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1481
FridayJanuary 19, 1996
Part III
Department ofHealth and HumanServices
National Institutes of HealthRecombinant DNA Research: ActionsUnder the Guidelines; Notice
 
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Federal Register
 /Vol. 61, No. 13/Friday, January 19, 1996/Notices
DEPARTMENT OF HEALTH ANDHUMAN SERVICESNational Institutes of HealthRecombinant DNA Research: ActionsUnder the Guidelines
AGENCY
:
National Institutes of Health,PHS, DHHS.
ACTION
:
Notice of Actions under the NIHGuidelines for Research InvolvingRecombinant DNA Molecules (59 FR34496, 59 FR 40170, 60 FR 20726).
SUMMARY
:
This notice sets forth anaction to be taken by the Director,National Institutes of Health (NIH),under the NIH Guidelines for ResearchInvolving Recombinant DNA Molecules.
FOR FURTHER INFORMATION CONTACT
:
Additional information can be obtainedfrom Dr. Nelson A. Wivel, Director,Office of Recombinant DNA Activities(ORDA), Office of Science Policy andTechnology Transfer, National Institutesof Health, Suite 302, 6000 ExecutiveBoulevard, MSC 7010, Bethesda,Maryland 20892–7010, (301) 496–9838.
SUPPLEMENTARY INFORMATION
:
Today’saction is being promulgated under theNIH Guidelines for Research InvolvingRecombinant DNA Molecules. Thisproposed action was published forcomment in the
Federal Register
of August 18, 1994 (58 FR 44098),November 8, 1994 (59 FR 55796),February 8, 1995 (60 FR 7630), and May22, 1995 (60 FR 27207), and reviewedand recommended for approval by theNIH Recombinant DNA AdvisoryCommittee (RAC) at its meeting on June8–9, 1995.
I. Background Information andDecisions on Actions Under the NIHGuidelines
 A. Amendments to Sections II, III, IV, V, Appendices B, C, H, and Q of the NIH Guidelines Regarding Updating theClassification of Microorganisms
In a letter dated June 24, 1993, Dr.Diane Fleming, President of the Mid-Atlantic Biological Safety Associationrequested the revision and updating of Appendix B, Classification of Microorganisms on the Basis of Hazard.The Mid-Atlantic Biological SafetyAssociation submitted an updated list of the classification of microorganisms forthe Recombinant DNA AdvisoryCommittee to review which includedthe latest taxonomy and agent risk groupclassifications as defined by the Centersfor Disease Control and Prevention.During the September 9–10, 1993,meeting, the Recombinant DNAAdvisory Committee recommended byconsensus that the current classificationof etiological agents described in theBiosafety in Microbiological andBiomedical Laboratories, 3rd edition,May 1993, U.S. Department of Healthand Human Services, should beendorsed by the Committee. TheCommittee retained the option to adoptany modifications to the Centers forDisease Control and Prevention listing.The Committee recommended that therevised Appendix B, Classification of Microorganisms on the Basis of Hazard,submitted by Dr. Fleming should not beadopted until the Committee receivedletters of concurrence from both theCenters for Disease Control andPrevention and the NIH Division of Safety.In a telephone call on October 20,1994, Dr. Fleming stated that AppendixB, Classification of Microorganisms onthe Basis of Hazard, would be reviewedby experts from the Centers for DiseaseControl and Prevention and theAmerican Society for Microbiology. Therevised Appendix B was submitted tothe Recombinant DNA AdvisoryCommittee December 1–2, 1994,meeting for review and discussion.During the December 1994 meeting, theCommittee recommended publishingthe revised Appendix B in the
FederalRegister
for public comment, withfurther review of this proposal andpossible approval during the March 6–7, 1995, meeting.During the March 6–7, 1995 meeting,the Recombinant DNA AdvisoryCommittee deferred approval of theproposed amendments to Appendix Bpending additional revisions to theremaining sections and appendices of the NIH Guidelines that are required toadequately accommodate the revisedAppendix B (Sections II, III, IV, V,Appendices C, H, and Q). The motionfor deferral included a recommendationthat a subcommittee consisting of Dr.Stephen Straus (Chair of theSubcommittee), ad hoc experts, andOffice of Recombinant DNA Activitiesstaff would meet to develop the requiredmodifications. The motion passed by avote of 17 in favor, 0 opposed, and