Technical Discussion Sessions Regulatory Modernization for Therapeutic Products

Day 1 - Market Authorization & Access

Topic A:  Pre-submission Meetings and Market Authorization - General Requirements

• 6 month pre-filing notification considered overly burdensome and not appropriate for all product lines; suggestion that timelines and filing requirements remain flexible
• Comment that information available at pre-filing stage may be limited and subject to change, as product continues to be developed
• General requirements considered acceptable if the distinct product line frameworks include further tailoring
• Need for clarification of terms such as "efficacy" and "effectiveness"

Topic B:  Access Issues - Regulatory Frameworks for Drug Shortages, Discontinuances, Special Access Program and Drugs for Rare Diseases

SAP Application Requirements

• Suggestion to better define and consider medium and larger sized populations, serious / life-threatening
• Understanding that Health Canada's role as regulator includes  judgement/discretion

Discontinuances/Shortages

• Suggestion to incorporate flexibility with respect to notification and timeframes
• Concern that the release of shortage information to the public may be considered confidential business information (CBI)
• Comment to define or further clarify 'drug shortage', 'public health impact'
• Note that drug authorization does not guarantee market availability
• Potential for use for foreign approvals in shortage, special access, or public health emergency situations
• Point raised about the importance of informed consent

Drugs for Rare Diseases

• Suggestion to further clarify or define 'rare disease'
• Flexibility suggested for information requirements to support application
• Note that a separate office to handle applications may be needed, also to incorporate representation from patient groups
• Possibility of a committee with external experts was discussed
• Need for flexibility to gather safety and efficacy information beyond formal clinical trials
• Suggestion for regulatory incentives for drugs for rare diseases

Day 2 - Market Authorization Requirements by Product Line

Topic A:  Prescription Pharmaceuticals

• Need for clarity around the definition and evidence or requirements for "effectiveness"
• Evidence from all test batches used in any studies was felt to be restrictive and flexibility was suggested
• Requirement for public registration of clinical trials should be in line with requirements from other major regulatory authorities
• Clarification and consistency regarding vigilance plans suggested
• Engaging the regulator early in the process was considered a good mechanism to assist in any clarifications and planning
• Comment that some information could be provided after filing but before review (e.g. evaluation of brand name, packaging label, proposed vigilance plan, proposed conditions of market authorization)

Topic B:  Generic Pharmaceuticals

• Comment that the introduction of a new class of generic products ("pharmaceutically similar" rather than "pharmaceutically equivalent") raises interchangeability and intellectual property issues, and may need further discussion
• Suggestion that labelling information for generics should be subject to an evaluation of the label by consumers/patients as required with innovator drugs
• Opposition expressed to the regulator removing the option of using a foreign-sourced reference product for demonstrating equivalence

Topic C:  Non-prescription Pharmaceuticals

• Recommendation that a separate risk-based framework be established for non-prescription products with different levels of evidence
• Other participants noted that the standard and level of evidence for non-prescription products should be similar to those for prescription products
• Improved post-market surveillance was recommended
• Product switches between prescription and non-prescription status was highlighted as a possible area needing further consideration
• Appropriate consumer information and labelling was noted to be important for this product line, and it was suggested that manufacturers conduct labelling comprehension studies with end users

Topic D:  Biologics

• Suggestion that the 6 month notification requirement be captured in guidance, or made more flexible
• Comment that some information could be provided after filing but before review (e.g. evaluation of brand name, packaging, label, proposed vigilance plan, proposed conditions of market authorization)
• Recommendation for flexibility around the "integrated" summaries
• Suggestion that further education and awareness campaigns be developed for biologic drugs
• Comments about how the current Division 4 would be incorporated in the new framework

Topic E:  Subsequent Entry Biologics

• Suggestion that the regulator consider requiring unique non-proprietary names for subsequent-entry biologics (SEBs) to ensure traceability and reporting of adverse events
• One comment that vaccines, blood products and their recombinant equivalents and cellular/gene therapies be explicitly excluded from the SEB framework
• Concern raised regarding the use of a non-Canadian reference product, and HC's ability to ensure product similarity throughout the lifecycle of the SEB
• General agreement that SEB applications undergo the same rigorous, safety/vigilance requirements as innovator biologics
• One suggestion to establish a Declaration of Similarity with market approval
• Consensus that labelling is critical with an SEB drug

