Federal Register / Vol. 62, No. 161 / Wednesday, August 20, 1997 / Notices 44387

Dated: August 11, 1997.

LaVerne Y. Stringfield,

Committee Management Officer, NIH.

[FR Doc. 97–22029 Filed 8–19–97; 8:45 am]

BILLING CODE 4140–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Recombinant DNA Research:

Proposed Actions Under the

Guidelines

AGENCY: National Institutes of Health

(NIH), PHS, DHHS.

ACTION: Notice of Proposed Actions

Under the NIH Guidelines for Research

Involving Recombinant DNA Molecules

(NIH Guidelines).

SUMMARY: This notice sets forth

proposed actions to be taken under the

NIH Guidelines for Research Involving

Recombinant DNA Molecules (59 FR

34496, amended 59 FR 40170, 60 FR

20726, 61 FR 1482, 61 FR 10004, 62 FR

4782). Interested parties are invited to

submit comments concerning these

proposals. These proposals will be

considered by the Recombinant DNA

Advisory Committee (RAC) at its

meeting on September 12, 1997. After

consideration of these proposals and

comments by the RAC, the NIH Director

will issue decisions in accordance with

the NIH Guidelines.

DATES: Interested parties are invited to

submit comments concerning this

proposal. Comments received by

September 5, 1997, will be reproduced

and distributed to the RAC for

consideration at its September 12, 1997,

meeting. After consideration of this

proposal and comments by the RAC, the

NIH Director will issue decisions in

accordance with the NIH Guidelines.

ADDRESSES: Written comments and

recommendations should be submitted

to Debra Knorr, Office of Recombinant

DNA Activities, National Institutes of

Health, MSC 7010, 6000 Executive

Boulevard, Suite 302, Bethesda,

Maryland 20892–7010, Phone 301–496–

9838, FAX 301–496–9839.

All comments received in response to

this notice will be considered and will

be available for public inspection in the

above office on weekdays between the

hours of 8:30 a.m. and 5:00 p.m.

FOR FURTHER INFORMATION CONTACT:

Background documentation and

additional information can be obtained

from the Office of Recombinant DNA

Activities, National Institutes of Health,

MSC 7010, 6000 Executive Boulevard,

Suite 302, Bethesda, Maryland 20892–

7010, Phone 301–496–9838, FAX 301–

496–9839. The Office of Recombinant

DNA Activities web site is located at

Http://www.nih.gov/od/orda for further

information about the office.

SUPPLEMENTARY INFORMATION: The NIH

will consider the following actions

under the NIH Guidelines for Research

Involving Recombinant DNA Molecules

(NIH Guidelines):

A. Amendment to the Submission

Requirements—Human Gene Transfer

Experiments Under Appendix M of the

NIH Guidelines

During the June 12–13, 1997, RAC

meeting, the following motions were

approved by the Committee:

(1) A motion was made to eliminate

the point-by-point responses to

Appendix M–II, Description of the

Proposal; however, the questions raised

in Appendix M–II must be addressed in

the clinical protocol. The motion passed

by a vote of 8 in favor, 0 opposed, and

1 abstention.

(2) A motion was made that the RAC

should not review any gene transfer

protocol until the investigator has

provided ORDA with evidence of

protocol submission to the Institutional

Biosafety Committee (IBC). IBC

notification is needed in order to avoid

the circumstances in which the RAC

might review a protocol that has not

been submitted to the IBC. The motion

passed by a vote of 8 in favor, 1

opposed, and no abstentions.

(3) A motion was made to delete prior

IBC and Institutional Review Board

(IRB) approvals, responses to Appendix

M–II through M–V, and vector sequence

diskettes from Appendix M–I,

Submission Requirements—Human

Gene Transfer Experiments. The RAC

accepted the submission requirements

as follows:

‘‘Appendix M–I, Submission

Requirements—Human Gene Transfer

Experiments’’

‘‘Investigators must submit the

following material to the Office of

Recombinant DNA Activities, National

Institutes of Health/MSC 7010, 6000

Executive Boulevard, Suite 302,

Bethesda, Maryland 20892–7010, 301–

496–9838 (see exemption in Appendix

M–IX–A, Footnotes of Appendix M).

