessed in a pre-marketing research trial, but the adverse reactions produced by the drug are monitored ².

Drug approval process in Canada:

The drugs and medical devices for human use in Canada are regulated by Health Canada’s Therapeutic Products Directorate (TPD). Health Canada will ensure the safety and effectiveness of all drugs which are used by the public. They are also responsible for ensuring that drug manufacturers have tested the drugs before marketing.

The role of regulatory drug submission evaluation in Canada is to critically assess both the data submitted by the sponsor’s explanation of data in order to reach evidence to potential benefits/risks of the drug. The Therapeutic Products Directorate must approve all the drugs which are sold in Canada. Canadian pharmaceutical is the one of the largest market in the world.

New drug submission is necessary for drugs which require an approval for marketing in Canada, and those drugs which are not sold in the market before for ensuring the safety and efficacy which includes production information, labeling use, and adverse effects. If a new drug submission is submitted to TPD of Health Canada, the first step is the screening procedure for ensuring all necessary part of the application is included in the NDS. The screening procedure should be completed within 45 days of receipt of an NDS. The next step of NDS is reviewing of drugs for a therapeutic region. TPD completes a standard NDS review by 300-day performance guidelines³.

Types of drug submissions that are accepted for review by Health Canada:

· Clinical Trial Application (CTA)

· New Drug Submission (NDS)

· Abbreviated New Drug Submission (ANDS)

· Clinical Trial Application Amendment (CTA-A)

· Investigational New Drug Submission- veterinary drugs (INDS)

· Abbreviated New Drug Submission- veterinary drugs (ABNDS)

· Supplemental New Drug Submission (SNDS)

· Supplemental Abbreviated New Drug Submission (SANDS)

· Supplemental Abbreviated New Drug Submission- veterinary drugs (ABSNDS)

· Notifiable Change Submission (NC)

· Drug Identification Number (DIN-A)

· Drug Identification Number- Biologics (DIN-B)

· Drug Identification Number- Disinfectants (DIN-D)

· Drug Identification Number- Category IV (DIN-F)

· Prescription to OTC Switch (Rx to OTC)

· Administrative manufacturer name/ product name change/ licensing agreements (ADMIN)

A Clinical Trial Application (CTA) must be filled by a sponsor to request approval to start a human drug trial. Whenever a sponsor wishes to conduct human trials in Canada CTA approval is required. Health Canada audits the CTA document to ensure that the study design prevents participants from being exposed to excessive risk. Good Clinical Practices (GCP) must be followed. If the outcomes of the trial are significant and the sponsor is satisfied that the drug is more beneficial than the risk, the sponsor will be able to file a New Drug Submissions (NDS) to get drug approval for registration.

The New Drug Submission (NDS) - The New Drug Submission (NDS) contains particular data about both the medication substance and the medication item identifying with security, quality and adequacy. The NDS incorporates the preclinical and clinical testing regarding information about production of the drug substance and the drug product and also information on packaging, labeling, stability and validation procedures. An NDS is required whenever a drug product meets the definition of a “new drug” as found in the Drug Regulations. The definition of a new drug includes new drug substances as well as “new” indications, dosage forms or combinations of drugs, which have not been sold in Canada.

Abbreviated New Drug Submission (ANDS) - It is filed for obtaining an approval for a generic drug product. The applicant shows that the drug product is safe and effective as the innovator drug which is also known as ‘Canadian Reference Product’ for an ANDS prepared. The generic product must be shown to be bioequivalent with the innovator drug. The ANDS submission is filed with the Canadian reference Product with NOC/ status.

A Supplemental NDS (SNDS) is filed when the applicant wants to make important changes to an already approved NDS or ANDS.

Less critical changes are documented as Notifiable Change (NC) Submissions (SNDS) require pre-endorsement by Health Canada and are approved by means of 'new Notice of Compliance' (NOC). NC Submissions are subject to a target 90-day review and are approved via a “letter of no objection” meaning that Health Canada does not object to the implementation of the proposed change⁴.

