Groupement provincial de l’industrie du médicament (GPIM): Final record of decisions April 21, 2022
Health Canada, Health Products and Food Branch (HPFB)
Bilateral Meeting Program
Virtual
April 21, 2022 1:00 p.m. to 2:45 p.m.
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Participants and observers
GPIM participants
Stéphane Lévesque, GPIM (Co-Chair)
Pierre Morin, GPIM
Ysabelle Foisy, Biomed Pharma Inc.
Antoine Poncy, Ethypharm Inc.
Clemence Odot, Ethypharm Inc.
Bruno Zauhar, Euro-Pharm International Canada Inc.
Danny Germain, Jamp Pharma Inc.
Françoise Moffette, Jamp Pharma Inc.
Sophie Vincent, Laboratoire Riva Inc.
Hind Ray-David, Mantra Pharma
Vincent Brault, Nora Pharma
Nathalie Toutant, Stéri-Med Pharma
Marie Christine-Régis, Stéri-Med Pharma Inc.
Nathalie Lévesque, Stéri-Med Pharma Inc.
Amalia Tasillo, Stéri-Med Pharma Inc.
Shira Lechter, Stéri-Med Pharma Inc.
Health Canada participants
John Patrick Stewart, Director General, Pharmaceutical Drugs Directorate (PDD), Co-chair
Mandy Collier, Acting Senior Executive Director, PDD
Scott Appleton, Bureau of Pharmaceutical Sciences (BPS), PDD
Denis Arsenault, Biologic and Radiopharmaceutical Drugs Directorate (BRDD)
Rita Beregszaszy, Bureau of Policy, Science and International Programs (BPSIP), PDD
Marc Berthiaume, Bureau of Medical Science (BMS), PDD
Isabel Brazeau, Regulatory Project Management Division (RPMD), PDD
Janet Brunette, Office of Planning, Performance and Review Services (OPPRS), PDD
Pamela Chu, OPPRS, PDD
David Duguay, Marketed Health Products Directorate (MHPD)
Émile Geoffroy, OPPRS, PDD
Colin Gunning, MHPD
Debra Haltrecht, Policy, Planning and International Affairs Directorate (PPIAD)
Melissa Hunt, BMORS, PDD
Magda Joseph, Regulatory Operations and Enforcement Branch (ROEB)
Marc Legrand, BPSIP, PDD
Susan Lum, BPS, PDD
Natasha Rastogi, BPSIP, PDD
Aara Sidenius, PPIAD
Craig Simon, MHPD
Taranum Singh, Bureau of Gastroenterology, Infection and Viral Diseases (BGIVD), PDD
Andrew Slot, Bureau of Cardiology, Allergy and Neurological Sciences (BCANS), PDD
Jeffrey Skene, BCANS, PDD
Evelyn Soo, BGIVD, PDD
Emma Spreekmeester, BPS, PDD
Donna Watt, OPPRS, PDD
Bruce Wozny, MHPD
Veronica Yip, BGIVD, PDD
Kristen Zorn, BPSIP, PDD
Observer
Sophie Gaudreault, BPS, PDD
Meeting minutes
Welcome and introductions
John Patrick Stewart, Director General, Pharmaceutical Drugs Directorate (PDD), welcomed participants to the virtual bilateral meeting between the Groupement provincial de l'industrie du médicament (GPIM) and Health Canada. He thanked participants for their flexibility with the continuing virtual format and for taking the time to participate in this meeting. COVID-19 has continued to be a major priority since the last bilateral meeting in April of 2021. As part of the government's response to the pandemic, Health Canada introduced innovative and agile regulatory measures through the use of Interim Orders. These measures expedited the regulatory review of COVID-19 health products without compromising safety, efficacy and quality standards. Following the expiry of many of the Interim Orders in the fall of 2021, Health Canada brought forward transition regulations that has allowed many of the flexibilities to remain in place on a longer-term basis.
