scire-lb.orgscire-lb.org/.../uploads/2016/06/IBC-SOP-09-08-15.docx · Web viewVA Long Beach Healthcare System. Research and Development ________________________________________ Institutional

VA Long Beach Healthcare SystemResearch and Development

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Institutional Biosafety Committee (IBC)

Standard Operating Procedures

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Rescission: 10/02/14Review: Annually by the IBC and R&D Committees

________________________________________ __________________James Lohaus, Ph.D. DateInstitutional Biosafety Committee Chair

________________________________________ __________________Steven Schreiber, MD DateResearch and Development Committee Vice-Chair

IBC Standard Operating Procedures VA Long Beach Healthcare System/Research and Development

TABLE OF CONTENTS

Purpose ...................................................................................................................................................... 4 Scope .......................................................................................................................................................... 4 Policy........................................................................................................................................................... 4 Abbreviations .............................................................................................................................................. 5 Definitions ................................................................................................................................................... 6 Responsibilities of the Subcommittee on Research Safety (SRS)............................................................... 9 Infrastructure of the Institutional Biosafety Committee................................................................................. 9 Number and Qualification of Members................................................................................................ 9 Core Membership............................................................................................................................... 9 Ex-Officio Members (voting and non-voting)

10 Appointment of Members

10Quorum and Voting

11 Meetings

11 Review Procedures

11 Review of the Research Protocols11

Categories of Research 12

Full IBC Review14

Review Materials14

Risk Assessment14

Containment14

Containment Guidelines15

Resources 18

Training18

Compliance18

ICF Document18

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Amendments & Modifications 18

Review of Policies and Procedures18

Annual Reviews18

Inventory Controls19

Remediation and Follow-up 19

Non-Recurrent Processes19

Autoclave Verification19

Waste Management19

Animal Disposal 19

Actions 20

Training21

IBC Members21

Principal Investigators21

Research Staff21

BSL-3 Training21

Quality Improvement and Assurance22

Record Keeping 23

Roster 23

Biographical Sketches23

Training Reports23

Incident Reports 23

External Inspections23

Internal Inspections23

Emergency Response Plans and SOPs)23

Agendas and Minutes24

Content24

Distribution and Public Disclosure24

Regulatory Non-Compliance 25

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Audits 25

Actions24

Reporting 24

Annual Report24

Significant Problems24

Routine Actions25

References27

Appendices28

Application for Approval, Appendix A28

Risk Assessment, Appendix B29

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INTRODUCTION

Purpose

This Standard Operating Procedure (SOP) describes the operating procedures of the Institutional Biosafety Committee (IBC).

Scope

a. At VALBHS, the Institutional Biosafety Committee is a subcommittee of the Research and Development Committee.

b. The IBC has overlapping functions with the Subcommittee for Research Safety (SRS) and, at VALBHS; the members of the IBC are also the members of the SRS.

c. The IBC is charged by the R&D Committee with the responsibility to maintain a Research Biosafety program that is consistent with VA policies, and NIH Biosafety Guidelines of the National Institutes of Health (NIH).

d. The “NIH Guidelines for Research Involving Recombinant DNA Molecules” are referred to in this SOP as the “NIH Guidelines”.

e. The provisions of this SOP apply to all research that is conducted completely or partially in VA facilities, conducted in approved off-site locations and facilities, or conducted by VA researchers while on VA official duty time. The research may be VA funded, funded from extra-VA sources, or conducted without direct funding. As a minimum, facility safety personnel must verify that other or remote facilities adhere to health and safety standards that are equivalent to VA standards.

Policy:

All recombinant DNA research to be conducted by, or is under the authority of, the VALBHS must be in compliance with NIH guidelines.

Research at VALBHS will adhere to the intent of NIH guidelines that govern recombinant DNA research as well to their specifics.

All recombinant DNA research must be reviewed and approved by the IBC before any experimental procedures may take place.

In addition to the IBC, research proposals must be approved by all applicable committees before any experimental procedures may be initiated.

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The VALBHS does not currently conduct experiments that involve recombinant DNA research in plants.

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ABBREVIATIONS

ACOS Associate Chief of Staff AO Administrative OfficerCFR Code of Federal RegulationsCHP Chemical Hygiene PlanCOS Chief of StaffIBC Institutional Biosafety CommitteeIRB Institutional Review BoardNIH National Institutes of HealthOBA Office of Biotechnology Activities (NIH)ORD Office of Research and Development, VA Central OfficeORO Office of Research OversightOSHA Occupational Safety and Health AdministrationPI Principal InvestigatorRAC Recombinant DNA Advisory CommitteeR&D Research & DevelopmentRCO Research Compliance OfficerRPSS Research Protocol Safety Survey (VA Form 10-0398)SAS Subcommittee for Animal StudiesSCIRE Southern California Institute for Research and EducationSOP Standard Operating ProceduresSOPP Standard Operating Policies and ProceduresUCI University of California, IrvineVA Veterans AdministrationVAMC VA Medical CenterVMO Veterinary Medical OfficerWOC Without Compensation

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DEFINITIONS

Approval Date: The IBC SOP Approval Date is the date that the IBC approval memo for a project is signed as approved by the IBC Chair or his/her designee.

Audit: A systematic and independent examination of trial-related activities and documents to determine whether the evaluated trial-related activities were conducted, and the data were recorded, analyzed, and accurately reported according to the (GCP), operating procedures (SOPs), good clinical practice and the applicable regulatory requirement(s) (ICH 1.6).protocol, sponsor’s standard operating procedures.

Biosafety Level (BL): A description of the degree of physical containment being employed to confine organisms containing recombinant DNA molecules and to reduce the potential for exposure of laboratory workers, persons outside of the laboratory, and the environment. In Appendix G of the NIH Guidelines these are graded from BL-1 (the least stringent) to BL-4 (the most stringent).

Conflict of Interest: A convergence of an investigator's private interests with his or her research interests, such that an independent observer might reasonably question whether the investigator's professional actions or decisions are improperly influenced by considerations of personal financial gain.

Documentation: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records; and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors affecting a trial, and the actions taken. (ICH 1.22)

Investigator: An individual who is under the direction of the principal investigator (PI) who is involved in some or all aspects of the research project, including the design of the study, conduct of the study, analysis and interpretation of the collected data, and writing of resulting manuscripts. An investigator may be either compensated by VA, be appointed to work without compensation (WOC), or may be an employee assigned to VA through the Intergovernmental Personnel Act of 1970. The FDA considers an investigator and a principal investigator to be synonymous.

Principal Investigator: An individual who conducts a research investigation, i.e., under whose immediate direction research is conducted, or in the event of an investigation conducted by a team of individuals, is the responsible leader of that team. The FDA considers an investigator and a principal investigator to be synonymous.

Protocol: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a trial. The protocol usually also gives the

Biological Safety Officer (BSO). An individual appointed by an institution to oversee management of biosafety risks. The NIH Guidelines require that a BSO be appointed when the institution is engaged in large-scale research or production activities, or in research requiring containment at BL-3 or BL-4. The duties of the BSO are described in section IV-B-3 of the NIH Guidelines.

