Final Record of Decisions October 2, 2018 Meeting: Groupement provincial de l’industrie du médicament (GPIM)
Health Canada - Health Products and Food Branch (HPFB)
Bilateral Meeting Program
Holland Cross, 1600 Scott Street, Tower B Room 2048, Ottawa, Ontario
October 2, 2018
(1:00 p.m. to 4:10 p.m.)
Stéphane Lévesque, GPIM
Pierre Morin, GPIM
Elise Maheu (3M Canada)
Barry Poole (DRA Pharmadev Canada)
Elsa Reyes (DRA Pharmadev Canada)
Vassilios Christodoulopoulos (Euro-Pharm)
Bruno Zauhar (Euro-Pharm)
Patrizia Franco (Jamp Pharma)
Guiseppe D’Aprano (Groupe KDA)
Alexandre Ostiguy (Laboratoire Atlas)
Danny Germain (Laboratoires RIVA)
Jacques Lavoie (Laboratoires RIVA)
Caroline Roy (Laboratoires RIVA)
Martin Frappier (Mantra Pharma)
Marie Christine Régis (Pharmalab)
André Côté (SaniMarc)
Health Canada Participants
Celia Lourenco, Senior Executive Director, Therapeutic Products Directorate (TPD)
Manon Bombardier, Natural and Non-Prescription Health Products Directorate (NNHPD)
Léo Bouthillier, Bureau of Cardiology, Allergy and Neurological Sciences (BCANS), TPD
Ingrid Brown, Office of Planning, Performance and Review Services (OPPRS), TPD
Claudia Casimiro, Office of Submissions and Intellectual Property (OSIP), TPD
Julie Chateauvert, Policy, Planning and International Affairs Directorate, (PPIAD)
Mandy Collier, OPPRS, TPD
Gary Condran, Bureau of Pharmaceutical Sciences (BPS), TPD
Dino Covone, NNHPD
Émile Geoffroy, OPPRS, TPD
Stephanie Hardy, Biologics and Genetic Therapies Directorate (BGTD)
Melissa Hunt, Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS), TPD
Gayatri Jayaraman, Marketed Health Products Directorate (MHPD)
Waleed Jubran, OSIP, TPD
Joseph Mikael, OSIP, TPD
Katerina Paschakis, Resource Management and Operations Directorate (RMOD)
Irena Pastorekova, OSIP, TPD
Isabel Renart-McGowan, Director General’s Office (DGO), TPD
Jeffrey Skene, Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD), TPD
Andrew Slot, MHPD
Kathy Soltys, MHPD
Donna Watt, OPPRS, TPD
Johanne Veenstra, BGTD
Thanh Vu, MHPD (by teleconference)
Bill Wilson, MHPD
Veronica Yip, BGIVD, TPD
Paul Litowitz, MHPD
Merryl Ndema-Moussa, Food and Drugs Act Liaison Office (FDALO)
- Welcome and Introductions
Celia Lourenco, Senior Executive Director, Therapeutic Products Directorate (TPD), welcomed participants and thanked the representatives of GPIM companies who travel to attend these meetings. She also indicated that Health Canada appreciates the valuable feedback that GPIM members have provided for the many recent and important consultations in the branch.
Many changes have taken place at Health Canada since the last bilateral meeting with GPIM was held in November 2017. Celia Lourenco will transition to the role of Director General of the Biologics and Genetic Therapies Directorate effective November 19, 2018; Rhonda Kropp has become the Director General of the Marketed Health Products Directorate (MHPD); and Kelly Robinson, previously with TPD, has joined the Biologics and Genetics Therapies Directorate (BGTD) as Director of the Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics. For other organizational updates within TPD, Melissa Hunt is the Interim Director and Craig Simon is Associate Director of the Bureau of Metabolism, Oncology, and Reproductive Sciences (BMORS); Marc Berthiaume is Director of the Bureau of Medical Sciences (BMS); David Boudreau is Director of the Medical Devices Bureau (MDB); Jeffrey Skene is Associate Director of the Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD); and Kristen Zorn has become an Associate Director in the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS).