Topic F:  Medical Devices

• Suggestion that the 6 month notification requirement not apply to devices, or be captured in guidance for flexibility
• General agreement with the use of the term "clinical investigation", and recommendation to align trial requirements with other regulators
• Suggestion that implant registration be eliminated from the framework; this concept was not supported by contributors such as patient groups
• Suggestion to further clarify labelling provisions for electronic labelling for professional use devices
• Issue of single-use devices was discussed in the context of reprocessing and reuse, as well as labelling

Day 1 - Market Authorization and Post Authorization Requirements

Topic A:  Market Authorizations - Issuance, Conditions & Content

MA Issuance

• Comment about the use of foreign information being included in the framework
• Recommendation against widening the gap between non-prescription drugs and other low-risk products such as natural health products
• Some participants not supportive of posting negative decisions, however, other contributors felt it important to make this important information available for the public
• Need for further discussion and clarity around the positing of information

Standard & Special Conditions

• Suggestion that the standard and special conditions be tailored appropriately to the product line, including generics
• Operational issues raised around filing of amendments and who would review them
• Consensus against the proposal for a special or unique symbol on labels of products with special conditions
• One suggestion about the 6 month notification of a withdrawal or shortage to apply only when faced with a safety issue
• Instead of a 3 year marketing requirement, it was suggested that marketing decisions are in the hands of the authorization holder
• Health Canada reiterated that special conditions would be very rare for non-prescription drugs
• One suggestion that regulatory oversight be extended to off-label use
• Comment about importance of consumer education on standard and special conditions, including any symbols or labelling changes

Topic B:  Market Authorizations - Amendments

• Some suggestions that lower risk changes should be addressed in guidance rather than regulation
• Consensus for the need to clearly define types of amendments/notification
• Health Canada reiterated that the emphasis is on the change type, not the product type
• Operational and resource concerns raised regarding regulator's ability to review on time

Day 2 - Post Authorization Activities

Topic A:  Product Register

• Industry raised concerns regarding posting of information that would be considered by them to be confidential business information, including negative decisions made by the regulator and correspondence with the regulator
• For devices, it was suggested that Health Canada's "medical devices active licence listing" could be further refined to capture all relevant product information and risk communication
• Suggestion that authorization holders be given the opportunity to make representations to Health Canada prior to posting information in the register
• Suggestion that Health Canada conduct a needs assessment for the register, including engaging patients and consumers

Topic B:  Requiring Information/Label Changes

Provision of requested information

• Need for additional clarity around timing and details of requirements, as well as opportunity to make representations
• General interest amongst participants regarding what information would be captured in the register

Requests for label changes

• Industry supported having the opportunity to make representations before label change is required.
• Industry commented that off-label use information is not readily available to them, and should be gathered by other means; contributors suggested that information about off-label use be collected and monitored

Topic C:  Requiring Tests/Studies

• Industry raised concerns regarding the situation where there are multiple authorization holders with 'same' products and who would be required to lead the study or test
• Suggestion to have a consultation with authorization holders prior to issuing the request for additional studies or tests
• Health Canada reiterated that there are a number of accountable parties in the evolving post-market environment
• Recommendation for a coordinated strategy and communication approach
• Comment that ongoing collection of information involves all stakeholders, not only authorization holders

Day 1 - Post Authorization Activities and Combination Products

Topic A:  Requesting Benefit /Risk Reassessment, Establishing Advisory Committees

Benefit/Risk Reassessment

• It was indicated that pharmaceutical industry already conducts benefit/risk reassessments, which can result in the filing of a submission to make a change to the product or its labelling when the outcome is 'significant' and 'unfavourable'
• Circumstances under which Health Canada would require an authorization holder to conduct a benefit/risk reassessment would need to be further defined either in regulation or guidance
• Suggestion that Health Canada consult with authorization holders prior to issuing the request for benefit/risk reassessment
• Suggestion to clarify relationship of benefit/risk reassessment with  suspensions and revocation
• Indication that "off-label" use could be a significant trigger for benefit/risk reassessment
• Suggestion that public should be informed when a product is undergoing a benefit/risk reassessment and the outcome
• Indication that Health Canada as the regulator should remain at arms length from the industry to assure an unbiased approach
• Health Canada is not lowering the standards for product approval

Establishing Advisory Committees

• Concerns regarding release of confidential business information to advisory committee members
• Concerns regarding affiliation of committee members and whether this may bias committee activities
• Suggestion that public should have the ability to input
• Committee activities suggested to be available publicly in a timely manner and in sufficient detail
• Suggestion that performance evaluation should be an integral aspect of advisory committees
• Suggestion that committee experts not include representatives from industry
• Suggestion that committee advice be referenced in any related Health Canada decisions, and that clear linkages and timelines between committee activities and Health Canada decision-making be made

