How long does it take a drug product to be approved in Canada?

How long does it take a drug product to be approved in Canada?

 

WHAT ARE HEALTH CANADA’S TIMELINES TO PROVIDE AUTHORIZATION FOR A DRUG TO BE SOLD ON THE CANADIAN MARKET?

The Canadian review timeline for a New Drug Submission (NDS) is competitive.

  • A standard review consists of a maximum of 10 days eCTD validation,
  • followed by 45 days administrative screening where it is verified that the content is acceptable and that no key information is missing,
  • following the screening period, a 300-day scientific review of the quality, non-clinical and clinical data packages, applies

Therefore, a total of 355 review days applies, before a sponsor obtains a final review decision.

Should the NDS qualify for an accelerated review either under a Priority Review or a Notice of Compliance with condition, the review timelines are shorter.

Please read our Canadian Drug Review & Approval  Guide for further information on the drug approval process in Canada. 


 

For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.


How does Canada’s Application process compare to USA and EU?

How does Health Canada’s Clinical Trial Application process compare to the USA and EU?

 

HOW DOES HEALTH CANADA’S CLINICAL TRIAL APPLICATION PROCESS COMPARE TO THE SUBMISSION PROCESSES IN THE US OR EU?

When the process is properly understood and the sponsor or the representatives have established contacts with Health Canada, the clinical trial application in Canada is relatively simple and so is the review process. The actual submission structure is also simple, and the content requirements are actually less than in the US and Europe.

There are no non-clinical, nor clinical study reports needed in the clinical trial application. What is needed is the administrative documents plus key scientific documents, which are the protocol, the informed consent form and the investigators brochure. There’s two Canadian specific templates required that we need to generate: the protocol summary as well as the overall quality summary. All of these are quite easy to prepare.

The review process is also efficient. A 30-day default review period applies. If questions are raised during the dossier review a response must be provided within two calendar days (exceptions may apply). And by way of comparison, in Canada there is no clinical hold period like in the United States. The review period is always 30 days, whereas in some European countries the review period can be as long as 60 days or more, and in the US it can vary.

Due to the standard 30-day review period in Canada, I believe it does facilitate the ethics review submission planning, which speeds up clinical trial start times. Also, there are efficient clinical trials start-up experts in Canada that can help with streamlining the study start-up process in parallel or after the clinical trials application approval.

Are Health Canada’s safety policies and guidelines more stringent than those imposed by the FDA?

The requirements are similar in Canada and in the U.S. for clinical trial applications as well as for post-approval initiatives.


 

For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.

 
 


The Ultimate Glossary of Drug Regulatory Terms for Canada

The Ultimate Glossary of Drug Regulatory Terms for Canada

 

What’s with all these Drug Regulatory Acronyms and Definitions in Canada?

The pharmaceutical industry is complex. The terms, expressions, abbreviations and industry vernacular are also as complex and confusing. We have attempted to put some order within this process by providing what we call the ultimate glossary of the most common abbreviations and terms used in the drug regulatory industry in Canada.

All terms and acronyms have been organized alphabetically.


What is Annual Drug Notification – ADN?


Annual Drug Notification is a notification sent to Health Canada annually, before October, by a drug sponsor/manufacturer, confirming that all information previously supplied with regard to that drug is correct, in order to comply with section C.01.014.5 of the Food and Drug Regulations. The Annual Drug Notification Form (ADNF) is available to assist manufacturers in complying with the said regulations.

 

What is Adverse Drug Reaction – ADR?


Adverse drug reaction is a noxious and unintended response to a drug, which occurs at doses normally used or tested for the diagnosis, treatment or prevention of a disease or the modification of an organic function. It includes lack of efficacy.

 

What is Adverse Event – AE?


Adverse event is any adverse occurrence in the health of a clinical trial subject who is administered a drug, that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.

 

What is Abbreviated New Drug Submission – ANDS?


Abbreviated new drug submission is a regulatory dossier that needs to be submitted and approved by Health Canada for a manufacturer to be granted authorizations to sell (Marketing Authorization) a generic drug on the Canadian market. This dossier typically requires a Bioequivalence study or a physico-chemical comparison (or both) against the Canadian Reference Product (innovator) plus a complete Chemistry and Manufacturing (Quality) package. Some exceptions can apply.

 

What is Adverse Reaction – AR?


Adverse reaction is a noxious and unintended response to a marketed health product and includes Adverse Drug Reaction as defined in the Food and Drug Regulations and Adverse Reaction as defined in the Natural Health Products Regulations. In the later regulations, AR means a noxious and unintended response to a natural health product that occurs at any dose used or tested for the diagnosis, treatment or prevention of a disease or for modifying an organic function.

 

What is Biologic and Genetic Therapies Directorate – BGTD?


Canadian regulatory authority of biological drugs (products made from living sources) and radiopharmaceuticals (drugs that have radioactivity) for human use in Canada. It is one of Health Product and Food Branch Directorates. Before giving permission to sell these therapies, the directorate must see scientific evidence of it’s safety, effectiveness, and quality, as required by the Food and Drugs Act and Regulations.

 

What is Canadian Agency for Drugs and Technologies in Health – CADTH?


An independent, not-for-profit organization responsible for providing health care decision-makers with objective evidence to help make informed decisions about the optimal use of health technologies, including: drugs, diagnostic tests, medical, dental, and surgical devices and procedures. In addition to evidence, we also provide advice, recommendations, and tools.

This agency was initially established in 1989 as the Canadian Coordinating Office for Health Technology Assessment (CCOHTA), CADTH adopted its new name in April 2006 to better reflect their broad activities.

 

What is Clinical Assessment Package – CAP?


A clinical assessment package is a document which needs to be prepared and submitted to Health Canada’ appropriate review Bureau along with a written request to obtain a Priority Review Status, in advance of the filing of New Drug Submission (NDS).

 

What is a Category IV Drug Product?


Category IV Products makes reference to products that have Category IV Monographs, that are developed for drugs that have a well characterized safety and efficacy profile under specific conditions of use. A manufacturer may reference a Category IV Monograph in a drug submission when the product and its labelling are consistent with the information set out in the document. Products subject to Category IV Monographs, can obtain a DIN through a DINF application.

 

What is Canadian Blood Services – CBS?


Canadian Blood Services was founded in 1998, based on recommendations from the Krever Report on the tainted blood scandal of the early 1990s. CBS is regulated as a biologics manufacturer by Health Canada and primarily funded by the provincial and territorial ministries of health. Canadian Blood Services is a not-for-profit charitable organization.

 

What is the Canadian Institute for Health Information – CIHI?


A Canadian health agency that collects and reports on clinical and non-clinical data.

 

What is the Council for International Organization of Medical Sciences – CIOMS?


The CIOMS refers essentially to the CIOMS I Form, which provides a standardized format for the reporting of suspected adverse reactions to any particular medical product, in Canada as well as worldwide.  The Council plays an important role in the current pharmacovigilance practice.

 

What is a Common Drug Review – CDR?


A common drug review is a national review process for non-oncology drugs that focuses on the cost effectiveness of a drug vs. current therapies. CDR issues a recommendation to the government drug plans (except Quebec – see INESSS) as to whether or a not a  drug should be publicly funded for patients who need access.

