59032 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Recombinant DNA Research: Actions

Under the Guidelines

AGENCY: Notice of Actions Under the

NIH Guidelines for Research Involving

Recombinant DNA Molecules (NIH

Guidelines) (59 FR 34496, amended 59

FR 40170, 60 FR 20726, 61 FR 1482, 61

FR 10004, 62 FR 4782).

FOR FURTHER INFORMATION CONTACT:

Additional information can be obtained

from Debra Knorr, Acting Director,

Office of Recombinant DNA Activities

(ORDA), Office of Science Policy,

National Institutes of Health, MSC 7010,

6000 Executive Boulevard, Suite 302,

Bethesda, Maryland 20892–7010, Phone

301–496–9838, FAX 301–496–9839.

ORDA’s web site is located at http://

www.nih.gov/od/orda for further

information about the office.

SUPPLEMENTARY INFORMATION: Today’s

actions are being promulgated under the

NIH Guidelines for Research Involving

Recombinant DNA Molecules. These

Proposed Actions were published for

comment in the Federal Register of July

8, 1996 (61 FR 7108), and August 20,

1997 (62 FR 44387). The Proposed

Actions were reviewed and

recommended for approval by the NIH

Recombinant DNA Advisory Committee

(RAC) at its meetings on December 9,

1996, March 6–7, 1997, and September

12, 1997.

I. Background Information and

Decisions on Actions Under the NIH

Guidelines

I–A. Amendment to the Overall

Procedures for Human Gene Transfer

Protocols

I–A–1. Notice of Intent—July 1996

On July 8, 1996, the NIH Director

published a Notice of Intent to Propose

Amendments to the NIH Guidelines for

Research Involving Recombinant DNA

Molecules Regarding Enhanced

Oversight of Recombinant DNA

Activities (61 FR 35774). This Notice of

Intent proposed modifications in the

NIH oversight of human gene transfer

research. Specifically, it was proposed

that RAC would be terminated and that

all approval responsibilities for

recombinant DNA experiments

involving human gene transfer would be

relinquished to the Food and Drug

Administration (FDA), which retains

statutory authority for such approval.

Under this revised structure, a newly

created ORDA Advisory Committee

(OAC) would preserve continued public

accountability for recombinant DNA

research. To ensure quality and

efficiency of public discussion of the

scientific merit and the ethical issues

relevant to gene therapy clinical trials,

it was proposed that the NIH Director

implement a regular series of Gene

Therapy Policy Conferences (GTPCs).

Finally, the proposal assured the

continuation of the publicly available

comprehensive NIH database of clinical

trials with human gene transfer,

including reporting of adverse events.

In response to the Notice of Intent,

NIH received 71 written comments (90

signatures) reflecting a broad spectrum

of public opinion on the proposed

changes. Comments were received from

a variety of stakeholders, including

individuals representing academia,

industry, patient advocacy

organizations, consumer advocacy

organizations, professional scientific

societies, ethicists, other Federal

agencies, NIH-funded investigators, past

and present RAC members, and private

citizens. Careful consideration was

given to each of the written comments

that was submitted.

I–B. Proposed Actions—November 1996

On November 22, 1996, the NIH

Director published the Notice of

Proposed Actions Under the NIH

Guidelines for Research Involving

Recombinant DNA Molecules (61 FR

59725). These Proposed Actions were

prepared in response to public opinion

and in keeping with the NIH Director’s

intent to increase the usefulness and

productivity of public discussion of

human gene transfer research.

In the Proposed Actions, the NIH

Director proposed to: (1) Retain RAC,

while modifying its roles and

responsibilities relevant to human gene

therapy research, (2) continue RAC

discussion of novel human gene transfer

experiments, without RAC approval of

individual human gene transfer

experiments; (3) regularly convene

GTPCs; and (4) maintain public access

to human gene transfer clinical trial

information. The following summarizes

the roles and responsibilities of the NIH

Director, RAC, ORDA, and local

institutions under the Notice of

Proposed Actions.

I–B–1. Proposed Roles and

Responsibilities in Accordance With

the NIH Guidelines

I–B–1–a. NIH Director

The roles and responsibilities of the

NIH Director in accordance with the

NIH Guidelines remain unchanged

except for the following: (1) Approval of

human gene transfer experiments by the

NIH Director will be relinquished to

FDA which already holds statutory

authority for such approval under 21

CFR, Chapter I, Subchapter D. (2) GTPCs

will be established and regularly

convened by the NIH Director.

I–B–1–b. Recombinant DNA Advisory

Committee (RAC)

The roles and responsibilities of RAC

related to human gene transfer research

remain the same except for the

following: (1) RAC will identify novel

human gene transfer experiments

deserving of public discussion by the

full RAC and will transmit its

comments/recommendations on specific

human gene transfer experiments or

categories of human gene transfer

experiments to the NIH Director, the

principal Investigator, the sponsoring

institution, and other Department of

Health and Human Services (DHHS)

components, as appropriate. (2) Novel

scientific, safety, social, and ethical

issues relevant to specific human

applications of gene transfer will be

identified by RAC, which will

recommend to the NIH Director

appropriate modifications to the Points

to Consider in the Design and

Submission of Protocols for the Transfer

of Recombinant DNA Molecules into

One or More Human Subjects (Points to

Consider) that will provide guidance in

the design and submission of human

gene transfer clinical trials. (3) RAC will

publicly review human gene transfer

clinical trial data submitted to NIH/

ORDA in accordance with the annual

data reporting requirements contained

in Appendix M–VII–B of the NIH

Guidelines. (4) Broad scientific,safety,

social, and ethical issues relevant to

human gene transfer research will be

identified by RAC and submitted to the

NIH Director as recommendations for

consideration as potential GTPC topics.

