key: cord-0040126-6x4a06sy
authors: Rainer, David; Cook, Susan
title: Overcoming regulatory gaps in biological materials oversight by enhancing IBC protocol review
date: 2016-02-19
journal: Ensuring National Biosecurity
DOI: 10.1016/b978-0-12-801885-9.00005-6
sha: 7b90a611cbd9c79f7702ba81380872a918c23eb5
doc_id: 40126
cord_uid: 6x4a06sy

In the United States, several regulations and federal policies govern the use of potentially biohazardous materials in research and industry. Part of this oversight is assigned by mandate to Institutional Biosafety Committees (IBCs). However, most research entities give additional responsibilities to their IBC to take advantage of a standing body with significant expertise in review and oversight of biohazardous research. Two case studies are provided to highlight functions of the IBC which are not mandated, yet are critical for safe and responsible research. There are also types of biohazardous work that are currently unregulated and receive no review from an IBC or other group of subject matter experts, leaving a gap in safety oversight. To mitigate the hazard of working with potentially hazardous unregulated biological material, the necessity of performing a risk assessment and of performing a hazard review by subject matter experts, such as those on an IBC, is of paramount importance.

Science may set limits to knowledge, but should not set limits to imagination.

Bertrand Russell [1] Scientists have boundless energy, initiative, independence, and imagination and excel at developing and changing research initiatives. So too must the safety review process evolve to help ensure the maintenance of a safe work environment.

Although the regulatory mandate related to the role of the Institutional Biosafety Committee (IBC) has evolved over 30 years and become more expansive, institutions are self-regulating and are therefore filling gaps in non-regulated research by having IBCs conduct safety reviews beyond their federally mandated requirements.

Most interesting is what is not prescribed in the NIH Guidelines for staffing IBCs [2] . The Guidelines are silent on the issue of staffing of an IBC administrator, environmental health and safety (EHS) professionals, and others who may be relevant to the safety review process. However, regulatory gaps in safety review oversight are effectively being managed by including many of these professionals on IBCs and in "scope creep" of IBCs. Scope creep is having a profound impact on the types of research these committees review, the way IBCs operate and the time it takes these committees and their dedicated appointees to perform their jobs related to review. We will detail the evolving responsibilities-both those already realized and those likely to be in the future-later in this chapter.

By way of an example, North Carolina State University requires investigators, diagnostic lab directors, and course instructors to receive IBC approval prior to obtaining or using any of the biological materials listed below [3] :

• Recombinant or synthetic nucleic acid molecules including their use in animals (including arthropods) and plants • Human and other primate-derived substances (blood, body fluids, cell lines or tissues)

• Organisms or viruses infectious to humans, animals, or plants (e.g., parasites, viruses, bacteria, fungi, prions, rickettsia) or biological materials that may contain these microorganisms • Select Agents or Toxins (human, animal, or plant)

• Biologically active agents (e.g., toxins, venoms) that may cause disease in humans or cause significant impact if released to the environment.

Agkistrodon piscivorus, Agkistrodon contortrix, Boulengerina annulata, Naja mossambica, Naja haje annulifera, Thelotornis capensis, Micrurus fulvius. Unsure of what these are? So was the North Carolina State's Institutional Animal Care and Use Committee (IACUC) when it went on a herpetology facility inspection and asked for an up-to-date species list to better understand the potential hazard of the venomous snakes available for milking and research on the campus. When the species names were translated to common names, cottonmouth, copperhead, ringed water cobra, spitting cobra, Egyptian cobra, twig snake and coral snake, there was some significant anxiety over the presumed hazard especially since the snakes were being milked to collect venom to analyze chemical make-up and potential use for medical treatment.

But who would be tasked to more fully understand the hazards and make recommendations about risk tolerance associated with the snake research? The IBC, of course, with subject matter experts including the state zoo herpetologist and state science museum reptile curator. Not only did the IBC assess the level of risk but it also went on to assess safe snake-handling practices, facility design and containment, signage to alert emergency facility responders, security, and campus emergency response to snake bites. The IBC also initiated hospital contact to ensure local emergency rooms could respond appropriately.

After initial IBC deliberations about risk tolerance associated with the research program with these snakes the committee made a recommendation to the Principal Investigator (PI) and Vice Chancellor for Research to send back some of the snakes to their owners (some of the snakes were on loan) due to lack of antivenin and the likelihood of significant medical emergency or death resulting from a bite. The recommendations were immediately accepted and an IBC representative oversaw the packing and shipping of some specimens back to their owners (if you are envisioning snakes on a plane, you are correct).