What is a Clinical Trial – CT?


A clinical trial is an investigation with a drug for use in human subjects, intended to discover or verify the clinical, pharmacological or pharmacodynamic effects of the drug, identify any adverse events, study the absorption, distribution, metabolism and excretion of the drug, or ascertain the safety or efficacy of the drug.

 

What is a Clinical Trial Application – CTA?


A clinical trial application is a regulatory dossier that needs to be submitted to Health Canada and given a No Objection Letter (NOL) from Health Canada prior to the sponsor proceeding with a clinical trial with an investigational pharmaceutical, biological and radiopharmaceutical product in the Canadian population / patients. In the the context of clinical trial management activities, CTA can also mean Clinical Trial Agreement (which is the agreement between the clinical trial investigational sites/center and the sponsor, in order to conduct the aimed study).

CTA also means Clinical Trial Authorization, the equivalent to a Clinical Trial Application required in Europe (EMA). In the USA (FDA), IND (Investigational New Drug) is the equivalent of the Clinical Trial Application.

 

What is a Clinical Trial Application – Amendment/Notification – CTA-A/N?


CTA-A: Changes to the clinical trial protocol or quality dossier, after the original CTA submission, that will impact the safety of the subjects, will affect the analysis and the interpretation of the safety and efficacy of the drug(s) under investigation or, that may affect the quality or safety of the clinical trial drug supplies.  A 30-day review period applies before these changes can be implemented.

CTA-N:  Changes that do not meet the criteria for a CTA-A, which may be implemented immediately, but Health Canada must be informed in writing, within 15 calendar days of the day of the change.

 

What is a Common Technical Document – CTD?


A common technical document is a globally harmonized Submission format that is accepted by many regions, in an effort to avoid the need to compile different registration dossiers for different regulatory authorities. The CTD format was adopted by Health Canada in 2003.

 

What is a Clinical Trial Site – CTS?


The location where clinical trial-related activities are conducted.

 

What is a Clinical Trial Site Information Form – CTSIF?


Form that is required to be completed and submitted to Health Canada by the sponsor or its representative for each clinical trial site, prior to commencement of the clinical trial or implementation of a Clinical Trial Application-Amendment, at that site.

 

What is a Drug Establishment License – DEL?


A drug establishment license is a license issued to a person in Canada allowing them to conduct licensable activities in a building which has been inspected and assessed as being in compliance with the requirements of the Food and Drug Regulations. Activities covered under a DEL are: fabrication, packaging, labelling, testing, importation, distribution or wholesaling. DEL applies for active pharmaceutical ingredients, finished dosage drugs or bulk process intermediates.

 

What is a Drug Identification Number – DIN?


A drug identification number is an eight (8) digit numerical code assigned to each drug product approved under the Food and Drugs Act and Regulations (except for Schedule C drugs – radiopharmaceuticals). A DIN identifies the following product characteristics: manufacturer, brand name, medicinal ingredient(s), strength of medicinal ingredient(s), pharmaceutical form, route of administration.

 

What is an Application for a DIN – DINA?


When a product is not subject to Division 8 of the Food and Drug Regulations, the application is called a DIN submission.

Note: Under the provisions of section C.01.014 of the Food and Drug Regulations, no manufacturer shall sell a drug in dosage form unless a drug identification number (DIN) has been assigned for that drug and the assignment of the number has not been cancelled pursuant to section C.01.014.6. In the case of a new drug, a new drug submission filed pursuant to Division 8 of the Food and Drug Regulations is regarded as an application for a DIN.

  • A DINB is an Application for a DIN specific to a Biologic Product.
  • A DIND is an Application for a DIN specific to a Disinfectant Product.
  • A DINF is an Application for a DIN specific to a Category IV Product.

 

What is the Food and Drug Act – FDA?


An Act respecting food, drugs, cosmetics and therapeutic devices.

 

What is are Food and Drug Regulations – FDR?


The legislation that oversees and sets out requirements for the manufacture, packaging, labelling, storage, importation, distribution and sale of foods, and prescription and non-prescription drugs in Canada. Requirements for drug clinical trials are also set out in the regulations. Health Canada develops and enforces regulations under Government of Canada legislation. The Department consults with the Canadian public, industry and other interested parties in the development of laws that protect health and safety. They also prepare guidelines and policies in order to help interpret and clarify the legislation surrounding drugs and health products. The purpose of the legislation is to protect the health and safety of Canadians with respect to the sales of food and drug products.

 

What is Good Clinical Practice – GCP?


Generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of clinical trial subjects and other persons, and the good clinical practices referred to in section C.05.010 of the Regulations.

 

What is Good Manufacturing Practices – GMP?


The part of quality assurance ensuring that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization. Part of the Health Products and Food Branch Inspectorate (Inspectorate) program is to conduct inspections of establishments that are involved in activities covered by the Establishment Licensing framework.

 

What is Health Canada – HC?


Health Canada is the Federal department responsible for helping Canadians maintain and improve their health, while respecting individual choices and circumstances.

 

What is a Health Product – HP?


Health Products in Canada are products regulated under the Food and Drugs Regulations (drugs) and the Natural Health Products Regulations (natural health products). Drugs include both prescription and non-prescription pharmaceuticals; biotechnology products and biologically-derived products such as vaccines, serums, and blood derived products; disinfectants; and radiopharmaceuticals.  

 

What is the Health Product and Food Branch – HPFB?


The health product and food branch is a Health Canada Branch mandated to manage the health-related risks and benefits of health products and food by: 1) minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; 2) providing information to Canadians so they can make healthy, informed decisions about their health. The HPFB activities are carried out under various Directorates and Offices, including the Therapeutic Product Directorate, the Biologic and Genetic Therapies Directorate and the Marketed Health product Directorate.

 

What is the Health Product and Food Branch Inspectorate – HPFBI?


The health product and food branch inspectorate conducts inspections of establishments that are involved in activities covered by the Establishment Licensing framework. These inspections are conducted to verify the compliance with GMP (Part C, Division 2 of the Food and Drugs Regulations) which is a requirement for the issuance of an establishment licence.

 

What is Héma Québec – HQ?


Meets the needs of the Québec population for quality blood and other biological products of human origin.

 

What is Health Technology Assessment – HTA?


A health Technology assessment is the process followed to provide an evidenced based recommendation on whether a health technology merits being publicly funded.

 

What is an Investigator’s Brochure – IB?


An investigator’s brochure, in respect of a drug, is a document containing the nonclinical and clinical data on the drug that are described in section C.05.005(e) of the Regulations.

 

What is an Informed Consent Form – ICF?


An informed consent form is a document that describes: The risks and anticipated benefits to his or her health arising from participation in the clinical trial; and all other aspects of the clinical trial that are necessary for that person to make the decision to participate in the clinical trial.

 

What is the International Conference on Harmonization – ICH?


International initiative to harmonize efficacy, safety and quality (chemistry and manufacturing) requirements globally for the registration of drugs (pharmaceuticals, biologicals, genetic therapies, …) for human use. This initiative include standard information organization for new drug registration applications.

 

What is Institut national d’excellence en santé et en services sociaux – INESSS?


