Regulatory roadmap for biologic (Schedule D) drugs in Canada

From: Health Canada

This regulatory roadmap gives comprehensive, general information about the regulation of biologic drugs for human use in Canada.

All drugs that are marketed in Canada are subject to the Food and Drugs Act and Regulations.

The Biologics and Genetic Therapies Directorate (BGTD) reviews and provides market authorization of all drug submissions for biologic drugs for human use. Market authorization by Health Canada is required before a biologic drug can be sold in Canada.

On this page

Who this document is for

We wrote this roadmap for:

  • sponsors
    • wanting to bring a biologic drug to market in Canada
    • wanting to conduct a biologic drug clinical trial in Canada
    • seeking information about post-market requirements and post-approval changes
  • other interested stakeholders, such as academics and patients

About biologics

Biologic drugs come from living organisms or from their cells and are often made using advanced biotechnology processes. They are used to treat diseases and medical conditions, including:

  • anemia
  • diabetes
  • psoriasis
  • genetic conditions
  • hormone deficiency
  • rheumatoid arthritis
  • some forms of cancer
  • inflammatory bowel disease

Biologic drugs are also used for replacement therapies for blood proteins and include vaccines to prevent bacterial and viral infectious diseases.

Biologic drugs are typically larger and more complex than chemically produced pharmaceutical drugs. In Canada, biologic drugs are listed in Schedule D of the Food and Drugs Act.

A sponsor must collect enough scientific evidence about a biologic before Health Canada’s BGTD can consider approving it. The evidence must show the biologic is:

  • safe
  • effective
  • of suitable quality

Biologics are unique

Biologics are more variable than chemically synthesized drugs and require additional regulatory oversight. This is because they are isolated from or manufactured by using living organisms.

Biologic drugs are sensitive to changes in the starting materials and manufacturing process. This makes them difficult to consistently produce and characterize.

Along with the information needed for approving other drugs, more detailed chemistry and manufacturing information is required for biologics approvals. This extra information is needed to help ensure the purity and quality of the product. For example, specific processes are required to help ensure that the product is not contaminated by an undesired microorganism or by another biologic.

For these reasons, the BGTD has unique programs for biologic drugs:

  • on-site evaluation
  • lot release program

On-site evaluation

The on-site evaluation (OSE) is unique to biologics in Canada. An OSE is a product-specific assessment that the BGTD may conduct at the manufacturing site of a Schedule D drug. An OSE supports the review of the quality (chemistry and manufacturing) component of a drug submission. It also confirms the overall ability of the manufacturer to consistently produce a safe biologic drug.

For more information, refer to the New Drug Submissions on-site evaluation.

Lot release

Health Canada’s lot release program covers both the pre- and post-market stages for biologic drugs. Each lot of a biologic drug is subject to the lot release program before sale.

Health Canada bases the level of regulatory oversight (testing and/or protocol review) on the degree of risk linked to the product. The BGTD will assign the product to 1 of 4 different risk-based evaluation groups:

Group 1: Pre-Approval Stage

  • Group 1A: Clinical Trial Materials
  • Group 1B: Consistency Testing

Group 2: Sample Testing and Protocol Review
Group 3: Protocol Review and Periodic Testing
Group 4: Notification and Periodic Testing

Consult the Guidance for Sponsors: Lot Release Program for Schedule D (biologic) Drugs  for more information.

Post-market monitoring

Health Canada and the Public Health Agency of Canada work together to:

  • investigate complaints and problem reports
  • monitor the reporting of biologic adverse events
  • assure compliance with Good Manufacturing Practices (GMP)
  • maintain post approval surveillance and manage recalls, as required

Roadmap for biologic (Schedule D) drugs

Health Canada provides guidance, information and support on meeting Health Canada’s regulatory requirements for biologic drugs.

A guidance document is an official document that provides information that helps external stakeholders to:

  • follow governing Acts and regulations or
  • harmonize with international guidance documents and standards

Guidance documents also assist staff in implementing Health Canada’s mandate and objectives in a way that is:

  • fair
  • effective
  • consistent

Health Canada is an official member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The department has adopted a number of ICH guidance documents covering topics related to:

Know the requirements and the process before making an application or a submission to Health Canada for a biologic drug.

