Final Record of Decisions June 5, 2018 Meeting: Canadian Generic Pharmaceutical Association (CGPA)
Health Canada - Health Products and Food Branch (HPFB)
Bilateral Meeting Program
1600 Scott Street, Holland Cross, Tower B, 5th Floor, Boardroom 2048, Ottawa, Ontario
June 5, 2018
(1:00 p.m. to 3:40 p.m.)
Len Arsenault, Sandoz (Co-Chair)
Duane Terrill, Apotex
Sandra D’Agostino-Ferlisi, Apotex
Swamy Subramanian, Apotex
Suresh Arvapalli, Marcan Pharmaceuticals
Joanne Manley, Mylan
Gaetano Gallo, Odan Laboratories
Marie-Eve Latendresse, Omega Laboratories
Deirdre Cozier, Pharmascience
Sonia Gallo, Sandoz Canada
Fong Chan, Sterimax
Lul Ogba-Ghebriel, Taro
Mathi Mathivanan, Teva
Alpa Jani, Teva
Anne Wilkie, CGPA
Jody Cox, CGPA
Health Canada Participants
John Patrick Stewart, Director General, Therapeutic Products Directorate (TPD), Co-chair
Bruce Randall, Director, Bureau of Pharmaceutical Sciences (BPS), TPD, Co-chair
Marilena Bassi, Bureau of Policy, Science and International Programs (BPSIP), TPD
Janet Brunette, Office of Planning, Performance and Review Services (OPPRS), TPD
Michèle Chadwick, Biologics and Genetic Therapies Directorate (BGTD)
Heather Cherry, Regulatory Project Management Division, OPPRS, TPD
Mandy Collier, OPPRS, TPD
Gary Condran, BPS, TPD
Émile Geoffroy, OPPRS, TPD
Karen Johns, Bureau of Medical Sciences (BMS), TPD
Tanja Kalajdzic, Marketed Health Products Directorate (MHPD)
Christine Leroux, OPPRS, TPD
Rania Mouchantaf, MHPD
Jennifer Reid, OPPRS, TPD
Elizabeth Smith-Kawasaki, BPSIP, TPD
Kathy Soltys, MHPD
Johanne Veenstra, BGTD
Veronica Yip, Bureau of Gastroenterology, Infection and Viral Diseases, TPD
Donna Watt, OPPRS, TPD
Welcome and Introductions
Bruce Randall, Director, Bureau of Pharmaceutical Sciences, Therapeutic Product Directorate (TPD) welcomed everyone to the meeting. He thanked CGPA members for providing valuable feedback on the many recent and important consultations in the branch. It continues to be an active time in TPD with a high number of key ministerial and branch priorities underway, including: Regulatory Review of Drugs and Devices (R2D2); 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. A roundtable of introductions followed.
There have been a number of organizational changes within TPD since the last bilateral meeting in November 2017. Celia Lourenco has become the Senior Executive Director; Melissa Hunt is the Interim Director of the Bureau of Metabolism, Oncology, and Reproductive Sciences (BMORS) Craig Simon has become Associate Director of 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); Kristen Zorn has become an Associate Director in the Bureau of Cardiology, Allergy and Neurological Sciences (BCANS); Stéphanie Parra has become the manager of the New Drugs Quality Division (NDQD) within the Bureau of Pharmaceutical Sciences (BPS). Krishnan Tirunellai, BPS, TPD, will be retiring in July 2018.
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. Rhonda Kropp has become the Director General of the Marketed Health Products Directorate (MHPD).
Len Arsenault, CGPA Co-Chair, indicated that the association appreciates the opportunity to have these bilateral meetings. It is a busy time for the generics industry. CGPA also appreciates all of the initiatives that Health Canada is working on and noted that all of its main issues are on this agenda. John Patrick Stewart, TPD Director General, joined the meeting shortly afterwards.
Review of Agenda
There were no changes to the agenda.
Approval of Meeting Notes / Action Items of the November 30, 2017 Meeting
All action items from the November 30, 2017 meeting were completed.