I–B–1–c. Gene Therapy Policy

Conferences (GTPCs)

In order to enhance the depth and

value of public discussion relevant to

scientific, safety, social, and ethical

implications of gene therapy research,

the NIH Director will convene GTPCs at

regular intervals. As appropriate, the

NIH Director may convene a GTPC in

conjunction with a regularly scheduled

RAC meeting. GTPCs will be

administered by NIH/ORDA. Conference

participation will not involve a standing

committee membership but rather will

offer the unique advantage of

assembling numerous participants who

possess significant scientific, safety,

social, and ethical expertise and/or

interest that is directly applicable to a

specific gene therapy research issue. At
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59033

least one member of RAC will serve as

Co-chair of each GTPC and report the

findings of each GTPC to RAC at its next

scheduled meeting. The RAC

representative for each GTPC will be

chosen based on the participant’s area of

expertise relative to the specific gene

therapy research issue to be discussed.

GTPCs will have representation from

other Federal agencies, including FDA

and the Office for Protection from

Research Risks (OPRR). GTPCs will

focus on broad overarching policy and

scientific issues related to gene therapy

research. Proposals for GTPC topics may

be submitted by members of RAC,

representatives of academia, industry,

patient and consumer advocacy

organizations, other Federal agencies,

professional scientific societies, and the

general public. GTPC topics will not be

limited to discussion of human

applications of gene therapy research,

i.e., they may include basic research on

the use of novel gene delivery vehicles

or novel applications of human gene

transfer. GTPC findings will be

transmitted to the NIH Director and will

be made publicly available. The NIH

Director anticipates that this public

policy forum will serve as a model for

interagency communication and

collaboration, concentrated expert

discussion of novel scientific issues and

their potential societal implications, and

enhanced opportunity for public

discussion of the potential impact of

such applications on human health and

the environment.

I–B–1–d. The Office of Recombinant

DNA Activities (ORDA)

ORDA is an organizational unit of the

NIH Office of Science Policy within the

Office of the Director. The roles and

responsibilities of NIH/ORDA remain

unchanged except for the following: (1)

Serving as the focal point for public

access to summary information

pertaining to human gene transfer

experiments. (2) Transmitting to the

NIH Director comments/

recommendations arising from public

RAC discussion of a novel human gene

transfer experiment. RAC

recommendations shall be forwarded to

the Principal Investigator(s), the

sponsoring institution, and other DHHS

components, as appropriate. (3)

Collaborating with Principal

Investigators, IBCs, Institutional Review

Boards (IRBs), and other DHHS

components, to ensure human gene

transfer experiment registration

compliance. (4) Administering GTPCs as

deemed appropriate by the NIH

Director. (5) Publishing announcements

of GTPCs and tentative agendas in the

Federal Register at least 15 days in

advance.

I–B–1–e. Institutional Biosafety

Committees (IBCs)

The roles and responsibilities of IBCs

related to human gene transfer

experiments remain unchanged, except

when the institution participates in or

sponsors recombinant DNA research

involving human subjects, the

institution must ensure that: (a) The IBC

has adequate expertise and training

(using ad hoc consultants as deemed

necessary), and (b) all aspects of

Appendix M, Points to Consider, have

been appropriately addressed by the

Principal Investigator prior to

submission to NIH/ORDA.

I–C. Proposed Actions—December 1996

RAC Meeting

On November 22, 1996, the NIH

Director published a Notice of Proposed

Actions Under the NIH Guidelines for

Research Involving Recombinant DNA

Molecules (61 FR 59725). The Notice of

Proposed Actions was prepared in

response to public opinion and in

keeping with the NIH Director’s intent

to increase the usefulness and

productivity of public discussion of

human gene transfer research. As a

result of its December 9, 1996,

deliberations of the Proposed Actions

under the NIH Guidelines, RAC

proposed the following modifications to

the November 22, 1996, Notice of Intent:

I–C–1. Triggering Mechanism for RAC

Discussion

A motion was made that: (1) The

capacity for Principal Investigators and

institutional representatives to request

RAC discussion of an individual human

gene transfer protocol should be

deleted. (2) The NIH Director or an

appropriate FDA representative may

request RAC review of an individual

protocol. (3) Rather than a majority vote,

RAC recommendations for full review of

an individual protocol should be

changed to a minimum of three

members. (4) The decision regarding

necessity for RAC discussion should be

made within 15 working days. The

motion passed by a vote of 16 in favor,

0 opposed, and no abstentions.

