Risk analysis is a structured process for identifying, assessing, and managing potential problems, which helps to achieve the appropriate level of safety. Briefly, it consists of hazard identification, risk assessment, risk management, and risk communication. The process of risk analysis includes:

• Identifying harms that might result from the particular activity that is under consideration
• Considering the possible pathways by which that activity might cause harm to human or animal health, the environment, or socioeconomic welfare
• Evaluating the likelihood that the harm will occur and the likely consequences under scenarios relevant to the planned actions, which will characterize the risks associated with the activity
• Preparing plans to avoid or reduce any identified risks through risk management.
• Communicating with involved decision-makers and stakeholders throughout the process to enable them to identify concerns, contribute ideas, and decide upon the acceptability of any identified risks. The process culminates in decision-making by national authorities and stakeholders about the acceptability of any remaining risks in the context of potential benefits.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.oie.int/fileadmin/Home/eng/Health_standards/aahc/2010/chapitre_import_risk_analysis.pdf
https://www.fao.org/3/ba0092e/ba0092e00.pdf

Risk assessment is a critical part of the risk analysis process. The concept of risk takes into account both the likelihood and magnitude of harm arising from an identified hazard (an unwanted event that could have a negative impact, or harm). Risk assessment is a structured and objective process to identify what hazards are relevant (hazard identification and characterization), how likely they are to happen (exposure assessment), and how significant their consequences could be (consequence assessment). Altogether, this will facilitate an understanding of the level of concern that is appropriate for each hazard.

For more information:

https://bch.cbd.int/protocol/text/ (see Annex III)
https://www.oie.int/fileadmin/Home/eng/Health_standards/aahc/2010/chapitre_import_risk_analysis.pdf
https://www.fao.org/3/ba0092e/ba0092e00.pdf

Risk assessment will take place at many different points in the development pathway, and will be conducted by:

• Product developers: The World Health Organization has recommended that developers of a gene drive technologies should conduct a risk assessment before each new testing phase or expansion of test releases, with the aim of gathering the most informative data in support of creating a safe and effective product. Developers might conduct risk assessment themselves, or may commission an external risk assessment to be conducted by experts with no vested interest in the success of the product. The results of these risk assessments will help developers understand what data they need to collect, and what management plans they need to put in place to reduce any risks to an acceptable level. This information will be helpful in preparing applications to regulatory authorities.
• Regulators: National regulatory authorities will conduct a risk assessment as part of their review of applications submitted by developers. For regulators, the types of risks that are considered are circumscribed by the legal mandates and authorities granted to the agencies charged with the risk assessment. The scope of jurisdiction for these agencies is defined by national laws, and their enabling regulations and policies. Therefore, the scope of the risk analysis for regulators is not open-ended, and is also under legally prescribed timeframes for completion.

For more information:

https://www.who.int/publications/i/item/9789240025233
https://www.ajtmh.org/view/journals/tpmd/98/6_Suppl/article-p1.xml

Risk assessments will be conducted separately for each gene drive-modified product, taking into consideration the particular conditions under which it will be tested or used. Each individual product will reflect a unique combination of characteristics – including the target species, the method of engineering, the engineered features, and the planned purpose or use – and may have a unique set of relevant hazards and risks. Because of the diversity of potential applications of gene drive technology, both the Convention on Biological Diversity and the World Health Organization have recommended that risk assessments be conducted on a case-by-case basis.

For more information:

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-1
https://www.who.int/publications/i/item/9789240025233
https://bch.cbd.int/protocol/risk_assessment/cp-ra-ahteg-2020-01-04-en-2.pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9531641/

Risk communication involves an interactive exchange of information and opinions throughout the risk analysis process. One component of a robust risk analysis is providing opportunities for dialogue with stakeholders in an ongoing way, with information communicated clearly and comprehensibly to facilitate active input into risk assessment and risk management planning, and inform decision-making.

Communication with potentially affected communities prior to and during the risk assessment process will help developers with framing the scope of the risk assessment, identifying concerns that should be taken into account, and determining whether to move forward. Developers will need to provide answers to community questions, adjust their plans as necessary to respond to concerns, and seek community authorization for the study to be undertaken. The mechanism for community deliberation and agreement is best determined by the community itself according to its norms.

In most national regulatory processes, the input of citizens/communities is taken into consideration during the specific public consultation phases of the decision-making process. If their input identifies scientific issues that were not adequately addressed in the environmental risk assessment, that input might trigger a reconsideration of the risk assessment. In some countries, the use of genetically modified organisms is also subject to conduct of Strategic Environmental Assessment (SEA) and Environmental and Social Impact Assessment (ESIA). SEA facilitates consideration of impacts from a general class of intervention and is designed to support policy and political decision-making. ESIA is suited to the implementation of specific projects and examines their potential positive and negative impacts in the areas of environment, socioeconomics, and health. Both SEA and ESIA require substantial stakeholder input.

