Institutional Biosafety Committee Member Training September 2017

Background Recombinant DNA work is covered under NIH Office of Biotechnology Activities (NIH OBA) in: NIH GUIDELINES FOR RESEARCH INVOLVING RECOMBINANT OR SYNTHETIC NUCLEIC ACID MOLECULES (April 2016) Purpose of Guidelines: specify the practices for constructing and handling: (i) recombinant nucleic acid molecules (rDNA), (ii) synthetic nucleic acid molecules (sNA), including those that are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules, (iii) cells, organisms, and viruses containing such molecules.

Institutional Biosafety Committee Institutional Biosafety Committee (IBC) Reviews all research that involves the use of rDNA/sNA Use the NIH/OBA rDNA Guidelines as reference document Reviews research involving the use of infectious agents, NOT rDNA/sNA Uses the CDC BMBL as a reference document Inclusive of subcommittees-needlestick and healthcare

Biosafety Levels Biosafety levels are a combination of facilities, equipment and practices. Level 1 (BSL1): basic lab, good lab practices Level 2 (BSL2): limited lab access, specific training and practices Level 3 (BSL3): containment (biosafety cabinet), specific training and practices Level 4 (BSL4): full containment; specific facility, training and practices

Risk Assessment Factors Pathogenicity Route of Transmission Agent Stability Infectious Dose Concentration Availability of effective prophylaxis, treatment Availability of medical surveillance Host susceptibility

Risk Assessment Organism Hosts Vector Expression of foreign gene Protein produced Containment Facility Laboratory-specific protocol Training & expertise of personnel

History of the Guidelines The NIH Guidelines were implemented in response to public and scientific concern over the emerging science of rDNA technologies in the early 1970’s. By 1976, NIH had published the first set of guidelines which have been amended over time to allow for greater public access and a greater emphasis on safety.

Section I: Scope and Applicability If your institution receives NIH funding for rDNA research, then it must comply with the NIH Guidelines. Even if a project is privately sponsored, that research must still be conducted in accordance with the NIH Guidelines if conducted at an institution subject to the NIH Guidelines.

Section II: Safety Considerations (Risk Assessment) Risk Group 1 (RG1): Agents that are not associated with disease in healthy adult humans. Risk Group 2 (RG2 ): Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available. Risk Group 3 (RG3 ): Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available. Risk Group 4 (RG4 ): Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available .

Section II: Safety Considerations (Containment) Containment should be a combination of standard microbiology practices, engineering controls, laboratory facilities and design. Containment is defined in: Appendices G, P, & Q of the NIH Guidelines Laboratory Safety Monograph (historical document) Biosafety in Microbiological and Biomedical Laboratories (BMBL)

Section III: Experiments covered by the NIH Guidelines III-A: Transfer of drug resistance III-B: Cloning of lethal toxins III-C: Human gene transfer research III-D: Infectious agents as vectors & transgenic animals III-E: Generation of transgenic rodents III-F: Exemptions

Experiments Covered by the NIH Level of Review Section Research Example IBC, RAC review and NIH Director review and approval III-A Cipro resistant Bacillus anthracis IBC approval and NIH review for containment determination III-B Cloning botulinum toxin expression into adenovirus IBC and IRB approval and NIH review before research particpant enrollment III-C Human gene transfer IBC approval before initiation III-D Expression of a nonnative protein in Staphylococcus aureus IBC notification at initiation III-E Germline alteration of rodents which may be housed in BL-1 Exempt III-F Purchased transgenic rodents

III-A: Major Actions Requires: IBC Approval, RAC Review, NIH Director Approval Before Initiation of Work Transfer of therapeutically useful drug resistance to organisms which may compromise human health/agriculture/medicine

III-B: Toxin Transfer Requires: NIH/OBA, IBC Review and Approval Before Initiation of Work Deliberate cloning of toxin molecules lethal to vertebrates at an LD50 of less than 100 nanograms/Kg of body weight (e.g., botulinum toxin) Containment determined by NIH/OBA

III-C: (Deliberate Transfer of rDNA into Research Participants, ex III-C: (Deliberate Transfer of rDNA into Research Participants, ex. Gene Therapy) Requires: RAC Review Determination, IBC and IRB Approval Before Participant Enrollment Human gene transfer (HGT) protocols All HGT trials except those covered under vaccine exemption require RAC registration. 20-30% will be publicly reviewed and may require public review prior to participant enrollment.