I–C–2. Reporting Requirements

A motion was made to request that

FDA report back to the RAC on how

RAC recommendations on an individual

protocol were implemented. RAC

should require investigator to provide

additional information if FDA is unable

to provide the necessary information.

The motion failed by a vote of 3 in

favor, 7 opposed, and 4 abstentions.

Another motion was made to require

investigators to submit a written report

to the RAC that includes the following

information: (1) How the investigator(s)

responded to RAC’s recommendations

on the protocol (if applicable), and (2)

any modifications to the protocol as

required by FDA. The motion passed by

a vote of 12 in favor, 1 opposed, and 1

abstention.

I–C–3. Relationship of RAC and GTPCs

A motion was made that the RAC,

with the NIH Director’s approval,

should have the primary responsibility

for: (1) planning GTPC agendas, and (2)

summarizing GTPC recommendations in

the form of a report back to the NIH

Director. The close GTP/RAC

relationship should not preclude other

parties from suggesting GTPC topics and

GTPCs should be convened in

consultation with FDA and OPRR. The

motion passed by a vote of 13 in favor,

0 opposed, and 2 abstentions.

I–C–4. Proposed Actions—Structural

Changes

A motion was made to accept the

overall structural changes put forward

in the Proposed Actions as published in

the November 22, 1996, Federal

Register (61 FR 59725). However, RAC

recommended that promulgation of the

final actions should be postponed to the

March 6–7, 1997, RAC meeting, in order

to more fully address these unresolved

issues. The structural changes endorsed

by RAC were as follows: (1) Retain RAC,

while modifying its roles and

responsibilities relevant to human gene

therapy research, (2) continue RAC

discussion of novel human gene transfer

experiments without RAC approval of

individual human gene transfer

experiments; (3) regularly convene

GTPCs; and (4) maintain public access

to human gene transfer clinical trial

information. RAC members noted that

several minor modification still

remained unresolved, particularly with

regard to the format for future

discussion of gene therapy protocols

and defining the role of RAC relative to

GTPCs. The motion passed by a vote of

12 in favor, 0 opposed, and 2

abstentions.

I–D. Proposed Action—March 1997

On February 14, 1997, the NIH

Director published a revised Notice of

Proposed Actions Under the NIH

Guidelines for Research Involving

Recombinant DNA Molecules (62 FR

7108). The Notice of Proposed Actions

was in response to public opinion and

in keeping with the NIH Director’s

intent to increase the usefulness and

productivity of public discussing of
59034 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

human gene transfer research. During its

March 6–7, 1997, meeting, RAC

recommended the following changes to

the February 14, 1997, Proposed Actions

under the NIH Guidelines.

I–D–1. Relationship of RAC and GTPCs

A motion was made to include the

following modifications will regard to

the role of RAC relative to GTPCs: (1)

One member of RAC will co-chair each

GTPC. (2) GTPCs will be held in

conjunction with RAC meetings when

appropriate (preferably on the first day).

(3) All RAC members will be invited to

attend GTPCs. The motion passed by a

vote of 8 in favor, 0 opposed, and no

abstentions.

I–D–2. IBC Approval Requirements

A motion was made to modify IBC

approval requirements for human gene

transfer protocols under Section III–C–

a of the NIH Guidelines. Specifically,

RAC proposed that IBC approval must

be obtained from each institution at

which recombinant DNS material will

be administered to human subjects (as

opposed to each institution involved in

the production of vectors for human

application and each institution at

which there is ex vivo transduction of

recombinant DNA material into target

cells for human application). The

motion passed by a vote of 6 in favor,

0 opposed, and 2 abstentions.

I–D–3. NIH Human Gene Therapy

Database

A motion was made to identify the

objectives of the human gene transfer

database. As a result of RAC’s

deliberation on this issue, the following

five objectives were identified: (1)

Maintain and institutional memory, (2)

provide administrative details of

protocol registration, (3) provide annual

status reports of protocols, (4) facilitate

risk assessment of individual

applications of human gene transfer,

and (5) enhance public awareness of

relevant scientific, safety, social, and

ethical issues. The motion passed by a

vote of 7 in favor, 0 opposed, and 1

abstention.

I–E. Requirement for Submission of

Appendix M to FDA

In a letter dated November 20, 1996,

Dr. Andra Miller, Cytokine and Gene

Therapy Branch, Center of Biologics

Evaluation and Research, FDA,

requested that the NIH Guidelines

should be amended regarding

procedures for simultaneous submission

of Appendix M material to RAC and

FDA. In her November 20, 1996, letter,

Dr. Miller states:

‘‘(1) Remove the requirement for submission

of Appendix M to FDA. FDA does not accept

Appendix M in place of an IND submission.

FDA is not proposed to be and need not be

included in the decisionmaking process to

identify protocols to undergo full RAC

review. Therefore, there is no reason for

sponsors to submit Appendix M materials to

FDA.

‘‘(2) Explore the feasibility of a unified

format for submission of protocols to RAC

and FDA. This would relieve the sponsor of

the burden of preparing duplicative

submission to satisfy each agency.

