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Canadian Generic Pharmaceutical Association (CGPA): Final record of decisions June 7, 2022

Health Canada, Health Products and Food Branch (HPFB)
Bilateral Meeting Program
Virtual
June 7, 2022, 1:00 p.m. to 3:30 p.m.

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Participants and observers

Meeting minutes

Welcome and introductions

Bruce Randall, Senior Executive Director, Pharmaceutical Drugs Directorate (PDD) welcomed participants to the virtual bilateral meeting between the Canadian Generic Pharmaceutical Association (CGPA) and Health Canada and introduced Deirdre Cozier as CGPA co-chair. While the fall 2021 bilateral meeting was postposed due to the federal election, there has been a lot of engagement with CGPA over the last several months on key priorities.

The Therapeutic Products Directorate has been renamed to the Pharmaceutical Drugs Directorate (PDD). This is not a change in mandate but a reflection of the fact that, two years ago, the Medical Devices Bureau became a separate directorate. Therefore, the focus of PDD is now on pharmaceutical drugs. There have been some changes in senior management since the last bilateral meeting on June 3, 2021. Dr. John Patrick Stewart has recently retired from his role as Director General of the Pharmaceutical Drugs Directorate (PDD). Nancy Hamzawi has been appointed as Assistant Deputy Minister of the Health Products and Food Branch (HPFB) following the retirement of Pierre Sabourin.

COVID-19 has continued to be a major priority for Health Canada. PDD thanked CGPA's members for working collaboratively with Health Canada to respond to the pandemic, to help find solutions and to provide access to products to improve and maintain the health of Canadians. Health Canada has brought forward transition regulations that have allowed many of the flexibilities introduced for COVID-19 products to remain in place on a longer-term basis.

Deirdre Cozier, CGPA co-chair, thanked Health Canada for all of the flexibilities introduced during the pandemic and for helping the association through the last 2 years of disruptions with supply chains. CGPA announced that 2 new members, Mint Pharmaceuticals and Delmar Chemicals, have joined the association. Within CGPA, Deirdre Cozier has been appointed as the new chair of the Scientific Advisory Committee and Sonia Gallo of Sandoz has taken on the role of vice-chair. The association announced that its current Vice President of Scientific Affairs, Anne Wilkie, will be retiring and that Kristen Willemsen will be taking on the role.

Review of agenda

There were no changes to the agenda.

Approval of meeting notes / action items of the June 4, 2019 meeting

There were no action items from the June 3, 2021 meeting. The record of decisions was approved.

Nitrosamine contaminants

CGPA requested a discussion of the impact of the current nitrosamine requirements on the generic industry with regard to continuity of supply and patient safety. The association indicated that this is a top priority for industry and is seeking ways to mitigate the impact. CGPA commended Health Canada for all of its efforts during the pandemic to ensure that the products that are available on the Canadian market are safe.

Chris Rose, Director, Emma Spreekmeester, Associate Director, Gary Condran, Manager, Bureau of Pharmaceutical Sciences, PDD, and Christine Taillon, Health Product Compliance Directorate, Regulatory Operations and Enforcement Branch addressed this item. Nitrosamine impurities in pharmaceutical products continue to be a top priority for Health Canada. The department acknowledges the challenges posed to industry and international regulators regarding the assessment and control of these impurities. As nitrosamine impurities pose safety risks to Canadians, Health Canada expects market authorization holders (MAHs) to take steps to mitigate these risks, including conducting risk assessments, confirmatory testing, and filing changes to the market authorization where necessary. Health Canada is sensitive to the impact that drug shortages have on the health care system and industry. The department endeavors to minimize these negative impacts through various mechanisms, including expedited reviews and the use of interim limits higher than the established acceptable intake (AI) limits, where appropriate.

