Discussion paper for consultation - Review of Part 6 of the Canadian Environmental Protection Act, 1999 (CEPA) and the New Substances Notification Regulations (Organisms) [NSNR (Organisms)]

1. Purpose of the pre-consultation

The purpose of this pre-consultation is for the New Substances (NS) program to engage with stakeholders on the New Substance Notification Regulations (Organisms) (NSNR (Organisms)). The NSNR (Organisms) are established under the Canadian Environmental Protection Act, 1999 (CEPA), Part 6 (“Animate Products of Biotechnology”). The NS program is administered by Environment and Climate Change Canada (ECCC) and Health Canada (HC). Both departments welcome your participation in this pre-consultation session.

To this end, this discussion paper has been developed to:

• provide context on biotechnology and the regulation of animate products of biotechnology (that is living organisms) in Canada and internationally
• provide information on the 3 major themes/drivers for this regulatory review, namely:
  • improving openness and transparency
  • responding to advances in science and technology
  • reducing inefficiencies identified by the NS program, stakeholders and others
• seek feedback from stakeholders on the issues highlighted in the discussion document

The feedback the NS program receives will contribute to analyzing issues and to identify options for addressing identified issues. Ultimately, the NS program will use feedback to provide recommendations to resolve the identified issues. It will use regulatory amendments and policy options as required. However, if the analysis of issues shows that improving authorities under CEPA Part 6 is necessary, these can be addressed with legislative changes later.

2. Background

2.1 Biotechnology in Canada

Biotechnology is a powerful enabling technology with applications in many sectors such as health, agriculture, aquaculture and the environment. CEPA defines biotechnology as "the application of science and engineering in the direct or indirect use of living organisms or parts or products of living organisms in their natural or modified forms.”

Humans have used biotechnology for thousands of years. Examples include the making of cheese and bread and fermenting wine and beer. These examples involve micro-organisms like bacteria or fungi. Over time, we have also domesticated and selectively bred certain animals and plants to meet environmental and human needs. The invention of vaccines and antibiotics harnessed the power of biotechnology. Medical innovation in the field of biotechnology continues to be important to human health (as the NS program further elaborates in section 4.2.1). Examples include the development of SARS-CoV-2 vaccines during the COVID-19 pandemic. They also include personalized medicine and cell/gene therapies to treat genetic diseases and cancer. Examples of other commercially important sectors of biotechnology include food, feed, probiotics, cosmetics, biofuel production, microbial-based cleaning products, bioplastics, and cleaning contaminated sites. Many applications of biotechnology will make use of ‘wild’ (naturally occurring) organisms. However, efficiency may be increased by amplifying certain traits (for example, enzyme production) or suppressing others (for example, virulence genes).

Emerging applications of biotechnology include:

• genetic control of pests with gene drive technology, which increases the chance of passing a gene or genes from parents to offspring
• cellular agriculture (that is production of animal-sourced foods from cell cultures)
• genome-editing technologies to fight climate change, such as drought resistant, high-yield, and long-storage crops
• nano-biotechnology for therapeutic applications (for example nanocapsules, protein nanotubes)

The Canadian Biotechnology Strategy (CBS) has been in place since 1998. The CBS describes the broad objectives and principles for supporting regulation and research in biotechnology at the federal level. CBS objectives include promoting effective and efficient regulations. These must ensure Canadians have confidence and access to beneficial, safe, and effective biotechnology-based products and services. The CBS also describes the importance of promoting awareness and maintaining excellence in Canada’s biotechnology regulatory system. For example, by continuing to enforce high standards for protecting health, safety and the environment. This aspect of the CBS is also reflected in ECCC’s mandate to build a cleaner, greener future for Canadians. This could include leveraging Canada’s biotechnology sector to deal with climate-related challenges and create clean jobs.

In July 2021, the Minister of Innovation, Science and Industry and the Minister of Health published Canada’s biomanufacturing and life sciences strategy (BLSS). The BLSS outlines a five-pillar approach to grow Canada's capacity to develop and produce vaccines with better capabilities across the value chain. This is in order to improve pandemic readiness and sector growth. One priority area of the BLSS is to enable innovation by ensuring world class regulations, to promote made-in-Canada solutions to global challenges. The review of CEPA Part 6 and the NSNR (Organisms) is an opportunity for the federal government to help implement the CBS and BLSS. It also serves to better respond to advances in biotechnology.

2.2 Regulatory framework for animate products of biotechnology in Canada

In Canada, there are many Acts and regulations that regulate animate products of biotechnology (that is living organisms). Some of these Acts and regulations also have provisions for assessing the risk posed by living organisms to the environment.

One of the key pieces of legislation is CEPA, which is an integral part of the federal government’s pollution prevention strategy. CEPA is a “substance-based”^{Footnote 1} regime, and Part 6 of CEPA applies to animate products of biotechnology (living organisms). CEPA requires persons wishing to manufacture or import a new^{Footnote 2} living organism in Canada to notify the federal government of their intent to do so. This allows the federal government to conduct an assessment prior to the beginning of any activity.

These notification and assessment requirements apply to all new living organisms, unless they are manufactured or imported for a use regulated under an Act or regulation listed in Schedule 4 of CEPA. Substances regulated under Acts or regulations listed in Schedule 4 of CEPA are exempt from notification and assessment requirements under Part 6 of CEPA and the NSNR (Organisms). In this way, Part 6 of CEPA and the NSNR (Organisms) act as a safety net. This is because they regulate living organisms and activities not covered by other federal legislation listed in Schedule 4 of CEPA.

The Food & Drugs Act (F&DA), Human Pathogens and Toxins Act (HPTA), and Plant Protection Act^{Footnote 3} (PPA) are examples of Acts that do not appear on Schedule 4 of CEPA. New living organisms that fall under these Acts also require notification and assessment under CEPA and the NSNR (Organisms). This is to help protect human health and the environment.

