Canada’s regulatory approach to drugs for rare diseases: orphan drugs

There are particular challenges associated with designing and conducting trials in populations with rare diseases. We encourage sponsors to request regulatory advice from Health Canada before filing their applications. This advice can take a few different forms depending on the nature of the question. In some cases a teleconference or email is sufficient. In other cases an in-person meeting may be appropriate for a more detailed discussion.

Advice will vary according to the stage of development of the drug.

Sponsors should address requests for advice to the appropriate Bureau's or Centre's Director, found on the Pre-Clinical Trial Application Consultation Meeting website. Requests should include adequate information such as:

• who needs to be invited
• questions to be addressed
• the purpose of the meeting
• a brief description of the product to be discussed at the meeting

This will help us to:

• determine the type of meeting
• identify appropriate staff needed to discuss the proposed issues

We give advice to drug sponsors at any stage of development, including advice on:

• acceptability of patient safety considerations in trial designs
• acceptability of trial design to inform a market authorization
• pediatric considerations
• regulatory requirements regarding chemistry and manufacturing (quality)

Meetings can be arranged as clinical trials application consultation meetings or in preparation for a New Drug Submission(NDS) or Supplemental New Drug Submission (S/NDS).

In some cases several consultations may be needed in between these milestones and can be requested by the sponsor.

In addition, sponsors may refer to the:

• European Medicines Agency (EMA) Guideline on Clinical Trials in Small Populations
• Food and Drug Administration (FDA) Guidance for Industry Rare Diseases Common Issues in Drug Development

Market authorization

Most new drugs have a review target of 300 days.

In addition to the usual new drug submission process, we have other pathways for accelerating the regulatory review process. These pathways are for drugs to treat diseases and conditions that are:

• serious
• life-threatening or
• severely debilitating

If you are a sponsor of a drug for a rare disease, your drug may qualify for one of the accelerated pathways listed on this page.

Notice of Compliance with Conditions

A drug submission reviewed under the Notice of Compliance with Conditions has a review performance standard of 200 days.

The Notice of Compliance with Conditions guidance applies to a New Drug Submission (NDS) or Supplemental New Drug Submission (S/NDS). The guidance provides early access to promising new drugs for patients suffering from serious, life-threatening or severely debilitating diseases or conditions 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

Priority Review

A drug submission reviewed under the Priority Review policy has a review performance standard of 180 days.

The Priority Review policy applies to a New Drug Submission (NDS) or Supplemental New Drug Submission (S/NDS) for a serious, life-threatening or severely debilitating disease or condition for which there is substantial evidence of clinical effectiveness to show that the drug provides:

• 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

Data protection

Data protection in Canada gives 8 years of market exclusivity for drugs, if they meet the definition of an "innovative drug."

More information is available in Health Canada's Guidance Document: Data Protection under C.08.004.1 of the Food and Drug Regulations.

A six-month pediatric extension to the 8-year term of market exclusivity is available if relevant requirements are met. Pediatric clinical studies must be:

• submitted with the innovator's New Drug Submission or
• contained in a supplement filed within 5 years of the issuing of the Notice of Compliance for the New Drug Submission

The Minister must determine that clinical trials were:

• designed and conducted to increase knowledge of the use of the innovative drug in pediatric populations and
• that this knowledge provides a health benefit to those populations

Knowledge gained from the clinical trials must be communicated to the public, for example, through the approved labeling or in the Product Monograph.

Patents

An innovator may apply to list patents on Health Canada's Patent Register against an approved drug. The patents are assessed to ensure they meet the regulatory requirements for listing on the Patent Register. The Patented Medicines (Notice of Compliance) Regulations ensure that a Notice of Compliance is not issued for a subsequent entry drug (generic or biosimilar) until the patents that are listed on the Patent Register have been addressed. For more information, refer to Health Canada's Guidance Document: Patented Medicines (Notice of Compliance) Regulations. To search Canadian patent information, refer to the Canadian Patents Database.

Certificates of Supplementary Protection (CSP) provide patented drugs with an additional period of protection of up to 2 years.

To be eligible for a CSP, among other requirements a drug must meet 'first authorization' and 'timely filing' criteria. For further information, refer to the Guidance Document - Certificate of Supplementary Protection Regulations.

The Special Access Programme (SAP) authorizes a manufacturer to sell a drug that cannot otherwise be sold or distributed in Canada.

When conventional treatments have failed, are unsuitable or unavailable, SAP considers requests for access to these drugs from health care providers treating patients with serious or life-threatening conditions.

Drugs considered for release by the SAP include pharmaceutical, biologic and radiopharmaceutical products.

More information on SAP and access to required forms is available.

Current Fee Mitigation

In some cases it is possible that a fee payer would qualify for a fee mitigation or deferral. Mitigation or deferral would be to reduce the potential negative impact of paying the associated fee.

Fees can be deferred for a year or two if the company has not completed their first full fiscal or calendar year of operations. Fees can also be capped at a percentage of product sales.

Future Changes to Fee Mitigation

As of April 2019, Health Canada is proposing to implement new fee mitigation measures aimed at assisting Small Business. Information about the proposed changes can be found in the Revised Fee Proposal for Drugs and Medical Devices.

