Working towards better adapted policies - NSNR(O)

The context

More than minimally manipulated, vector-modified human cells have been triggering an extensive environmental review by Environment and Climate Control Canada (ECCC) under the New Substances Notification Regulations for Organisms (NSNR(O)) in addition to that reviewed by Health Canada within the clinical trial application (CTA). Vector-modified cells were not developed yet when these regulation were created, thus explaining why the regulatory framework is not adapted to the current reality and the concerns of the cell manufacturing community. Furthermore, the two processes are not aligned as the CTA has a 30-day review period while the ECCC environmental review has a 120-day review period upon proper completion of a Schedule 1 form. It is our view that human cells, especially those used in autologous therapies (one’s own cells) should never trigger review as new organisms, since by scientific definition human cells cannot be an organism on their own, nor may they be incorporated into a different species and thrive. 

Why it matters

• 100% of the Cell Manufacturing Facilities (CMFs) that are part of the CellCAN Network are impacted by this.
• Where multiple options exist, industry sponsors are choosing to invest in jurisdictions where such delays and excessive redundancies do not exist (e.g. Japan).
• These overbearing regulations cause resource wasting.
• Ultimately, this could delay patient access to novel cell-based therapies in Canada.

What we are doing

In collaboration with BIOTECanada, CellCAN organized a workshop at the Biologics and Genetics Therapeutic Directorate (BGTD) at Health Canada in March 2018 to discuss overdue changes to the NSNR(O). Senior-level decision makers were invited to represent various stakeholders from the cell and gene therapy manufacturing sector, including academic and industrial CMFs and biotech and biopharma companies as a united voice, and actionable outcomes were generated from the meeting. Fifteen government   stakeholders from the BGTD, NSN (HC), Science Policy Branch (HC), Innovation, Science and Economic Development (ISED), ECCC and Public Health Agency of Canada were represented (31 participants in all). Recommendations (see below) that could be implemented at the level of the Act, Regulations, Guidelines and Policy (from most difficult change requiring legislative modifications to the most easily adaptable and rapid change implementation) were proposed to the government stakeholders.

Following the workshop, an article (see full reference at the bottom of this page) was published in Frontiers in Medicine in March 2019: Recommendations for Regulating the Environmental Risk of Shedding for Gene Therapy and Oncolytic viruses in Canada¹. We invite you to click the link and read the full article for a complete overview and understanding of the concerns at hand. The following main recommendations (cited from article) were the focus of the workshop:

1) A regulatory policy to clarify Canadian Environmental Protection Act (CEPA)'s definition of “living organism.” This is currently defined as “a substance that is an animate product of biotechnology.” A regulatory policy could potentially exempt “human cells touched by biotechnology for use in human medicinal products” from this definition to clarify any unintended overreach of CEPA, particularly as it applies to non-genetically modified cell therapies.
2) A guidance document to better interpret NSNR(O) Schedule 1 requirements by CTA/NDS sponsors to satisfy the environmental review process.
3) An amendment at the level of regulations, to the NSNR (O) to create a deferment to postpone environmental assessment of micro-organisms used in the manufacturing during investigational clinical trials (pre-market stage). The regulations would apply at the time of market authorization evaluation and review, when sufficient clinical data on vector shedding has been collected, as part of the investigational clinical trials.
4) Amendment to Schedule 4 of the CEPA to include the Food and Drugs Act and Regulations (Food and Drugs Act /FDR) as an exclusion to the application of CEPA. This would remove the current dual regulation of cell and gene therapies by both CEPA and Food and Drugs Act /FDR.

If adopted these recommendations will significantly streamline the current regulatory burden and harmonize environmental assessment requirements with other jurisdictions.

The results to date

Government stakeholders recognized the tremendous burden that the NSNR(O) place on sponsors and agreed that it was never the intent of the Act to capture human cells (especially for autologous therapies), but these technologies did not exist when the Canadian Environmental Protection Act was passed in 1999.

Members of the BGTD, NSN and ECCC agreed that requiring full environmental assessment at initial CTA filing was a Policy that could be changed so it is required only at the full market authorization stage (after later phase clinical trial) when substantial safety data has been collected, rather than at the beginning when no such data has been generated (see recommendation #3). Following the workshop, this change had the most traction and both stakeholder groups have taken steps to explore the adoption, implementation, and dissemination of this policy change.

Recommendation #2 also had a good grasp and steps towards the creation of a guidance document to better interpret NSNR(O) Schedule 1 requirements by CTA/NDS sponsors to satisfy the environmental review process are being a taken.

Finally, policies are currently under review to explore how the ECCC environmental review period could be aligned with the one of CTA as well as reduce from 120 days to 30 days.

Next steps

A second workshop is planned to be held in 2019. Further discussions focusing on the 4 recommendations will constitute the core of the agenda as well as establishing the path to implementing them/reduce the burden currently existing with the current state of the regulation/legislation.

References