Canadian Federal Acts and Regulations pertaining to new living organisms or animate products of biotechnology include:

• Federal Acts and Regulations listed under Schedule 4 of CEPA:
  • Feeds Act, Seeds Act, Fertilizers Act, and Health of Animals Act and their respective Regulations are regulated by the Canadian Food Inspection Agency (CFIA)
  • Pest Control Products Act and Regulations are regulated by the Pest Management Regulatory Agency (PMRA)
• Federal Acts and Regulations not listed under Schedule 4 with risk assessments conducted under CEPA/NSNR (Organisms) include:
  • the Food and Drugs Act and Regulations, which cover novel foods, drugs, medical devices, natural health products, and cosmetics
  • the Human Pathogens and Toxins Act and Regulations, which manage human pathogens and toxins
  • the Plant Protection Act and Regulations, which oversee plant pathogens
  • other legislation for living organisms whose use is not regulated by an Act or regulation on Schedule 4 of CEPA

2.3 NSNR (Organisms) under CEPA

The NSNR (Organisms) sets the information and data that a person must submit to ECCC. This must be done before manufacturing or importing a new living organism in Canada. This allows ECCC and HC to determine if it is harmful or potentially harmful to the environment and/or to human health, respectively^{Footnote 4}. The NSNR (Organisms) requires information on the organism and the environment where it is intended to be used or released. This information is then used in the NSNR (Organisms) risk assessment process.

The information and data required under the NSNR (Organisms) include the organism’s biological and ecological properties, such as its potential for:

• pathogenicity or toxin production
• ability to shed, survive, reproduce or replicate in a given environment
• impact on biodiversity
• any modifications made to the organism

In addition, information on the intended and potential uses along with other exposure information are required. The NSNR (Organisms) impose fewer information and data reporting requirements for organisms used in ways that are less likely to result in exposure to humans and/or the environment. For example, micro-organisms used in contained facilities. Organisms that are used in ways that are more likely to result in exposure are subject to more stringent information and data requirements. For example, micro-organisms used outside of contained facilities and released into the environment.

2.3.1 Types of living organisms (animate products of biotechnology) covered under CEPA/NSNR (Organisms)

New living organisms can be micro-organisms, such as bacteria, fungi, yeasts, protozoa, algae, viruses, or eukaryotic cell culture. They can also be organisms other than micro-organisms (that is higher organisms). This includes animals and plants that are not native to Canada or that are genetically modified.

CEPA and the NSNR (Organisms) use a “substance-based” approach. This means all new living organisms are subject to oversight irrespective of the technology used to develop them. This includes selection, mating, mutation, recombinant nucleic acids or gene-drives^{Footnote 5}.

2.3.2 Living organisms on the Domestic Substances List

The Domestic Substances List (DSL) is the sole basis to determine whether a living organism is considered new under CEPA and the NSNR (Organisms). Organisms on the DSL do not require notification.

Several micro-organisms were added to the DSL because they were already in use between 1984 and 1986. Through policy, certain living organisms are not considered ‘new’ by the NS program even if they are not listed on the DSL. These organisms are therefore not subject to notification requirements. More information is available on the guidelines for the notification and testing of New Substances: Organisms. These organisms include:

• common domestic animals and livestock species, and their offspring produced through traditional breeding^{Footnote 6}, artificial insemination or surrogate hosting
• animals kept in public zoos, aquariums and circuses, and their offspring produced through traditional breeding, artificial insemination or surrogate hosting
• wild animals that naturally live in Canada, and their offspring produced through traditional breeding^{Footnote 7}, artificial insemination or surrogate hosting

New living organisms, both micro-organisms and higher organisms, have been added to the DSL. These were added after their notification and assessment under the NSNR (Organisms).

2.3.3 Assessment timelines

The environmental and human health risk assessments for new living organisms must be completed within a specified time period. The NS program must assess these organisms before manufacture or importation into Canada. A new living organism must be notified under one of the Schedules mentioned below.

The Notification Schedules and assessment period for new organisms under CEPA/NSNR (Organisms) are as follows:

• Schedule 1 is for micro-organisms introduced anywhere in Canada, or in accordance with confinement procedures, with a 120-day assessment period
• Schedule 2 is for micro-organisms used in a contained facility or for export only, with a 30-day assessment period
• Schedule 3 is for micro-organisms used in an experimental field study, with a 90-day assessment period
• Schedule 4 is for micro-organisms manufactured and introduced at the same site where they are isolated, with a 30-day assessment period
• Schedule 5 is for organisms other than micro-organisms (higher organisms) introduced anywhere in Canada, with a 120-day assessment period

2.3.4 Risk assessment outcomes

Possible outcomes of environmental and human health risk assessments are as follows:

• If there is no potential for the living organism to be “toxic” under section 64 of CEPA, then it can be manufactured in or imported into Canada
• If the federal government finds that an organism has the potential to become toxic when used for activity other than the notified use, then it may apply a Significant New Activity (SNAc) provision
  • SNAc provisions may require further declarations before certain activities are undertaken
• If an organism is identified as toxic or potentially toxic to the environment, its biodiversity, or to human health for its notified use, then additional steps may follow:
  • request for additional information
  • imposition of control measures to manage any risks
  • prohibition of the manufacture and import of the organism

3. International context

The biotechnology sector is growing in Canada and globally. International alignment of regulation ensures data requirements and testing methods as similar as possible. This could lead countries to recognize and even accept each other’s assessments of products of biotechnology. Having similar regulations across countries promote efficiency in global supply chains. It strengthens the protection of human health and the environment between jurisdictions. It also ensures consistency between different regulatory systems.

