Discuss the history of rDNA oversightOutline the rDNA program at the Office of Biotechnology Activities (OBA)Identify the NIH Guidelines and responsibilities associated with themIntroduce the Institutional Biosafety Committee (IBC)Outline training requirementsLocate guidance materials and helpful resources
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BIO 100 - Introduction to the NIH Guidelines for Recombinant DNA
This course is an introduction to the National Institute of Health (NIH) Guidelines for recombinant DNA (rDNA). In this training, we will:
Enhancing Public Access
Enhancing Public Access (new addition to the guidelines in 1978)At least two, and no less than twenty percent, of IBC members had to represent the general public and have no connection to the institutionThe “important records” of the IBC’s had to be made publicly availableIn addition to meeting minutes these include MUAs (Memorandum of Understanding Agreements), reports of violations, and other materials submitted to the federal government“Major actions” (such as human gene therapy trials) can only be carried out on the advice of the RAC and after public and Federal agency comments are receivedPublic participation continues to be a hallmark of rDNA oversight
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Asilomar Scientific Summit
A big turning point in rDNA work was the Asilomar Scientific Summit (1975) which was organized by a group of scientists with the following results:The Premise:Scientists taking responsibility for the risks of their own research activitiesThe Outcomes:Reaffirmation of the need for rDNA guidelinesThe establishment of a new federal oversight committee
Click each item below to learn more.
Asilomar Scientific Summit
First NIH Guidelines
The First NIH Guidelines for rDNAWere published in July 1976These guidelines established responsibilities for both investigators AND institutionsThe Guidelines are a scientifically-responsive document that will continue to evolveThey have already undergone multiple revisions since 1976Visit the Office of Biotechnology Activities website for the latest version
Emergence of rDNA
The emergence of rDNA technology in the mid 1970’s led to:Concerns among both the scientific community and the general public with regard to:Public health and safetyEnvironmental impact, andPotential ethical and social implicationsAs a result, a subsequent National Academy of Sciences (NAS) Committee Report (July 1974) called for:A moratorium on certain experiments, andThe development of NIH guidelines for the conduct and review of rDNA experiments
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The RAC
Local Community Involvement
First NIH Guidelines
Local Community InvolvementLocal communities (e.g., Cambridge, Massachusetts) begin establishing their own oversight frameworksLocal review and citizen involvement are key characteristics of oversight
The RAC
The NIH Recombinant DNA Molecule Program Advisory Committee (the “RAC”)Is the first federal advisory committeeLaunched the process of developing NIH guidelines for rDNA oversightMade recommendations about local oversight of rDNANIH grants using rDNA can be awarded only after review of risks by an institutional “biohazards” review committee or an IBC (Institutional Biosafety Committee)This includes review of the physical containment and facilities available for the experiments, andConsideration of local circumstances
Emergence of rDNA
A Brief History of rDNA Oversight
Enhancing Public Access
Hasn’t history proven the technology to be safe?Why do we have a technology-based approach to oversight instead of one that is based on the risks of individual products?Are there really Any Residual Concerns?The public here and abroad is still concerned about many aspects of this technology. Our oversight system has provided scientifically-based surveillance of this research that has reassured the public and permitted the science to move forward safely.
Human gene transfer, however, continues to raise many safety, ethical, and scientific issues in need of public discussion and analysis.
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Questions and Concerns
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The rDNA oversight entity - the NIH Office of Biotechnology Activities (OBA):Lies administratively within the Office of Science Policy of the Office of the Director of the NIHHas five programs which oversee the following:Recombinant DNA (RAC)Genetics (SACGHS – Secretary’s Advisory Committee on Genetics, Health and Society; issues regarding genetics and genomics technology and society)Xenotransplantation - the use of live animal cells, tissues and organs in the treatment or mitigation of human disease (SACX)Biosecurity (NSABB)Outreach and Education
The OBA
rDNA Program at OBARecombinant DNA Program at OBA:
Oversees recombinant DNA research, including human gene transferManages the Recombinant DNA Advisory Committee (RAC)Administers the NIH Guidelines for Research Involving Recombinant DNA MoleculesPartners with Institutional Biosafety Committees in the oversight of recombinant DNA researchDisseminates information on technical and policy matters concerning recombinant DNA research, such as:RAC recommendations on clinical protocolsInterpretations of the NIH GuidelinesScientific symposia and policy conferencesDevelops and contributes to public policy on recombinant DNA researchInteragency oversight of biotechnology
The NIH Guidelines Apply to…Recombinant DNA research that is:
Funded by the NIHPerformed at or sponsored by an institution that receives any NIH funding for recombinant DNA researchRationale: For biosafety to be meaningful, it has to be observed by all investigators at an institution
Are the NIH Guidelines Optional?
“Guidelines” does not mean “optional”They are a term and condition of NIH funding for recombinant DNA researchIf ANY NIH grants are received by your Institution, then all of the projects involving recombinant DNA at your institution, even those which are privately funded, are then subject to the requirements of the Guidelines.
