Requirements for market entry of gene drive-modified mosquitoes for control of vector-borne diseases: analogies to other biologic and biotechnology products.

Gene drive-modified mosquitoes (GDMMs) are proposed as new tools for control and elimination of malaria and other mosquito-borne diseases, and promising results have been observed from testing conducted in containment. Although still at an early stage of development, it is important to begin now to consider approval procedures and market entry strategies for the eventual implementation of GDMMs in the context of disease control programs, as these could impact future research plans. It is expected that, as for other types of new products, those seeking to bring GDMMs to market will be required to provide sufficient information to allow the regulator(s) to determine whether the product is safe and effective for its proposed use. There already has been much emphasis on developing requirements for the biosafety components of the "safe and effective" benchmark, largely concerned with their regulation as genetically modified organisms. Other potential approval requirements have received little attention, however. Although GDMMs are expected to be implemented primarily in the context of public health programs, any regulatory analogies to other public health products, such as pharmaceuticals, vaccines, or chemical pesticides, must take into account the characteristics of live mosquito products. Typical manufacturing standards related to product identity, potency or quality will need to be adapted to GDMMs. Valuable lessons can be drawn from the regulatory approval processes for other whole organism and genetically modified (GM) organism products. Supply chain requirements, such as scale of production, location and design of production facilities, and methods of distribution and delivery, will be dependent upon the characteristics of the particular GDMM product, the conditions of use, and the region to be served. Plans for fulfilling supply chain needs can build upon experience in the development of other live insect products for use in public health and agriculture. Implementation of GDMMs would benefit from additional research on enabling technologies for long-term storage of mosquito life stages, efficient mass production, and area-wide delivery of GDMMs. Early consideration of these practical requirements for market entry will help to mitigate downstream delays in the development of these promising new technologies.

Regulatory and policy considerations for the implementation of gene drive-modified mosquitoes to prevent malaria transmission.

Gene drive-modified mosquitoes (GDMMs) are being developed as possible new tools to prevent transmission of malaria and other mosquito-borne diseases. To date no GDMMs have yet undergone field testing. This early stage is an opportune time for developers, supporters, and possible users to begin to consider the potential regulatory requirements for eventual implementation of these technologies in national or regional public health programs, especially as some of the practical implications of these requirements may take considerable planning, time and coordination to address. Several currently unresolved regulatory questions pertinent to the implementation of GDMMs are examined, including: how the product will be defined; what the registration/approval process will be for placing new GDMM products on the market; how the potential for transboundary movement of GDMMs can be addressed; and what role might be played by existing multinational bodies and agreements in authorization decisions. Regulation and policies applied for registration of other genetically modified organisms or other living mosquito products are assessed for relevance to the use case of GDMMs to prevent malaria in Africa. Multiple national authorities are likely to be involved in decision-making, according to existing laws in place within each country for certain product classes. Requirements under the Cartagena Protocol on Biodiversity will be considered relevant in most countries, as may existing regulatory frameworks for conventional pesticide, medical, and biocontrol products. Experience suggests that standard regulatory processes, evidence requirements, and liability laws differ from country to country. Regional mechanisms will be useful to address some of the important challenges.

Lessons learned from the introduction of genetically engineered crops: relevance to gene drive deployment in Africa.

The application of gene drives to achieve public health goals, such as the suppression of Anopheles gambiae populations, or altering their ability to sustain Plasmodium spp. infections, has received much attention from researchers. If successful, this genetic tool can contribute greatly to the wellbeing of people in regions severely affected by malaria. However, engineered gene drives are a product of genetic engineering, and the experience to date, gained through the deployment of genetically engineered (GE) crops, is that GE technology has had difficulty receiving public acceptance in Africa, a key region for the deployment of gene drives. The history of GE crop deployment in this region provides good lessons for the deployment of gene drives as well. GE crops have been in commercial production for 24 years, since the planting of the first GE soybean crop in 1996. During this time, regulatory approvals and farmer adoption of these crops has grown rapidly in the Americas, and to a lesser extent in Asia. Their safety has been recognized by numerous scientific organizations. Economic and health benefits have been well documented in the countries that have grown them. However, only one transgenic crop event is being grown in Europe, and only in two countries in that region. Europe has been extremely opposed to GE crops, due in large part to the public view of agriculture that opposes "industrial" farming. This attitude is reflected in a highly precautionary regulatory and policy environment, which has highly influenced how African countries have dealt with GE technology and are likely to be applied to future genetic technologies, including gene drives. Furthermore, a mistrust of government regulatory agencies, the publication of scientific reports claiming adverse effects of GE crops, the involvement of corporations as the first GE crop developers, the lack of identifiable consumer benefit, and low public understanding of the technology further contributed to the lack of acceptance. Coupled with more emotionally impactful messaging to the public by opposition groups and the general tendency of negative messages to be more credible than positive ones, GE crops failed to gain a place in European agriculture, thus influencing African acceptance and government policy. From this experience, the following lessons have been learned that would apply to the deployment of gene drives, in Africa:It will be important to establish trust in those who are developing the technology, as well as in those who are making regulatory decisions. Engagement of the community, where those who are involved are able to make genuine contributions to the decision-making process, are necessary to achieve that trust. The use of tools to facilitate participatory modeling could be considered in order to enhance current community engagement efforts.Trusted, accurate information on gene drives should be made available to the general public, journalists, and scientists who are not connected with the field. Those sources of information should also be able to summarize and analyze important scientific results and emerging issues in the field in order to place those developments in the proper context. Engagement should involve more opportunities for participation of stakeholders in conceptualizing, planning, and decision-making.Diversifying the source of funding for gene drive research and development, particularly by participation of countries and regional bodies, would show that country or regional interests are represented.Efforts by developers and neutral groups to provide the public and decisionmakers with a more thorough understanding of the benefits and risks of this technology, especially to local communities, would help them reach more informed decisions.A better understanding of gene drive technology can be fostered by governments, as part of established biosafety policy in several African countries. Developers and neutral groups could also be helpful in increasing public understanding of the technology of genetic engineering, including gene drives.Effective messaging to balance the messaging of groups opposed to gene drives is needed. These messages should be not only factual but also have emotional and intuitive appeal.

