Principal Investigator rDNA/Gene Transfer Training on NIH Guidelines

Principal Investigator rDNA/Gene Transfer Training on NIH Guidelines
The University of Texas at Austin Office of Research Support and Compliance Pat Levin IBC Program Coordinator Environmental Health and Safety Rachel LeBansky Safety Specialist IV

Recombinant DNA Program
The office of Biotechnology Activities at the NIH oversees rDNA research, including human gene transfer Manages the rDNA Advisory Committee (RAC) Administers the NIH Guidelines for Research Involving Recombinant DNA Molecules Partners with Institutional Biosafety Committees (IBC) in the oversight of rDNA research Office of Biotechnology Activities at the NIH

Definitions Recombinant DNA-
(i) molecules that are constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that are replicated in a living cell or (ii) molecules that result from the replication of those described in (i) above (www4.od.nih.gov/oba/Rdna.htm) Select Agents – specific microbiological agents and toxins of biological origin that have the potential to be weaponized and are regulated by the CDC/USDA. ( Examples of Select agents and Toxins: Bacillus anthracis, Bordetella pertussis, Brucella species, Burkholderia mallei/pseudomallei (formally pseudomonas), Camphlobacter species, Chlamydia species, Clostridium species and toxins, Francisellia tularensis, Helicobactor species, Legionella/Legionella like agents, Leptospira, Listeria monocytogenes, Mycobacterium species, Neisseria meningitidis, Salmonella species, Shigella species and toxin, Treponema pallidunm, and Yersinia pestis. Also included are several fungal such as Cryptococcus, Viral such as Ebola and Hantavirus, Arborviruses such as West Nile, Parasitic such as Trematode parasites, and Rickettsia such as Spotted Fever group. Recombinant DNA/RNA Defined as creating recombinant DNARNA constructs (vector + gene) And/or regardless of method for joining or source and size of the genetic material it is recombinant Also included are molecules that result from the replication of the recombinant material

Why is Training Required for PI’s and lab personnel?
NIH Guidelines requires training for all PI’s and their lab personnel conducting recombinant DNA (rDNA) research Regardless of source of funding. Noncompliance can result in suspension, limitation, or termination of NIH funds for rDNA research for the entire institution. The compliance with the NIH Guidelines is manditory, as such it also realizes that appropriate training is key to ensuring that mandate. The negative impact that could result from a non-compliant researcher are stringent enough to encourage voluntary compliance.

NIH Guidelines Content
Section I – Scope Section II – Safety Considerations Section III – Types of Experiments Covered Section IV – Roles and Responsibilities Appendices The document is organized into 4 sections which describe Scope of the Guidelines Safety considerations for recombinant DNA research A description of the types of experiments covered and the levels of review these experiments require. There is a section describing the roles and responsibilities of individuals and entities involved in the conduct and oversight of recombinant DNA research And there are the appendices which cover specific topics in greater detail.

NIH Guidelines Section I
Scope of the NIH Guidelines Purpose Definition of rDNA Molecules General Applicability Compliance with NIH Guidelines General Definitions Section 1 discusses the purpose of the Guidelines, which is to specify practices for constructing and handling recombinant DNA molecules. A definition of what a recombinant DNA molecule is, in the context of the Guidelines, I just mentioned. The first section then goes on to describe when, and to what, the Guidelines are applicable.

The NIH Guidelines Apply to…
rDNA research that is Funded by the NIH Performed at or sponsored by an institution that receives any NIH funding for recombinant DNA research Rationale: For biosafety to be meaningful, it has to be observed by all investigators at an institution As is true of all NIH grant requirements, the Guidelines cover all recombinant DNA research that is funded by the NIH. What is a little special about the Guidelines is the fact that if your institution receives any NIH grants for projects involving recombinant DNA, then all of the projects involving recombinant DNA conducted at or sponsored by your institution, even those that are privately funded, are then subject to the requirements of the Guidelines. The reasoning behind this is, that for biosafety review and oversight to be meaningful, it has to be observed by all of the investigators at an institution.

Are the NIH Guidelines optional?
What are potential consequences of noncompliance with the NIH Guidelines? Suspension, limitation, or termination of NIH funds for recombinant DNA research at the institution Additional requirement for prior NIH approval of any or all recombinant DNA projects at the institution Non compliance with the Guidelines may result in suspension or termination of NIH funds for recombinant DNA research, or the requirement to have all recombinant DNA projects at the institution receive prior NIH approval. This could lead to significant delays to research for a large number of PI’s at this institution.

The Advent of Recombinant DNA Technology
Emergence of recombinant DNA technology (mid- 1970’s) Concerns among both scientific community and general public Public health and safety Environmental impact Potential ethical and social implications By way of providing a little background, I’m going to start with a very brief history of the evolution of the oversight system. As you can see from this cover page of Time magazine from the mid 70’s, that along a gripping expose of a day in the life of Jimmy Carter, there was quite public debate among both the scientific community and general public about the safety and environmental impact of recombinant DNA technology.