A question was raised by CGPA in regard to Roundtable Item c): Proposed Modification to Bioequivalence Standards for Multiphasic Modified-Release Drug Products: During the review of the Record of Decisions from the November 30, 2017 meeting, CGPA requested a revision to the summary relating to the discussion on Bioequivalence standards for Multiphasic Modified Release Drug Products. CGPA requested that the Record of Decisions be revised to state that the demonstration of the multiphasic release profile should be reflected in the Product Monograph for the innovator product as understood from the previous meeting, rather than it being one of the options (as per the current wording).
Update: Since the requested revision to the Record of Decisions for the November 30, 2017 meeting, there has been further discussion regarding this topic between BPS and CGPA. In order to gain clarity, CGPA is encouraged to request a copy of Health Canada’s responses to stakeholder comments obtained during the comment period (July 27, 2017- September 25, 2017) from the Bureau of Policy, Science and International Programs at the following e-mail address: email@example.com
Pause the Clock
Michèle Chadwick, Co-Lead, Pause the Clock, Regulatory Review of Drugs and Devices, Biologics and Genetic Therapies Directorate (BGTD) presented this item. A pause the clock mechanism is proposed as part of the new penalty model to ensure that Health Canada is only accountable for the time it spends on a particular submission/application. The implementation date for Pause the Clock is anticipated to be April 1, 2019.
BGTD requested feedback from CGPA on the proposed pause the clock triggers for drugs, which include: requests for extensions to respond to a Clarifax; Clarifaxes occurring simultaneously in all review streams; and expert Advisory Panel advice sought. CGPA noted that the triggers would assume that the sponsor is given the full 15 days to respond. CGPA requested clarification on why two days are given to respond to a Clarifax when it is possible to have 15 days. TPD indicated that the priority is to keep the file moving so less time is given for minor clarifications. BGTD indicated that the clock would formally pause but that work could continue in other review streams while waiting for the Clarifax response. However, when there is a Clarifax issued for all review streams, it would not be possible to continue the review until a response is received.
BGTD noted that the first pause the clock trigger is requested by the sponsor. CGPA requested information on whether 1) a pause would be less likely to result in proceeding to Review 2; 2) if extended, would that increase the number of Clarifaxes up front; and 3) would it be more efficient to channel a submission through Pause the Clock than receive a Notice of Compliance (NON). BGTD indicated that it would consider these questions.
BGTD requested feedback from CGPA as to whether the pause clock period should have a minimum and maximum time and whether there should be a maximum number of triggers per submission/application. CGPA responded that there does not need to be a minimum. CGPA recommended that the use of ‘pause the clock’ and associated timelines become part of the performance metrics tracked by TPD going forward.
After discussion with CGPA, considering the need for predictability, BGTD asked if CGPA would prefer if Health Canada would not be able to ask for the clock to be stopped in the last 45 days of review but industry could make the request. CGPA appreciated this suggestion as it could encourage earlier adoption of the mechanism but also expressed that there may be situations where they would want to pause to clock for an extension close to the end of the review. The association noted that it appreciated that Health Canada is taking everything into consideration and keeping an open mind. BGTD indicated that there will be formal consultations online and that it is looking forward to receiving further input from CGPA on the design of the Pause the Clock process.
Federal Action on Opioids and Risk Management Plans (RMPs)
As part of the Federal Action on Opioids, Regulations Amending the Food and Drug Regulations (Opioids) were published in Canada Gazette, Part II on May 2, 2018. These regulations require a mandatory warning sticker be applied on containers and an information handout be provided to patients for all dispensed (prescription) opioids as well as requiring mandatory risk management plans for all opioids. CGPA indicated that it recently met with Pierre Sabourin, ADM of the Health Products and Food Branch, and agreed with the need for actions to address the current opioid crisis but noted that the implementation of mandatory Risk Management Plans (RMPs) is a major concern for companies that market opioid products. CGPA noted that it is critical to have clear guidance with respect to Risk Management Plans.