Celia Lourenco indicated that it continues to be an active time in TPD with a high number of key ministerial and branch priorities underway; including: the Health Products and Food Branch’s initiative to improve the Regulatory Review of Drugs and Devices (R2D2); the Treasury Board led Regulatory Review to modernize our regulations; the Federal Action Plan on Antimicrobial Resistance and Use; the Federal Action on Opioids; the proposed approach to the Regulation of Cannabis; Public Release of Clinical Information; and the Cost Recovery Renewal Initiative. TPD recognized GPIM’s support for these initiatives.
Stéphane Lévesque, GPIM Co-chair, indicated that GPIM’s priorities are the same as those of Health Canada. GPIM suggested that Health Canada prioritize its initiatives and changes. As Plain Language Labelling (PLL) is now a priority for Health Canada, GPIM also suggested that TPD use plain language when developing policies. Health Canada agreed that it has undergone many changes recently and that it is important to prioritize. A roundtable of introductions followed.
Review of Agenda
There were no changes to the agenda.
Approval of Meeting Notes of November 16, 2017 / Action Items
The November 16, 2017 meeting notes were approved.
Increasing Regulatory Requirements vs. Decreasing Pricing for Generic Drugs
GPIM indicated that regulatory requirements for Canadian drug submissions are becoming increasingly demanding (in both cost and development cycle times) for generic drugs while public payers are continuously reducing prices and restricting marketing conditions. GPIM noted that this potentially hinders market access to high-quality Canadian-manufactured products, and impacts the market viability of low-volume, medically necessary generic molecules. GPIM indicated that if Division 1 drugs are being held to the same standard as Division 8, it is not worthwhile for a company to put them on the market. For example, the requirements for Vitamin D are more than what is needed to demonstrate product quality. GPIM noted that certain vitamins regulated in Canada as prescription drugs, because of their strength (e.g. Vitamin D in excess of 1,000 IU per dosage unit), are subjected in Canada to the same requirements as high-risk drug products.
Gary Condran, Associate Director of the Bureau of Pharmaceutical Sciences, addressed this item. Gary Condran updated that TPD has been active on the development and finalization of several policy issues and guidance documents for generics which contributed to the elimination of the backlog for generic submissions in August 2018. He added that TPD takes a risk-based approach to review (e.g., including ensuring the safety of Division 1 sterile products). TPD will take into consideration that requirements for lower risk products such as Vitamin D should reflect the risk level. Gary Condran, TPD indicated that it would be useful to hear from GPIM about its priorities and to have a focused discussion about some of the specifics. A separate discussion could be held on the topic.
Notices of Non-compliance (NONs) or Notices of Deficiencies (NODs) Issued Late in Review without Prior Warning
GPIM indicated that there appears to be an increase in submissions under review where a NON or an NOD is issued without prior warning in the last two or three weeks of review. The association noted that the issues raised could be identified at screening or dealt with by a clarifax. The association noted that a NON or a NOD is very costly for sponsors because it results in additional fees plus the costs of re-organising production schedules and storage of quarantined raw materials. GPIM requested that major issues that could lead to a NON or NOD be identified earlier and that the status of the review be communicated to sponsors.
Gary Condran, Associate Director of the Bureau of Pharmaceutical Sciences, addressed this item. A NON or NOD indicates that major deficiencies have been identified that prevents the approval of a submission. The major issues (e.g., those requiring additional data) are then identified in the NON or NOD letter under the “Major Objections” heading while the clarifax type comments are captured under “Minor Objections” and sent as one letter. While a goal is to have an increase in first cycle reviews, it remains the responsibility of the sponsor to include information for generic Abbreviated New Drug Submissions (ANDSs) as outlined in the Quality Guide that was published in 2017. It is recommended that sponsors contact their Regulatory Project Manager for status updates on their submissions. Gary Condran, TPD, indicated that the review divisions would look into giving a heads-up to companies if a submission is expected to receive a NON or a NOD.
GPIM requested that TPD provide a list of the most common shortcomings in order to improve submissions. The association indicated that it underwent a similar exercise in 2012 and that resulted in significant improvements in positive decisions. TPD indicated that it has been sharing that information through workshops but has focused its resources on clearing the recent backlog. Gary Condran reported that BPS has prepared a summary document outlining guiding principles for communicating deficiency comments to companies and mentioned that it could be made available to GPIM.