The First NIH Guidelines
Published in July 1976 Established responsibilities of investigators and institutions After the Asilomar meeting in 1975 with a meeting of scientists the consensis was the need for guidelines, hence The first NIH Guidelines published in July 1976 Newly formed RAC embarked on drafting guidelines for the safe containment and conduct of recombinant DNA research Established responsibilities of investigators and institutions

PUBLIC CONCERN Public concerns about the potential public health and environmental consequences of rDNA and gene transfer research such as: Expanding programs of biodefense research Emerging infectious disease threats (SARS, Avian flu) Human gene transfer continues to raise many safety, ethical, and scientific issues in need of public discussion and analysis Advances in technology which enable unprecedented research Reverse engineering of 1918 flu virus Synthesis of the polio virus Safety issues for public health and clinical studies are obvious from a research and scientific standpoint, but also public perception is important. Ethics are key issues that rDNA research must also satisfy to retain public trust and continued funding. Adverse events stemming from recombinant research undermine these programs but also point to shortcomings in the review or compliance aspect of conducting this type of research. Several well publicized examples exist especially in clinical research utilizing rDNA/gene therapy U Penn, 1998, treatment for metabolic disorder, 19 yr old Jessie Gelsinger died following gene therapy for a rare metabolic disorder. Gelsinger's treatment sparked a severe reaction of his immune system, a so-called inflammatory response that caused multiple organs to fail. Also in France, gene therapy for severe combined immunodeficiency (SCID), three patients developed leukemia from the treatment. It has since been realized that the replacement gene sometimes inserts itself next to genes that can cause cancer, called proto-oncogenes. Or the most recent when this past July. A midwest woman died from histoplasmosis, 22 days after genetically engineered viruses were injected into her right knee in an experimental treatment for her rheumatoid arthritis. At the time of her death, the woman was taking conventional immune-suppressing drugs for her arthritis. One of the drugs, Humira, is known to make patients susceptible to histoplasmosis. These cases have marked changes in gene therapy policy, and the need to be both transparent and forthcoming with the regulating bodies. They also represent the public backlash that occurs when things go wrong. With the globalization of business and air travel attainable/affordable to all but the severely impoverished, emerging infectious disease threats are more difficult to contain. Public concern about possible pandemics and bioterrorism will also play into the public perception of rDNA research. Within this context there is the possibilities for large gains or losses in public opinion.

NIH Guidelines for Research Involving Recombinant DNA Molecules
A scientifically-responsive document that will continue to evolve Has undergone multiple revisions since 1976 Latest version -April 2002 The NIH Guidelines are the framework of oversight of recombinant DNA research. As mentioned earlier, they were written in 1976, and as science and technology has evolved, so have the Guidelines. There have been multiple revisions, with the latest version published in 2002.

Specifics vs. Intent “The NIH Guidelines will never be complete or final since all conceivable experiments involving recombinant DNA cannot be foreseen. Therefore, it is the responsibility of the institution and those associated with it to adhere to the intent of the NIH Guidelines as well as to the specifics.” Good judgment is key UT IBC can help It is very important to appreciate that the Guidelines will continue to evolve. Science and technology is continually advancing and it is impossible to foresee all conceivable experiments with recombinant DNA. Because of this, it is crucial that all those involved with the conduct of recombinant DNA research adhere to the intent as well as the specifics of the guidelines. Often this will simply entail employing good judgment and common sense, but if you have any uncertainty, UT IBC is always available to help with interpretation of the Guidelines or seek help from OBA.

NIH Guidelines – Section II
Section 2 of the Guidelines focuses on safety considerations. This is where risk assessments are described, and the criteria for risk groups are articulated.

NIH Guidelines Section II
Safety Considerations Risk assessments: (Appendix B) RG 1 RG 2 RG 3 RG 4 Agents that are not associated with disease in healthy adult humans Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk) Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk) Risk assessments and the criteria for risk groups are articulated here.The hazard classification is based on the potential effect of a biological agent on a healthy human adult. Appendix B lists biological agents known to infect humans as well as selected animal agents that have the potential to infect humans. Risk assessment for biological materials is not as straightforward as say, placing a classification of hazard on a chemical. Living agents don’t fit nicely into rigid categories such as ‘corrosive’ or ‘flammable solid’ but rather fall on a continuous spectrum. It is, however, possible to determine the relative risk of agents and to place then into one of four groups which reflect increasing risk to the user and/or the environment. Risk group 1 agents are those not associated with disease in healthy adults, whereas at the other end of the spectrum, risk group 4 agents are likely to cause serious or lethal disease for which preventative or therapeutic intervention is not usually available. These pose high risk to both the user and the community

NIH Guidelines Section II
BSL4 BSL3 BSL2 BSL1 Containment Physical (Appendix G Practices Equipment/Facilities Section 2 also describes physical and biological containment. In terms of physical containment, 4 biosafety levels are described. These biosafety levels consist of a combination of lab practices and techniques, safety equipment, and lab facilities appropriate for the operations being performed. Biosafety Level 4 provides the most stringent containment conditions, biosafety level 1 the least stringent. Biological containment on the other hand is the application of highly specific biological barriers. Such barriers limit either the infectivity of a vector for specific hosts, or its dissemination and survival in the environment. Vectors can be genetically designed to decrease, by many orders of magnitude, the probability of dissemination of recombinant DNA outside the lab. Criteria of Biological Agents Biological (Appendix I) Survival/Transmission