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The NIH Guidelines – Section I
The Guidelines specify appropriate practices for constructing and handling:Recombinant DNA molecules
Organisms and viruses containing recombinant DNA moleculesDefinition of rDNA:Constructed outside living cells by joining natural or synthetic DNA segments to DNA molecules that can replicate in a living cell
Molecules resulting from the replication of those described above
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So what happens if we ignore the Guidelines?What are potential consequences of noncompliance with the NIH Guidelines?
Non compliance with the Guidelines does have potential consequences which could include:
The suspension, limitation, or termination of NIH funds for recombinant DNA research at the institution, orA requirement for prior NIH approval of any or all recombinant DNA projects at the institution (a time-consuming operation given that the OBA has limited staff available for this task).
NIH Guidelines
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NIH Guidelines – Sections II and III
RG1RG2RG3RG4
Agents that are not associated with disease in healthy adult humans Agents that are associated with human disease which is rarely serious and for which preventive or therapeutic interventions are often available Agents that are associated with serious or lethal human disease for which preventive or therapeutic interventions may be available (high individual risk but low community risk) Agents that are likely to cause serious or lethal human disease for which preventive or therapeutic interventions are not usually available (high individual risk and high community risk)
Section III - Levels of Review.
NIH Guidelines, Section III covers Levels of Review (see course PDF for details).
Section II - Safety ConsiderationsRisk assessments for the organisms and DNA source organisms: agents are classified into four risk groups by the NIH and the CDC based upon the following criteria (Appendix B):
Containment of DNA
Containment of DNA and organisms can be either:Physical (outlined in Appendix G)Lab PracticesSafety Equipment/facilities; or Biological (outlined in Appendix I)Survival in the environmentTransmission of genetic elements or disease
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Incident reporting for BSL2 and higher experiments:Spills and accidents which result in overt exposures to organisms containing recombinant DNA molecules are immediately reported to the Institutional Biosafety Committee and NIH/OBA.Reports to NIH/OBA shall be sent to:Office of Biotechnology Activities, National Institutes of Health
6705 Rockledge Drive, Suite 750, MSC 7985
Bethesda, MD 20892-7985 (20817 for non-USPS mail)
Phone: (301) 496-9838
Fax: (301) 496-9839
Medical evaluation, surveillance, and treatment are provided as appropriate, and written records are maintained.
NIH Guidelines - Appendix G-II-B-2-k
Responsibilities under the NIH Guidelines
InstitutionalArgonne shall:
Establish and implement policies for the safe conduct of recombinant DNA researchEstablish an Institutional Biosafety CommitteeAssist and ensure compliance with the NIH Guidelines by investigatorsEnsure appropriate training for IBC members and staff, Principal Investigators (PIs), laboratory staffDetermine necessity for health surveillance of personnelReport any significant problems or violations to OBA within 30 days
Institutional
Principal Investigator
The NIH Guidelines will never be complete or final since all conceivable experiments involving recombinant DNA cannot be foreseen. Therefore, it is the responsibility of the institution and those associated with it to adhere to the intent of the NIH Guidelines as well as to the specifics.Good judgment is keyOBA can help
Principal Investigator
The Principal Investigator (PI) shall (among other things):Initiate or modify no recombinant DNA research which requires IBC review until approval is grantedDetermine whether experiments are covered under III-E or F and notify the IBC as appropriateBe adequately trained in good microbiological techniquesAdhere to IBC emergency plans for spills and personnel contaminationReport any significant problems or violations to OBA within 30 days
NIH OBA rDNA ExperimentsDeliberate transfer of drug resistance trait to microorganisms not known to acquire the trait naturally, if it could compromise disease controlCloning of toxin molecules with LD50 <100 ng/Kg bodyweightDNA from restricted agents transferred to nonpathogenic prokaryotes or lower eukaryotesDNA from nonpathogenic prokaryotes or lower eukaryotes transferred to restricted agentsUse of infectious or defective restricted poxviruses in presence of helper virus
NIH OBA rDNA Experiments
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NIH OBA
NIH OBA (on behalf of the NIH Director) is responsible for:Managing the RACConducting and supporting training of IBCs, BSOs, investigators, laboratory staffConvening Scientific Symposia and Gene Therapy Policy ConferencesReview of human gene transfer protocols and certain basic recombinant DNA experiments“Minor actions” - changes not requiring approval by the NIH DirectorBasic recombinant DNA experiments reviewed by NIH OBA
NIH OBA
IBC
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Additional expertise
Registering an IBC
Register the IBC with OBA and file annual membership updatesA roster of IBC membersClearly indicate chair, contact person, and special expertise as appropriate (BSO, animal, plant, human gene transfer)Biographical sketches of all membersPurpose of registration and annual membership updates
Provides assurance of local review of biosafety risksAllows OBA to see that IBC expertise consistent with the NIH GuidelinesIndicates institutional point of contactProvides census of the field - where recombinant DNA research is being conducted
Additional expertiseBiological safety, and physical containmentKnowledge of institutional commitments and policies, applicable law, professional standards, community attitudes, and environmentLaboratory technical staff (recommended)
MembershipNo fewer than 5 individualsAppropriate recombinant DNA expertise collectivelyPlant and animal experts, biosafety officer as appropriateExpertise in assessment of risk to environment and public healthAt least two members not affiliated with the institution
Non-institutional membersRepresentatives of community interests with respect to health and protection of the environmentFor example, officials of state or local public health or environmental authorities, local government bodies, persons with medical, occupational, or environmental expertiseThey can also be the individuals who “represent community attitudes”
Institutional Biosafety Committees:Are the key institutional component of a national system of oversightAre “sentinels” at the local level, identifying new safety and policy issues for NIH OBA and RAC considerationAre established specifically for the review of recombinant DNA researchOften review other research with biohazardous risksInfectious agents, carcinogensBroader purview is a matter of institutional discretion
Registering an IBC
Membership
Non-institutional members
Click each item below to learn more about assembling and registering an IBC.