The pandemic has highlighted the important role that small business plays in the therapeutic product supply chain in Canada, and Health Canada remains sensitive to the needs of these companies. The Department continues to offer small business fee reductions for human and veterinary drugs and medical devices. For senior management changes since the last bilateral meeting, Nancy Hamzawi has been appointed as Assistant Deputy Minister of the Health Products and Food Branch (HPFB).
GPIM noted that drug products are significantly more expensive to maintain in Canada than in other countries. For example, a pharmaceutical submission can be provided for almost all of the countries in Europe at the same time. GPIM added that Canada only represents one to two percent of the world economy and that is why not many pharmaceutical companies are interested in setting up businesses here. The association suggested that Health Canada could emphasize to the pan-Canadian Pharmaceutical Alliance (pCPA) that Canada's regulations are stricter than those of other countries. The association also indicated that the pCPA should aim for more of a fair and equitable price, not only for the population, but also for the industry. GPIM highlighted that it is important to support the Canadian pharmaceutical industry rather than relying on other countries. More effort should be placed into developing the Canadian market rather than importing products. The pandemic emphasized that transferring all production of pharmaceuticals overseas posed a number of challenges. GPIM noted that there are likely to be other situations that arise in the future and if Canada continues to look only at the price of products rather than considering the whole picture, it will harm its own interests.
GPIM indicated that while manufacturing costs continue to increase, the sale price of the products has not increased at the same pace. The association noted that it is important to make the distinction between generic drugs and innovator drugs whose prices are high. GPIM added that the prices for generic drugs have not increased for more than 25 years and have even decreased. No other industry has experienced the same constraints. GPIM indicated that it used to be profitable to make pharmaceuticals in Canada but this is not the case anymore.
Review of agenda
There were no changes to the agenda.
Approval of meeting notes of April 15, 2021 / Action items
The April 15, 2021 meeting notes were approved. The action item was completed. A response relating to the substitution of the Active Substance Master File was sent to GPIM by e-mail on April 16, 2021. GPIM indicated that it circulated the response to its members on April 19, 2021.
Agile licensing
Debra Haltrecht, Director, Office of Legislative and Regulatory Modernization (OLRM), Policy, Planning and International Affairs Directorate (PPIAD) presented this item. OLRM is a centre of expertise that works with the Directorates to develop their regulations. One of the key files that OLRM is currently working on as part of Health Canada's modernization agenda is the Agile Licensing for Drugs initiative. From July 31, 2021 to October 28, 2021, Health Canada consulted on proposed targeted amendments to the Food and Drug Regulations and Medical Devices Regulations through a Notice of Intent published in Canada Gazette, Part I. This Notice outlined the proposed changes to the requirements for drugs and medical devices, Risk Management Plans for drugs, drug submissions, and finally, the modernization of the regulations for biologics. As the first phase on this initiative, these proposed amendments are based on agile regulatory tools tested through the COVID-19 response and others aimed at addressing long-standing industry irritants.
OLRM has received a lot of feedback from various stakeholders who were, in general, in agreement with the intent of the proposed changes. However, it was clear that stakeholders wanted more detail, not only on the regulations but also on their implementation. Stakeholders also indicated that it is important to take the time to do this in a comprehensive way. OLRM has continued to analyze the feedback received from stakeholders in order to inform the development of the draft regulations and also considerations related to implementation. As a result of the feedback, the planned publication of the draft regulations has been postposed from Spring to the Fall of 2022 It is expected to be published in Canada Gazette, Part I, along with the draft guidance documents.
GPIM commended Health Canada's approach to agile licensing. The association believes that Canada Gazette, Part I provides Health Canada with the agility to broaden the regulations. OLRM indicated that it is the first dossier that it is looking at with respect to agility and there may be more of these types of files in the future. OLRM is interested in hearing about any flexibilities that can be put into place. PDD noted that, even with agile regulation, it is important to have clear criteria for drug approvals. There can be some flexibility with respect to the guidelines. Specific situations with files need to be looked at on a case by case basis. Regulations need to move forward to support innovation but it is necessary to have clear criteria in order to have a measure of consistency with drug approvals.
