Association Bilateral Meeting - BIOTECanada - Meeting Minutes - 2011-11-16

Bilateral meeting between BIOTECanada and Health Canada

Wednesday, November 16, 2011
1:30 – 3:30pm
200 Tunney's Pasture Driveway, Ottawa, Ontario

Table of Contents

1.0 Attendees

BIOTECanada members

Present: John Cockhill (Meeting Chair), Graeme Fraser, Maria Klapka, lise Lotter, Cathy Lau, Jennifer Chan, Judith Mergl, Maria Perrotta, Vratislav Hadrava, Anita Hammer, Larry Colero, Lynn Buchanan, Rocelyn DelCarmen, Sandra Usik, Bin Huang

Government officials

Present: Angela Briginshaw (Meeting Chair), Agnes Klein, Cathy Parker, Georgette Roy, Greg Monsour, Kwasi Nyarko, Martin Nemec, Peter Ganz, Julie Wallace, Lateef Adewoye, Janice Lobo-Dale, Joanne Garrah, Natalie Gibb

Regrets: David K Lee, Lindsay Elmgren

2.0 Welcome and introductions

Angela Briginshaw, Acting Director General, Biologics and Genetic Therapies Directorate (BGTD), Health Products and Food Branch (HPFB) informed all participants of Elwyn Griffiths' recent retirement and the competitive staffing process that is underway to fill the position, and following the recent departure of Supriya Sharma, Barbara Sabourin has been appointed the Acting Director General, TPD. Another important management change in BGTD included the retirement of Alan Mortimer in June from his role as Director, Centre for Vaccines Evaluation. Lindsay Elmgren, who has joined the department from the Canadian Food Inspection Agency, has assumed the position of Director, Centre for Vaccines Evaluation.

On other matters, Angela Briginshaw highlighted the current economic environment and the challenges facing the Directorate and Government as a whole. The Branch is exploring opportunities to increase efficiencies and reduce expenditures while still meeting performance targets under the new cost recovery regulations. Performance targets continue to be met by BGTD, 100% of the time despite the ongoing challenge of an increasing workload.

Of note, the Branch will proceed with an active regulatory modernization agenda, and international collaboration and harmonization will remain as a high priority, and the Branch will continue to collaborate with key partners with a global market context. In addition, the Branch will continue to work closely with regulators in other countries and to provide training to countries with developing regulatory systems. The Branch recently hosted over 90 participants from other regulatory agencies at its third annual international regulatory forum.

Angela Briginshaw expressed BGTD's appreciation for the cooperation and input from BIOTECanada at these meetings.

John Cockhill, Chair, BIOTECanada provided a brief overview to link the agenda items for this bilateral meeting with those that were discussed at a planning session that took place in June 2011 with BIOTECanada members. At that planning session, key areas and priorities were discussed for the purpose of avoiding overlap with future agenda items for these bilateral meetings with BGTD. The four key priorities that were identified included new technologies with the example given of biomarkers and personalized medicines, global regulatory collaboration for the purpose of international harmonization, good regulatory review practices for increased efficiency and high quality of submissions, and the advancement of legislative and regulatory modernization initiatives for subsequent entry biologics, orphan drugs and product labelling.

3.0 Approval of the agenda

The agenda was accepted with changes to the order of two items in particular: the update on Subsequent Entry Biologics (SEBs) and the presentation on Drug Shortages were moved up in the agenda to accommodate participants who had to attend/present at other meetings.

4.0 Status update: SEBs

Presenters: Kwasi Nyarko, Office of Policy and International Affairs, Biologics and Genetic Therapies Directorate, Health Canada

BIOTECanada requested the update on SEBs and are interested in knowing if a new regulatory submission pathway will be formalized. Also, of interest to BIOTECanada are the European Medicines Agency (EMA) guidance on monoclonal antibodies and the agency's perspective on the extrapolation of indications.

BGTD informed BIOTECanada that the existing regulatory pathway for SEBs and the respective guidance document will continue to be used. BGTD will continue to evaluate international approaches and build on experience gained from submissions.