III-D: General Work Requires: IBC Review and Approval Prior to the Initiation of Work Involves RG 2-4 agents, host/vector system Cloned DNA from RG 2-4 agents into non-pathogenic prokaryotes RG 2-4 agents into whole animals, usually transgenic Recombinant plants Large scale experiments greater than 10L Generation of any transgenic animal other than BSL-1 rodents

III-E: Less Restrictive Work Requires: IBC Notification at the Initiation of Work (BSL-1 Containment), and Subsequent IBC Review and Approval rDNA molecules that contains less than 2/3 of any eukaryotic viral genome Generation of transgenic rodents with BSL-1 containment (crossbreeding of transgenics now exempt at BSL-1) Whole plants that require minimal containment Anything else NOT covered under sections III-A through III-D & III-F

III-F: Exemptions Exempt from the NIH Guidelines and Does Not Require IBC Review or Approval rDNA molecules that are: Not in organisms or viruses Not a risk to health or the environment -See Appendix C Note: exceptions to exemptions!

FAQ Review process for human gene transfer protocols https://osp.od.nih.gov/biotechnology/faq-onthe-nih-review-process-for-human-gene-transfer-trials/ Vaccine exemptions https://osp.od.nih.gov/biotechnology/faqs-on-the-nih-guidelines-vaccine-exemption/ Major actions under the guidelines https://osp.od.nih.gov/biotechnology/faqs-about-major-actions-under-section-iii-a-of-the-nih-guidelines-for-research-involving-recombinant-or-synthetic-nucleic-acid/ IBC committee minutes https://absa.org/wp-content/uploads/2017/01/IBC_Meetings_and_Minutes_FAQs.pdf

FAQ Transgenic animals https://osp.od.nih.gov/biotechnology/faqs-on-genetically-modified-transgenic-animals-and-the-use-of-recombinant-or-synthetic-nucleic-acid-molecules-in-animals/ and https://osp.od.nih.gov/wp-content/uploads/Animal_Activities_Table.pdf Experiments that are exempt https://osp.od.nih.gov/biotechnology/faqs-about-experiments-that-are-exempt-from-the-nih-guidelines/

Section IV: Roles and Responsibilities Responsibilities of the Institution: Ensure compliance with NIH Guidelines Establish an IBC Appoint a Biosafety Officer if conducting BSL-3, BSL-4, or large-scale work Ensure IBC has expertise in the research that is reviewed Establish a medical surveillance program as needed Report all incidents to the NIH OBA

Section IV: Roles and Responsibilities Responsibilities of the IBC: Review rDNA research, and approve those research projects that are found to conform with the NIH Guidelines. This review shall include: independent assessment of the containment levels required by the NIH Guidelines for the proposed research; assessment of the facilities, procedures, practices, and training and expertise of personnel involved in rDNA research; ensuring that all aspects of Appendix M have been appropriately addressed by the PI; and ensuring compliance with all surveillance, data reporting, and adverse event reporting requirements set forth in the NIH Guidelines.