It is the PI’s Responsibility to determine Risk Group
Examples of the four Risk Groups: Risk Group 1: Klebsiella oxytoca, asporogenic B.subtilis Risk Group 2: Bortedella pertussis, Chlamydia trachomastis, E. coli, C. diphtheriae, Shigella, Vibrio cholerae, Yersinia entercolitica, all human adenovirus types, Grp A Arboviruses, hepatitis A-E virus, Herpes viruses, Influenza Types A, B,& C, all human papilloma viruses, retroviruses HIV, SIV, HTLV, VSV Risk Group 3: Brucella abortus, Coxiella burnetii, Francisella tularensis, M. tuberculosis, R. Typhi, Yersinia pestis, Coccidioides immitis, Histoplasma capsulatum, Lassa virus, Ebola & Marburg viruses Risk Group 4: There is no RG4 work done at UT These are just examples of different virulent, pathogenic and toxin producing bacteria, fungi, and viruses. A more comprehensive list would include the CDC Select Agents and Select Toxins, USDA list in addition to the NIH listing of Risk Group 1 thru 4 Etiological Agents.

NIH Guidelines – Section III
IBC, RAC, NIH Director IBC, OBA (in consult with experts) IBC, IRB, RAC IBC IBC (notification) Exempt Section 3 describes the levels of review necessary for recombinant DNA research. There are 6 categories of experiments under the Guidelines. These categories reflect the risk of the research, with more stringent review required for the higher risk experiments.

NIH Guidelines Section III - Levels of Review
Level of review Example of rDNA research involving animals Relevant section(s) of the NIH Guidelines IBC, RAC review, and NIH Director review and approval Experiments that compromise the control of disease agents in medicine through deliberate transfer of a drug resistance trait III-A IBC approval and NIH review for containment determinations Experiments conducted with a recombinant DNA modified restricted agent in a whole animal III-B IBC and IRB approval and NIH review before research participant enrollment Not applicable III-C IBC approval before initiation Creating stable germline alterations of an animal’s genome, or testing viable rDNA modified microorganisms on whole animals, where BL-2 containment or greater is necessary III-D IBC notice at initiation Creating stable germline alterations of rodents using recombinant DNA when these experiments require only BL-1 containment III-E Exempt from the NIH Guidelines. IBC registration not required if experiment not covered by Sections III-A, III-B, or III-C Purchase or transfer of transgenic rodents III-F Section three There are six categories of experiments. These categories are graded by risk, with more stringent review required for the higher risk experiments. Experiments that are not considered to pose a risk to human health or the environment are exempt from the Guidelines and do not require review, an example of this would be the purchase of transgenic animals for say, a behavioral study. At the other end of the spectrum are experiments which pose great risk to human health, such as the deliberate transfer of antibiotic resistance into a pathogen, if that transfer would then compromise the use of that drug to treat the disease. Such experiments not only require review and approval from the Institutional Biosafety Committee, but also require approval from the Director of the NIH.

Key Portions of the NIH Guidelines for Animal Research
Section III-D-4 Experiments Involving Whole Animals – IBC Approval Before Initiation Experiments in which: the animal’s genome has been altered by stable introduction of rDNA into germline, or rDNA modified microorganisms are tested on whole animals BL2 or BL2-N or greater containment I know many of you here today use animals in your research, so at this juncture I wanted to highlight some of the sections of the Guidelines that pertain specifically to research with animals. Section III-D-4 describes experiments with animals which would require IBC approval along with IACUC approval before the work could commence. Examples of these experiments would be the creation of transgenic animals or the testing of recombinant microorganisms in animals (transgenic or otherwise). Transgenic insects fall into this category.

Section III-D-5 Experiments Involving Whole Plants – IBC Approval Before Initiation Experiments in which: Plants genetically engineered by rDNA methods, or Plants are used with recombinant DNA-modified insects Generally BL2-P through BL4-P, depending on risk I would also draw your attention to section III-D-5 which describes experiments involving whole plants. Trangenic plant research may also fall under USDA guidelines. If recombinant DNA modified insects are to be used with plants, then IBC approval is needed before the work can start.

Section III-E-3 Experiments Involving the Generation of Transgenic Rodents – IBC Notice at Initiation Experiments in which: Rodent’s genome has been altered by stable introduction of rDNA into germline BL1 containment is appropriate Section III-E describes a class of experiments which require registration with the IBC at the time of initiation. The key word here is stable. These are all experiments which can be conducted at Biosafety Level One. The IBC still reviews and approves these experiments but this review does not need to occur before the experiment commences.

Section III-F (and Appendix C-VI) - Exempt Experiments The purchase or transfer of rodents for experiments that require BL-1 containment Further manipulations of these animals with recombinant DNA are not necessarily exempt from the NIH Guidelines The purchase and transfer of rodents that require Biosafety Level 1 containment is an activity that is exempt from the guidelines, however that does not necessarily exempt the use of these animals for research that is covered under the Guidelines.

NIH Guidelines Section IV
Roles and Responsibilities Principal Investigator (PI) Biological Safety Officer (BSO) Institutional Biosafety Committee (IBC) Institutional Officer (IO) NIH This is the reporting order for incidents, accidents, or spills Section 4 discusses the roles and responsibilities of individuals and entities involved in the conduct and oversight of recombinant DNA research. This includes the institution, the IBC, the principal investigator and the NIH itself. This is the reporting order for spills.

