Chapter 2: Approval of Research Projects

What Needs Approval

PIs planning to conduct research using recombinant or synthetic nucleic acid molecules and/or hazardous biological materials that pose a potential risk to the health of humans, animals, or plants, either directly through infection or indirectly through damage to the environment, must submit an IBC Application entitled “Biological Use Authorization” (BUA) to the IBC Program for review and approval by the IBC.
Researchers using any of the following must complete and submit a “Biological Use Authorization” (a.k.a. IBC protocol) for review and approval:

• Recombinant and synthetic nucleic acid molecules;
• Hazardous biological agents (e.g., virus, bacteria, fungi, parasite, prion, rickettsia etc.);
• Other potentially infectious materials (e.g., human or non-human primate blood, serum, plasma, body fluids, unfixed tissue, organ and cells);
• Inactivated Biological Samples derived from BSL3 or higher agents;
• Select agents and biological Toxins;
• Transgenic animals or plants;
• Human gene transfer;
• Sheep and any tissues derived from them (these tissues can transmit Coxiella burnetii, the causative agent of Q-fever); and
• Field studies with wild animals and vectors and their tissues potentially infected or would be experimentally infected with BSL2 or higher agents.

For work with potentially infectious agents on human subjects or experimental animals, IBC review is necessary in addition to review by the appropriate IRB or IACUC.

PIs whose research will involve the above mentioned category agents or infectious materials are required to complete a BUA and obtain IBC approval prior to receiving such materials or commencing such research. PIs are also required, where applicable, to maintain a medical surveillance program for laboratory employees (see Appendix P). Relevant federal, state, and local governmental regulations include the following (see Chapter 3 for more details):

• NIH Guidelines for Research Involving Recombinant or synthetic nucleic acid molecules (NIH Guidelines);
• BPHC regulations governing labs in the city of Boston:
  • Recombinant DNA Technology: Use Regulations
  • Biological Laboratory Regulation with accompanying Guidelines;
• Disease Surveillance and Reporting Regulation with accompanying Guidelines;
• OSHA Bloodborne Pathogens Standard;
• OSHA Tuberculosis Standard;
• OSHA Laboratory Standards;
• Massachusetts State Regulations:
  • Minimum Requirements for the Management of Medical or Biological Waste
  • Reportable Diseases, Surveillance, and Isolation and Quarantine Requirements;
• Biosafety in Microbiological and Biomedical Laboratories (BMBL) 6th edition;
• The Centers for Disease Control and Prevention (CDC) and United States Department of Agriculture (USDA) Select Agent regulations; and
• International, federal, and state transport regulations.

Types of IBC Protocols

New Applications

A new BUA must be submitted and reviewed by the IBC program for any research mentioned previously. PIs seeking IBC approval for the first time also need to submit a curriculum vitae (CV) or two-page NIH biosketch with their application. Applications need to be submitted via the Research Information Management System (RIMS).

The PI may designate others to assist in completing the application, however, only the PI may submit the application. The BU IBC requires that all PIs be members of the faculty. Projects from post-docs or other non-faculty members require a faculty PI sponsor.

All individuals listed on a new BUA must complete the following training and ROHP medical health clearance requirements before engaging in any approved protocol related activities:

• Laboratory Safety Training
• Health Questionnaire (must be filled out, submitted, reviewed, and cleared by ROHP); and
• Laboratory Specific Training.

All Principal Investigators (PIs) listed on a new BUA, and all individuals listed on a new BUA involving recombinant or synthetic nucleic acids, must complete the following training before engaging in any approved protocol related activities:

• IBC Policy /Recombinant DNA Training and Quiz.

Personnel will need a RIMS Training Profile in order to complete these requirements. Other training will be required based on the nature of project including, but not limited to: BSL3 annual training; shipping biologicals training; select agent training; and agent specific training for Francisella tularensis, Mycobacterium tuberculosis, and Yersinia pestis.

All applications must be received by the meeting date deadline to allow time for review by the committee members and a Biological Use Authorization Site Assessment by EHS. Meeting date deadlines can be found on the IBC Program website. Each application will be assigned to a primary and secondary reviewer. Reviewer comments will be discussed at a convened IBC meeting.

Renewals

A renewal of the original BUA approval must the completed in RIMS at the third year after initial approval of a protocol. Email notice of 3-Year Renewal will be sent to the PIs. Detailed instructions on completing the 3-Year Renewal in RIMS is found in the IBC website. The PI is asked to list all proposed modifications from the protocol as initially approved (or since the last renewal notice), including: changes in laboratory location or equipment, changes in laboratory staff working on the project, any project titles to be added, and any agent of experimental changes.