Canada is party to several international agreements, such as the Convention on Biological Diversity (CBD). Canada also participates in a number of organizations, including:

• the Organization for Economic Cooperation and Development (OECD)
• the World Health Organization (WHO)
• the Food and Agricultural Organization of United Nations (FAO)

Through these organizations, Canada contributes to the development of biotechnology regulations. Canada also contributes to and leverages from best practices and approaches developed internationally.

To compare Canada’s approach with international examples, the Discussion Paper refers to several countries and political unions:

• Australia
• New Zealand
• the European Union (EU)
• the United States of America (USA)
• Singapore
• Brazil

These jurisdictions were chosen because they all have strong biotechnology sectors. Many of them are also members of the OECD.

4. Drivers for the review of Part 6 of CEPA and the NSNR (Organisms)

In February 2022, the federal government introduced Bill S-5 (Strengthening Environmental Protection for a Healthier Canada Act). This Bill was designed to amend CEPA. As part of the announcement to amend CEPA, the Government of Canada committed to a comprehensive review of the NSNR (Organisms). The goal is to respond effectively to advances in biotechnology and to make use of new tools and techniques for the risk assessment of living organisms^{Footnote 8}.

The drivers for modernizing CEPA Part 6 and the NSNR (Organisms) are covered in 3 key themes, namely:

• improving openness and transparency, including recommendations from the Standing Committee on Environment and Sustainable Development (ENVI) in 2017
• responding to advances in science and technology
• reducing inefficiencies identified by the NS Program, stakeholders, and others

In addition to the drivers, certain principles of CEPA have guided this work. These include:

• sustainable development
• pollution prevention
• virtual elimination
• ecosystem approach
• precautionary principle
• intergovernmental cooperation
• polluter-pays principle
• maintaining science-based decision making

More information is available at the Canadian Environmental Protection Act at a glance.

4.1 Improving openness and transparency

4.1.1 Openness in risk assessments and decision-making

Openness and transparency in the regulation of new organisms is important for Canadians to make informed choices about the products they use and substances in the environment. They also help strengthen confidence in both the regulatory process and regulatory decisions. As such, we are committed to improving openness and transparency. This is especially in those areas of the regulatory process that are of the greatest concern for Canadians.

Under CEPA, openness and transparency are legally required for certain regulatory decisions. For example, if an information requirement is waived for an organism, the waiver must be published in the Canada Gazette. Ministerial conditions and prohibitions imposed on a new living organism must also be published. Since 2013, ECCC and HC have also proactively published risk assessment summaries for living organisms assessed under the NSNR (Organisms). This practice aligns with other departments and agencies that publish decision summaries for novel food assessments and substances regulated under the Feeds Act and Seeds Act.

4.1.1.1 Voluntary public engagement initiative

In 2017, the Standing Committee on Environment and Sustainable Development (ENVI) committee recommended the need for:

• meaningful public consultation
• increased transparency
• better communication on the risk assessment process and regulatory decisions for new living organisms

Currently, there are no legislative requirements for mandatory stakeholder engagement during the risk assessment process. This includes the selection of some risk management instruments, such as Ministerial conditions described under section 109 of CEPA. In response to ENVI’s recommendations, the federal government launched a voluntary public engagement initiative (VPEI) in 2018.

Through the VPEI, risk assessment reports for higher organisms are published for a public comment period. The aim of the VPEI is to:

• provide for public participation
• allow stakeholders to share information related to potential risks to the environment or human health from new living organisms, such as:
  • scientific information
  • test data
  • traditional knowledge
• incorporate relevant information early in the risk assessment process

The VPEI also gives an opportunity for Canadians to provide input into the risk assessment process.

So far, VPEI has been used to solicit comments from the public for 15 different fish species. Please visit Consultations on certain living organisms new to Canada for information on active and past engagement initiatives. Most comments focused on the possible environmental impact of the organism, and the risk assessment process itself. Most comments the NS program received have not been scientific information, test data, and traditional knowledge that it originally sought. However, the initiative has nonetheless given stakeholders a chance to participate. This has helped to promote confidence in the regulatory process.

Despite these efforts, stakeholders are calling for greater public engagement. Suggestions include making VPEI mandatory or extending VPEI to micro-organisms. It is important to recognize the benefits and challenges of increasing transparency and public participation in regulatory decision-making. The benefits to expanding transparency are:

• it builds public trust and improves the credibility of the regulatory process
• it provides Canadians the opportunity to have their voices heard and contribute to the regulatory process
• it improves the overall openness and accessibility of the regulations to the public

However, an increase in meaningful public participation can result in longer assessment periods. It may also increase the resources and time to reach a regulatory decision. There is cost and time associated with:

• administering public comment periods
• processing comments and feedback
• incorporating changes into regulatory decision-making

Longer assessment timelines may cause inconsistencies with premarket assessment processes in other international jurisdictions. They may misalign with parallel approvals for substances also regulated under the F&DA. Long regulatory processes can act as a barrier to innovation and prolong market access to products of biotechnology. This can be especially problematic for critical technologies, such as life-saving biologic drugs (see section 4.2.1 for examples). It may also complicate rapid access to novel ecological technologies environment which could benefit the environment (that is reduce greenhouses gases). Any regulatory change to the NSNR (Organisms) or CEPA must support the need for agile and responsive regulation of the biotechnology sector. This is outlined in Canada's Biomanufacturing and Life Sciences Strategy.

Participation in public comment periods tends to be highly variable. Some reports receive many comments, while others receive very few. Any potential expansion of the VPEI should focus resources on submissions of greatest public interest. It should not delay decision-making and market access for critical and time-sensitive applications.