For more information:

https://www.who.int/publications/i/item/978924002523

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w https://library.oapen.org/bitstream/handle/20.500.12657/30733/1/Science%20and%20the%20politics%20%20of%20openness.pdf#page=191

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-4

https://www.youtube.com/watch?v=71VYXRoz_4k
https://www.youtube.com/playlist?list=PLbopRNGowKJ9BGgg2BHu-VWYZgXpe0iLS

No. Gene drive-modified organisms possess characteristics that must be taken into account in risk assessment, such as the ability of the modification to spread into wild populations of the targeted species and the possible irreversibility of self-sustaining drives. However, several experts have expressed the opinion that these are not entirely novel and can be approached within existing risk assessment and regulatory frameworks, such as those used for other biocontrol agents and genetically modified organisms.

For more information:
https://www.isaaa.org/webinars/2022/genedrivewebinar2/default.asp
https://www.sciencedirect.com/science/article/pii/S1462901119311098?via%3Dihub
https://www.efsa.europa.eu/en/efsajournal/pub/6297

A. Mathematical and computer simulation modelling can aid in planning for data collection to inform risk assessment, and can support risk assessment and risk management by predicting the spread and efficacy of gene drive-modified organisms at large spatial scale under a range of assumptions. Modelling also can play a role in assessing some of the biosafety and cost considerations for gene drive-modified organisms.

For more information:

https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-020-00834-z

https://www.frontiersin.org/articles/10.3389/fitd.2022.828876/full

https://www.youtube.com/playlist?list=PLbopRNGowKJ9WKPho-gyrCngfAJq5EmF4

https://www.youtube.com/playlist?list=PLbopRNGowKJ9t6tPlg5dme3ljau1WgJh7

All risk assessment paradigms follow the standard accepted principles of problem formulation, hazard identification, hazard characterization, exposure and consequence assessment, and risk characterization. There are different risk assessment methodologies, however. Qualitative risk assessment uses descriptive terms to categorize assessment outputs, such as “high”, “medium”, or “low”. Semi-quantitative risk assessment evaluates risks with a score that is more reflective of probability. Quantitative risk assessment uses numbers and graphs to convey a more specific numerical estimate of risk. All methods are useful to arrive at accurate risk assessments and have both strengths and weaknesses. The critical issue is understanding the circumstances under which a particular methodology is most suitable.

For more information:

https://www.fao.org/3/i1134e/i1134e00.htm
https://www.youtube.com/playlist?list=PLbopRNGowKJ9t6tPlg5dme3ljau1WgJh7
https://www.youtube.com/playlist?list=PLbopRNGowKJ9WKPho-gyrCngfAJq5EmF4

In addition to a project-specific technical risk assessment, the regulatory authority may also require an impact assessment. The need for and extent of this requirement may be legally defined and influenced by the perceived potential for adverse effects. Some jurisdictions limit impact assessment to the analysis of effects on the biophysical environment, while others include the social, economic and cultural impacts of the project. This impact-based assessment will focus on potential adverse, neutral or beneficial changes that could result from the project, and may consider other alternatives to meet the stated need. Impact assessment can be broad in scope, covering areas of environment, socioeconomics and health.

For more information:

https://www.cbd.int/impact/

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://genedrivenetwork.org/videos#mxYouTubeR88da54c719d7acb5beb6a53f64c5214b-3

Before a new vector control product is brought to market, it is standardly tested in a series of expanding clinical or field trials. This phased testing pathway allows developers and regulators to learn whether the new product works and is safe to use. Research on new products begins with extensive testing in the laboratory. Developers will submit laboratory results to regulatory authorities, who will determine whether and how the product can move to clinical or field testing. Upon regulatory approval, testing will begin at a very small scale under conditions that minimize risk to people or the environment. If results from such small-scale testing look promising, regulators may approve moving to larger scale trials of safety and efficacy. Based on those results, regulators will decide whether and under what conditions the product can be made publicly available. If at any phase of the pathway the product fails to demonstrate agreed upon safety and efficacy characteristics it should not move forward, and developers will need to decide whether and how it might be improved to restart the testing process.

For more information:

https://www.fda.gov/patients/drug-development-process/step-3-clinical-research

https://www.cancerresearchuk.org/about-cancer/find-a-clinical-trial/what-clinical-trials-are/phases-of-clinical-trials

https://apps.who.int/iris/bitstream/handle/10665/259688/WHO-HTM-NTD-VEM-2017.03-eng.pdf

https://nap.nationalacademies.org/catalog/23405/gene-drives-on-the-horizon-advancing-science-navigating-uncertainty-and

The recommended pathway involves four phases.

• Phase 1 involves initial studies on safety and efficacy, conducted in the laboratory and in cages that contain a small number of mosquitoes. All of these studies are conducted indoors under appropriate containment to prevent escape of the modified mosquitoes into the environment. If the modified mosquitoes demonstrate the desired biological and functional characteristics, testing may move forward.
• Phase 2 expands contained testing under conditions of physical or ecological confinement, intended to limit outward migration of the modified mosquitoes by studying them in large outdoor cages or under geographic/spatial/climatic isolation. This will examine whether the modified mosquitoes continue to show expected characteristics that predict an ability to reduce disease transmission. Depending on Phase 2 results, testing may proceed to Phase 3 of revert to conduct additional studies.
• Phase 3 includes open release trials to assess performance under various disease transmission conditions. In this phase, the ability of the modified mosquitoes to reduce the incidence or prevalence of infection or disease can be directly measured. If Phase 3 testing demonstrates sufficient efficacy and safety, regulators and policy makers may consider wider implementation of the product as a public health tool.
• Phase 4 entails ongoing monitoring of the product’s effectiveness and safety under operational conditions.