The issue of interchangeability, the safety concerns related to products being declared therapeutically equivalent, and the lack of a regulatory mechanism to deal with interchangeability was noted by L. Colero. BGTD (C. Parker) responded, that Health Canada does not take a position on interchangeability because the department does not have the authority to declare interchangeability. A. Klein also clarified that Health Canada only makes a declaration on bio-equivalence (not interchangeability or substitution).

BGTD is collaborating with the EMA on approaches to the regulation of biosimilars, but is not adopting EMA guidance documents on SEBs. On October 24, 2011, the EMA hosted a meeting on the development of a guidance document on the evaluation of biosimilar monoclonal antibodies and BGTD attended the meeting. EMA's position on the extrapolation of indications is similar to that of BGTD's; the approval of indications would be based on the evidence in the submission package, and all indications would not be automatically applied on the basis of a single bio-equivalence study. The EMA guidance document is expected to be finalized by the EMA in early 2012.

5.0 Standing item: regulatory performance

Presenter: Georgette Roy, Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate, Health Canada

BIOTECanada has asked BGTD to include this item as a standing agenda item at bilateral meetings.

Georgette Roy informed BIOTECanada that a quarterly summary report has been posted on the Health Canada website. A full report can be obtained upon request. In summary, BGTD continues to meet its performance targets and this is a result of an excellent working relationship amongst the regulatory team. The results of BGTD's 1st quarter's performance on regulatory decisions were: 50% of regulatory decisions were issued on the target date, with 10% issued three months ahead of the target date and 40% issued 1-3 days ahead of the target date.

Standing item: legislative and regulatory modernization

Presenter: Joanne Garrah, Office of Legislative and Regulatory Modernization, Health Products and Food Branch, Health Canada

BIOTECanada has asked BGTD to include this item as a standing agenda item at bilateral meetings.

Joanne Garrah indicated that although moving ahead on new legislation for health products and food is not a priority for the government as a whole, the Branch will develop a plan for moving forward with the modernization of its regulations. Key drivers for legislative and regulatory modernization are red tape reduction, regulatory cooperation, and the impact on Canadians.

From September to October, Branch staff were consulted on a roadmap for renewal of its regulations. Comments received from staff will be incorporated into a new version of the roadmap document and this will then be shared with stakeholders for an external consultation in late December 2011.

The Branch roadmap will be a 3-4 year plan and will describe the following: where the Branch is situated and the current environment; key challenges; changes the Branch would like to make across its product lines; and how the Branch expects to implement change. The Branch plan would also involve a phased approach considering the many regulatory packages that need to move forward. At the top of the deliverables list are food additives, plain language labeling, and orphan drugs for rare diseases. The timeframe for these deliverables is Spring 2012 or early Fall 2012. Although there is not yet a confirmed sequencing for future phases, BGTD noted that modernizing Division 8 of the existing regulations would include SEB regulation, and also confirmed that all policy work for Division 4 was complete.

6.0 Drug shortages and working group activities

Presenter: John Cockhill, Grifols, BIOTECanada John Cockhill informed BGTD that in response to a request from the Minister of Health, a working group of industry and professional associations had written to the Minister of Health in September 2011 with a proposed path forward for communicating information about drug shortages. Related correspondence and proposed direction of the working group were shared with meeting participants. It was indicated in the letter to the Minister of Health that on an interim basis two pre-existing websites will be used host information related to drug shortages. These sites will begin accepting drug shortage information from companies and/or industry associations in the coming weeks; in the longer term, a single national system for reporting shortages will be developed. In September 2011, Paul Glover, Assistant Deputy Minister, Health Products and Food Branch (HPFB) attended the Multi-stakeholder Working Group on Drug Shortages.

BIOTECanada was thanked for sharing the proposal with Health Canada. It was noted that this proposal is a good first step and it demonstrates transparency. It was also noted that a mechanism to clearly differentiate between drug discontinuation and drug shortages is necessary. It was recommended that the working group continue to meet and that meeting notices and information continue to be shared with Health Canada.