To achieve an appropriate balance, public participation with informed, science-based input on regulatory decision-making could be increased. This is especially relevant for new or first-in-class products^{Footnote 9} where market access is not critically time-sensitive. These new products may be of greater interest to the public. They may also receive additional information and perspectives. Such input could be helpful in the risk assessment processes and risk management outcomes. Similar voluntary processes are already conducted by other federal departments. The federal government will consider further options to enhance the transparency and openness in the assessment of new living organisms. This process seeks to balance enhanced transparency with timely regulatory decisions making.

In an international context, Canada’s efforts like the publication of risk assessment reports and the implementation of VPEI for notifications of higher organisms have helped keep Canada aligned with the level of transparency offered by other countries. For example: Australia, New Zealand, the USA, Singapore and Brazil allow regulators to initiate a public consultation, public hearing, or otherwise consult with or inform the public. The EU Directive regarding the release of Genetically Modified Organisms (GMOs) and the regulations for GMOs use in food and feed products require mandatory public engagement^{Footnote 10}.

4.1.2 Labelling of animate products of biotechnology

CEPA and NSNR (Organisms) are responsible for protecting the environment and human health from potential risks posed by animate products of biotechnology. Labels for living organisms under CEPA and the NSNR (Organisms) can only be required they are found to be toxic under section 64. Labelling is only applied if it will help address the risk that the organism poses.

Many other federal laws provide the government authority to impose labelling requirements at various stages in a product’s life cycle. These include the F&DA, the Pest Control Products Act (PCPA) and the HPTA. Products of biotechnology, including genetically modified organisms, are not required to be labelled. However, this does not apply if the NS program finds risks are for the environment and/or human health. Any changes to this risk-mitigation approach to labelling would have broader consequences for other Acts. For example, reduced efficiency and increased cost of complying with the law. Reducing regulatory duplication and its administrative burden is important for labelling. The F&DA provides authority to require labels for products with identified health and safety concerns. These concerns include potential for allergic reactions, changes to the composition of food, or changes to the nutritional quality of the food. Adding similar requirements under CEPA may be redundant.

Labelling all animate products of biotechnology, under CEPA Part 6, to distinguish between GM and non-GM organisms may pose problems. The labelling of organisms regulated under more than one Act or set of regulations can create a negative impression of animate products when labels are added without health and safety concerns.

The NS program has made efforts to increase transparency, such as VPEI and publication of risk assessment summaries for living organisms. However, some stakeholders and members of the public are concerned about available and visible information on certain biotechnology products. These concerns are raised especially for consumer products that fall under CEPA and NSNR (Organisms). Stakeholders mostly request labelling of organisms that are products of biotechnology, especially GMOs.

With respect to the labelling of GMOs internationally, Australia^{Footnote 12} is similar to Canada. Australia allows for voluntary labelling of food products. It has regulatory provisions for the labelling of GMOs, where a safety concern has been identified. It does not specifically require labelling of such products. New Zealand, USA, and Brazil have similar approaches to labelling of GMOs. However, they have additional provisions that make labelling or disclosure mandatory of GMO food products intended for human consumption^{Footnote 13, Footnote 14}. Singapore requires labelling for all GMOs used in research, with the level of information increasing based on the risk posed by the organism^{Footnote 15, Footnote 16}. EU Directives and regulations require labelling of GM products that are intended for use outside of contained facilities, regardless of any identified risk or hazard^{Footnote 17}.

4.2 Responding to advances in science and technology

The NSNR (Organisms) have not been significantly updated since 2005, while biotechnology has advanced. The use of both genetically modified and unmodified living organisms has increased since CEPA and the NSNR (Organisms) first came into force. This is reflected in the growing number of notifications that the NS program has received in recent years. The average number of notifications received per year tripled between 2014 and 2021, compared to the period between 2005 and 2013 (Annex – Figure 1). The number of notifications will continue to grow along with the growth of the Canadian biotechnology sector. Updating the NSNR (Organisms) to respond to advances in science and technology is important. The regulation need to respond to Canada’s Biomanufacturing and Life Sciences Strategy while continuing to protect human health and the environment.

Most notifications under NSNR (Organisms) were for micro-organisms that can be used outside of contained facilities (total number of notifications: 180). Next are notifications for micro-organisms for use in contained facilities (total number of notifications: 117). Notifications for higher organisms have also increased since 2017 (Annex – Figure 6). Although higher organism notifications still do not represent a large number of notifications, the NS program notes their increasing frequency as a potential indicator of future trends.

Another notable trend since 2020 has been the increase in notifications for organisms used in food or therapeutic applications (F&DA uses) (Annex-Figures 1 and 2). Prior to 2020, notifications for organisms with industrial applications (total number of notifications: 238) were more common than F&DA organisms (total number of notifications: 120). The increase in the number of F&DA notifications since 2020 has largely been for GMOs (Annex – Figure 3). The most common use for F&DA organisms has been in cell and gene therapies (CGT) (Annex– Figure 4). Notifications for GMOs (total number of notifications: 276) have been consistently more frequent than notifications for unmodified organisms (total number of notifications: 82) since 2005 (Annex - Figure 5).

CEPA and the NSNR (Organisms) use a “substance-based” approach when assessing the potential risk of an organism.^{Footnote 18} This means that CEPA and the NSNR (Organisms) are “technology-neutral” in terms of risk assessment. The NS program must assess All new living organisms irrespective of the technology used. For example, it must assess organisms resulting from genetic modifications or selective growth media. By adopting this substance-based approach, CEPA and the NSNR (Organisms) provide oversight for organisms derived from new technologies and emerging applications. Examples include:

• organisms containing gene-drives (that is a gene or subset of genes that can rapidly spread from one generation to another generation)
• genome-editing (that is genes altered, deleted or added, using precise nucleic acids cutting techniques).