Quebec’s review process to evaluate therapeutic value and cost-effectiveness of oncology and non-oncology drugs. INESSS issues a recommendation to Quebec’s Minister of Health and Social Services as to whether or not a drug should be publicly funded for patients who need access

 

What is an Investigational Testing Application – ITA?


The equivalent of a CTA but for a Medical Device.

 

What is a Marketing Authorization Holder – MAH?


A marketing authorization holder is the entity that holds the Notice of Compliance, the Drug Identification Number (DIN), the Natural Product Number (NPN), the Homeopathic Medicine Number (DIN-HM), or the product license.

 

What is a Medical device License Application – MDLA?


A medical device license application is equivalent to a CTA but for Investigating the efficacy and safety of a Medical Device.

 

What is a Master File – MF


A master file, formerly known as Drug Master File is a reference that provides information about specific processes or components used in the manufacturing, processing, or packaging of a drug. The MF is a useful vehicle for providing information to Health Canada, where that information is of a proprietary nature [i.e., confidential business information] and is not available to the manufacturer of the dosage form or to the sponsors of a drug submission or clinical trial application (also referred to as the applicants).

 

What is a New Active Substance – NAS?


A new active substance is a chemical or biological substance not previously authorized for sale in Canada as a drug;

  • Isomer, derivative or salt of a chemical substance previously authorized for sale as a drug in Canada, but differing in properties with regard to safety and efficacy;
  • Biological substance previously authorized for sale in Canada as a drug, but differing in molecular structure, nature of the source material or manufacturing process.

 

What is a Notifiable Change – NC?


Notifiable changes are Level II Changes and are classified either as:

Moderate Quality Changes (chemistry and manufacturing) which have a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. This level of change does not apply to Human Pharmaceuticals.

Risk Management Change (clinical) defined as a change to the label that has the potential to improve the management of risk to the population currently indicated for use of, or in any other way exposed to the drug. These changes are classified as either 90-day review changes (more urgent changes) or 120-day review changes.

 

What is a New Drug Submission – NDS?


A new drug submission is a regulatory dossier that needs to be submitted and approved by Health Canada for a manufacturer to be granted authorizations to sell a new drug (i.e. pharmaceutical, biologic, vaccine, biotechnology product). This dossier typically requires complete Pre-clinical, Clinical and Chemistry and Manufacturing (Quality) package. Specific requirements may differ depending on the drug type, the pathology treated, the aimed patient population, amongst other elements.

 

What is a Natural Health Product – NHP?


A substance set out in Schedule 1 of the Natural Health Products Regulations or a combination of substances in which all the medicinal ingredients are substances set out in Schedule 1 of the Natural Health Products Regulations, a homeopathic medicine or a traditional medicine.

 

What is a Notice of Compliance – NOC?


A notice of compliance is a notification issued by Health Canada indicating that a manufacturer has complied with the requirements of the Food and Drug Regulations at the end of the review of an NDS, ANDS, S/NDS or S/ANDS.

 

What is a Notice of Compliance with Conditions Qualifying Notice -NOC/c-QN?


A notice of compliance with conditions qualifying notice is a notification issued by the Director of the responsible reviewing Bureau/Centre upon completion of a review, should a submission be determined to qualify for further consideration under the NOC/c policy. The NOC/c – QN will indicate that the submission qualifies for a NOC, under the NOC/c policy, as well as outline the additional clinical evidence to be provided in confirmatory studies, post-market surveillance responsibilities and any requirements related to advertising, labeling, or distribution. Submission review will cease upon issuance of the Qualifying Notice.

This applies to products that has promising evidence of clinical effectiveness with acceptable safety profile intended for the treatment, prevention or diagnosis of a serious, life-threatening or severely debilitating disease or condition for which there is no existing therapy available in Canada which possesses  a similar therapeutic profile or for which the new drug submission demonstrates a significant improvement in the benefit/risk profile over the available alternative product.

 

What is a Notice of Deficiency – NOD?


A notice of deficiency is a notice issued if deficiencies and/or significant omissions that preclude continuing the review are identified during the review of a submission.

 

What is a No Objection Letter – NOL?


A no objection letter is a letter emitted by Health Canada after the review of a Clinical Trial Application or a Notifiable Change, if the application is deemed acceptable to them. It confirms that a sponsor can proceed with its Clinical Trial in Canada or can implement the changes presented in the Notifiable Change.

 

What is a Notice of Non Compliance – NON?


A notice of non compliance is a notice issued after the comprehensive review of a submission is complete, if the submission is deficient or incomplete in complying with the requirements outlined in the Food and Drugs Act and Regulations.

 

Not Satisfactory Notice –

NSN


A notice issued by the Director of the responsible reviewing Bureau/Centre if deficiencies are identified during the review of a Clinical Trial Application, Clinical Trial Application-Amendment or Notifiable Change. The deficiencies will be specified and review of the submission will stop on the date of the Not Satisfactory Notice.

 

Pharmaceutical Advertising Advisory Board –

PAAB


An independent and not-for-profit organization funded on a fee-for-service basis. It is the only regulator whose preclearance service is recognized by Health Canada for advertising directed to healthcare professionals. PAAB works to protect Canadians by ensuring that healthcare product advertising meets the regulatory, scientific, therapeutic, and ethical standards outlined in the Code of Advertising Acceptance. All PAAB approved materials bear the PAAB logo.

 

Periodic Benefit Risk Evaluation Report –

PBRER


A pharmacovigilance document intended to provide a comprehensive, concise, and critical analysis of new or emerging information on the risks of the health product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile. The current ICH guidance ensures that PSURs for marketed drugs have the role of being periodic benefit-risk evaluation reports by covering: Safety evaluation, evaluation of all relevant available information accessible to sponsors/MAHs and benefit-risk evaluation.

 

pan-Canadian Pharmaceutical Alliance –

pCPA


National mechanism designed to achieve greater value for government drug plans. pCPA negotiates with a drug company to determine both the cost and criteria under which governments will pay for a medication, concluding with a Letter of Intent to fund the drug.

 

Patented Medicine Price Review Board –

PMPRB


A board that protects and informs Canadian consumers by ensuring that the prices of patented medicines sold in Canada are not excessive, and by reporting on pharmaceutical trends.

 

Priority Review –

PR


A status granted by Health Canada to an NDS or an SNDS for a serious, life-threatening or severely debilitating disease of condition for which there is substantial evidence of clinical effectiveness that the drug provides: 1) effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; or 2) a significant increase in efficacy and/or a 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.

 

Protocol Safety and Efficacy Assessment Template – Clinical Trial Application –

PSEAT-CTA 


A protocol summary to be prepared and submitted within the CTA. The summary is expected to contain: protocol identification, background and rationale, trial objectives, study design and duration, total number of sites (including number of Canadian sites), investigators, sample size, patient population, inclusion & exclusion criteria, drug formulation, dosage regimen, washout period, screening & baseline evaluation, treatment & assessment visits, concomitant & rescue medication, risk management, withdrawal/discontinuation criteria, efficacy & safety variables and analysis, statistical analysis.

PSUR – Periodic Safety Update Report
Mechanism for summarizing interval safety data, and for conducting an overall safety evaluation. It is a tool for sponsors to conduct systematic analyses of safety data on a regular basis. In addition to covering ongoing safety issues, the PSUR should also include updates on emerging and/or urgent safety issues, and major signal detection and evaluation that are addressed in other documents.