CGPA indicated that the expansion of scope from simple to complex nitrosamines has added enormous challenges for both regulators and industry in terms of resources and finances. The association noted that one of its biggest concerns with nitrosamines has been the completion dates for step 2 (confirmatory testing) and step 3 (changes to market authorization). A discussion regarding nitrosamines took place at a meeting held on May 31, 2022 between CGPA, company CEOs, and senior-level Health Canada representatives. CGPA had requested a de-linking of timelines for steps 2 and 3 along with an extension. CGPA appreciated that Health Canada indicated at the meeting that it is reviewing the timelines for completion of step 2 and Step 3. Health Canada is open to having a sector-specific meeting with the generic industry.

Health Canada has made efforts to provide transparency through a number of channels, including a nitrosamines webpage and an updated nitrosamines guidance document (posted in April 2022). CGPA indicated that the guidance contains valuable information such as:

CGPA requested that the timing of the review of risk assessments for drug submissions be expedited. Any major items noted during review are a significant issue as they require a full assessment and this has an impact on approval timelines. Health Canada indicated that while it strives to initiate reviews as early as possible, submission volume, submission complexities, and other organizational priorities create circumstances where it may not be possible to initiate the review of a nitrosamine risk assessment immediately after the submission has been filed. While PDD has received increased resources, it has also received a significantly higher number of submissions. PDD is working to address the increase in scope for the nitrosamine issue and the potential impact that this work will have.

Health Canada is actively working with international regulatory partners, through the Nitrosamines International Strategic Group (NISG) and Nitrosamines International Technical Working Group (NITWG), to share knowledge and harmonize, wherever possible, on scientific and regulatory aspects of the nitrosamine issue. An important aspect of this international collaboration involves discussing issues and suggestions raised by stakeholders, including those from CGPA and its members. PDD suggested that the Health and Environmental Sciences Institute (HESI) could be a potential avenue for addressing some of the ongoing challenges with nitrosamines and for CGPA to be engaged at the international level. Health Canada is a member of this new initiative and attended its first meeting in May 2022.

Update: CGPA has contacted HESI regarding generic industry representation.

Health Canada has been involved in discussions regarding molar versus mass at the international level. At this time, there is no consensus to move forward on this topic as there are several technical issues that need further discussion.

Update: CGPA has worked with its sister organization in the United States, the Association for Accessible Medicines (AAM), to align and submit its technical report on molar mass calculation to the US FDA.

Health Canada remains committed to collaborating with international partners, CGPA, its members, and other stakeholders to find solutions to address the complex challenges created by the nitrosamine impurity issues. Further discussions between CGPA and the Bureau of Pharmaceutical Sciences, PDD, on the topic will be held at the end of June 2022.

Pause the clock issues

CGPA thanked Health Canada for the 'pause the clock' initiative as it provides the opportunity to address questions that require more days than the allocated time to respond to a deficiency response. However, CGPA expressed concern that its members have been asked to extend their proposed timelines which negatively impacts target decision dates.

Denis Arsenault, Co-Lead, Pause the Clock, Manager-Policy Development, Office of Policy and International Collaboration, BRDD and Mona Walsh, Pause the Clock Working Group member, Regulatory Project Management Division, Office of Planning, Performance and Review Services, PDD addressed this item. As outlined in the guidance document on the management of drug submission and applications, sponsors can request an extension to respond to a clarification request if they are unable to respond to the request in time. When there is a pause, the target date is shifted to account for the amount of time the clock is paused. In so doing, Health Canada would not be penalized for that delay in terms of meeting its performance targets. Health Canada can only request a 'pause the clock' extension in order to seek advice from an external advisory committee regarding a submission. HPFB's Pause the Clock Working Group met on February 15, 2022 to ensure consistency across the branch and confirmed that pauses are to be tracked concurrently and not consecutively. PDD has been counting pauses concurrently.

PDD indicated that if 'pause the clock' is granted for 1 of the review streams such as chemistry, manufacturing and control (CMC), the guidance document clarifies that other review streams such as labelling and clinical can continue. However, the target date for review would be pushed out, so in that sense, the pause affects all of the streams that are in review at that time. PDD clarified that there is no specific time when it is too late to obtain a 'pause the clock' as each 1 is decided on a case by case basis.