Section IV: Roles and Responsibilities Responsibilities of the IBC: Notify the PI of the results of the IBC’s review and approval. Lower containment levels for certain experiments as specified in Section III-D-2-a, Experiments in which DNA from Risk Group 2, Risk Group 3, Risk Group 4, or Restricted Agents is Cloned into Nonpathogenic Prokaryotic or Lower Eukaryotic Host-Vector Systems. Set containment levels as specified in Sections III-D-4-b, Experiments Involving Whole Animals. Periodically review rDNA research conducted at the institution to ensure compliance with the NIH Guidelines. Adopt emergency plans covering accidental spills and personnel contamination resulting from rDNA research

Section IV: Roles and Responsibilities Responsibilities of the IBC: Report any significant problems with or violations of the NIH Guidelines and any significant research-related accidents or illnesses to the appropriate institutional official and NIH/OBA within 30 days. The IBC may not authorize initiation of experiments which are not explicitly covered by the NIH Guidelines until NIH establishes the containment requirement.  Perform such other functions as may be delegated to the IBC.

Section IV: Roles and Responsibilities Responsibilities of the Biological Safety Officer (BSO) Periodic inspections to ensure that laboratory standards are rigorously followed;  Report to the IBC and the institution any significant problems, violations of the NIH Guidelines, and any significant research-related accidents or illnesses of which the BSO becomes aware;  Develop emergency plans for handling accidental spills and personnel contamination and investigating laboratory accidents involving rDNA research;  Provide advice on laboratory security;  Provide technical advice to PIs and the IBC on research safety procedures.

Section IV: Roles and Responsibilities Responsibilities of the Principal Investigator (PI) Initiate or modify no recombinant DNA research which requires IBC approval prior to initiation until that research or the proposed modification thereof has been approved by the IBC and has met all other requirements of the NIH Guidelines;  Determine whether experiments are covered by Section III-E, and ensure that the appropriate procedures are followed;  Report any significant problems, violations of the NIH Guidelines, or any significant research-related accidents and illnesses to the BSO, Animal Facility Director (where applicable), IBC, NIH/OBA, and other appropriate authorities (if applicable) within 30 days;   Report any new information bearing on the NIH Guidelines to the Institutional Biosafety Committee and to NIH/OBA   Be adequately trained in good microbiological techniques;  Adhere to IBC approved emergency plans for handling accidental spills and personnel contamination;   Comply with shipping requirements for rDNA molecules.

Section IV: Roles and Responsibilities Responsibilities of the PI: Responsible for full compliance with the NIH Guidelines in the conduct of rDNA research. Responsible for ensuring that the reporting requirements are fulfilled and will be held accountable for any reporting lapses. Prior to initiating research: Make available to all laboratory staff the protocols that describe the potential biohazards and the precautions to be taken;  Instruct and train laboratory staff in: (i) the practices and techniques required to ensure safety, and (ii) the procedures for dealing with accidents; and  Inform the laboratory staff of the reasons and provisions for any precautionary medical practices advised or requested (e.g., vaccinations).

Section IV: Roles and Responsibilities Responsibilities of the PI: During conduct of research: Supervise the safety performance of the laboratory staff to ensure that the required safety practices and techniques are employed;  Investigate and report any significant problems pertaining to the operation and implementation of containment practices and procedures in writing to the BSO, Animal Facility Director (where applicable), IBC, NIH/OBA, and other appropriate authorities (if applicable)   Correct work errors and conditions that may result in the release of rDNA materials; and Ensure the integrity of the physical containment (e.g., biological safety cabinets) and the biological containment (e.g., purity and genotypic and phenotypic characteristics).

No fewer than 5 members who exhibit: IBC Requirements No fewer than 5 members who exhibit: rDNA Knowledge Community interest Research expertise Required to annually submit IBC roster update including curriculum vitae of new members, brief biographical sketch and any significant updates of existing members to OBA

Dual Use Consider the potential for dual use if any agents/toxins from the below list are used: a) Avian influenza virus (highly pathogenic) b) Bacillus anthracis c) Botulinum neurotoxin d) Burkholderia mallei e) Burkholderia pseudomallei f) Ebola virus g) Foot-and-mouth disease virus h) Francisella tularensis i) Marburg virus j) Reconstructed 1918 Influenza virus k) Rinderpest virus l) Toxin-producing strains of Clostridium botulinum m) Variola major virus n) Variola minor virus o) Yersinia pestis