PI Responsibilities NIH Guidelines
IBC approval approval must be granted prior to initiating or modifying any recombinant DNA research covered under sections III-A to III-D. Determine whether experiments are covered under NIH Guidelines and notify the IBC as appropriate. *Be adequately trained in good microbiological techniques*. Adhere to IBC emergency plans for spills and personnel contamination. Report any incidents, accidents, or spills to BSO and IBC.. The principal investigator should not commence or modify any research which requires IBC approval until that approval is granted. The investigator should adhere to all approval conditions imposed by the IBC. It is also expected that the investigator has expertise and training to conduct the proposed experiments safely.

NIH Guidelines UT- Austin Responsibilities
Establish and implement policies for the safe conduct of recombinant DNA research. Establish an Institutional Biosafety Committee. Assist and ensure compliance with the NIH Guidelines by investigators. Ensure appropriate training for IBC Members and PI’s PI’s are responsible for the actions of their lab and compliance with the guidelines Determine necessity for health surveillance of personnel. PI’s work with IBC in reporting any significant incidents to NIH-OBA. It is the responsibility of the institution to establish and implement polices for the safe conduct of recombinant DNA research. In addition, a key responsibility is the establishment of an institutional biosafety committee. It is also the responsibility of the institution to report any significant incidents or violations of the NIH Guidelines to the Office of Biotechnology Activities. Examples of significant incidents would be those involving injury or loss of containment. Other significant problems might include violations of safety procedures or failure to follow approval conditions imposed by the IBC.

NIH Guidelines Appendices
Appendix A – Exemptions: Natural Exchangers Appendix B – Classification of Etiologic Agents Appendix C – Exemptions under III-F Appendix D – Major Actions Appendix E – Certified Host-Vector Systems Appendix F – Biosynthesis of Toxic Molecules Appendix G – Physical Containment Appendix H – Shipment Appendix I – Biological Containment Lastly, there are 15 appendices which provide greater detail on various aspects of the Guidelines. Just to highlight the ones you are most likely to consult when reviewing research: Appendix B provides a classification of agents by risk group. Appendix G and H describe physical and biological containment respectively.

NIH Guidelines Appendices
Appendix J – Biotechnology Research Subcommittee Appendix K – Large Scale Physical Containment Appendix L – Gene Therapy Policy Conferences Appendix M– Points to Consider in Human Gene Transfer Research Appendix P– Physical and Biological Containment: Plants Appendix Q– Physical and Biological Containment: Animals Appendix M describes points to consider in the design and submission of protocols for the transfer of recombinant DNA molecules into human research participants. And Appendices P and Q describes containment practices for certain research involving plants and animals respectively.

Key Portions of the NIH Guidelines Appendix B
Classification of human etiologic agents on the basis of hazard Bacterial Fungal Virus Prion Parasites Microsporum RG2 Fasciola hepatica RG2 Appendix B is where you will find a list of human etiologic agents and zoonotic agents classified on the basis of hazard. This should be your starting point when conducting a risk assessment for the agent you are using in your work. Brucella abortus RG3 Epstein Barr RG2 Ebola virus RG4

Key Portions of the NIH Guidelines Appendix G
Specifies details of containment and confinement for standard laboratory practices Defines Biosafety Level 1 through Biosafety Level 4 Appropriate for animals that are worked with in a laboratory setting Appendix G specifies physical containment practices for the standard laboratory and applies to research with animals in a lab setting. This is where biosafety levels 1 through 4 are defined, and details are provided on the standard microbiological practices and any special procedures that should be followed, along with the containment equipment required for each level.

Key Portions of the NIH Guidelines Appendix I
Biological containment barriers Limit the infectivity of a vector or vehicle (plasmid or virus) for specific hosts Limit dissemination and survival of a vector in the environment Vectors can be genetically designed to decrease, by many orders of magnitude, the probability of dissemination of recombinant DNA outside the laboratory Appendix I describes biological containment barriers. These are the natural barriers that limit either the infectivity of a vector for specific hosts, or the dissemination and survival of the vector in the environment. Vectors can be genetically designed to decrease, by many orders of magnitude, the probability of the dissemination of recombinant DNA outside the laboratory.

Key Portions of the NIH Guidelines Appendix Q
Applies when research animals are of a size or have growth requirements that preclude laboratory containment For example, cattle, swine, sheep, goats, horses, poultry, etc. Addresses containment and confinement practices in animal facilities (BL1-N to BL4-N) Lastly Appendix Q applies instead of Appendix G when research is conducted in animals that are of a size that precludes the use of lab containment. This would include research with large agricultural animals such as cattle or pigs. As in Appendix G, there are four levels physical containment, in this case referred to as Animal Biosafety Levels BL1-N to BL4-N which are equivalent to the BL-Ag designations of the US Department of Agriculture.

Primates - Appendix G or Q? Depends on the conditions under which the primates are being housed and used in experimentation Primates used in high-level, laboratory containment conditions; Appendix G applies In other settings, primates may be worked with in settings akin to those described in Appendix Q Professional judgment is key - IBC/IACUC can help! We often receive questions about whether research with primates is covered by appendix G or Q. The answer depends on the conditions in which the primates are housed. If the primates are contained in laboratory conditions then Appendix G applies but in other setting Appendix Q might be more appropriate. IBC and IACUC can always assist in making such determinations if you have concerns about the proper approach.