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background and rationale for the trial, but these could be provided in other protocol referenced documents (ICH 1.44)

Quorum: More than half of the voting members are present including at least one non-scientist. In order for research to be approved, it must receive the approval of a majority of those members present at the meeting

Recusal: When an IBC or R&D Committee or other committee member declines to participate in a matter because of a potential conflict of interest under the Code of Ethics. As distinguished from abstention, the official recusing him/herself will not be present in or participate in deliberations or voting on the matter where there are potential conflicts of interest.

Regulatory Noncompliance: Failure to adhere to institutional policies and procedures, state laws, federal laws or other regulations governing the conduct of human subjects research including failure to follow the requirements of VHA Handbook 1200.08. This includes such acts as failure to obtain or maintain approval for research or to adhere to an approved protocol, failure to submit applications for study continuing review, or adhere to the Safety Plan.

Research: as defined by the Department of Health and Human Services regulations means a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. [45 CFR 46.102(d)]

Researcher: Principal investigator or the investigator

IBC approval: The determination of the IBC that the research has been reviewed and may be conducted at an institution within the constraints set forth by the R&D Committee and by other institutional and Federal requirements.

Institution: In the context of the NIH Guidelines an institution is any public or private entity, including federal, state, and local governments.

Institutional Biosafety Committee (IBC): An institutional committee created under the NIH Guidelines to review research involving recombinant DNA. The role of IBC’s has evolved over time, and many committees also review other forms of research that entail biohazardous risks as part of their institutionally assigned responsibilities.

Institutional Review Board (IRB): An institutional committee created under Federal law that has the authority and responsibility for the review of research that involves the involvement of human subjects.

National Institutes of Health (NIH): One of the world's foremost medical research institutions and the preeminent federal funder of medical research in the U.S. The NIH, comprised of 27 separate Institutes and Centers, is one of eight health agencies within the Public Health Service, which is an agency within the U.S. Department of Health and Human Services. The goal of NIH research is to acquire knowledge to help prevent,

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detect, diagnose, and treat disease and disability. The NIH mission is to uncover knowledge that will lead to better health for everyone.

NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines): A document created in 1976 that outlines principles for the safe conduct of research employing recombinant DNA technology. The NIH Guidelines detail practices and procedures for the containment of various forms of recombinant DNA research, for the proper conduct of research involving genetically modified plants and animals, and for the safe conduct of human gene transfer research.

Office of Biotechnology Activities (OBA).The NIH office responsible for developing, implementing, and monitoring NIH policies and procedures for the safe conduct of recombinant DNA activities, including human gene transfer.

Recombinant DNA Advisory Committee (RAC). An NIH advisory committee whose principal role is to provide advice and recommendations to the NIH Director on (1) the conduct and oversight of research involving recombinant DNA, including the content and implementation of the NIH Guidelines, and (2) other NIH activities pertinent to recombinant DNA technology. A major element of this role is to examine the science, safety, and ethics of clinical trials that involve the transfer of recombinant DNA to humans.

Recombinant DNA molecules: Under the current NIH Guidelines these are molecules constructed outside of living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell, or molecules that result from their replication.

Standard Operating Policy and Procedures (SOPs): Detailed, written instructions to achieve uniformity of the performance of a specific function (ICH 1.55).

Subcommittee for Animal Studies (SAS): An institutional committee created under Federal law and VA guidelines that has the authority and responsibility over research that involves the use of animals.

Suspension: An action recommended by the IBC to the R&D Committee that temporarily or permanently stops all or some of the research activities must stop until issues have been satisfactorily resolved.

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http://oba.od.nih.gov/oba/rac/guidelines_02/NIH_Guidelines_Apr_02.htm

http://oba.od.nih.gov/oba/rac/guidelines_02/NIH_Guidelines_Apr_02.htm


SECTION 01

RESPONSIBILITIES OF THE BIOSAFETY SUBCOMMITTEE

The IBC is responsible for:

Conducting an assessment of the containment levels required by the NIH Guidelines when reviewing proposed research.

Assessing the facilities, procedures, practices, and training and expertise of personnel involved in recombinant DNA research.

Periodically reviewing recombinant DNA research to ensure compliance with NIH Guidelines.

SECTION 02INFRASTRUCTURE OF THE INSTITUTIONAL BIOSAFETY SUBCOMMITTEE (IBC)

1. NUMBER AND QUALIFICATION OF MEMBERS

The Institutional Biosafety Committee must be comprised of no fewer than five members so selected that they collectively have experience and expertise in recombinant DNA technology and the capability to assess the safety of recombinant DNA research and to identify any potential risk to public health or the environment.

At VALBHS, the members of the SRS also serve as members of the IBC. Therefore, the members of the IBC must also fulfill the requirements of the SRS. These requirements

include ex officio membership of a liaison to the R&D Committee. The SRS membership requirements are described separately in the SRS SOP. The RCO serves as a

consultant to the SRS/IBC and is a permanent invited guest.

2. CORE MEMERSHIP (voting). Voting members of the IBC will include:

A. Two Unaffiliated Members. At least two members shall not be affiliated with the institution (apart from their membership on the Institutional Biosafety Committee) and who represent the interest of the surrounding community with respect to health and protection of the environment (e.g., 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).

B. One Animal Research Scientist. The Institutional Biosafety Committee shall include at least one scientist with expertise in animal containment principles.

3. EX-OFFICIO MEMBERS (voting). Ex-officio voting members must include:

A. The Biological Safety Officer (BSO). BSO membership is mandatory if the institution conducts recombinant DNA research at BL3, BL4, or Large Scale (greater than 10 liters).

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4. EX-OFFICIO MEMBERS (non-voting). Ex-officio non-voting members will include:

A. The Administrative Officer (AO) for R&D or other non-voting representative from the R&D office.

5. APPOINTMENT OF MEMBERS

A. The IBC nominates candidates to serve as members on the committee and forwards the nominations to the R&D committee.

B. The R&D committee selects candidates and forwards their selections to the medical center Director. The R&D committee is responsible to the Director for assuring that the IBC membership fulfills the requirements outlined in section 1 above. The IBC committee coordinator maintains a roster of committee members that specifies the qualifications that each member fulfills.

C. The medical center Director must officially appoint members in writing.

D. Alternate members may be appointed. Alternate members are members who may substitute for regular members if the regular members are unable to attend a meeting. If alternate members are appointed then the roster must specify the person(s) for whom they may substitute. Alternate members should have similar expertise to the regular member that they serve as an alternate for.

E. The facility Director appoints the IBC chairperson for the term of 1 year. The IBC Chairperson may be re-appointed without any lapse in time. The IBC chairperson may not simultaneously chair the R&D Committee or another research subcommittee with one exception. That exception is that the IBC Chair person may also serve as the chair of the SRS due to the overlapping responsibilities of these two subcommittees.

F. Appointment Letters must specify:

The term of the appointment The type of appointment, i.e. Chair, Core or Ex Officio Whether the appointment is for a Regular or Alternate member. The Voting Status

6. Contact Person. The AO/R&D will serve as the contact person for the IBC.

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SECTION 03QUORUM AND VOTING

All research projects involving recombinant DNA research must be approved by IBC and then by the R&D Committee prior to commencement. The IBC must review proposed research at convened meetings at which a quorum (majority of voting members) is present.

