{blr 2345} rac - dr. harold varmus

16 Biotechnology Law Report 170 (Number 2, March-April 1997)

{BLR 2345} RAC-

Dr. Harold Varmus.

NEW RESPONSIBILITIES SPECIFIED FOR RAC— Varmus Wants Committee to Focuson "Novel and Unusual" Issues

BETHESDA, MD 2/14/97—

Saying that he had "underestimated thehistorical purpose and significance" of the Recombinant DNA AdvisoryCommittee (RAC), National Institutes of Health Director Dr. Harold Varmusearlier this year pulled back from his plan to disband the committee (see <BLR2320> and <BLR 2338>, vol. 16, no. 1, Jan.-Feb 1997). Today's FederalRegister contains the proposed new responsibilities for RAC (for text, see belowin this issue at <BLR 2385>), which will be considered by the Committee at itsmeeting in early March.

The revised guidelines note, among other things, that "[t]he NIHGuidelines will never be complete or final since all conceivable experimentsinvolving recombinant DNA cannot be foreseen," and that it is therefore theresponsibility of each institution to "establish[ ] accountability for safe conduct ofthe research at the local level." The minimum responsibilities of institutionalbiosafety committees are set out, including the reporting of "any significantresearch-related accidents or illnesses." A subsequent section specifies theresponsibilities of the principal investigator.

Under the new guidelines, the duties of the RAC would include advisingthe NIH Director on gene therapy issues, identifying novel experimentswarranting public discussion and informing the Director of its recommendationspertaining thereto, reviewing clinical trial data, and specifying scientific andethical/social issues for consideration at policy conferences and in thedevelopment of informed consent documents.

# # #

{BLR 2346} Databases-

Technology Transfer.

FREE TRIAL OF FEDERAL BlO-TECHNOLOGYTRANSFER DATABASE AVAILABLE

The Federal Bio-Technology Transfer Directory is now available as anInternet Web database at http://www.bioinfo.com/biotech/fbdhome.html. Thedatabase has more than 4000 records covering all federal laboratory (e.g., NIH)inventions and technology transfers in the biomédical, medical biotechnology,and pharmaceutical areas from 1980 to the present and includes:

• 2,764 inventions (1,747 patents and 1,017 patent applications);• 1,468 patent licenses (966 nonexclusive and 502 exclusive);• 1,038 collaborative research and development agreements (CRADAs).


{BLR 2385}7108 Federal Register / Vol. 62, No. 31 / Friday. February 14, 1997 / Notices

DEPARTMENT OF HEALTH ANDHUMAN SERVICESNational Institutes of Health

Recombinant DNA AdvisoryCommittee; MeetingPursuant to Pub. L. 92-463, notice is

hereby given of a meeting of theRecombinant DNA Advisory Committeeon March 6-7, 1997. The meetingwillbe held at the National Institutes ofHealth. Building 31C, 6th Floor,Conference Room 10, 9000 RockvillePike, Bethesda, Maryland 20392,starting on March 6, 1997, atapproximately 9 a.m., and will recess atapproximately 5 p.m. The meeting willreconvene on March 7, 1997, atapproximately 8:30 a.m. and willadjourn at approximately 5 p.m. Themeeting will be open to the public todiscuss Proposed Actions under the NIHGuidelines for Research InvolvingRecombinant DNA Molecules (59 FR34496) and other matters to beconsidered by the Committee. TheProposed Actions to be discussed willfollow this notice of meeting.Attendance by the public will be limitedto space available. Members of thepublic wishing to speak at this meetingmay be given such opportunity at thediscretion of the Chair.Ms. Debra W. Knorr, Acting Director,

Office of Recombinant DNA Activities,National Institutes of Health, MSC 7010,6000 Executive Boulevard. Suite 302,Bethesda. Marvland 20892-7010, Phone(301) 496-9838, FAX (301) 496-9839.will provide materials to be discussed atthis meeting, roster of committeemembers, and substantive programinformation. Individuals who plan toattend and need special assistance, suchas sign language interpretation or otherreasonable accommodations, shouldcontact Ms. Knorr in advance of themeeting. A summary of the meeting willbe available at a later date.OMB's "Mandatory Information

Requirements for Federal AssistanceProgram Announcements" (45 FR39592. June 11, 1980) requires astatement concerning the officialgovernment programs contained in theCatalog of Federal Domestic Assistance.Normally NIH lists in itsannouncements the number and title ofaffected individual programs for theguidance of the public. Because theguidance in this notice covers not onlyvirtually every NIH program but alsoessentially every Federal researchprogram in which DNA recombinantmolecule techniques could be used, ithas been determined not to be costeffective or in the public interest to

attempt to list these programs. Such alist would likely require severaladditional pages. In addition, NIH couldnot be certain that every Federalprogram would be included as manyFederal agencies, as well as privateorganizations, both national andinternational, have elected to follow theNIH Guidelines. In lieu of theindividual program listing, NIH invitesreaders to direct questions to theinformation address above aboutwhether individual programs listed inthe Catalog of Federal DomesticAssistance are affected.Dated: January 30, 1997.

Paula N. Hayes,ActingCommitteeManagement Officer,National Institutes ofHealth.(FR Doc. 97-3736 rued 2-12-97; 8:45 amiBILUNG CODE 414O-01-U

DEPARTMENT OF HEALTH ANDHUMAN SERVICES

National Institutes of Health

Recombinant DNA Research:Proposed Actions Under theGuidelinesAGENCY: National Institutes of Health(NIH), PHS, DHHS.ACTION: Notice of Proposed ActionsUnder the NIH Guidelines for ResearchInvolving Recombinant DNA Molecules.

summary: This notice sets forthproposed actions to be taken under theNIH Guidelines for Research InvolvingRecombinant DNA Molecules (59 FR34496, amended 59 FR 40170, 60 FR20726, 61 FR 1482, 61 FR 10004, 62 FR4782). Interested parties are invited tosubmit comments concerning theseproposals. There proposals will beconsidered by the Recombinant DNAAdvisory Committee (RAC) at itsmeeting on March 6-7, 1997. Afterconsideration of these proposals andcomments by the RAC, the NIH Directorwill issue decisions in accordance withthe NIH Guidelines.DATES: Interested parties are invited tosubmit comments concerning thisproposal. Comments received byFebruary 27, 1997. will be reproducedand distributed to the RAC forconsideration at its March 6-7, 1997,meeting. After consideration of thisproposal and comments by the RAC, theNIH Director will issue decisions inaccordance with the NIH Guidelines.ADDRESSES: Written comments andrecommendations should be submittedto Debra Knorr, Office of RecombinantDNA Activities, National Institutes of

Health. MSC 7010, 6000 ExecutiveBoulevard, Suite 302. Bethesda,Maryland 20892-7010, or by FAX to301-496-9839.All comments received in response to

this notice will be considered and willbe available for public inspection in theabove office on weekdays between thehours of 8:30 a.m. and 5 p.m.FOR FURTHER INFORMATION CONTACT:Background documentation andadditional information can be obtainedfrom the Office of Recombinant DNAActivities, National Institutes ofHealth,MSC 7010, 5000 Executive Boulevard.Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-9838. FAX 301-496-9839.SUPPLEMENTARY INFORMATION: The NIHwill consider the following actionsunder the NIH Guidelines for ResearchInvolving Recombinant DNA Molecules:I. Amendment to the OverallProcedures for Human Gene TransferProtocolsI-A. Notice ofIntentOn July 3, 2996, the NIH Director

published a Notice of Intent to ProposeAmendments to the NIH Guidelines forResearch Involving Recombinant DNAMolecules Regarding EnhancedOversight of Recombinant DNAActiviües (61 FR 35774). This Notice ofIntent proposed modifications in NIHoversight of human gene transferresearch. Specifically, it was proposedthat the RAC would be terminated andthat all approval responsibilities forrecombinant DNA experimentsinvolving human gene transfer would berelinquished to the Food and DrugAdministration (FDA), which retainsstatutory authority for such approval.Under this revised oversight structure, a

newly created ORDA AdvisoryCommittee (OAC) would preservecontinued public accountability forrecombinant DNA research. To ensurequality and efficiency of publicdiscussion of the scientific merit andthe ethical issues relevant to genetherapy clinical trials, it was proposedthat the NIH Director implement aregular series of Gene Therapy PolicyConferences (GTPC). Finally, theproposal assured the continuation of thepublicly available comprehensive NIHdatabase of clinical trials with humangene transfer, including reporting ofadverse events.In response to the Notice of Intent, the

NIH received 71 written comments (90signatures) reflecting a broad spectrumof public opinion orí the proposedchanges. Comments were received froma variety of stakeholders, includingindividuals representing academia.


Federal Register / Vol. 62, No. 31 / Friday. February 14, 1997 / Notices 7109

industry, patient advocacyorganizations, consumer advocacyorganizations, professional scientificsocieties, ethicists, other Federalagencies, NTH-funded investigators, pastand present RAC members, and privatecitizens. Careful consideration wasgiven to each of the written commentsthat were submitted.I-B. Proposed Actions—November 1996

On November 22, 1996, the NIHDirector published Notice of ProposedActions Under the NIH Guidelines forResearch Involving Recombinant DNAMolecules (61 FR 59725). The Notice ofProposed Actions was in response topublic opinion and in keeping with theNIH Director's intent to increase theusefulness and productivity of publicdiscussion of gene therapy.In the Proposed Actions, the NIH

Director proposed to: (1) Retain theRAC. while modifying its roles andresponsibilities relevant to human genetherapy research, (2) continue RACdiscussion of neve! human gene transfarexperiments without RAC approval ofindividual human gene transferexperiments: (3) reduce the membershipof RAC from 25 members to 15members; (4) regularly convene GTPC:and (5) maintain public access to humangene transfer clinical trial information.The following summarizes the roles andresponsibilities of the NIH Director, theRAC, the ORDA, and the localinstitutions under the Notice ofProposed Actions.I-B-l. Proposed Roles andResponsibilities in Accordance with theNIH GuidelinesI-B-l-a. The NIH Director

The roles and responsibilities of theNIH Director remain unchanged exceptfor relinquishing approval of humangene transfer experiments, andestablishing and convening GeneTherapy Policy Conferences. The NIHDirector is responsible for establishingthe NIH Guidelines, overseeing theirimplementation, and their finalinterpretation; promulgatingrequirements as necessary to implementthe NIH Guidelines; establishing andmaintaining the RAC; establishing andmaintaining ORDA; conducting andsupporting training programs inlaboratory safety for InstitutionalBiosafety Committee members,Biological Safety Officers and otherinstitutional experts (if applicable).Principal Investigators, and laboratorystaff; and establishing and conveningGene Therapy Policy Conferences.