 

Qualified Health Care Professional – QHCP


A person who is a member in good standing of a professional medical, nursing, pharmacists’ or other health care practitioner association and entitled to provide health care under the laws of the jurisdiction in which the person is located, and other individuals retained by the Marketing Authorization Holder who have the appropriate health care education and therapeutic expertise.

 

Qualified Investigator


The person responsible to the sponsor for the conduct of the clinical trial at the clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located.

 

Qualified Investigator Undertaking


The undertaking that must be completed by the qualified investigator responsible for the conduct of the clinical trial at the clinical site and retained by the clinical trial sponsor for a period of 25 years. This undertaking should not be submitted to Health Canada unless requested.

 

Quality Overall Summary – QOS


Summary template that follows the scope and the outline of the Quality Body of Data (of CTD Module 3.2). Specific QOS templates exists for Clinical Trial Applications Phases I, II & III; for Bioavailability studies and for DIN applications. The QOS for new chemical entities is presented below.

 

Quality Overall Summary – Chemical Entities (CTA) – QOS-CE


Summary template that follows the scope and the outline of the Quality Body of Data (of CTD Module 3.2). This template can be used by sponsors to summarize the Quality information for New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) containing drug substances and their corresponding products of synthetic or semi-synthetic origin that are filed with Health Canada pursuant to Part C, Division 8 of the Food and Drug Regulations.

This would exclude submissions for Biotechnological/Biological (Schedule D) and Radiopharmaceutical (Schedule C) drugs. Nonetheless in reality, the referenced QOS-CE is used to summarize the Quality information for Schedule D New Drug Submissions (NDSs); sections of the template are then bonified with the requirements of the Schedule D NDS guidance. A Quality Information Summary (QIS) is available for radiopharmaceuticals, upon request from Health Canada.

 

Research Ethics Board – REB


A body that is not affiliated with the sponsor, mandated to approve the initiation of, and conduct periodic reviews of, biomedical research involving human subjects in order to ensure the protection of their rights, safety and well-being. The body needs at least five members, that are in majority Canadian citizens or permanent residents under the Immigration Act, and composed of both men and women. Additional criteria apply.

 

Risk Minimization Activity


Risk minimization activities are interventions intended to prevent or reduce the occurrence of adverse reactions associated with the exposure to a medicine, or to reduce their severity or impact on the patient should adverse reactions occur. These measures may include warnings in the label or minimization activities beyond routine, such as health care provider educational material.

 

Risk Management Plan


A document that describes a set of pharmacovigilance activities and interventions designed to identify, characterize, prevent or minimize risks related to drug products, and the assessment of the effectiveness of those interventions (adopted from the European Medicines Agency definition of a Risk Management System).

 

Supplemental Abbreviated New Drug Submission – S/ANDS


Same as for a S/NDS presented below but for generic products.

 

Supplemental New Drug Application – S/NDS


Submission required for Level I Quality or Safety & Efficacy (Clinical) Changes that have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product or a change to the label of a drug that has the potential to increase the exposure levels of the drug, either by expanding the population that is exposed, or by increasing individual exposure.

 

Special Access Program


Program that allows access to nonmarketed drugs for practitioners treating patients with serious or life-threatening conditions when conventional therapies have failed, are unsuitable, or unavailable. The SAP authorizes a manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada. Drugs considered for release by the SAP include pharmaceutical, biologic, and radio-pharmaceutical products not approved for sale in Canada.

 

Serious Adverse Drug Reaction – SADR


An adverse drug reaction that requires in-patient hospitalization or prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.

 

Serious Adverse Reaction


A noxious and unintended response to a natural health product that occurs at any dose and that requires in-patient hospitalization or a prolongation of existing hospitalization, that causes congenital malformation, that results in persistent or significant disability or incapacity, that is life threatening or that results in death.

 

Senior Executive Officer


The most senior person with policy and operational decision making authority within the sponsor, or is an official who has this delegated authority in respect of a clinical trial.  The SEO is responsible for providing an attestation with respect to the Clinical Trial Application/Amendment at the time of filing the CTA to Health Canada.

 

Serious Unexpected Adverse Drug Reaction – SUADR


A serious adverse drug reaction that is not identified in nature, severity or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.

 

Therapeutic Products Directorate

Canada’s regulator of prescription drugs and medical devices for human use. Before giving permission to sell a product, the directorate must see scientific evidence of the product’s safety, effectiveness, and quality, as required by the Food and Drugs Act and Regulations.

 

Yearly Biologic Product Report – YBPR


A report that must be submitted annually by manufacturers of all Schedule D (Biologic) drugs in accordance with Guidance for Sponsors: Lot Release Program for Schedule D (Biologics) Drugs. The report contains production information on both drug substance and drug product lots, including test methods and results, reasons for any recalls and corrective action taken, as well as other pertinent post-market information.

Overcoming Obstacles in the Drug Approval Process in Canada

Staying abreast of drug regulatory landscapes is understandably a challenge; the environment can be challenging to master because of its complexity and the fact that it is continuously changing. Innovations in both science and data collection/reporting methods keep the landscape fluid; it takes rigor and devotion to stay current.

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The Drug Regulatory & Approval Process in Canada – FAQ

FAQ on The Drug Regulatory & Approval Process in Canada

For questions on the Drug Regulatory & Approval Process in Canada or other drug regulatory affairs questions not covered in this FAQ, please go ahead and contact us directly.

 

WHY IS IT IMPORTANT FOR SPONSORS/DRUG MANUFACTURERS TO WORK WITH SOMEONE WITH SPECIFIC EXPERTISE IN CANADIAN REGULATORY AFFAIRS?

Having a Canadian regulatory expert is important to facilitate the global Canadian submission process and all post-approval activities. It’s also important to know that Health Canada prefers speaking with individuals that understand the Canadian medical as well as regulatory environment, whether they are the sponsors or their representatives. The support of a Canadian regulatory consultant is key for the submission of clinical trial applications, New Drug Submissions, or other regulatory initiatives. But it is most important for the global product development strategy, particularly when dealing with niche products used for treating orphan or life-threatening diseases. By understanding Canadian as well as foreign regulatory environments, a Canadian consultant can provide the best strategic initiative for timely access to the Canadian market, keeping the global regulatory initiatives in mind.

The regulatory paths for market access in Canada are essentially threefold. First there is the standard regulatory new drug submission path, then there is the notice of compliance with conditions (NOC/c) path, usually applicable for oncology or other niche products, and finally there is the priority review path. The latest two have shorter review standards at Health Canada.


WHAT ARE HEALTH CANADA’S TIMELINES TO PROVIDE AUTHORIZATION FOR A DRUG TO BE SOLD ON THE CANADIAN MARKET?

The Canadian review timeline for a New Drug Submission (NDS) is competitive. A standard review consists of a maximum of 10 days eCTD validation, followed by 45 days administrative screening where it is verified that the content is acceptable and that no key information is missing. Following the screening period, a 300-day scientific review of the quality, non-clinical and clinical data packages, applies. Therefore, a total of 355 review days applies, before a sponsor obtains a final review decision.