If there are significant modifications to the protocol, especially those that affect the biosafety containment level (e.g., new study on organisms, a new host-vector-donor system, or any other modifications that may affect the containment level), the IBC Program will send the protocol for committee review and approval. When a project is renewed, the PI and all staff listed on the protocol must complete the “Laboratory Safety Annual Refresher Training” and the annual ROHP clearance update (contact ROHP at rohp@bu.edu or at (617) 358-7647), and any other training requirements applicable to the project.

Amendments

Amendments must be submitted to the IBC Program for changes within an approved project. All changes should be detailed in RIMS and submitted to the IBC Program and the IBC must review and approve the amendment prior to implementing the changes. Detailed instructions on completing the amendment in RIMS are found in the IBC Amendment Instructions document. Title additions approval may be applied to several different granting agencies, but all grant titles must be registered with the IBC Program. Approval of lab space additions applies only to work performed in registered lab space.

For non-PI personnel changes, individuals must complete the “Initial Laboratory Safety Training” and “ROHP Clearance” requirements. Individuals on protocols involving recombinant or synthetic nucleic acids, must also complete the IBC Policy /Recombinant DNA Training and Quiz. Additions of titles, lab space, and personnel are reviewed administratively reviews and approvals, and do not to go the full IBC.

Some amendments may require full committee review and when extensive, may require the PI to submit a completely new application. A change in PI also requires submission of an amendment where CV (or NIH biosketch) of the new PI must be attached to the amendment, and this must be reviewed by the IBC Chair and the BSO.

The IBC Program will notify the PI when the Amendment has been processed and approved. IBC approval is required before any changes in the work can commence.

Protocol Review Outcomes

The IBC has the authority to decide to approve, conditionally approve, defer or withhold approval of the proposed research activity. These actions will be taken by a vote of a majority of the members present. At the conclusion of discussion during its scheduled meeting, the IBC determines the outcome of its review, which will be one of the following:

Approved

A protocol that receives full approval requires no (additional) changes or clarifications to comply with IBC policies. Work may commence immediately upon full approval of a protocol. Approval is valid for the study as described in the protocol form for a period of three years from the original approval date. PIs must complete a renewal form tri-annually (annually in the first year for BSL 3 and BSL4) after the first and second year following initial approval and must submit a new application to continue the work beyond the approved three-year time period.

Conditionally Approved

“Conditionally Approved” is a determination that the IBC makes when minor changes or clarifications are required to bring the protocol into compliance with IBC policies. The investigator must respond in writing to the IBC’s notice of conditional approval.

Deferred

“Deferred” is used when numerous and/or major changes or clarifications are required to bring the protocol into compliance with IBC policies or there is insufficient time at the IBC meeting to conduct a thorough review.

Withhold Approval

The IBC may withhold approval of a protocol if it fails to meet one or more criteria used by the IBC for approval of research.

Use of Materials that Require Clarification for the IBC Approval

Biohazardous and Potentially Infectious Materials

Biohazardous agents and potentially infectious materials present a risk or potential risk to the health of humans or animals, either directly through infection or indirectly through damage to the environment. Infectious agents have the ability to replicate and give rise to potentially large populations in nature when small numbers are released from a controlled situation.

PIs should follow the instructions in the BUA carefully to ensure that all appropriate sections of the application are completed. It is important that the PI clarifies the intended use of the agents, how risks associated with its handling are mitigated, and the management of the wastes generated from such work. If a PI intends to use biological agents that are not listed in this section, he or she should contact the IBC Program or BSO for advice regarding proper completion of the BUA.

For the list of biological agents with the potential to cause Laboratory Acquired Infection (LAI) see the Appendix G. The ROHP has developed additional “Agent Information Sheets” that are available on the IBC website. Where applicable, agent specific vaccines will be offered at no charge to all persons who are approved by the IBC to work with or could potentially get exposed to these materials.

Recombinant or synthetic nucleic acid Materials

When a BUA protocol involves the use of recombinant or synthetic nucleic materials, most of those work require IBC approval before initiation of work. The NIH Guidelines for Recombinant and Synthetic Nucleic Acids provide specific guidelines on the facility containment and specific regulatory requirements depending on the exact detail of the proposed work. A PI must follow the defined containment directive. There may be experiments not covered by the guidelines that would require review and approval by outside agencies before initiation. If the experimental protocol is not covered by the NIH’s guidelines, contact the BSO at (617) 358-7840 at BUMC and (617) 353-4094 at CRC to determine further review requirements.