Léo Bouthillier, Director, Bureau of Cardiology, Allergy and Respiratory Sciences (BCANS), TPD, Kathy Soltys, Director, Marketed Pharmaceuticals and Medical Devices Bureau, and Tanja Kalajdzic, Scientific Evaluator, from the Marketed Health Products Directorate presented this item. A panel was convened in March 2017 to update the labelling of opioids. The panel provided recommendations that included the threshold dose, limiting the quantity of opioids for acute pain, no more than seven days, warnings for pregnant women and patients with a history of substance abuse. TPD indicated that only guidance is provided rather than a formal guideline so that there is some prescribing flexibility.
CGPA was provided with the proposed opioid warning sticker and the patient information handout. The regulations that were passed relating to the sticker and the handout will be mandatory by the end of December 2018. With regard to the labelling update of opioids, generic companies have started receiving advisement letters to update their Product Monograph (PM) according to the update of the innovator product. At this time, Health Canada is on track to complete the labelling update in November 2018.
A phased implementation of the Canadian Specific Opioid targeted Risk Management Plan (CSO-tRMP) is scheduled to start June 2018. The first consultation period will last 90 days. Risk Management Plans (RMPs) will be required to be submitted 180 days after the Notice of Intent to Issue Terms and Conditions first goes out. The focus will be on high priority opioids (eg. fentanyl, hydrocodone, hydromorphone, methadone, morphine, normethadone, opium, oxycodone, and oxymorphone). CGPA asked how RMPs for the same molecule but submitted by different companies would be reviewed. Health Canada does not expect that they would be 100% identical but encourages companies with the same opioid ingredient to work together.
Health Canada is looking to industry to show leadership in working to solve the opioid problem. CGPA responded that its members are working collaboratively to find solutions. TPD asked CGPA if it has any relations with Provincial/Territorial governments. CGPA indicated that it does through the pan-Canadian Pharmaceutical Alliance (pCPA) but that the scope might be different. At CGPA’s request, a Marketed Health Products Directorate/TPD/CGPA meeting on opioids and Risk Management Plans (RMPs) took place following this meeting.
TPD Review Performance
Christine Leroux, Office of Planning, Performance and Review Services and Bruce Randall, Director, Bureau of Pharmaceutical Sciences, TPD addressed this item. A Cost Recovery Performance Summary for FY 2017-18; TPD on-time performance for fiscal year 2017-18; a Performance on Time Action Plan; TPD workload for fiscal year to 2018-19 (as of March 31, 2018); received vs. forecasted submissions; and a pipeline data summary was provided to CGPA. CGPA indicated that it would be helpful for planning purposes to receive information on Review 2 more than once a year as this has an impact on the second metric, Time to Notice of Compliance (NOC).
TPD noted that it is in the process of increasing staffing, improving processes and tools in order to improve performance and noted that with increased funding comes increased expectations to meet performance on time. TPD requested information on CGPA’s anticipated submission volume for Abbreviated New Drug Submissions (ANDSs). CGPA responded that it continues to evaluate barriers to entry, lack of regulatory pathways for complex products and the requirements to bring products to market vs. the diminishing reward. CGPA is hoping that R2D2 will provide more clarity for complex products as they sometimes have higher drivers and there is a lack of clear guidance.
CGPA suggested that Health Canada leverage existing guidances from other jurisdictions to develop regulatory pathways for complex products and encourage companies to bring their products to Canada. TPD indicated that it is open to receiving information from CGPA about changes it has noticed in other jurisdictions. CGPA noted that in order to increase access to generic products, it is important to have access to the reference product. CGPA is currently having discussions with the Competition Bureau at Innovation, Science and Economic Development Canada on the topic and is pursuing regulatory amendments to support access.
Cannabis and Prescription Drugs
CGPA requested information on what is required to have a cannabis containing product approved as a prescription drug. Marilena Bassi, Director, Bureau of Policy, Science and International Programs (BPSIP), TPD, addressed this item. Under the existing legislative framework, cannabis is recognized as both a controlled substance as well as a drug. Accordingly, the Controlled Drugs and Substances Act and the Food and Drugs Act work together to establish strict parameters for the sale of drugs containing cannabis.