Topic B:  Market Authorization Suspension, Revocation

• Suggestion that Health Canada consult with authorization holder prior to issuing a suspension or revocation
• Recommendation that the role and use of advisory committee in suspension or revocation process be clarified
• Level of evidence to trigger a suspension or revocation needs to be clearly defined (e.g. difference between "opinion of Minister" and "reasonable grounds to believe")
• Clarity needed regarding extent of suspension or revocation, i.e. in whole or in part
• Suggested that suspension or revocation should also be available as an option to deal with Quality issues (e.g. manufacturing or testing)
• Questions under what circumstances generic versions would be subject to a suspension or revocation if applied to the innovator
• Timelines for representations by the authorization holder suggested to be fixed and reasonable so as not to allow lengthy extension of market authorization
• Public should be informed immediately of any suspension or revocation
• Consider a "graded approach" when moving from suspension to revocation

Topic C:  Combination Products

• Disagreement on merits of a unique "blended requirement" model over the current classification system
• Suggested that a separate "Office of Combination Products" be formed
• Challenges foreseen in post-market reporting requirements and how to apply them

Day 2 - Information Requirements

Topic A:  Mandatory Reporting

• Concerns that insufficient information will be reported, and suggestion that serious expected drug reactions should be reported as well as unexpected
• Observation that public feedback to Health Canada may lead to better reporting rates
• Comment that it would likely be difficult to enforce mandatory reporting in a hospital setting
• Recommendation to consider linking reporting with Statistics Canada and the Public Health Agency of Canada
• Health Canada should encourage determining root cause of events as more important than simply reporting (i.e. active surveillance)
• Use of 3rd party accreditation suggested for ensuring compliance

Topic B:  Labelling

• Strong support for requiring clear, accurate and easily understandable labelling
• Concerns that too much information may be requested by Health Canada
• Concerns regarding when a final label should be provided to Health Canada
• Some indicated that certain label changes should not require notification or review by Health Canada
• Much debate regarding minimum font size on a label or package
• Concerns that proposals would remove flexibility, particularly in adapting labelling for small containers
• No consensus regarding the use or utility of special symbols
• Standardization of labelling/packaging suggested as a means to reduce medication errors
• Possibility of providing information in languages other than English or French was suggested
• Information should be readily available and accessible to consumers to allow informed choices regarding personal benefit/risk decisions
• Machine-readable coding on label may be useful means to provided additional information, so long as it is the Health Canada-approved information

Topic C:  Advertising

• Strong support by all participants (other than from industry) to eliminate all forms of direct to consumer advertising (DTCA) for prescription drugs
• Agreement  that differentiating between labelling and advertising is sometimes difficult and a robust definition/guidance is required
• Impact of proposals with respect to trade show activities (i.e. for medical devices) was questioned
• Suggestion that rules banning DTCA should be incorporated in legislation to remove any possibility of changes being made through regulation
• Ease of access to information on the internet/social media age has to be considered
• Comment that fines/penalties need to be increased
• Suggestion that all forms of "advertising" should be considered (i.e. industry sponsored conferences, advocacy groups, etc.)

Day 3 - Compliance and Enforcement

Topic A:  Inspection - A Graduated Approach to Establishment Licensing

• Timelines/inspection cycles need to be well defined
• Indicated that approach to quality management systems (QMS) for medical devices is different than establishment licensing (EL) and good manufacturing practices (GMP) for drugs and needs to be considered
• Question as to whether the proposal would also apply to manufacturers of the active pharmaceutical ingredient (API)
• Clarification required as to what activities could be carried out under an interim license and by whom
• Consideration needed to address combination products

Topic B:  Importation, Importation for Exportation, and Exportation

• Concerns regarding importation of remanufactured single-use medical devices
• Questions regarding importing and quarantining product prior to gaining market authorization (indication that interim licence may address this)
• Questions regarding how drugs for special access would be treated
• Concern that drugs not approved in Canada would be allowed for export

Topic C:  Anti-Counterfeiting and Deception

• Strong support for proposals
• Need seen for larger fines and penalties
• Proposals should be flexible enough to adapt to technologies to control counterfeiting, and bar coding may no longer be appropriate
• Suggestion that all who conduct controlled activities should be subject to EL/GMP or QMS (e.g. filling of medical gas cylinders by hospitals)

Topic D:  Recall, Stop Sale, and Corrective Actions

• Cautious support of proposals by industry
• Indication that recall and circumstances that trigger a recall need further defining and should include recalling for Quality issues as well as safety or effectiveness issues
• Question as to how quarantine and corrective action by manufacturer relates to recall