Should the NDS qualify for an accelerated review either under a Priority Review or a Notice of Compliance with condition, the review timelines are shorter.


WHAT IS THE DIFFERENCE BETWEEN THE NOTICE OF COMPLIANCE WITH CONDITIONS AND THE PRIORITY REVIEW?

These two processes apply to drugs used to treat conditions that are serious, life-threatening or for a severely debilitating disease (such as Alzheimer’s disease, cancer, AIDS, or Parkinson’s Disease).

Priority Review (PR) applies to drugs that shows substantial evidence of clinical effectiveness at the end of the clinical trial phases, that is, once the clinical development is completed. The total review timeline is reduced from 355 days to 215 days.

On the other hand, the Notice of Compliance with condition (NOC/c) applies to drugs with promising evidence of clinical effectiveness throughout the clinical trial phases. In summary, the NOC/c can be granted with less clinical data than usually expected, that is with Phase II study results or interim reports of Phase III studies. Approval would be granted to a manufacturer to market and sell that drug in Canada with the condition that the manufacturer execute additional studies to confirm the drug’s benefit and safety.  The total review timeline is reduced from 355 days to 235 days.

The condition needs to be agreed to with Health Canada. Some of the conditions of the NOC/c may include a requirement to closely monitor the drug for safety and adverse reactions and to provide HPFB with regular updates. Once the conditions are met, the designation of “with condition” is removed from the NOC.

To be considered for PR or NOC/c, the drug considered need to meet specific Health Canada criteria, that can be summarized as follows:

  • Offer effective treatment, prevention or diagnosis of a disease or condition for which no drug is available in Canada; or
  • Offer an improved benefit/risk profile over existing therapies, preventatives or diagnostic agents for a disease or condition, not adequately managed by a drug marketed in Canada.

Again, discussing with a Canadian regulatory expert in the early drug development stages can be an advantage for early input to establish the ideal regulatory strategy, as well as to help navigate through the requirements that are specific to Canada, while keeping in mind the global market strategy.


  

WHAT IS A DRUG IDENTIFICATION NUMBER? IS IT SPECIFIC TO CANADA?

A Drug Identification Number (DIN) is a unique eight-digit number assigned to each drug product considered to be compliant to the Food and Drug Act and its Regulations in Canada. It does not apply to radiopharmaceuticals. A DIN uniquely identifies the product manufacturer, product name, active ingredients, strengths, pharmaceutical form and route of administration. This number is assigned to a drug product, provided to the sponsor along with a Notice of Compliance.


WHAT TYPE OF DATA PROTECTION IS APPLICABLE IN CANADA AND HOW DOES IT APPLY?

All drug products containing a new chemical entity are eligible to an eight-year period of market exclusivity. Should the drug product be aimed for a pediatric population, a further six-month extension can apply if the acceptable pediatric data are submitted within the first 5 years of the 8-year period. Health Canada will conduct a preliminary assessment while the drug is under review (NDS) and the sponsor will be notified of the outcome.

Consequently, a subsequent-entry manufacturer is not allowed to file a submission for a generic drug for the first six years of the eight-year period. For products with eligible patents, submission of patent forms within the planned NDS and SNDS is critical to avoid loss of rights and generic entries to the market earlier than the market allows.


IS IT TRUE THAT HEALTH CANADA BASES THEIR DECISIONS IN GREAT PROPORTIONS ON FOREIGN DECISIONS?

This is a major miss-conception. I have seen in many instances, new drugs or new indications approved in Canada while the approval was on hold or refused in foreign countries. Health Canada makes their own independent decisions. However, it is possible (and recommended) to submit the major Q & As issued during the foreign review, along with the Foreign Agency Reviewers Reports. If the submission includes foreign review report, it is recommended to include a completed Foreign Review Attestation Template.  The extent to which Health Canada will use foreign reviews varies. The Canadian regulatory decision can be based on a critical assessment of the foreign reviews, on the Canadian review only or on a mixture of both.


WHY IS IT THAT HEALTH CANADA ASKS FOR FOREIGN REVIEWS?

The provision of foreign review reports in an NDS is not mandatory, but highly recommended. Indeed, they are usually requested at screening if not included within the original submission.

In addition, within the Screening Acceptance letter, Health Canada usually requests the sponsor to share the Questions from foreign regulatory agency reviews and the sponsor’s answers, during the review of the NDS.

In my experience and through my discussions with Health Canada, when the Canadian agency has questions that have already been addressed in a response to questions from a foreign agency, it likely reduces the number of questions to be raised to the sponsor, accordingly.


HOW HAS THE EVOLUTION OF REGULATORY AFFAIRS AFFECTED THE WAY CLINICAL TRIALS ARE CONDUCTED NOW VERSUS 10 YEARS AGO?

With regards to clinical trial applications, Health Canada’s requirements have not changed much. However, they’ve had no choice but to open up to new strategies – novel agents, personalized medicines, or orphan drugs for which there is no official designation yet – and accept novel trial designs. Health Canada is very open to hear how novel therapies can help Canadians and there’s a clear openness and opportunity for collaboration.


WHAT ADJUSTMENTS HAVE DRUG DEVELOPERS HAD TO MAKE TO RESPOND TO CHALLENGES ASSOCIATED WITH TARGETED THERAPEUTICS?

The key adjustments for drug developers have been to increase transparency with the authorities and open up to pre-submission or scientific advice meetings. These meetings become even more efficient when you bring in local experts and key opinion leaders.

The purpose of this is to discuss strategies and requirements with the authorities and to come up with agreements for the drug development activities. Meeting with Health Canada is not a requirement, but it’s highly recommended for novel therapies that would not have the same clinical data package that would usually be required or expected in Canada for market access.

With regards to submission content, contrary to common belief, Health Canada follows similar requirements to those of the FDA and EMA, therefore, usually only minor adjustments are necessary from a FDA or EMA dossier when submitting a marketing application in Canada.


WHAT ROLE DOES CANADA AND CANADIAN DATA PLAY IN THE SPONSORS’ OVERALL REGULATORY STRATEGY?

We know we can’t compete in terms of population, but Canada does have numerous strengths, making it a very attractive host for early phase clinical trials. These strengths include highly trained clinicians, the presence of key opinions leaders, world-class investigators, renowned medical care standards and a well-diversified population, all of which are desirable for testing new drugs. In addition, Canada is one of the top countries for biomedical research productivity and international reputation.


WHAT ADVICE CAN YOU OFFER DRUG DEVELOPERS ABOUT CONDUCTING THEIR CLINICAL RESEARCH IN CANADA?

Canada is an attractive region for clinical trials and we clearly recommend that drug developers come to Canada early in their drug development process, for many reasons.

First of all, we have expert physicians in various therapeutic fields, key opinion leaders with internationally renowned reputations, that are clearly interested in participating in Canadian clinical trials. In addition, we have efficient regulatory experts, CROs and clinical trial start-up facilitators helping with the Canadian process efficiency.

Adding Canadian sites to a multi-centre trial is a great initiative to expose expert physicians as well as patients to novel therapies that will eventually come to market, raising interest, awareness and knowledge. The fact that the Canadian population is very similar to that of the US, makes Canada an interesting extension of the U.S. initiative for patient recruitment.  This way, our Canadian population can benefit from these novel therapies, while adding to the global clinical trial recruitment initiative.