I-B-l-b. The Recombinant DNAAdvisory CommitteeThe RAC will remain a chartered

public advisory committee to the NIHDirector regarding recombinant DNAresearch conducted in compliance withthe NIH Guidelines. The RACwillconduct quarterly meetings. RACmembers will continue to be appointedby the DHHS Secretary or his/herdésignée for 4-year terms. RACmembership will be reduced from 25 to15 members. At least eight of thesemembers shall be knowledgeable in thefields of molecular genetics, molecularbiology, recombinant DNA research, orother related fields and at least four ofthese members shall be personsknowledgeable in applicable law,standards of professional conduct andpractice, public attitudes, theenvironment, public health,occupational health, or related fields.Representatives of Federal agenciesshall continue to serve as non-votingmembers.The RAC will be responsible for: (1)

Identifying novel human gene transferexperiments deserving of publicdiscussion by the full RAC andtransmitting comments/recommendations about specific humangene transfer experiments or categoriesof human gene transfer experiments tothe NIH Director. (2) Identifying novelethical issues relevant to specific humanapplications of gene transfer andrecommending appropriatemodifications to the Points to Considerthat will provide guidance in thepreparation of relevant InformedConsent documents. (3) Identifyingnovel scientific and safety issuesrelevant to specific human applicationsof gene transfer and recommendingappropriate modifications to the Pointsto Consider that will provide guidancein the design and submission of humangene transfer clinical trials. (4) Publiclyreviewing human gene transfer clinicaltrial data captured by NIH/ORDA Inaccordance with the annual datareporting requirements. (5) Identifyingbroad scientific and ethical/social issuesrelevant to gene therapy research aspotential Gene Therapy PolicyConference topics.The RAC will advise the NIH Director

on the following actions: (1) Adoptingchanges in the NIH Guidelines. (2)Assigning containment levels, changingcontainment levels, and approvingexperiments considered as MajorActions under the NTH Guidelines, i.e.,the deliberate transfer of a drugresistance trait to microorganisms thatare not known to acquire die traitnaturally, if such acquisition could

compromise the use of the drug tocontrol disease agents in humans,veterinary medicine, or agriculture. (3)Promulgating and amending lists ofclasses of recombinant DNA moleculesto be exempt from the NIH Guidelinesbecause they consist entirely of DNAsegments from species that exchangeDNA by known physiological processesor otherwise do not present a significantrisk to health or the environment. (4)Certifying new host-vector systems.I-B-l-c. Gene Therapy PolicyConferences (GTPCs)In order to enhance the depth and

value of public discussion relevant toscientific, safety, and ethical/societalimplications of gene therapy research,the NTH Director will convene GTPC atregular intervals. As appropriate, theNIH Director may convene GTPCimmediately following scheduled RACmeetings. GTPC will be administered bythe NIH/ORDA. Conferenceparticipationwill not Involve a standingcommittee membership but rather willoffer the unique advantage ofassembling numerous participants whopossess significant scientific, ethical,and legal expertise and/or interest thatis directly applicable to a specific genetherapy research issue. At least onemember of the RAC will serve as Co-chair of each GTPC and report thefindings of the GTPC to the fullcommittee at its next scheduledmeeting. The RAC representative foreach GTPC will be chosen based on theparticipant's area of expertise relative tothe specific gene therapy research issueto be discussed. GTPC will haverepresentation from other Federalagencies, including the FDA. GTPCswill focus on broad over-arching policyand scientific issues related to genetherapy research. Proposals for GTPCtopics may be submitted by members ofthe RAC, representatives of academia,industry, patient and consumer

advocacy organizations, other Federalagencies, professional scientificsocieties, and the general public. GTPCtopics will not be limited to discussionof human applications of gene therapyresearch, i.e.. they may include basicresearch on the use of novel genedelivery vehicles, or novel applicationsof gene transfer. The findings of theGTPC will be transmitted to the NIHDirector and will be made publiclyavailable. The NIH Director anticipatesthat this public policy forum will serveas a model for interagencycommunication and collaboration.concentrated expert discussion of novelscientific issues and their potentialsocietal implications, and enhancedopportunity for public discussion of the


7110 Federal Register / Vol. 62, No. 31 / Friday. February 14, 1997 / Notices

potential impact of such applications onhuman health and the environment.I-B-l-d. The Office of RecombinantDNA Activities (ORDA)ORDA is an organizational unit of the

NIH Office of Science Policy within theOffice of the Director. ORDA shall serveas a focal point for information onrecombinant DNA activities and provideadvice to all within and outside NIHincluding institutions. Biological SafetyOfficers, Principal Investigators. Federalagencies, state and local governments,and institutions in the private sector.ORDA's responsibilities include (but arenot limited to) the following: (1) Servingas the focal point for public access tosummary information pertaining tohuman gene transfer experiments. (2)Serving as the focal point for datamanagement of human gene transferexperiments. (3) Administering theannual data reporting requirements (andsubsequent review) for human genetransfer experiments. (4) Transmittingcomments/recommendations arisingfrom public RAC discussion of a novelhuman gene transfer experiment to theNIH Director. RAC recommendationsshall be forwarded to the PrincipalInvestigator, sponsoring institution, andother Department of Health and HumanServices (DHHS) components, asappropriate. (5) Collaborating withPrincipal Investigators, InstitutionalBiosafety Committees, InstitutionalReview Boards, and other DHHScomponents, to ensure human genetransfer experiment registrationcompliance. (6) Administering GeneTherapy Policy Conferences as deemedappropriate by the NIH Director. (7)Reviewing and approving experimentsin conjunction with ad hoc expertsinvolving the cloning of genes encodingfor toxin molecules that are lethal forvertebrates at an LD5o of less than or

equal to 100 nanograms per kilogrambody weight in organisms other thanEscherichia coli K-12. (8) Serving as theexecutive secretary of the RAC. (9)Publishing in the Federal Register theannouncements of RAC meetings andtentative agendas at least 15 days inadvance, announcements of GeneTherapy Policy Conferences andtentative agendas at least 15 days inadvance, proposed Major Actions atleast 15 days prior to the RAC meeting:and (10) Reviewing and approving themembership of an institution'sInstitutional Biosafety Committee.I-B-l-e. Local InstitutionsThe Notice of Proposed Actions

would change the roles andresponsibilities of local institutions,Institutional Biosafety Committees,

Biosafety Officers, PrincipalInvestigators, Animal Facility Directors,Greenhouse Supervisors, and HumanGene Therapy experts relevant torecombinant DNA research conductedin compliance with the NIH Guidelines.These changes now include thefollowing requirements: (1) When theinstitution conducts recombinant DNAresearch that requires InstitutionalBiosafety Committee approval, theinstitution shall appoint at least oneindividual with expertise in plant, plantpathogen, or plant pest containmentprinciples (who is also a member of theInstitutional Biosafety Committee); (2)when the institution conductsrecombinant DNA research that requiresInstitutional Biosafety Committeeapproval, the institution shall appoint atleast one individual with expertise inanimal containment principies (who isalso a member of the InstitutionalBiosafety Committee); and (3) when theinstitution participates in or sponsorsrecombinant DNA research involvinghuman subjects, the institution mustensure that: (a) The InstitutionalBiosafety Committee has adequateexpertise and training (using ad hocconsultants as deemed necessary) and(b) all aspects of Appendix M, Points toConsider in the Design and Submissionof Protocols for the Transfer ofRecombinant DNA Molecules into Oneor More Human Subjects (Points toConsider), have been appropriatelyaddressed by the Principal Investigatorprior to submission to NIH/ORDA.I-C. Recombinant DNA AdvisoryCommittee Meeting—December 1996During the December 9, 1996,

Recombinant DNA Advisory Committeemeeting, the following motions weremade:I-C-l. Future RAC Membership-Committee Motion 1A motion was made to invite former

RAC members back to serve as ad hocconsultants in order to ensureinstitutional continuity of the RAC. Themotion passed by a vote of 15 in favor,0 opposed, and no abstentions.I-C-2. Triggering Mechanism for RACDiscussion—Committee Motion 2A motion was made that: (1) The

capacity for principal investigators andinstitutional representatives to requestpublic RAC discussion of an individualgene transfer protocol should bedeleted. (2) A decision by the RAC torequire full review of an individualprotocol should not have to be approvedby the NIH Director. (3) The NIHDirector or an appropriate FDArepresentative may also request RAC

review of an individual protocol. (4)Rather than a majority vote. RACrecommendations for full review of anindividual protocol should be changedto a minimum of three members. (5) Thedecision regarding necessity for RACdiscussion should be made within 15working days. The motion passed by avote of 16 in favor, 0 opposed, and noabstentions.I-C—3. Feedback Mechanism—Committee Motion 3A motion was made to request FDA to

report back to the RAC how the RACrecommendations on an individualprotocol were implemented. The RACshould require investigators to provideadditional information if the FDAinformation is not adequate. The motionfailed by a vete of 3 in favor, 7 opposed,and 4 abstentions.I-C—4. Feedback Mechanism—Committee Morion 4A motion was made to require

investigators to report back to the RACin writing in a timely fashion. Thereport should include a statement ofhow the investigators have responded toRAC's recommendations and anymodifications to the protocol followingFDA review. The motion passed by avote of 12 in favor, 1 opposed, and 1abstention.I-C-5. Relationship of the RAC andGTPC—Committee Motion 5A motion was made that the RAC,

with the NIH Director's approval,should have the primary responsibilityfor: (1) Planning the GTPC agendas, and(2) summarizing GTPCrecommendations in the form of a reportback to the NIH Director. The closeGTPC/RAC relationship should notpreclude other parties from suggestingGTPC topics and GTPC should beconvened in consultation with FDA.The motion passed by a vote of 13 infavor, 0 opposed, and 2 abstentions.I-C-6. Proposed Actions Concepts—Committee Motion 6A motion was made to accept the

overall concepts put forward in theProposed Actions as published in theNovember 22, 1996, Federal Register(61 FR 59725). Specifically: (1) Retainthe RAC, while modifying its roles andresponsibilities relevant to human genetherapy research, (2) continue RACdiscussion of novel human gene transferexperiments without RAC approval ofindividual human gene transferexperiments; (3) reduce the membershipof RAC from 25 members to 15members; (4) regularly convene GTPC;and (5) maintain public access to human


Federal Register / Vol. 62. No. 31 / Friday, February 14. 1997 / Notices 7111

gene transfer clinical trial information.The members of the RAC noted thatseveral minor modifications stillremained unresolved, particularlywithregard to the future discussion of genetherapy protocols and defining the roleof the RAC relative to the GTPCs. TheRAC recommended that final acdon onthe Proposed Actions should bepostponed to the March 6-7, 1997, RACmeeting, in order to more fully addressthese unresolved issues. The motionpassed by a vote of 12 in favor, 0opposed, and 2 abstentions.II. Meetings Between the NIH and FDARegarding Simultaneous Submission toHuman Gene Transfer Protocols to theNIH and the FDA

In a letter dated November 20, 19S6,Dr. Andra Miller. Cytokine and GeneTherapy Branch, Center of BiologiesEvaluation and Research, FDA,requested that the NIH Guidelinesshould be amended regardingprocedures for simultaneous submissionof Appendix M material to the RAC andFDA. In her November 20, 1996, letter,Dr. Miller states:" * * * (1) Remove the requirement

for submission ofAppendix M to theFDA. The FDA does not acceptAppendix M in place of an INDsubmission. The FDA is not proposed tobe and need not be included in thedecision making process to identifyprotocols to undergo full RAC review.Therefore, there is no reason forsponsors to submit Appendix Mmaterials to the FDA."(2) Explore the feasibility of a

unified format for submission ofprotocols to the RAC and FDA. Thiswould relieve the sponsor of the burdenof preparing duplicative submission tosatisfy each agency."(3) Establish a mechanism for FDA

staff to bring general issues of noveltyand concern to the RAC for discussion.This will provide a mechanism forpublic input toward the resolution ofissues we all must consider and providedirection for policy development andgrowth in the field of gene therapy."On January 27. 1997. NIH and FDA

staff met to consider amendments to theNIH Guidelines that incorporate therecommendations of both the NIH andthe FDA with regard to simultaneoussubmission of human gene transferprotocols. The recommendations of NIHand FDA staff are incorporated below inthe Proposed Actions Regarding theOverall Procedures for Human GeneTransfer Protocol.

III. Proposed Actions Regarding theOverall Procedures for Human GeneTransfer ProtocolsThe NIH will consider the following

proposed actions under the NIHGuidelines for Research InvolvingRecombinant DNA Molecules:[Note: Editorial changes and updating ofreferences have been incorporated to clarifythe document]ni-A. ProposedAmendments to SectionI, Scope oftheNIH GuidelinesSection 1 is proposed to be amended

to read:Section I. Scope of the NIH GuidelinesSection I-A. Purpose[This section remains unchanged.]Section I-A-l. Any recombinant DNA

experiment, which according to the NIHGuidelines requires approval by theNIH, must be submitted to the NTH orto another Federal agency that hasjurisdiction for review and approval.Once approvals, or other applicableclearances, have been obtained from aFederal agency other than the NIH(whether the experiment is referred tothat agency by the NIH or sent direcdythere by the submitter), the experimentmay proceed without the necessity forNIH review or approval. (See exceptionin Section I-A-l-a regardingrequirement for human gene transferprotocol registration.)Section I-A-l-a. Experiments

involving the deliberate transfer ofrecombinant DNA or DNA or RNAderived from recombinant DNA intohuman subjects (human gene transfer)cannot be initiated withoutsimultaneous submission to both NIH/ORDA and the FDA of such informationon the proposed experiment as isprescribed by those agencies.Submission of human gene transferprotocols to the NIH will be in theformat described in AppendixM-i,Submission Requirements—HumanGene Transfer Experiments, of the NIHGuidelines. Submission to NIH shall befor registration purposes and will ensurecontinued public access to relevanthuman gene transfer informationconducted in compliance with the NIHGuidelines. Submission of human genetransfer protocols to the FDA will be inthe format described in 21 CFR, ChapterI, Subchapter D, Part 312. Subpart B.Section 23, IND Content and Format.If a determination is made that an

experimentwill undergo full RACdiscussion, NIH/ORDAwillimmediately notify the PrincipalInvestigator. RAC members may forwardrequests for additional informationrelevant to a specific protocol through

NIH/ORDA to the Principal Investigator.In making a determination whether anexperiment is novel, and thus deservingof full RAC discussion, reviewers willexamine the scientific rational,scientific content (relative to otherproposals reviewed by the RAC).whether the preliminary in vitro and invivo data were obtained in appropriatemodels and are sufficient, and whetherquestions related to safety, efficacy, andsocial/ethical contest have beenresolved. RAC's recommendation(s) on a

specific human gene transferexperimentwill be forwarded to theNIH Director, the Principal Investigator,the sponsoring institution, and to otherDepartment of Health and HumanServices (DHHS) components, asappropriate.Section I-B. Definition of RecombinantDNA Molecules[This section remains unchanged.]