The assessment considers both the organism and the process or technology used to create the organism. However, new and powerful technologies also raise challenges. Some advances are used to produce first-in-class products like gene drives and products available for use to amateur scientists and the public. These warrant consideration of the current regulatory approach, which is not well suited for users and products leveraging these advances.

In line with CBS, the federal government prioritizes ensuring that the NSNR (Organisms) keep pace with advances in biotechnology while protecting the health of Canadians and the environment.

4.2.1 Innovative medicines

Biotechnology has applications which are critically important to human health. Many advancements are being made in:

• gene therapies, which may replace or inactivate disease-causing genes or introduce a new or modified gene to treat or stop disease
  • This includes the treatment of hemophilia, immune-related diseases, and many other inherited genetic disorders
• cell-based gene therapies, which use modified immune cells to target and eliminate cancer cells while not impacting non-cancer cells of patients
  • This includes genetically modified immunocellular therapies for cancer
• cell therapies, which include hematopoietic stem cells, as well as adult and embryonic stem cells
• vaccine development, such as vaccines for SARS-CoV-2 developed during the COVID 19 pandemic as well as yearly flu shots

Under the NSNR (Organisms), the risk assessment considers the removal of problematic genes, the inclusion of genes of interest or that are advantageous to human health. It also considers the nature, source and function of genes. The assessment also considers the potential impact on the environment and increasing use of these technologies.

These technologies reduce the burden on the healthcare system by potentially treating previously untreatable diseases or disorders. They may also increase quality of life for people living with chronic or life-threatening conditions. Moving forward, it is imperative that Canadians have timely access to these technologies. This is because they have the potential to treat or mitigate a wide range of disease and disorders.

4.2.2 Facilitating access to products of biotechnology, including biologic drugs subject to the F&DA

Personalized medicine, oncolytics, novel vaccines, and CGT represent a growing class of important innovative medicines. These products leverage biotechnology to improve human health. Safety, efficacy and quality (SEQ) reviews of these products are conducted under the F&DA. However, the F&DA is not listed on Schedule 4 of CEPA. The F&DA does not require the environmental assessment of organisms used in biological drugs. Such assessments must be conducted under CEPA and the NSNR (Organisms) before a new organism can be manufactured in or imported into Canada.

Several issues exist with the assessment of biologic drugs under the CEPA and the NSNR (Organisms):

• Under the F&DA, clinical trial applications (CTA) are authorized within 30 days, whereas the regulatory timeline for Schedule 1 of the NSNR (Organisms) allows up to 120 days
  • Assessments under Schedule 1 may be conducted within a shorter timeline if requested
  • Differences in timelines may cause delays at the clinical trial stage
  • This may deter sponsors from bringing clinical trials to Canada or seeking market authorization for highly promising and innovative life-saving biologic drugs
• Under the NSNR (Organisms), Schedule 1 information requirements designed for industrial/environmental applications may be difficult to address for biologic drugs
  • These include effects on biogeochemical cycling due to cell and gene therapies
  • Schedule 1 includes the most comprehensive information requirements for micro-organisms, irrespective of the level of exposure of biologic drugs and whether they are used for clinical trials (for example study conducted with a small subset of patients under confined procedures) or commercialization (for example vaccination of Canadians)
  • For Schedule 1, all potential future activities (such as commercialization of the drug and manufacture in Canada) must be considered in the risk assessment
  • For clinical trials stage, some of the information needed to assess future activities may be lacking as it has not yet been generated or is unknown, causing some uncertainty
• There may be opportunities to improve alignment with other international regulators (for example Australia, US, EU) to facilitate access to products of biotechnology including biologic drugs

There is a need to streamline and coordinate the environmental risk assessment of biologic drugs. This is particularly important during the clinical trial stage, to better align with approval timelines under the F&DA. Delays at this stage could result in increased time to market for critical technologies. These include important biologic drugs, such as potentially lifesaving technologies.

As part of Bill S-5, amendments to the F&DA would enable the creation of an environmental notification, risk assessment and risk management framework for drugs under the F&DA. This framework will result in both the SEQ and the environmental risk assessments of drugs being conducted under the F&DA. This proposed framework will minimize the existing delays for clinical trials involving organisms. It will also reduce regulatory burden on industry while continuing to protect human health and the environment. It will take time to finalize and implement. However, the proposed NSNR (Organisms) amendments are on a faster track. They will improve regulatory alignment and patient access to innovative medicines.

Internationally, Australia and the EU have regulations that include exemptions for unmodified (that is non-GM) organisms used in clinical trials and biologic drugs. The USA has similar exemptions, but these also include some GM organisms and applications (for example gene therapies). Canada is, similar to New Zealand. Both countries require environmental risk assessments for both modified and unmodified living organisms. including those used in biologic drugs.

4.2.3 Ease of accessibility and affordability of living organisms resulting from advanced tools

CEPA/NSNR (Organisms) was introduced when amateur and “Do-It-Yourself” (DIY) participation in the biotechnology sector was minimal. The increasing accessibility and affordability of advanced tools and technologies (for example DIY gene-editing kits) has changed this. These tools allow amateur scientists, members of the public and/or biohackers to develop new living organisms. These may be subject to CEPA and the NSNR (Organisms). The manufacture of micro-organisms using DIY kits may also be subject to the Human Pathogens and Toxins Act (HPTA). However, the production of higher organisms (for example genetically modified frogs) using DIY kits are not subject to more oversight. The release or disposal of DIY manufactured organisms into the environment without any regulatory oversight could pose risks to the environment, biodiversity and human health. DIY-biologists and amateur scientists may not be aware that they need to comply with CEPA/NSNR (Organisms) prior to manufacture or import of new living organisms using DIY kits. Enhancing awareness among the DIY-biologists and amateur scientists could help to ensure new living organisms using DIY kits are not released into the environment without having undergone an environmental risk assessment. This assessment would identify and mitigate the potential risks posed by the organisms.