Key Portions of the NIH Guidelines Appendix M
Points to Consider in the design and submission of protocols for the transfer of recombinant DNA Molecules into one or more human research participants. Requirements for Protocol Submission, Review, and Reporting Appendix M describes points to consider in the design and submission of protocols for the transfer of recombinant DNA molecules into human research participants. You'll be hearing a lot more about this section when research at this university progresses to this point.

Appendix M Applies to human gene transfer experiments Includes many considerations related to preclinical studies with animals Expedited safety reporting requirements amended to include specifically the reporting of animal data “that suggest a significant risk for human research participants.” Appendix M applies to human gene transfer experiments but includes many considerations related to preclinical studies with animals. This is an application of Appendix M that may apply to some of the faculty. In particular, any finding from tests in laboratory animals that suggests a significant risk for human research participants including reports of mutagenicity, or carcinogenicity must be reported to OBA under the expedited reporting requirements. This is a process that must involve the UT IBC.

Questions?

Institutional Biosafety Committees: The Linchpin of Local Oversight

Institutional Biosafety Committee
IBCs were originally established specifically for the review of rDNA research, but includes more oversight now Reviews research with biohazardous risks Infectious agents Highly toxic chemicals Biological toxins The Guidelines require that IBCs are established specifically for the review of recombinant DNA research, although our committee will review other research with biohazard risks, for example work covered by the blood borne pathogens standard. The review of research not involving recombinant DNA is not a requirement of the Guidelines, but is a task that our institution delegates to the IBC because of the expertise of the committee members.

IBC Membership No fewer than 5 individuals
Appropriate rDNA expertise collectively Plant and animal experts, biosafety officer as appropriate Expertise in assessment of risk to environment and public health At least two public/community members not affiliated with the institution Appointed by Institutional Official (VP for Research) In terms of membership, IBCs should be comprised of no fewer than 5 members. These members should have the appropriate expertise to be able to review the research conducted at the institution. IBC’s were patterned after Institutional Review Boards in many respects, one notable difference however, is that while IRBs are required to have one non-affiliated member, for IBCs at least two of the members of the committee must not be affiliated with the institution. This difference derives from the founding principle of the system of oversight which was that IBC review and oversight be transparent and involve public participation. The requirement for 2 non-affiliated members is a reflection of this emphasis on public transparency.

Biological Safety Officer
BSO must be appointed and made a member of the IBC if research is: Large scale (>10 L) BL-3 The BSO’s duties include: Periodic inspection of labs Reporting to the IBC and institution of any problems, violations, research-related accidents or illnesses Developing emergency plans for handling accidental spills and personnel contamination Advice on lab security Technical advice to PIs and IBCs on research safety procedures The institution must appoint a Biological Safety Officer, who serves on the IBC if any recombinant DNA research is conducted at Biosafety Level 3 or 4, or if there is any large scale research – that is using cultures of greater than ten liters.

IBC Responsibilities Recombinant DNA research for conformity with the NIH Guidelines Minimize potential risk to environment and public health Containment levels per NIH Guidelines Adequacy of facilities, SOPs, PI and lab personnel training Institutional and investigator compliance; e.g., adverse event reports So what exactly do IBCs review? Well IBCs must review recombinant DNA research for conformity with the NIH Guidelines. In addition they assess the research for potential risks to health and the environment. This is accomplished by reviewing physical and biological containment for the research and ensuring the researchers are adequately trained to conduct the work they are proposing safely.

IBC Responsibilities In basic and preclinical research, IBCs have the authority to: Lower containment levels for certain experiments in which DNA from Risk Group 2-4 is cloned in non-pathogenic organisms Set containment levels for experiments involving whole plants and animals Periodically review institutional compliance with NIH Guidelines Adopt emergency plans covering spills, contamination, other accidents For basic and preclinical research, IBC have the responsibility to periodically review research at the institution for compliance with the Guidelines. The IBC should also adopt emergency plans for dealing with accidents and incidents. In addition to these responsibilities, the IBC has the authority to lower containment levels for certain experiments. The IBC can always imposed more stringent requirements than those outlined in the NIH Guidelines if they feel the situation warrants it.

The Importance of IBCs and BSOs to Investigators
The IBC and BSO can help you to: Ensure that you are working with recombinant DNA safely Meet all compliance requirements associated with NIH funding for research involving recombinant DNA Avoid preventable accidents and incidents that might cause harm or undermine public confidence in your research activities Obtain biosafety advice on an ongoing basis

IBCs and Other Institutional Oversight Committees
IRB IACUC We consider the IBC as an element of a triumbrant of oversight at institutions. IBCs, IRBs and IACUCs have joint purview over a number of types of research, and ideally collaborate in the review of such research.