Section I-C. General ApplicabilitySection I-C-l. The NIH Guidelines

are applicable to:Section I-C-l-a. All recombinant

DNA research within the United States(U.S.) or its territories that is within thecategory of research described in eitherSection I-C-l-a-(l) or Section I-C-l-a-(2).Section I-C-l-a-(l). Research that is

conducted at or sponsored by aninstitution that receives any support forrecombinant DNA research from theNIH, including research performeddirecdy by the NIH. An individual whoreceives support for research involvingrecombinant DNA must be associatedwith or sponsored by an institution thatassumes the responsibilities assigned inthe NIH Guidelines.Section I-C-l-a-(2). Research that

involves testing in humans of materialscontaining recombinant DNA developedwith NIH funds, if the institution thatdeveloped those materials sponsors orparticipates in those projects.Participation includes researchcollaboration or contractual agreements,not mere provision of researchmaterials.Section I-C-l-b. All recombinant

DNA research performed abroad that iswithin the category of researchdescribed in either Section I-C-l-b-(l)or Section I-C-l-b-(2).Section l-C-l-b-(l). Research

supported by NIH funds.Section I-C-l-b-(2). Research that

involves testing in humans of materialscontaining recombinant DNA developedwith NIH funds, if the institution thatdeveloped those materials sponsors orparticipates in those projects.Participation includes research


7112 Federal Register / Vol. 62, No. 31 / Friday, February 14, 1997 / Notices

collaboration or contractual agreements,not mere provision of researchmaterials.Section I-C-l-b-(3). If the host

country has established rules for theconduct of recombinant DNA research,then the research must be in compliancewith those rules. If the host countrydoes not have such rules, the proposedresearch must be reviewed andapproved by an NIH-approvedInstitutional Biosafety Committee or

equivalent review body and accepted inwriting by an appropriate nationalgovernmental authority of the hostcountry. The safety practices that areemployed abroad must be reasonablyconsistent with the NIH Guidelines.Section I-D. Compliance With the NIHGuidelinesAs a condition for NIH funding of

recombinant DNA research, institutionsshall ensure that such researchconducted at or sponsored by theinstitution, irrespective of the source offunding, shall comply with the NIHGuidelines.Information concerning

noncompliance with the NIH Guidelinesmay be brought forward by any person.It should be delivered to both NIH/ORDA and the relevant institution. Theinstitution, generally through theInstitutional Biosafety Committee, shalltake appropriate action. The institutionshall forward a complete report of theincident recommending any furtheraction to the Office of RecombinantDNA Activities, National Institutes ofHealth/MSC 7010. 6000 ExecutiveBoulevard. Suite 302, Bethesda.Maryland 20892-7010, (301) 496-9838.In cases where NIH proposes to

suspend, limit, or terminate financialassistance because of noncompliancewith the NIH Guidelines, applicableDHHS and Public Health Serviceprocedures shall govern.The policies on compliance are as

follows:Section I-D-l. All NIH-funded

projects involving recombinant DNAtechniques must comply with the NIHGuidelines. Non-compliance may resultin: (i) Suspension, limitation, ortermination of financial assistance forthe noncompliant NIH-funded researchproject and of NIH funds for otherrecombinant DNA research at theinstitution, or (ii) a requirement forprior NIH approval of any or allrecombinant DNA projects at theinstitution.Section I-D-2. All non-NIH funded

projects involving recombinant DNAtechniques conducted at or sponsoredby an institution that receives NIHfunds for projects involving such

techniques must comply with the NIHGuidelines. Noncompliance may resultin: (i) Suspension, limitation, ortermination of NIH funds forrecombinant DNA research at theinstitution, or (ii) a requirement forprior NIH approval of any or allrecombinant DNA projects at theinstitution.[The remainder of Section I is proposedto be renumbered to reflect abovechanges.]ni-3. ProposedAmendments to SectionII, Safety ConsiderationsThe second paragraph of Section II-

A-3 is proposed to be amended to read:Section II-A-3. Comprehensive RiskAssessment* * * A final assessment of risk based

on these considerations is then used toset the appropriate containmentconditions for the experiment (seeSection II-B, Containment). Thecontainment level required may beequivalent to the Risk Groupclassification of the agent or it may beraised or lowered as a result of theabove considerations. The InstitutionalBiosafety Committee must approve therisk assessment and the biosafetycontainment level for recombinant DNAexperiments described 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, III-C, Experiments thatRequire Institutional BiosafetyCommittee and Institutional ReviewBoard Approvals and NIH/ORDARegistration Before Initiation, and III—D.Experiments that Require InstitutionalBiosafety Committee Approval BeforeInitiation * * *

III-C. ProposedAmendments to SectionIII, Experiments Covered by the NIHGuidelinesSection III is proposed to be amended

to read:Section III. Experiments Covered by theNIH GuidelinesThis section describes six categories

of experiments involving recombinantDNA: (i) Those that require InstitutionalBiosafety Committee (IBC) approval,RAC review, and NIH Director approvalbefore initiation (see Section III—A), (ii)those that require NTH/ORDA andInstitutional Biosafety Committeeapproval before initiation (see SectionIII—B), (iii) those that requireInstitutional Biosafety Committee andInstitutional Review Board approvals

and NIH/ORDA registration beforeinitiation (see Section III-C), (iv) thosethat require Institutional BiosafetyCommittee approval before initiation(see Section III-D), (v) those that requireInstitutional Biosafety Committeenotification simultaneous withinitiation (see Section III—E). and (vi)those that are exempt from the NIHGuidelines (see Section HI-F).Note: If an experiment falls into Sections

ID-A, m-B. orm-C and one of the othersections, the rules pertaining to Sections Til—A, m-B. orm-C shall be followed. Ifanexperiment falls into Section Ü1-F and intoeither Sections HI-D or lil-E as well, theexpriment is considered exempt from theNIH Guidelines.Any change in containment level,

which is different from those specifiedin the NIH Guidelines, may not beinitiated without the express approvalofNIH/ORDA (see Section IV-C-l-b-(2) and its subsections, Minor Actions).Section ni-A. Experiments That RequireInstitutional Biosafety CommitteeApproval, RAC Review, and NIHDirector Approval Before Initiation(See Section IV-C-l-b-(l), MajorActions)Section III—A—1. Major Actions Underthe NIH GuidelinesExperiments considered as Major

Actions under the NIH Guidelinescannot be initiated without submissionof relevant information on the proposedexperiment to the Office of RecombinantDNA Activities, National Institutes ofHealth/MSC 7010. 6000 ExecutiveBoulevard, Suite 302, Bethesda,Maryland 20892-7010, (301) 496-9838,the publication of the proposal in theFederal Register for 15 days ofcomment, review by the RAC, andspecific approval by the NIH. Thecontainment conditions or stipulationrequirements for such experiments willbe recommended by the RAC and set bythe NIH at the time of approval. Suchexperiments require InstitutionalBiosafety Committee approval beforeinitiation. Specific experiments alreadyapproved are included in Appendix D,Major Actions Taken under the NIHGuidelines, which may be obtainedfrom the Office of Recombinant DNAActivities, National Institutes ofHealth/MSC 7010, 6000 Executive Boulevard,Suite 302, Bethesda, Maryland 20892-7010, (301) 496-9838.Section III-A-1-a. The deliberate

transfer of a drug resistance trait tomicroorganisms that are not known toacquire the trait naturally (see SectionV-B, Footnotes and References ofSections I-IV), if such acquisition couldcompromise the use of the drug to


Federal Register / Vol. 62, No. 31 / Friday. February 14, 1997 / Notices 7113

control disease agents in humans,veterinary medicine, or agriculture, willbe reviewed by the RAC.Section III—B. Experiments That RequireNIH/ORDA and Institutional BiosafetyCommittee Approval Before InitiationExperiments in this category cannot

be initiated without submission ofrelevant information on the proposedexperiment to NIH/ORDA. Thecontainment conditions for suchexperimentswill be determined by NIH/ORDA in consultation with ad hocexperts. Such experiments requireinstitutional Biosafety CommitteeaoDroval before initiation (see SectionrV-B-2-b-(l), Institutional BiosafetyCommittee).Section III—B—1. Experiments Involvingthe Cloning ofToxin Molecules WithLD50 of Less Than 100 Nanograms perKilogram Body WeightDeliberate formation of recombinant

DNA containing genes for thebiosynthesis of toxin molecules lethalfor vertebrates at an LD50 of less than100 nanograms per kilogram bodyweight (e.g.. microbial toxins such asthe botulinum toxins, tetanus toxin,diphtheria toxin, and Shigelladysenteriae neurotoxin). Specificapproval has been given for the cloningin Escherichia coi/K-12 of DNAcontaining genes coding for thebiosynthesis of toxic molecules whichare lethal to vertebrates at 100nanograms to 100 micrograms perkilogram body weight. Specificexperiments already approved underthis section may be obtained from theOffice of Recombinant DNA Activities,National Institutes of Health/MSC 7010,6000 Executive Boulevard, Suite 302,Bethesda. Maryland 20892-7010, (301)496-9838.Section III—C. Experiments That RequireInstitutional Biosafety Committee andInstitutional Review Board Approvalsand NIH/ORDA Registration BeforeInitiationSection III—C—1. Experiments Involvingthe Deliberate Transfer of RecombinantDNA or DNA or RNA Derived FromRecombinant DNA Into Human SubjectsExperiments involving the deliberate

transfer of recombinant DNA or DNA orRNA derived from recombinant DNAinto human subjects (human genetransfer) cannot be initiated withoutsimultaneous submission of relevantinformation on the proposed experimentto both NIH/ORDA and the FDA.Submission to NIH/ORDA shall be forregistration purposes and will ensurecontinued public access to relevanthuman gene transfer information

conducted in compliance with the NIHGuidelines. Submission of human genetransfer protocols to the NIH will be inthe format described in AppendixM-I,Submission Requirements—HumanGene Transfer Experiments, of the NIHGuidelines. Submission of human genetransfer protocols to the FDA will be inthe format described in 21 CFR, ChapterI. Subchapter D, Part 312, Subpart B,Section 23, IND Content and Format.Prior to submission of a human genetransfer experiment to NIH/ORDA. thePrincipal Investigator must obtainInstitutional Biosafety Committee (IBC)approval from each institution that willhandle recambir.ant DMA material thatis to be administered to human subjectsand Institutional Review Board approvalfrom each institution in which humansubjectswill undergo gene transfer.Specifically: (1) Any institutioninvolved in the production of thevectors for human application, (2) anyinstitution at which there is ex vivotransduction of the recombinant DNAmaterial into target cells for humanapplication, and (3) any institution atwhich the recombinant DNA materialwill be direcdy administered to humansubjects. These local committeeapprovals and relevant protocoldocumentation shall be submitted toNIH/ORDA for registration purposesand determination regarding thenecessity of full RAC review andapproval/disapproval,the RAC prefeiprefers that submission toNIH/ORDA in accordance withAppendix M-I, SubmissionRequirements—Human Gene TransferExperiments, of the NIH Guidelines,contain no proprietary data or tradesecrets, enabling all aspects of thereview to be open to the public.Following receipt by NIH/ORDA,relevant information shall be enteredinto the NIH human gene transferdatabase for registration purposes.Summary information pertaining to thehuman gene transfer protocol will beforwarded to RAC members. The NIH/ORDA summary information shallinclude comparisons to previouslyregistered protocols. Specific items ofsimilarity to previous experimentsinclude (but are not limited to): (i) Genedelivery vehicle, (ii) functional gene,(iii) marker gene, (iv) packaging cell (ifapplicable), (v) disease application, (vi)route of administration, and (vii) patientselection criteria.RAC members shall notify NIH/ORDA