Proposals will be submitted in the

following order: (1) Scientific abstract;

(2) non-technical abstract; (3) protocol

(including discussion of issues in

Appendix M–II through M–V); (4)

Informed Consent document prepared

for IRB submission (see Appendix M–

III, Informed Consent); (5) letter stating

that submission has been made to the

IBC; (6) appendices (including tables,

figures, and manuscripts); and (7)

curricula vitae for each key professional

person in biographical sketch format.’’

The motion passed by a vote of 7 in

favor, 0 opposed, and 1 abstention.

B. Amendment to Institutional

Biosafety Committee (IBC) Approvals of

Experiments Involving Transgenic

Rodents Under Section III of the NIH

Guidelines

Section III–C–4, Experiments

Involving Whole Animals, of the NIH

Guidelines stipulates that all transgenic

animal experiments are subject to IBC

approval before initiation. In

correspondence dated April 22, 1997,

Dr. George Gutman, an IBC

representative of the University of

California, Irvine, California, inquired

whether experiments involving the

production or use of transgenic mice

under Biosafety Level 1 containment

could be initiated simultaneously with

IBC notification. Current requirements

under the NIH Guidelines require that

IBC approval be obtained prior to

initiation of such experiments. The RAC

discussed this issue during its June 1997

meeting, recommending that this

requirement be changed to initiation

simultaneous with IBC notification. The

RAC agreed that the requirement of IBC

approval prior to initiation is

unnecessary and recommended that the

NIH Guidelines should be amended

such that: (1) The generation of

transgenic rodents at the Biosafety Level

1 containment (not all animals) can be

initiated simultaneous with IBC

notification, and (2) the purchase and

use of transgenic rodents should be

exempt from the NIH Guidelines.

A motion was made that these

proposed changes to the NIH Guidelines

should be published in the Federal

Register for consideration at the

September 12, 1997, RAC meeting. The

proposed action would allow: (1) The

generation of transgenic rodents that

require Biosafety Level 1 containment to

be included under Section III–D,

Experiments that Require IBC Notice

Simultaneous with Initiation; and (2)

the purchase and use of transgenic

rodents should be exempt from the NIH

Guidelines. The motion passed by a vote

of 9 in favor, 0 opposed, and no

abstentions.

C. The Dissociation of Simultaneous

Submission of Responses to Appendix

M of the NIH Guidelines to NIH/ORDA

and the Food and Drug Administration

(FDA)

In a letter dated November 20, 1996,

Dr. Andra Miller, Food and Drug

Administration, requested that the NIH

Guidelines should be amended
44388 Federal Register / Vol. 62, No. 161 / Wednesday, August 20, 1997 / Notices

regarding procedures for simultaneous

submission of Appendix M material to

the RAC and FDA. In her November 20,

1996, letter, Dr. Miller states:

‘‘* * * To remove the requirement for

submission of Appendix M to the FDA.

The FDA does not accept Appendix M

in place of an IND submission. The FDA

is not proposed to be and need not be

included in the decision making process

to identify protocols to undergo full

RAC review. Therefore, there is no

reason for sponsors to submit Appendix

M materials to the FDA.’’

During its December 9, 1996, and

March 6–7, 1997, meetings, the RAC

discussed this issue. The consensus of

the RAC was that the requirement for

submission of responses of Appendix M

to the FDA should be removed, since

FDA does not accept responses to

Appendix M in place of an

Investigational New Drug (IND)

application. However, the RAC stated

that all human gene transfer protocols

should include discussion of issues

raised in Appendix M–II through M–V

of the NIH Guidelines in the clinical

protocols.

The NIH will consider the following

proposed actions under the NIH

Guidelines:

A. Proposed Amendments to Section I–

A. Purpose

Section I–A–1–a is proposed to be

amended to read:

‘‘Section I–A–1–a’’

‘‘Section I–A–1–a. Experiments

involving the deliberate transfer of

recombinant DNA or DNA or RNA

derived from recombinant DNA into

human subjects (human gene transfer)

cannot be initiated without submission

to NIH/ORDA of such information on

the proposed experiment as is

prescribed by this agency. Submission

of human gene transfer protocols to the

NIH will be in the format described in

Appendix M–I, Submission

Requirements—Human Gene Transfer

Experiments, of the NIH Guidelines.

