Initial Draft Discussion Document for a canadian Orphan Drug Regulatory Framework

Initial Draft Discussion Document for A Canadian Orphan Drug Regulatory Framework

Table of Contents

Preamble

Background

What is a rare disease?

What is an orphan drug?

Unique Challenges of Regulating Drugs for Rare Diseases

International Context

Common features found in international frameworks include:

• 
  Orphan drug designation (including common application process)
  
• 
  Scientific and clinical protocol advice
  
• 
  Better information sharing to support transparency
  
• 
  Post-market authorization monitoring obligations
  
• 
  Incentives for drug development including market exclusivity, fee reduction, priority application review
  

Operating in an internationally aligned manner has allowed foreign regulators to maximize limited resources and coordinate their regulatory efforts in other areas including better information sharing in pre-market assessment and monitoring of post-market obligations (e.g. pharmacovigilance).

The design of the Canadian orphan drug regulations would allow Health Canada to operationally align and participate in well-established activities of the US and the EU including designation, scientific/protocol advice and pre- and post-market information sharing. Pooling of resources will be essential for operational efficiency and excellence in science. The lack of internationally aligned activities for orphan drugs has been identified as a burden for orphan drug development in Canada by the Red Tape Reduction Commission in one of the 90 specific recommendations in its report.

Canadian Context

While these paths worked in the past they are limited in both providing access to orphan drugs and information gathering and sharing since they were not designed to address the unique challenges of rare diseases.

Proposed Regulatory Framework for Orphan Drugs under the Food and Drugs Act

Objective

Overview

As an early deliverable in the Regulatory Roadmap for Health Products and Food, the life-cycle concepts first introduced in this regulatory framework will drive all other modernization efforts for drugs and medical devices that will follow.

The regulation of orphan drugs will rely on many existing provisions of the Food and Drug Regulations including for:

• 
  Labelling and packaging (Part A and Part C, Divisions 1, 3 and 4)
  
• 
  Clinical Trials (Part C, Division 5, with potential exceptions)
  
• 
  Establishment Licensing and Good Manufacturing Practices (Part C, Divisions 1A and 2, with potential exceptions)
  
• 
  Market exclusivity (Part C, Division 8)
  

Recognizing that greater uncertainties may exist for orphan drugs given the complexities of the diseases, the small and vulnerable populations and the treatment environment itself, greater abilities to plan for and resolve those uncertainties are needed once the drug is on the market that will not compromise pre-market authorization requirements.

Greater transparency to improve gathering and sharing of information amongst patients, health care professionals, researchers, payers and international regulatory partners including advancing the quality of knowledge for better decision-making are key components of the new framework necessary to resolve uncertainties.

Key new features of the framework found in other orphan drug regulations include:

Orphan Drug Designation

Regulatory Advice from Health Canada

Expert Advice and Patient Representation to Health Canada

Application for Market Authorization

Market Authorization for Orphan Drugs

Post-Market Authorization Plans

Ability for Minister to obtain information and reassess a market authorization

Technical Description of the Proposed Regulatory Framework

1. General

Overview and application

The regulatory framework would apply to orphan drugs for human use and include provisions relating to:

• 
  Orphan drug designation
  
• 
  Regulatory advice
  
• 
  Expert and patient advice
  
• 
  Market Authorization
  
• 
  Post-market authorization obligations and abilities
  

It would rely, as necessary, on existing drug provisions of the Food and Drug Regulations, including those related to:

• 
  Labelling and packaging (Part A and Part C, Divisions 1, 3 and 4)
  
• 
  Clinical Trials (Part C, Division 5, with potential exceptions)
  
• 
  Establishment Licensing and Good Manufacturing Practices (Part C, Divisions 1A and 2, with potential exceptions)
  
• 
  Market exclusivity (Part C, Division 8)
  

Definitions

1. 
   The drug is intended for the diagnosis, treatment, mitigation or prevention of a life-threatening, seriously debilitating, or serious and chronic disease or condition affecting not more than five in 10 thousand persons in Canada; and
   
   
2. 
   The drug is not currently authorized by the Minister or if currently authorized, it will provide a potentially substantial benefit for the patient distinguishable from the existing therapy.
   