In addition, the Canadian regulatory agency provides a decision within an efficient standard review of 30 days. Also, early Canadian initiative can build the health authorities’ confidence with a sponsor and product by raising awareness, interest and knowledge. This can translate into facilitating the accelerated access to the Canadian market, should the product meet the requirements.

Should the drug be innovative and / or life-saving, we would recommend a strategic registration regulatory strategy, because of the possibility of having a faster approval granted either during the clinical trial phases or immediately upon completion. A meeting with Health Canada would be recommended to validate the strategy, secure agreements that would be part of meeting minutes, included in the upcoming registration initiative.


IS HEALTH CANADA’S CLINICAL TRIAL APPLICATION PROCESS  COMPLEX, SLOW AND INEFFICIENT COMPARED TO THE SUBMISSION PROCESSES IN THE US OR EU?

I’ve heard that many times before but it’s actually the opposite. When the process is properly understood and the sponsor or the representatives have established contacts with Health Canada, the clinical trial application in Canada is relatively simple and so is the review process. The actual submission structure is also simple, and the content requirements are actually less than in the US and Europe.

There are no non-clinical, nor clinical study reports needed in the clinical trial application. What is needed is the administrative documents plus key scientific documents, which are the protocol, the informed consent form and the investigators brochure. There’s two Canadian specific templates required that we need to generate: the protocol summary as well as the overall quality summary. All of these are quite easy to prepare.

The review process is also efficient. A 30-day default review period applies. If questions are raised during the dossier review a response must be provided within two calendar days (exceptions may apply). And by way of comparison, in Canada there is no clinical hold period like in the United States. The review period is always 30 days, whereas in some European countries the review period can be as long as 60 days or more, and in the US it can vary.

Due to the standard 30-day review period in Canada, I believe it does facilitate the ethics review submission planning, which speeds up clinical trial start times. Also, there are efficient clinical trials start-up experts in Canada that helps with streamlining the study start-up processes in parallel or after the clinical trials application approval.


IS HEALTH CANADA OPEN TO EARLY PHASE TRIAL DESIGNS OR PREFERS LATE PHASE STUDIES WITH COMPOUNDS CLOSE TO APPROVAL?

Health Canada is very open to all phases of clinical trials for both early and late phase. If the product is innovative or has the potential of being granted an NOC/c, we do recommend that sponsors meet with Health Canada early to ensure that the study trial design and the clinical development plan is aligned with the requirements for an accelerated access to market.


DOES HEALTH CANADA REQUIRE THAT ALL STUDY DOCUMENTS AND TOOLS BE TRANSLATED TO FRENCH?

Not at all. Both official languages in Canada, that is English and French, are accepted. That being said, the regulatory dossiers are usually submitted to Health Canada in English. French dossiers, or the supporting documents that are in French, are also acceptable, however, the review could be a little more challenging since most of the Health Canada reviewers are Anglophone. Even if it is not required to submit French documents to Health Canada, the French translation of the informed consent form must be generated and available for francophone patients. Also, there are specific language regulations to respect on Canadian labels. That being said, Health Canada has established standard target review timelines that they respect, which is not influenced by the selected submission language.


DOES HEALTH CANADA REQUIRE THAT ALL SPONSORS HAVE A LEGAL OR SCIENTIFIC REPRESENTATIVE THAT RESIDES IN CANADA FOR CLINICAL TRIAL APPLICATIONS?

A scientific or medical officer residing in Canada that represents the sponsor and who’s responsible for providing an attestation with respect to the clinical trial application or the amendment that is being filed, is required. There is no additional information available in the regulations or guidance related to the Canadian officer. Therefore, any Canadian scientific personnel that are authorized by the sponsor to submit the application on their behalf and to be the representative can be the signatory. Normally the regulatory agent or the CRO can sign the clinical trial application on behalf of the sponsor.


DOES HEALTH CANADA REQUIRE THAT ALL SPONSORS HAVE A LEGAL OR SCIENTIFIC REPRESENTATIVE THAT RESIDES IN CANADA FOR THEIR REGISTRATION DOSSIERS?

No, Health Canada does not. Nonetheless, if the sponsor is not located in Canada, a Canadian importer must be determined and their Drug Establishment Licence (DEL) submitted or amended at least 3 months prior to the submission of the marketing authorization submission (NDS or ANDS) in Canada. This is one of the Good Manufacturing Practice requirements.

That being said, having a Canadian regulatory point of contact in Canada is an advantage for the Canadian regulatory language with Health Canada as well as for dealing rapidly with questions, being in the same time zone as the reviewing regulatory agency.


DOES HEALTH CANADA REQUIRE THAT A NEW CLINICAL TRIAL APPLICATION SUBMISSION BE DONE FOR EACH AND EVERY PROTOCOL WITHOUT EXCEPTION?

This is partly false. Presently, drug developers may submit more than one protocol into one single clinical trial application (CTA), when the Application is submitted to the Therapeutic Drug Directorate (TPD). Each protocol would then be considered a different dossier with a different control number per protocol; an approval per protocol would apply. When the CTA is submitted to the Biologic and Genetic Therapies Directorate (BGTD), one protocol only can be submitted per CTA. The upcoming electronic submission requirements for the CTA will likely impose the submission of one protocol per CTA for both Directorates.

Even with these differences, globally the process is quite similar in the US and Canada, however, the terminology used is different and this can cause some confusion.

In the U.S., we see one IND per product under clinical development, which is open to adding new protocol amendments etc… Clinical holds can apply to these INDs and the duration of the holds may vary. In Canada, there is a clinical trial application process, whereby one or more protocols can be submitted at once. New protocols are submitted as new CTAs. There are amendments and notifications that can be brought to clinical trial applications that are approved.

An amendment is considered a major change to an approved protocol or quality dossier, and therefore requires the same 30-day default review period. Minor changes are submitted as notifications within 15 days of the implementation of the change and no review period applies. Now, as mentioned, a new protocol must be submitted via a new clinical trial application. However, cross-referencing to an approved clinical trial application already on file for sections that are not changed, is possible. For example, cross-referencing to an approved investigator’s brochure or to an approved quality dossier. Therefore, it reduces the submission requirement and content. The process is simple and very similar to an IND amendment in the U.S., even if it’s classified as a clinical trial application in Canada.


WILL HEALTH CANADA APPROVE CLINICAL TRIALS DESIGNED WITH MORE THAN ONE INVESTIGATIONAL PRODUCT?

Yes, definitely. With the appropriate quality information for both investigational products, Health Canada will review the dossier and approve it if it meets the Canadian requirements, and that will be under the same 30-day default review period.


ARE HEALTH CANADA’S SAFETY FOLLOW-UP POLICIES AND GUIDELINES MORE STRINGENT THAN THOSE IMPOSED BY THE FDA?

No. The requirements are similar in Canada and in the U.S. for clinical trial applications as well as for post-approval initiatives.


DO WE NEED TO PROVIDE HEALTH CANADA WITH THE LABELS OF CLINICAL TRIAL DRUG PRODUCTS?

No, clinical trial drug products labels do not need to be submitted at the time of the Clinical Trial Application. Labels must conform with section C.05.011 of the Food and Drug Regulations, in both official language, and should be provided to Health Canada upon request.



