1. Institutional Biosafety Committee Member Training
September 2017

2. 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.

3. 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

4. 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

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

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

7. 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.

8. 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.

9. 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 .

10. 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)

11. 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

12. 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

13. 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

14. 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

15. 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.

16. 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

17. 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

18. 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!

19. FAQ Review process for human gene transfer protocols
Vaccine exemptions
Major actions under the guidelines
IBC committee minutes

20. FAQ Transgenic animals
and
Experiments that are exempt

21. 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

22. 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.

23. 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

24. 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.

25. 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.

26. 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.

27. 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).

28. 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).

29. 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

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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

36. 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

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

38. 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

39. IBC Resources
NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules
Office of Biotechnology Activities
CDC/NIH Biosafety in Microbiological and Biomedical Laboratories (BMBL)

40. Questions?