Submission to NIH shall be for

registration purposes, a determination

regarding the necessity for full RAC

discussion, and to ensure continued

public access to relevant human gene

transfer information conducted in

compliance with the NIH Guidelines.’’

B. Proposed Amendments to 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), Major

Actions)

Section III–A–2 is proposed to be

amended to read:

‘‘Section III–A–2. Human Gene Transfer

Experiments’’

‘‘Investigators must submit their

human gene transfer proposal to the

NIH in a single submission format. This

format includes (but is not limited to)

the documentation described in

Appendix M–I, Submission

Requirements—Human Gene Transfer

Experiments. The NIH/ORDA in

consultation with the RAC, will

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 RAC and the NIH/

ORDA 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 the RAC requires review of the

submitted proposal, all documentation

described in Appendix M–I, Submission

Requirements—Human Gene Transfer

Experiments, 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 prefers that information

provided in the submission

documentation 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

conditions must 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

considered as a Major Action by the NIH

Director.

‘‘Note: For specific directives concerning

the use of retroviral vectors for gene delivery,

consult Appendix B–V–1, Murine Retroviral

Vectors.’’

C. Proposed Amendments to Section

III–C–4. Experiments Involving Whole

Animals

(Section III–C are experiments that

require Institutional Biosafety

Committee approval before initiation.)

Section III–C–4–c is proposed to be

amended to read:

‘‘Section III–C–4–c. Exceptions under

Section III–C–4.

‘‘Section III–C–4–c–(1). Experiments

involving the generation of transgenic

rodents that require BL1 containment

are described under Section III–D–3,

Experiments Involving Transgenic

Rodents.

‘‘Section III–C–4–c–(2). The purchase

and use of transgenic rodents is exempt

from the NIH Guidelines under Section

III–E, Exempt Experiments (see

Appendix C–VI, The Purchase and Use

of Transgenic Rodents).’’

D. Proposed Amendments to Section

III–D. Experiments That Require

Institutional Biosafety Committee

Notice Simultaneous With Initiation

Section III–D–3 is proposed to be

amended to read:

‘‘Section III–D–3. Experiments Involving

Transgenic Rodent’’

‘‘This section covers experiments

involving the generation of rodents in

which the animal’s genome has been

altered by stable introduction of

recombinant DNA, or DNA derived

therefrom, into the germ-line (transgenic

rodents). Only experiments that require

BL1 containment are covered under this

section; experiments that require BL2.

BL3, or BL4 containment are covered

under Section III–C–4, Experiments

Involving Whole Animals.’’

E. Section IV–C–1–b–(1)–(e).

Responsibilities of the NIH Director

Section IV–C–1–b–(1)–(e) is proposed

to be deleted.

‘‘Section IV–C–1–b–(1)–(e).

Recommendations made by the NIH

Director to the FDA Commissioner

regarding RAC reviewed human gene

transfer experiments (see Appendix M–

III–E, RAC Recommendations to the NIH

Director;’’

(The rest of Section IV–C–b–(1) will

be renumbered.)

F. Proposed Amendments to Appendix

C, Exemptions Under Section III–E–6

A new section, Appendix C–VI, is

proposed to read:
Federal Register / Vol. 62, No. 161 / Wednesday, August 20, 1997 / Notices 44389

‘‘Appendix C–VI. The Purchase and Use

of Transgenic Rodents’’

‘‘The purchase and use of transgenic

rodents for experiments that require BL1

containment are exempt from the NIH

Guidelines.’’

(The old Appendix C–VI, Footnotes

and References of Appendix C, will be

renumbered to Appendix C–VII through

Appendix C–VII–E.)

G. Proposed Amendments to Appendix

M, The Points to Consider in the Design

and Submission of Protocols for the

Transfer of Recombinant DNA

Molecules Into the Genome of One or

More Human Subjects (Points to

Consider)

The preamble of Appendix M is

proposed to be amended to read:

‘‘Appendix M applies to research

conducted at or sponsored by an

institution that receives any support for

recombinant DNA research from the

NIH. Researchers not covered by the

NIH Guidelines are encouraged to use

Appendix M.