Pre-submission meetings and managing the quality of submissions
GPIM indicated that Health Canada reviewers spend time re-reviewing drug submissions that received a Notice of Non-compliance (NON) or a Notice of Deficiency (NOD) at first review. The association suggested that the best way to avoid this second review is to improve the quality of submissions submitted by the generic companies. GPIM indicated that the approval rate at first review for new drugs is around 70% and the association is interested in achieving a similar rate for generics. GPIM noted that, according to the statistics provided by PDD, the association's members are about 10% above the average while the large pharmaceutical companies are below these averages. GPIM suggested that Health Canada provide: training courses for companies; clarifications for the guidelines; and a Q&A of recurring questions for industry.
Emma Spreekmeester, Associate Director, Bureau of Pharmaceutical Sciences (BPS), PDD addressed this item. PDD agreed with GPIM's comment that poor submission quality takes a lot of resources and that it is important to improve this. BPS has been working on consolidating a list of common reasons for deficiencies to share with industry. The objective is to improve the quality of the submissions and increase the number of approvals for the first review. PDD indicated that it is in the process of renewing many guidance documents but this takes time and it needs to choose its priorities. PDD offered to meet with GPIM when the list of common problems with submissions is ready.
PDD reminded GPIM that industry can request a pre-submission meeting. PDD also provides sponsors with detailed written responses. This has the added benefit of reducing the waiting time for a meeting and also of providing the industry with a written record of Health Canada's recommendations. GPIM indicated that since PDD has a heavy workload, scheduling pre-submission meetings can be a challenge. The association added that sponsors who have difficulty with the requirements would benefit from pre-submission meetings. PDD responded that pre-submission meetings are voluntary. PDD noted that it includes details with any Notices of Deficiency. GPIM agreed that these are good steps towards improving the quality of submissions.
GPIM indicated that the timeframe is now more than 60 days to receive a written answer to questions. This delay results in some companies having to choose whether to wait for the response or submit the dossier and receive the response over the course of the review. PDD responded that the 60 day response time is an international standard. Even though the Bureau of Pharmaceutical Sciences, PDD receives over 800 requests each year, it aims to respond before 60 days. PDD suggested that if the questions submitted by industry were better researched, this would reduce response time.
PDD agreed with GPIM's point that there is an opportunity to improve the guidances and share a list of common problems with submissions. The main reason that submissions receive a NON or a NOD relates to the quality of the information provided by sponsors. There are many factors that determine the quality, including the quality of the Active Pharmaceutical Ingredient (API) in the Master File. PDD is looking at various different options to improve the situation. There is an opportunity to do activities, updates, guidance documents and more. Innovative tools such as podcasts and webinars might be a good way to provide clearer direction with regards to the important points of preparing a submission. PDD and GPIM can have discussions to determine the best way to ensure that the manufacturer understands the criteria so that a submission can succeed in receiving an approval.
Labelling of products under licensing agreements - PDD and the Natural and Non-prescription Health Products Directorate (NNHPD)
GPIM requested clarification regarding the issue that during administrative processing of submissions and applications for human drugs or disinfectants, licensees must produce all labels of products registered by licensors regardless of the drug format(s) actually sold by the licensee. The association remarked that this creates a significant workload for both industry and Health Canada reviewers. GPIM added that only two out of 20 labels may be used by the licensee when products are marketed so it would save time for Health Canada's drug submission reviewers if they did not have to review all 20 labels.