Upon removal of cannabis from the Controlled Drugs and Substances Act and enactment of the proposed Cannabis Act, drug companies will be required to comply with applicable provisions of the Food and Drugs Act and the Cannabis Act. This means that Health Canada will continue to maintain a scientific, evidence-based approach for the oversight of health products containing or for use with cannabis to ensure that they are safe, effective, and of high quality. Health Canada will continue to accept new applications through the current approval process for prescription drugs containing cannabis, medical devices used for consuming cannabis for medical/therapeutic purposes, natural health products and veterinary health products that contain permitted cannabis parts and no more than 10 ppm tetrahydrocannabinol (THC).
For packaging and labelling, it is proposed that prescription drugs with cannabis only be subject to the requirements of the Food and Drugs Act and its regulations. With respect to any potential new non-prescription drugs and natural health products containing cannabis, it is anticipated that there will be a 75 day consultation in fall 2018 on the appropriate level of regulatory oversight and evidence requirements for those products.
The Senate will be voting on the Cannabis Act on June 7, 2018 and after it has been passed, it will go back to the House of Commons. Health Canada is working internally on a guidance document regarding health products containing cannabis or for use with cannabis. The guidance will be published at the same time as the regulations to support the coming-into-force of the Cannabis Act. TPD indicated that it will be doing a targeted mailout to stakeholders which will include a link to a single window cannabis information page. The single window manages questions about submissions and applications for health products containing or for use with cannabis.
Policy and Guidance Update
Marilena Bassi, Director, Bureau of Policy, Science and International Programs, TPD addressed this item. A written policy and guidance document update was provided to CGPA in advance of the meeting. CGPA noted that a discussion may be needed on foreign risk communications. The association requested information on bioequivalence of proportional formulations. TPD indicated that there are internal discussions but the topic might be better suited for an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) meeting.
Regulatory Review of Drugs and Devices (R2D2)
CGPA requested an update on the scope and status of the 15 projects that were identified under the regulatory review initiative, with specific emphasis and details on those projects pertaining to generic reviews, market access and regulatory convergence, e.g. foreign reviews, pre-submission advice, priority review pathways, special access program, healthcare system needs. Michèle Chadwick, Lead, Regulatory Review of Drugs and Devices Initiative, Biologics and Genetic Therapies Directorate provided a presentation for this item.
CGPA requested information on whether there is a place for generics in the expansion of priority review pathway. TPD indicated that it is looking at the use of foreign reviews and use of third party data. If a product needed by the health care system has significant international post-market experience, identical/similar indications and chemistry and manufacturing (C&M), is approved in at least two respected jurisdictions, then Health Canada could examine the possibility of relying on a foreign decisions to issue a Health Canada authorization. Health Canada is also looking at how there can be more support for the generic industry to be able to provide more affordable products to the public.
CGPA questioned where the line will be drawn in terms of using foreign reviews based on health care system needs. TPD indicated that it does not want to build pathways that disincentivize products to come to Canada early.
CGPA indicated that R2D2 is a positive initiative that is helpful to Canadians, but it does not adequately address priorities of the generic industry such as pathways for complex products and access to Canadian Reference Products (CRPs). The association is looking for opportunities to work together to develop pathways for complex products. CGPA noted that it is an ongoing challenge to obtain the reference standard in order to do comparative testing. The association indicated that it would appreciate assistance in obtaining access to reference drugs sooner. CGPA suggested that maybe a different approach for generics would be more helpful. If the reference product cannot be obtained, the company cannot make a drug submission. This blocks the development of products where the patent is near to expiry or already expired. The association indicated that a path is needed where these products can be made available.
CGPA requested information on whether there is an oversight forum to connect everything such as the use of foreign review in the Special Access Programme (SAP). TPD responded that there have been planning sessions on how to align the various projects in the 15 pillars. The R2D2 website is updated on a monthly basis.
International Regulatory Collaboration and Convergence
CGPA requested an update on Health Canada’s participation in international activities as they relate to the generic industry. Gary Condran, Associate Director, Bureau of Pharmaceutical Sciences, TPD addressed this item.
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
There has not been an ICH meeting since the last bilateral meeting on November 30, 2017. An ICH meeting is currently underway in Kobe, Japan. A draft reflection paper prepared by the United States Food and Drug Administration (FDA) titled, “FDA Reflection on Further Opportunities for Regulatory Harmonization of Standards for Generic Drugs” was recently shared with the ICH Assembly. The paper discusses the potential to harmonize generic standards and might facilitate developments and approval of generic drugs. CGPA is a member of the International Generic and Biosimilar Association (IGBA), which is a member of ICH. The IGBA would have access to this reflection paper.