This chapter will cover a range of subject areas related to what IBCs do. But, as is already apparent, since there are no limits to scientists' imaginations, campuses will always be challenged to assess and review new research protocols with all manner of biologically active agents and toxins. A logical place for review is the IBC because of its diverse make up and reporting structure through senior university administration. This chapter will also discuss regulatory gaps that exist in oversight of research with infectious agents and recombinant or synthetic nucleic acids.

In Chapter 1, Zelicoff defined the terms biosecurity and biosafety. "The term biosecurity refers to the protection, control of, and accountability for high-consequence biological agents and toxins and critical relevant biological materials and information within laboratories to prevent unauthorized possession, loss, theft misuse, diversion or intentional release. Biosecurity is achieved through an aggregate of practices including the education and training of laboratory personnel, security risk assessments, Biological Select Agent and Toxin (BSAT) access controls, physical security (facility) safeguards and the regulated transport of BSAT. Achieving effective biosecurity for BSAT is a shared responsibility between the Federal Government and facilities/ individuals that possess, use or transfer BSAT." "Complementary to, but distinct from biosecurity is biosafety based on principles of containment and risk assessment in the laboratory." Containment includes: "the microbiological practices, safety equipment, and facility safeguards that protect laboratory workers, the environment and the public from exposure to infectious micro organisms that are handled in the laboratory," whereas risk assessment is "the process that enables the appropriate selection of microbiological practices, safety equipment, and facility safeguards that can prevent laboratory-associated infections." In short, biosecurity refers to the tools to manage threats, whereas biosafety procedures mitigate risks.

The NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines) are constantly evolving and are extremely comprehensive for managing recombinant or synthetic nucleic acid research [4] . As stated in the scope, "The purpose of the NIH Guidelines is to specify the practices for construction and handling of: (i) recombinant nucleic acid molecules, including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules, and (ii) cells, organisms, and viruses containing such molecules" [4] .

Also according to the Guidelines, Section IV-B-2-b Functions, the IBC is responsible for, among other things: 1. Reviewing recombinant or synthetic nucleic acid molecule research conducted at or sponsored by the institution, including containment levels required; assessment of the facilities, procedures, practices, training, and expertise of personnel involved; 2. Assuring conformance to Section M of the Guidelines for research involving the transfer of recombinant or synthetic nucleic acid molecules into one or more human research participants, and 3. Adopting emergency plans covering accidental spills and personnel contamination.

The reality is that the types and complexity of research programs are increasing and disciplines like engineering, chemical engineering, mechanical and aerospace engineering, material science and other physical sciences are moving beyond the traditional boundaries of their respective research roles and looking at biologically active systems and toxins.

While the Guidelines provide an extremely important regulatory and health and safety framework, one should not lose sight of the fact that from the operational and regulatory perspective of a campus EHS group, safety oversight and safety reviews are required for innumerable projects not explicitly covered by the Guidelines. So, how can academic EHS staff piggyback on the Guidelines to provide practical project review? What gaps exist in current government-mandated safety reviews? And how do EHS programs support risk assessment and hazard review in a timely manner so as to manage the risks of working with biological systems and agents? A brief brainstorming session among EHS staff may identify many programs with biological systems and agents and toxins requiring review, including but not limited to the following: The reality is that many organizations are using the expertise and organizational structure of their respective IBCs to support safety and health reviews of items like those listed above which are not defined within the scope of the NIH Guidelines. Because IBCs by nature are interdisciplinary teams, they are uniquely positioned to support safety and health reviews and serve as a safety gatekeeper for many kinds of research protocols. This can be both a blessing and a curse because the committees provide a framework and structure for conducting safety reviews recognizing that the time commitment may be onerous and academic departments may not reward participation on safety and health committees. In the long term though, the benefit of using an IBC to conduct health and safety reviews is a worthy initiative and serves to protect the institution, its employees, and students by managing risk. The physical damage to life and limb, inadvertent exposure to biological agents or toxins to persons or the environment and potential damage to reputation caused by laboratory and research program accidents should convince anyone who questions this expansion of IBC duties to pause and see the logic of supporting IBC safety reviews outside the boundaries of their traditional role.

Let's suppose that your institution is thinking about a Center for Programmable Plants (CePP) [5, 6] . The Center will be looking at the whole plant to improve economically relevant traits in plants such as improving shelf life, limiting potential for damage/ bruising during shipment, and maximizing food safety. The CePP will bring together expertise in mathematical modeling and engineering with plant system biologists to understand the underlying networks that contribute to yield variability and traits most wanted by consumers.