IBC and IACUC Review of Animal Research Utilizing Recombinant DNA
IBC Review Risks to human health Transfer of genetically altered material, viral vectors etc. Risks to the environment Escape and establishment in the wild Interbreeding with wild stock Consumption by other animals IACUC Review Animal welfare Pain and distress from adverse phenotypes (behavioral, anatomical and physiological abnormalities) Risks to other animals in the facility from the inadvertent spread of vectors Of course the focus of review for the IBC is somewhat different to that of the IACUC. The IBC is concerned with risks of the research to human and animal health and the environment… … whereas the IACUC is concerned with reviewing the research from an animal welfare point of view… such as evaluating the pain and distress resulting from a particular phenotype, and the risks to other animals in the facility. Never the less, both committees have to review and approve research protocols involving recombinant DNA and animals.

IBCs and IACUCs Animal Research
Joint purview, and ideally collaborative review, over certain types of research Transgenic or cloned animals Use of recombinant DNA molecules in animals Pre-clinical studies and data assessment for human gene transfer protocols To focus on IBCs and IACUCS These two committees have joint purview over research including the use of transgenic of cloned animals, and the use of recombinant DNA molecules in animals. Ideally these two committees collaborate in the review of this type of research.

Animal Research with rDNA: Points to Consider
Containment procedures (SOP’s) Physical and biological Plans for recapture of escapees Consequences should containment fail Procedures for transfer of animals Transportation procedures Disposal and destruction methods Breeding SOP’s Occupational biosafety concerns Personal protective equipment Decontamination Here are several points that are considered when reviewing animal research involving recombinant DNA. This list is far from exhaustive. Containment protocols are of course very important to consider, as are occupational biosafety concerns for personnel handling the animals. Transportation and disposal methods might also be of special concern depending on the protocol.

IRB and IBC Human Gene Transfer Research
IRB Review IBC Review Conducts risk/benefit assessment relative to individual research participants (physical, psychological, social harms) Selection of subjects and the informed consent process Data monitoring provisions to ensure the safety of subjects Provisions to protect subject privacy and confidentiality of data Injuries or any other unanticipated problems Compliance with regulations rDNA research for conformity with the NIH Guidelines Potential risk to environment and public health (risks to close contacts, HCWs, and the community, as well as to individual research participants Containment levels per NIH Guidelines Adequacy of facilities, SOPs, PI and other personnel training Institutional and investigator compliance (e.g., adverse event reports) Reviews trial design, biosafety and containment, and compliance with NIH Guidelines IBCs and IRBs have joint oversight over human gene transfer research, and again the focus of these two committees is somewhat different. IRBs Conducts risk/benefit assessments relative to individual research participants. Their focus is on the physical and psychological risks to the participant…. ….In contrast the IBC reviews trial design, biosafety and containment, and compliance with NIH Guidelines.Their focus is to minimize risks to the environment and the public health…for example close contacts, health care workers, and the community, as well as to individual research participants

IBC Meetings Frequency
Required to meet least quarterly, currently scheduled as bi-monthly. IBC meeting dates are posted on the web Open Meetings IBC meetings are open to the public How often does the IBC need to meet? Well the frequency is really determined by the number of protocols requiring review. We are required to meet 4 times a year, but will meet on a bi-monthly basis unless need dictates otherwise. An important thing to remember is that it is the responsibility of the IBC to conduct surveillance of the research at UT. From this point of view, it is desirable to have the committee meet at least once a year to review ongoing protocols, to ensure compliance When it comes to the actual meeting, the Guidelines encourage institutions to accommodate public attendance. Because the intent of the Guidelines is to provide open access to the public regarding the review of the safety of recombinant DNA research IBCs should be convened in a matter that allows for the fulfillment of this expectation. This can be achieved in a number of ways… obviously there is the traditional face to face meeting, but sometimes it may by more convenient for your members to participate via video or teleconferencing. These modes also allow public access to an interactive meeting.

Heightened Institutional Responsibility for Security
Select Agent Rule Agents and toxins as listed by CDC/USDA/HHS Must be registered with agency Must develop written security plans Federal agencies may not release information about the location of Select Agents. The implementation of the Select Agent Rule post 911 has heightened institutional responsibility and awareness with respect to security. Covered entities must develop written security plans and federal agencies may not release information about the location of Select Agents and so on.

Training, Professional Development, and Outreach
The NIH Guidelines emphasize the importance of training and place responsibility on: Institutions to train IBC Members, BSO, PI, and laboratory staff NIH also conducts and support training programs at local institutions The NIH Guidelines place a great deal of emphasis on the importance of training. This responsibility is in part borne by NIH, to conduct and support training programs, but largely falls on the institutions to ensure IBC members, investigators, lab staff and others are appropriately trained. Hence UT has implemented lab safety, blood borne pathogens and biohazardous materials training and now this program to inform PI’s and key lab personnel of their respective responsibilities. This course also seeks to provide the information and training necessary for the evaluation an implementation of rDNA and/or biohazardous material research in compliance with both institutional policies and procedures and the NIH guidelines

Enhancing the Quality of IBC
NIH OBA: Conducts proactive not-for-cause site visits Educate about IBC requirements Provide on-site advice Identify opportunities for improvement Develop a body of information for the development of “best practices” May also conduct for cause site visits. Offices of Research Support and Compliance and Environmental Health and Safety have been re-evaluating policies and procedures, increased research community training and lab inspections, added personnel to facilitate communications between the IBC and the research community, assist with research rDNA and/or biohazardous material assessment criteria, and compliance questions. A new e-protocol database will be implemented before the end of the year. Again ORSC and EH&S have been working together with programmers to develop a submission process that encompasses both biosafety considerations and compliance-regulatory issues in a single, user friendly format.