within 15 working days if the protocolhas been determined to represent novelcharacteristics requiring further publicdiscussion.Full RAC review of an individual

human gene transfer experiment can be

initiated by the NIH Director orrecommended to the NIH Director by: (i)Three or more RAC members, or (ii)other Federal agencies. An individualhuman gene transfer experiment that isrecommended for full RAC reviewshould represent novel characteristicsdeserving of public discussion. RACrecommendations on a specific humangene transfer experiment shall beforwarded to the NIH Director, thePrincipal Investigator, the sponsoringinstitution, and other Department ofHealth and Human Services (DHHS)components, as appropriate.Note: For specific directives concerning the

use oí retroviral vectors for gene delivery,consult Appendix B-V-l, Murine RetroviralVectors.Section HI-D. Experiments That RequireInstitutional Biosafety CommitteeApproval Before Initiation[This section remains unchanged exceptfor renumbering and reference changesdue to renumbering.]Section III—E. Experiments That RequireInstitutional Biosafety CommitteeNotice Simultaneous With Initiation[This section remains unchanged exceptfor renumbering and reference changesdue to renumbering.]Section III—F. Exempt Experiments[This section remains unchanged exceptfor renumbering and reference changesdue to renumbering.]III-D. Proposed Amendments to SectionTV, Roles and ResponsibilitiesSection IV is proposed to be amended

to read:SECTION rV. ROLES ANDRESPONSIBILITIESSection rV-A. PolicyThe safe conduct of experiments

involving recombinant DNA depends onthe individual conducting suchactivities. The NIH Guidelines cannotanticipate every possible situation.Motivation and good judgment are thekey essentials to protection of healthand the environment. The NIHGuidelines are intended to assist theinstitution, Institutional BiosafetyCommittee, Biological Safety Officer,and Principal Investigator indetermining safeguards that should beimplemented. The NIH Guidelines willnever be complete or final since allconceivable experiments involvingrecombinant DNA cannot be foreseen.Therefore, it is the responsibility of theinstitution and those associated with itto adhere to the intent of the NIHGuidelines as well as to their specifics.Each institution (and the Institutional


7114 Federal Register / Vol. 62. No. 31 / Friday, February 14, 1997 / Notices

Biosafety Committee acting on itsbehalf) is responsible for ensuring thatall recombinant DNA researchconducted at or sponsored by thatinstitution is conducted in compliancewith the NIH Guidelines. Generalrecognition of institutional authorityand responsibility properly establishesaccountability for safe conduct of theresearch at the local level. The followingroles and responsibilities constitute anadministrative framework in whichsafety is an essential and integral part ofresearch involving recombinant DNAmolecules. Further clarifications ana

interpretations of roles andresponsibilities will be issued by theNIH as necessary.Section rV-B. Responsibilities of theInstitutionSection IV-B-1. General InformationEach institution conducting or

sponsoring recombinant DNA researchwhich is covered by the NIH Guidelinesis responsible for ensuring that theresearch is conducted in full conformitywith the provisions of the NIHGuidelines. In order to fulfill thisresponsibility, the institution shall:Section IV-B-1-a. Establish and

implement policies that provide for thesafe conduct of recombinant DNAresearch and that ensure compliancewith the NIH Guidelines. As part of itsgeneral responsibilities forimplementing the NIH Guidelines, theinstitution may establish additionalprocedures, as deemed necessary, togovern the institution and itscomponents in the discharge of itsresponsibilities under the NIHGuidelines. Such procedures mayinclude: (i) statements formulated by theinstitution for the generalimplementation of the NIH Guidelines,and (ii) any additional precautionarysteps the institution deems appropriate.Section IV-B-1-b. Establish an

Institutional Biosafety Committee thatmeets the requirements set forth inSection IV-B-2-a and carries out thefunctions detailed in Section IV-B-2-b.Section IV-B-l-c. Appoint a

Biological Safety Officer (who is also amember of the Institutional BiosafetyCommittee) if the institution: (i)Conducts recombinant DNA research atBiosafety Level (BL) 3 or BL4, or (ii)engages in large scale (greater than 10liters) research. The Biological SafetyOfficer carries out the duties specifiedin Section IV-B-3.Section IV-B-l-d. Appoint at least

one individual with expertise in plant,plant pathogen, or plant pestcontainment principles (who is also amember of the Institutional Biosafety

Committee) if the institution conductsrecombinant DNA research that requiresInstitutional Biosafety Committeeapproval in accordance with AppendixP, Physical and Biological Containmentfor Recombinant DNA ResearchInvolving Plants.Section rV-B-l-e. Appoint at least

one individual with expertise in animalcontainment principles (who is also amember of the Institutional BiosafetyCommittee) if the institution conductsrecombinant DNA research that requiresInstitutional Biosafety Committeeapproval In accordance with AppendixQ, Physical and Biological Containmentfor Recombinant DNA ResearchInvolving Animals.Section rV-B-l-f. When the

institution participates in or sponsorsrecombinant DNA research involvinghuman subjects, the institution mustensure that: (i) The InstitutionalBiosafety Committee has adequateexpertise and training (using ad hocconsultants as deemed necessary) and(ii) all aspects ofAppendix M, Points toConsider in the Design and Submissionof Protocols for the Transfer ofRecombinant DNA Molecules into Oneor More Human Subjects (Points toConsider), have been appropriatelyaddressed by the Principal Investigatorprior to submission to NIH/ORDA.Institutional Biosafety Committeeapproval must be obtained from eachinstitution that will handle recombinantDNA material that is to be administeredto human subjects.Section rV-B-l-g. Assist and ensure

compliance with the NIH Guidelines byPrincipal Investigators conductingresearch at the institution as specified inSection IV-B-4.Section rV-B-l-h. Ensure appropriate

training for the Institutional BiosafetyCommittee Chair and members.Biological Safety Officer and othercontainment experts (when applicable),Principal Investigators, and laboratorystaff regarding laboratory safety andimplementation of the NIH Guidelines.The Institutional Biosafety CommitteeChair is responsible for ensuring thatInstitutional Biosafety Committeemembers are appropriately trained. ThePrincipal Investigator is responsible forensuring that laboratory staff areappropriately trained. The institution isresponsible for ensuring that thePrincipal Investigator has sufficienttraining; however, this responsibilitymay be delegated to the InstitutionalBiosafety Committee.Section rV-B-l-i. Determine the

necessity for health surveillance ofpersonnel involved in connection withindividual recombinant DNA projects;and ifappropriate, conduct a health

surveillance program for such projects.The institution shall establish andmaintain a health surveillance programfor personnel engaged in large scaleresearch or production activitiesinvolving viable organisms containingrecombinant DNA molecules whichrequire BL3 containment at thelaboratory scale. The institution shallestablish and maintain a healthsurveillance program for personnelengaged in animal research involvingviable recombinant DNA-containingmicroorganisms that :winnifQ BL2orgreater containment in the laboratory.The Laboratory Safety Monographdiscusses various components of such a

program (e.g., records of agents handled,active investigation of relevant illnesses,and the maintenance of serial serumsamples for monitoring sérologiechanges that may result from theemployees' work experience). Certainmedical conditions may place a

laboratoryworker at increased risk inany endeavor where infectious agentsare handled. Examples cited in theLaboratory Safety Monograph includegastrointestinal disorders and treatmentwith steroids, immunosuppressivedrugs, or antibiotics. Workers with suchdisorders or treatment should beevaluated to determine whether theyshould be engaged in research withpotentially hazardous organisms duringtheir treatment or illness. Copies of theLaboratory Safety Monograph areavailable from the Office ofRecombinant DNA Activities, NationalInstitutes of Health/MSC 7010. 6000Executive Boulevard, Suite 302,Bethesda, Maryland 20892-7010, (301)496-9838.Section rV-B-l-j. Report any

significant problems, violations of theNIH Guidelines, or any significantresearch-related accidents and illnessesto NIH/ORDA within thirty days, unlessthe institution determines that a reporthas already been filed by the PrincipalInvestigator or Institutional BiosafetyCommittee. Reports shall be sent to theOffice of Recombinant DNA Activities,National Institutes of Health/MSC 7010,6000 Executive Boulevard, Suite 302,Bethesda. Maryland 20892-7010. (301)496-9838.Section IV-B-2. Institutional BiosafetyCommittee (IBC)The institution shall establish an

Institutional Biosafety Committee whoseresponsibilities need not be restricted torecombinant DNA. The InstitutionalBiosafety Committee shall meet thefollowing requirements:


Federal Register / Vol. 62. No. 31 / Friday, February 14, 1997 / Notices 7115

Section IV-B-2-a. Membership andProcedures

Section IV-B-2-a-(l). TheInstitutional Biosafety Committee mustbe comprised of no fewer than fivemembers so selected that theycollectively have experience andexpertise in recombinant DNAtechnology and the capability to assessthe safety of recombinant DNA researchand to identify any potential risk topublic health or the environment. Atleast two members shall not be affiliatedwith the institution (apart from theirmembership on the InstitutionalBiosafety Committee) and who representthe interest of the surroundingcommunity with respect to health andprotection of the environment (e.g.,officials of state or local public health orenvironmental protection agencies,members of other local governmentalbodies, or persons active in medical,occupational health, or environmentalconcerns in the community). TheInstitutional Biosafety Committee shallinclude at least one individual withexpertise in plant, plant pathogen, orplant pest containment principles whenexperiments utilizing Appendix P,Physical and Biological Containment forRecombinant DNA Research InvolvingPlants, require prior approval by theInstitutional Biosafety Committee. TheInstitutional Biosafety Committee shallinclude at least one scientist withexpertise in animal containmentprinciples when experiments utilizingAppendix Q, Physical and BiologicalContainment for Recombinant DNAResearch Involving Animals, requireInstitutional Biosafety Committee priorapproval. When the institution conductsrecombinant DNA research at BL3. BL4,or Large Scale (greater than 10 liters), aBiological Safety Officer is mandatoryand shall be a member of theInstitutional Biosafety Committee (seeSection rV-B-3, Biological SafetyOfficer). When the institutionparticipates in or sponsors recombinantDNA research involving humansubjects, the institution must ensurethat: (i) The Institutional BiosafetyCommittee has adequate expertise andtraining (using ad hoc consultants asdeemed necessary) and (ii) all aspects ofAppendix M. Points to Consider in theDesign and Submission of Protocols forthe Transfer of Recombinant DNAMolecules into One or More HumanSubjects (Points to Consider), have beenappropriately addressed by thePrincipal Investigator prior tosubmission to NIH/ORDA. InstitutionalBiosafety Committee approval must beobtained from each institution that will

handle recombinant DNA material thatis to be administered to human subjects.Note: Individuals, corporations, and

institutions not otherwise covered by the NIHGuidelines, are encouraged to adhere to thestandards and procedures set forth inSections I through IV (see Section IV-E,Voluntary Compliance. The policy andprocedures for establishing an InstitutionalBiosafety Committee under VoluntaryCompliance, are specified in Section IV-E-2,Institutional Biosafety Committee Approval).Section rV-B-2-a-(2). In order to

ensure the competence necessary toreview and approve recombinant DNAactivities, it is recommended that theInstitutional Biosafety Committee: (i)Include persons with expertise inrecombinant DNA technology.biological safety, and physicalcontainment; (ii) include or haveavailable as consultants personsknowledgeable in institutionalcommitments and policies, applicablelaw, standards of professional conductand practice, community attitudes, andthe environment, and (iii) include atleast one member representing thelaboratory technical staff.Section rV-B-2-a-(3). The institution

shall file an annual reportwith NIH/ORDA which includes: (i) A roster of allInstitutional Biosafety Committeemembers clearly indicating the Chair,contact person. Biological Safety Officer(if applicable), plant expert (ifapplicable), and animal expert (ifapplicable); and (ii) biographicalsketches of all Institutional BiosafetyCommittee members (includingcommunity members).Section IV-B-2-a-(4). No member of

an Institutional Biosafety Committeemay be involved (except to provideinformation requested by theInstitutional Biosafety Committee) inthe review or approval of a project inwhich he/she has been or expects to beengaged or has a direct financialinterest.Section rV-B-2-a-(5). The institution,

that is ultimately responsible for theeffectiveness of the InstitutionalBiosafety Committee, may establishprocedures that the InstitutionalBiosafety Committee shall follow in itsinitial and continuing review andapproval of applications, proposals, andactivities.Sectíon rV-B-2-a-(6). When possible

and consistent with protection ofprivacy and proprietary interests, theinstitution is encouraged to open itsInstitutional Biosafety Committeemeetings to the public.Section TV-B-2-a-P). Upon request,

the institution shall make available tothe public all Institutional BiosafetyCommittee meeting minutes and any

documents submitted to or receivedfrom funding agencies which the latterare required to make available to thepublic. If public comments are made onInstitutional Biosafety Committeeactions, the institution shall forwardboth the public comments and theInstitutional Biosafety Committee'sresponse to the Office of RecombinantDNA Activities. National Institutes ofHealth/MSC 7010. 6000 ExecutiveBoulevard, Suite 302, Bethesda,Maryland 20892-7010, (301) 496-9838.Section ¡V-B-2-b. FunctionsOn behalf of the institution, the