The plant disease group will be looking at plant disease, plant biotic stress, plantfungal interaction, transgenic plants for disease resistance, virus disease, sustainable agriculture in the developing world, and the ecology of plant biotic interactions.

The abiotic stress group will be studying drought stress, extremophile genes for engineering plant stress tolerance, systems biology, plant metabolic engineering, physiological ecology of plants, climate change, drought ecology, and the intersection of time and temperature on the control of plant response to osmotic stresses.

The nutrient stress and availability group will be evaluating systems biology, plant iron and nutrient stress, modeling of regulatory pathways, characterizing soil microorganisms and microbial processes using culture-dependent and independent methods.

Because the CePP is a major program for discovery and innovation and will bring together interdisciplinary teams and require business and academic partnerships this plant science initiative will require a world-class facility to bring the ideas to life ( Figure 5 .1).

Assuming that a project with this scope and breadth has the approvals of senior university administration, it is also apparent that this project (really several interlocking projects) will require navigation through multiple complex reviews and approvals that need to complement each other. Although only a portion of the project requires the construction and handling of recombinant nucleic acid molecules meeting the criteria defined for review under the Guidelines, many campuses would use the resources of the IBC to begin a review. So what is a logical first step?

Since this project will require intramural and extramural funding, let's assume the project has the needed on-campus approvals from the appropriate Deans and university executive staff to proceed. As the project concept moves forward, there needs to be an administrative process to assure the engagement of the applicable academic and administrative departments: everyone from the University Architect (new building siting, design, aesthetics, budget), EHS (building safety, biosafety, risk assessment, fire safety), Research Administration (contracts, grants, regulatory reviews), and others must be included. One of the initial reviews should be through the IBC and one of the first questions that should be answered by IBC review is: Is the scope of the project sufficiently defined so that a conclusion may be drawn regarding safe conduct of that research on your campus? This question, challenging in both depth and breadth, must be evaluated both in the context of your campus's safety, regulatory and risk management process as well as in the context of whether or not the proposed facility is adequate in terms of design and operation to support the research program. 

Based on NIH Guidelines (section IV-B-2-a-c1), the minimum number of IBC members is five. The Guidelines specify that the members "collectively have experience and expertise in recombinant or synthetic nucleic acid molecule technology and the capability to assess the safety of recombinant or synthetic nucleic acid molecule research and to identify any potential risk to public health or the environment" [4] .

However, as IBCs move beyond their traditional scope and evaluate all manner and types of projects the expertise represented by committee members will inevitably move beyond traditional boundaries.

It is clear from the scope of the research program outlined above that it is not likely that a five-member committee could have all of the requisite expertise to review an expansive research program like the CePP, and we will discuss the additional expertise required as part of this case study. A more well-rounded committee and a committee structure more likely found in an organization with a complex research agenda may preferentially include: scientists, clinical investigators and administrators (with a mix of tenured and non-tenured faculty) that have varied technical expertise (e.g., recombinant DNA; virology, microbiology, agents infectious to humans, animals or plants; acute toxins of biological origin, risk assessment, medicine, veterinary medicine, physical security), and other expertise relevant to the type of protocols being reviewed.

Community representation NIH Guidelines stipulate that at least two members of the IBC not be affiliated (non-affiliated members) with the institution, but represent the interests of the local community and general population. Community members may include officials of state or local public health or environmental protection agencies, members of other local governmental bodies, or persons active in medical, occupational health, or environmental concerns in the community. While the NIH Guidelines do not stipulate a particular educational background for a non-affiliated member, this person(s) must be able to understand the basic concepts of the registration(s) submitted to the committee, understand relevant biosafety and IBC review procedures at the respective institution and must have a conflict-of-interest statement on file with the institution. For example, NC State community members have expertise in plant and molecular biology and bioterrorism and emerging pathogens.

The IBC should also have ex-officio members: by virtue of their administrative or regulatory positions, the Biosafety Officer (BSO), the Director of EHS, and other relevant compliance personnel should be ex-officio members of the IBC. Based on the NIH Guidelines (Section IV-B-3-b) the BSO is a voting member if the institution engages in recombinant or synthetic nucleic acid molecule activities requiring BSL-3 containment and/or large-scale (>10 L) recombinant or synthetic nucleic acid molecule activities. However, we believe that it always makes sense for the BSO to be a voting committee member.