Questions?

Policies and Procedures
The University of Texas at Austin

UT Austin IBC Policies and Procedures Use of rDNA/Biohazardous Material
Covers: All relevant research sponsored by the university, conducted by university personnel, using university property or stored at university facilities This includes all faculty, staff, students, visitors, and agents and their employees engaged in activities and/or research involving rDNA and/or biohazardous materials The UT Policies and Procedures covers all relevant research done by anyone, anywhere, by anything associated with UT. This can include visitors and work contracted outside the physical site. If the money goes through UT then it is included in UT’s P&P.

IBC Policies and Procedures Use of rDNA/Biohazardous Materials
Outlines the processes that must be followed when obtaining, using, storing, transferring, or destroying rDNA/biohazardous material Ensures compliance with relevant laws, regulations pertaining to receipt, using, storing, or transferring of rDNA/biohazardous material Minimizes risks to researchers, staff, students, facilities, the community, and environment while using biohazardous materials and recombinant DNA during teaching and research Outlines All responsibilites surrounding rDNA/biohazardous material Compliance issues surrounding rDNA/biohazardous material Risk and safety issues surrounding rDNA/biohazardous material

IBC Policies & Procedures are Based On:
NIH Guidelines for Research Involving Recombinant DNA Molecules Biosafety in Microbiological and Biomedical Laboratories (BMBL), 5th ed., published by the CDC and NIH Select Agents and Select Toxins- HHS and CDC regulations- 42 CFR Part 73, and USDA regulations- 9 CFR Part 121 The 3 federal publications that guide policy on rDNA/biohazardous material research are: NIH Guidelines BMBL, CDC now in the 5th ed Select Agents and Select Toxins, USDA, HHS, and CDC All of these publications are directed at defining and directing guidelines for research that may pose a risk to individual or public health or risk to the food supplies.

IBC Responsible Parties
PI’s who obtain, possess, or use rDNA and/or biohazardous material. The Biological Safety Officer (BSO) who is a member of the IBC Institutional Biosafety Committee (IBC) Vice President for Research is the Institutional Officer (IO) Defines the Chain of Command of responsibilities.

Protocols Responsibilities of the PI
Not initiate or modify any research involving rDNA/biohazardous materials subject to IBC approval under these IBC Policies or NIH Guidelines until the research or proposed modification has been approved by the IBC Make initial risk assessment of the rDNA and/or biohazardous material Identify proposed biosafety level of the rDNA and/or biohazardous material Determine whether experiments are covered by any section of the NIH Guidelines, and ensure that the appropriate procedures are followed PI’s must: Make the initial risk assessment of the materials and research to be conducted. Identify the appropriate biosafety level to conduct that research, Evaluate to research by NIH guidelines to determine if proposed work is exempt from NIH guidelines and ensure compliance with procedures. To not initiate or modify any research that is appliicable to NIH Guidelines without approval from IBC.

Training Responsibilities of the PI
Complete mandatory training modules prior to receiving approval for the research protocol Provide training to staff on hazard risks, SOP’s, Personal Protective Equipment (PPE), occupational health and emergency procedures All training should be documented and will be periodically reviewed To initiate rDNA/biohazardous material research PI must have: 1 completed all required institutional training and instructed laboratory personnel to do so. 2. Trained lab personnel to the specific (SOP) protocol for the rDNA/biohazardous material in application, and provide biosafety level appropriate personal protective gear. 3.Review with personnel occupational health and emergency procedures 4. Document training and periodically review.

Safety Responsibilities of the PI
Develop and follow laboratory specific safety SOP Provide personal protective equipment to staff Provide occupational health as needed (i.e. immunizations, base line serums) Limit access and ensure material is physically secured Have available an IBC-approved emergency plan available to all staff in lab (can be part of safety SOP). This must include current list of contact phone numbers in case an incident occurs To provide a safe environment to work PI must: Develop and train lab personnel to SOP specific to the materials being used and a lab emergency plan with contact phone numbers and what to do if an incident occurs. Provide personal protective equipment to lab staff and occupational health as needed Maintain a controlled environment for rDNA/biohazardous work and secure storage.

Reportable violations and incidents Responsibilities of the PI
Investigate and report any significant research related incident to the BSO and IBC. Correct work errors and conditions. Ensure integrity of physical and biological containment Comply with all reporting requirements for spills or accidents resulting in an overt exposure in > BL2 or potential exposure in BL3 or BL4 Investigate and report any significant research related accidents and illnesses or operational problem to the BSO, IBC, and any other appropriate parties. Correct work errors and conditions that may result in release of rDNA Ensure integrity of physical containment (BSC) and biological containment Comply with all reporting requirements for spills or accidents resulting in an overt exposure in > BL2 or potential exposure in BL3 or BL4

