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Citation: 60 Fed. Reg. 20728 1995

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### Federal Register / Vol. 60, No. 81 / Thursday, April 27, 1995 / Notices

submissions even if RAC review is not required.

(3) The RAC and FDA will broaden their scope ofreview for human gene transfer proposals tojointly and prospectively address global issues on a regularbasis, e.g., ethical consideration in the implementation ofgene therapy patient registry, access for "orphan" genetic disease patients to therapies, criteria for prenatal gene therapy, and transgenic technology for xenotransplantation.

(4) The RAC, NHI/ORDA, and FDA will establish aworking group to enhance data monitoring efforts.

(5) A RAC, NIHIORDA, and FDA working group will be established to propose long-term consolidation. The working group will have input from public, academic, and corporate

sources.

The RAC approved amotion to (1) accept the FDA proposal submitted by Dr. Noguchi; (2) adopt the Categories for Accelerated Review that were approved by the RAC at its March 3-4, 1994, meeting as guidelines for proposals that will not require RAC review; (3) establish a working group to examine the review process for human gene transfer protocols (inresponse to Dr. Varmus' request to establish such a group); (4) theRAC prefers that any stipulation requirements shouldbe satisfactorily met prior to forwarding its recommendation for approval to the NIH Director; and (5) accept the proposed amendments to the NIH Guidelines to reflect this revised consolidated-review process (including acceptance ofarevised Appendix M and incorporation ofminor editorial changes). The motion was approved by

a vote of15 in favor, 0 opposed, and 1 abstention.

On October 26, 1994, NIH/ORDA forwarded the revised actions to the NIH Director.for approval and the FDA Commissioner forconcurrence. FDA legal counsel expressed concern that implementation ofthese actions would require amendment to the FDA Investigational New Drug Application Regulations (21 CFR Part 312) to accommodate therelease ofproprietary information. To resolve this concern, a waiver for release ofinformation from the FDA to the NIH was proposed. While the NIH Guidelines could require such a waiver for NIH-funded investigators, it would bevoluntary for others submitting proposed human gene transfer experiments to the FDA. The NIH expressed concern that failure to comply withvoluntary waiver procedures may result in the loss of critical information necessary to maintain: (1) The human gene therapy 

### database, (2) "real-time" reporting of serious adverse events, and (3) comprehensive overview (by category) by the RAC in a public forum. Public review and access to submission, review, and follow-up information is critical to the safe and focused advancement ofhuman genetherapy research. As aresult ofthese concerns, the NIH and FDA agreed on a compromise proposal that would accommodate the single submission format proposed atthe July 18-19, 1994,- 

### meeting ofthe National TaskForce on AIDS Drug Development, yetmaintain public access tocritical information and "real-time" reporting ofadverse events. The compromise proposal involves simultaneous submission ofhuman genetransfer protocols to bothNIH and the FDA in a single submission format. This format includes (butis not limited to) the documentation described in Appendices M-Ithrough M-V, ofthe NIH Guidelines. NIH/ORDA and the FDA will simultaneously evaluate the proposal regarding the necessity for RACreview.

These revisions to theconsolidated reviewprocess were discussed during the March 6-7, 1995, RAC meeting (publishedfor public comments in the Federal Register, February 8, 1995 (60 

### FR7630)). The following motions were made inresponse to the February 24, 1995, comments submittedby Ms. Sheryl Osborne ofViagene, Inc., San Diego, California: (1)Amotion to retain the current requirement for obtaining Institutional Review Board (IRB) approval prior to RAC submission. A friendly amendment-was made and accepted that ORDA shouldnotify the Director ofthe Office forProtection from Research Risks regarding the necessity forIRB adherence to the detailed questions contained inAppendices M-II thioughM-V ofthe NIHGuidelines (Informed Consent issues). The amended motion was approved by a vote of 17 in favor, 0 opposed, and 1 abstention. (2) A motionwas made that the RAC should continue to review and approve Phase Ifollow-up studies, i.e., Phase II andPhase III trials. Such studies maybe submitted through the Accelerated Review process; however, the RAC retains the option torequire full RAC review. The motion passedby

a vote of 18 in favor, 0 opposed, and no abstentions.