Sponsors should also consult the Guidance for Industry: Management of Drug Submissions. It outlines the way Health Canada’s BGTD manages information and material submitted by the sponsor, as well as performance standards. This guidance applies to all drug submission types, including:

  • Clinical Trial Applications (CTA) and Amendments (CTA-A)
  • New Drug Submission (NDS)
  • Supplement to a New Drug Submission (SNDS)
  • Supplement to a New Drug Submission - Confirmatory (SNDS-C)
  • Abbreviated New Drug Submission (ANDS)
  • Supplement to an Abbreviated New Drug Submission (SANDS)
  • Notifiable Change (NC), and
  • Drug Identification Number application for a biologic product (DINB)

Other submission types in this guidance include:

  • Drug Safety Update Report (DSUR)
  • Yearly Biologic Product Report (YBPR)
  • Post-Authorization Division 1 Change-Biologics (PDC-B)
  • Extraordinary Use New Drugs (EUNDs)
  • Supplement to an Extraordinary Use New Drug Submission (EUSNDS)

A Notice of Compliance (NOC) and a Drug Identification Number (DIN) are issued by Health Canada when the:

  • evidence supports the safety, efficacy and quality claims for an NDS or an SNDS
  • benefits outweigh the risks

The NOC and the DIN indicate that Health Canada has approved the drug for sale in Canada.

A drug in dosage form must have a DIN before the manufacturer can sell it in Canada.

All Canadian DIN owners require a Drug Establishment Licence (DEL). For more information, refer to Good Manufacturing Practices/Establishment Licensing.

Prescription Drug List

Many biologic drugs approved by Health Canada are on the prescription drug list.

For more information on the prescription drug list, consult:

Cancellation of a Drug Identification Number

Sponsors who discontinue the sale of a drug in Canada must follow certain requirements. The Cancellation of a Drug Identification Number and Notification of the Discontinuation of Sales guidance document contains this information.

Clinical Trial Applications

A Clinical Trial Application (CTA) is required to conduct a clinical trial in Canada.

Sponsors are encouraged to seek advice from Health Canada about their CTA during a pre-CTA meeting with Health Canada. Health Canada gives advice at no cost to clinical trial sponsors.

Refer to the Guidance for Clinical Trial Sponsors: Clinical Trial Applications to learn how to request a pre-CTA consultation meeting.

Some substances in drugs, such as cell-based and other therapies, may require an environmental assessment under the:

This is pursuant to the Canadian Environmental Protection Act, 1999. The assessment must occur before the drug can be manufactured or imported into Canada. The sponsor needs to contact the New Substances Program’s Environmental Assessment Unit before the start of the CTA. They will help the sponsor to find out if a New Substances Notification is required.

For information about the New Substances Notification Regulations (NSNR), please consult the New Substances Program page.

For questions about the NSNR, please contact the Environmental Assessment Unit by:

  • phone
    • 613-948-3591
    • 1-866-996-9913
  • email: HC.eau-uee.SC@canada.ca

Formatting for Clinical Trial Applications

An eCTD Pilot for Clinical Trial Regulatory Activities is ongoing.

To help understand formatting requirements, consult these guidance documents:

Requirement for good clinical practices

If you conduct a clinical trial, you must comply with good clinical practices. For more information, refer to the good clinical practices guidance document.

How to prepare a Clinical Trial Application

The clinical trial sponsors: clinical trial applications guidance document contains instructions on how to:

  • prepare a CTA
  • request a pre-CTA consultation meeting

You may also wish to consult these links:

Investigator’s Brochures

You must include an Investigator’s Brochure for each product in a CTA. The brochure must include all currently available pre-clinical and clinical safety and efficacy information. It should also include the global status of what the product is approved for and where.

Refer to the Good Clinical Practice: Integrated Addendum to E6(R1)ICH Topic E6(R2) guidance document for more information. Refer to the ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance for suggested format of the Investigator’s Brochure.

You should submit annually updated Investigator’s Brochures that include all safety and efficacy information and global status. Any new information and changes in the updated Investigator's Brochure should be highlighted to help our review and evaluation. If an Investigator's Brochure is updated more than once a year, submit it as required.

Quality: chemistry and manufacturing

Consult these links to learn more about how to prepare the quality information for the drug submission. This is the chemistry and manufacturing part of the drug submission:

Lot release

The lot release program applies to clinical trials as well as to marketed biologics. Refer to Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs for information.

Related resources

Health Canada's Clinical Trials Database lists specific information about Phase I, II and III clinical trials in patients. The database provides a source of information about Canadian clinical trials involving human pharmaceutical and biologic drugs.