Institutional Biosafety Committee isresponsible for:Section rV-B-2-b-(l). Reviewing

recomoinant DNA research conducted ator sponsored by the institution forcompliance with the NIH Guidelines as

specified in Section III. ExperimentsCovered by the NIH Guidelines, andapproving those research projects thatare found to conform with the NIHGuidelines. This review shall include:(i) Independent assessment of thecontainment levels required by the NIHGuidelines for the proposed research;(ii) assessment of the facilities,procedures, practices, and training andexpertise of personnel involved inrecombinant DNA research; and (iii)ensuring compliance with allsurveillance, data reporting, and adverseevent reporting requirements requiredby the NIH Guidelines.Section IV-B-2-b-(2). Notifying the

Principal Investigator of the results ofthe Institutional Biosafety Committee'sreview and approval.Section rV-B-2-b-(3). Lowering

containment levels for certainexperiments as specified in Section III-C-2-a. Experiments in which DNA fromHuman or Animal Pathogens (RiskGroup 2, Risk Group 3, Risk Group 4, orRestricted Agents is Cloned intoNonpathogenic Prokaryotic or LowerEukaryotic Host-Vector Systems.Section rV-B-2-b-(4). Settingcontainment levels as specified inSections III-C-4-b, ExperimentsInvolvingWhole Animals, and III—C—5.Experiments Involving Whole Plants.Section TV-B-2-b-ß). Periodically

reviewing recombinant DNA researchconducted at the institution to ensurecompliance with the NIH Guidelines.Section rV-B-2-b-(6). Adopting

emergency plans covering accidentalspills and personnel contaminationresulting from recombinant DNAresearch.Note: The Laboratory Safety Monograph

describes basic elements for developingspecific procedures dealing with major spillsof potentially hazardous materials in the


7116 Federal Register / Vol. 62, No. 31 / Friday. February 14. 1997 / Notices

laboratory, including information andreferences about decontamination andemergency plans. The NIH and the Centersfor Disease Control and Prevention areavailable to provide consultation and directassistance, if necessary, as posted in theLaboratory Safety Monograph. Theinstitution shall cooperate with the state andlocal public health departments by reportingany significant research-related illness oraccident that may be hazardous to the publichealth.Section IV-B-2-b-(7). Reporting any

significant problems with or violationsof the NIH Guidelines and anysignificant research-related accidents orillnesses to the appropriate institutionalofficial and NIH/ORDA within 30 days,unless the Institutional BiosafetyCommittee determines that a report hasalready been filed by the PrincipalInvestigator. Reports to NIH/ORDA shallbe sent to the Office of RecombinantDNA Activities, National Institutes ofHealth/MSC 7010. 6000 ExecutiveBoulevard, Suite 302, Bethesda,Man/land 20892-7010, (301) 496-9838.Section IV-B-2-b-(8). The

Institutional Biosafety Committee maynot authorize initiation of experimentswhich are not explicitly covered by theNIH Guidelines until NIH (with theadvice of the RAC when required)establishes the containmentrequirement.Section IV-B-2-b-(9). Performing

such other functions as may bedelegated to the Institutional BiosafetyCommittee under Section IV-B-2,Institutional Biosafety Committee.Section IV-B-3. Biological SafetvOfficer (BSO)Section IV-B-3-a. The institution

shall appoint a Biological Safety Officerif it engages in large scale research or

production activities involving viableorganisms containing recombinant DNAmolecules.Section IV-B-3-b. The institution

shall appoint a Biological Safety Officerif it engages in recombinant DNAresearch at BL3 or BL4. The BiologicalSafety Officer shall be a member of theInstitutional Biosafety Committee.Section IV-B-3-C. The Biological

Safety Officer's duties include, but arenot limited to:Section IV-B-3-c-(l). Periodic

inspections to ensure that laboratorystandards are rigorously followed;Section IV-B-3-c-(2). Reporting to the

Institutional Biosafety Committee andthe institution any significant problems,violations of the NIH Guidelines, andany significant research-relatedaccidents or illnesses of which theBiological Safety Officer becomes awareunless the Biological Safety Officer

determines that a report has alreadybeen filed by the Principal Investigator;Section rv-B-3-c-(3). Developing

emergency plans for handling accidentalspills and personnel contamination andinvestigating laboratory accidentsinvolving recombinant DNA research;Section rV-B-3-c-(4). Providing

advice on laboratory security;Section rV-B-3-c-(5). Providing

technical advice to PrincipalInvestigators and the InstitutionalBiosafety Committee on research safetyprocedures.Note: See the Laboratory Safety Monograph

for additional information on the duties ofthe Biological Safety Officer.Section IV-B-4. Plant, Plant Pathogen,or Plant Pest Containment ExpertWhen the institution conducts

recombinant DNA research that requiresInstitutional Biosafety Committeeapproval in accordance with AppendixP, Physical and Biological Containmentfor Recombinant DNA ResearchInvolving Plants, the institution shallappoint at least one individual withexpertise in plant, plant pathogen, orplant pest containment principles (whois also a member of the InstitutionalBiosafety Committee).Section IV-B-5. Animal ContainmentExpertWhen the institution conducts

recombinant DNA research that requiresInstitutional Biosafety Committeeapproval in accordance with AppendixQ, Physical and Biological Containmentfor Recombinant DNA ResearchInvolving Animals, the institution shallappoint at least one individual withexpertise in animal containmentprinciples (who is also a member of theInstitutional Biosafety Committee).Section rV-B-6. Human Gene TherapyExpertWhen the institution participates in or

sponsors recombinant DNA researchinvolving human subjects, theinstitution must ensure that: (i) TheInstitutional Biosafety Committee hasadequate expertise and training (usingad hoc consultants as deemednecessary) and (ii) all aspects ofAppendix M, Points to Consider in theDesign and Submission of Protocols forthe Transfer ofRecombinant DNAMolecules into One or More HumanSubjects (Points to Consider), have beenappropriately addressed by thePrincipal Investigator prior tosubmission to NIH/ORDA. InstitutionalBiosafety Committee approval must beobtained from each institution that willhandle recombinant DNA material thatis to be administered to human subjects

Section IV-B-7. Principal Investigator(PI)On behalf of the Institution, the

Principal Investigator is responsible forfull compliance with the NIHGuidelines in the conduct ofrecombinant DNA research.Section rV-B-7-a. GeneralResponsibilitiesAs part of this general responsibility,

the Principal Investigator shall:Section TV-B-7-a-(l). Initiate or

modify no recombinant DNA researchwhich requires Institutional BiosafetyCommittee approval prior to initiation{see Sections III-A. ffi-3, ni-C, and III-D. Experiments Covered by the NIHGuidelines) until that research or theproposed modification thereof has beenapproved by the Institutional BiosafetyCommittee and has met all otherrequirements of the NIH Guidelines;Section TV-B-7-a-(2). Determine

whether experiments are covered bySection ITl-D, Experiments that RequireInstitutional Biosafety CommitteeNotice Simultaneous with Initiation,and that the appropriate procedures arefollowed;Section rV-B-7-a-(3). Report any

significant problems, violations of theNIH Guidelines, or any significantresearch-related accidents and illnessesto the Biological Safety Officer (whereapplicable), Greenhouse/AnimalFacility Director (where applicable).Institutional Biosafety Committee, NIH/ORDA. and other appropriateauthorities (if applicable) within 30days. Reports to NIH/ORDA shall besent to the Office of Recombinant DNAActivities, National Institutes of Health/MSC 7010, 6000 Executive Boulevard,Suite 302, Bethesda. Maryland 20892-7010, (301) 496-9838;Section rV-B-7-a-(4). Report any new

information bearing on the NIHGuidelines to the Institutional BiosafetyCommittee and to NIH/ORDA (reports toNIH/ORDA shall be sent to the Office ofRecombinant DNA Activities, NationalInstitutes ofHealth/MSC 7010, 6000Executive Boulevard, Suite 302,Bethesda, Maryland 20892-7010, (301)496-9838);Section rV-B-7-a-(5). Be adequatelytrained in good microbiological

techniques;Section TV-B-7-a-(6). Adhere to

Institutional Biosafety Committee-approved emergency plans for handlingaccidental spills and personnelcontamination; and ,

Section rV-B-7-a-(7). Comply withshipping requirements for recombinantDNA molecules (see Appendix H.Shipment, for shipping requirements


Federal Register / Vol. 62, No. 31 / Friday, February 14, 1997 / Notices 7117

and the Laboratory Safety Monographfor technical recommendations).Section rV-B-7-b. Submissions by thePrincipal Investigator to the NIH/ORDAThe Principal Investigator shall:Section rV-B-7-b-(l). Submit

information to NIH/ORDA forcertification of new host-vector systems;Section rV-B-7-b-(2). Petition NIH/

ORDA, with notice to the InstitutionalBiosafety Committee, for proposedexemptions to the NIH Guidelines;Section rV-B-7-b-(3). Petition NIH/

ORDA, with concurrence of theInstitutional Biosafety Committee, forapproval to conduct experimentsspecified in Sections III—A—1. MajorActions under the NIH Guideiines, andIII-B. Experiments that Require NIH/ORDA and Institutional BiosafetyCommittee Approval Before Initiation;Section rV-B-7-b-(4). Petition NIH/ORDA for determination of containmentfor experiments requiring case-by-casereview; andSection IV-B-7-b-(5). Petition NIH7

ORDA for determination of containmentfor experiments not covered by the NIHGuideiines.Section rV-B-7-b-(6). Ensure that all

aspects of Appendix M, Points toConsider in the Design and Submissionof Protocols for the Transfer ofRecombinant DNA Molecules into Oneor More Human Subjects, have beenappropriately addressed prior tosubmission of human gene therapyexperiments to NIH/ORDA.Section rV-B-7-c. Submissions by thePrincipal Investigator to theInstitutional Biosafety CommitteeThe Principal Investigator shall:Section IV-B-7-c-(l). Make an initial

determination of the required levels ofphysical and biological containment inaccordance with the NIH Guidelines;Section IV-B-7-c-(2). Select

appropriate microbiological practicesand laboratory techniques to be used forthe research;Section IV-B-7-c-(3). Submit the

initial research protocol and anysubsequent changes (e.g., changes in thesource of DNA or host-vector system), ifcovered under Sections III—A, III-B, III-C, or III—D (Experiments Covered by theNIH Guidelines), to the InstitutionalBiosafety Committee for review andapproval or disapproval; andSection rV-B-7-c-(4). Remain in

communication with the InstitutionalBiosafety Committee throughout theconduct of the project.Section IV-B-7-d. Responsibilities ofthe Principal Investigator Prior toInitiating ResearchThe Principal Investigator shall:

Section JTV-B-7-d-(l). Make availableto all laboratory staff the protocols thatdescribe the potential biohazards andthe precautions to be taken;Section rV-B-7-d-(2). Instruct and

train laboratory staff in: (1) The practicesand techniques required to ensuresafety, and (ii) the procedures fordealing with accidents; andSection IV-B-7-d-(3). Inform the

laboratory staff of the reasons andprovisions for any precautionarymedical practices advised or requested(e.g., vaccinations or serum collection).Section rV-B-7-e. Responsibilities ofthe Principal Investigator During theConduct of the ResearchThe Principal Investigator shall:Section rV-B-7-e-(l). Supervise the

safety performance of the laboratorystaff to ensure that the required safetypractices and techniques are employed:Section rV-B-7-e-(2). Investigate and

report any significant problemspertaining to the operation andimplementation of containmentpractices and procedures in writing tothe Biological Safety Officer (whereapplicable), Greenhouse/AnimalFacility Director (where applicable), theInstitutional Biosafety Committee, NIH/ORDA, and other appropriateauthorities (if applicable) (reports to theNIH/ORDA shall be sent to the Office ofRecombinant DNA Activities, NationalInstitutes of Health/MSC 7010, 6000Executive Boulevard, Suite 302,Bethesda, Maryland 20892-7010, (301)496-9838);Section rV-B-7-e-(3). Correct work

errors and conditions that may result inthe release of recombinant DNAmaterials; andSection rV-B-7-e-(4). Ensure the

integrity of the physical containment(e.g., biological safety cabinets) and thebiological containment (e.g., purity andgenotypic and phenotypiccharacteristics).Section rV-B-7-e-(5). Comply with

annual data reporting and adverse eventreporting requirements for human genetransfer experiments (see AppendixM-VII, Reporting Requirements—HumanGene Transfer Protocols).Section rV-C. Responsibilities of theNational Institutes ofHealth (NIH)Section rV-C-1. NIH DirectorThe NIH Director is responsible for: (i)

Establishing the NIH Guidelines, (ii)overseeing their implementation, and(iii) their final interpretation. The NIHDirector has responsibilities under theNIH Guidelines that involve ORDA andthe RAC. ORDA's responsibilities underthe NIH Guidelines are administrative.