The Drug Review and Approval Process in Canada – An eGuide

The Drug Review and Approval Process in Canada - an eGuide

 

How are drugs reviewed and approved in Canada?

How are drugs reviewed in Canada is a question often asked. What follows is a summary of the Drug Review and Approval Process in Canada – an eGuide in accordance with the Food and Drugs Act (FDA), the Food and Drug Regulations (FDR), the related policies and Health Canada guidelines

For a drug, a biologic or a genetic therapy, a medical device, a combination product, a natural health product or other health product company seeking approval of their product for sale in Canada, it is important to understand that the approval process is subject to close scrutiny by the governing regulatory body.

However, the review process and preparing for that review process does not have to be complex, intimidating, nor frustrating. The key is to know, follow and/or clarify the process related to the health product of interest and ensure preparedness with proper data and documentation.

 


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    How are drugs reviewed and authorized for sale in Canada?

    Most health products, including drugs to be marketed or sold in Canada are reviewed and authorized by the Health Products and Food Branch (HPFB) of Health Canada, more precisely, under the Therapeutic Product Directorate (TPD) or the Biologic and Genetic Therapies Directorate (BGTD), for drugs and biologic, respectively. Each of these Directorates have specific offices and bureaus. Drugs are authorized to reach that market only once they have successfully gone through the relevant Bureau review process, responsible for assessing their safety, efficacy and quality, and, received a favorable decision. Even after a health product receives a favorable decision and can proceed with its sale in Canada, monitoring of its effectiveness and safety continues.

    What is Canada’s 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.


     

    WHAT IS THE DRUG DEVELOPMENT PROCESS IN CANADA?

    We have categorized the drug development process in 5 stages and have provided a graphic below to accompany the text.

    STAGE 1: INITIAL DRUG RESEARCH

    Researchers start by discovering and identifying various chemical, biological substances or other products on the way towards developing a drug. This can be done through new information regarding a disease process, many tests of molecular compounds to find possible beneficial effects, existing treatment that have unanticipated effect and new technologies. Once the researchers have identified a promising compound, they perform testing for activity, efficacy, toxicity and ultimately, gather preliminary information on its effectiveness and safety. This initial research can take a few years of experimentation. If the results are promising, researchers will proceed to the next step of development.

    A representation of the Drug Development Process is presented in the graphic below:

     

    STAGE 2: PRE-CLINICAL STUDIES IN CANADA

    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 IN CANADA

    All drugs authorized to be marketed or sold in Canada must have been studied in clinical trials. The information gathered from these trials are then included in the relevant regulatory dossiers to be reviewed for the drug to be eventually authorized for sale in Canada by the HPFB, through its relevant Directorate. The results of clinical trials conducted in humans are key components of the review process by the HPFB. The purpose of a trial is to gather clinical information about a drug’s effectiveness, safety, determine best dosing/usage in humans, evaluate any adverse drug reactions and compare results to already existing treatments for the same disease or condition or, to placebo when no treatment already exists for the aimed pathology (when ethically possible).

    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 (see New Drug Submission process section below).

    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.

    What is the Clinical Trial Application?:
    The Canadian CTA dossier consists of the following documents (exceptions are possible): administrative form, protocol, protocol summary (Health Canada’s template), Informed Consent Form, Investigator’s Brochure and quality dossier summary (Health Canada’s template per study phase).

    Health Canada reviews the CTA and notifies the sponsor within 30 calendar days from the date that the application is considered complete. Questions may be issued during the review, and the sponsor will have 2 calendar days to provide the response (exceptions can apply). Note that CTAs are required for phases I to III clinical trials. The authorization (No Objection Letter) is mandatory prior to initiating the trial and importing the investigational product(s) in Canada.

    If the HPFB provides authorization, the study can be underway with human subjects that are informed and have given their consent to be administered the drug for their participation. Note that a Canadian Ethic Committee must also approve the study material (protocol, Investigator’s Brochure and Informed Consent Form). Tests are conducted in a controlled environment where drug administration procedures and results are closely tracked, monitored and analyzed.

    What are the Clinical Trial Phases?

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

    Phase 1 – The Safety phase
    This phase usually tests an investigational drug on a small group of healthy individuals for the first time (except when not ethically acceptable to do so). The purpose is to determine the pharmacokinetics/pharmacological action of the drugs, find a safe dosage range and identify adverse drug reactions.

    Phase 2 – The Effectiveness phase
    In this phase, the drug is given to a larger group of individuals with the pathology to be treated (usually several hundred). The purpose is to obtain data on the effectiveness of the drug, to further assess the drug’s safety and to determine the best dose.

    Phase 3 – The Confirmation Phase
    If the results from Phase 2 look promising, the drug manufacturer would proceed into Phase 3 trials. In this phase, the drug is given to even larger groups of patients (usually in the thousands). The purpose of this phase is to confirm the drug’s effectiveness, monitor side effects, compare the drug to other commonly used treatments and to collect further information that will allow the drug to be used and marketed safely.

    Phase 4 – The Monitoring phase
    Phase 4 trials are done after the drug is already approved and sold on the market. The purpose of this phase is to gather more information on the best ways to use a drug, and the long-term benefits and risks to the population. 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.

    If the drug is to be used outside the terms of the market approval (that is in a different population, for a different indication, using a different dose, etc.), the study will not be considered a phase IV. Consequently, in these cases, a CTA will need to be submitted to Health Canada in order to obtain a No Objection Letter.

     

    STAGE 4: THE DRUG APPROVAL PROCESS IN CANADA

    What is New Drug Submission Health Canada (NDS)?
    If 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 done in Canada or in other countries. The NDS must include the results of the quality (Chemistry and manufacturing), preclinical and clinical studies, whether done in Canada or in other countries.

    The drug’s efficacy and safety data is evaluated and the Risk/Benefit analysis is performed, before reaching a decision.

    The information requested by Health Canada as part of an NDS application must be detailed enough that Health Canada can make an assessment on the safety and effectiveness of the new drug. All submissions must be provided to Health Canada in an electronic Common Technical Document (eCTD) format.

    For a more complete look at NDS, please review our article on the New Drug Submission Health Canada Process

    What is a Common Technical Document?
    The CTD format originates from the International Conference on Harmonization (ICH) initiatives, in their effort to harmonize efficacy, safety and quality (chemistry and manufacturing) requirements globally for the registration of drugs (pharmaceuticals, biologicals, genetic therapies, …) for human use. This initiative includes standard information organization for new drug registration applications. The CTD format is divided into five modules: Module 1 contains region-specific information and Modules 2–5 contain common clinical, nonclinical and quality information with some regional variations.

    The CTD format is presented below.

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

    • Administrative form
    • Product Monograph
    • Mock-up of Inner and Outer labels
    • Certified Product Information Document
    • Brand Name Analysis
    • Risk Management Plan
    • Etc

    What is an 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/and bioequivalent with the innovator’s drug. For the purpose of an ANDS the sponsor may need to perform a bioequivalence study or a physico-chemical comparison (parenteral drugs or drugs for which it is not ethical to conduct the study on healthy volunteer).