For the research to be approved, it must receive the approval of a majority of those voting members present at the meeting. A quorum must be maintained for each vote to occur. If a quorum is not maintained, the protocol must be tabled and only non-protocol related issues may be discussed.

SECTION 04MEETINGS

1. Frequency. The IBC will meet as needed or at least yearly, at a date and frequency determined by the Chair and the Safety Committee Coordinator.

2. Agenda. An agenda is to be developed before each IBC meeting and distributed to IBC members at least one week before the meeting.

3. Recusals. IBC members are informed of potential conflicts through a review of meeting agendas. Agendas are distributed no later than one week prior to each IBC meeting and contain information about the investigators, sponsors and primary reviewers of each project that will be under review. IBC members review the agenda and will declare any potential conflicts of interest prior to the beginning of project reviews.

In general, the IBC member will recuse him or herself from participation in the discussion and vote. If there is any question as to whether or not a conflict exists then the full IBC will discuss the conflict of interest without the member present to determine if a conflict of interest is present. If a conflict of interest is present then recusal will be required.

SECTION 05REVIEW PROCEDURES

1. Review of Research Protocols. The IBC is responsible for reviewing annually all active research protocols involving biological, chemical, physical, and radiation hazards, regardless of funding status or source.

Principal investigators (PI’s) are responsible for identifying any procedures that may involve the use of recombinant DNA research. PI’s will make this disclosure on VHA form 10-0398. The Subcommittee for Research Safety (SRS) will review PI disclosures and will refer the matter to the IBC if it is determined that the procedures may involve the use of recombinant DNA research.

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A. Categories of Research. The IBC, or the IBC Chair acting on behalf of the IBC, will first determine the category of the proposed research.

a. Excluded Research. Investigators who wish to perform this type of research should contact the ACOS R&D. The LBVA does not currently permit research that involves recombinant DNA in the following categories:

Whole plants Experiments involving more than 10 liters of culture.

b. Exempt Research. The following recombinant DNA molecules are exempt from the NIH Guidelines and registration with, and review by theIBC is not required:

i. Those that are not in organisms or viruses.

ii. Those that consist entirely of DNA segments from a single non-chromosomal or viral DNA source, though one or more of the segments may be a synthetic equivalent.

iii. Those that consist entirely of DNA from a prokaryotic host including its indigenous plasmids or viruses when propagated only in that host (or a closely related strain of the same species), or when transferred to another host by well established physiological means.

iv. Those that consist entirely of DNA from a eukaryotic host including its chloroplasts, mitochondria, or plasmids (but excluding viruses) when propagated only in that host (or a closely related strain of the same species).

v. Those that consist entirely of DNA segments from different species that exchange DNA by known physiological processes, though one or more of the segments may be a synthetic equivalent. A list of such exchangers may be found in the NIH Guidelines (See Appendices A-I through A-VI, Exemptions Under Section III-F-5--Sublists of Natural Exchangers, for a list of natural exchangers that are exempt from the NIH Guidelines.)

vi. Those that do not present a significant risk to health or the environment as specified in the NIH Guidelines (See Appendix C, Exemptions under Section III-F-6 for other classes of experiments which are exempt from the NIH Guidelines.)

c. External Review Required. If the research is not excluded or exempt then the IBC, or the IBC Chair acting on behalf of the IBC, will next determine if prior review and approval by an external agency is required. If external review is required, then the IBC, or the IBC Chair, will verify that

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the approval has been obtained before the research is submitted to the IBC for review.

Review by RAC and Approval of NIH Director Required. i. Major Actions. Experiments considered as Major Actions under the NIH Guidelines cannot be initiated without submission of relevant information on the proposed experiment to the Office of Biotechnology Activities (OBA), the publication of the proposal in the Federal Register for 15 days of comment, review by the Recombinant DNA Advisory Committee (RAC), and specific approval by NIH. The containment conditions or stipulation requirements for such experiments will be recommended by RAC and set by NIH at the time of approval.

ii. Transfer of Drug Resistance. The deliberate transfer of a drug resistance trait to microorganisms that are not known to acquire the trait naturally, if such acquisition could compromise the use of the drug to control disease agents in humans, veterinary medicine, or agriculture.

iii. Transfer to Human Subjects. Experiments Involving the Deliberate Transfer of recombinant DNA, or DNA or RNA Derived from Recombinant DNA, into One or More Human Research Participants.

Review by NIH/OBA Required.iv. Genes for Toxin Molecules. Deliberate formation of recombinant DNA

containing genes for the biosynthesis of toxin molecules lethal for vertebrates at an LD50 of less than 100 ng./kg. body weight (e.g., microbial toxins such as the botulinum toxins, tetanus toxin, diphtheria toxin, and Shigella dysenteriae neurotoxin). Specific approval has been given for the cloning in Escherichia coli K-12 of DNA containing genes coding for the biosynthesis of toxic molecules which are lethal to vertebrates at 100 ng./kg. to 100 ug./kg.body weight. Specific experiments already approved under this section may be obtained from the Office of Biotechnology Activities, National Institutes of Health, 6705 Rockledge Drive, Suite 750, MSC 7985, Bethesda, MD 20892-7985 (20817 for non-USPS mail), 301-496-9838, 301-496-9839 (fax). The containment conditions for such experiments will be determined by NIH/OBA in consultation with ad hoc experts

d. IRB Review Required. i. Transfer to Human Subjects. Experiments involving the deliberate

transfer of recombinant DNA, or DNA or RNA derived from recombinant DNA, into one or more human research participant(s). If IRB approval is required, then the IBC Chair will advise the IRB Chair that the protocol is under review. The IBC Chair will work with the IRB Chair to coordinate the review process.

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e. Other Review Not Required. Experiments in this category are not exempt or excluded and do not require prior external approval, or approval by the IRB. Review and approval by the R&D Committee and all relevant subcommittees (including the IBC) is still required before any experiment may be initiated.

B. Full IBC Review.

i. Review Materials. The Principal Investigator must submit a registration document to the IBC which contains the following information:

the source(s) of DNA. the nature of the inserted DNA sequences. the host(s) and vector(s) to be used if an attempt will be made to obtain

expression of a foreign gene, and if so, indicate the protein that will be produced.

an initial risk assessment using appendix B of the NIH Guidelines. the containment conditions that will be implemented as specified in the

NIH Guidelines. The Informed Consent Document (if the agent is to be given to human

subjects)

The registration document shall be dated, signed by the Principal Investigator, and filed with the IBC.

ii. Risk Assessment. The IBC will review the preliminary risk assessment submitted by the PI. The IBC will then perform a comprehensive risk assessment using the procedures specified in the NIH Guidelines Appendix B (Classification of Human Etiologic Agents on the Basis of Hazard). The IBC will determine the risk level according to the following risk group (RG) classification:

RG1 agents are not associated with disease in healthy adult humans. RG2 agents are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available. RG3 agents are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available. RG4 agents are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available.

NOTE: BSL 4 agents and BSL 4 experiments are not currently permitted in the VA.

iii. Containment. The IBC will utilize the Risk Level as a guide to determining the containment procedures that will be required.