Action: Gary Condran, TPD, indicated that he would provide GPIM with a list of common deficiencies that are found in generic submissions.
Completed: Gary Condran, TPD, has forwarded the document Guiding Principles for Communicating Deficiency Comments to Submission Sponsors (dated 2015-05-05) for distribution to GPIM. The document includes examples of common deficiencies in drug submissions that companies should avoid.
Pause the Clock
Johanne Veenstra, Senior Regulatory Officer, Office of Policy and International Collaboration, Biologics and Genetic Therapies Directorate (BGTD) and Stephanie Hardy, Manager, Policy Unit, Office of Policy and International Collaboration, BGTD presented this item. Within the new Fee Proposal for Drugs and Medical Devices, a penalty model is proposed whereby financial rebates are paid on all individual submissions/applications exceeding performance standards. To ensure that only Health Canada’s active review time is counted against performance target standards, there is a need for a pause the clock mechanism to be in place. A triggered pause clock model is being considered that consists of only pausing the clock during the review process when pre-specified conditions are met (triggers).
BGTD requested feedback from GPIM on the proposed pause the clock triggers for drugs, which include requests for extensions to respond to a Clarifax and Expert Advisory Panel advice sought. BGTD invited GPIM to provide comments on the pause the clock proposal that has been posted on the website August 10, 2018 for a 60 day consultation period
GPIM asked whether a sponsor could use “pause the clock” to add data that is missing from a submission. The association indicated that if a sponsor realizes that information is missing from a submission just before the clock is due, it costs the sponsor a lot of money. BGTD responded that new data would require a new submission. Acceptance of new data is something that could be discussed as part of a separate project, but “pause the clock” cannot be used to add new data to a submission. “Pause the clock” is a tool that is used when the review is running and that time is added to the submission target date. It applies to all products except for Natural Health Products. BGTD invited GPIM to submit comments on the proposal before October 9, 2018.
Guidance Document - Admin Processing of Submissions and Applications Involving Human or Disinfectant Drugs
GPIM requested that affected products that were on the market prior to the implementation of the guidance be excluded. The association suggested that a product pass through a labeling review process for the first change, and then be admissible for the administrative pathway when the safety change is the only one being made. GPIM noted that if a strength has been discontinued, any safety labeling update from the innovator currently needs to be submitted as a labeling submission, with associated costs and review time.
Waleed Jubran, Manager, Regulatory Affairs Divisions, and Claudia Casimiro, Acting Regulatory Affairs Supervisor, Office of Submissions and Intellectual Property, TPD addressed this item. Health Canada responded that while the first change could be labelling only, other things may come up during review that would need to be addressed. It would be difficult to switch a submission from labelling only to the administrative pathway. GPIM provided the example that if a product has four strengths, the sponsor may leave two aside that are never used. Health Canada indicated that the extra strengths could be removed. Health Canada has only 45 days to process the labelling only submissions and there is no time to switch between pathways.
GPIM noted that it is difficult to determine the definition of a minor change, eg. a slight change in logo size or the way dosage is expressed. Health Canada indicated that it does allow certain variations that it recognizes cannot be identical to the parent product. A minor change to the label would be one that involves using a different company.
GPIM asked if it should follow the licensor label when it is not in compliance with Health Canada and has not been updated. Health Canada responded that the guidance documents are clear that the licensor needs to keep up to date. If the licensor has not filed a plain language labelling mock up, the onus is on licensee to develop mock up labels to include with the submission to Health Canada. If there are major changes that are not similar to the parent product, those would be labelling only. The administrative path is limited to simple cross-licencing and brand name changes.
GPIM indicated that if a licensor needs to change its label, up to 10 licensees need to make the same change. GPIM proposed that the first time a label change is reviewed, Health Canada could keep it on file and refer to that change. Health Canada indicated that the guidance will be updated in the near future and that GPIM’s suggestion would be taken into consideration.
Regulatory Enrolment Process (REP) and electronic Common Technical Document (eCTD) Updates
Joseph Mikhael and Irena Pastorekova, Office of Submissions and Intellectual Property (OSIP), TPD presented this item. REP consists of a set of web-based templates that capture sponsor provided information in a structured XML (Extensible Markup Language) format. REP facilitates the filing and processing of information related to a company, dossier, regulatory activity and regulatory transaction. This information is currently being provided to Health Canada using the Submission Application forms. Once fully implemented, the REP templates will replace existing Health Canada forms such as the HC 3011 form and Fee forms.