‘‘(3) Establish a mechanism for FDA staff

to bring general issues of novelty and

concern to RAC for discussion. This will

provide a mechanism for public input toward

the resolution of issues we all must consider

and provide direction for policy development

and growth in the field of gene therapy.’’

On January 27, 1997, NIH and FDA

staff met to consider amendments to the

NIH Guidelines that incorporate the

recommendations of both NIH and FDA

with regard to simultaneous submission

of human gene transfer protocols.

During its December 9, 1996, and

March 6–7, 1997, meetings, RAC

discussed the proposed changes to the

NIH Guidelines submitted by Dr. Miller.

The consensus of RAC was that the

requirement for submission of responses

to Appendix M to FDA should be

removed since FDA does not accept

responses to Appendix M in place of an

Investigational New Drug (IND)

application. However, 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 proposed action was

published in the Federal Register of

August 20, 1997, for public comment.

No comment was received from the

public with regard to the proposed

action.

During the September 12, 1997, RAC

meeting, RAC approved the

amendments to the NIH Guidelines to

eliminate the requirement for

submission of responses to Appendix M

of the NIH Guidelines to FDA. The

motion passed by a vote of 12 in favor,

0 opposed, and 0 abstentions.

I–F. Environmental Assessment—

October 1997

As a prerequisite to amending the NIH

Guidelines for the purpose of

relinquishing the requirement for NIH

Director approval of individual human

gene transfer experiments, NIH prepared

an Environmental Assessment for the

Proposed Actions in accordance with

requirements of the National

Environmental Protection Act of 1969,

42 U.S.C. This Environmental

Assessment that was completed in

October 1997 included a finding of no

significant impact on the environment.

Copies of the Environmental

Assessment are available from the Office

of Recombinant DNA Activities,

National Institutes of Health, MSC 7010,

6000 Executive Boulevard, Suite 302,

Bethesda, Maryland, 20892–7010, (301)

496–9838.

These actions under the NIH

Guidelines are detailed in Section II—

Summary of Actions. I accept these

recommendations, and the NIH

Guidelines will be amended

accordingly.

II. Summary of Actions

NIH will take the following action

under the NIH Guidelines for Research

Involving Recombinant DNA Molecules:

Note: Editorial changes and updating of

references have been incorporated to clarify

the document.

II–A. Amendments to Section I, Scope

of the NIH Guidelines

Section I is amended to read:

‘‘SECTION I. SCOPE OF THE NIH

GUIDELINES

‘‘Section I–A. Purpose’’

[This section remains unchanged.]

‘‘Section I–A–1. Any recombinant

DNA experiment, which according to

the NIH Guidelines requires approval by

NIH, must be submitted to 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 NIH (whether

the experiment is referred to that agency

by 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–1-a regarding requirement for human

gene transfer protocol registration.)

‘‘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

simultaneous submission to both NIH/

ORDA and FDA of such information on

the proposed experiment as is

prescribed by those agencies.

Submission of human gene transfer

protocols to NIH shall 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 and will ensure

continued public access to relevant

human gene transfer information

conducted in compliance with the NIH
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59035

Guidelines. Investigational New Drug

(IND) applications shall be submitted to

FDA in the format described in 21 CFR,

chapter I, subchapter D, part 312,

subpart B, section 23, IND Content and

Format.

‘‘If a determination is made that an

experiment will undergo full RAC

discussion, NIH/ORDA will

immediately notify the Principal

Investigator. RAC members may forward

requests for additional information

relevant to a specific protocol through

NIH/ORDA to the Principal Investigator.

In making a determination whether an

experiment is novel and deserving of

full RAC discussion, reviewers will

examine the scientific rational,

scientific content (relative to other

proposals reviewed by RAC), whether

the preliminary in vitro and in vivo

safety data were obtained in appropriate

models and are sufficient, and whether

questions related to relevant social and

ethical issues have been resolved. RAC’s

recommendation(s) on a specific human

gene transfer experiment will be

forwarded to the NIH Director, the

Principal Investigator, the sponsoring

institution, and other DHHS

components, as appropriate.

‘‘Section I–B. Definition of Recombinant

DNA Molecules’’

[This section remains unchanged.]

‘‘Section I–C. General Applicability

‘‘Section I–C–1. The NIH Guidelines

are applicable to:

Section I–C–1–a. All recombinant

DNA research within the United States

(U.S.) or its territories that is within the

category of research described in either

Section I–C–1–a–(1) or Section I–C–1–

a–(2).

‘‘Section I–C–1–a–(1). Research that is

conducted at or sponsored by an

institution that receives any support for

recombinant DNA research from NIH,

including research performed directly

by NIH. An individual who receives

support for research involving

recombinant DNA must be associated

with or sponsored by an institution that

assumes the responsibilities assigned in

the NIH Guidelines.

‘‘Section I–C–1–a–(2). Research that

involves testing in humans of materials

containing recombinant DNA developed

with NIH funds, if the institution that

developed those materials sponsors or

participates in those projects.

Participation includes research

collaboration or contractual agreements,

not mere provision of research

materials.

‘‘Section I–C–1–b. All recombinant

DNA research performed abroad that is

within the category of research

described in either Section I–C–1–b–(1)

or Section I–C–1–b–(2).