The containment level required may be equivalent to the Risk Group classification of the agent or it may be raised or lowered. Factors to be

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considered in determining the level of containment include agent factors such as: virulence, pathogenicity, infectious dose, environmental stability, route of spread, communicability, operations, quantity, availability of vaccine or treatment, and gene product effects such as toxicity, physiological activity, and allergenicity. Any strain that is known to be more hazardous than the parent (wild-type) strain should be considered for handling at a higher containment level. Certain attenuated strains or strains that have been demonstrated to have irreversibly lost known virulence factors may qualify for a reduction of the containment level compared to the Risk Group assigned to the parent strain.

If the research is specified by a category that requires external review (section A above) then the minimal containment procedures will be those specified by the NIH review.

d. Containment Guidelines.i. Experiments Using Risk Group 2, Risk Group 3, Risk Group 4, or

Restricted Agents as Host-Vector Systems (III-D-1) Experiments involving the introduction of recombinant DNA into Risk Group 2 agents will usually be conducted at Biosafety Level (BL) 2 containment. Experiments with such agents will usually be conducted with whole animals at BL2 or BL2-N (Animals) containment.

Experiments involving the introduction of recombinant DNA into Risk Group 3 agents will usually be conducted at BL3 containment. Experiments with such agents will usually be conducted with whole animals at BL3 or BL3-N containment.

Note: Experiments involving the introduction of recombinant DNA into Risk Group 4 agents are not currently permitted by the VA.

d. Experiments in Which DNA From Risk Group 2, Risk Group 3, or Restricted Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems (III-D-2) Experiments in which DNA from Risk Group 2 or Risk Group 3 agents is transferred into nonpathogenic prokaryotes or lower eukaryotes may be performed under BL2 containment.

The IBC may approve the specific lowering of containment for particular experiments to BL1. Many experiments in this category are exempt from the NIH Guidelines (see NIH Guidelines Section III-F, Exempt Experiments).

Experiments involving the formation of recombinant DNA for certain genes coding for molecules toxic for vertebrates require NIH/OBA approval (see NIH Guidelines Section III-B-1, Experiments Involving the Cloning of Toxin Molecules with LD50 of Less than 100 Nanograms Per Kilogram Body Weight ) or shall be conducted under NIH specified conditions as described in the NIH Guideline Appendix F, Containment Conditions for Cloning of Genes Coding for the Biosynthesis of Molecules Toxic for Vertebrates.

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Containment conditions for experiments in which DNA from restricted agents is transferred into nonpathogenic prokaryotes or lower eukaryotes shall be determined by NIH/OBA following a case-by-case review (see NIH Guidelines Section V-L, Footnotes and References of Sections I-IV). A U.S. Department of Agriculture permit is required for work with plant or animal pathogens (see Section V-G, Footnotes and References of Sections IIV).

i. Experiments Involving the Use of Infectious DNA or RNA Viruses or Defective DNA or RNA Viruses in the Presence of Helper Virus in Tissue Culture Systems (III-D-3)

Caution: Special care should be used in the evaluation of containment levels for experiments which are likely to either enhance the pathogenicity (e.g., insertion of a host oncogene) or to extend the host range (e.g., introduction of novel control elements) of viral vectors under conditions that permit a productive infection. In such cases, serious consideration should be given to increasing physical containment by at least one level.

Note: Recombinant DNA or RNA molecules derived there from, which contain less than two-thirds of the genome of any eukaryotic virus (all viruses from a single Family (see NIH Guidelines Section V-J, Footnotes and References of Sections I-IV) being considered identical (see Section V-K, Footnotes and References of Sections I-IV), are considered defective and may be used in the absence of helper under the conditions specified in the NIH Guidelines Section III-E-1, Experiments Involving the Formation of Recombinant DNA Molecules Containing No More than Two-Thirds of the Genome of any Eukaryotic Virus.

Experiments involving the use of infectious or defective Risk Group 2 viruses (see NIH Guidelines Appendix B-II, Risk Group 2 Agents) in the presence of helper virus may be conducted at BL2.

Experiments involving the use of infectious or defective Risk Group 3 viruses (see NIH Guidelines Appendix B-III-D, Risk Group 3 (RG3) - Viruses and Prions) in the presence of helper virus may be conducted at BL3.

Experiments involving the use of infectious or defective Risk Group 4 viruses are not currently permitted by the VA.

Experiments involving the use of infectious or defective restricted poxviruses (see NIH Guidelines Sections V-A and V-L, Footnotes and References of Sections I-IV) in the presence of helper virus shall be determined on a case-by-case basis following NIH/OBA review. A U.S. Department of Agriculture permit is required for work with plant or animal pathogens (see Section V-G, Footnotes and References of Sections I-IV).

Experiments involving the use of infectious or defective viruses in the presence of helper virus which are not covered in Sections III-D-3-a through III-D-3-d may be conducted at BL1.

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ii. Experiments Involving Whole Animals (III-D-4). This section covers experiments involving whole animals in which the animal's genome has been altered by stable introduction of recombinant DNA, or DNA derived therefrom, into the germ-line (transgenic animals) and experiments involving viable recombinant DNA-modified microorganisms tested on whole animals. For the latter, other than viruses which are only vertically transmitted, the experiments may not be conducted at BL1-N containment. A minimum containment of BL2 or BL2-N is required.

Caution - Special care should be used in the evaluation of containment conditions for some experiments with transgenic animals. For example, such experiments might lead to the creation of novel mechanisms or increased transmission of a recombinant pathogen or production of undesirable traits in the host animal. In such cases, serious consideration should be given to increasing the containment conditions.

Recombinant DNA, or DNA or RNA molecules derived therefrom, from any source except for greater than two-thirds of eukaryotic viral genome may be transferred to any non-human vertebrate or any invertebrate organism and propagated under conditions of physical containment comparable to BL1 or BL1-N and appropriate to the organism under study (see NIH Guidelines Section V-B, Footnotes and References of Sections I-IV). Animals that contain sequences from viral vectors, which do not lead to transmissible infection either directly or indirectly as a result of complementation or recombination in animals, may be propagated under conditions of physical containment comparable to BL1 or BL1-N and appropriate to the organism under study. Experiments

involving the introduction of other sequences from eukaryotic viral genomes into animals are covered under NIH Guidelines Section III-D-4-b, Experiments Involving Whole Animals. For experiments involving recombinant DNA-modified Risk Groups 2, 3, or restricted organisms, see NIH Guidelines Sections V-A, V-G, and V-L, Footnotes and References of Sections I-IV. It is important that the investigator demonstrate that the fraction of the viral genome being utilized does not lead to productive infection. A U.S. Department of Agriculture permit is required for work with plant or animal pathogens (see NIH Guidelines Section V-G, Footnotes and References of Sections I-IV).

For experiments involving recombinant DNA, or DNA or RNA derived therefrom, involving whole animals, including transgenic animals, and not covered by NIH Guidelines Sections III-D-1, Experiments Using Human or Animal Pathogens (Risk Group 2, Risk Group 3, or Restricted Agents as Host-Vector Systems, or

III-D-4-a, Experiments Involving Whole Animals, the appropriate containment shall be determined by the Institutional Biosafety Committee.

iii. Exceptions for Animal Research under NIH Guidelines(III-D-4-c). Section III-D-4, Experiments Involving Whole Animals.