2. Orphan Drug Designation

Application for orphan drug designation

1. 
   The name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the sponsor and the sponsor’s representative in Canada in the case of a foreign sponsor;
   
   
2. 
   When available, information on the manufacturer(s) of the drug if the drug is not manufactured by the sponsor;
   
   
3. 
   The medicinal ingredients of the drug;
   
   
4. 
   The proposed indication;
   

5. 
   Sufficient information to demonstrate that the criteria under the orphan drug definition are met;
   
   
   
6. 
   A description of the stage of drug development, including indications expected; and,
   

7. 
   A summary of the regulatory status of the drug in Canada and in foreign countries, including current investigational uses, previous market authorizations, orphan drug designation status, and any regulatory actions taken, where available.
   

Application for orphan drug designation based on a foreign designation

Alternately, a sponsor may submit an application for orphan drug designation on the basis of a designation from a recognized country, if the proposed orphan drug and indication in Canada is the same to that under which the foreign designation was issued. The application must be signed and dated by the sponsor and contain the following information:

1. 
   The name, address and telephone number and, if applicable, the facsimile number and electronic mail address of the sponsor and the sponsor’s representative in Canada in the case of a foreign sponsor;
   
   
2. 
   The medicinal ingredients of the drug;
   

3. 
   A copy of the foreign designation;
   
   
4. 
   A statement that:
   

1. 
   The proposed orphan drug and indication in Canada is the same to that under which the foreign designation was issued; and
   
   

Request for Additional Information

The Minister would be able to consider the application to be withdrawn if the sponsor fails to provide a response by the time indicated in the request, unless the sponsor has requested for an extension and the Minister has agreed to it.

Issuance of an orphan drug designation

Transparency

Sponsor’s Obligations

Sponsors would be required to notify the Minister when a designation is being transferred to another sponsor and provide updated contact information.

Cancellation of a designation

The sponsor would have an opportunity to make representations prior to the cancellation.

3. Regulatory Advice

1. 
   Both the Minister and the person that received the regulatory advice deem it necessary to do so; or
   
   
   
2. 
   The type and amount of information identified in the regulatory advice is no longer sufficient for the Minister to assess the benefits and harms associated with the use of the orphan drug.
   

4. Expert and Patient Advice
   
   

1. 
   Making a decision to issue, refuse or cancel an orphan drug designation;
   
   
   
2. 
   Providing regulatory advice in respect of an orphan drug;
   
   
   
3. 
   Making a decision to issue, amend, refuse to issue or amend, suspend or cancel a market authorization for an orphan drug; or
   

4. 
   Making a decision to maintain, amend or suspend a market authorization of an orphan drug that is the subject of a reassessment
   

5. Clinical Trials
   
   

6. Market Authorization for an Orphan Drug

Application for a Market Authorization

A person may submit an application for a market authorization of an orphan drug. The application must contain the following information:

1. 
   The name, address and telephone number, and if applicable, the facsimile number and electronic mail address of the applicant and the applicant’s representative in Canada in the case of a foreign applicant;
   
   
2. 
   A statement, signed and dated by the applicant’s senior executive officer in Canada and senior medical or scientific officer, that all information contained in, or referenced by, the application is complete and accurate and is not false or misleading;
   

3. 
   A copy of the Canadian orphan drug designation;
   

4. 
   Information as to the designation and regulatory status in other countries;
   

5. 
   The brand name under which the orphan drug is proposed to be sold;
   

6. 
   A quantitative list of the medicinal and non-medicinal ingredients contained in the orphan drug, by their proper names and common names;
   

7. 
   The recommended conditions of use for the orphan drug, including:
   

1. 
   its recommended use or purpose;
   
2. 
   its dosage form and strength;
   
3. 
   its recommended route of administration;
   
4. 
   its recommended dose;
   
5. 
   information about its harms, including any cautions, warnings, contra-indications or known adverse reactions associated with its use.
   