7.0 Status update: guidance documents

Presenter: Catherine Parker, Office of Policy and International Collaboration, Biologics and Genetic Therapies Directorate, Health Canada; Peter Ganz, Centre for Blood and Tissues Evaluation, Biologics and Genetic Therapies Directorate, Health Canada

Since the last bilateral meeting in March 2011, several guidance documents have been released and/or developed. Under the new cost recovery framework, three new guidance documents have been released: Fees for the Review of Drug Submissions and Applications, Drug Establishment Licenses and Drug Establishment Licensing Fees, and Fees for the Right to Sell Drugs. Two draft guidance documents are expected to be released in early 2012: Extraordinary Use of New Drugs and the revision to the guidance on the inclusion of women in clinical trials. Comment periods have closed on the following draft guidance documents: Preparations of Drug Submissions and Applications in the Common Technical Document Format and Regulatory Framework for Allergenic Substances of Biological Origin used for the Diagnostic or Treatment of Allergic Diseases. Comments will be accepted as notified on the following guidance documents: Patented Medicines (Notice of Compliance) Regulations, Post-Notice of Compliance (NOC) Changes: Framework Document, Post-Notice of Compliance (NOC) Changes: Quality Document, and the revised Guidance Document for Clinical Trial Sponsors – Clinical Trial Applications.

Also, in development is a draft guidance document to stakeholders on cellular therapies. Between April and June of 2011, meetings took place with academia, the Stem Cell Network and the Canadian Institute of Health Research to affirm the need for such Guidance. In Canada, oversight for stem cell therapies is provided by the Food and Drugs Act and Regulation, the Cell, Tissues and Organs for Human Transplantation Regulations, and the Assisted Human Reproduction Regulations. On the global stage, the World Health Organization (WHO) hosted a meeting on October 20, 2011, to discuss three items in particular: the development of a global approach to regulating cell therapies, standardizing cell banks, and the development of guidance documents. At the International Conference of Drug Regulatory Authorities (ICDRA), representatives from WHO, the International Conference on Harmonization (ICH) and the Asian-Pacific Economic Cooperation (APEC) discussed ways to coordinate approaches and initiatives amongst each other and member states so as not to duplicate efforts. In summary, BGTD is engaged with the aforementioned groups in the development of such Guidance to inform interested parties as to the specific clinical and chemistry and manufacturing requirements for submission of cell therapy applications.

Status update: pre-filing effectiveness project

Presenter: Agnes Klein, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, Biologics and Genetic Therapies Directorate, Health Canada

A pilot project will commence in December with the intended purpose of looking at ways to increase the effectiveness of submitting data requirements and to look at factors that will allow for a reasonable timeframe for a decision to be rendered. It was noted that disagreements between sponsor and Health Canada, while not common, are often related to the importance and power of clinical data. Divergence of opinions in science, especially in biological sciences, is a relatively common occurrence. There is no clear right or wrong in these instances, and the issues that are often at the root of such divergence include: the quality of the data, the organization of the file; files that are not aligned with Canadian Practice Guidelines.

It was noted by BGTD that the most common (and recommended) procedure to minimize disagreements and maximize positive outcomes for submissions, is to hold frequent meetings with industry (from Clinical Trial stage to NDS) and to have open and timely communications with the sponsor of the submission. Since a prospective evaluation of the effectiveness of such pre-filing activities would take years to produce results, BGTD is instead conducting a retrospective analysis on a sampling of major submissions (SNDS and NDS). Factors to be reviewed will likely include: Disposition on dossier; number of meetings held (advice given; advice followed; relationship to disposition; and other elements that might become evident); Consequences for Product Monographs; Relationship to standards of practice; etc. BIOTECanada members were asked to provide input on this project. Specifically: What data do you think Health Canada should look at? Do you have a specific submission that should be included in the evaluation?

Participants from BIOTECanada expressed their interest and support for this initiative, and committed to provide BGTD with suggestions for elements to be evaluated as part of the project, as well as a list of submissions that could be included. It was also suggested that it might be useful to pilot this same project at the Therapeutic Products Directorate.

Status update: clarifaxes and the regulatory review cycle

Presenter: Georgette Roy, Office of Regulatory Affairs, Biologics and Genetic Therapies Directorate, Health Canada

This was a follow-up item from the last BGTD-BIOTECanada bilateral meeting, where concern had been expressed by BIOTECanada over the use of Clarifaxes (i.e. lengthy lists of consolidated questions issued to sponsors just before the target decision date).