Action: Mona Walsh, PDD to provide feedback to CGPA on the impact of pause the clock on risk management plan (RMP) approval.

Labelling challenges

CGPA indicated that it appreciates the practical advice it has received from the Labelling Division in PDD on many issues. However, CGPA indicated that it has received requests for labelling changes during the review of product monographs that it feels go beyond what the current policy requires. For example, sponsors have been receiving requests for inserts for bottles to align with the brand. CGPA noted that the majority of products of bottles packaging format are either:

CGPA indicated that creating inserts for bottle packaging may not add any significant value for patient safety when the patient will not receive the insert when the product is dispensed in the pharmacy.

Veronica Yip, Manager, Labelling Division, Bureau of Gastroenterology and Viral Diseases (BGIVD), PDD addressed this item. PDD responded that a package insert is not required to be included with every prescription drug according to the Food and Drug Regulations. The Labelling Division, PDD has met with CGPA, along with clinical colleagues from Health Canada and has heard CGPA's concerns regarding the bottle packaging format. If there are waivers that can be granted with regard to the inclusion of inserts, the Labelling Division will communicate those to the company. PDD indicated that it is having discussions with stakeholder groups as well as internal partners in order to leverage IT tools to ensure that Canadian labelling material is dispensed in pharmacies.

CGPA indicated that it is important for sponsors to know in advance if an insert will be required.

Action: PDD to update the list of all products that require a package insert that was previously shared with stakeholders and the National Association of Pharmacy Regulatory Authorities (NAPRA).

Update: Action completed.

PPD indicated that if sponsors need more time to verify any archived data to update the comparative bioavailability summary tables, the Labelling Division will work with the team to decide if that change needs to be included as part of the current submission or if it can be applied afterwards at the next filing. The Labelling Division is willing to coordinate with companies to find reasonable solutions.

CGPA expressed concern that the change of format to the 2020 template is causing submissions to escalate from generic-only submissions to labelling-only submissions. PDD responded that for products with risk management plans (RMPs), at the time of screening, the Regulatory Project Management Division (RPMD) will confirm with the Marketed Health Products Directorate (MHPD) whether the product and the labelling safety updates impact an existing RMP. If the proposed change does not impact the RMP, the submission can go through the generic-only fee line. If MHPD confirms there is a need for a RMP, the submission will go into the labelling-only review stream.

In order to discuss labelling challenges related to specific submissions, CGPA members can reach out to Veronica Yip (Veronica.Yip@hc-sc.gc.ca), Labelling Division, BGIVD, PDD or Sandra Alderdice (Sandra Alderdice@hc-sc.gc.ca) supervisor of the Bureau of Pharmaceutical Sciences, PDD labelling team. For any questions related to the labelling-only and administrative fee structures, CGPA can contact Mona Walsh (Mona.Walsh@hc-sc.gc.ca), Regulatory Project Management Division, PDD.

Public release of clinical trial information (PRCI)

CGPA recognized that the Health Canada PRCI team has provided support for its member companies who have received requests. However, CGPA added that PRCI has been an extensive investment as most of these reviews need to be outsourced.

Andre Molgat, Manager, Resource Management and Operations Directorate (RMOD) addressed this item. Regulatory amendments supporting the public release of clinical information (PRCI) came into effect in March 2019. Since then, Health Canada has published over 6.5 million pages of clinical data associated with 261 therapeutic products (230 drugs, 31 medical devices). The publication of clinical information occurs proactively, in accordance with PRCI guidance, and on request. Fifty percent of requests for clinical information have been received from academia. RMOD clarified that chemistry, manufacturing and controls (CMC) information from module 3 would never be requested through PRCI. However, composition information in 2.74 in the module 2 summary of the submission could be requested as this information is often found in the public domain. The scope of PRCI is defined in appendix A and B of the guidance document on public release of clinical information. According to the regulations, everything with respect to clinical trial ceases to be confidential business information and there are limited exceptions. Specific cases can be considered.