Phases 1 through 3 may need to be repeated to improve the technology and refine the procedures until the requirements for moving to the next phase are met. If the genetic modification is a self-sustaining gene drive that is expected to persist in the environment, the phased testing pathway may be more realistically conceived as a continuum of expanding releases.

Decisions to move forward from one testing phase to the next will require appropriate regulatory authorization and the agreement of the communities hosting the trials.

For more information:

https://www.who.int/publications/i/item/9789240025233
http://www.ajtmh.org/content/journals/10.4269/ajtmh.18-0083

Phase 1 studies can be conducted in appropriately contained laboratory and cage facilities anywhere, as long as the mosquito species of interest can be maintained there. All field studies and trials will necessarily have to be conducted in environments where the target mosquito species exists naturally. Phase 3 testing, which measures safety and efficacy for reducing disease, must be conducted in areas where the disease of interest is actively transmitted.

A hazard is any potential source of harm, or adverse effect, to something or someone. Risk is the probability of harm due to a particular hazard.

Hazard identification is an early step in risk assessment, which attempts to comprehensively identify all the characteristics or conditions that might possibly lead to the occurrence of a negative outcome i.e. a harm. In a subsequent step, the likelihood of that harm occurring under certain defined conditions and the magnitude (seriousness) of that harm if it did occur are considered together to determine the risk due to that hazard. Thus, during risk assessment, it may be determined that an identified hazard does not pose significant or unacceptable risk.

For more information: https://www.youtube.com/watch?v=_GwVTdsnN1E

Typically, risk assessment utilizes a variety of data and information sources, giving them different weight. Data generated using the particular organism (species), modification (engineered trait), and receiving environment will have the highest weight. To date, no gene drive-modified organism has been released into the environment. Experimental data from contained testing in small and large cages will be most informative, along with knowledge of the biology and behavior in nature of the host insect, of related naturally occurring gene drives, and of the environment where the modified insects will be used. Various predictive tools, including mathematical modelling, can provide insights into aspects of the behavior of the gene drive-modified insects upon release, such how time, seasonality, or use of other control measures might affect their spread through the local population of the target organism. Nonetheless, in the initial absence of data on the field performance of engineered gene drives, risk assessment may have to accommodate a range of uncertainties. Some of these may be addressable through specific risk mitigation methods and monitoring. While, several risk assessment experts have published that current risk assessment frameworks are suitable for evaluating gene drive-modified organisms, they also have noted areas where additional guidance would be helpful. Work to provide such guidance is underway in several venues, including the Convention on Biological Diversity and the European Food Safety Authority. This will add to existing internationally accepted risk assessment guidelines.

For more information:

https://www.sciencedirect.com/science/article/abs/pii/S1462901119311098

https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/j.efsa.2020.6297

https://bch.cbd.int/protocol/risk_assessment/cp-ra-ahteg-2020-01-04-en-2.pdf

https://www.nature.com/articles/s41467-023-37483-z

https://www.liebertpub.com/doi/10.1089/vbz.2019.2606?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04183-w

https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2017.4971

The WHO Guidance Framework for Testing Genetically Modified Mosquitoes calls for monitoring of efficacy and safety at each phase of testing as well as a period of post-implementation monitoring for ongoing effectiveness and safety under operational conditions after a decision is made to deploy gene drive-modified mosquitoes as public health tools (also see How will mosquitoes with gene drive be tested?). The Guidance Framework provides specific recommendations on the types of data that can be collected at each phase.

For more information:

https://www.who.int/publications/i/item/9789240025233

National regulators will determine monitoring requirements as part of the approval process for release of gene drive-modified mosquitoes, according to relevant laws, implementing regulations, and policies. In general, potential harms associated with the proposed activities will be characterized during case-specific pre-release risk assessment. Pertinent information, such as prior experience with gene drive-modified and other related genetically modified mosquitoes as well as knowledge of the biology and behavior or the mosquito species, of the modified trait(s), and of the receiving environment (geography, weather, land use, built environment, etc.) will be considered in the risk characterization. Regulatory authorities will provide a recommendation of acceptable risks and those that need to be managed or mitigated, as well as any strategies to provide such management or mitigation. These recommendations will form the basis for the terms of reference for use of an approved gene drive-modified mosquito product. Once approved and released, it will be necessary to monitor the effectiveness and sufficiency of the risk management measures. Thus, requirements of post-approval monitoring are expected to focus largely on those issues where there is ongoing uncertainty about safety and efficacy that was not resolved during risk assessment. Monitoring endpoints, frequency, and duration can be altered based on post-approval data resolving the remaining uncertainty.