Health Canada is currently piloting the REP templates and process with pharmaceutical and biologic human drugs filed in eCTD format. This fall, Health Canada will be expanding the pilot to include transactions in non-eCTD format as well (Division 8 and Division 1). All sponsors are encouraged to take advantage of this opportunity.
Health Canada has commenced planning for a Medical Device Pilot implementation intended for winter 2019, a veterinary drugs REP pilot and a clinical trials pilot intended for spring 2019.
GPIM expressed concern that it has a 75% rejection rate for its submissions. The association noted that its submissions never fit into the actual format. Health Canada indicated that it is aware of that and has reached out to the Natural and Non-prescription Health Products Directorate. Module 1 is being revised and there will be a new section for disinfectants specific documents that do not fit to the ICH structure in modules 2, 3 and 4. It is anticipated that the revisions will be ready in January 2019 and GPIM will have a chance to comment. If anything does not fit the structure, GPIM members should contact Health Canada. A consultation on the structure (if required) prior to posting the guidance document in a form of a Webex can be held to ensure submissions are not failed due to the actual format. GPIM is to contact the Health Canada e-review group if such meeting is required.
Any comments and questions on REP and eCTD can be sent to: email@example.com
Mandatory Reporting of Serious Adverse Drug Reactions (ADRs) and Medical Device Incidents (MDIs) by Hospitals
Gayatri Jayaraman, Director, Bill Wilson, A/Manager, and Thanh Vu, Regional Coordinator, Marketed Health Products Safety and Effectiveness Bureau (MHPSEIB), of the Marketed Health Products Directorate presented this item. The proposed mandatory reporting regulations would amend the Food and Drug Regulations and the Medical Devices Regulations to require hospitals to provide reports of serious adverse drug reactions (ADRs) and medical device incidents (MDIs) directly to Health Canada. This is to ensure that serious ADRs and MDIs are reported to Health Canada so that there is enough information to detect safety problems.
The draft regulations were posted on Canada Gazette, Part I (CGI), and stakeholders had until August 29, 2018 to provide their feedback on the proposal. The draft guidance document was also available for comment. After analyzing the feedback, Health Canada will consider if any changes to the proposal are necessary before posting the final regulations on Canada Gazette, Part II (CGII). Health Canada is interested in determining the best way to ensure that analyses from the adverse reports submitted to Health Canada flows back out to those who need the information for action.
Currently, for ADRs, all domestic post-market reports are posted to the Health Canada website, via the Canada Vigilance Adverse Reaction Online Database. For MDIs, Health Canada is currently exploring the possibility of releasing data in line with the methods used for ADR reports. Health Canada indicated that it is interested in hearing about any implications that this proposal would have for GPIM. GPIM noted that it would have an impact on industry as the type of analyses being done is important to the association.
Letter of Terms and Conditions for Prescription Opioid-containing Products
GPIM indicated that a few of its members have recently received a letter from the Marketed Health Products Directorate (MHPD) requesting sponsors of opioid drug products to submit a Canadian-specific opioid targeted risk management plan (RMP) to Health Canada. GPIM expressed concern that this request will have a major negative impact on small generic businesses due to the heavy workload involved. GPIM made a number of suggestions as to how this workload could be distributed. The association noted that pharmacists and doctors are more likely to have the requested information.
Andrew Slot, Manager, and Kathy Soltys, Director of the Marketed Pharmaceuticals and Medical Devices Bureau, MHPD addressed this item. MHPD responded that the small business lens is being considered. The best way is for companies to work together but each will need to submit its own Risk Management Plan. GPIM indicated that small companies do not have the resources to manage studies and surveys and noted that it is difficult to share resources with other companies. MHPD responded that the Risk Management Plan is about quality and safety and a small plan is all that is required at this time. The sponsor should include any information that it has already collected and all of the activities that it is already doing, eg. labelling, etc. If a company has recently passed a pharmacovigilance audit, this information should also be included. Health Canada is willing to work with the sponsor. MHPD indicated that it recognizes that different companies have the same active ingredient. The timeline is mid-November 2018. MHPD indicated that if a sponsor is not promoting a product, then nothing needs to be done for that portion of the request.