Full implementation of the PRCI initiative, which will include the proactive release of abbreviated new drug submissions (ANDSs), will occur in 2023. The stages of implementation were defined 5 years ago and were established through consultation and therefore cannot be delayed. In March 2022, PRCI moved into stage 3 and incorporated supplemental submissions. ANDSs are a small proportion of what is currently published. The expansion in 2023 broadens the initiative to make all clinical information and all regulatory submissions publically available for devices and drugs.

CGPA expressed concern about the proactive release of information through PRCI. The association indicated that it would like to better understand:

RMOD responded that all information published through PRCI is redacted for confidential business information and is subject to terms of use found in appendix H of the PRCI guidance. The terms of use prohibit the re-identification of trial subjects and personnel, as well as the commercial use of the disclosed data. Health Canada collects minimal information on who is requesting the information for privacy reasons. The regulatory amendments have defined that this information is no longer confidential and can therefore be made publically available.

Pharmaceutical Drugs Directorate (PDD) performance review

CGPA indicated that it is important for sponsors, and ultimately for the patients and payers, that generic medicines are reviewed and granted market authorization as quickly as possible. CGPA acknowledged the efforts made by PDD to date and the ability to achieve consistent performance standards for generic approvals over the last few years, particularly throughout the pandemic. The association requested an update on PDD's review performance.

Christine Leroux, Planning and Reporting Unit, Office of Planning, Performance and Review Services (OPPRS), PDD provided a presentation on:

PDD thanked CGPA members for participating in the pipeline initiative and indicated that it is helpful in order to align resources and plan workload. Pipeline data can be submitted at any time if there are significant changes. PDD thanked CGPA members for providing pipeline information as this is used regularly to forecast workload and revenue projections for planning purposes. PDD noted that some of the projections are very accurate.

CGPA indicated that market authorization holders (MAHs) have noted that Health Canada is issuing last minute requests close to the end of the 45 day screening period. Mona Walsh, Regulatory Project Management Division (RPMD), OPPRS, PDD addressed this item. RPMD manages and screens all non-administrative drug submissions filed to the Pharmaceutical Drugs Directorate's premarket review bureau. In accordance with the guidance document on the management of drug submissions and applications, there is a 45 day screening performance standard for most submissions types reviewed by BPS. RPMD ensures that screening performance targets are met almost consistently 100% of the time. While some screening decisions are issued towards the end of the screening period, due in part to increasing workload and complexity of submissions, they are still within the 45 day screening period.

CGPA indicated that Health Canada has been issuing notices of deficiency (NODs) close to the review target date without first sending any clarifaxes. PDD responded that it makes every effort to review submissions in a timely manner and it follows what is set out in the guidance document on the management of drug submissions and applications when it issues a clarifax. PDD indicated that if additional data, testing or supporting studies are required to prove quality, that would be communicated in a negative letter such as a notice of non-compliance (NON) or a NOD as opposed to a clarifax. PDD offered to look into any specific examples that CGPA provides. 'Pause the clock' is an option if a company needs an additional time to respond to a clarifax but it is not intended to replace a NON or a NOD.

Action: Gary Condran, Bureau of Pharmaceutical Sciences (BPS), PDD, to re-send CGPA the 2015 Bureau of Pharmaceutical Sciences guiding principles on communicating deficiency comments to submission sponsors as it contains a few examples of what would be communicated in a negative letter such as NON versus a clarifax.

Update: Action completed.

Action: Chris Rose, BPS, PDD to provide CGPA with statistics on filings related to resolving deficiencies in nitrosamine assessments.

Action: Chris Rose, PDD, to provide CGPA with a common list of quality deficiencies regarding drug submissions.