The RAC approved amotion to approve the proposed amendments to Sections I,III, IV, V, and Appendices C, F, G,I,and M ofthe NIH Guidelines regarding NIH and FDA consolidated review ofhuman gene transfer protocols, by avote of 18 in favor, 0 opposed, and no abstentions. The actions are detailed in Section II-Summary ofActions. Iaccept these recommendations, and the NIH Guidelines willbe amended accordingly.

I. Summary ofActions

A. Amendments to SectionI,Scopeof theNIH Guidelines

The amended version ofSection I-A, Purpose, reads:
Section I-A. Purpose

The purpose ofthe NIHGuidelines is to specify practices for constructing and handling: (i)Recombinant deoxyribonucleic acid (DNA) molecules, and (ii) organisms and viruses containing recombinant DNA molecules.

Section I-A-1. Anyrecombinant DNA experiment, which according to the NIH Guidelines requires approval by the NIH, must be submitted to the NIH or to another Federal agency that has jurisdiction for review and approval. Once approvals, orother applicable clearances, have been obtained from a Federal agency other than the NIH (whetherthe experiment isreferred to that agency bythe NIH or sent directly thereby the submitter), the experiment mayproceed without the necessity for NIH review or approval (see exception in Section I-A---a).

Section I-A-I-a. Inthe interest of maximizing the resources ofboth the NIH and the Food and Drug Administration (FDA) and simplifying the method and period forreview, research proposals involving the deliberate transfer ofrecombinant DNA

or DNA orRNA derived from recombinant DNA into human subjects (humangene transfer)willbe considered through a consolidated review process involving boththe NIH and the FDA. Submission ofhuman gene transfer proposalswillbe in the format described in Appendices M-I through M-V ofthe Points to Consider. Investigators must simultaneously submit their human gene transfer proposal toboth the NIH and the FDA in a single submission format. This format includes (butis notlimited to) the documentation described in Appendices M-I throughM-V, ofthe Points to Consider.NIH/ORDA and the FDA will simultaneously evaluate the proposal regarding the necessity for RAC review.

B.Amendments'to SectionIII, ExperimentsCoveredby theNIH Guidelines

The amended version ofSection I beginning paragraphs reads: 20728 '

HeinOnline -- 60 Fed. Reg. 20728 1995

### Federal Register / Vol. 60, No. 81 / Thursday, April 27, 1995 / Notices

This section describes five categories ofexperiments involving recombinant DNA: (i) Those that require Institutional Biosafety Committee (IBC) approval, RACreview, and NIH Director approval before initiation (see Section III-A), (ii) those that requireNIH/ORDA and Institutional Biosafety Committee approval before initiation (see Section III-B), (iii) those thatrequire Institutional Biosafety Committee approvalbefore initiation (see Section III-C), (iv)those that require Institutional Biosafety Committee notification simultaneous with initiation (see Section Ill-D), and (v) those that are exempt from the NIH Guidelines (see Section III-E).

Note: Ifan experiment falls into either Section 111-A or Section Ill-B and one ofthe other categories, therules pertaining to Section 

### Il-A orSection III-B shall be followed. If anexperiment falls into Section Il-E and into either Sections 11--C orIII-D categories as well,the experiment is considered exempt from theNIH Guidelines.

Any change in containment level, which is different from those specified in the NIH Guidelines, may notbe initiated without the express approval of NIH/ORDA (see MinorActions, Section IV-C-1-b-(2) and its subsections).

The amended version ofSection IIIA reads: Section III-A. Experiments that Require Institutional Biosafety Committee Approval, RAC Review; and NIH Director Approval Before Initiation (see Section IV--C-1-b-(1)).

Section III-A-1. Major Actions Under the NIH Guidelines

Experiments considered as Major Actions under the NIH Guidelines

cannot be initiated without submission ofrelevant information on the proposed -xperiment to the Office ofRecombinant DNA Activities, National Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda, Maryland 20892-7052, (301) 496-9838, the publication ofthe proposal in the Federal Register for 15 days of comment, review by the RAC, and specific approval by the NIH (see Appendix M for submission requirements on human gene transfer experiments). The containment conditions or stipulationrequirements for such experiments will be recommended by the RAC and set by the NIH atthe time ofapproval. Such experiments require Institutional Biosafety Committee approval before initiation. Specific experiments already approved are included in Appendix D which i- ay be obtained from the Office ofRecombinant DNA Activities, National Institutes ofHealth, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda, Maryland 20892-7052, (301) 496-9838.