Human Gene Transfer

All protocols involving human gene transfer must be submitted to both the IBC and the IRB for review. However a public review and discussion by the NIH Recombinant DNA Advisory Committee (RAC) is no longer required as it has been decided that existing FDA guidelines and requirements for the review of gene therapy protocol is sufficient. The NIH Office of Science Policy will also not accept annual reports, safety reports, amendments or other documentation for any previously registered human gene transfer protocols under the NIH Guidelines. The roles and responsibilities of local IBCs will continue as described in the NIH Guidelines 2019 Section III-C. These studies remain subject to FDA and other clinical trial regulations, and only after FDA, IBC, and other relevant approvals are in place can these protocols proceed.

However, the deliberate transfer of recombinant or synthetic nucleic acids into one human research participant, conducted under a Food and Drug Administration (FDA) regulated individual patient expanded access Investigational New Drug (IND) or protocol, including for emergency use, is not research subject to the NIH Guidelines and thus does not need to be submitted to an IBC for review and approval.

For more details about IBC approval of human gene therapy protocols, contact the IBC Office at (617) 358-7910 or ibc@bu.edu. For information about IRB submissions, contact the BUMC IRB at (617) 358-5372 or the CRC IRB at (617) 358-6115.

Use of Animals

All PIs planning to use recombinant or synthetic nucleic acid molecules and/or biohazardous materials in their laboratory or in research animals must receive IBC approval prior to commencing the work. The use of animals in research also requires compliance with the “Animal Welfare Act,” administered by the USDA’s Animal and Plant Health Inspection Service (APHIS); the “Public Health Service Policy on Humane Care and Use of Laboratory Animals,” administered by NIH’s Office of Laboratory Animal Welfare (OLAW); and all applicable state, local or University regulations covering the care and use of animals. All protocols involving the use of live animals must be reviewed and approved by the IACUC before their implementation.

Transgenic Animals

PIs who create transgenic animals, either in the PI’s lab or through the BU Transgenic Core facility, as well as PIs who use transgenic animals at ABSL2, or at ABSL1 if not considered exempt under the NIH Guidelines (Section III-E, Appendix C-VIII), must complete an IBC application and submit it to the IBC for approval prior to initiation of experimentation. In addition, the IACUC must approve the protocol. The IACUC can be reached at (617) 358-5586 (BUMC) or (617) 358-3867 (CRC).

Tissue Culture/Cell Lines

All tissue and cell cultures derived from humans are considered potentially infectious under the OSHA Bloodborne Pathogens Standard, Title 29 Code of Federal Regulations (CFR) Part 1910.1030 and must be handled in a laboratory using BSL2 principles, practices and facilities (the concept of “universal precautions”). Nonhuman primate tissues and cell cultures are also considered potentially infectious and must be handled in the BSL2 laboratory. Persons who are exposed to these materials in the laboratory are considered to have potential exposure to bloodborne pathogens, such as human immunodeficiency virus (HIV) and hepatitis B virus (HBV), and must be included in the Bloodborne Pathogens program. These persons must be offered the HBV vaccination and complete annual bloodborne pathogens training.

When cell cultures are known to contain any Risk Group 3 and higher organism, the cell line will be classified at the same higher containment level. Consequently, they must be handled using BSL3 and higher containment criteria.

Select and Biological Toxins

Use of biological toxins including the select agent toxins generally needs approval by the IBC (see Appendix F “Guidelines for Work with Toxins of Biological Origin” for more details). Please check with IBC staff directly if you have questions for a particular biological toxin. Use of select agent toxins such as Abrin, Bacillus cereus Biovar anthracis, Botulinum neurotoxins, Botulinum neurotoxin producing species of Clostridium, Conotoxins (Short, paralytic alpha conotoxins containing the following amino acid sequence X1CCX2PACGX3X4X5X6CX7) Diacetoxyscirpenol (DAS), Ricin, Saxitoxin, Staphylococcal Enterotoxins (Subtypes A, B, C, D, and E), T-2 toxin, Tetrodotoxin requires IBC approval.

Testing and Certification of Containment Equipment Required

Handling infectious or potentially infectious materials could potentially generate infectious aerosols. Such work must be performed in the Biological Safety Cabinet (BSC) and wearing appropriate PPE. All BSCs are required to be tested and certified when they are first installed. They are also required to be tested and recertified annually. BU works with an outside vendor that is experienced and certified to test and repair this equipment. Laboratories must ensure that their BSCs certifications are current before initiation of protocols. EHS will verify their status during BUA follow up of protocols under review by the IBC.