Risk management recommendations for environmental releases of gene drive modified insects.

The ability to engineer gene drives (genetic elements that bias their own inheritance) has sparked enthusiasm and concerns. Engineered gene drives could potentially be used to address long-standing challenges in the control of insect disease vectors, agricultural pests and invasive species, or help to rescue endangered species. However, risk concerns and uncertainty associated with potential environmental release of gene drive modified insects (GDMIs) have led some stakeholders to call for a global moratorium on such releases or the application of other strict precautionary measures to mitigate perceived risk assessment and risk management challenges. Instead, we provide recommendations that may help to improve the relevance of risk assessment and risk management frameworks for environmental releases of GDMIs. These recommendations include: (1) developing additional and more practical risk assessment guidance to ensure appropriate levels of safety; (2) making policy goals and regulatory decision-making criteria operational for use in risk assessment so that what constitutes harm is clearly defined; (3) ensuring a more dynamic interplay between risk assessment and risk management to manage uncertainty through closely interlinked pre-release modelling and post-release monitoring; (4) considering potential risks against potential benefits, and comparing them with those of alternative actions to account for a wider (management) context; and (5) implementing a modular, phased approach to authorisations for incremental acceptance and management of risks and uncertainty. Along with providing stakeholder engagement opportunities in the risk analysis process, the recommendations proposed may enable risk managers to make choices that are more proportionate and adaptive to potential risks, uncertainty and benefits of GDMI applications, and socially robust.

Regulatory approaches for genome edited agricultural plants in select countries and jurisdictions around the world.

Genome editing in agriculture and food is leading to new, improved crops and other products. Depending on the regulatory approach taken in each country or region, commercialization of these crops and products may or may not require approval from the respective regulatory authorities. This paper describes the regulatory landscape governing genome edited agriculture and food products in a selection of countries and regions.

Edit at will: Genotype independent plant transformation in the era of advanced genomics and genome editing.

The combination of advanced genomics, genome editing and plant transformation biology presents a powerful platform for basic plant research and crop improvement. Together these advances provide the tools to identify genes as targets for direct editing as single base pair changes, deletions, insertions and site specific homologous recombination. Recent breakthrough technologies using morphogenic regulators in plant transformation creates the ability to introduce reagents specific toward their identified targets and recover stably transformed and/or edited plants which are genotype independent. These technologies enable the possibility to alter a trait in any variety, without genetic disruption which would require subsequent extensive breeding, but rather to deliver the same variety with one trait changed. Regulatory issues regarding this technology will predicate how broadly these technologies will be implemented. In addition, education will play a crucial role for positive public acceptance. Taken together these technologies comprise a platform for advanced breeding which is an imperative for future world food security.

Pathway to Deployment of Gene Drive Mosquitoes as a Potential Biocontrol Tool for Elimination of Malaria in Sub-Saharan Africa: Recommendations of a Scientific Working Group†.

Gene drive technology offers the promise for a high-impact, cost-effective, and durable method to control malaria transmission that would make a significant contribution to elimination. Gene drive systems, such as those based on clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein, have the potential to spread beneficial traits through interbreeding populations of malaria mosquitoes. However, the characteristics of this technology have raised concerns that necessitate careful consideration of the product development pathway. A multidisciplinary working group considered the implications of low-threshold gene drive systems on the development pathway described in the World Health Organization Guidance Framework for testing genetically modified (GM) mosquitoes, focusing on reduction of malaria transmission by Anopheles gambiae s.l. mosquitoes in Africa as a case study. The group developed recommendations for the safe and ethical testing of gene drive mosquitoes, drawing on prior experience with other vector control tools, GM organisms, and biocontrol agents. These recommendations are organized according to a testing plan that seeks to maximize safety by incrementally increasing the degree of human and environmental exposure to the investigational product. As with biocontrol agents, emphasis is placed on safety evaluation at the end of physically confined laboratory testing as a major decision point for whether to enter field testing. Progression through the testing pathway is based on fulfillment of safety and efficacy criteria, and is subject to regulatory and ethical approvals, as well as social acceptance. The working group identified several resources that were considered important to support responsible field testing of gene drive mosquitoes.