It was noted by BGTD that a clarifax is a tool used to assist the regulator in meeting the target date for rendering a decision on a submission application. However, BGTD is trying to minimize the number of clarifaxes issued within one month of the known target date. Instead, the questions are sometimes sent via email with a shorter timeline and a teleconference may be proposed, if needed between the regulatory review team and the manufacturer.

As assessment of 15 recent clarifaxes from BGTD was presented by G. Roy:

  • 5 were issued within one month of the NOC date,
  • 6 were issued within two days to three weeks prior to the NOC date, and
  • 4 were issued four to five months before the target date.

Details of the size or content of the clarifaxes were not available and it was agreed that this information could be discussed at the next bilateral meeting. In addition, a more comprehensive summary will be provided at the next bilateral meeting.

BIOTECanada suggested that use of clarifaxes be included as a data element to be evaluated in the pre-filing effectiveness project (see above). BGTD agreed to include a component on clarifaxes within this pilot project

Status update: YBPR template – summary of comments

Presenter: Martin Nemec, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, Biologics and Genetic Therapies Directorate, Health Canada

BIOTECanada requested an update on the YBPR template. Those who provided their comments on the template were interested in knowing how those comments will be incorporated.

Martin Nemec distributed copies of the compiled comments and agreed to share an electronic version of this same document. It was noted that Health Canada proposed to make changes to the template to limit the burden on Industry, and that Industry will have a certain degree of flexibility in determining how information is presented in the YBPR.

Based on the complexity of the template, the level of detail regarding certain comments, and the technical nature of the data elements included, J. Chan suggested that face-to-face meetings would provide the best forum for further discussions. There was agreement from BGTD on this proposal, and a commitment to arrange such a meeting.

Next steps in the process involve assessing all received comments and reformatting the template. Once the template has been redrafted, this information will be communicated with BIOTECanada, and the BGTD will identify a date for face-to-face discussions with industry to further refine the template.

Status update: survey results from the evaluations of the effectiveness of risk management tools

This agenda item was not presented due to the lack of time remaining in the meeting. The presenter agreed to provide a verbal update at the next bilateral meeting.

8.0 Use of foreign reviews

Presenter: Catherine Parker, Office of Policy and International Collaboration, Biologics and Genetic Therapies Directorate, Health Canada

A slide deck was presented. It was noted that all submission reviews consider foreign regulatory information. The Branch is continuing its efforts in formalizing its approach to the use of foreign reviews and initiated the pilot phase of its Use of Foreign Reviews framework in October, 2011. The pilot phase will continue until March 2013. A companion Guidance Document for Industry has been posted on the website and comments from industry on the Guidance Document will be accepted until the end of the pilot phase (March 2013).

9.0 DSEN-generated information and the drug review process

Presenter: Agnes Klein, Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics, Biologics and Genetic Therapies Directorate, Health Canada

A slide deck was presented. The level of transparency shared in the deck was acknowledged by BIOTECanada. A working group of the Drug Safety and Effectiveness Network (DSEN) was formed with a focus on ranking criteria. The intent of which is to avoid duplication with the CIHR collaborating centres. A. Klein indicated that she would recommend that DSEN avoid duplication of effort in commissioning studies by consulting with industry about any planned/ongoing studies prior to initiating proposals. It was also noted that BGTD would almost always go to a sponsor to discuss issues before approaching DSEN (the only possible exception being issues across a class of products).

Regulatory authorities do consider the information given to them by DSEN, and it was noted that this would be handled in the same way as any other Phase IV study.

10.0 Roundtable

Maria Klapka, Pfizer, BIOTECanada announced her retirement and thanked the participants for the experience that she had with this bilateral meeting program.

Graeme Fraser, BIOTECanada announced his departure from BIOTECanada to assume new challenges at Janssen Inc.

11.0 Next steps, closing remarks, and adjournment of meeting

Meetings will continue to take place twice annually. The next meeting is tentatively scheduled for March-April 2012.

A meeting summary report of this meeting will be developed and shared with members for comment and approval prior to it being posted on Health Canada's Internet site, in advance of the next meeting.

Meeting adjourned at 3:45 PM.

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