Most important if a registration is outside the area of expertise of IBC members, the IBC Chair should always be authorized to seek counsel from one or more individuals knowledgeable in the subject matter. This person could be someone external to the organization as necessary. Recall that in the introduction to this chapter the IBC was tasked to make risk management decisions related to the use of venomous snakes and the Vice Chancellor of Research wisely asked subject matter experts from the state zoo (herpetologist) and state science museum (reptile curator) to participate in the review.

Research projects utilizing specialized materials or incorporating novel systems such as the use of nanoparticles would certainly warrant bringing in outside subject matter expertise. Another issue requiring expertise is physical security. Whether it be your committee's recommendation that drives physical security enhancements based on a risk assessment or regulatory entity request, deploying appropriate security systems requires a knowledge base distinct from biological and physical sciences.

In summary, as you consider the makeup of your IBC and the expertise of committee members, recognize that a diversity of expertise and disciplines in committee makeup helps effectively carry out expected responsibilities.

Standardizing the IBC review process Figure 5 .2 provides a schematic layout for an IBC review process. The NIH Guidelines outline the minimum responsibilities for the institution, IBC, BSO, PI, and subject matter experts. As discussed elsewhere in this chapter, many institutions choose to assign additional responsibilities to the IBC, BSO, PI, and subject matter experts. For ease of discussion, we will take North Carolina State University (NC State) as an example of a typical academic research institution, and will discuss the overall IBC review process, as well as the specific responsibilities assigned to each party.

This particular institution (NC State) has chosen to assign its IBC the responsibility of reviewing all research with biohazard risks that include the following biological materials:

1. Recombinant or synthetic nucleic acid molecules in organisms 2. Creation of transgenic plants or animals 3. Human and other primate-derived substances (blood, body fluids, cell lines, or tissues) 4. Organisms and viruses infectious to humans, animals, or plants (e.g., parasites, viruses, bacteria, fungi, prions, rickettsia) 5. Biologically active agents (i.e., toxins, allergens, venoms) that may cause disease or injury to other living organisms or cause significant impact to the environment or community.

The IBC provides recommendations to administration officials responsible for conduct of research at the university. These administrators have the responsibility to facilitate carrying out the recommendations of the IBC. EHS staff usually process administrative tasks of the IBC. IBC responsibilities extend and apply to all instructional and research projects conducted at the university, regardless of location on the property, including all rented or leased facilities. Requirements also apply if work is being done off-site. The local IBC may accept the approval of another IBC or may officially delegate an external IBC to act on its behalf.

The IBC establishes, recommends, and/or approves policies on the proper use of biohazardous agents including, but not limited to: recombinant or synthetic nucleic acid molecules, transgenic animals and plants, infectious agents, acute biological toxins, and venomous animals/poisonous plants. Policy objectives are to protect staff, research subjects, the general public, and the environment from biohazardous agents. In the unlikely event that a laboratory persists in following procedures in violation of compliance regulations and IBC policies, the Committee will recommend the imposition of sanctions by Department Heads, Deans, and/or Provost.

In summary, The IBC shall:

1. Establish and monitor policy, practices, and procedures for work involving biohazardous agents at the university. 2. Ensure that adopted policies, practices, and procedures for work with biohazardous agents meet applicable regulatory standards and guidelines. 3. Review biological research conducted at or sponsored by the university for compliance with adopted policies, regulations, and guidelines. This review shall include an independent assessment of the biological containment required, and an assessment of the facilities, training, and expertise of personnel involved in the research. The IBC shall ensure that the PI is provided with the results of the review and determination of approval in a timely manner. 4. Assess proposed containment facilities and practices for research projects. The IBC will use the biosafety levels (BSL) published by the Centers for Disease Control and Prevision (CDC), National Institutes of Health (NIH), and US Department of Agriculture (USDA) as the usual standards of containment to be set for work with a given biological agent. To the extent allowed by Federal law and regulation, the IBC may, at its discretion, increase or reduce the BSL depending on the circumstances presented by a specific project. 5. Review any findings of the BSO in investigating any significant violation of policies, practices, and procedures; participate in an investigation of any significant research-related accidents or illnesses; and recommend to university administration appropriate disciplinary action if an investigation reveals significant violations. 6. Perform such other functions as may be delegated to the IBC by the university administration. Members of the committee review research protocols. However, it is not the responsibility of the IBC to critique a PI's research program. Applications are reviewed for biological containment and biological safety concerns only.