Dual Use Consider the potential for dual use if any agents/toxins from the previous list are used in the below categories of experiments: a) Enhances the harmful consequences of the agent or toxin b) Disrupts immunity or the effectiveness of an immunization against the agent or toxin without clinical and/or agricultural justification c) Confers to the agent or toxin resistance to clinically and/or agriculturally useful prophylactic or therapeutic interventions against that agent or toxin or facilitates their ability to evade detection methodologies d) Increases the stability, transmissibility, or the ability to disseminate the agent or toxin e) Alters the host range or tropism of the agent or toxin f) Enhances the susceptibility of a host population to the agent or toxin g) Generates or reconstitutes an eradicated or extinct agent or toxin listed in 6.2.1

Dual Use Dual Use is reviewed by the Institutional Review Entity (IRE). At UTHealth, the IBC serves as the IRE for Dual Use review. The IRE/IBC has the following responsibilities: Reviewing research projects that have been designated by the PI as potential DURC and conducting a risk assessment to determine if they are indeed DURC Notifying the USG funding agency and/or NIH within 30 calendar days that DURC has been identified Working with the PI to determine the benefits of the research and, in conjunction with the previously developed risk assessment, developing a risk mitigation plan for the research Providing the draft risk mitigation plan to the USG funding agency and/or NIH within 90 calendar days

Dual Use The IRE/IBC has the following responsibilities (cont.): Ensuring implementation of the risk mitigation plan Reviewing annually all active risk mitigation plans Notifying the USG funding agency and/or NIH within 30 calendar days of any changes that would affect active risk mitigation plans or instances of non-compliance Maintaining records of DURC reviews and risk mitigation plans for at least the term of the research grant/contract plus three years but not less than eight years Providing education and training on DURC to research personnel Ensuring compliance with the policy among lab personnel

UTHealth IBC Membership Full Members Serve staggered two year terms (FY18-FY19) 3+ faculty members with rDNA experience and/or biological safety and containment 2 individuals not associated with the institution (community member) At least 1 member from each school At least 1 with animal containment At least 1 with infectious disease expertise 1 student member BSO (Director, Environmental Health & Safety) Ex-Officio Members Representative from Risk Management/Legal Affairs Representative from Health Services VP, SHERM Executive Vice President for Research Biological Safety Manager Environmental Protection Program Manager

Expectations: Members Active participation on the Committee Sharing expertise and experience Question and scrutinize protocols Ensure protocols meet requirements of NIH Guidelines, BMBL and other biosafety guidelines Participate as a member of a Subcommittee during preliminary reviews Timely response as a member of a Subcommittee Participate in member training, at least annually

UTHealth Protocol Review Submitted to Biosafety for assessment Communication with PI to produce protocol Submitted to Subcommittee for review Submit protocol to IBC for full review Protocol accepted Protocol rejected, tabled or pending

Approval Memos Once a protocol is approved the appropriate memo is sent out Approval memo Conditional approval memo

Conditionally Exempt Protocols To be a conditionally exempt protocol, proposed work must meet the following conditions: No work that falls under the NIH Guidelines No rDNA/sNA used Collection of human samples (i.e. blood, urine, tissue, etc.) for processing for storage and/or manipulation for research Collection/use of human cell lines for processing, storage, and/or manipulation for research. Biological safety office reviews and approves protocols Protocol MUAs appear in meeting packets

IBC Resources NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules https://osp.od.nih.gov/biotechnology/nih-guidelines/ Office of Biotechnology Activities https://osp.od.nih.gov/biosafety-biosecurity-and-emerging-biotechnology/ CDC/NIH Biosafety in Microbiological and Biomedical Laboratories (BMBL) http://www.cdc.gov/biosafety/publications/bmbl5/BMBL.pdf

Questions?