Terms Used:

1. Notice of Deficiency (NOD):

If the review process does not continue due to deficiency or major omission of the file.

2. Notice of Non- compliance (NON):

If the complete review is submitted and if the information is short in the submission, not usually serve as NOD.

3. Notice of Deficiency Withdrawal (NOD/w):

The insufficient response to a NOD, the TPD will issue a NOD/w letter which representing the company should withdraw the submission.

4. Notice of Non- compliance Withdrawal (NON/w):

The Company must withdraw the submission if the response to a NON is insufficient.

5. Notice of Compliance (NOC):

Once if all the issues have been determined, the TPD will issue a NOC to the sponsor of the drug. If the Health Canada is not satisfied with all issues, have been satisfied, the TPD will issue either NOC/w or NON/w, i.e Notice of Compliance Withdrawal.

6. Priority Review:

It is a review status for a new drug submission, i.e. the drug will target a shorter review. The priority review is granted for a request submitted by the innovator or sponsor ⁵.

Pre- Submissions:

· This familiarizes reviewers with the product.

· The pre-submission identifies the studies on which the sponsor is relying to set up the drug effectiveness.

· It allows the sponsor to discuss with Health Canada and obtain the feedbacks.

· Gives the information regarding the areas of potential and priority review (meeting requests and pre-submission packages).

Pre- NDS or SNDS Meetings: It includes,

· An agenda requested before NDS/SNDS meeting.

· The cover letter.

· The sponsor must address a list of specific issues.

· Required a brief summary of drug product for Pre- NDS meeting.

· The overview of the foreign regulatory status and the history of the product being marketed.

Filing of Submission:

A duplicate copy of the submission is filed to the TPD by the sponsor and it should undergo a screening procedure. The review under NOC or sponsor looking for priority review regulations must submit a request for the advance filing of the submission ⁶.

Submission Holds:

The sponsors submit information to Health Canada and after evaluation, the administrative hold on a certain submission may be necessary⁷. Examples include:

· Cost-recovery Hold

· Division Hold

· Regulatory Hold

· Switch Hold

· SIPD (Submission and Information Policy) Hold.

Screening Process:

The screening process is carried out by the TPD of Health Canada to ensure that the process is completed and is in a suitable format. The process includes all technical review and information. Screening is done as an administrative review and for a new drug submission, it is completed only after 45 calendar days by TPD. If the screening process is completed and accepted, the technical review of the submission is carried out by TPD. Once the screening identifies any deficiencies in new drug submissions the sponsor has 45 days to respond. The identified deficiencies should be resolved by the sponsor.

Evaluation of Submissions:

The evaluation should be completed in 300 calendar days by the Therapeutic Products Directorate (TPD).

The drug Application Review process in Canada:

In Canada, application for the drug product is reviewed by scientists in the Health Products and Food Branch (HPFB) of Canada. The experts outside Canada are also called upon to review a particular drug’s safety, quality and efficacy occasionally.

Summary of the drug review process includes the following steps.

1. When a sponsor likes to market the new drug in Canada, first file an NDS to Health Canada with HPFB. NDS should include all safety, quality and efficacy information. It should also include the preclinical study reports and clinical study reports which are done in Canada or outside. The summary of details regarding production, packaging, labeling, therapeutic claims and side effects of the drug etc. are required to review.

2. In Canada, HPFB reviews the information that the sponsor proposes to provide healthcare practitioners and consumers about the drug.

3. To assess all potential benefits and risks of the drug, HPFB evaluates the safety, efficacy and quality data.

4. Using external consultants and advisory committees, a systematic review done on information which is submitted by HPFB.

5. Once the review is completed, the conclusion is that the benefit obtained by the drug is more than the risks associated with the drug and Notice of Compliance (NOC) as well as Drug Identification Number (DIN) will be issued. This indicates the drugs official approval in Canada and permits the sponsor to market the drug in Canada.

