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Modernize NSNR

Mr. Michel Lortie
Manager, ECCC
Via email:  substances@ec.gc.ca

Re: Review of the New Substances Notification Regulations (Organisms): Proposed Approach to Modernize NSNR (Organisms). Stakeholder Engagement Document (Pre-Canada Gazette, Part I Consultation)

BIOTECanada supports the Government’s initiatives to establish a world class regulatory modernization initiative referenced by Canada’s Biomanufacturing and Life Sciences Strategy, and welcomes this early opportunity to provide the department with initial perspectives.

An effective regulatory environment is an essential driver for the introduction, acceleration, and adoption of biotechnology innovation as well as a protector of Canadian patients.  The speed at which our governments responded to the COVID-19 pandemic, whether to create and launch relief programs, simplify and shorten procurement processes or expedite clinical trials, shows us that we can and must aim higher. A high performing regulatory system is predictable, efficient, consistent and transparent, so as not to present barriers to business investment, innovation and ultimately, economic growth and values improved outcomes that benefits Canadians. A competitive regulatory system will accelerate the growth of Canadian companies and facilitate the attraction of innovation to Canada for Canadian patients. Canada’s ambition to be a world leading regulator is key, particularly as new game-changing technologies are developed, manufactured in Canada, and deployed such as mRNA, cell and gene therapies. In this context, industry strongly supports government’s regulatory ambition and corresponding work to modernize regulatory oversight, including the NSNR. Canada must implement modernized regulatory processes, aligned globally and harmonized to attract technology to Canada to ensure Canada establishes regulatory capacity to draw the next generation of technologies into use for and by Canadians.

As a guiding principle, Canada’s regulatory approach for NSNR should closely align with the US. Health Canada has been taking a leading role in many international collaboration and harmonization efforts with like-minded regulators, with requirements being similar to those implemented by other trusted regulatory authorities. The same approach should be applied to NSNR for the environmental risk evaluation of new innovative biologic therapies and vaccines.

BIOTECanada supports the Government’s proposals to exempt some human cell therapies in clinical use and commercial use as medicines in the Engagement Paper.  However, there are certain proposals in the NSNR which are out of step with the approaches used by other regulators, importantly including the US FDA, and will undermine the industry’s global competitiveness if implemented unamended.

In this context, the Canadian NSNR approach should be amended to more closely align with the US FDA regulatory approach as follows:

  1. The proposed “tiered” approach of environmental evaluation and review timelines in Section 4.2.1 of the present Engagement Paper should align with the United States where such described instances are exempt from environmental assessment.
  2. The use of microorganisms in a contained facility and/or clinical setting is subject to the controls set out in the Canadian Biosafety Standard and overseen by the Public Health Agency of Canada (PHAC).  An additional requirement for an environmental assessment of microorganisms presents an unnecessary additional layer of oversight which will add no additional environmental protection but will create additional work and uncertainty for biomanufacturing and clinical trials in Canada.  This disparity in regulatory requirements is a competitive disadvantage for Canada such that biomedical companies will choose to conduct clinical trials elsewhere, and /or source their product from manufacturers in other more efficient regulatory environments such as the US.  
  3. CEPA’s New Substances Notification Regulations (Organisms) (SOR/2005-248) (NRNR(O)) pose an additional regulatory burden on manufacturing using organisms by requiring manufacturers to conduct an environmental assessment of microorganisms.  Importantly, the United States’ Environmental Protection Agency does not require environmental assessment of microorganisms if they comply with the National Institutes of Health (NIH) Guidelines for Research Involving Recombinant DNA molecules and are not defined as intergeneric microorganisms.1 The industry strongly recommends Canada’s regulatory framework be more aligned with that used by the US EPA to enable biomanufacturing and clinical trials in Canada.
  4. In the US for a Biologics License Application (BLA), if the substance comprises naturally occurring elements but has a sequence different from that of a naturally occurring substance, and when approval of the application does not significantly alter the concentration or distribution of the substance, its metabolites or degradation products in the environment, the need for an environmental assessment is categorically excluded because the products would not significantly affect the quality of the environment.2 In Canada, any investigational product regulated under the Food and Drug Regulations Division 5 is reviewed for benefit: risk and safety as part of a Clinical Trial Application (CTA). Use in the specific clinical trial is evaluated by Health Canada. As a risk assessment is already performed in the context of the clinical trial, there should be no additional risk assessments for unmodified living organisms for clinical trials.  Development of provisions for review of biologics solely by Health Canada without an additional review by ECCC is highly encouraged, given the amendments made to the FD&A in 2023 expanding the regulation making authority for FDA biologics. Regardless of proposed streamlining of requirements and shortened timelines, any additional review by ECCC results in additional regulatory burden.