Advice from the RAC is primarilyscientific, technical, and ethical. Incertain circumstances, there is specificopportunity for public comment withpublished response prior to final action.Section rV-C-l-a. GeneralResponsibilitiesThe NTH Director is responsible for:Section rV-C-l-a-(l). Promulgating

requirements as necessary to implementthe NIH Guidelines;Section rV-C-l-a-(2). Establishing

and maintaining the RAC to carry outthe responsibilities set forth in SectionrV-C-2, Recombinant DNA AdvisoryCommittee (RAC membership isscecified in its charter and in SectionIV-C-2);Section TV-C-l-a-(3). Establishingand maintaining NTH/ORDA to carry out

the responsibilities defined in SectionIV-C-3, Office ofRecombinant DNAActivities;Section rV-C-l-a-(4). Conducting and

supporting training programs inlaboratory safety for InstitutionalBiosafety Committee members,Biological Safety Officsrs and otherinstitutional experts (if applicable),Principal Investigators, and laboratorystaff.Section rV-C-l-a-(5). Establishing

and convening Gene Therapy PolicyConferences as described in AppendixM, Points to Consider in the Design andSubmission of Protocols for the Transferof Recombinant DNA Molecules intoOne or More Human Subjects.Section rV-C-l-b. SpecificResponsibilitiesIn carrying out the responsibilities set

forth in this section, the NIH Director,or a désignée shall weigh each proposedaction through appropriate analysis andconsultation to determine whether itcomplies with the NIH Guidelines andpresents no significant risk to health orthe environment.Section IV-C-l-b-(l). Major ActionsTo execute Major Actions, the NIH

Director shall seek the advice of theRAC and provide an opportunity forpublic and Federal agency comment.Specifically, the Notice ofMeeting andProposed Actions shall be published inthe Federal Register at least 15 daysbefore the RAC meeting. The NIHDirector's decision/recommendation (athis/her discretion) may be published inthe Federal Register for 15 days ofcomment before final action is taken.The NIH Director's final decision/recommendation, along with responsesto public comments, shall be publishedin the Federal Register. The RAC andInstitutional Biosafety Committee Chairs


7118 Federal Register / Vol. 62. No. 31 / Friday, February 14, 1997 / Notices

shall be notified of the followingdecisions:Section rV-C-l-b-d)-(a). Changing

containment levels for types ofexperiments that are specified in theNIH Guidelines when a Major Action isinvolved;Section rV-C-l-b-(l)-(b). Assigning

containment levels for types ofexperiments that are not explicitlyconsidered in the NIH Guidelines whena Major Action is involved;Section rV-C-I-b-d)-(c).

Promulgating and amending a list ofclasses of recombinant DNA moleculesto be exempt from the NIH Guidelinesbecause they consist entirely of DNAsegments from species that exchangeDNA by known physiological processesor otherwise do not present a significantrisk to health or the environment;Section IV-C-l-b-(l)-(d). Permitting

experiments specified by Section III—A,Experiments that Require InstitutionalBiosafety Committee Approval, RACReview, and NIH Director ApprovalBefore Initiation;Section IV-C-l-b-d)-(e). Certifying

new host-vector systemswith theexception of minor modifications ofalready certified systems (the standardsand procedures for certification aredescribed in Appendix I—II, Certificationof Host-Vector Systems). Minormodifications constitute (e.g., those ofminimal or no consequence to theproperties relevant to containment); andSection IV-C-l-b-(l)-(f). Adopting

other changes in the NIH Guidelines.Section IV-C-l-b-(2). Minor ActionsNIH/ORDA shall carry out certain

functions as delegated to it by the NIHDirector (see Section IV-C-3. Office ofRecombinant DNA Activities). MinorActions (as determined by NIH/ORDAin consultation with the RAC Chair andone or more RAC members, asnecessary) will be transmitted to theRAC and Institutional BiosafetyCommittee Chairs:Section IV-C-l-b-(2)-(a). Changing

containment levels for experiments thatare specified in Section III, ExperimentsCovered by the NIH Guidelines (exceptwhen a Major Action is involved);Section IV-C-l-b-(2)-(b). Assigning

containment levels for experiments notexplicitly considered in the NIHGuidelines;Section TV-C-l-b-(2)-(c). Revising the

Classification of Etiologic Agents for thepurpose of these NIH Guidelines (seeSection V-A. Footnotes and Referencesof Sections I-IV).Section IV-C-l-b-(2)-(d). Interpreting

the NIH Guidelines for experiments towhich the NIH Guidelines do notspecifically assign containment levels;

Section TV-C-l-b-(2)-(e). Settingcontainment under Sections HI-C-1-d,Experiments Using Risk Group 2, RiskGroup 3, Risk Group 4, orRestrictedAgents as Host-Vector Systems, and III—C-2-b, Experiments in which DNA fromRisk Group 2, Risk Group 3, Risk Group4, or Restricted Agents is Cloned intoNonpathogenic Prokaryotic or LowerEukaryotic Host-Vector Systems;Section TV-C-l-b-(2)-(f). Approving

minor modifications of already certifiedhost-vector systems (the standards andprocedures for such modifications aredescribed in Appendix I—II, Certificationof Host-Vector Systems);Section TV-C-l-b-(2)-{g). Decertifying

already certified host-vector systems;Section rV-C-l-b-(2)-(h). Adding

new entries to the list of molecules toxicfor vertebrates (see Appendix F,Containment Conditions for Cloning ofGenes Coding for the Biosynthesis ofMolecules Toxic for Vertebrates); andSection rV-C-l-b-(2)-(i). Determining

appropriate containment conditions forexperiments according to case

precedents developed under Section IV-C-l-b-(2)-(c).Section rV-C-2. Recombinant DNAAdvisory Committee (RAC)The RAC is responsible for carrying

out specified functions cited below aswell as others assigned under its charteror by the DHHS Secretary and the NIHDirector. The RAC consists of 15 votingmembers including the Chair, appointedby the DHHS Secretary or his/herdésignée, at least 8 of whom are selectedfrom authorities knowledgeable in thefields of molecular genetics, molecularbiology, recombinant DNA research, orother scientific fields. At least 4members of the RAC shall be personsknowledgeable in applicable law,standards of professional conduct andpractice, public attitudes, theenvironment, public health,occupational health, or related fields.Representatives from Federal agenciesshall serve as non-voting members.Nominations for the RAC may besubmitted to the Office of RecombinantDNA Activities, National Institutes ofHealth/MSC 7010, 6000 ExecutiveBoulevard, Suite 302, Bethesda,Maryland 20892-7010, (301) 496-9838.All meetings of the RAC shall be

announced in the Federal Register,including tentative agenda items, 15days before the meeting. Final agendas,ifmodified, shall be available at least 72hours before the meeting. No itemdefined as a Major Action under SectionrV-C-l-b-(l) may be added to an

agenda following Federal Registerpublication.The RAC shall be responsible for:

Section rV-C-2-a. Advising the NIHDirector on the following actions: (1)Adopting changes in the NIHGuidelines. (2) Assigning containmentlevels, changing containment levels, andapproving experiments considered as

Major Actions under the NTHGuidelines, i.e.. the deliberate transferof a drug resistance trait tomicroorganisms that are not known toacquire the trait naturally, if suchacquisition could compromise the use ofthe drug to control disease agents inhumans, veterinary medicine, oragriculture. (3) Promulgating andamending lists of classes of recombinantDNA molecules to be exempt from theNIH Guidelines because they consistentirely of DNA segments from speciesthat exchange DNA by knownphysiological processes or otherwise donot present a significant risk to healthor the environment. (4) Certifying newhost-vector systems.Section rV-C-2-b. Identifying novelhuman gene transfer experimentsdeserving of public discussion by thefull RAC;Section TV-C-2-C. Transmitting

specific comments/recommendationsabout: (i) a specific human gene transferexperiment, or (ii) a category of humangene transfer experiments, to the NIHDirector;Section rV-C-2-d. Publicly reviewing

human gene transfer clinical trial dataand relevant information evaluated andsummarized by NIH/ORDA inaccordance with the annual datareporting requirements; andSection rV-C-2-e. Identifying broad

scientific and ethical/social issuesrelevant to gene therapy research as

potential Gene Therapy PolicyConference topics.Section rV-C-2-f. Identifying novel

ethical issues relevant to specific humanapplications of gene transfer andrecommending appropriatemodifications to the Points to Considerthat will provide guidance in thepreparation of relevant InformedConsent documents;Section IV-C-3. Office of RecombinantDNA Activities (ORDA)ORDA shall serve as a focal point for

information on recombinant DNAactivities and provide advice to allwithin and outside NIH includinginstitutions. Biological Safety Officers,Principal Investigators, Federalagencies, state and local governments.and institutions in the private sector.ORDA shall carry out such otherfunctions as may be delegated to it bythe NIH Director. ORDA'sresponsibilities include (but are notlimited to) the following:


Federal Register / Vol. 62, No. 31 / Friday. February 14. 1997 / Notices 7119

Section rV-C-3-a. Serving as the focalpoint for public access to summaryinformation pertaining to human genetransfer experiments;Section rV-C-3-b. Serving as the focal

point for data management of humangene transfer experiments;Section rV-C-3-c. Administering the

annual data reporting requirements (andsubsequent review) for human genetransfer experiments (see AppendixM-VII, Reporting Requirements—HumanGene Transfer Protocols);Section rV-C-3-d. Transmitting

comments/recommendations arisingfrom public RAC discussion ofa novelhuman gene transfer experiment to theNIH Director. RAC recommendationsshall be forwarded to the PrincipalInvestigator, the sponsoring institution,and other Department of Health andHuman Services (DHHS) components,as appropriate.Section rV-C-3-e. Collaborating with

Principal Investigators, InstitutionalBiosafety Committees, InstitutionalReview Boards, and other DHHScomponents (including the FDA andOffice for Protection from ResearchRisks); to ensure human gene transferexperiment registration compliance inaccordance with Appendix M-I,Submission Requirements, Human GeneTransfer Experiments of the NIHGuidelines.Section IV-C-3-f. Administering Gene

Therapy Policy Conferences as deemedappropriate by the NIH Director.Section rV-C-3-g. Reviewing and

approving experiments in conjunctionwith ad hoc experts involving thecloning of genes encoding for toxinmolecules that are lethal for vertebratesat an LD;o of less than or equal to 100nanograms per kilogram body weight inorganisms other than Escherichia coliK-12 (see Section III-B-1, ExperimentsInvolving the Cloning of ToxinMolecules with LD50 of Less than 100Nanograms Per Kilogram Body Weight,Appendix F-I. Containment Conditionsfor Cloning of Genes Coding for theBiosynthesis of Molecules Toxic forVertebrates—General Information, andAppendix F—II. Cloning ofToxinMolecules Genes in Escherichia coli K-12);Section rV-C-3-h. Serving as the

executive secretary of the RAC;Section rV-C-3-i. Publishing in the

Federal Register:Section rV-C-3-i-(l). Announcements

of RAC meetings and tentative agendasat least 15 days in advance (Note—If theagenda for a RAC meeting is modified,ORDA shall make the revised agendaavailable to anyone upon request inadvance of the meeting):

Section TV-C-3-l-(2). Announcementsof Gene Therapy Policy Conferences andtentative agendas at least 15 days inadvance;Section rV-C-3-l-ß). Proposed Major

Actions (see Section rV-C-l-b-(l).Major Actions) at least 15 days prior tothe RAC meeting; andSection rV-C-3-J. Reviewing and

approving the membership of aninstitution's Institutional BiosafetyCommittee, and where it finds theInstitutional Biosafety Committee meetsthe requirements set forth in Section IV-B-2, Institutional Biosafety Committee(IBC). giving its approval to theInstitutional Biosafety Committeemembership.Section IV-C-4. Other NIH ComponentsOther NIH components shall be

responsible for certifying maximumcontainment (BL4) facilities, inspectingthem periodically, and inspecting otherrecombinant DNA facilities as deemednecessary.Section rV-D. Voluntary ComplianceSection rV-D-1. Basic Policy-Voluntary ComplianceIndividuals, corporations, and

institutions not otherwise covered bythe NIH Guidelines are encouraged tofollow the standards and procedures setforth in Sections I through IV. In orderto simplify discussion, referenceshereafter to 'institutions' are intended toencompass corporations and individualswho have no organizational affiliation.For purposes of complying with the NIHGuidelines, an individual intending tocarry out research involvingrecombinant DNA is encouraged toaffiliate with an institution that has anInstitutional Biosafety Committeeapproved under the NIH Guidelines.Since commercial organizations have

special concerns, such as protection ofproprietary data, some modificationsand explanations of the procedures are

provided in Sections rV-E-2 throughrV-E-5-b, Voluntary Compliance, inorder to address these concerns.