    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 labelling, as well as, information about the drug’s therapeutic claims and side effects. What Doctors and patients will be told about the drug will also be reviewed, through the drug’s monographs and information sheets. All drugs allowed to be sold in Canada are reviewed to ensure that they meet the requirements of the Food and Drugs Act and its Regulations. Once these requirements are met, the sponsor (usually the Marketing Authorization Holder) would receive a Notice of Compliance, confirming the dossier’s compliance with the Food and Drugs Act and its Regulations.

    How long does the Health Canada drug review process take?
    The target review timeline ranging 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 amount 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).

     

    HEALTH CANADA DECISION

    What is the Notice of Compliance from Health Canada?: 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’s 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 is a Notice of Non-Compliance from Health Canada? 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: to supply additional information to the HPFB, to re-submit a submission at a later date with additional supporting data (without prejudice), or to ask that HPFB to reconsider its decision.

    What is an Accelerated Review Process from Health Canada?
    For health conditions that are serious, life-threatening or for a severely debilitating disease (such as Alzheimer’s disease, cancer, AIDS, or Parkinson’s Disease), the HPFB can provide faster authorization of a drug as follows:

    1. What is a Priority Review? (PR): Applies to drugs that shows substantial evidence of clinical effectiveness at the end of the clinical trial phases.
    2. What is a Notice of Compliance with conditions? (NOC/c): 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 execute 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 condition” is removed from the NOC.

     

    STAGE 5: AFTER HEALTH CANADA 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. In addition, Life Cycle Management activities (post approval submissions to Health Canada, for new indications, new dosage forms, new strengths, manufacturing changes, etc.) are required to ensure the maintenance of the product License with its related improvements. In summary, sponsors need to ensure its continued compliance with the Food and Drug Regulations, while their products 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, health insurance funding rules, among others.

    All of these topics are worthy of their own article and are beyond the scope of this one.

     

    SUMMARY

    Health Canada is the federal body that regulates the drug approval process under the Food and Drugs Act (FDA) and its regulations (FDR), its related policies and guidance. Before a drug can be distributed and sold in Canada, its manufacturer must receive a Notice of Compliance (NOC) from Health Canada, and the drug must be assigned a Drug Identification Number (DIN), uniquely identifying all drug products sold in a dosage form in Canada. New drugs must also go through extensive testing before being granted an NOC.

    It can take anywhere from 6 months to 2 years for Health Canada to review drug safety and efficacy information before providing a decision on whether an NOC is to be granted. Once granted, it represents that the drug meets the required standards under the Food and Drugs Act and its regulations, for use in humans. The monitoring for drug safety continues even once the drug finally makes it to consumers.

    The process of marketing and selling any new drug in Canada can certainly seem complex or intimidating. However, for drug companies seeking approval of their new drug in Canada, a number of strategies are recommended to make the process more effective. Focusing on preparedness, having proper data and documentation from research & trials and following proper guidelines are valuable recommendations to follow.

    Another recommendation is for drug companies or sponsors to work in collaboration with Canadian regulatory experts so as to optimize the registration process to ensure the best strategic registration initiatives, to anticipate the health authority’s potential concerns and to help in finding proactive solutions prior to submitting to Health Canada. Working with regulatory experts or consultants can help avoid unwanted review complications and delays and therefore, reduce cost consequences of potential market entry delays.

    Following the above recommendations will help turn a seemingly complex or intimidating Drug approval process into a more manageable and predictable one.

     

    INFOGRAPHIC & FURTHER INFORMATION

    For a more complete look at NDS, please review our article on the New Drug Submission Process

    For an infographic rendering of the above drug review and approval process in Canada, please click on the image below to have the option of downloading it in either PDF or JPEG version.

    For further information about the drug review & approval process in Canada, please contact Spharm directly.

    Drug Review and Approval Process in Canada - Infographic

    Drug Review & Approval Process in Canada – An Infographic

    THE DRUG REVIEW & APPROVAL PROCESS IN CANADA
    AN INFOGRAPHIC


    What follows is a graphical representation, an Infographic, of the eGuide we published titled “The Drug Review Approval Process in Canada – An eGuide

    DOWNLOAD JPEG VERSION HERE
    DOWNLOAD PDF VERSION HERE


    Drug Review and Approval Process in Canada

    For further information about the drug review & approval process in Canada, please visit our FAQ section or contact SPharm directly.

    Has Regulatory Affairs in Canada changed from a decade ago?

    How has Regulatory Affairs in Canada changed from a decade ago?

     


     

    HOW HAS THE EVOLUTION OF REGULATORY AFFAIRS AFFECTED THE WAY CLINICAL TRIALS ARE CONDUCTED NOW VERSUS 10 YEARS AGO?

    With regards to clinical trial applications, Health Canada’s requirements have not changed much. However, they’ve had no choice but to open up to new strategies – novel agents, personalized medicines, or orphan drugs for which there is no official designation yet – and accept novel trial designs. Health Canada is very open to hear how novel therapies can help Canadians and there’s a clear openness and opportunity for collaboration.

     


     

    For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.

     

    Does Health Canada require all documents be translated to French?

     

    Does Health Canada require that all documents be translated to French?

     


     

    DOES HEALTH CANADA REQUIRE THAT ALL DOCUMENTS BE TRANSLATED TO FRENCH?

    Not at all. Both official languages in Canada, that is English and French, are accepted. That being said, the regulatory dossiers are usually submitted to Health Canada in English. French dossiers, or the supporting documents that are in French, are also acceptable, however, the review could be a little more challenging since most of the Health Canada reviewers are Anglophone. Even if it is not required to submit French documents to Health Canada, the French translation of the informed consent form must be generated and available for francophone patients. Also, there are specific language regulations to respect on Canadian labels. That being said, Health Canada has established standard target review timelines that they respect, which is not influenced by the selected submission language.


     

    For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.

     

    Are Sponsors required to have a legal representative reside in Canada?

     

    Does Health Canada require Sponsors to have a legal representative reside in Canada?

     

     

    DOES HEALTH CANADA REQUIRE SPONSORS TO HAVE A LEGAL REPRESENTATIVE RESIDE IN CANADA?

    A scientific or medical officer residing in Canada that represents the sponsor and who’s responsible for providing an attestation with respect to the clinical trial application or the amendment that is being filed, is required. There is no additional information available in the regulations or guidance related to the Canadian officer. Therefore, any Canadian scientific personnel that are authorized by the sponsor to submit the application on their behalf and to be the representative can be the signatory. Normally the regulatory agent or the CRO can sign the clinical trial application on behalf of the sponsor.

    With respect to having Sponsors having a legal representative residing in Canada for the Registration Process, the answer is no, Health Canada does not require Canadian residence. Nonetheless, if the sponsor is not located in Canada, a Canadian importer must be determined and their Drug Establishment License (DEL) submitted or amended at least 3 months prior to the submission of the marketing authorization submission (NDS or ANDS) in Canada. This is one of the Good Manufacturing Practice requirements.

    That being said, having a Canadian regulatory point of contact in Canada is an advantage for the Canadian regulatory language with Health Canada as well as for dealing rapidly with questions and being in the same time zone as the reviewing regulatory agency.


     

    For questions about the Canadian Drug Review & Regulatory approval process that is not covered in this section, please go ahead and contact us directly.