Like Canada, most countries are yet to adopt an approach for addressing issues posed by the DIY-genetic modification community. However, Australia and Singapore have taken steps to promote awareness of GMOs and ensure that the public is aware of their legal obligations. For example, an Australian factsheet [PDF] released in 2021 informs citizen scientists and biohackers about the laws concerned with GMOs.

4.2.4 Strengthening post-assessment monitoring information requirements for achieving sustainability goals

When an organism meets or is suspected to meet the definition of toxic in section 64 of CEPA, it means that it may cause harm to the environment or its biodiversity, or human health. If the NS program finds this during its assessment, it can specify additional conditions and/or information requirements to mitigate the risks posed by that organism. The NS program use tools such as Significant New Activity notices (Significant New Activity publications under the Canadian Environmental Protection Act, 1999 - open government portal) and Ministerial Conditions (New substances: Ministerial conditions) to manage risk. This approach gives oversight from the production to the disposal of an organism.

However, the future may bring unpredictable circumstances which cannot be accounted for during the risk assessment process. Examples include:

• changing environmental conditions resulting from climate change (for example warming oceans)
• living organisms contributing to climate change

This can result in different environmental conditions than those that were the basis of the initial risk assessment. For example, if a GMO could survive in the warming ocean while it could not when the NS program assessed it. Changing environmental conditions can significantly alter the nature of exposure for any given organism. If circumstances change, it is possible that an organism that had no potential to cause any harm could become a concern in the future. An approach to respond to this unpredictability would be to strengthen post-assessment information requirements. This could include establishing additional regulatory oversight for environmental monitoring on a regular basis or within a defined timeframe. It is important to consider the benefit of such monitoring, especially for organisms not suspected of being toxic under CEPA (that is meet criteria under Sections 64). Additional monitoring could require notifiers who manufacture and/or import an organism to collect and maintain records for the defined period of time. The NS program would also need the additional authority to monitor organisms that are not suspected of being toxic under CEPA.

Climate change has a role in the risk assessment of living organisms. Therefore, the ongoing review process is an opportunity to consider CEPA and the NSNR (Organisms) in promoting environmental sustainability. Expanding Part 6 of CEPA and/or the NSNR (Organisms) to include aspects of animate products relevant to sustainability or climate change could help the federal government’s commitment to address climate change.

4.2.5 Demonstration of need for new living organisms, including GMOs, and their impacts on biodiversity and ecosystem sustainability

Some stakeholders are concerned about the possible impacts of modified living organisms. This especially relates to GMOs developed through emerging technologies, such as gene-drives, on biodiversity and the environment. They recommend that a need for the living organism should be demonstrated before it is released into the environment. The NS program obtains comprehensive information on the impact of a living organism, including GMOs, on the receiving environment under the NSNR (Organisms). It obtains this prior to manufacture and import of the organism into Canada. However, neither CEPA nor the NSNR (Organisms) currently require a demonstration of need for the living organism.

Risk assessment under CEPA and the NSNR (Organisms) is science-based. It relies on scientific data and information relevant to an organism’s:

• hazard potential
• level of exposure
• likelihood of it to cause adverse effects to the environment, biodiversity and human health.

This includes information such as intended use, biological and ecological characteristics, pathogenicity, etc. Socio-economic, ethical, philosophical, and other non-science-based considerations are not included as part of the science-based risk assessment process. A “demonstrable need” is an entirely new concept and represents a significant departure from the risk-based approach. Internationally, none of the other jurisdictions referred in this paper require a demonstration of “need” for animate products of biotechnology in their legislation. International coherence of the new concept would be important to ensure safety of humans and the environment, and to facilitate innovation and trade.

4.3 Reducing identified inefficiencies

The review of the NSNR (Organisms) provides an opportunity to address inefficiencies, redundancies and unnecessary regulatory requirements, activities or processes. The goal is to create a less burdensome and efficient process for both regulators and regulated parties.

4.3.1 Streamlining the regulatory scope for unmodified organisms

The definitions of “biotechnology” and “living organisms” in CEPA includes all living organisms used or developed through the application of science and engineering. This includes both modified and unmodified organisms. Thus, the NSNR (Organisms) applies to manufacture and import of any new living organism. This includes organisms that are:

• not on the DSL or not regulated under other federal legislation listed in Schedule 4
• isolated from a natural environment, genetically modified or created synthetically
• subjected to selection, mating, cloning or enrichment
• scaled up in a lab
• used in an entirely new activity (for example introduced in large quantities to a different ecozone in Canada)

Some stakeholders have raised concerns on over-regulation of unmodified living organisms in Canada compared to other international counterparts (for example US Environmental Protection Agency [US EPA] and Australia). Canada is one of the few jurisdictions to regulate both unmodified and modified organisms, and organisms that are already present and naturalized in Canada, under the same regulations and provisions.

Canada regulates unmodified and modified organisms, including organisms already present and naturalized in Canada. This is because propagating, scaling up and using or releasing unmodified organisms without any regulatory oversight cannot be assumed to be safe to the environment, human health or biodiversity. For example, microbial-based cleaning products may contain unmodified Bacillus species that are present naturally in the environment. However, some of them (for example Bacillus cereus and Bacillus anthracis) are hazardous to human health. The production and uncontained use of these products without oversight could therefore result in harm to human health. This could occur despite these organisms being unmodified and naturally occurring. Other examples include unmodified Coxsackie virus for immunotherapy purposes, which could present risks to general and vulnerable populations. Exotic insects imported for protein extraction could be released into the environment in large quantities with unknown impacts. For example, the potential to become invasive.