5. 
   Information relating to the benefits, harms and uncertainties of the orphan drug when it is used in accordance with the recommended conditions of use, including a plan to support the ongoing assessment and management of the benefits, harms and uncertainties associated with the use of the orphan drug. The plan must be proportionate to the benefits, harms and uncertainties of the orphan drug and must contain the following elements:
   

1. 
   Drug information
   Medicinal ingredient(s), brand name(s), drug class as described in the label, indications, dosage form, strength(s), applicant’s name and address
   
   
2. 
   Contact information
   Name and contact information for the person(s) responsible for the plan
   

3. 
   Summary of the benefits, harms and uncertainties associated with the use of the orphan drug
   The summary is meant to form the basis for the activities and interventions described in paragraphs iv. and v. below. For example, the summary would include a description of the identified harms, potential harms and uncertainties that may have an impact on the assessment of the benefits, harms and uncertainties associated with the use of the orphan drug.
   

4. 
   Detailed description of activities to monitor the benefits, harms and uncertainties associated with the use of the orphan drug once on the market and detect any change, including the assessment of the effectiveness of those activities.
   The activities would be proportionate to the benefits, harms and uncertainties of the orphan drug. For example, they can include:
   

• 
  Routine vigilance activities such as standard ADR reporting (as required by the regulations);
  
• 
  Additional activities where routine vigilance activities are not sufficient for monitoring the benefits and harms and resolving uncertainties. Additional activities can include specific requirements for monitoring and reporting of ADRs (which differ from standard regulatory requirements) or post-authorization studies (both clinical or quality studies)
  

5. 
   Detailed description of interventions designed to optimize benefits, prevent or minimize harms and clarify uncertainties associated with the use of the orphan drug, including the assessment of the effectiveness of those interventions.
   

• 
  Routine interventions (e.g. labelling as required by the regulations);
  
• 
  Additional interventions, when essential for the safe and effective use of the orphan drug, including communications which aim to augment the information in the label (e.g. communications to healthcare professionals or patients/consumers, educational materials), controlled distribution systems (including restrictions)
  
  
  

6. 
   Timetable for the submission of assessments of the effectiveness of the activities and interventions, including reporting schedule.
   

7. 
   Summary of the plan.
   

8. 
   Documentation that all clinical trial evidence was collected in accordance with accepted ethical standards, regardless of where the trials were conducted.
   

9. 
   Documentation that all clinical trials performed or sponsored by the applicant were publically registered no later than 21 days after the first subject is enrolled, in accordance with internationally accepted standards.
   

10. 
    Mock-ups of labels and packages to be used in conjunction with the orphan drug.
    
    
11. 
    The names and addresses of the manufacturers of each of the ingredients of the orphan drug and the names and addresses of the manufacturers of the orphan drug in the dosage form in which it is proposed to be sold.
    
    
12. 
    A detailed description of the orphan drug and of its ingredients that contains the following information:
    

1. 
   A statement of all properties and qualities of the ingredients that are relevant to the manufacture and use of the orphan drug, including the identity, potency and purity of the ingredients,
   
2. 
   A detailed description of the methods used for testing and examining the ingredients; and,
   
3. 
   A statement of the tolerances associated with the properties and qualities of the ingredients.
   

13. 
    A description of the plant and equipment to be used in the manufacture, preparation and packaging of the orphan drug.
    

14. 
    Details of the method of manufacture and the controls to be used in the manufacture, preparation and packaging of the orphan drug.
    

15. 
    Details of the tests to be applied to control the potency, purity, stability and safety of the orphan drug.
    

16. 
    Evidence that all test batches of the orphan drug used in any studies conducted in connection with the application for market authorization were manufactured and controlled in a manner that is representative of market production.
    