Completion of Laboratory Safety Trainings

The PI and all laboratory personnel that are listed on the protocol must complete their required lab safety trainings. The trainings are available on BioRAFT and can be accessed online. These trainings must be completed prior to initiation of lab work and they need to be refreshed annually. EHS will verify that the PI and personnel that are listed on the protocol have completed the required training during BUA follow up of protocols under review by the IBC.

What does the IBC Review?

When reviewing a research protocol the IBC is responsible for assessing:

• Recombinant or synthetic nucleic acid molecule research for compliance with the NIH rDNA Guidelines;
• Use of hazardous biological materials in the laboratory;
• Use of hazardous biological materials on animals;
• Potential risk to the lab personnel, environment and public health;
• Appropriate Risk Category and BSL/ABSL Containment levels per NIH Guidelines and CDC BMBL 6th edition;
• Adequacy of facilities, safety equipment. PPE, procedures, practices, training, transport and shipping of specimen samples, and experience and expertise of personnel;
• Adverse event report.

Risk Group Definition

The investigator must make an initial risk assessment based on the Risk Group (RG) of an agent. Agents are classified into four RGs according to their relative pathogenicity for healthy adult humans by the following criteria:

As a general rule, a biosafety level should be used that matches the highest risk group classification of the agents involved (see chapter 4). More information can be found in Appendix B of NIH Guidelines.
For information about the risk group of a specific pathogen, please check the resource below:

• Pathogen Safety Data Sheets and Risk Assessment (from Public Health Agency of Canada)
• Risk Group Classification for Infectious Agents (from American Biological Safety Association)
• Classification Of Human Etiologic Agents On The Basis Of Hazard (Appendix B of NIH Guidelines)

Biohazardous Pathogen Examples

Tuberculosis

Since 1985, the incidence of tuberculosis in the United States has been increasing steadily, reversing a 30-year downward trend. Recently, drug-resistant strains of Mycobacterium tuberculosis have become a serious concern. Outbreaks of tuberculosis, including drug-resistant strains, have occurred in health-care environments.

In 2005 the CDC published Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-care Settings. MMWR 2005; 54 (No. rr-17, 1-141). (Errata published September 25, 2006.) The guidelines contain specific information on ventilation requirements, respiratory protection, medical surveillance, and training for those personnel who are considered at-risk for exposure to tuberculosis. For more information, contact the BSO.

PIs intending to work with Mycobacterium tuberculosis in the laboratory must obtain full approval from the IBC via the IBC application process before beginning work. Propagation and manipulation of Mycobacterium tuberculosis cultures must be performed at BSL3. PI’s and all other persons approved to work with Mycobacterium tuberculosis are required to undergo semi-annual tuberculosis screenings.

Vaccinia Virus

PIs wishing to use vaccinia virus must obtain full approval from the IBC via the application process. BSL2 practices and procedures must be followed. All employees who directly handle cultures or animals contaminated or infected with vaccinia virus, recombinant or defective vaccinia viruses, or other orthopox viruses that infect humans shall be offered the smallpox vaccine. PI’s and all other persons approved to work with the vaccinia virus shall be offered the vaccinia virus vaccine at no charge. Individuals that decline the vaccinia virus vaccine must sign a declination form which will be kept on file with ROHP.

Francisella tularensis Bacteria

Tularemia, or rabbit fever, is a bacterial disease associated with both animals and humans. According to the CDC, “Tularemia is a potentially serious illness that occurs naturally in the United States. It is caused by the bacterium Francisella tularensis found in animals (especially rodents, rabbits, and hares).” PI’s and all other persons approved to work with F. tularensis shall be offered the tularemia vaccine at no charge. Individuals that decline the tularemia vaccine must sign a declination form that will be kept on file with ROHP.

The use of tularemia-causing bacteria is strictly regulated by the IBC and must be conducted in designated BSL3 facilities.

Herpes B virus

Cercopithecine herpesvirus 1 (Herpesvirus simiae or B-virus) is an endemic infection in Old World primates of the genus Macaca, which is the species most commonly used in biomedical research. It is assumed that all existing animals in the United States are carriers.
Although herpes B virus is relatively benign in the macaque monkey, it can cause rapidly ascending encephalomyelitis in humans with a fatality rate of approximately 80%. The most common routes of transmission of the virus are through bites, scratches, splashes, or cuts.

All research involving non-human primates must be approved by both the IACUC and the IBC. Additional occupational health screening and PPE requirements are described in this manual.

For a detailed description of a specific pathogen that has the potential to cause a laboratory acquired infection (LAI), please check on ROHP website for “Agent Information Sheets”.