Health Canada encourages sponsors to register clinical trials within 21 days of the start of the trial.

Sponsors may also use a publicly available registry that conforms to international standards for registries. Examples include the U.S. National Institutes of Health’s ClinicalTrials.gov and the ISRCTN registry.

Clinical Trial Application amendments

Before a sponsor can make changes to a clinical trial, a CTA-A must be authorized by Health Canada. If a sponsor proposes to make changes:

  • to clinical trial drug supplies, they must file a Quality CTA-A
  • to a previously authorized protocol, they must file a Clinical CTA-A

For biologics, some changes in production will result in reclassifying the CTA-A application as a CTA. This is because they are considered beyond the scope of the previously authorized CTA.

For more information, refer to Clinical Trial Application Amendments.

New Drug Submissions

A sponsor must prepare an NDS for the Health Products and Food Branch. This occurs when that sponsor wants to seek market authorization for a new drug in Canada. The NDS contains:

  • information and data about the drug's
    • safety
    • quality
    • effectiveness
  • results of the pre-clinical and clinical studies, whether done in Canada or elsewhere
  • details regarding the production of the drug
  • packaging and labelling details
  • information regarding therapeutic claims and side effects

Before submitting its NDS for a biologic (Schedule D) drug, the sponsor can make a brief presentation to the BGTD. This meeting gives the sponsor a chance to discuss details of the submission with the regulator. It also provides a chance to get feedback about any areas of concern.

Small and medium-sized biotech companies are especially encouraged to request a pre-submission meeting. The sponsor should request a pre-submission meeting at least 3 months before the proposed meeting date.

The sponsor may also seek eligibility for alternate review pathways, such as Priority Review or a Notice of Compliance with Conditions. For information about alternate pathways, refer to Accelerated Pathways for Drug Approval.

More information is available on how to request a pre-submission meeting in the Guidance for Industry: Management of Drug Submissions.

Also refer to:

Substances in biologic products may require an environmental assessment under the:

  • New Substances Notification Regulations (Organisms) or
  • New Substances Notification Regulations (Chemicals and Polymers)

This is pursuant to the Canadian Environmental Protection Act, 1999. The assessment must occur before the biologic product can be manufactured or imported into Canada.

The sponsor needs to contact the New Substances Program’s Environmental Assessment Unit before the start of the NDS. They will help the sponsor to find out if a New Substances Notification is required.

For information about the New Substances Notification Regulations (NSNR), consult the New Substances Program page. 

For questions about the NSNR, please contact the Environmental Assessment Unit by:

  • phone
    • 613-948-3591
    • 1-866-996-9913

email: HC.eau-uee.SC@canada.ca

Format for the New Drug Submission

Health Canada accepts drug submissions in the eCTD format. The ICH developed the CTD format to harmonize drug submissions worldwide.

Consult eCTD Common Technical Document guidance documents for applications and submissions to learn how to file a submission in the eCTD format.    

Guidance on the New Drug Submission

Refer to these links for helpful information about guidance:

Technical requirements

Health Canada is an official member of the ICH and is committed to adopting and implementing ICH guidance and standards. Once adopted by Heath Canada, ICH guidelines become official Health Canada guidance documents for:

  • safety
  • quality
  • efficacy
  • multidisciplinary topics

Clinical: safety and efficacy

Refer to relevant ICH guidelines on:

Product monograph guidance and templates are available to assist sponsors in developing product monographs with acceptable format and content.

When submitting non-clinical study data to support a submission or application, sponsors should refer to:

Quality: chemistry and manufacturing

Refer to relevant ICH guidelines on:

Multidisciplinary guidelines and ICH Considerations documents that are not labelled as quality have implications for quality. Consult all ICH Multidisciplinary guidelines for more information.

Along with relevant ICH guidelines, sponsors may refer to:

On-site evaluation

As part of the drug submission process, biologic manufacturers must provide significant detail of the biologic’s manufacturing method. This is because slight variations can result in a different final product.

The BGTD may conduct an on-site evaluation (OSE) of the production processes and facilities for the biologic drug (intermediate or finished). The decision to conduct an OSE is based on a risk assessment.

The objectives of the OSE are to:

  • Confirm the overall ability of the manufacturer to consistently produce a safe biologic drug for use
  • Assess and confirm the process and conditions of manufacture according to the submission under review

When an OSE is conducted, it becomes an important part of the review process. The outcome of the OSE directly impacts the regulatory decision about the review of the biologic drug.