An applicant may cross-reference information referred to above if:

1. 
   The application relates to a new indication for a drug for which a NOC has been issued under section C.08.004 of the Food and Drug Regulations, and
   
   
2. 
   The information is not different from that which was originally submitted under C.08.002(2) of the Food and Drug Regulations.
   

Assessment of an application for Market Authorization

The Minister would be able to request that the applicant provides additional information as necessary if the information and documents submitted in the application for market authorization are insufficient to enable the Minister to determine whether the market authorization should be issued.

The Minister would be required to, following the assessment of the application, notify the applicant in writing of any deficiencies if the application does not comply with the requirements and provide an opportunity for the applicant to address the deficiencies by filing additional information.

Market Authorization Issuance

1. 
   Issue a market authorization if the Minister is of the opinion, taking into account the extent and nature of the uncertainties associated with the benefits and harms and the small size of the patient population, that the benefits associated with the use of the orphan drug outweigh the harms, and that uncertainties of the benefits and harms do not prevent the Minister from issuing the market authorization; or
   
   
2. 
   Refuse to issue a market authorization if:
   

1. 
   The Minister is of the opinion that the harms associated with the use of the orphan drug outweigh the benefits
   
   
2. 
   The uncertainties of the benefits and harms prevent the Minister from issuing the market authorization; or
   
   
3. 
   The applicant has failed to address the deficiencies in the deficiency notice.
   

The applicant would have an opportunity to make representations where the Minister has refused to issue a market authorization.

The Minister would be required to reconsider the decision after giving the applicant that opportunity.

Drug Identification Number

Contents of Market Authorization

• 
  Name and address of the market authorization holder
  
• 
  Common name and brand name of the orphan drug
  
• 
  Recommended conditions of use for the orphan drug
  
• 
  Drug Identification Number assigned by the Minister
  
• 
  Label
  
• 
  Plan summary
  

Transparency

The Minister would be required to make available to the public negative decisions.

7. Changes to a Market Authorization

Changes to a market authorization requiring the filing of an amendment application

The market authorization holder would be required to submit an amendment application including the information set out in the market authorization application section that is relevant to the change, when proposing to make one or more of the following changes:

1. 
   Any change to the information supporting an orphan drug where that change has the potential to significantly change the benefits, harms and uncertainties associated with the use of the orphan drug;
   
   
   
2. 
   Any change to the plan authorized under the market authorization;
   
   
   
3. 
   Changes in any administrative details on the market authorization such as the name or address of the market authorization holder;
   

4. 
   Changes to the brand name of the orphan drug.
   
   
   

Assessment of an application to amend a market authorization

The Minister would be required to, following the assessment of the amendment application, notify the applicant in writing of any deficiencies if the application does not comply with the requirements and provide an opportunity for the applicant to address the deficiencies by filing additional information.

Amendment of a market authorization

1. 
   Amend a market authorization if the Minister is of the opinion, taking into account the extent and nature of the uncertainties associated with the benefits and harms and the small size of the patient population, that the benefits associated with the use of the orphan drug outweigh the harms, and that uncertainties of the benefits and harms do not prevent the Minister from amending the market authorization; or
   
   
2. 
   Refuse to amend a market authorization if:
   

1. 
   The Minister is of the opinion that the harms associated with the use of the orphan drug outweigh the benefits;
   
   
2. 
   The uncertainties of the benefits and harms prevent the Minister from amending the market authorization; or
   
   
3. 
   The applicant has failed to address the deficiencies in the deficiency notice.
   

The Minister would be required to reconsider the decision after giving the market authorization holder that opportunity.

Changes to a market authorization requiring the filing of a notification

The market authorization holder would be permitted to implement notified changes XX days following notification unless otherwise directed by the Minister.