Though regulating unmodified living organisms does not align Canada with other international jurisdictions, not doing so would reduce oversight. This would result in potential regulatory gaps, as these organisms might not be captured under other federal legislation.

Canada and New Zealand both regulate GMOs and unmodified organisms under the same legislation and regulations. In comparison, Australia, the EU, Singapore, and Brazil all have separate legislation and/or regulatory requirements for GMOs and unmodified organisms. However, an organism can be subject to multiple acts depending on how it is used. For example, a GMO used in a medicinal product may be regulated under both GMO legislation and regulations for organisms in medicinal products. In the US, several laws regulate environmental releases of micro-organisms. Intergeneric micro-organisms (that is micro-organisms containing synthetic or foreign DNA) are assessed by US EPA under the Toxic Substances Control Act (TSCA). Micro-organisms without synthetic or foreign DNA are not regulated by the TSCA. Under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), all micro-organisms are assessed when they are notified to the US EPA as a Microbial Pest Control Agent (MPCA). This occurs regardless of genetic modification or natural occurrence.

The federal legislation listed in Schedule 4 of CEPA regulates both unmodified and modified living organisms. The NS program aims to establish approaches to streamline the regulation of unmodified naturally occurring organisms in the Canada while protecting the health of Canadians, and the environment and its biodiversity.

4.3.2 Refining the NSNR (Organisms) definitions for micro-organism and research and development organisms

The current review of the NSNR (Organisms) has revealed 2 issues related to the definitions in these regulations. The first issue is the definition of “micro-organism” and the absence of a definition for “animate” in both the NSNR (Organisms) or CEPA. The second issue is the definition of “research and development organism”. Both issues may lead to regulatory inefficiencies and gaps in oversight for some animate products of biotechnology.

The NS program has received many inquiries regarding the New Substance Notification requirements for:

• human or animal blood
• cells or cell lines
• organs or tissues
• vegetative or reproductive cells.

These inquires also cover their uses in various applications such as biologic drugs. This shows a need to clearly define how the NSNR (Organisms) applies to such biological materials. There is also a need to clarify whether human or animal cells or cell lines, blood, organs, tissues, used in biologic drugs are subject to, or exempt from the NSNR (Organisms) and NSNR (Chemicals & Polymers)^{Footnote 19}.

Adding to this complexity of definitions is the biopharmaceutical industry’s development of novel substances. They have classified these as virus-like particles (VLPs) and sub-viral particles (SVPs). These products are regulated by the NSNR (Organisms) because the definition of “micro-organism” makes reference to VLPs and SVPs. However, the terms “VLP” and “SVP” can refer to both animate and inanimate substances. Some of these products may not actually be considered as living micro-organisms under the NSNR (Organisms). To address situations where VLPs and SVPs are inanimate, the NS program developed an interim policy. Non-living VLPs or SVPs that are not capable of replication are notified under the NSNR (Chemicals & Polymers) rather than the NSNR (Organisms)^{Footnote 20}.

A final issue for the definition of “micro-organism” is the inclusion of cultured human cells commonly used in cell and gene therapies. These substances are generally accepted to be of low hazard to the environment and indirect human health through environmental exposure. However, they still require notification under Schedule 1 of the NSNR (Organisms) which has the highest data requirements for micro-organisms. Revising the definition of “micro-organism” would enable the NS program to “right-size” its regulations. It would therefore focus its efforts on micro-organisms with greater potential risk.

The NSNR (Organisms) definition of “research and development organism” also has limitations that need to be addressed. This definition does not capture organisms such as:

• those used as experimental controls
• those used in quality assurance and control (QA/QC)
• those used as models for studying human diseases

Potential notifiers may not know if organisms used in these activities meet the definition of “research and development organism”. If this definition clearly captured these cases, such organisms would be exempt from notification as long as they meet the other research and development exemption criteria under the NSNR (Organisms).

Also worth noting about research and development organisms is that they are exempt from notification requirements when manufactured in a contained facility when:

• less than 1000 L is present in the facility for risk group (RG) 1 micro-organisms
• less than 250 L is present for other micro-organisms
• they are imported to a contained facility in a quantity less than 50 ml or 50 g

It would be more valuable for a risk assessment to include the concentration of the organism rather than just the volumes. Volumes alone do not provide the actual quantity of the research and development organism.

4.3.3 Streamlining the regulations for higher organisms according to the level of intended release

Currently, new higher organisms are subject to Schedule 5 regardless of whether they are intended to be fully released into the environment or not. The NSNR (Organisms) does not have a specific Schedule for assessing activities of higher organisms that do not involve full environmental release. For example, contained use, experimental field studies, and release under confinement procedures. This places an unnecessary regulatory burden on notifiers intending to use higher organisms in contained scenarios. Furthermore, this diverges from comparable regulatory requirements in Australia, Brazil, the EU, New Zealand, Singapore, and the USA. In these countries, requirements for information used in risk assessments vary based on the level of intended release^{Footnote 21}. In the case of the EU and Singapore, different regulations apply to higher organisms with different levels of intended release.

4.3.4 Accidental release of living organisms

The accidental release of living organisms during R&D activities, import, transit, and manufacturing represents a regulatory gap under CEPA. Without containment standards or guidelines for higher organisms, researchers may have difficulty applying appropriate measures to guard against accidental releases of research and development living organisms. This also includes their genetic material and other materials that could lead to toxicity. This creates challenges to meet requirements of subsection 2(4) of the NSNR (Organisms). Gaps also exist between the Transportation of Dangerous Goods Act and CEPA for living organisms that are imported or transported between contained facilities. Lack of incident reporting authority and guidelines presents a further risk for the accidental release of living organisms. Strengthening risk mitigation measures for accidental release of living organisms would be important for strengthening the environmental protection provided by the NSNR (Organisms).