A BSO position in EHS assists the IBC and the research community in meeting the compliance requirements of the NIH Guidelines. The BSO is also responsible for the development, implementation, and maintenance of a comprehensive Biosafety Program. The IBC and its policies complement and support the objectives of this Biosafety Program and the BSO is often the primary intermediary between PIs and the IBC. The specific tasks for the BSO are to:

1. Manage the Biosafety Program and support implementation of IBC policies and procedures.

Maintain an active IBC and recommend the appointment of the IBC Chair, Vice-Chair, and committee members to the university administration. 3. Assist laboratories in conforming to pertinent regulatory guidelines and IBC policies by providing training, facility inspections, and communication of Biosafety Program and related regulatory requirements.

Laboratories [7] , and the OSHA Bloodborne Pathogens Standard as applicable. 5. Screen research protocols submitted by PIs and make recommendations to the IBC. 6. Prepare periodic reports for institutional management regarding IBC activities and Biosafety Program status. 7. Screen protocols submitted to the IACUC for identification of biological hazards; consult with animal facility management, veterinarians, and PIs regarding appropriate containment procedures for biohazardous agents. 8. Ensure preparation of minutes of IBC meetings. 9. Monitor federal, state, and local regulatory trends, and communicate any changes to the IBC. 10. Submit required annual reports to NIH Office of Biotechnology Activities.

The Director of the Environmental Health and Safety Center, through the BSO and the IBC, implements a program to help ensure that research is conducted in full conformity with local, state, and federal policies and regulations. In order to fulfill this responsibility, the Director of the Environmental Health and Safety Center's tasks are to:

1. Establish and implement policies that provide for the safe conduct of research and teaching involving biohazardous agents.

PIs conducting research at the university.

agents and biosafety procedures, including training programs and workshops. 4. Review resources for medical surveillance measures to protect the health and safety of employees.

The PI is defined as the faculty member or other person acting in their official capacity as a university representative who leads the research effort and is ultimately responsible for the conduct of research within the space assigned to his/her. The PI is responsible for full compliance with the policies, practices, and procedures set forth by the university. This responsibility extends to all aspects of biosafety involving all individuals who enter or work in the PI's laboratory or collaborate in carrying out the PI's research. Although the PI may choose to delegate aspects of the Biosafety Program in his/her laboratory to other laboratory personnel (laboratory directors or supervisors) or faculty, this does not absolve the PI of his/her ultimate responsibility. The PI remains accountable for all activities occurring in his/her laboratory. Documentation of training and compliance with appropriate biosafety practices and procedures is essential. The PI is responsible for assuring the appropriate safety training of employees and for correcting errors and unsafe working conditions.

As part of general responsibilities the PI shall 1. Develop and implement written laboratory-specific biosafety procedures that are consistent with the nature of current and planned research activities and make available copies of the specific biosafety procedures in each laboratory facility. The PI shall ensure that all laboratory personnel, including other faculty members, understand and comply with these laboratory-specific biosafety procedures.

Ensure that all laboratory personnel, maintenance personnel, and visitors who may be exposed to any biohazardous agents are informed in advance of their potential risk and of the behavior required to minimize that risk. It is essential that everyone who may have potential exposure to biohazardous agents be informed of such hazards and appropriate safety practices before entering or working around or with such hazards.

Ensure that all maintenance work in, on or around contaminated equipment is conducted only after that equipment is thoroughly decontaminated by the laboratory staff or PI. 4. Ensure that research materials are properly decontaminated before disposal and that all employees are familiar with the appropriate methods of waste disposal. 5. Report any significant problems or violations of policies, practices, or procedures to the BSO as soon as reasonably possible. 6. Notify the BSO immediately if: a. A laboratory-acquired infection is known or suspected, or b. A spill of any quantity involving an agent infectious to humans, plants, or animals occurs in a public area. 7. Receive training in standard microbiological techniques. 8. Ensure that all research personnel are appropriately trained in biosafety and receive appropriate medical surveillance when needed. The PI should contact the BSO for assistance with all biosafety training needs. 9. Coordinate with the BSO and develop emergency plans for handling accidental spills and personnel contamination. 10. Create and foster an environment in the laboratory that encourages open discussion of biosafety issues, problems, and violations of procedure. The PI will not discipline or take any adverse action against any person for reporting problems or violations to the IBC, BSO, Risk Management, or State or Federal agencies. 11. Comply with shipping requirements for biohazardous agents and select agents.