RestrictionsThe IBC MAY NOT:
Authorize initiation of rDNA experiments not explicitly covered by the NIH Guidelines until NIH (with the advice of the RAC when required) establishes the containment requirement.
In basic and preclinical research, IBCs have authority to:Lower containment levels for certain experiments in which DNA from Risk Group 2-4 is cloned in non-pathogenic organismsSet containment levels for experiments involving whole plants and animalsReview periodically institutional compliance with NIH GuidelinesAdopt emergency plans covering spills, contamination, other accidentsIn a nutshell, what must IBCs review?Recombinant DNA research for conformity with the NIH GuidelinesPotential risk to environment and public healthWhat do IBCs assess in reviewing recombinant DNA research?Containment levels per NIH GuidelinesAdequacy of facilities, SOPs, PI and lab personnel trainingInstitutional and investigator compliance; e.g., adverse event reports
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Do IBCs determine what research is exempt? Does the PI?A matter of institutional policy – at Argonne all rDNA work is registered with the IBCIBC may wish to designate member, chair, or BSO as first line of review to make determinations about what is exempt and what requires full reviewNIH OBA can help with determinations
IBC Responsibilities
Content of Meeting MinutesNot prescribed in the NIH GuidelinesGenerally accepted principles existRobert’s Rules of OrderNeed to document IBC fulfillment of review and oversight responsibilitiesAvoid extremesTranscripts are probably not necessaryDon’t simply state, “We met. We adjourned.”Use good judgment and common sense
Convening an IBC
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Section IV-B-2-a-(6) states:“When possible and consistent with protection of privacy and proprietary interests, the institution is encouraged to open its Institutional Biosafety Committee meetings to the public.”
Institution has latitude in determining how to create public awareness of meetingsLetter of the NIH GuidelinesIBCs are encouraged to open meetings to the publicInstitution shall make IBC minutes available to the public upon requestIntent of the NIH GuidelinesInteractive (face-to-face, video or teleconferencing)
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Access to Minutes
RedactionSection IV-B-2-a-(6) of the NIH Guidelines acknowledges that the protection of private or proprietary information is a basis for closing meetings to the publicSince minutes are records of meetings, it is logical to extend protection of such information to minutes through redactionRedaction must be judicious and consistentForms of accessMail, e-mail, Web site (open or password protected)Requiring on-site inspection generally not appropriatecan be excessively burdensome on requestorcould be considered a deterrent
Special proceduresNothing in the NIH Guidelines precludes institutions from applying or complying with specific procedures in releasing minutesState institutions are often subject to state public disclosure laws; Federal facilities are subject to FOIAFollowing public disclosure laws is not inherently in conflict with the NIH Guidelines; reasonable fees to cover costs are acceptable
Section IV-B-2-a-(7) states:Upon request, the institution shall make available to the public all Institutional Biosafety Committee meeting minutes and any documents1 submitted to or received from funding agencies which the latter are required to make available to the public.
1 Generally, rosters and biosketches
OBA Outreach and EducationElectronic communication tools
Listserv: “OBA_NEWS”Policy notices, meeting announcements, compliance reminders Email inbox for queries: oba@od.nih.govQuestions on interpretation of the NIH Guidelines, status of protocols, scientific and medical issues
The NIH Guidelines emphasize the importance of training and place responsibility on:Institutions to train IBC members, BSO, PI, and laboratory staff; andNIH to conduct and support training programsInstitutional Training Programs should:
Provide information on federal requirementsInclude information on institutional policies, procedures, and requirementsBe tailored to the audience – investigators vs. administrators vs. lab staff
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Training
Contact Information6705 Rockledge Drive, Suite 750
Bethesda, Maryland 20892-7985
Phone (301) 496-9838
Fax (301) 496-9839
http://www4.od.nih.gov/oba/
oba@od.nih.gov
Course credit
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Exam
This concludes BIO 100
Introduction to the NIH Guidelines for Recombinant DNA
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