Experiments Involving Transgenic Rodents (III-E-3). This section covers experiments involving the generation of rodents in which the animal's genome has been altered by stable introduction of recombinant

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DNA, or DNA derived therefrom, into the germ-line (transgenic rodents). Only experiments that require BL1 containment are covered under this section; experiments that require BL2, or BL3 containment are covered under the NIH Guideline .

The purchase or transfer of transgenic rodents is exempt from the NIH Guidelines under NIH Guidelines Section III-F, Exempt Experiments (see NIH Guidelines Appendix C-VI, The Purchase or Transfer of Transgenic Rodents).

e. Resources. The IBC review will determine if the investigative plan provides for adequate facilities and personnel to ensure the safe handling of the agent.

f. Training.i. The IBC will determine if the Investigator has adequate

qualifications and training to supervise the proposed research.ii. The IBC will determine if the Investigators plan for the training of

personnel is adequate for the safe handling of the agent.

g. Compliance. The IBC will determine if the Investigator has demonstrated a willingness, knowledge, and ability to perform the reporting that is required for projects of this nature. This reporting includes all surveillance, data reporting, and adverse event reporting requirements required by the NIH Guidelines.

h. ICF Document. The IBC will review the Informed Consent Document if the agent will be given to human subjects. The IBC should review the ICF from the perspective of risks associated with the use of recombinant DNA. If the IBC requires changes to the ICF, then the IRB must review and approve the ICF after the changes have been made.

C. Amendments and Modifications. Research protocol changes in the original application must be documented on an amended Research Protocol Safety Survey (RPSS) (see App. A, VA Form 10-0398) and must be submitted to and reviewed by IBC prior to the implementation of the changes.

2. Review of Policies and Procedures.

A. Annual Reviews. The IBC will annually review and forward the following policies and procedures to the R&D Committee for approval:

a. The IBC SOP. b. The BSL3 SOP (if the BSL3 is used for research that involves recombinant

DNA).c. The Emergency Preparedness and Response Plan (recombinant DNA

section).d. The NIH Self-Assessment Tool (from the OBA website at:

http://www4.od.nih.gov.gov/oba

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3. Inventory Controls. Inventory control includes maintaining an up-to-date record of non-exempt recombinant DNA that is part of experiments that require IBC approval before initiation (such as the BSL-3 experiments) and where the agents are stored and utilized. The AO R&D will maintain this inventory and will make it available to the IBC, the IRB, the R&D committee, as well as to regulatory and emergency personnel as required.

4. Remediation & Followup. The Safety Coordinator will track progress made in the remediation plan and will report progress and problems to the IBC at regularly scheduled meetings.

5. Non-Recurrent Processes.

A. Spills, Exposure, and Emergency Procedures. Emergency procedures are specified in the Emergency Preparedness Plan. The IBC will review any emergency actions at the next scheduled meeting and will conduct a formal analysis.

B. Autoclave Verification. The procedures used for autoclave verification are contained within the Chemical Hygiene Plan.

C. Waste Management. All material that contains recombinant DNA must be disposed of using standard microbiological practices. The procedures for waste management are contained within the Chemical Hygiene Plan.

D. Animal Disposal. When an animal containing recombinant DNA or a recombinant DNA-derived organism is euthanized or dies, then the carcass shall be disposed of to avoid its use as food for human beings or animals.

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SECTION 06ACTIONS

If quorum is not attained, the IBC may only vote to defer review.If quorum is attained, the IBC may vote to:

Table Approve Conditional Approval Approval Withheld

Or Disapprove

Projects may be Conditionally Approved with minor stipulations. Conditional Approvals are not Approved until the stipulations have been met. The IBC must clearly state in the meeting minutes the nature of the stipulations. The IBC Chair must communicate the required actions to the Principal Investigator within 10 working days of the IBC determination. Unless it is otherwise specified in the meeting minutes, the primary reviewer is responsible for ensuring that the stipulations are fulfilled.

Projects are not normally disapproved unless there is some aspect of the design that would violate VALBHS polices or procedures.

If a project is Disapproved, then the Chair of the IBC will notify the Chair of the R&D Committee and the Principal Investigator (PI) in writing within 10 working days of the decision. This notification must specify the reasons for the disapproval and must inform the PI of the conditions for reconsideration. The PI must provide a rebuttal and request for reconsideration within 2 weeks of receipt of the disapproval notification. If the IBC chooses to allow the project to be reconsidered then the status will be changed to Approval Withheld. If the IBC does not choose to reconsider, then the PI may petition the R&D committee. The R&D committee will work closely with the IBC to resolve the matter.

If Approval is Withheld or the action is Tabled, then the Chair of the IBC will notify the Principal Investigator in writing within 10 working days of the decision. This notification must specify the reasons that the action was tabled or approval was withheld and the actions that are required for reconsideration.

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SECTION 07TRAINING

All individuals (VA employees appointed as full-time, part-time or intermittent paid employees, and WOC employees, as well as contractors) who’s work involves the use of recombinant DNA and is subject to the approval and oversight of the IBC must be appropriately trained to ensure both safety and security within research laboratories and the safe handling of and security of select agents, toxins or other hazardous agents. The training must include training on the Laboratory’s Emergency Preparedness and Response Plan.

1. IBC Members. The IBC and the R&D Committee will review the qualifications and

education of IBC members on an annual basis. IBC members will review the NIH guidelines and this SOP on a yearly

basis. The IBC will also review relevant educational items at regularly scheduled

meetings.

2. Principal Investigators. The IBC will review the education, experience, and certifications of the principal investigator at the time of initial review. The Principal investigator must:

Have adequate training to ensure the safe handling and appropriate use of recombinant DNA materials.

Know the appropriate responses to take in the event of unanticipated problems.

Be familiar with the provisions and requirements for Principal Investigators as contained in the NIH guidelines.

3. Research Staff. The Principal Investigator is responsible for the training of Research Staff with regard to uses and precautions that are specific to the recombinant DNA material or the procedures to be used in the experimental design. The Principal Investigator must keep a record of all training sessions that includes:

The date of training. The topics covered. Who attended.

4. BSL-3 Training. The IBC will ensure that special training requirements have been satisfied for projects that involve the use of The BSL-3 facility. These training requirements are specified in the BSL-3 SOP.

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SECTION 08QUALITY IMPROVEMENT AND ASSURANCE

The IBC will:

Review the NIH guidelines and this SOP on a yearly basis.

Conduct a yearly program review to:

Ensure the review of investigation reports of all lost-time injuries and all significant adverse environmental events.

Ensure the proper reporting of injury and illness trends to the R&D Committee, as appropriate.

Request, when appropriate, the appointment of an ad hoc committee (consisting of members with appropriate expertise) to investigate and report on occupational injuries, illnesses, and adverse environmental events.

Monitor the status of ongoing health surveillance of personnel in connection with individual recombinant DNA projects, and if appropriate, conduct a health surveillance program for such projects.