‘‘Section I–C–1–b–(1). Research

supported by NIH funds.

‘‘Section I–C–1–b–(2). Research that

involves testing in humans of materials

containing recombinant DNA developed

with NIH funds, if the institution that

developed those materials sponsors or

participates in those projects.

Participation includes research

collaboration or contractual agreements,

not mere provisions of research

materials.

‘‘Section I–C–1–b–(3). If the host

country has established rules for the

conduct of recombinant DNA research,

then the research must be in compliance

with those rules. If the host country

does not have such rules, the proposed

research must be reviewed and

approved by an NIH-approved

Institutional Biosafety Committee or

equivalent review body and accepted in

writing by an appropriate national

governmental authority of the host

country. The safety practices that are

employed abroad must be reasonably

consistent with the NIH Guidelines.

‘‘Section I–D. Compliance with the NIH

Guidelines

‘‘As a condition for NIH funding of

recombinant DNA research, institutions

shall ensure that such research

conducted at or sponsored by the

institution, irrespective of the source of

funding, shall comply with the NIH

Guidelines.

‘‘Information concerning

noncompliance with the NIH Guidelines

may be brought forward by any person.

It should be delivered to both NIH/

ORDA and the relevant institution. The

institution, generally through the

Institutional Biosafety Committee, shall

take appropriate action. The institution

shall forward a complete report of the

incident recommending any further

action 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.

‘‘In cases where NIH proposes to

suspend, limit, or terminate financial

assistance because of noncompliance

with the NIH Guidelines, applicable

DHHS and Public Health Service

procedures shall govern.

‘‘The policies on compliance are as

follows:

‘‘Section I–D–1. All NIH-funded

projects involving recombinant DNA

techniques must comply with the NIH

Guidelines. Non-compliance may result

in: (i) Suspension, limitation, or

termination of financial assistance for

the noncompliant NIH-funded research

project and of NIH funds for other

recombinant DNA research at the

institution, or (ii) a requirement for

prior NIH approval of any or all

recombinant DNA projects at the

institution.

‘‘Section I–D–2. All non-NIH funded

projects involving recombinant DNA

techniques conducted at or sponsored

by an institution that receives NIH

funds for projects involving such

techniques must comply with the NIH

Guidelines. Noncompliance may result

in: (i) Suspension, limitation, or

termination of NIH funds for

recombinant DNA research at the

institution, or (ii) a requirement for

prior NIH approval of any or all

recombinant DNA projects at the

institution.’’

[Previously numbered Section I–D,

General Definitions, will be

renumbered to Section I–E.]

II–B. Amendments to Section II, Safety

Considerations

The second paragraph of Section II–

A–3 is amended to read:

‘‘Section II–A–3. Comprehensive Risk

Assessment

‘‘* * * A final assessment of risk based

on these considerations is then used to

set the appropriate containment

conditions for the experiment (see

Section II–B, Containment). The

containment level required may be

equivalent to the Risk Group

classification of the agent or it may be

raised or lowered as a result of the

above considerations. The Institutional

Biosafety Committee must approve the

risk assessment and the biosafety

containment level for recombinant DNA

experiments described in Sections III–A,

Experiments that Require Institutional

Biosafety Committee Approval, RAC

Review, and NIH Director Approval

Before Initiation; III–B, Experiments that

Require NIH/ORDA and Institutional

Biosafety Committee Approval Before

Initiation; III–C, Experiments that

Require Institutional Biosafety

Committee and Institutional Review

Board Approvals and NIH/ORDA

Registration Before Initiation; and III–D,

Experiments that Require Institutional

Biosafety Committee Approval Before

Initiation * * *’’

II–C. Amendments to Section III,

Experiments Covered by the NIH

Guidelines

Section III is amended to read:

‘‘SECTION III. EXPERIMENTS

COVERED BY THE NIH GUIDELINES

‘‘This section describes six categories

of experiments involving recombinant
59036 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

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

II–B), (iii) those that require

Institutional Biosafety Committee and

Institutional Review Board approvals

and NIH/ORDA registration before

initiation (see Section III–C), (iv) those

that require Institutional Biosafety

Committee approval before initiation

(see Section III–D), (v) those that require

Institutional Biosafety Committee

notification simultaneous with

initiation (see Section III–E), and (vi)

those that are exempt from the NIH

Guidelines (see Section III–F).

‘‘Note: If an experiment falls into Sections

III–A, III–B, or III–C and one of the other

sections, the rules pertaining to Sections II–

A, II–B, or III–C shall be followed. If an

experiment falls into Section III–F and into

either Sections III–D or III–E 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 Section IV–C–1–b–

(2) and its subsections, Minor Actions).

‘‘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–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

experiment 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,

the publication of the proposal in the

Federal Register for 15 days of

comment, review by RAC, and specific

approval by NIH. The containment

conditions or stipulation requirements

for such experiments will be

recommended by RAC and set by NIH

at the time of approval. Such

experiments require Institutional

Biosafety Committee approval before

initiation. Specific experiments already

approved are included in Appendix D,

Major Actions Taken under the NIH

Guidelines, which may be obtained

from the Office of Recombinant DNA

Activities, National Institutes of Health/

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 to

microorganisms that are not known to

acquire the trait naturally (see Section

V–B, Footnotes and References of

Sections I–IV), if such acquisition could

compromise the use of the drug to

control disease agents in humans,

veterinary medicine, or agriculture, will

be reviewed by RAC.