Section III-A-I-a. The deliberate transfer of adrug resistance trait to microorganisms that are not known to acquire thetrait naturally (see Section V-B), ifsuch acquisition could compromise the use ofthe drug to control disease agents in humans, veterinary medicine, or agriculture, will bereviewed by the RAC.

Section III-A-2. Human Gene Transfer Experiments

Investigators must simultaneously submit their human gene transfer proposal to both the NIH and the FDA in a single submission format. This format includes (butis not limited to) the documentation described in Appendices M-I through M-V, ofthe Points to Consider. The NIH/ORDA and the FDA will simultaneously evaluate the proposal regarding the necessity for RAC review.

Factors that may contribute to the necessity forRAC review include: (i) New vectors/new gene delivery systems, (ii)new diseases, (iii)unique applications ofgene transfer, and (iv) other issues considered to require further public discussion. Among the experiments that may be considered exempt from RAC review are those determined by the NIH/ORDA and FDA
notto represent possible riskto human health orthe environment (see Appendix M-VII, Categories ofHuman Gene Transfer Experiments that May Be Exempt from RAC Review). Whenever possible, investigators will be notified within 15 working days following receipt ofthe submission whether RAC review will be required. In the event that NIH/ORDA orthe FDA require RAC review ofthe submitted proposal, the documentation described in Appendices M-I through M-V ofthe Points to Consider, will be forwarded to the RAC primary reviewers for evaluation. RAC meetings will be open to the public except where trade secrets and proprietary information are reviewed. The RAC and FDA prefer that information provided in response to Appendix M contain no proprietary data

ortrade secrets, enabling all aspects of the review to be open to the public. The RAC will recommend approval or disapproval ofthe reviewed proposal to the NIH Director. In the event that a proposal is contingently approved by the RAC, the RAC prefers that the conditions be satisfactorily met before the RAC's recommendation for approval is submitted to the NIH Director. The NIH Director's decision on the submitted proposal will be transmitted

to the FDA Commissioner and considered as a MajorAction by the NIH Director.

The amended version ofSection IIIB reads:

SectionIII-B. Experiments That Require NIH/ORDA and Institutional Biosafety Committee Approval Before Initiation

Section III-B-1. Experiments Involving the Cloning ofToxin Molecules with LD50 ofLess than 100 Nanograms per Kilogram Body Weight

Deliberate formation ofrecombinant DNA containing genes for the biosynthesis oftoxin molecules lethal for vertebrates at an LD 50 ofless than 100 nanograms per kilogram body weight (e.g., microbial toxins such as thebotulinum toxins, tetanus toxin, diphtheria toxin, and Shigella dysenteriae neurotoxin). Specific approval has been given for the cloning inEscherichia coli K-12 ofDNA containing genes coding for the biosynthesis oftoxic molecules which

are lethal to vertebrates at 100
nanograms to 100 micrograms per kilogram body weight. Specific experiments already approved under this section may be obtained from the Office ofRecombinant DNA Activities, National Institutes of Health, Suite 323, 6006 Executive Boulevard, MSC 7052, Bethesda, Maryland 20892-7052, (301) 496-9838.

Section III-B-l-(a). Experiments in this category cannQt be initiated without submission ofrelevant information on the proposed experiment to NIH/ORDA. The containment conditions for such experiments will be determined by NIH/ ORDA in consultation with ad hoc experts. Such experiments require Institutional Biosafety Committee approval before initiation (see Section IV-B-2-b-(1)).

The following section, Section III-C7, is deleted:

Section III-C-7. Human Gene Transfer Experiments Not Covered by Sections III-A-2, III-B-2, III-B-3, and Not Considered Exempt under Section V-U

Certain experiments involving the transfer ofrecombinant DNA or DNA or RNA derived from recombinant DNA into one or more human subjects that

are not covered by Sections III-A-2, IIIB-2, III-B-3, and that are not considered exempt under Section V-U
mustbe registered with NIH/ORDA. Tne relevant Institutional Biosafety Committee and Institutional Review Board must review and approve all experiments in this category prior to their initiation. 

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