‘‘The acceptability of human somatic

cell gene therapy has been addressed in

several public documents as well as in

numerous academic studies. In

November 1982, the President’s

Commission for the Study of Ethical

Problems in Medicine and Biomedical

and Behavioral Research published a

report, Splicing Life, which resulted

from a two-year process of public

deliberation and hearings. Upon release

of that report, a U.S. House of

Representatives subcommittee held

three days of public hearings with

witnesses from a wide range of fields

from the biomedical and social sciences

to theology, philosophy, and law. In

December 1984, the Office of

Technology Assessment released a

background paper, Human Gene

Therapy, which concluded: civic,

religious, scientific, and medical groups

have all accepted, in principle, the

appropriateness of gene therapy of

somatic cells in humans for specific

genetic diseases. Somatic cell gene

therapy is seen as an extension of

present methods of therapy that might

be preferable to other technologies. In

light of this public support, the

Recombinant DNA Advisory Committee

(RAC) is prepared to consider proposals

for somatic cell gene transfer.

‘‘The RAC will not at present

entertain proposals for germ line

alterations but will consider proposals

involving somatic cell gene transfer. The

purpose of somatic cell gene therapy is

to treat an individual patient, e.g., by

inserting a properly functioning gene

into the subject’s somatic cells. Germ

line alteration involves a specific

attempt to introduce genetic changes

into the germ (reproductive) cells of an

individual, with the aim of changing the

set of genes passed on to the

individual’s offspring.

‘‘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 review process

involving both the NIH/ORDA and the

RAC. Public review of human gene

transfer protocols will serve to inform

the public about the technical aspects of

the proposals as well as the meaning

and significance of the research.

Investigators must submit human gene

transfer protocols to the NIH/ORDA in

the format described in Appendix M–I.

Submission Requirements—Human

Gene Transfer Experiments. NIH/ORDA

and the RAC will 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 RAC and the NIH/

ORDA 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 and the RAC require

RAC review of the submitted proposal,

the documentation described in

Appendix M–I. Submission

Requirements—Human Gene Transfer

Experiments, 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 prefers that information

provided in the submission

documentation contains 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

conditions must 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

considered as a Major Action by the NIH

Director.

‘‘Public review of human gene

transfer proposals will serve to inform

the public about the technical aspects of

the proposals as well as the meaning

and significance of the research.

‘‘In its evaluation of human gene

transfer proposals, the RAC and NIH/

ORDA will consider whether the design

of such experiments offers adequate

assurance that their consequences will

not go beyond their purpose, which is

the same as the traditional purpose of

clinical investigation, namely, to protect

the health and well being of human

subjects being treated while at the same

time gathering generalizable knowledge.

Two possible undesirable consequences

of the transfer of recombinant DNA

would be unintentional: (i) Vertical

transmission of genetic changes from an

individual to his/her offspring, or (ii)

horizontal transmission of viral

infection to other persons with whom

the individual comes in contact.

Accordingly, Appendices M–I through

M–V requests information that will

enable the RAC and NIH/ORDA to

assess the possibility that the proposed

experiment(s) will inadvertently affect

reproductive cells or lead to infection of

other people (e.g., medical personnel or

relatives).

‘‘In recognition of the social concern

that surrounds the subject of human

gene transfer, the RAC and NIH/ORDA

will cooperate with other groups in

assessing the possible long-term

consequences of the proposal and

related laboratory and animal

experiments in order to define

appropriate human applications of this

emerging technology.

‘‘Appendix M will be considered for

revisions as experience in evaluating

proposals accumulates and as new

scientific developments occur. This

review will be carried out periodically

as needed.’’

Appendix M–I is proposed to be

amended to read:

‘‘Appendix M–I. Submission

Requirements—Human Gene Transfer

Proposals’’

‘‘Investigators must submit the

following material to the Office of

Recombinant DNA Activities, National

Institutes of Health/MSC 7010, 6000

Executive Boulevard, Suite 302,

Bethesda, Maryland 20892–7010, 301–

496–9838 (see exemption in Appendix

M–IX–A, Footnotes of Appendix M).

