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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 of review for human gene

transfer proposals to jointly and

prospectively address global issues on a

regular basis, e.g., ethical consideration

in the implementation of gene 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 a working 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 a motion 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 (in response to Dr.

Varmus' request to establish such a

group); (4) the RAC prefers that any

stipulation requirements should be

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 of a revised Appendix M

and incorporation of minor editorial

changes). The motion was approved by

a vote of 15 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 for concurrence. FDA

legal counsel expressed concern that

implementation of these actions would

require amendment to the FDA

Investigational New Drug Application

Regulations (21 CFR Part 312) to

accommodate the release of proprietary

information. To resolve this concern, a

waiver for release of information from

the FDA to the NIH was proposed.

While the NIH Guidelines could require

such a waiver for NIH-funded

investigators, it would be voluntary for

others submitting proposed human gene

transfer experiments to the FDA. The

NIH expressed concern that failure to

comply with voluntary 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 of human gene therapy

research. As a result of these concerns,

the NIH and FDA agreed on a

compromise proposal that would

accommodate the single submission

format proposed at the July 18-19, 1994,-

meeting of the National Task Force on

AIDS Drug Development, yet maintain

public access to critical information and "real-time" reporting of adverse events.

The compromise proposal involves

simultaneous submission of human

gene transfer protocols to both NIH and

the FDA in a single submission format.

This format includes (but is not limited

to) the documentation described in

Appendices M-I through M-V, of the

NIH Guidelines. NIH/ORDA and the

FDA will simultaneously evaluate the

proposal regarding the necessity for

RAC review.

These revisions to the consolidated

review process were discussed during

the March 6-7, 1995, RAC meeting

(published for public comments in the

Federal Register, February 8, 1995 (60

FR 7630)). The following motions were

made in response to the February 24,

1995, comments submitted by Ms.

Sheryl Osborne of Viagene, Inc., San

Diego, California: (1) A motion 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 should notify the

Director of the Office for Protection from

Research Risks regarding the necessity

for IRB adherence to the detailed

questions contained in Appendices M-II

thiough M-V of the NIH Guidelines

(Informed Consent issues). The

amended motion was approved by a

vote of 17 in favor, 0 opposed, and 1

abstention. (2) A motion was made that

the RAC should continue to review and

approve Phase I follow-up studies, i.e.,

Phase II and Phase III trials. Such

studies may be submitted through the

Accelerated Review process; however,

the RAC retains the option to require

full RAC review. The motion passed by

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

abstentions.

The RAC approved a motion to

approve the proposed amendments to

Sections I, III, IV, V, and Appendices C,

F, G, I, and M of the NIH Guidelines

regarding NIH and FDA consolidated

review of human gene transfer

protocols, by a vote of 18 in favor, 0

opposed, and no abstentions.

The actions are detailed in Section

II-Summary of Actions. I accept these

recommendations, and the NIH

Guidelines will be amended

accordingly.

I. Summary of Actions

A. Amendments to Section I, Scope of

the NIH Guidelines

The amended version of Section I-A,

Purpose, reads:

Section I-A. Purpose

The purpose of the NIH Guidelines 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. Any recombinant 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, or other applicable

clearances, have been obtained from a

Federal agency other than the NIH

(whether the experiment is referred to

that agency by the NIH or sent directly

there by the submitter), the experiment

may proceed without the necessity for

NIH review or approval (see exception

in Section I-A---a).

Section I-A-I-a. In the interest of

maximizing the resources of both the

NIH and the Food and Drug

Administration (FDA) and simplifying

the method and period for review,

research proposals involving the

deliberate transfer of recombinant DNA

or DNA or RNA derived from

recombinant DNA into human subjects

(human gene transfer) will be

considered through a consolidated

review process involving both the NIH

and the FDA. Submission of human

gene transfer proposals will be in the

format described in Appendices M-I

through M-V of the Points to Consider.

Investigators must simultaneously

submit their human gene transfer

proposal to both the NIH and the FDA

in a single submission format. This

format includes (but is not limited to)

the documentation described in

Appendices M-I through M-V, of the

Points to Consider. NIH/ORDA and the

FDA will simultaneously evaluate the

proposal regarding the necessity for

RAC review.

B. Amendments'to Section III,

Experiments Covered by the NIH

Guidelines

The amended version of Section 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

of experiments involving recombinant

DNA: (i) Those that require Institutional

Biosafety Committee (IBC) approval,

RAC review, and NIH Director approval

before initiation (see Section III-A), (ii)

those that require NIH/ORDA and

Institutional Biosafety Committee

approval before initiation (see Section

III-B), (iii) those that require

Institutional Biosafety Committee

approval before 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: If an experiment falls into either

Section 111-A or Section Ill-B and one of the

other categories, the rules pertaining to

Section Il-A or Section III-B shall be

followed. If an experiment falls into Section

Il-E and into either Sections 11--C or III-D

categories as well, the experiment is

considered exempt from the NIH Guidelines.

Any change in containment level,

which is different from those specified

in the NIH Guidelines, may not be

initiated without the express approval

of NIH/ORDA (see Minor Actions,

Section IV-C-1-b-(2) and its

subsections).

The amended version of Section 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

of relevant information on the proposed

-xperiment to the Office of Recombinant

DNA Activities, National Institutes of

Health, Suite 323, 6006 Executive

Boulevard, MSC 7052, Bethesda,

Maryland 20892-7052, (301) 496-9838,

the publication of the 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 stipulation requirements

for such experiments will be

recommended by the RAC and set by

the NIH at the time of approval. 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

of Recombinant DNA Activities,

National Institutes of Health, Suite 323,

6006 Executive Boulevard, MSC 7052,

Bethesda, Maryland 20892-7052, (301)

496-9838.

Section III-A-I-a. The deliberate

transfer of a drug resistance trait to

microorganisms that are not known to

acquire the trait naturally (see Section

V-B), if such acquisition could

compromise the use of the drug to

control disease agents in humans,

veterinary medicine, or agriculture, will

be reviewed 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 (but is not limited to)

the documentation described in

Appendices M-I through M-V, of the

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 for RAC review include: (i)

New vectors/new gene delivery systems,

(ii) new diseases, (iii) unique

applications of gene 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

not to represent possible risk to human

health or the environment (see

Appendix M-VII, Categories of Human

Gene Transfer Experiments that May Be

Exempt from RAC Review). Whenever

possible, investigators will be notified

within 15 working days following

receipt of the submission whether RAC

review will be required. In the event

that NIH/ORDA or the FDA require RAC

review of the submitted proposal, the

documentation described in Appendices

M-I through M-V of the 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

or trade secrets, enabling all aspects of

the review to be open to the public. The

RAC will recommend approval or

disapproval of the 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 Major Action by the NIH

Director.

The amended version of Section IIIB reads:

SectionIII-B. Experiments That Require

NIH/ORDA and Institutional Biosafety

Committee Approval Before Initiation

Section III-B-1. Experiments Involving

the Cloning of Toxin Molecules with

LD50 of Less than 100 Nanograms per

Kilogram Body Weight

Deliberate formation of recombinant

DNA containing genes for the

biosynthesis of toxin molecules lethal

for vertebrates at an LD50 of less than

100 nanograms per kilogram body

weight (e.g., microbial toxins such as

the botulinum toxins, tetanus toxin,

diphtheria toxin, and Shigella

dysenteriae neurotoxin). Specific

approval has been given for the cloning

in Escherichia coli K-12 of DNA

containing genes coding for the

biosynthesis of toxic 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 of Recombinant 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 of relevant 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 of recombinant 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

must be 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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HeinOnline -- 60 Fed. Reg. 20729 1995