In submitting proposed work to the IBC, the PI shall 1. Make an initial determination of the required levels of physical and biological containment in accordance with the requirements set forth by the NIH Guidelines and the CDC publication Biosafety in Microbiological and Biomedical Laboratories [7] , as applicable.

Select appropriate microbiological practices and laboratory techniques to be used for the research. 3. Submit any significant changes in a given project to the BSO for review and approval.

Prior to initiating research, the PI shall coordinate with the BSO to 1. Make available to all laboratory staff and involved facilities staff (such as animal care staff) the protocols that describe the potential biohazards and the precautions to be taken.

a. Identification of the biohazard(s) present b. Practices and techniques required to ensure safety and reduce potential exposure c. Procedures for dealing with accidents, spills, and exposures. 3. Inform the laboratory staff of the reasons and provisions for any precautionary medical practices advised or requested (e.g., vaccinations or serum collection). 4. Ensure that collaborators are made aware in advance of any biohazardous agents sent to them, and comply with all applicable packaging and shipping requirements. These materials are often regulated for shipment and must only be shipped by personnel who have received proper training and are authorized by the university to ship such materials on its behalf.

include the approximate quantity of the materials and where it is stored in the laboratory.

During the conduct of the research the PI shall 1. Supervise the safety performance of the laboratory staff to ensure that required safety practices are employed.

Investigate and report in writing to the IBC any significant problems pertaining to the operation and implementation of containment practices and procedures. 3. Immediately notify the BSO of any laboratory spills, accidents, containment failure, or violations of biosafety practice which result in the release of biohazardous agents and/or the exposure of laboratory personnel (or the public) to infectious agents. The IBC may be consulted by the BSO if necessary. 4. Correct work errors and conditions that may result in the release of biohazardous agents. 5. Ensure the integrity of all containment systems used in the project. 6. Restrict access as required by the laboratory-specific biosafety practices and procedures, and by the biosafety containment level approved by the IBC. 7. Immediately notify the BSO if a Select Agent has been isolated and confirmed from environmental and/or diagnostic specimens.

All new members are required to complete training on the regulatory responsibilities and functions of the IBC. This training must be completed before participation in voting activities of the committee. The IBC Chair or his/her designee will administer training. All IBC members must also complete annual retraining, covering topics that will enhance the committee's understanding of biosafety-related issues and institutional research review policies.

Although the role of the IBC is increasingly broad, gaps in regulatory oversight still exist. The following sections will discuss these gaps and the potentials risks they introduce.

The NIH Guidelines apply to all researchers at an institution if anyone at that institution accepts NIH funding for recombinant or synthetic nucleic acid research. This often means that even researchers who accept no NIH money must adhere to the NIH Guidelines. The NIH Guidelines do not apply to institutions in the United States that receive no NIH funding, however, including pharmaceutical companies, other private companies performing research with recombinant or potentially infectious materials, or private individuals. This regulatory gap allows for the possibility of risky work with recombinant DNA proceeding without any oversight. Pharmaceutical companies, by nature, are investigating agents that will be used as therapeutics and are designed to have a favorable risk-benefit ratio. This may lead people working with these agents to believe that the agents have no hazards associated with them. However, many genetically modified study drugs are targeted against conditions with poor prognoses, so these potential therapeutics can have significant adverse side effects and still have a favorable risk-benefit ratio for the trial participant. If the clinical trial is supported solely by private funding and is performed only at clinical care centers that receive no NIH funding (e.g., private cancer centers) then the clinical trial does not fall under the NIH Guidelines. This means that the trial does not need to undergo public discussion through submission to NIH's Recombinant DNA Advisory Committee (RAC) or have local review by an IBC [8] . These trials would still be required to undergo Food and Drug Administration (FDA) review and local IRB review, but those bodies review different aspects than the RAC and IBC do. For example, the FDA and local IRB focus primarily on the safety of the recipients by ensuring the ethical conduct of the trial [9] . While the RAC and IBC also consider participant safety, they bring specific technical expertise needed for the assessment of the risks to close contacts of the recipient as well as the healthcare professionals preparing and administering the agent. Genetically modified viruses or other gene therapy agents may have the potential to modify the genetic code of the recipient's reproductive cells, making effective barrier contraception critical. Unlike traditional drugs which are metabolized and eventually broken down in the recipient's body, investigational agents created from microbes or modified human cells may be capable of replicating and expanding. This increases the opportunity for contamination of hospital rooms, personal bathrooms, or shared items such as eating utensils. Live agents, genetically modified or not, can pose risk of serious harm to individuals with immune deficiencies caused by organ transplant, infectious disease, pregnancy, or other conditions. Recipients of these agents must be instructed on how, and for how long, to minimize their contact with these high-risk individuals and how to properly clean and disinfect their homes to minimize the risk of transmission of potentially infectious study drug through bodily fluids. IBCs are responsible for reviewing the informed consent documents to verify that these instructions are adequately explained.