GPIM suggested that Health Canada’s Opioid Response Team be involved in this issue. The association expressed concern that smaller companies that have Drug Identification Numbers (DINs) for opioids will take them off the market and this could lead to a shortage. Kathy Soltys, MHPD, indicated that a separate meeting could be arranged in order to make the timelines reasonable for everyone.
Update: MHPD contacted GPIM by e-mail on October 12, 2018 and the association responded that a further meeting on the topic is not needed at this time.
Self Care Framework
a) Plain Language Labelling (PLL) for Natural Health Products (NHPs)
On July 24th, 2018, a GPIM member received an e-mail from the Natural and Non-prescription Health Products Directorate (NNHPD), in which it was mentioned that Health Canada plans to introduce amendments to the Natural Health Products Regulations to improve the labelling of natural health products. GPIM expressed concern that these amendments will subject natural health product applicants to the same Plain Language Labelling requirements as Drug applicants. GPIM wanted to know about the approach to labelling allergens. NNHPD indicated that the same model used for the priority allergens on the food side would be followed, and that GPIM would receive additional information during the November 2018 technical session.
b) Convergence of Self Care Framework Implementation vs. Plain Language Labelling Engagement Calendar - GPIM expressed concern that Health Canada appears to be converging the implementation of the Self-Care Framework with Plain Language Labelling (PLL) engagement activities. According to the Engagement Calendar, selected revised Monographs will be sent out for consultation by stakeholders in parallel to the implementation of PLL components. GPIM requested an update on the proposed Self-Care Framework product classification so that stakeholders can develop strategies for appropriate Plain Language Labelling implementation.
c) Health Canada Product Classification and Certification in the Context of the Proposed Self Care Framework - GPIM indicated that agents in export countries are often asked to provide official letters issued by Health Canada confirming the classification of a given product. These agencies are now seeking more validation by Health Canada. The NHP/drug dichotomy creates confusion in export markets. Typically, the registration of a medicine in export countries requires a Certificate of Pharmaceutical Product (CPP), which cannot be obtained for a natural health product. GPIM proposed that a harmonized certification process be put in place, where all products, either registered or licensed, can obtain a CPP from Health Canada.
Manon Bombardier, Director General, Natural and Non-prescription Health Products Directorate (NNHPD) and Dino Covone, Director, Bureau of Consumer Health Products Modernization provided a presentation on the upcoming changes to labelling that industry can start to prepare for. GPIM discussed the impacts and concerns associated with the labelling requirements. See the Health Canada Self-Care Framework Website.
Natural and Non-prescription Health Products Directorate (NNHPD) - Quality Review of Modified Natural Health Products (NHPs)
GPIM noted that certain modified-release products (e.g. Potassium Chloride Extended Release Tablets) are now regulated as natural health products. The association expressed concern that, because of the absence of Chemistry, Manufacturing and Controls (CMC) data in Product Licence Applications (PLAs), products not meeting expected acceptance criteria may pose a health risk. GPIM suggested that modified-release products should be subject to, at minimum, a Class II Product Licence Application, and should include additional CMC data, such as a certificate of analysis of one pilot batch, supporting the proposed drug product specifications. GPIM requested that these proposals be integrated into the upcoming Self-Care Regulatory Framework.
Manon Bombardier, Director General, Natural and Non-prescription Health Products Directorate and Dino Covone, Director, Bureau of Consumer Health Products Modernization, NNHPD addressed this item. Health Canada indicated that it is aware of the issue and that adjustments have been made for safety and quality certificates. An audit is being undertaken which will examine how to improve quality. GPIM has been invited to a multilateral meeting in November 2018 to discuss the topic. NNHPD also indicated that changes to the quality model for natural health products are being considered for Phase 3 of the new framework.
There were no roundtable items.
Closing Remarks and Meeting Adjournment
Celia Lourenco, TPD, and Stéphane Lévesque, GPIM, thanked everyone for participating. Pierre Morin, GPIM, indicated that the association is looking forward to the next meeting.
The meeting was adjourned at 4:10 PM.
Original Signed by:
Senior Executive Director
Therapeutic Products Directorate
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