Lot Release Program

Refer to Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs for information on the lot release program.

Risk Management Plan

Sponsors should submit a Risk Management Plan as part of their drug submission for a biologic drug. The Guidance Document on Submission of Risk Management Plans and Follow-up Commitments has more information.

Labelling

The BGTD reviews the labels for biologic drugs. This includes:

  • package inserts
  • inner and outer labels
  • the product monograph/prescribing information

Health Canada also reviews the proposed brand name(s) for the drug. Unique brand names play a critical role in distinguishing among biologics drugs, including biosimilars, that share a non-proprietary (proper/common) name. Sponsors should refer to Health Canada's Policy Statement on the Naming of Biologic Drugs.

Consult these guidance documents for more information:

Accelerated Pathways for Drug Approval

Health Canada offers sponsors 2 different accelerated pathways for drug approval, which can shorten review times. Drugs for serious, life-threatening or severely debilitating diseases or conditions may qualify for 1 of these pathways.

If it is a new drug with substantial evidence of clinical effectiveness, read the Priority Review Policy. This will allow you to see if the biologic drug could qualify for this drug review pathway. To learn more, read the Guidance for Industry: Priority Review of Drug Submissions.

If it is a new drug with promising evidence of clinical effectiveness, read the Notice of Compliance with Conditions policy. This policy will help you find out if the biologic drug could qualify for this drug review pathway.

How to ask Health Canada to reconsider certain negative decisions about a human drug submission

A drug sponsor may formally request Health Canada to reconsider its decision about a human drug submission. This applies only to certain negative decisions that are issued.

The guidance document Reconsideration of Decisions Issued for Human Drug Submissions provides guidance about the formal reconsideration process, including:

  • how and when sponsors may request reconsideration
  • how and when the BGTD will respond
  • the process provided to reach a resolution

Extraordinary Use New Drugs pathway

Health Canada's Extraordinary Use New Drugs (EUND) pathway allows a means for the authorization of human drugs based on:

  • non-clinical information
  • limited clinical information

This occurs when there are circumstances in which sponsors cannot reasonably provide substantial evidence to demonstrate the safety and efficacy of a new drug in humans. These are logistical or ethical challenges in conducting the appropriate human clinical trials.

Refer to the Guidance Document: Submission and Information Requirements for Extraordinary Use New Drugs for more information. This will be helpful if the biologic drug meets the description of an extraordinary use new drug.

Third-party data

Certain drug submissions, including biologic drugs, may meet the conditions and requirements for a Submission Relying on Third-Party Data. These criteria are set out in the Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience).

Sponsors should understand the implications of using third party data as laid out in the Guidance Document: Patented Medicines (Notice of Compliance) Regulations.

Use of foreign reviews

When filing with Health Canada, refer to its information on the Use of Foreign Reviews when including a foreign review in:

  • a submission
  • an application
  • other data packages

Drug Identification Number application for a biologic product

A sponsor with a biologic drug regulated under Division 1 of the Food and Drug Regulations makes a DINB submission. Many of the same principles for new drugs regulated under Division 8 also apply to drugs regulated through Division 1.

When submitting a DIN application, the sponsor must provide the information required by the Food and Drug Regulations. For DINB submissions, the DIN Certification Form (in lieu of Submission Certification Form included with NDS/SNDS/NC) should be included with the filing.

Master Files

Master Files are always assessed together with a:

  • CTA
  • DIN application
  • biologic drug submission

Therefore, decisions made on the quality-related data in a Master File relate to the biologic drug seeking:

  • market authorization or
  • clinical trial authorization

A Master File Holder submits a Master File to Health Canada. This is only in cases where the company does not wish to disclose Confidential Business Information to the applicant of the drug submission.

There is a fee for filing and re-filing.

Format

Refer to these links for tips and help with formatting:

Guidance

The Guidance Document: Master Files Procedures and Administrative Requirements contains helpful information about guidance.

Good Manufacturing Practices and Establishment Licensing

The Health Product Compliance Directorate within the Regulatory Operations and Regions Branch is responsible for Good Manufacturing Practices and Establishment Licensing.