‘‘Section III–B. Experiments That

Require NIH/ORDA and Institutional

Biosafety Committee Approval Before

Initiation

‘‘Experiments in this category cannot

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), Institutional Biosafety

Committee).

‘‘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,

diphteria 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/MSC 7010,

6000 Executive Boulevard, Suite 302,

Bethesda, Maryland 10892–7010, (301)

496–9838.

‘‘Section III–C. Experiments That

Require Institutional Biosafety

Committee and Institutional Review

Board Approvals and NIH/ORDA

Registration Before Initiation

‘‘Section III–C–1. Experiments

Involving the Deliberate Transfer of

Recombinant DNA or DNA or RNA

Derived From Recombinant DNA Into

One or More Human Subjects

‘‘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 NIH/ORDA and RAC.

Investigators shall submit relevant

information on the proposed human

gene transfer experiments to NIH/

ORDA. Submission of human gene

transfer protocols to NIH will be in the

format described in Appendix M–I,

Submission Requirements—Human

Gene Transfer Experiments. Submission

to NIH/ORDA shall be for registration

purposes and will ensure continued

public access to relevant human gene

transfer information in compliance with

the NIH Guidelines. Investigational New

Drug (IND) applications should be

submitted to FDA in the format

described in 21 CFR, chapter I,

subchapter D, part 312, subpart B,

section 23, IND content and Format.

‘‘Institutional Biosafety Committee

approval must be obtained from each

institution at which recombinant DNA

material will be administered to human

subjects (as opposed to each institution

invovled in the production of vectors for

human application and each institution

at which there is ex vivo transduction of

recombinant DNA material into target

cells for human application).

‘‘RAC prefers that submission to NIH/

ORDA in accordance with Appendix M–

I, Submission Requirements—Human

Gene Transfer Experiments, contain no

proprietary data or trade secrets,

enabling all aspects of the review to be

open to the public. Following receipt by

NIH/ORDA, relevant information shall

be entered into the NIH human gene

transfer database for registration

purposes. Summary information

pertaining to the human gene transfer

protocol will be forwarded to RAC

members. NIH/ORDA summary

information shall include comparisons

to previously registered protocols.

Specific items of similarity to previous

experiments include (but are not limited

to): (i) Gene delivery vehicle, (ii)

functional gene, (iii) marker gene, (iv)

packaging cell (if applicable), (v) disease

application, (vi) route of administration,

and (vii) patient selection criteria.
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59037

‘‘RAC members shall notify NIH/

ORDA within 15 working days if the

protocol has been determined to

represent novel characteristics requiring

further public discussion.

‘‘Full RAC review of an individual

human gene transfer experiment can be

initiated by the NIH Director or

recommended to the NIH Director by: (i)

Three or more RAC members, or (ii)

other Federal agencies. An individual

human gene transfer experiment that is

recommended for full RAC review

should represent novel characteristics

deserving of public discussion. RAC

recommendations on a specific human

gene transfer experiment shall be

forwarded to the NIH Director, the

Principal Investigator, the sponsoring

institution, and other DHHS

components, as appropriate.

‘‘Note: For specific directives concerning

the use of retroviral vectors for gene delivery,

consult Appendix B–V–1, Murine Retroviral

Vectors.’’

[Previously numbered Section III–C,

Experiments that Require Institutional

Biosafety Committee Approval Before

Initiation, will be renumbered to

Section III–D. References in this

section will be changed due to

renumbering.]

[Previously numbered Section III–D,

Experiments that Require Institutional

Biosafety Committee Notice

Simultaneous with Initiation, will be

renumbered to Section III–E.

References in this section will be

changed due to renumbering.]

[Previously numbered Section III–E,

Exempt Experiments, will be

renumbered to Section III–F.

References in this section will be

changed due to renumbering.]

II–D. Amendments to Section IV, Roles

and Responsibilities

Section IV is amended to read:

‘‘SECTION IV. ROLES AND

RESPONSIBILITIES

‘‘Section IV–A. Policy

‘‘The safe conduct of experiments

involving recombinant DNA depends on

the individual conducting such

activities. The NIH Guidelines cannot

anticipate every possible situation.

Motivation and good judgment are the

key essentials to protection of health

and the environment. The NIH

Guidelines are intended to assist the

institution, Institutional Biosafety

Committee, Biological Safety Officer,

and the Principal Investigator in

determining safeguards that should be

implemented. The NIH Guidelines will

never be complete or final since all

conceivable experiments involving

recombinant DNA cannot be foreseen.

Therefore, it is the responsibility of the

institution and those associated with it

to adhere to the intent of the NIH

Guidelines as well as to their specifics.