Review all citations issued by regulatory agencies and ensure that appropriate committee members and PIs take prompt corrective actions, and coordinate the necessary responses to regulatory agencies.

The Biological Safety Officer is charged with performing periodic inspections to ensure that laboratory standards are rigorously followed. Any significant problems that are encountered as a result of these inspections will be promptly reported to the IBC. The BSO will use the NIH Self-Assessment Tool to meet this requirement.

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SECTION 09RECORD KEEPING

The AO R&D will be responsible for maintaining the following records:

1. Roster. A roster of all IBC members clearly indicating:

The Chair Contact Person Biological Safety Officer Animal gene transfer expert Human gene transfer expert R&D liaison Non-affiliated members.

2. Biographical sketches of all IBC members. Biographical sketches will be in the NIH format and will be no longer than 2 pages.

3. Training Records. Including the records of training required under Section 07 (1) for employees of the Research HCG and records of training required of laboratory personnel under section 07 (2,3) above. A mechanism must be implemented to ensure that all records (written, computer databases, spreadsheets, etc.) are accurate and one, which allows for the authenticity of these, records being verified.

4. Incident Reports. Safety and Security Incident Reports including:

All incidents reported to ORO, NIH, the VISN and VA Central Office.

5. External Inspections. A record must be kept of all inspections of the VA research laboratories covered by this Handbook, including:

Inspections by authorized entities such as CDC, VA OIG, USDA, GAO, ORD, ORO, the VA facility, and VISN Safety and Health officials.

All inspections of the VA research laboratories covered and required by this SOP.

6. Internal Inspections. A record of all findings, deficiencies and corrective action based on the inspections listed in SOP.

7. Emergency Response Plans and SOP’s. Records must also include a record of when last reviewed, the mechanism used to disseminate the plan, and new changes to affected research staff.

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8. IBC Meeting Agendas and Minutes.

The IBC will provide written notification of the results of IBC review to the R&D Committee, the Research Office, and the PI. Written notification will be through the use of meeting minutes.

IBC meetings will normally be in conjunction with SRS meetings. In such cases the IBC Agendas and Minutes will be included within a separate section of the SRS minutes. Agendas and meeting minutes will be prepared and maintained by the Safety Committee Coordinator.

If the IBC meets separately from the SRS then the agendas and minutes of the Subcommittee on Research Safety (IBC) must be prepared according to the format specified within the SRS SOP.

A. Content. Regardless of whether the IBC minutes are included within the SRS minutes or are independent of the SRS minutes, the discussion section of the minutes will address the following minimal issues:

a. Evidence of the review of the submitted information concerning: The Agent Characteristics (E.g. virulence, pathogenicity, environmental

stability) Types of manipulations planned source(s) of the inserted DNA

sequences (e.g., species) Nature of the inserted DNA sequences (e.g., structural gen, oncogene) Host(s) and vectors(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 producedb. IBC categorization of the proposed experiments.c. IBC determination of the Risk Groupd. Containment conditions to be implementede. Applicable section of the NIH Guidelines (e.g., Section III-D-1. Section III-E-1,

etc.)

In general, the meeting minutes should offer sufficient detail about the discussion of these matters to document the committee’s rationale for particular decisions.

B. Distribution & Public Disclosure. Meeting minutes are distributed within VALBHS as described in the Reporting Section. Copies of meeting minutes may be requested by the general public under the Freedom of Information Act. Requests should be made through the office of the medical center Director.

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SECTION 10REGULATORY NON-COMPLIANCE

1. Audits. The IBC will initiate a review if there is any allegation or other evidence that there has been a violation of safety policies or procedures. The IBC has the authority to examine all records that have a direct impact on safety. The IBC may also choose to review the working environment at any time and without notice.

The IBC will consider the evidence and will determine by vote if the non-compliance is confirmed.

2. Actions. If non-compliance is confirmed then the noncompliance will be reported as described below.

If the non-compliance is confirmed the IBC will determine by vote if the non-compliance is Serious or Continuing.

The IBC will consider the non-compliance to be Serious if it involves an immediate threat to the safety or health of animals, research participants, or staff.

The IBC will consider the non-compliance to be Continuing if the PI has failed to take corrective remedial action after a previous finding of non-compliance for the same violation, or if there have been more than 3 findings of non-compliance (all projects for a PI) within 3 years.

If the IBC determines that a violation is Serious or Continuing, the IBC may recommend that the R&D committee Suspend or Terminate the Project.

SECTION 11REPORTING

Reporting procedures are described in detail in the “SOP for the Reporting of Research Events to Institutional Officials and External Oversight Offices”. The procedure describe in this SOP is a summary.

IBC reporting requirements include:

1. Annual Report. The IBC must submit to NIH/OBA at least annually:

A. A roster of all IBC members clearly indicating the Chair, contact person, biological safety Officer, Animal gene transfer expert, human gene transfer expert, and non-affiliated members.

B. Biographical sketches of all IBC members

2. Significant Problems.

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A. NIH Reporting. Any significant problems, violations of the NIH Guidelines, or any significant research related accidents and illnesses must be reported to NIH/ORDA within 30 days, unless it can be verified that a report has already been filed by the Principal Investigator. Reporting procedures are described in the “SOP for the Reporting of Research Events to Institutional Officials and External Oversight Offices”

B. VISN 22 and ORO Reporting. Unanticipated problems that involve risks to human or animal subjects or others, serious problems, and continuing problems must be reported as described in the “SOP for the Reporting of Research Events to Institutional Officials and External Oversight Offices”.

C. IRB Reporting . The IBC Chair will inform the IRB Chair immediately if serious problems involve the treatment of human subjects. IRB reporting will follow the procedures defined in the IRB SOP.

D. SAS Reporting . The IBC Chair will inform the SAS Chair immediately if serious problems involve research that utilizes animal subjects. SAS reporting will follow the procedures defined in the SAS SOP.

3. Routine Actions. The IBC will forward meeting minutes to the R&D Committee through the Research Office. Minutes will be complete and approved at least within 30 days following an IBC meeting.

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References

NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines)Guidance on the Content of Minutes of Institutional Biosafety Committee Meetings.

VHA Handbook 1200.06, 1200.08

Effective June 24, 1994, Published in Federal Register, July 5, 1994 (59 FR 34496)Amendment Effective July 28, 1994, Federal Register, August 5, 1994 (59 FR 40170)Amendment Effective April 17, 1995, Federal Register, April 27, 1995 (60 FR 20726)Amendment Effective December 14, 1995, Federal Register, January 19, 1996 (61 FR 1482)Amendment Effective March 1, 1996, Federal Register, March 12, 1996 (61 FR 10004)Amendment Effective January 23, 1997, Federal Register, January 31, 1997 (62 FR 4782)Amendment Effective September 30, 1997, Federal Register, October 14, 1997 (62 FR 53335)Amendment Effective October 20, 1997, Federal Register, October 29, 1997 (62 FR 56196)Amendment Effective October 22, 1997, Federal Register, October 31, 1997 (62 FR 59032)Amendment Effective February 4, 1998, Federal Register, February 17, 1998 (63 FR 8052)Amendment Effective April 30, 1998, Federal Register, May 11, 1998 (63 FR 26018)Amendment Effective April 29, 1999, Federal Register, May 11, 1999 (64 FR 25361)Amendment Effective October 2, 2000, Federal Register, October 10, 2000 (65 FR 60328)Amendment Effective December 28, 2000 Federal Register, January 5, 2001 (66 FR 1146)Amendment Effective December 11, 2001 Federal Register, December 11, 2001 (66 FR 64051)Amendment Effective December 19, 2001 Federal Register, November 19, 2001 (66 FR 57970)Amendment Effective January 10, 2002 Federal Register, December 11, 2001 (66 FR 64052)Amendment Effective January 24, 2002 Federal Register, November 19, 2001 (66 FR 57970)

Rescission: VALBHS Policy No. 09-151: Safety “Safety of Personnel Engaged in Research.”