(An addendum is attached to this letter with additional specific recommendations for consideration.)

Recommendations:

  • Canada’s regulatory system should be aligned with other jurisdictions (particularly the US EPA). 
  • The Canadian government should take steps to reduce regulatory burden and overlap of the Canadian Environmental Protection Act (CEPA) and related regulations to facilitate the use of microorganisms in clinical trials and within contained biomanufacturing facilities.

The industry recognizes and supports the important role of Health Canada and Environment and Climate Control Canada in the health of Canadians and the environment.  Accordingly, the industry has indicated it is prepared to work collaboratively and constructively with the government on its health and environment policy agendas.   Ultimately, real and effective consultation and dialogue will be critical to the health, economic and social objectives that the government has identified for the advancement of advanced biotechnology products.

Sincerely,
Andrew Casey
President & CEO

Reference:

  1. United States Environmental Protection Agency. 2012. Microbial Products of Biotechnology – Summary of Regulations under the Toxic Substances Control Act. July 10, 2019. < https://www.epa.gov/sites/production/files/2015-08/documents/biotech_fact_sheet.pdf>
  2. https://www.fda.gov/media/91425/download

Additional Specific Recommendations

  • Section 4.3.3 Streamlining the regulatory scope for unmodified organisms

“Notifiers of unmodified micro-organisms that have previously been classified as low risk to public health (i.e. Species classified as Risk Group 1 on Public Health Agency of Canada’s ePathogen database), that are isolated from the Canadian environment, and that are notified for manufacture and use within a contained facility without release would be able to request waivers from certain information requirements under the NSNR (Organisms), or else indicate that some information requirements are “not applicable”.”

–    This is a step in the right direction, as RG1 organisms pose low risk to the public. However, for clarity, wording should be revised to: “…that are isolated from the Canadian environment, and that are notified for manufacture and use within a contained facility without release”. Do the organisms need to actually be isolated from the Canadian environment, or are they organisms that could be found in the Canadian environment? 

– To note, PHAC does not regulate the use of RG1 organisms.

“NS Program would need to clearly define terminology surrounding modified, unmodified, and naturally occurring in the context of the regulations, and provide guidance for applications of biotechnology that result in organisms that are substantially the same as organisms produced through traditional breeding practices”

–    Providing clear terminology and guidance on modified and unmodified organisms would be helpful, as there are many modified RG1 organisms (that remain RG1) that would pose very little risk/the same risk to the environment as their wildtype counterparts.

The proposed approach on page 14 seems reasonable; however, consultation on the development of key terms and guidance for modified, unmodified organisms is encouraged.

  • Section 4.3.4 Addressing Regulatory Gaps and Overlaps with Human Pathogens and Toxins Act and Regulations (HPTA)/(HPTR)

The program is proposing to: 

– Develop policy or guidance to provide insight to the MOU in place between PHAC and the NS Program to provide regulated parties with a better understanding of how information is shared between the two groups.

– Develop policy or guidance to indicate that Risk Group (RG) 2, RG3 and RG4 human and animal pathogens cannot be notified under the NSNR (Organisms) under Schedules inherently involving environmental release (i.e. Schedules 3 & 4) if the release of the micro-organism would contravene the conditions of a license issued by PHAC under the HPTA/HPTR. If these organisms are used in contained facilities with a HPTA license, notifiers may request for waiver for certain information requirements such as Schedule 2 paragraph 2 (c) provided a copy of PHAC license and description of containment level specified in the PHAC license is provided.

Overall, the proposed approach is reasonable, i.e., working with PHAC and harmonize the approach to regulating RG2, 3 and 4 microorganisms and toxins. However, it is recommended to consult with stakeholder groups on the draft MOU, policy and guidance.

  • Section 4.3.7 Definition of Research & Development (R&D) Organisms

Based on the aforementioned considerations the program proposes to:

–    Amend the NSNR (Organisms) to change the definition of R&D organism to include control organisms used in a research context (e.g., QA/QC organisms used in research, organisms used as experimental control, experimental models for studying human disease).

–    Amend the NSNR (Organisms) guidelines to clarify what activities are included in the amended definition and what activities fall outside the scope of the R&D exemption.

For the clarification of activities that are included/exempt, more details would be helpful. For example, at what point during the use of an organism does the NS program apply (e.g., if an organism is used for manufacturing, but is inactivated prior to removal from the contained facility)? It would be helpful to have more guidance on this.