Proposals will be submitted in the

following order: (1) Scientific abstract;

(2) non-technical abstract; (3) clinical

protocol (including discussion of all

issues raised in Appendix M–II through
44390 Federal Register / Vol. 62, No. 161 / Wednesday, August 20, 1997 / Notices

M–V); (4) Informed Consent document

prepared for IRB submission (see

Appendix M–III, Informed Consent); (5)

letter stating that submission has been

made to the IBC; (6) appendices

(including tables, figures, and

manuscripts); and (7) curricula vitae for

each key professional person in

biographical sketch format.

‘‘Note: Final IBC and IRB approvals should

be submitted to NIH/ORDA upon receipt of

the following: (1) NIH notification of

exemption from full RAC discussion, or (2)

subsequent to full RAC discussion (if

applicable). Human gene transfer protocols

shall not be initiated prior to submission of

final IBC and IRB approvals to the NIH/

ORDA.’’

Appendix M–VI–A is proposed to be

amended to read:

‘‘Appendix M–VI–A. Categories of

Human Gene Transfer Experiments

That Require RAC Review’’

‘‘Factors that may contribute to the

necessity for RAC review include, but

are not limited to: (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.

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 RAC review is deemed

necessary by the NIH and the RAC, the

proposal will be forwarded to the RAC

primary reviewers for evaluation. In

order to maintain public access to

information regarding human gene

transfer protocols, NIH/ORDA will

maintain the documentation described

in Appendix M–I (including protocols

that are not reviewed by the RAC).’’

Appendix M–VI–B is proposed to be

amended to read:

‘‘Appendix M–VI–B. RAC Primary

Reviewers’ Written Comments’’

‘‘In the event that NIH/ORDA or the

RAC recommends RAC review of the

submitted proposal, the documentation

described in Appendix M–I will be

forwarded to the RAC primary reviewers

for evaluation.’’

Appendix M–VI–E is proposed to be

amended to read:

‘‘Appendix M–VI–E. RAC

Recommendations to the NIH Director’’

‘‘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 considered

as a Major Action by the NIH Director.’’

Appendix M–VII is proposed to be

amended to read:

‘‘Appendix M–VII. Categories of Human

Gene Transfer Experiments That May Be

Exempt from RAC Review’’

‘‘A proposal submitted under one of

the following categories may be

considered exempt from RAC review

unless otherwise determined by NIH/

ORDA and the RAC on a case-by-case

basis (see Appendix M–VI–A, Categories

of Human Gene Transfer Experiments

that Require RAC Review).

Note: For proposals that are exempt from

RAC review, the documentation described in

Appendix M–I will be maintained by NIH/

ORDA for compliance with annual data

reporting and adverse event reporting

requirements (see Appendix M–VIII,

Reporting Requirements—Human Gene

Transfer Protocols). Any subsequent

modifications to proposals that were not

reviewed by the RAC must be submitted to

NIH/ORDA in order to facilitate data

reporting requirements.’’

OMB’s ‘‘Mandatory Information

Requirements for Federal Assistance

Program Announcements’’ (45 FR

39592) requires a statement concerning

the official government programs

contained in the Catalog of Federal

Domestic Assistance. Normally NIH lists

in its announcements the number and

title of affected individual programs for

the guidance of the public. Because the

guidance in this notice covers not only

virtually every NIH program but also

essentially every Federal research

program in which DNA recombinant

molecule techniques could be used, it

has been determined to be not cost

effective or in the public interest to

attempt to list these programs. Such a

list would likely require several

additional pages. In addition, NIH could

not be certain that every Federal

program would be included as many

Federal agencies, as well as private

organizations, both national and

international, have elected to follow the

NIH Guidelines. In lieu of the

individual program listing, NIH invites

readers to direct questions to the

information address above about

whether individual programs listed in

the Catalog of Federal Domestic

Assistance are affected.

Dated: August 4, 1997.

Lana R. Skirboll,

Associate Director for Science Policy,

National Institutes of Health.

[FR Doc. 97–22030 Filed 8–19–97; 8:45 am]

BILLING CODE 4140–01–P