Veronica Yip, Manager, Labelling Division, Bureau of Gastroenterology, Infection and Viral Diseases, PDD thanked GPIM for the feedback regarding over-the-counter products. PDD clarified that, typically, Health Canada does not require labels for products that will not be marketed. There are flexibilities in the Guidance Document - Plain Language Labelling Regulations for Prescription Drugs that are designed to avoid this challenge. Choosing a 'Labelling Only' path will enable a sponsor to submit only the labels for products that will be marketed. If a product will not be marketed yet, a sponsor can provide the label at the time that is expected to be marketed. For any questions regarding the labelling of products, GPIM members can contact Veronica Yip (Veronica.Yip@hc-sc.gc.ca).
GPIM pointed out that the 'Labelling Only' path has a review time of about 6 months versus 45 days for the administrative processes and that is a significant difference in approval time. Submitting one or two labels would require additional review time and a different cost. PDD responded that while mock-up filings requirements to support proposed labelling changes are outlined in the Plain Language Labelling Regulations and its associated guidance documents, submission screening and/or review timelines are set out in the Management of Drug Submission and Application Guidance Document and the Cost-Recovery Framework. PDD indicated that any proposed changes to these existing guidances would need to be discussed with their leads in the Health Products and Food Branch. Post meeting note: As per the Management of Drugs Submissions and Applications, submissions filed as Labelling-only have a review time of 120 days (4 months).
GPIM expressed concern regarding the fact that labels that sponsors place on pharmaceutical bottles are often not provided to the patient. For example, when there is compounding, medications are often placed into bottles that do not have labels. Another example is that leaflets for medication bottles may be thrown out by pharmacists. GPIM added that 50% of the time, pharmacists cover up the original labels on bottles with their own labels. GPIM asked whether there is a way to align with the way things are done in the different pharmacies across the different provinces.
PDD responded that the management of pharmacist behaviour is a provincial authority. PDD does not have the authority to require what pharmacists do in their practice. PDD's responsibility is to verify that the label has the necessary information for patients to use the product properly and to ensure that the risk is well communicated. PDD is implementing various electronic tools to assist with the distribution of important information. In this way, Part III of the Product Monograph (Prescribing/Patient Medication Information) could be made available to patients and also pharmacists.
Drug submissions relying on third-party data
GPIM requested information as to whether sponsors were able to meet the clinical safety and efficacy requirements outlined in Health Canada's guidance document Drug Submissions Based on Third Party Data (Literature and Market Experience). The association asked Health Canada to provide the number of drug submissions that were based on third party data and also the number of products approved under this guideline.
Dr. Marc Berthiaume, Director, Bureau of Medical Sciences, PDD addressed this item. Health Canada follows and implements the Food and Drugs Act, and the Food and Drug Regulations. The guidance document "Drug Submissions Relying on Third-Party Data (Literature and Market Experience)" is applicable under these two authorities. Drug sponsors may seek market authorization for drug products based on literature and market experience. As required by the Food and Drug Regulations, before a new drug is authorized for sale in Canada, the sponsor is responsible for providing the necessary scientific evidence to allow drug regulatory decision making. PDD provided GPIM with the statistics of Drug Submissions Relying on Third-Party Data (SRTD) over the last five years (2017 to 2021). The success rate of SRTDs is very high, with 85% positive decisions over the last five years, and only 2021 did not have a 100% success rate. PDD noted that the SRTD pathway is not appropriate for all products. PDD outlined the reasons why some of the 2021 SRTD did not receive a Notice of Compliance. There was only one instance over the last five years where there was a bioequivalence issue that led to a negative decision. The statistics indicate that this is not something that is preventing this pathway from being useful.
GPIM expressed surprise at the high level of approvals for SRTDs. The association requested information on how to bridge the gap between clinical trial data and products its members are interested in marketing. For literature-based submissions, GPIM indicated that it is a challenge to find the product, the lot, and the name. The association indicated that, in one case, it contacted the authors of an article so that they could specify that it is the same product as the one to be marketed in Canada but they could not get any information. PDD responded that it is only involved in a fraction of these types of submissions. PDD added that it may be possible to obtain the information without contacting the authors. For example, studies that have been reviewed by other regulatory agencies such as the FDA may be posted online and may include the name of the product. PDD emphasized that it is important to follow the regulatory requirements. There must be a link between the product being studied and the product to be marketed, otherwise it does not respect the spirit of the regulation.