8. Market Authorization Holder’s Obligations
   
   

1. 
   Label and package the orphan drug in accordance with the requirements set out in the Food and Drug Regulations;
   
   
   
2. 
   Show the drug identification number (DIN) assigned by the Minister on the principal display panel of both the inner and outer label of the orphan drug (equivalent requirement to that under section C.01.005 of the Food and Drug Regulations);
   
   
   

3. 
   Ensure that the orphan drug is manufactured, handled and stored in accordance with the applicable good manufacturing practices referred to in Divisions 2 to 4 of the Food and Drug Regulations;
   
   
   

4. 
   Report to the Minister serious adverse drug reactions within 15 days after receiving or becoming aware of the information (this requirement should be equivalent to that under section C.01.017)
   
   
   

5. 
   Report to the Minister new information which might impact the assessment of the benefits, harms and uncertainties of the orphan drug concerned;
   

6. 
   Implement the plan authorized under the market authorization, including reporting to the Minister within a time specified in the plan;
   
   
   
7. 
   Update the plan as necessary when new information becomes available and report of any change by filing an amendment application to the Minister in accordance with the requirements of the new orphan drug regulations;
   
   
   

8. 
   Notify the Minister in accordance with C.01.051 of any recalls of an orphan drug;
   

9. 
   Notify the Minister within 30 days after commencing sale of an orphan drug, indicating the date on which the orphan drug was first sold in Canada (similar to the requirement under paragraph C.01.014.3(c));
   
   
10. 
    Notify the Minister of the discontinuation of sale of an orphan drug at least 6 months in advance of a planned discontinuance. The notification should include the company name and contact, product details; and anticipated date of discontinuation.
    

11. 
    Notify the Minister annually in accordance with section C.01.014.5 to confirm that the information previously submitted in the market authorization with respect to the orphan drug is correct;
    

12. 
    Notify the Minister, within a reasonable delay, of any change in regulatory status in other countries in the following situations:
    

• 
  Recall of the drug with the same medicinal ingredient
  
• 
  Withdrawal of the drug or an indication
  
• 
  Suspension of authorizations
  

13. 
    Establish and maintain records in a manner that enables an audit to be made.
    

9. Post-market Authorization Abilities

Ability for Minister to request information

Ability for Minister to require a market authorization holder to compile information

The Minister would be required to give the market authorization holder an opportunity to make representations. After considering any representations, the plan authorized under the market authorization may be amended, if necessary.

Ability for the Minister to require a change to the label or package of an orphan drug

The Minister would be required to give the market authorization holder an opportunity to make representations.

Ability for Minister to conduct the reassessment of an orphan drug

The Minister would be required to, after assessing the information provided by the market authorization holder, confirm in writing whether to:

1. 
   Maintain the market authorization;
   
   
   
2. 
   Amend the market authorization; or
   
   
   
3. 
   Suspend the market authorization.
   

Ability for the Minister to direct a person to stop the sale of an orphan drug

The Minister would be required to lift a direction to stop the sale of an orphan drug if the circumstances that gave rise to the direction have been addressed.

Ability for the Minister to suspend a market authorization – contravention or harm

1. 
   The market authorization holder has contravened a provision of the Act or the regulations; or
   
2. 
   The harms associated with the use of the orphan drug outweigh the benefits.
   

The Minister would be required to, after considering any representations, confirm in writing whether to:

1. 
   Maintain the market authorization;
   
   
   
2. 
   Amend the market authorization; or
   
   
   
3. 
   Suspend the market authorization.
   
   
   

Ability for the Minister to suspend a market authorization – immediate suspension

The market authorization holder would have an opportunity to make representations any time following the suspension.

The Minister would be able to do the following, after considering any representations, if he or she is of the opinion that the market authorization holder has addressed the initial grounds for suspension, as identified in the suspension notification:

1. 
   Reinstate the market authorization; or
   
   
   
2. 
   Reinstate and amend the market authorization.
   
   
   

Ability for the Minister to cancel a market authorization – contravention

The market authorization holder would have an opportunity to make representations, prior to the cancellation.

1. 
   Maintain the market authorization;
   
   
   
2. 
   Amend the market authorization; or
   
   
   
3. 
   Cancel the market authorization.
   

Ability for the Minister to cancel a market authorization – benefits do not outweigh harms

Ability for the Minister to cancel a market authorization – consent

10. Market exclusivity