Each institution (and the Institutional

Biosafety Committee acting on its

behalf) is responsible for ensuring that

all recombinant DNA research

conducted at or sponsored by that

institution is conducted in compliance

with the NIH Guidelines. General

recognition of institutional authority

and responsibility properly establishes

accountability for safe conduct of the

research at the local level. The following

roles and responsibilities constitute an

administrative framework in which

safety is an essential and integral part of

research involving recombinant DNA

molecules. Further clarifications and

interpretations of roles and

responsibilities will be issued by NIH as

necessary.

‘‘Section IV–B. Responsibilities of the

Institution

‘‘Section IV–B–1. General Information

‘‘Each institution conducting or

sponsoring recombinant DNA research

which is covered by the NIH Guidelines

is responsible for ensuring that the

research is conducted in full conformity

with the provisions of the NIH

Guidelines. In order to fulfill this

responsibility, the institution shall:

‘‘Section IV–B–1–a. Establish and

implement policies that provide for the

safe conduct of recombinant DNA

research and that ensure compliance

with the NIH Guidelines. As part of its

general responsibilities for

implementing the NIH Guidelines, the

institution may establish additional

procedures, as deemed necessary, to

govern the institution and its

components in the discharge of its

responsibilities under the NIH

Guidelines. Such procedures may

include: (i) Statements formulated by

the institution for the general

implementation of the NIH Guidelines,

and (ii) any additional precautionary

steps the institution deems appropriate.

‘‘Section IV–B–1–b. Establish an

Institutional Biosafety Committee that

meets the requirements set forth in

Section IV–B–2–a and carries out the

functions detailed in Section IV–B–2–b.

‘‘Section IV–B–1–c. Appoint a

Biological Safety Officer (who is also a

member of the Institutional Biosafety

Committee) if the institution: (i)

Conducts recombinant DNA research at

Biosafety Level (BL) 3 or BL4, or (ii)

engages in large scale (greater than 10

liters) research. The Biological Safety

Officer carries out the duties specified

in Section IV–B–3.

‘‘Section IV–B–1–d. Appoint at least

one individual with expertise in plant,

plant pathogen, or plant pest

containment principles (who is a

member of the Institutional Biosafety

Committee) if the institution conducts

recombinant DNA research that requires

Institutional Biosafety Committee

approval in accordance with Appendix

P, Physical and Biological Containment

for Recombinant DNA Research

Involving Plants.

‘‘Section IV–B–1–e. Appoint at least

one individual with expertise in animal

containment principles (who is a

member of the Institutional Biosafety

Committee) if the institution conducts

recombinant DNA research that requires

Institutional Biosafety Committee

approval in accordance with Appendix

Q, Physical and Biological Containment

for Recombinant DNA Research

Involving Animals.

‘‘Section IV–B–1–f. Ensure that when

the institution participates in or

sponsors recombinant DNA research

involving human subjects: (i) The

Institutional Biosafety Committee has

adequate expertise and training (using

ad hoc consultants as deemed

necessary), and (ii) all aspects of

Appendix M, Points to Consider in the

Design and Submission of Protocols for

the Transfer of Recombinant DNA

Molecules into One or More Human

Subject (Points to Consider), have been

appropriately addressed by the

Principal Investigator prior to

submission to NIH/ORDA. Institutional

Biosafety Committee approval must be

obtained from each institution at which

recombinant DNA material will be

administered to human subjects (as

opposed to each institution involved in

the production of vectors for human

application and each institution at

which there is ex vivo transduction of

recombinant DNA material into target

cells for human application).

‘‘Section IV–B–1–g. Assist and ensure

compliance with the NIH Guidelines by

Principal Investigators conducting

research at the institution as specified in

Section IV–B–4.

‘‘Section IV–B–1–h. Ensure

appropriate training for the Institutional

Biosafety Committee Chair and

members, Biological Safety Officer and

other containment experts (when

applicable), Principal Investigators, and

laboratory staff regarding laboratory

safety and implementation of the NIH

Guidelines. The Institutional Biosafety

Committee Chair is responsible for

ensuring that Institutional Biosafety

Committee members are appropriately

trained. The Principal Investigator is
59038 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

responsible for ensuring that laboratory

staff are appropriately trained. The

institution is responsible for ensuring

that the Principal Investigator has

sufficient training; however, this

responsibility may be delegated to the

Institutional Biosafety Committee.

‘‘Section IV–B–1–i. Determine the

necessity for health surveillance of

personnel involved in connection with

individual recombinant DNA projects;

and if appropriate, conduct a health

surveillance program for such projects.

The institution shall establish and

maintain a health surveillance program

for personnel engaged in large scale

research or production activities

involving viable organisms containing

recombinant DNA molecules which

require BL3 containment at the

laboratory scale. The institution shall

establish and maintain a health

surveillance program for personnel

engaged in animal research involving

viable recombinant DNA-containing

microorganisms that require BL3 or

greater containment in the laboratory.