Reportable violations and incidents Responsibilities of the PI
Any spill or accident involving rDNA/biohazardous material that leads to personal injury or illness. -or- a breach of containment ie: direct contact with agent, needle stick, escape of transgenic animal, improper disposition of a transgenic animal, or- spills of high-risk recombinant/biohazardous material occurring outside of a biosafety cabinet. In BSL 3 labs or >RG2 agents, possible exposure, or aerosol exposure are considered a reportable incident with all appropriate notifications required. Also any incident where medical attention is advised and sought is reportable. These reports are issued through the Office of the Vice President for Research to the NIH-OBA

If such an event occurs then the following must take place:
Reportable incidents What do you do If such an event occurs then the following must take place: 1. Isolate area and if possible contain spill. 2. Contact the Biosafety Officer at EHS Immediately Mr Dennis Nolan Ph# or EHS If Mr Nolan is not on campus or you are unable to reach him, his alternate is IBC Chair, Dr Woody Davis at Ph# or 3.Once containment is established and BSO contacted, the PI is responsible for conducting and recording an internal investigation of his/her laboratory incident. A copy of the findings to be submitted to IBC Chair as soon as possible.

Experiments that Require IBC Review
Transfer of drug resistance to microorganisms that are not known to acquire the trait naturally The deliberate transfer of rDNA/DNA/RNA derived from rDNA into human research participants (human gene transfer) The deliberate formation of rDNA containing genes for the biosynthesis of toxin molecules lethal for vertebrates at an LD50 of less than 100 ng/kg Using Risk Group 2/3 agents as host-vector systems The cloning of DNA from Risk Group 2/3 agents into non-pathogenic prokaryotes or lower eukaryotic host-vector systems Any work with recombinant infectious viruses, not just > RG 2

Experiments that Require IBC Review continued
Whole animals in which the animal's genome has been altered by stable introduction of rDNA or DNA derived into the germ-line (transgenic animal) Viable rDNA-modified microorganisms tested on whole animals Genetically engineered plants by rDNA methods Protocols involving more than 10 liters of culture The formation of rDNA molecules containing no more than 2/3 of the genome of a eukaryotic virus

IBC Review of rDNA/Biohazardous Protocols
Experiments using BL-2 or BL-3 containment must be reviewed and approved prior to the initiation of experiments. Experiments using BL-1 containment must also undergo IBC review. Experiments requiring BL-4 containment will not be approved at UT-Austin at this time

IBC Submission Process
Protocols must be submitted electronically Additional documents may be required Lab safety and specific emergency plans Certification letters Risk assessments Emergency plans See ORSC website for details

IBC Protocol Information to be Included on Form
Electronic application form (e-protocol) Agent characteristics (e.g., virulence, pathogenicity, environmental stability). Types of manipulations planned. (sonication, centrifugation) Source(s) of the inserted DNA sequences (e.g., species). Nature of the inserted DNA sequences (e.g., structural gene, oncogene). Host(s) and vector(s) to be used. Whether an attempt will be made to obtain expression of a foreign gene, and if so, the protein that will be produced. Containment conditions to be implemented. Applicable section of the NIH Guidelines (e.g., Section III-D-1, Section III-E-1, etc.).

Laboratories will be inspected at least bi-annually by the IBC
IBC Inspections Laboratories will be inspected at least bi-annually by the IBC May be more frequent depending on risk or funding source requirements

Inspection will include:
IBC Inspections Inspection will include: Periodic review of protocol registration for any changes in personnel, agents, or manipulation Rigorous lab inspections at frequency commensurate with risk. Review of documentation for personnel training, lab safety inspections, safety equipment, biohazardous material inventory and storage Review of SOP, emergency lab plans, and incident reporting

IBC Compliance Oversight and Corrective Action
The IBC has authority to address non-compliance with these procedures, NIH Guidelines, BMBL, or other regulatory requirements. Non-compliance can result in the IBC taking one or more of the following actions: Suspending use of the rDNA/biohazardous material Termination of the approval for the rDNA/biohazardous material Confiscation of the rDNA/biohazardous material Destruction of the rDNA/biohazardous material Any other action necessary to protect the public and/or the university Reporting to the NIH

Need more information? Institutional Biosafety Officer
Institutional Biosafety Committee Lab Safety Issues Personal protective equipment for personnel Disposal of waste Decontamination of laboratory and equipment Containment facilities Accidents (emergency plans and response) Other great sources of information is the EH&S biosafety officer and the IBC. We can also provide information on lab safety issues, as well as risk assessments and local policies and requirements.

IBC Training Acknowledgment
I agree to comply with the NIH Guidelines pertaining to the shipment and transfer of recombinant materials. I acknowledge my responsibility for the conduct of this research in accordance with Section IV-B-7 of the NIH Guidelines. In addition, I agree to comply with the registration and guidelines for the use of select agents and toxins as described in the CDC’s BMBL, 5th ed., and the USDA/HHS Federal Register for select agents and toxins. Any modifications to rDNA/biohazardous protocols need to be submitted for IBC review and approval

Questions?

Contact Information 6705 Rockledge Drive, Suite 750 Bethesda, Maryland Phone (301) Fax (301) Thank you

Office of Research Support and Compliance (512) 471-8871
IBC Resources Office of Research Support and Compliance (512) Environmental Health and Safety (512)

Principal Investigator rDNA/Gene Transfer Training on NIH Guidelines

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Principal Investigator rDNA/Gene Transfer Training on NIH Guidelines

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