Good Manufacturing Practices

Drugs that are for sale in Canada or used in clinical trials must be fabricated, packaged/labelled, tested and stored in compliance with the Good Manufacturing Practices in the Food and Drug Regulations.  These requirements apply to:

  • fabricators
  • packagers/labellers
  • testers
  • distributors
  • importers
  • wholesalers

Consult these links to learn more about GMP:

Establishment Licensing

You must hold an establishment licence if you carry out any licensable activities on drugs as described in the Food and Drug Regulations. This includes:

  • fabricating
  • packaging/labelling
  • testing
  • importing
  • distributing
  • wholesaling

A licence must also list any foreign building involved in the fabricating, packaging/labelling or testing of an imported drug. These licensable activities include those related to bulk process intermediates used in making dosage forms of biologic (Schedule D) drugs.

Consult these links for more information on establishment licences:

Post-market requirements and post-approval changes

Once a drug is approved for sale in Canada, the next phase of the drug's life cycle begins. There are post-market requirements the sponsor needs to follow.

If a sponsor wants to make a change to a drug post-approval, they must refer to the post-notice of compliance guidance documents.

Annual Drug Notification Report

Every drug manufacturer must submit an Annual Drug Notification Form (ADNF) before October each year. This confirms that all information previously supplied for that drug is correct.

Changes have been made to the information that is included in the ADNF. Approved and dormant products are added to the ADNF. For all discontinued drug products, manufacturers are now required to provide the:

  • lot number
  • discontinuation date
  • expiry date of the last lot sold

Yearly Biologic Product Report

Manufacturers of biologic (Schedule D) drugs must submit a Yearly Biologic Product Report (YBPR) each year. This is in accordance with the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs. The YBPR is submitted directly to the Office of Submissions and Intellectual Property.

To learn more, refer to:

Summary Reports: Periodic Safety Update Reports or Periodic Benefit-Risk Evaluation Report

The risk management plan outlines preparation and submission details for:

  • periodic safety update reports (PSURs)
  • periodic benefit-risk evaluation reports (PBRERs)

For more information, consult these helpful links:

Marketed Products Risk Communications

The Marketed Health Products Directorate has guidance documents on risk communications for marketed products:

Post-market Changes

Sponsors may make changes to any drugs that have received an NOC pursuant to the Food and Drug Regulations. Refer to the Post-NOC Changes guidance documents to learn about when:

  • supporting data is recommended for post-NOC changes
  • not to submit supporting data

When in doubt about the classification or supporting documentation, sponsors are encouraged to contact Health Canada in writing for clarification.

Post-Notice of Compliance Changes

These Post-Notice of Compliance Changes guidance documents provide criteria for the 4 levels of post-approval changes to a drug. They are based on modern risk management principles.

  1. A Level I change is a change to the label of a drug that has the potential to increase the exposure levels of the drug. This occurs either by expanding the population it is exposed to or by increasing individual exposure.
  2. A Level II (90 day) Risk Management Change is 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.
  3. A Level II (120 day) change is any change to the label that does not affect the conditions of use (it does not involve risk management, nor does it have the potential to increase exposure level of the drug) but for which prior approval by Health Canada is required.
  4. A Level III (annual notification) change is any change to the label that is not expected to impact the safety, efficacy and/or effective use of the drug. The changes included in this reporting category may be implemented by the sponsor without prior review by Health Canada of the data supporting such a change.

Refer to these links for more information on post-NOC changes:

Management of Safety Updates

When Health Canada orders label changes of a biologic drug, the sponsor will receive an Advisement Letter. For these label changes, sponsors should follow the guidance and information provided in the Advisement Letter.

For more information, please consult:

Post-Market Monitoring

Market Authorization Holders of biologic (Schedule D) drugs can find assistance for post-market adverse reaction reporting in:

Fees

Health Canada is updating its fees. Fee-related information will change in spring 2019 as a result.

Sponsors pay fees so that Health Canada can recover the cost of regulating drug products. The Fees for the Review of Drug Submissions and Applications and the Fees in Respect of Human Drugs and Medical Devices covers this information.

There are also Drug Establishment Licensing Fees.

The manufacturer that holds the DIN assigned to a biologic drug is charged an annual fee for the right to sell that drug. This fee is charged each year the drug is on the market in Canada. Refer to Guidance Document: Fees for the Right to Sell Drugs for more details.

A sponsor who intends to export a biologic drug product may apply for a Certificate of a Pharmaceutical Product. The sponsor must also pay a fee. The fee form is contained within the Guidance Document on the Application for a Certificate of a Pharmaceutical Product GUI-0024.

There is no fee for submitting a CTA to Health Canada.

Contact

For more information or assistance, you can contact us by email at HC.bgtd.ora.SC@canada.ca.

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