Pharmaceutical companies also produce much greater quantities of product than academic research labs, introducing different risks. Gene therapy vectors based on modified viruses (e.g., adeno-associated virus, adenovirus, or retrovirus) generally do not pose an aerosol exposure risk when used in laboratory-scale quantities. At the volumes and concentrations used in manufacturing, however, these viruses may overcome their normal route of infection and present an aerosol infection risk. In addition to the direct effects of the gene therapy product or virus itself, an accident that results in exposure to manufacturing-scale quantities may induce a strong enough immune response or allergic reaction to lead to serious illness or death. Most pharmaceutical companies choose to have safety committees, but the membership and responsibilities of these safety committees are not clearly defined and may differ greatly from company to company.

The NIH Guidelines also do not apply to the growing number of individuals who perform recombinant or synthetic nucleic acid experiments as a hobby. Some of these hobbyists belong to community organizations, such as DIYBio [10] or BioBricks, [11] , that provide connections between amateur researchers and biosafety professionals. Others may be unaware that such safety resources are available to them or may actively avoid professional advice in pursuit of the "DIY Ethic." Sale of most equipment used in recombinant DNA research is not regulated or controlled and it is relatively simple to acquire the necessary supplies to create a modest but fully functional laboratory. Online auction sites have thousands of listings for PCR machines, electrophoresis equipment, pipettes, and other basic equipment and supplies. Instructions for genetically modifying Escherichia coli and other bacteria are readily discoverable through Internet search engines and various online communities exist to bring together "biohackers" to discuss projects and techniques. At least one company was recently founded to provide a way for research universities to sell their surplus reagents to other universities and community members. Unlike model rockets or soccerplaying robots, modified pathogens generated by DIY biologists may be capable of replicating and spreading to others who are not actively participating in the hobby. These genetically modified organisms may pose a larger community risk than other, more-traditional hobbies if the modifications introduce resistance to therapeutic drugs or allow the microbes to spread more easily or survive longer in the environment.

The NIH Guidelines outline several types of experiments that are deemed to be low enough risk that they are exempt from the requirements of the NIH Guidelines. Among these are purchase and transfer of transgenic animals, use of non-viral plasmids in cell culture lines, and expression of recombinant proteins in standard laboratory strains of bacteria and yeast. Some IBCs continue to review these experiments to confirm the investigator's assessment that the work is exempt and to provide institutional assurances that all recombinant DNA work is being performed responsibly. It may also be administratively easier to train investigators to submit all of their work to the IBC rather than ask them to be familiar enough with the NIH Guidelines to distinguish between exempt experiments and experiments that require review and approval prior to initiation.

Research involving microbes and toxins deemed to be the most likely agents of bioterrorist attacks is regulated in the United States by the Select Agent Regulations [12] . Before work with any of the more than 60 agents begins, the institution must write detailed safety and security plans and be inspected by the Division of Select Agents and Toxins (DSAT) to verify that the proposed safety and security practices are sufficient to contain the agent from theft, loss, or accidental release to the environment. The Select Agent Regulations have several exemptions or exclusions, however. Select agent toxins are only regulated when a single individual possesses more than a threshold amount (0.5-100 mg, depending on the toxin). Institutions may have more than the threshold amount of toxin on their premises but remain exempt from the Select Agent Regulations because no one individual has more than the threshold quantity of toxin in their possession.

Nucleic acids from select agents or hybrid viruses that combine genes from select agent viruses with non-select agent viruses may not be regulated depending on the specific viruses and genes involved. Determining whether or not the hybrid virus is regulated as a select agent can be difficult and is the responsibility of the institution performing the work (after consulting the select agent and toxin list as updated by the responsible regulatory agencies, USDA and HHS). Consequently, different institutions may come to different conclusions about what is, or isn't, regulated, and work with potentially dangerous hybrid viruses may be carried out in standard laboratory settings rather than in laboratories with the enhanced security features required by the Select Agent Regulations. Because of their expertise in recombinant DNA risk assessment, IBCs are often tasked with helping the institution's Responsible Official determine whether these chimeric viruses should be treated as regulated select agents or not. At institutions where no IBC is present, no oversight body would be available to educate investigators on the possible safety and regulatory implications of mixing genes from select agent viruses with non-regulated viruses and potentially dangerous chimeric viruses may be inadvertently created. If investigators do not realize that these chimeric viruses are more pathogenic than the parent strain then they may not use the proper safety precautions or laboratory facilities. This, in turn, could lead to occupational exposures or environmental releases that could place the surrounding community at risk.