6. Before and after authorization process, the HPFB will test some biological products in the laboratories by a process known as Lot Release Process (LRP) in order to check safety, quality and efficacy of the drug product ⁸.

Some of the drugs are not really approved in Canada because the information submitted by the sponsor is insufficient or there is a lack of information which is required for the drug application. In this case, HPFB will not grant the license for marketing authorization for certain drugs. In such cases, the sponsor will provide additional information for resubmission of the application and resubmit with sufficient data at a later date to Health Canada. On the other hand, the drugs which are reviewed to meet all the requirements of the Food and Drugs Act in Canada for ensuring the marketing authorization procedures in the country.

The length of medication audit process in Canada depends on the item which is submitted like size, nature of entries and its impact on HPFB workload. For the serious disease conditions like AIDS, Cancer, Parkinson’s disease, there are few useful therapies now on the market, and the HPFB’s “priority review process” will allow a faster drug review for those therapies. Once a drug is approved by the priority review should undergo all the required clinical studies like normal review process, and this review is completed within 180 days ⁹.

Review Report:

The sponsors will be provided a reviewer reports within a week following the issuance of a NOD, a NON or a NOD/w. For the issuance of NOC, the sponsor must request for a reviewer report within a month.

Marketing:

Before the drug distribution process, the drug manufacturer should obtain a Notice Of Compliance (NOC) from Health Canada and also a Drug Identification Number (DIN). The NOC represents the information about a new drug to be marketed, which meets all necessary standards for human use and the DIN represents that the drug manufactured has been authorized and evaluated for marketing and sale in Canada. The manufacturer obtains a ‘Notice of Compliance’ by submitting a New Drug Submission (NDS); or an Abbreviated New Drug Submission (ANDS) for generic drugs in Health Canada. The approval process for generic drugs in Canada is costly and difficult ¹⁰. To make this approval process simple and more cost-effective, the ANDS scheme was implemented with the hope that the cost of drugs for regional governments and members of the public would in turn, be reduced. The manufacturer must confirm that the product is pharmaceutically equivalent and bioequivalent to receive a Notice of Compliance (NOC) under an ANDS, because of the decision on whether a medication will be listed on the prescription. The Drug List is made during the review of the New Drug Submissions and therefore requires a prescription before the drug is distributed to a patient. The non prescription drugs, prescription drugs and over the counter (OTC) medications all should run through the NDS process ¹¹.

Drug Monitoring:

The regulatory controls continue, once a drug is on market. Health Canada monitors the safety of marketed drugs by analyzing, collecting and assessing adverse reaction reports that are submitted by various applicants. In addition, it reviews the scientific literature and the department uses all these information to determine whether any advance reactions, from which protect the public¹². The department is responsible for ensuring the benefits of using a drug is more important than the risks associated with the drug. It fulfills the responsibility by implement measures necessary to reduce the risk associated with the marketed drugs.

CONCLUSION:

To develop a new drug, various research programs are done in manufacturing, clinical and pre-clinical testing, chemistry and control of drugs. The drug review in Health Canada is responsible for ensuring and evaluating the safety, efficacy, and quality of newly developed drugs, before serving it to public health. Different rules and regulations are implemented by TPD (Therapeutic Products Directorate) of HPFB (Health Products and Food Branch) in Canada and they issued the marketing guidelines for drugs which is a new product in the Canadian market, should follow before marketing. Prior to any medication can be sold on the Canadian market, it must follow a strict evaluation process led by HPFB of Health Canada. On occasion, external experts are also called upon to evaluate a particular drugs safety, effectiveness, and quality. When a company is seeking to have a drug to be approved for sale in Canada, the review process can be long and expensive.

ACKNOWLEDGEMENT:

The authors would like to thank to the authorities of NGSM Institute of Pharmaceutical Sciences and Nitte (Deemed to be University) for providing necessary facilities for preparing this review article.

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Received on 06.02.2019 Modified on 05.03.2019

Research J. Pharm. and Tech. 2019; 12(7):3206-3210.

DOI: 10.5958/0974-360X.2019.00538.9