PDD indicated that Health Canada is currently working on policy and regulatory initiatives which would open flexible pathways, including the use of information from foreign regulators. Health Canada already has various collaborative agreements with other regulatory agencies. At this point, there is nothing in the short term but there are other approaches that could be considered. PDD understands the challenges that GPIM members have with bridging products that are in use in other jurisdictions to the Canadian market. While Health Canada must follow the regulatory requirements, it is also exploring other regulatory avenues and other ways of using the data for products that are marketed internationally.
Manufacturing Active Pharmaceutical Ingredients (API) in Canada: An unmissable opportunity
GPIM noted that the current pandemic has highlighted the fragility of drug supply chains as the vast majority of active pharmaceutical ingredients and finished products come from other countries. The association suggested that building Canadian capacity to produce active pharmaceutical ingredients to meet the needs of its pharmaceutical industry will contribute significantly to public safety. GPIM proposed a way to build this capacity in Canada. A project to manufacture active pharmaceutical ingredients by a chemical process called continuous flow synthesis is currently under development in Quebec. Reportedly, it would be able to produce an identical version of any known active pharmaceutical ingredient. The "Médicaments Québec" project that was initially led by the Director of the Department of Chemistry at the University of Montreal, will receive a grant from the Government of Quebec. The project will continue under the leadership of the University of Montreal in collaboration with the faculties of medicine in other universities in Quebec and the participation of drug manufacturers. Continuous flow synthesis has received active funding from the Natural Sciences and Engineering Research Council of Canada and the Canada Foundation for Innovation.
GPIM proposed that Health Canada designate a team of its scientists to the "Médicaments Québec" continuous flow synthesis project to support sponsors and guide them in regulatory matters, good manufacturing practices and the preparation of Drug Master Files (DMFs). The association added that this could reduce the need for Canada to import pharmaceuticals from other countries.
Emma Spreekmeester, Associate Director, Bureau of Pharmaceutical Sciences, PDD and Magda Joseph, Regional Supervisor, Good Manufacturing Practices (GMP) Inspection-East, Health Product Compliance Directorate, Regulatory Operations and Enforcement Branch (ROEB) addressed this item. Health Canada indicated that it is aware of continuous flow technology which is an innovative way to manufacture ingredients. This type of manufacturing has the potential to have a transformative effect on the drug production industry. Health Canada commended the scientific innovation being led by the University of Montreal. The Department recognizes the importance of this work for the field of drug development and for Canadians. Unfortunately, Health Canada does not have the resources to designate a team of scientists to support the project. However, PDD and Health Canada's Health Product Compliance Directorate (HPCD), Regulatory Operations and Regions Branch would be available to provide guidance on the regulatory requirements. Health Canada is looking forward to receiving more information regarding this type of innovation.
With regards to regulatory guidance on the continuous flow chemistry, a draft ICH Q13 Guidance: Continuous Manufacturing of Drug Substances and Drug Products Step 2 document (2021), is available and reflective of global regulatory expectations (reference section 4 which outlines regulatory considerations and Annex I which provides further details for an example of continuous manufacturing of drug substances for chemical entities) as well as an overview presentation. Health Canada participated in the drafting of this guidance and is in the process of assessing stakeholder comments to the published Step 2 draft. For specific technical questions, subject matter experts within Health Canada may be contacted through the Bureau of Pharmaceutical Sciences at: bpsenquiries@hc-sc.gc.ca.