Results from the Workshop "Problem Formulation for the Use of Gene Drive in Mosquitoes".

Reducing the incidence of malaria has been a public health priority for nearly a century. New technologies and associated vector control strategies play an important role in the prospect of sustained reductions. The development of the CRISPR/Cas9 gene editing system has generated new possibilities for the use of gene-drive constructs to reduce or alter vector populations to reduce malaria incidence. However, before these technologies can be developed and exploited, it will be necessary to understand and assess the likelihood of any potential harms to humans or the environment. To begin this process, the Foundation for the National Institutes of Health and the International Life Sciences Institute Research Foundation organized an expert workshop to consider the potential risks related to the use of gene drives in Anopheles gambiae for malaria control in Africa. The resulting discussion yielded a series of consensus points that are reported here.

Genetically engineered trees for plantation forests: key considerations for environmental risk assessment.

Forests are vital to the world's ecological, social, cultural and economic well-being yet sustainable provision of goods and services from forests is increasingly challenged by pressures such as growing demand for wood and other forest products, land conversion and degradation, and climate change. Intensively managed, highly productive forestry incorporating the most advanced methods for tree breeding, including the application of genetic engineering (GE), has tremendous potential for producing more wood on less land. However, the deployment of GE trees in plantation forests is a controversial topic and concerns have been particularly expressed about potential harms to the environment. This paper, prepared by an international group of experts in silviculture, forest tree breeding, forest biotechnology and environmental risk assessment (ERA) that met in April 2012, examines how the ERA paradigm used for GE crop plants may be applied to GE trees for use in plantation forests. It emphasizes the importance of differentiating between ERA for confined field trials of GE trees, and ERA for unconfined or commercial-scale releases. In the case of the latter, particular attention is paid to characteristics of forest trees that distinguish them from shorter-lived plant species, the temporal and spatial scale of forests, and the biodiversity of the plantation forest as a receiving environment.

Biosafety education relevant to genetically engineered crops for academic and non-academic stakeholders in East Africa

Development and deployment of genetically engineered crops requires effective environmental and food safety assessment capacity. In-country expertise is needed to make locally appropriate decisions. In April 2007, biosafety and biotechnology scientists, regulators, educators, and communicators from Kenya, Tanzania, and Uganda, met to examine the status and needs of biosafety training and educational programs in East Africa. Workshop participants emphasized the importance of developing biosafety capacity within their countries and regionally. Key recommendations included identification of key biosafety curricular components for university students; collaboration among institutions and countries; development of informational materials for non-academic stakeholders and media; and organization of study tours for decision makers. It was emphasized that biosafety knowledge is important for all aspects of environmental health, food safety, and human and animal hygiene. Thus, development of biosafety expertise, policies and procedures can be a stepping stone to facilitate improved biosafety for all aspects of society and the environment.

Population size and incidence of virus infection in free-living populations of Cucurbita pepo.

Impact assessments of virus resistance transgene introgression into wild, free-living populations are important for determining whether these transgenes present a risk to agriculture or the environment. Transgenic virus-resistant Cucurbita pepo ssp. ovifera var. ovifera L. (squash) cultivars have been commercialized, and may be cultivated in close proximity to cross-compatible wild, free-living relatives (C. pepo subsp. pepo vars. ozarkana and texana). Therefore, the potential impact of these virus resistance transgenes was studied by surveying the incidence and fluctuations of virus infection (as assayed by ELISA), virus symptoms (which may not be seen in an infected plant) and population size in forty-three free-living C. pepo populations in Illinois, Missouri, Arkansas, Mississippi, Louisiana, and Texas. Ten of these populations were studied over three consecutive seasons. Depending on the year, 61% to 78% percent of the populations had at least one individual infected by at CMV, ZYMV or WMV2, but the median incidence of infection within populations was 13%. The observed infection level in free-living populations was consistent with levels defined as "low" in field plot experiments conducted by others, leading to the conclusion that transgenic virus resistance should not provide a significant fitness advantage to the free-living populations examined. Viral symptoms were detected in only 2% of plants observed, indicating that severity of viral infection was low. CMV, ZYMV, and WMV2 were not the only viruses infecting these populations, further reducing the likelihood that resistance to these viruses would release populations from constraints imposed by virus diseases.

Assessment of risk of insect-resistant transgenic crops to nontarget arthropods.

An international initiative is developing a scientifically rigorous approach to evaluate the potential risks to nontarget arthropods (NTAs) posed by insect-resistant, genetically modified (IRGM) crops. It adapts the tiered approach to risk assessment that is used internationally within regulatory toxicology and environmental sciences. The approach focuses on the formulation and testing of clearly stated risk hypotheses, making maximum use of available data and using formal decision guidelines to progress between testing stages (or tiers). It is intended to provide guidance to regulatory agencies that are currently developing their own NTA risk assessment guidelines for IRGM crops and to help harmonize regulatory requirements between different countries and different regions of the world.