International Pharmaceutical Regulators Programme (IPRP)
Following the consolidation of the International Generic Drug Regulators Programme (IGDRP) and the International Pharmaceutical Regulators Forum (IPRF), the International Pharmaceutical Regulators Programme (IPRP) was officially launched on January 1, 2018. An update was provided on the transition to the new entity, including the continued attention and work on issues of interest related to the regulation of generic products (e.g., with maintaining the IPRP Bioequivalence Working Group for Generics and the Quality Working Group for Generics). Feedback from the generics industry included how to continue the momentum from the International Generic Drug Regulators Programme (IGDRP). The next steps for the IPRP Workplan is to identify topics for harmonization at ICH.
IPRP has a Working Group for information on drug master files that is trying to collect non-proprietary administrative information for Active Pharmaceutical Ingredients (APIs) to see if there is any commonality in terms of filing submissions. This information could be useful for drug shortages. There will be an 18-month consent-based pilot to have administrative information reflected in a database.
Australia-Canada-Singapore-Switzerland (ACSS) Consortium - Generic Medicines Working Group:
The working group has continued to refine the operational procedures for the Generic Medicines Work Sharing Trial (GMWST), including broadening the scope of dosage forms that would be considered for the work sharing model. Since the last bi-lateral meeting with CGPA, the four Agencies of the ACSS Consortium have posted to their respective websites a notice and supporting documents inviting expressions of interest for applications for the pilot. See Health Products International Acivities.
The next step is that targeted letters will be sent to individual companies seeking potential candidates for a work-sharing trial. The group is looking at different mechanisms to enable the use of foreign assessment reports for generics.
Regulatory Cooperation Council (RCC)
Health Canada is continuing to work with the United States FDA to hold joint public consultation meetings on International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines currently under development. A United States-Canada RCC Stakeholder Event was also planned for early June in Washington D.C. to explore new regulatory work items and discuss industry proposals for inclusion under existing workplans. This event has recently been postponed and is tentatively rescheduled for Fall 2018. In terms of biowavers, the regulatory requirements for proportional formulations may be a potential topic for ICH harmonization. TPD noted that ICH is interested in looking at bioequivalence standards. Health Canada is working more closely with the European Medicines Agency (EMA). The Executive Director of the EMA, Guido Rasi, may be speaking at the HPFB Stakeholder Session that will be held on June 27, 2018. CGPA indicated that the exploratory Health Canada/EMA discussions sound promising and congratulated TPD for taking the initiative.
a) Schedule B - CGPA requested that Schedule B be a discussion topic at the next Bureau of Pharmaceutical Sciences/CGPA bilat.
b) Global Model - TPD requested information as to whether the global model is still working for CGPA. CGPA responded that it does not think in terms of geography, but rather in terms of core markets. The European Union is considered to be a core market. The number of submissions made to Canada by generic companies has been dropping. CGPA noted that Canadian specific development is a challenge and one member indicated that if it cannot rely on validation from other markets, it will not launch a product. CGPA added that if there are requests for specific changes in Canada that are different than other markets, it may put the global submission at risk. The association noted that if there is a product recall in Canada, e.g. because of tighter specifications, it puts the global product at risk. CGPA indicated that companies are unlikely to develop complex products for Canada only. A CGPA member indicated that while Canada is currently its biggest market, it is rethinking its strategy. The association added that these are challenging times for the generics industry and it hopes that, under R2D2, there will be some adjustment in how the regulatory framework works. CGPA added that it appreciated the quick feedback it received from TPD for biostudies and designs and that quick responses from Health Canada help its decision making process.
Closing Remarks and Adjournment
Co-chairs John Patrick Stewart, TPD, and Len Arsenault, CGPA thanked everyone for participating in the meeting. TPD indicated that it values the frank and open engagement.
Meeting adjourned at 3:40 p.m.
Original signed by:
John Patrick Stewart
Therapeutic Products Directorate
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