noabstentions.On May 5, 1995, the Appendix BSubcommittee met to finalize thedocument in terms of its listing of pathogens and the text of the NIHGuidelines related to Appendix B inother sections and appendices (SectionsII, III, IV, V, Appendices C, H, and Q).During the June 8–9, 1995 meeting, theRecombinant DNA Advisory Committeereviewed the document. There was aconcurrence that the Risk Groupclassification serves as an initialguidance to assign an appropriatecontainment level for a particularexperiment by the InstitutionalBiosafety Committees and theinvestigators. Since the new AppendixB is primarily concerned with humanpathogenicity, it addresses only thehuman etiologic agents and omits allanimal agents. The Committee observedthat this omission created a problembecause some of the animal agents,particularly the group of viruses knownas oncogenic viruses are frequently usedas vectors for gene transfer in thelaboratories or in human studies. TheRecombinant DNA Advisory Committeeapproved a motion to: (1) establish aworking group to recommendexemption of additional vector systemsin Appendix C (exempt host-vectorsystems), and (2) accept the proposedamendments to Appendix B with theprovision to develop a new AppendixB–V relating to animal viruses relevantto human studies, and to list specificexamples of agents under Appendix B–I, Risk Group 1 (RG1) Agents. Themotion was approved by a vote of 17 infavor, 0 opposed, and no abstentions.On June 13, 1995, the Office of Recombinant DNA Activities forwardedtwo versions of the Appendix B–V,Animal Viral Etiologic Agents inCommon Use to the Appendix BSubcommittee. Most of these agentswere previously listed as Class 2oncogenic viruses in two separatecategories of low and moderate risk agents in the original Appendix B. Sincenone of these animal etiologic agents areassociated with disease in healthyhuman adults, one version of AppendixB–V listed these agents as a single grouprecommended for Biosafety Level 1containment and another version listedthem in a two-tier system for eitherBiosafety Level 1 or Biosafety Level 2containment. Subsequent discussionwith the members of the Appendix BSubcommittee concluded that whilethere was no reason to have a separategroup of ‘‘moderate’’ risk agents in thislist, it was prudent to recommendconducting experiments under aBiosafety Level 2 containment withseveral agents that are capable of infecting human cells, e.g., amphotropicand xenotropic murine leukemia virus.During the September 11–12, 1995,meeting, the Recombinant DNAAdvisory Committee reviewed theupdated Appendix B along with othersections and appendices of the NIHGuidelines (Sections II, III, IV, V,Appendices C, H, and Q) relating toclassification of microorganisms. It wasobserved that some viruses in themoderate risk group could infect humancells but their replication was largelyrestricted to their animal hosts. SomeCommittee members pointed out that
 
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 /Vol. 61, No. 13/Friday, January 19, 1996/Notices
some viruses with oncogenes such asSV40 have been treated more cautiouslythan viruses without oncogenes;therefore, a two-tier list should be used.Dr. Wivel explained that listing a groupof animal viruses as ‘‘moderate risk’’agents introduces an inconsistency intoAppendix B. Some strains of theseviruses, although capable of infectinghuman cells, have not been shown to beassociated with any disease in healthyhuman adults. They fall within thedefinition of Risk Group 1 agents, i.e.,agents that are not associated withdisease in healthy adult humans. Twocommittee members inquired whyseveral viruses in the original AppendixB are not listed in the new version. Dr.Thomas Shih (Executive Secretary,Appendix B Subcommittee) explainedthat several rarely used viruses such aschick embryo lethal orphan virus aredeleted from the new list. The listincludes commonly used organisms,and it is not intended to be inclusivesince many other animal agents are notlisted. Dr. Walters (Chair, RecombinantDNA Advisory Committee) stated thatthe consensus of the committee is toaccept the list of animal viruses inAppendix B–V as a reasonablemodification of Appendix B.The actions are detailed in SectionII—Summary of Actions. I accept theserecommendations, and the NIHGuidelines will be amendedaccordingly.