Section rV-D-2. Institutional BiosafetyCommittee Approval—VoluntaryComplianceIt should be emphasized that

employment of an InstitutionalBiosafety Committee member solely forpurposes ofmembership on theInstitutional Biosafety Committee doesnot itself make the member aninstitutionally affiliated member. Exceptfor the unaffiliated members, a memberof an Institutional Biosafety Committeefor an institution not otherwise coveredby the NIH Guidelines may participatein the review and approval of a project

in which the member has a directfinancial interest so long as the memberhas not been, and does not expect to be.engaged in the project. Section IV-B-2-a-(4), Institutional Biosafety Committee,is modified to that extent for purposesof these institutions.Section rV-D-3. Certification of Host-Vector Systems—Voluntary ComplianceA host-vector system may be

proposed for certification by the NIHDirector in accordance with theprocedures set forth in Appendix I—II.Certification of Host-Vector Systems. Inorder to ensure protection forproprietary data, any public noticeregarding a host-vector system which isdesignated by the institution as

proprietary under Section IV-D,Voluntary Compliance, will be issuedonly after consultation with theinstitution as to the content of thenotice.Section IV-D-4. Requests forExemptions and Approvals—VoluntaryComplianceRequests for exemptions or other

approvals as required by the NIHGuidelines should be submitted basedon the procedures set forth in SectionsI through IV. In order to ensure

protection for proprietary data, anypublic notice regarding a request for anexemption or other approval which isdesignated by the institution as

proprietary under Section fV-E-5-a,Voluntary Compliance, will be issuedonly after consultation with theinstitution as to the content of thenotice.Section rV-D-5. Protection ofProprietary Data—VoluntaryComplianceSection rV-D-5-a. GeneralIn general, the Freedom of

Information Act requires Federalagencies to make their records availableto the public upon request. However,this requirement does not apply to,among other things, "trade secrets andcommercial or financial informationthat is obtained from a person and thatis privileged or confidential." Under 18U.S.C. 1905, it is a criminal offense foran officer or employee of the U.S. or anyFederal department or agency topublish, divulge, disclose, or makeknown "in any manner or to any extentnot authorized by law any informationcoming to him in the course of hisemployment or official duties or byreason of any examination orInvestigation made by. or return, reportor record made to or filed with, suchdepartment or agency or officer oremployee thereof, which information


7120 Federal Register / Vol. 62, No. 31 / Friday. February 14, 1997 / Notices

concerns or relates to the trade secrets,(or) processes * * * of any person, firm,partnership, corporation, orassociation." This provision applies toall employees of the FederalGovernment, including specialGovernment employees. Members of theRAC are "special Governmentemployees."In submitting to NIH for purposes of

voluntary compliance with the NIHGuidelines, an institution may designatethose items of information which theinstitution believes constitute tradesecrets, privileged, confidential,commercial, or financial information. IfNIH receives a request under theFreedom of Information Act forinformation so designated, NIH willpromptly contact the institution tosecure its views as to whether theinformation (or some portion) should bereleased. If the NIH decides to releasethis information (or some portion) inresponse to a Freedom of Informationrequest or otherwise, the institution willbe advised and the actual release will bedelayed in accordance with 45 Code ofFederal Regulations, section 5.65 (d)and (e).Section IV-D-5-b. PresubmissionReview

Any institution not otherwise coveredby the NIH Guidelines, which isconsidering submission of data orinformation voluntarily to NIH, mayrequest presubmission review of therecords involved to determine if NIHwill make all or part of the recordsavailable upon request under theFreedom of Information Act.A request for presubmission review

should be submitted to NIH/ORDAalong with the records involved to theOffice of Recombinant DNA Activities,National Institutes of Health/MSC 7010,6000 Executive Boulevard, Suite 302,Bethesda. Maryland 20892-7010, (301)496-9838. These records shall be clearlymarked as being the property of theinstitution on loan to NIH solely for thepurpose ofmaking a determinationunder the Freedom on Information Act.NIH/ORDA will seek a determinationfrom the responsible official underDHHS regulations (45 Code of FederalRegulations. Part 5) as to whether therecords involved, (or some portion) willbe made available to members of thepublic under the Freedom ofInformation Act. Pending such adetermination, the records will be keptseparate from NIH/ORDA files, will beconsidered records of the institutionand not NIH/ORDA, and will not bereceived as part of NIH/ORDA files. Nocopies will be made of such records.

NIH/ORDAwill inform the institutionof the DHHS Freedom of InformationOfficer's determination and follow theinstitution's instructions as to whethersome or all of the records involved areto be returned to the institution or tobecome a part ofNIH/ORDA files. If theinstitution instructs NIH/ORDA toreturn the records, no copies orsummaries of the records will be madeor retained by DHHS, NTH, or ORDA.The DHHS Freedom of InformationOfficer's determination will representthat official's judgment at the time of thedetermination as to whether the recordsinvolved (or some portion) would beexempt from disclosure under theFreedom on Information Act if at thetime of the determination the recordswere in NIH/ORDA files and a requestwas received for such files under theFreedom of Information Act.V-E. ProposedAmendments toAppendixA, Exemptions Under Sectionni-E-5—Subüsts ofNatural ExchangesAppendix A, first paragraph, is

proposed to be amended to reflectrenumbering of a previous section.rV-F. Proposed Amendments toAppendix C, Exemptions Under SectionIII-E-6

Appendix C is proposed to beamended to reflect renumbering of aprevious section.

rV-G. Proposed Amendments toAppendix I, Biological ContainmentAfter the first paragraph in Section I-

II-A, Responsibility, the following Noteis proposed to be added:Note. A host-vector system may be

proposed for certification by the NIH Directorin accordance with the procedures set forthin Appendix I—II. Certification of Host-VectorSystems. In order to ensure protection forproprietary data, any public notice regardinga host-vector system which is designated bythe institution as proprietary under SectionrV-D, Voluntary Compliance, will be issuedonly after consultation with the institution asto the content of the notice (see Section IV-D-3. Certification of Host-Vector Systems—Voluntary Compliance).III-H. Proposed Amendments toAppendix M, Points to Consider in theDesign and Submission ofProtocols forthe Transfer ofRecombinant DNAMolecules into One orMore HumanSubjectsAppendix M is proposed to be

amended to read:

Appendix M. The Points To Consider inthe Design and Submission of Protocolsfor the Transfer of Recombinant DNAMolecules into One or More HumanSubjects (Points To Consider)AppendixM applies to research

conducted at or sponsored by aninstitution that receives any support forrecombinant DNA research from theNIH. Researchers not covered by theNIH Guidelines are encouraged to use

Appendix M (see Section I-C, GeneralApplicability).The acceptability of human somaticcell gene therapy has been addressed inseveral public documents as well as innumerous academic studies. InNovember 1982. the President'sCommission for the Study of EthicalProblems in Medicine and 3iomedicaland Behavioral Research published a

report. Splicing Life, which resultedfrom a two-year process of publicdeliberation and hearings. Upon releaseofthat report, a U.S. House ofRepresentatives subcommittee heldthree days of public hearings withwitnesses from a wide range of fieldsfrom the biomédical and social sciencesto theology, philosophy, and law. InDecember 1984, the Office ofTechnology Assessment released a

background paper. Human GeneTherapy, which concluded: civic,religious, scientific, and medical groupshave all accepted, in principle, theappropriateness of gene therapy ofsomatic cells in humans for specificgenetic diseases. Somatic cell genetherapy is seen as an extension ofpresent methods of therapy that mightbe preferable to other technologies. Inlight of this public support, theRecombinant DNA Advisory Committee(RAC) is prepared to consider proposalsfor somatic cell gene transfer.The RAC will not at present entertain

proposals for germ line alterations butwill consider proposals involvingsomatic cell gene transfer. The purposeof somatic cell gene therapy is to treatan individual patient, e.g., by insertinga properly functioning gene into thesubject's somatic cells. Germ linealteration involves a specific attempt tointroduce genetic changes into the germ(reproductive) cells of an individual,with the aim of changing the set ofgenes passed on to the individual'soffspring.In the interest ofmaximizing theresources of both the NIH and the Foodand Drug Administration (FDA) andsimplifying the method and period forreview, research proposals involving thedeliberate transfer of recombinant DNAor DNA or RNA derived fromrecombinant DNA into human subjects


Federal Register / Vol. 62, No. 31 / Friday, February 14. 1997 / Notices 7121

(human gene transfer) will beconsidered through a consolidatedreview process involving both the NIH/ORDA and the FDA. Investigators shallsimultaneously submit their relevantinformation on the proposed humangene transfer experiments to both theNIH/ORDA and the FDA. Submission ofhuman gene transfer protocols to theNIH will be in the format described inAppendix M-I, SubmissionRequirements—Human Gene TransferExperiments, of the NIH Guidelines.Submission to NIH shall be forregistration purposes and will ensurecontinued public access to relevanthuman gene transfer informationconducted in compliance with the NIHGuidelines. Submission of human genetransfer protocols to the FDA will be inthe format described in 21 CFR, ChapterI, Subchapter D, Part 312, Subpart B.Section 23. IND Content and Format.Factors that may contribute to public

discussion of a human gene transferexperiment by the RAC include: (i) Newvectors/new gene delivery systems, (ii)new diseases, (iii) unique applicationsof gene transfer, and (iv) other issuesconsidered to require further publicdiscussion. Among the experiments thatmay be considered exempt from RACdiscussion are those determined not torepresent possible risk to human healthor the environment. Full RAC review ofan individual human gene transferexperiment can be initiated by the NIHDirector or recommended to the NIHDirector by: (i) three or more RACmembers, or (ii) other Federal agencies.An individual human gene transferexperiment that is recommended for fullRAC review should represent novelcharacteristics deserving of publicdiscussion. If the Director, NIH,determines that an experiment willundergo full RAC discussion, NIH/ORDA will immediately notify thePrincipal Investigator. RAC membersmay forward individual requests foradditional information relevant to aspecific protocol through NIH/ORDA tothe Principal Investigator. In making adetermination whether an experiment isnovel, and thus deserving of full RACdiscussion, reviewers will examine thescientific rationale, scientific context(relative to other proposals reviewed bythe RAC), whether the preliminary invitro and in vivo data were obtained inappropriate models and are sufficient,and whether questions related to safety,efficacy, and social/ethical context havebeen resolved. RAC recommendationson a specific human gene transferexperiment shall be forwarded to theNIH Director, the Principal Investigator,the sponsoring institution, and other

Department of Health and HumanServices (DHHS) components, asappropriate. Relevant documentationwill be included in the material for theRAC meeting at which the experiment isscheduled to be discussed. RACmeetings will be open to the publicexcept where trade secrets andproprietary information are reviewed(see Section IV-D-5, Protection ofProprietary Data). The RAC prefers thatinformation provided in response toAppendixM contain no proprietary dataor trade secrets, enabling all aspects ofthe review to be open to the public.Note: Anyapplication submitted toNIH/

ORDA should not be designated as"confidential" in its entirety. In the eventthat a sponsor determines that specificresponses to one or more of the itemsdescribed in AppendixM should beconsidered as proprietary or trade secret,each item should be clearly identified assuch. The cover letter (attached to thesubmitted material) should: (1) Clearlyindicate that select portions of theapplication contain information consideredas proprietary or trade secret, (2) a briefexplanation as to the reason that each ofthese items is determined proprietary ortrade secret.