ROEB noted that the GUI-104 Good manufacturing practices for active pharmaceutical ingredients guide which interprets the GMP requirements in the Food and Drug Regulations is also available. The Health Product Compliance Directorate, Regulatory Operations and Enforcement Branch has been engaged on multiple projects funded by the Strategic Innovation Fund, or other innovation funding. Recognizing the need for a strong bio-manufacturing industry in Canada, the program has a team of Good Manufacturing Practices experts that can provide a "white glove service" which consists of early engagement and compliance promotion sessions with the regulated party. As Heath Canada is a regulator, the advice is that it provides is general. GPIM was encouraged to contact Magda Joseph (Magda.Joseph@hc-sc.gc.ca) in ROEB for any questions related to Good Manufacturing Practices.
In order to avoid a shortage of raw materials in times of crises, GPIM proposed that certain companies or universities be pre-approved to produce active raw materials that are critical for manufacturers. GPIM indicated that it is important to prepare for the future and to have a pre-determined system that ensures that drugs could be produced immediately when needed. GPIM noted that Canada is a small market compared to the global market and companies who sell raw materials would sell to countries with the most people who are willing to pay a higher price. The association added that this happened with masks, protective gear, etc. in 2020 and 2021 and continues today. Canada needs to have a parallel measure that could be put into place quickly.
PDD responded that even if the pandemic has not yet ended, internal discussions about lessons learned during the pandemic have begun. There have been a lot of regulatory flexibilities and policies that have been advanced to deal with shortages of critical medicines. PDD indicated that it would consider the possibility of having pre-approval of some companies to manufacture certain types of products. Health Canada noted that this should be a strategic conversation between the Health Products and Food Branch, the Regulatory Operations and Enforcement Branch and the Public Health Agency of Canada (PHAC). Since PHAC has managed many aspects of the pandemic, it would be valuable to obtain their opinion on this topic.
Roundtable
Canada vigilance adverse reaction online database
Craig Simon, A/Director, Health Products Surveillance and Epidemiology Bureau, Marketed Health Products Directorate (MHPD) presented this item. Health Canada is developing a new interactive, web-based tool (termed a "dashboard") for this database. The dashboard is intended to make the data easier to search and displays results in a more user-friendly format, while maintaining the functionality of the existing database. MHPD requested GPIM's assistance to perform user testing of this dashboard in order to ensure that it meets the needs of stakeholders. Participation would involve performing 3-5 tasks and should take less than 30 minutes. MHPD will provide additional information prior to the start of user testing which is anticipated to begin in May 2022. If GPIM members are interested in participating, they can send an e-mail to the following Health Canada address: CVInterfaceFeedback.CommentairesInterfaceCV@hc-sc.gc.ca
Mandatory reporting by hospitals
Craig Simon, MHPD, presented this item. Health Canada is in the process of developing a second dashboard based on data from mandatory reporting of serious adverse drug reactions and medical device incidents by hospitals. This data is currently communicated to Canadian hospitals by means of MHPD's regular bulletin and also through outreach activities. Among the statistics that are presented are: the number of reports submitted over time; reports submitted by hospital size and geographic location; the severity of the reactions; and the main suspected product groups reported. MHPD's goal is to publish the report in early summer 2022 and will communicate the plans for this dashboard to hospitals through its regular newsletter.
Policy updates/questions
Rita Beregszaszy, Director, Policy, Science and International Programs (BPSIP), PDD provided this update. PDD provided GPIM with a detailed written response for policy updates and asked if the association had any questions. PDD recently had the opportunity to discuss some of Health Canada's modernization plans with Stéphane Lévesque and Pierre Morin of GPIM. GPIM indicated that its members may have questions once they have a chance to absorb the information.
Closing remarks and meeting adjournment
Dr. Stewart announced that he would be retiring in mid-May 2022 and that this would be his last bilateral meeting with GPIM. He thanked GPIM for their contribution and noted that he has found the exchange between GPIM and Health Canada to be very informative and useful. Stéphane Lévesque, GPIM Co-chair, thanked Dr. Stewart for his guidance and help through the years.
The meeting was adjourned at 2:45 PM.
Next meeting
Fall 2022
Signed by:
Mandy Collier
A/Senior Executive Director
Pharmaceutical Products Directorate
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