4.3.5 Consideration of vulnerable populations

Amendments are being proposed to CEPA through Bill S-5, the Strengthening Environmental Protection for a Healthier Canada Act. This bill currently being considered in Parliament highlights the importance in CEPA assessments of considering vulnerable populations^{Footnote 22}. It is also important to seek to minimize risks to the health of these populations and their local environment.

At present, the NSNR (Organisms) does not include specific information requirements to determine potential adverse effects on vulnerable populations. These groups may be more susceptible to exposure from living organisms intentionally released to the environment (that is micro-organisms and allergens). However, the NS program already considers risks to vulnerable populations in the microbial risk assessment framework it uses when conducting regulatory risk assessments. Even so, the NSNR (Organisms) could consider adding information requirements to better protect vulnerable populations.

4.3.6 Overlap and gaps with Human Pathogens and Toxins Act and Regulations

Since the Public Health Agency of Canada’s (PHAC) Human Pathogens and Toxins Act (HPTA) and Human Pathogens and Toxins Regulations (HPTR) came into effect in December 2015, regulatory duplication has been identified. This duplication occurs in the regulation of new living organisms under CEPA/NSNR (Organisms) and the HPTA/HPTR. It applies for manufacture or import of micro-organisms (RG 2-4 human pathogens and toxins), where specific controlled activities are performed. These controlled activities include possessing, handling, using, producing, storing, permitting any person access, transferring, importing, exporting, releasing, abandoning, disposing of a human pathogen or toxin.

The biomanufacturing and life sciences sector often uses micro-organisms under containment. It uses them to produce active pharmaceutical ingredients, biomolecules or enzymes for various applications. Regulated parties in this sector have noted the inefficiencies and unnecessary regulatory burden created by this duplication. As a result, PHAC, ECCC and HC signed a memorandum of understanding (MOU). The MOU facilitates information-sharing and streamlines the assessment processes associated with the HPTA, HPTR, CEPA and the NSNR (Organisms). The ongoing regulatory review recognizes a need to reduce regulatory duplication.

In addition to regulatory overlap between HPTA/HTPR and CEPA/NSNR (Organisms), it is also important to consider existing misalignments. These should not be worsened when overlap is reduced. For instance, under certain circumstances such as experimental field trials, the NSNR (Organisms) allows micro-organisms to be released into the environment after manufacture or import. However, this release would be a controlled activity if the micro-organism is also regulated under the HPTA/HPTR.

PHAC does not explicitly regulate animate products of biotechnology. Instead, it focuses on biological agents that meet the definitions of RG 2, 3 or 4 human pathogen or toxin and have the potential to cause harm to humans and terrestrial animals. Additionally, although disposal is a regulated activity under the HPTA/HPTR, there are no specific provisions for the monitoring of micro-organisms in solid effluents like soil. Finally, HPTA/HPTR only regulates RG 2-4 biological agents. Oversight under these instruments does not apply to higher organisms that fall under the purview of NSNR (Organisms). This means that higher organisms used in R&D would not benefit from additional oversight under the HPTA/HPTR if exempted from the NSNR (Organisms). The purpose of identifying these gaps is not to necessarily address them through the NSNR (Organisms). Instead, it demonstrates that while it is important to eliminate regulatory overlap, there needs to be continued oversight through NSNR (Organisms) and CEPA for certain organisms.

4.3.7 Inefficiencies in regulatory requirements for contained use (Schedule 2)

The notification Schedule for the use of micro-organisms in containment (Schedule 2) under the NSNR (Organisms) currently lacks some data requirements. These missing requirements are needed to ensure effective inactivation procedures for the disposal of micro-organisms. Without this information, it is difficult to accurately assess the risk associated with organisms notified for use under containment.

Under the NSNR (Organisms), containment standards are based on the US National Institutes of Health (NIH) guidelines Appendix K – Good Large Scale Practices and the Canadian Biosafety Standards 2^nd Edition. However, the US NIH guidelines for Good Large Scale Practices allow micro-organisms to be disposed of and handled outside of contained facilities. This runs counter to the intention of the contained use Schedule.

5. Next Steps: Directions to stakeholders on engagement/provision of feedback

To inform the review of the NSNR (Organisms), the NS program is looking for input from stakeholders. Feedback should be relevant to the issues identified above. It may include scientific information, analysis, experience working with the regulations and concerns or challenges with the NSNR (Organisms).

In order to participate, please visit our PlaceSpeak page, and follow the instructions to complete our poll, survey and discussion questions. If you wish to have a small group or individual meeting, please send a request to substances@ec.gc.ca. If you wish to provide written feedback, please use the “Noticeboard” feature on PlaceSpeak or provide feedback in writing to substances@ec.gc.ca.

6. Annex

Annex A. Trends in NSNR (Organisms) Notifications of Living Organisms from 2005-2021

Figure 1. Notifications received for industrial, and F&DA uses for various Schedules between 2005 and 2021.

Note: Figures are based on currently available data and may be subject to change as data is updated.

Figure 2. Notifications received for industrial, or F&DA uses between 2005 and 2021

Note: Figures are based on currently available data and may be subject to change as data is updated.

Figure 3. Notifications received for industrial and F&DA uses between 2005 and 2021 for unmodified organisms and GMOs.

Note: Figures are based on currently available data and may be subject to change as data is updated.

Figure 4. Notifications received for unmodified organisms and GMOs for F&DA uses between 2005 and 2021.

Note: Figures are based on currently available data and may be subject to change as data is updated.

Figure 5. Notifications received for GMOs and unmodified organisms for industrial and F&DA uses between 2005 and 2021.

Note: Figures are based on currently available data and may be subject to change as data is updated.