Select agents in their natural environments are also not subject to the Select Agent Regulations. Several select agents (including Francisella tularensis and Yersinia pestis) are endemic in different areas of the United States. Investigators collecting field specimens in these areas may unwittingly be collecting and storing select agent specimens. These specimens are not regulated until the select agents are identified (e.g., through nucleic acid sequencing) but they may pose significant health risks if there is an occupational exposure while handling the specimens.

In September 2014, the Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern was released [13] . This policy describes the requirements for local review, approval, and oversight of dual use research of concern (DURC). DURC is described in detail elsewhere in this book but, in short, DURC refers to research that produces valuable scientific information but may also be used in warfare or terror attacks. This federal policy requires that each institution designate an Institutional Review Entity (IRE) to review DURC projects and assist in creation of risk mitigation plans for these projects. The companion guide [14] that accompanies the federal policy suggests that IBCs are the most logical choice for the IRE since similar expertise is needed to assess the risks associated with recombinant DNA research and modifications of pathogens that may increase their transmissibility or pathogenicity. IBCs may not have the security expertise needed for these reviews, however, and consultants or ad hoc members may need to be added to fulfill the responsibilities assigned to the IRE. The DURC policy only applies to institutions that receive federal funding for life sciences research and is restricted to research involving 15 specific pathogens. Institutions or individuals that receive no federal funding are under no obligation to follow the DURC policy, nor are individuals who are working with pathogens other than the 15 specifically listed in the DURC policy. Many common human pathogens (e.g., Salmonella, E. coli, or influenza) are not on the list of pathogens covered by the DURC policy. Consequently, there is no regulatory reason why researchers cannot modify the pathogens to become more virulent. While this research would most likely be done to study the mechanisms that make pathogens more deadly and to better understand how to control natural infections with these pathogens, publication of this research may provide a roadmap for individuals who would use biological agents in terrorist attacks.

In October 2014, the White House announced a funding pause and voluntary moratorium on so-called "gain-of-function" research for three pathogens (influenza, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus) [15] . While gain-of-function (GOF) is not specifically defined in the White House memo, the general consensus is that GOF refers to any experiments that increase the pathogenicity or mammalian transmissibility of these pathogens. The White House memo also does not describe how GOF research should be identified or reviewed at institutions performing infectious disease research. Because GOF is similar to DURC, it seems most likely that institutions will ask their IREs to review GOF research in addition to DURC. This will increase the workload for IBCs which will now be tasked to make decisions about GOF research in the absence of clear guidance or policy statements from the federal government regarding what is, or isn't, GOF research. This funding pause is not yet a formal policy and it currently only applies to individuals receiving federal funding for these three specific agents so the number of researchers impacted is expected to be low.

Since the DURC policy and GOF funding pause only apply to federally funded research and IBCs are only required at institutions receiving NIH funding, a potentially dangerous gap exists in the oversight of recombinant DNA research with pathogens. A properly functioning IBC will have the expertise needed to anticipate whether proposed research has the potential to increase the pathogenicity of an agent and recommend additional safeguards to protect the individual researchers and the surrounding community from an accidental exposure or release. The DURC policy and GOF funding pause provide more guidance on how and when IBCs need to formalize these types of reviews and recommendations. Institutions or individuals that receive no federal funding may not have access to the expertise needed to assess the risks associated with the modifications they are making to lower-risk pathogens and may end up creating potentially dangerous infectious agents.

As discussed in this chapter, IBCs play a critical role in assessing the risks associated with recombinant DNA or synthetic nucleic acid research. This role is ever-expanding and includes such diverse topics as facility design, collection of wild animals, production of engineered nanomaterials, and medical surveillance. Even with all that IBCs are asked to do, there are still several areas of research that receive no IBC review because the research falls outside of the existing regulations. These gaps create the possibility for potentially dangerous, if well-intentioned, research to continue without appropriate safety oversight. But, it is highly likely that any new mandates for oversight responsibility will fall to the IBC at most universities and research establishments.

Bertrand Russell Quotes. Quotes.net -STANDS4 LLC

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