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APPENDIX A - Use VA Form 0398 for application for IBC Review

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APPENDIX B

Appendix B-I. Risk Group 1 (RG1) Agents RG1 agents are not associated with disease in healthy adult humans. Examples of RG1 agents include asporogenic Bacillus subtilis or Bacillus licheniformis (see Appendix C-IV-A, Bacillus subtilis or Bacillus licheniformis Host-Vector Systems, Exceptions); adeno- associated virus (AAV) types 1 through 4; and recombinant AAV constructs, in which the transgene does not encode either a potentially tumorigenic gene product or a toxin molecule and are produced in the absence of a helper virus. A strain of Escherichia coli (see Appendix C-II-A, Escherichia coli K-12 Host Vector Systems, Exceptions) is an RG1 agent if it (1) does not possess a complete lipopolysaccharide (i.e., lacks the O antigen); and (2) does not carry any active virulence factor (e.g., toxins) or colonization factors and does not carry any genes encoding these factors. Those agents not listed in Risk Groups (RGs) 2, 3 and 4 are not automatically or implicitly classified in RG1; a risk assessment must be conducted based on the known and potential properties of the agents and their relationship to agents that are listed. Appendix B-II. Risk Group 2 (RG2) Agents RG2 agents are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available. Appendix B-II-A. Risk Group 2 (RG2) - Bacterial Agents Including Chlamydia --Acinetobacter baumannii (formerly Acinetobacter calcoaceticus)--Actinobacillus--Actinomyces pyogenes (formerly Corynebacterium pyogenes)--Aeromonas hydrophila--Amycolata autotrophica--Archanobacterium haemolyticum (formerly Corynebacterium haemolyticum)--Arizona hinshawii - all serotypes--Bacillus anthracis --Bartonella henselae, B. quintana, B. vinsonii--Bordetella including B. pertussis --Borrelia recurrentis, B. burgdorferi--Burkholderia (formerly Pseudomonas species) except those listed in Appendix B-III-A (RG3))--Campylobacter coli, C. fetus, C. jejuni--Chlamydia psittaci, C. trachomatis, C. pneumoniae --Clostridium botulinum, Cl. chauvoei, Cl. haemolyticum, Cl. histolyticum, Cl. novyi, Cl. septicum, Cl. tetani--Corynebacterium diphtheriae, C. pseudotuberculosis, C. renale

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--Dermatophilus congolensis--Edwardsiella tarda--Erysipelothrix rhusiopathiae--Escherichia coli - all enteropathogenic, enterotoxigenic, enteroinvasive and strains

bearing K1 antigen, including E. coli O157:H7--Haemophilus ducreyi, H. influenzae--Helicobacter pylori--Klebsiella - all species except K. oxytoca (RG1)--Legionella including L. pneumophila --Leptospira interrogans - all serotypes--Listeria--Moraxella --Mycobacterium (except those listed in Appendix B-III-A (RG3)) including M. avium

complex, M. asiaticum, M. bovis BCG vaccine strain, M. chelonei, M. fortuitum, M. kansasii, M. leprae, M. malmoense, M. marinum, M. paratuberculosis, M. scrofulaceum, M. simiae, M. szulgai, M. ulcerans, M. xenopi

--Mycoplasma, except M. mycoides and M. agalactiae which are restricted animal pathogens --Neisseria gonorrhoeae, N. meningitidis --Nocardia asteroides, N. brasiliensis, N. otitidiscaviarum, N. transvalensis--Rhodococcus equi--Salmonella including S. arizonae, S. cholerasuis, S. enteritidis, S. gallinarum-pullorum,

S. meleagridis, S. paratyphi, A, B, C, S. typhi, S. typhimurium --Shigella including S. boydii, S. dysenteriae, type 1, S. flexneri, S. sonnei--Sphaerophorus necrophorus--Staphylococcus aureus--Streptobacillus moniliformis--Streptococcus including S. pneumoniae, S. pyogenes--Treponema pallidum, T. carateum--Vibrio cholerae, V. parahemolyticus, V. vulnificus--Yersinia enterocolitica Appendix B-II-B. Risk Group 2 (RG2) - Fungal Agents --Blastomyces dermatitidis--Cladosporium bantianum, C. (Xylohypha) trichoides --Cryptococcus neoformans --Dactylaria galopava (Ochroconis gallopavum)--Epidermophyton--Exophiala (Wangiella) dermatitidis --Fonsecaea pedrosoi--Microsporum--Paracoccidioides braziliensis--Penicillium marneffei--Sporothrix schenckii--Trichophyton

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Appendix B-II-C. Risk Group 2 (RG2) - Parasitic Agents --Ancylostoma human hookworms including A. duodenale, A. ceylanicum--Ascaris including Ascaris lumbricoides suum--Babesia including B. divergens, B. microti--Brugia filaria worms including B. malayi, B. timori --Coccidia--Cryptosporidium including C. parvum--Cysticercus cellulosae (hydatid cyst, larva of T. solium)--Echinococcus including E. granulosis, E. multilocularis, E. vogeli--Entamoeba histolytica--Enterobius--Fasciola including F. gigantica, F. hepatica--Giardia including G. lamblia--Heterophyes--Hymenolepis including H. diminuta, H. nana--Isospora--Leishmania including L. braziliensis, L. donovani, L. ethiopia, L. major, L. mexicana, L. peruvania, L. tropica--Loa loa filaria worms--Microsporidium--Naegleria fowleri--Necator human hookworms including N. americanus --Onchocerca filaria worms including, O. volvulus--Plasmodium including simian species, P. cynomologi, P. falciparum, P. malariae, P. ovale, P. vivax--Sarcocystis including S. sui hominis--Schistosoma including S. haematobium, S. intercalatum, S. japonicum, S. mansoni, S. mekongi--Strongyloides including S. stercoralis--Taenia solium--Toxocara including T. canis --Toxoplasma including T. gondii--Trichinella spiralis--Trypanosoma including T. brucei brucei, T. brucei gambiense, T. brucei rhodesiense, T. cruzi--Wuchereria bancrofti filaria worms Appendix B-II-D. Risk Group 2 (RG2) - Viruses Adenoviruses, human - all types Alphaviruses (Togaviruses) - Group A Arboviruses --Eastern equine encephalomyelitis virus--Venezuelan equine encephalomyelitis vaccine strain TC-83--Western equine encephalomyelitis virus