Public discussion of human genetransfer experiments (and access torelevant information) shall serve toinform the public about the technicalaspects of the proposals, the meaningand significance of the research,significant safety issues, and ethical/societal Implications of the research.RAC discussion is intended to ensuresafe and ethical conduct of gene therapyexperiments and facilitate publicunderstanding of this novel area ofbiomédical research.RAC recommendations on a specific

human gene transfer experiment shallbe forwarded to the NIH Director, thePrincipal Investigator, the sponsoringinstitution, and other Department ofHealth and Human Services (DHHS)components, as appropriate. In itsevaluation of human gene transferproposals, the RACwill considerwhether the design of such experimentsoffers adequate assurance that theirconsequences will not go beyond theirpurpose, which is the same as thetraditional purpose of clinicalinvestigation, namely, to protect thehealth and well being of human subjectsbeing treated while at the same timegathering generalizable knowledge. Twopossible undesirable consequences ofthe transfer of recombinant DNA wouldbe unintentional: (1) Verticaltransmission ofgenetic changes from anindividual to his/her offspring, or (ii)horizontal transmission of viralinfection to other persons with whom

the individual comes in contact.Accordingly, AppendicesM-I throughM-V request information that willenable the RAC. NIH/ORDA, and theFDA. to assess the possibility that theproposed experiment(s) willinadvertentiy affect reproductive cellsor lead to infection of other people (e.g..medical personnel or relatives).In order to enhance the depth andvalue of public discussion relevant toscientific safety, and ethical/societalimplications of gene therapy research,the NTH Directorwill convene GTPC atregular intervals. As appropriate, theNIH Directorwill convene GTPCimmediately following scheduled RACmeetings. GTPC will be administered bythe NIH/ORDA. Conferenceparticipationwill not Involve a standingcommittee membership but rather willoffer the unique advantage ofassembling numerous participants whopossess significant scientific, ethical,and legal expertise and/or interest thatis directly applicable to a specific genetherapy research issue. At least onemember of the RAC will serve as Co-chair of each GTPC and report thefindings of the GTPC to the fullcommittee at its next scheduledmeeting. The RAC representative foreach GTPCwill be chosen based on theparticipant's area of expertise relative tothe specific gene therapy research issueto be discussed. GTPC will haverepresentation from other Federalagencies, including the FDA. GTPCswill focus on broad over-arching policyand scientific issues related to genetherapy research. Proposals for GTPCtopics may be submitted by members ofthe RAC, representatives of academia,industry, patient and consumer

advocacy organizations, other Federalagencies, professional scientificsocieties, and the general public. GTPCtopicswill not be limited to discussionof human applications of gene therapyresearch, i.e., they may include basicresearch on the use of novel genedelivery vehicles, or novel applicationsof gene transfer. The findings of theGTPC will be transmitted to the NIHDirector and will be made publiclyavailable. The NIH Director anticipatesthat this public policy forum will serveas a model for interagencycommunication and collaboration,concentrated expert discussion of novelscientific issues and their potentialsocietal implications, and enhancedopportunity for public discussion ofspecific issues and potential impact ofsuch applications on human health andthe environment.AppendixM will be considered for

revisions as experience in evaluatingproposals accumulates and as new


7122 Federal Register / Vol. 62, No. 31 / Friday, February 14, 1997 / Notices

scientific developments occur. Thisreview will be carried out periodicallyas needed.

AppendixM-I. SubmissionRequirements—Human Gene TransferExperimentsInvestigators must submit the

following material to the Office ofRecombinant DNA Activities, NationalInstitutes of Health/MSC 7010. 6000Executive Boulevard, Suite 302,Bethesda, Maryland 20892-7010, (301)496-9838 (see exemption in AppendixM-VIII-A, Foouiotes ofAppendix M).Proposals to the NIH will be submittedin the following order: (1) Scientificabstract: (2) non-technical abstract: (3)Institutional Biosafety Committee andInstitutional Review Board approvalsand their deliberations pertaining toyour protocol; (4) Responses toAppendixM-II through M-V,Description of the Proposal, InformedConsent, Privacy and Confidentiality,and Special Issues; (5) clinical protocol(as approved by the local InstitutionalBiosafety Committee and InstitutionalReview Board); (6) Informed Consentdocument—approved by theInstitutional Review Board (seeAppendix M-III. Informed Consent); (7)appendices (including tables, figures,and manuscripts); (8) curricula vitae—2pages for each key professional personin biographical sketch format; and (9)two 3'/2-inch diskettes with thecomplete vector nucleotide sequence inASCII format. Investigators must submittheir human gene transfer protocols tothe FDA in the format described in 21CFR. Chapter I, Subchapter D, Part 312,Subpart B, Section 23, IND Content andFormat. Submissions should be sent tothe Division of Congressional andPublic Affairs. Document ControlCenter, HFM-99. Center for BiologiesEvaluation and Research. 1401Rockville Pike. Rockville, Maryland20852-1448.

Appendix M-II. Description of theProposai(This section remains unchanged.)

Appendix M-III. Informed Consent[This section remains unchanged.]

Appendix M-FV. Privacy andConfidentiality[This section remains unchanged.]

Appendix M-V. Special Issues[This section remains unchanged.]

Appendix M-VI. RAC Review—HumanGene Transfer ExperimentsIn order to maintain public access to

information regarding human gene

transfer protocols, NIH/ORDAwillmaintain the documentation describedin AppendicesM-I throughM-V(including protocols that are notreviewed by the RAC). The RAC prefersthat information provided in response toAppendix M. Points to Consider,contain no proprietary data or tradesecrets, enabling all aspects of thediscussion to be open to the public.AppendixM-VI-A. RACMembers '

Written CommentsFollowing receipt by NIH/ORDA,

summary information on each humangene transfer protocol will be forwardedto RAC members. Each RAC membershall notify NIH/ORDA within 15working days regarding the necessity forfull RAC discussion. Full RAC review ofan individual human gene transferexperiment can be initiated by the NTHDirector or recommended to the NIHDirector by: (i) Three or more RACmembers, or (ii) other Federal agencies.An individual human gene transferexperiment that is recommended for fullRAC review should represent novelcharacteristics deserving of publicdiscussion. If the Director, NIH,determines that an experiment willundergo full RAC discussion, NIH/ORDA will immediately notify thePrincipal Investigator. RAC membersmay forward individual requests foradditional information relevant to a

specific protocol through NIH/ORDA tothe Principal Investigator. In making adetermination whether an experiment isnovel, and thus deserving of full RACdiscussion, reviewers will examine thescientific rationale, scientific context(relative to other proposals reviewed bythe RAC), whether the preliminary invitro and in vivo data were obtained inappropriate models and are sufficient,and whether questions related to safety,efficacy, and social/ethical context havebeen resolved. RAC recommendationson a specific human gene transferexperiment shall be forwarded to theNIH Director, the Principal Investigator,the sponsoring institution, and otherDepartment of Health and HumanServices (DHHS) components, asappropriate.AppendixM-VII. ReportingRequirements—Human Gene TransferProtocols

AppendixM-VII-A. Annual DataReportingInvestigators shall comply with the

annual data reporting requirements.Annual Data Report forms will beforwarded by NIH/ORDA toinvestigators. Data submitted in thesereports will be evaluated by the RAC

and NIH/ORDA. and reviewed at afuture RAC meeting.Appendix M-VTI-B. Adverse EventReportingInvestigatorswho have received

approval from the FDA to initiate ahuman gene transfer protocol mustreport any serious adverse eventimmediately to the local InstitutionalReview Board, Institutional BiosafetyCommittee, Office for Protection fromResearch Risks (if applicable). NIH/ORDA, and FDA. followed by thesubmission of a written report filed witheach group. Reports submitted to NTH/ORDA shall be sent to the Office ofReccmbinant DHA. Activities, NationalInstitutes of Health/MSC 7010, 6000Executive Boulevard. Suite 302.Bethesda, Maryland 20892-7010. (301)496-9838.

AppendixM-VIE. Footnotes ofAppendixMAppendixM-VIII-A. Human studies

in which the induction or enhancementof an immune response to a vector-encoded microbial immunogen is themajor goal, such an immune responsehas been demonstrated in modelsystems, and the persistence of thevector-encoded immunogen is notexpected, are exempt from AppendixM-I. Submission Requirements, andAppendix M-VIII, ReportingRequirements-Human Gene TransferExperiments."rv. Addition to Appendix D of the NIHGuidelines Regarding a Human GeneTransfer Protocol/Dr. CrystalIn a letter dated January 8, 1997. Dr.

Ronald Crystal of New York-Hospital-Comell Medical Center, New York, NewYork, submitted a human gene transferprotocol entitled: Immune Response toIntradermal Administration of anAdenovirus Type 5 Gene TransferVector (ADGVCD.10) in NormalIndividuals (NIH Protocol #9701-171) tothe RAC for evaluation regarding thenecessity for RAC review and approval.V. Amendments to Appendix B of theNIH Guidelines RegardingClassification of Human EtiologicAgents on the Basis of HazardIn a letter dated January 21, 1997, Dr.

Diane Fleming, Chair of theSubcommittee on Laboratory Safety,American Society for Microbiology,Washington, D.C, requested thefollowing addition of certain selectagents not previously listed. The letterreads:

* * * Select agents were identified bythe Centers for Disease Control andPrevention as being subject to special


Federal Register / Vol. 62, No. 31 / Friday, February 14. 1997 / Notices 7123

site registration and handlingrequirements under 42 CFR Part 72.Only three of the special agents are notlisted in Appendix B, but they couldnow be added as follows:Appendix B-III-D. Risk Group 3

viruses. AddArenaviruses: Flexaljustification: Flexal is already covered

by 'other viruses listed in the referencesource' but now that it is on the list ofselect agents, it should be listed here aswell.Appendix B-rV-D. Risk Group 4

viruses. AddArenaviruses: SabiaParamyxoviruses: Equine morbilli

virusjustification: As Chairman of the

Subcommittee on Arboviral LaboratorySafety (SALS), Dr. Michael P. Kiley toldme that both Sabia and equine morbillivirus are to be handled under BiosafetyLevel 4 containment. (Dr. Michael P.Kiley, of the Federal Laboratories forHealth Canada and Agriculture andAgri-Food, Winnipeg, Manitoba,Canada, January 21, 1997, personalcommunication regarding the

classification of Sabia and equinemorbilli virus).• * • Recommendations for

corrections and changes to errors inAppendix B which may not require RACreview*• • • Appendix B-Ü-A, pg 1487Acinetobacter baumannii formerly

Acinetobacter calcoaceticus varanitratus is known as the Acinetobactercalcoaceticus-baumannii complex. Wecan add var. anitratus to the A.calcoaceticus.• * • Appendix n-B-rV-D. Remove

erroneous reference to Togaviruses,Group A now associated with theArenaviruses.• » » • »

OMB's "Mandatory InformationRequirements for Federal AssistanceProgram Announcements" (45 FR39592) requires a statement concerningthe official government programscontained in the Catalog of FederalDomestic Assistance. Normally NTH listsin its announcements the number andtitle ofaffected Individual programs forthe guidance of the public. Because theguidance in this notice covers not only

virtually every NIH program but alsoessentially every Federal researchprogram in which DNA recombinantmolecule techniques could be used, ithas been determined to be not costeffective or in the public Interest toattempt to list these programs. Such a

list would likely require severaladditional pages. In addition, NIH couldnot be certain that every Federalprogram would be included as manyFederal agencies, as well as privateorganizations, both national andinternational, have elected to follow theNIH Guidelines. In lieu of theindividual program listing, NIH invitesreaders to direct questions to theinformation address above aboutwhether individual programs listed inthe Catalog of Federal DomesticAssistance are affected.Dated: February 10. 1997.

Lana Skirboll.Associate Director for SciencePolicy,National Institutes ofHealth[FR Doc 97-3735 Filed 2-13-97; 8:45 am]BILLING CODE «140-01-4»

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