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 CGPA's assistance in identifying a few participants 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 September 2022. CGPA's contributions to this user testing will not only help improve the experience for its members, but also help to ensure health product safety for all people in Canada. If CGPA members are interested in participating, send an e-mail to: CVInterfaceFeedback.CommentairesInterfaceCV@hc-sc.gc.ca

Action: CGPA indicated that it would re-circulate the information to its members.

Update: Action completed.

Agile licensing for drugs

Debra Haltrecht, Director, Office of Legislative and Regulatory Modernization (OLRM), Policy, Planning and International Affairs Directorate (PPIAD) and Bruce Wozny, Senior Policy Officer, International and Regulatory Affairs, Marketed Health Products Directorate presented this item. The Agile Licensing for Drugs initiative is a key component of Health Canada's Regulatory Innovation Agenda. 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. 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.

Health Canada will continue to align risk management plan (RMP) requirements with international practices. The policy will focus on products that pose serious risks or significant uncertainties about their safety using a risk-based approach, which will avoid unnecessary burden to industry and to the regulator. The regulations and supporting guidance will clarify the types of risks and uncertainties that would trigger an RMP requirement. RMP requirements for individual products will continue to be determined on the basis of factors related to their safety profile. Health Canada's policy will be shared for comment along with the draft regulations which are expected to go to Canada Gazette, Part I in fall 2022.

PPIAD is seeking to add modifications to 2 pieces in division 1 of these draft regulations that it consulted on in fall 2021:

At Health Canada's request for costing data related to this measure, CGPA indicated that it was considering sending out Health Canada's costing questions around these 2 components. Health Canada indicated that it would appreciate receiving any data related to this survey.

GCPA requested an update on any progress towards making part or all of the innovator risk management plan (RMP) available to generic sponsors. MHPD responded that it is a priority to make RMPs consistently transparent and sponsors will be able to search online to find out whether there is an RMP and what it involves. Publishing RMPs involves considerations such as confidential business information. MHPD is trying to find the right balance because it understands that the generic industry needs a certain minimum of information.

Roundtable

Policy updates/questions

Rita Beregszaszy, Director, Policy, Science and International Programs (BPSIP), PDD provided this update. PDD provided CGPA with a detailed written response for a broad range of policy updates and regulatory files. CGPA indicated that the amendments to the Patented Medicines Notice of Compliance (PMNOC) Regulations, corresponding to the improving access to generics (IA2G) regulatory package, remain a significant concern for its members. CGPA has withdrawn its support for the IA2G regulatory package as long as it is coupled with the proposed amendments to the PM(NOC) regulations. PDD indicated that it has taken CGPA's comments and concerns into consideration and has had significant discussions with colleagues at Innovation, Science and Economic Development Canada (ISED). Both regulatory packages are currently slated to move forward in fall 2022. CGPA raised this topic at the meeting with the Deputy Minister of Health Canada, Stephen Lucas, during the first week of June 2022. The Associate Deputy Minister (ADM) of Health Canada's Health Product and Food Branch, Nancy Hamzawi, is planning to have a follow up conversation with colleagues at ISED.

PDD thanked CGPA for the thoughtful comments regarding the generic drugs Diagnostique. PDD has integrated as many of them as possible into the latest version of the document and will contact CGPA with next steps in the near future.

Closing remarks and adjournment

Bruce Randall, PDD co-chair, indicated that Health Canada appreciates these meetings and noted that Health Canada will continue to engage with CGPA. The next meeting between the Bureau of Pharmaceutical Sciences, PDD, and CGPA will take place at the end of June 2022. Deirdre Cozier, CGPA co-chair, indicated that the association values these collaborative meetings and would like to continue them in the future. Sonia Gallo, CGPA, thanked Health Canada for all of its work updating the various policy guidances.

Meeting adjourned at 3:30 p.m.

Next meeting

Fall 2022

Signed by:

Bruce Randall
Senior Executive Director
Pharmaceutical Drugs Directorate

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