Use of Foreign Reviews

In some cases it is possible that the amount and quality of information available from a foreign regulatory counterpart may be appropriate to inform Health Canada's review. However, health products must meet Health Canada's regulations and standards for them to be authorized for sale in Canada.

More information is available in:

• The Use of Foreign Reviews
• The Use of Foreign Decisions

Use of Third Party Data

Submissions relying on third-party data are defined as New Drug Submissions (NDSs) and Supplements to New Drug Submissions (SNDSs) that substantially rely on literature and market experience.

The Guidance Document: Drug Submissions Relying on Third-Party Data (Literature and Market Experience) sets out Health Canada's expectations for sponsors of NDSs and SNDSs in the absence of sponsor-led clinical trial investigations and reports of safety and efficacy. Sponsors are encouraged to review the established conditions and requirements carefully and discuss the details of their submission with the appropriate Health Products and Food Branch review areas before filing such a submission.

The Canada Revenue Agency (CRA) administers the Scientific Research and Experimental Development program (SR&ED) Tax Incentive Program. It is the largest single source of federal government support for encouraging research and development (R&D) in Canada. The program includes cash refunds and/or tax credits for expenditures on eligible R&D work done in Canada. The tax rebates from the SR&ED program represent approximately $4-billion annually to companies of all sizes in Canada. It is a permanent program.

Key features include:

• Refundable tax credits
• R&D expenditures that can be carried forward indefinitely
• salaries, material, contracts and incremental overhead
• tax deductible capital equipment for R&D
• tax incentives for research performed in Canada and funded by non-residents

All key features are subject to qualifying conditions.

There are other market incentives for developing new treatments for rare diseases. You can access these through various programs depending on:

• the nature of the product itself
• the stage of research in the drug development program

The Government of Canada invests in key research and development programs through several different departments and programs including Genome Canada and the Canadian Institutes of Health Research (CIHR).

Small and medium-sized enterprises receive guidance through the National Research Council's Concierge service.

Further industry support comes through Innovation, Science and Economic Development Canada.

Advancing therapies

The CIHR supports research on rare diseases and provides a leadership role by joining important international research initiatives, such as the International Rare Disease Research Consortium (IRDiRC).

This consortium aims to accelerate medical breakthroughs for people affected by rare diseases. It includes more than 40 organizations from 17 countries. As of 2016, this international Consortium has yielded medicinal products and therapies for 222 rare diseases. As of 2016, IRDiRC has bypassed this goal and a new goal of delivering 1000 new therapies has been set for the next 10 years.

Advancing diagnostics

CIHR and Genome Canada are also investing in the Care for Rare Project. This project aims to use new gene sequencing technologies to identify the genes implicated in many rare diseases.

By advancing genomic research, this project will support the continued development of personalized medicine-the tailored treatment of patients based on their unique genetic makeup.

This project has recruited over 4000 patients and family members to participate in research. They have studied 950 different rare diseases, have provided a diagnosis to over 1500 patients, have identified 135 novel rare disease genes, and are developing three experimental therapies.

Advancing collaborative research

Canada is also engaged in E-Rare, the European Union's main instrument for funding research in areas related to rare diseases. This initiative enables scientists in different countries to collaborate on a common interdisciplinary research project, with a clear translational approach. The European Research Area Network (ERA-Net) "E-Rare" for research programs on rare diseases has been extended to a third phase, "E-Rare-3" (2014 to 2019), to further help coordinate the research efforts and to implement the objectives of the IRDiRC. CIHR is a member of E-Rare-3, and has supported 25 projects since 2012 through its participation in 5 Joint Transnational Calls.

Advancing resource hubs

In addition, we are an active member of Orphanet. This online resource offers a directory of specialized information for people with rare diseases and health care providers. It includes information gathered from all over the world about:

• biobanks
• registries
• researchers
• clinical trials
• expert centres
• specialized clinics
• medical laboratories
• patient organizations

Health Canada is a member of the International Council for Harmonisation of Technical Requirements Pharmaceuticals for Human Use (ICH). The mission of ICH is to achieve greater harmonization of technical standards worldwide. Its intention is to ensure that safe, effective and high quality medicines are developed and authorized in the most resource-efficient manner.

International documents give key advice on technical requirements, which align with Canadian requirements. These include, but are not limited to the:

• ICH topic E6 - Good Clinical Practice
  • Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice, ICH Harmonized Tripartite Guideline, Topic E6(R2)
• ICH E8: General Considerations for Clinical Trials
• ICH Topic E9 - Statistical Principles for Clinical Trials
• ICH E10 - Choice of Control Group and Related Issues in Clinical Trials
• ICH E15 - Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories
• E16 Biomarkers Related to Drug or Biotechnology Product Development: Context, Structure and Format of Qualification Submissions
• ICH E17 - General Principles for the planning and design of multi-regional clinical trials (MRCTs)
• ICH E18 - Genomic Sampling and Management of Genomic Data
• ICH E11 - Clinical Investigation of Medicinal Products in the Pediatric Population
  • Addendum to ICH E11 (R1)