II. Summary of Actions
 A. Amendments to Section II, SafetyConsiderations (Previously the EntireSection II was Entitled Containment)
Section II is amended to read:Section II. Safety ConsiderationsSection II–A. Risk AssessmentSection II–A–1. Risk GroupsRisk assessment requires the exerciseof sound judgment by the investigator.The investigator must make an initialrisk assessment based on the Risk Group(RG) of an agent (see Appendix B,Classification of Human EtiologicAgents on the Basis of Hazard). Agentsare classified into four Risk Groups(RGs) according to their relativepathogenicity for healthy adult humansby the following criteria: (1) Risk Group1 (RG1) agents are not associated withdisease in healthy adult humans. (2)Risk Group 2 (RG2) agents areassociated with human disease which israrely serious and for which preventiveor therapeutic interventions are oftenavailable. (3) Risk Group 3 (RG3) agentsare associated with serious or lethalhuman disease for which preventive ortherapeutic interventions may beavailable. (4) Risk Group 4 (RG4) agentsare likely to cause serious or lethalhuman disease for which preventive ortherapeutic interventions are notusually available.Section II–A–2. Criteria for Risk GroupsClassification of agents is based on thepotential effect of a biological agent ona healthy human adult and does notaccount for instances in which anindividual may have increasedsusceptibility to such agents, e.g.,preexisting diseases, medications,compromised immunity, pregnancy orbreast feeding (which may increaseexposure of infants to some agents) (seeAppendix B, Classification of HumanEtiologic Agents on the Basis of Hazard).Personnel may need periodic medicalsurveillance to ascertain fitness toperform certain activities; they may alsoneed to be offered prophylactic vaccinesand boosters (see Section IV–B–1–f,Responsibilities of the Institution,General Information).Section II–A–3. Comprehensive Risk AssessmentIn deciding on the appropriatecontainment for an experiment, theinitial risk assessment from AppendixB, Classification of Human EtiologicAgents on the Basis of Hazard, shouldbe followed by a thorough considerationof the agent itself and how it is to bemanipulated. Factors to be consideredin determining the level of containmentinclude agent factors such as: virulence,pathogenicity, infectious dose,environmental stability, route of spread,communicability, operations, quantity,availability of vaccine or treatment, andgene product effects such as toxicity,physiological activity, and allergenicity.Any strain that is known to be morehazardous than the parent (wild-type)strain should be considered for handlingat a higher containment level. Certainattenuated strains or strains that havebeen demonstrated to have irreversiblylost known virulence factors mayqualify for a reduction of thecontainment level compared to the Risk Group assigned to the parent strain (seeSection V–B, Footnotes and Referencesof Sections I through IV).A final assessment of risk based onthese considerations is then used to setthe appropriate containment conditionsfor the experiment (see Section II–B,Containment). The containment levelrequired may be equivalent to the Risk Group classification of the agent or itmay be raised or lowered as a result of the above considerations. TheInstitutional Biosafety Committee mustapprove the risk assessment and thebiosafety containment level forrecombinant DNA experimentsdescribed in Sections III–A,Experiments that Require InstitutionalBiosafety Committee Approval, RACReview, and NIH Director ApprovalBefore Initiation, III–B, Experiments thatRequire NIH/ORDA and InstitutionalBiosafety Committee Approval BeforeInitiation, and III–C, Experiments thatRequire Institutional BiosafetyCommittee Approval Before Initiation.Careful consideration should be givento the types of manipulation planned forsome higher Risk Group agents. Forexample, the RG2 dengue viruses maybe cultured under the Biosafety Level(BL) 2 containment (see Section II–B);however, when such agents are used foranimal inoculation or transmissionstudies, a higher containment level isrecommended. Similarly, RG3 agentssuch as Venezuelan equineencephalomyelitis and yellow feverviruses should be handled at a highercontainment level for animalinoculation and transmissionexperiments.Individuals working with humanimmunodeficiency virus (HIV), hepatitisB virus (HBV) or other bloodbornepathogens should consult OccupationalExposure to Bloodborne Pathogens;Final Rule (56 FR 64175–64182). BL2containment is recommended foractivities involving all blood-contaminated clinical specimens, bodyfluids, and tissues from all humans, orfrom HIV- or HBV-infected orinoculated laboratory animals.Activities such as the production of research-laboratory scale quantities of HIV or other bloodborne pathogens,manipulating concentrated viruspreparations, or conducting proceduresthat may produce droplets or aerosols,are performed in a BL2 facility using theadditional practices and containmentequipment recommended for BL3.Activities involving industrial scalevolumes or preparations of concentratedHIV are conducted in a BL3 facility, orBL3 Large Scale if appropriate, usingBL3 practices and containmentequipment.Exotic plant pathogens and animalpathogens of domestic livestock andpoultry are restricted and may requirespecial laboratory design, operation andcontainment features not addressed inBiosafety in Microbiological andBiomedical Laboratories (see Section V–C, Footnotes and References of SectionsI through IV). For information regardingthe importation, possession, or use of these agents see Sections V–G and V–H,Footnotes and References of Sections Ithrough IV.
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