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Arenaviruses--Lymphocytic choriomeningitis virus (non-neurotropic strains) --Tacaribe virus complex--Other viruses as listed in the reference source (see Section V-C, Footnotes and

References of Sections I through IV) Bunyaviruses --Bunyamwera virus--Rift Valley fever virus vaccine strain MP-12--Other viruses as listed in the reference source (see Section V-C, Footnotes and

References of Sections I through IV) Caliciviruses Coronaviruses Flaviviruses (Togaviruses) - Group B Arboviruses--Dengue virus serotypes 1, 2, 3, and 4 --Yellow fever virus vaccine strain 17D--Other viruses as listed in the reference source (see Section V-C, Footnotes and

References of Sections I through IV) Hepatitis A, B, C, D, and E viruses Herpesviruses - except Herpesvirus simiae (Monkey B virus) (see Appendix B-IV-D, Risk Group 4 (RG4) - Viral Agents)--Cytomegalovirus--Epstein Barr virus--Herpes simplex types 1 and 2--Herpes zoster --Human herpesvirus types 6 and 7Orthomyxoviruses--Influenza viruses types A, B, and C--Other tick-borne orthomyxoviruses as listed in the reference source (see Section V-C,

Footnotes and References of Sections I through IV) Papovaviruses --All human papilloma viruses Paramyxoviruses--Newcastle disease virus--Measles virus--Mumps virus--Parainfluenza viruses types 1, 2, 3, and 4--Respiratory syncytial virus Parvoviruses--Human parvovirus (B19)

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Picornaviruses--Coxsackie viruses types A and B--Echoviruses - all types--Polioviruses - all types, wild and attenuated--Rhinoviruses - all types Poxviruses - all types except Monkeypox virus (see Appendix B-III-D, Risk Group 3 (RG3) - Viruses and Prions) and restricted poxviruses including Alastrim, Smallpox, and Whitepox (see Section V-L, Footnotes and References of Sections I through IV) Reoviruses - all types including Coltivirus, human Rotavirus, and Orbivirus (Colorado tick fever virus) Rhabdoviruses--Rabies virus - all strains--Vesicular stomatitis virus - laboratory adapted strains including VSV-Indiana, San Juan, and Glasgow Togaviruses (see Alphaviruses and Flaviviruses)--Rubivirus (rubella) Appendix B-III. Risk Group 3 (RG3) Agents RG3 agents are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available. Appendix B-III-A. Risk Group 3 (RG3) - Bacterial Agents Including Rickettsia --Bartonella--Brucella including B. abortus, B. canis, B. suis--Burkholderia (Pseudomonas) mallei, B. pseudomallei--Coxiella burnetii--Francisella tularensis--Mycobacterium bovis (except BCG strain, see Appendix B-II-A, Risk Group 2 (RG2) -

Bacterial Agents Including Chlamydia), M. tuberculosis--Pasteurella multocida type B -"buffalo" and other virulent strains

--Rickettsia akari, R. australis, R. canada, R. conorii, R. prowazekii, R. rickettsii, R,

siberica, R. tsutsugamushi, R. typhi (R. mooseri)

--Yersinia pestis Appendix B-III-B. Risk Group 3 (RG3) - Fungal Agents --Coccidioides immitis (sporulating cultures; contaminated soil)--Histoplasma capsulatum, H. capsulatum var.. duboisii

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Appendix B-III-C. Risk Group 3 (RG3) - Parasitic Agents None Appendix B-III-D. Risk Group 3 (RG3) - Viruses and Prions Alphaviruses (Togaviruses) - Group A Arboviruses --Semliki Forest virus--St. Louis encephalitis virus--Venezuelan equine encephalomyelitis virus (except the vaccine strain TC-83, see Appendix B-II-D (RG2))--Other viruses as listed in the reference source (see Section V-C, Footnotes and

References of Sections I through IV) Arenaviruses --Flexal--Lymphocytic choriomeningitis virus (LCM) (neurotropic strains) Bunyaviruses--Hantaviruses including Hantaan virus --Rift Valley fever virus Flaviviruses (Togaviruses) - Group B Arboviruses--Japanese encephalitis virus--Yellow fever virus--Other viruses as listed in the reference source (see Section V-C, Footnotes and

References of Sections I through IV) Poxviruses--Monkeypox virus Prions--Transmissible spongioform encephalopathies (TME) agents (Creutzfeldt-Jacob

disease and kuru agents)(see Section V-C, Footnotes and References of Sections I through IV, for containment instruction)

Retroviruses --Human immunodeficiency virus (HIV) types 1 and 2--Human T cell lymphotropic virus (HTLV) types 1 and 2--Simian immunodeficiency virus (SIV) Rhabdoviruses--Vesicular stomatitis virus Appendix B-IV. Risk Group 4 (RG4) Agents

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RG4 agents are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available. Appendix B-IV-A. Risk Group 4 (RG4) - Bacterial Agents None Appendix B-IV-B. Risk Group 4 (RG4) - Fungal Agents None Appendix B-IV-C. Risk Group 4 (RG4) - Parasitic Agents None Appendix B-IV-D. Risk Group 4 (RG4) - Viral Agents Arenaviruses--Guanarito virus--Lassa virus --Junin virus--Machupo virus--Sabia Bunyaviruses (Nairovirus)--Crimean-Congo hemorrhagic fever virus Filoviruses --Ebola virus--Marburg virus Flaviruses (Togaviruses) - Group B Arboviruses --Tick-borne encephalitis virus complex including Absetterov, Central European encephalitis, Hanzalova, Hypr, Kumlinge, Kyasanur Forest disease, Omsk hemorrhagic fever, and Russian spring-summer encephalitis viruses Herpesviruses (alpha) --Herpesvirus simiae (Herpes B or Monkey B virus) Paramyxoviruses--Equine morbillivirus Hemorrhagic fever agents and viruses as yet undefined Appendix B-V. Animal Viral Etiologic Agents in Common Use

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The following list of animal etiologic agents is appended to the list of human etiologic agents. None of these agents is associated with disease in healthy adult humans; they are commonly used in laboratory experimental work. A containment level appropriate for RG1 human agents is recommended for their use. For agents that are infectious to human cells, e.g., amphotropic and xenotropic strains of murine leukemia virus, a containment level appropriate for RG2 human agents is recommended. Baculoviruses Herpesviruses--Herpesvirus ateles--Herpesvirus saimiri--Marek's disease virus--Murine cytomegalovirus Papovaviruses--Bovine papilloma virus--Polyoma virus--Shope papilloma virus--Simian virus 40 (SV40) Retroviruses--Avian leukosis virus--Avian sarcoma virus--Bovine leukemia virus--Feline leukemia virus--Feline sarcoma virus--Gibbon leukemia virus--Mason-Pfizer monkey virus--Mouse mammary tumor virus--Murine leukemia virus--Murine sarcoma virus--Rat leukemia virus Appendix B-V-1. Murine Retroviral Vectors Murine retroviral vectors to be used for human transfer experiments (less than 10 liters) that contain less than 50% of their respective parental viral genome and that have been demonstrated to be free of detectable replication competent retrovirus can be maintained, handled, and administered, under BL1 containment.

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