The Laboratory Safety Monograph

discusses various components of such a

program (e.g., records of agents handled,

active investigation of relevant illnesses,

and the maintenance of serial serum

samples for monitoring serologic

changes that may result from the

employees’ work experience). Certain

medical conditions may place a

laboratory worker at increased risk in

any endeavor where infectious agents

are handled. Examples cited in the

Laboratory Safety Monograph include

gastrointestinal disorders and treatment

with steroids, immunosuppressive

drugs, or antibiotics. Workers with such

disorders or treatment should be

evaluated to determine whether they

should be engaged in research with

potentially hazardous organisms during

their treatment or illness. Copies of the

Laboratory Safety Monograph are

available from the Office 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–1–j. Report any

significant problems, violations of the

NIH Guidelines, or any significant

research-related accidents and illnesses

to NIH/ORDA within thirty days, unless

the institution determines that a report

has already been filed by the Principal

Investigator or Institutional Biosafety

Committee. Reports shall be sent 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.

‘‘Section IV–B–2. Institutional Biosafety

Committee (IBC)

‘‘The institution shall establish an

Institutional Biosafety Committee whose

responsibilities need not be restricted to

recombinant DNA. The Institutional

Biosafety Committee shall meet the

following requirements:

‘‘Section IV–B–2–a. Membership and

Procedures

‘‘Section IV–B–2–a–(1). The

Institutional Biosafety Committee must

be comprised of no fewer than five

members so selected that they

collectively have experience and

expertise in recombinant DNA

technology and the capability to assess

the safety of recombinant DNA research

and to identify any potential risk to

public health or the environment. At

least two members shall not be affiliated

with the institution (apart from their

membership on the Institutional

Biosafety Committee) and who represent

the interest of the surrounding

community with respect to health and

protection of the environment (e.g.,

officials of state or local public health or

environmental protection agencies,

members of other local governmental

bodies, or persons active in medical

occupational health, or environmental

concerns in the community). The

Institutional Biosafety Committee shall

include at least one individual with

expertise in plant, plant pathogen, or

plant pest containment principles when

experiments utilizing Appendix P,

Physical and Biological Containment for

Recombinant DNA Research Involving

Plants, require prior approval by the

Institutional Biosafety Committee. The

Institutional Biosafety Committee shall

include at least one scientist with

expertise in animal containment

principles when experiments utilizing

Appendix Q, Physical and Biological

Containment for Recombinant DNA

Research Involving Animals, require

Institutional Biosafety Committee prior

approval. When the institution conducts

recombinant DNA research at BL3, BL4,

or Large Scale (greater than 10 liters), a

Biological Safety Officer is mandatory

and shall be a member of the

Institutional Biosafety Committee (see

Section IV–B–3, Biological Safety

Officer). When the institution

participates in or sponsors recombinant

DNA research involving human

subjects, the institution must ensure

that: (i) The Institutional Biosafety

Committee has adequate expertise and

training (using ad hoc consultants and

deemed necessary) and (ii) all aspects of

Appendix M, Points to Consider in the

Design and Submission of Protocols for

the Transfer of Recombinant DNA

Molecules into One or More Human

Subjects (Points to Consider), have been

appropriately addressed by the

Principal Investigator prior to

submission to NIH/ORDA. Institutional

Biosafety Committee approval must be

obtained from each institution at which

recombinant DNA material will be

administered to human subjects (as

opposed to each institution involved in

the production of vectors for human

application and each institution at

which there is ex vivo transduction of

recombinant DNA material into target

cells from human application).

‘‘Note: Individuals, corporations, and

institutions not otherwise covered by the NIH

Guidelines, are encouraged to adhere to the

standards and procedures set forth in

Sections I through IV (see Section IV–E,

Voluntary Compliance. The policy and

procedures for establishing an Institutional

Biosafety Committee under Voluntary

Compliance, are specified in Section IV–D–

2, Institutional Biosafety Committee

Approval).

‘‘Section IV–B–2–a–(2). In order to

ensure the competence necessary to

review and approve recombinant DNA

activities, it is recommended that the

Institutional Biosafety Committee: (i)

Include persons with expertise in

recombinant DNA technology,

biological safety, and physical

containment; (ii) include or have

available as consultants persons

knowledgeable in institutional

commitments and policies, applicable

law, standards of professional conduct

and practice, community attitudes, and

the environment, and (iii) include at

least one member representing the

laboratory technical staff.

‘‘Section IV–B–2–a–(3). The

institution shall file an annual report

with NIH/ORDA which includes: (i) A

roster of all Institutional Biosafety

Committee members clearly indicating

the Chair, contact person, Biological

Safety Officer (if applicable), plan

expert (if applicable), animal expert (if

applicable), human gene therapy

expertise or ad hoc consultant (if

applicable); and (ii) biographical

sketches of all Institutional Biosafety

Committee members (including

community members).

‘‘Section IV–B–2–a–(4). No member of

an Institutional Biosafety Committee

may be involved (except to provide

information requested by the

Institutional Biosafety Committee) in

the review or approval of a project in

which he/she has been or expects to be

engaged or has a direct financial

interest.

‘‘Section IV–B–2–a–(5). The

institution, that is ultimately
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59039

responsible for the effectiveness of the

Institutional Biosafety Committee, may

establish procedures that the

Institutional Biosafety Committee shall

follow in its initial and continuing

review and approval of applications,

proposals, and activities.

‘‘Section IV–B–2–a–(6). When

possible and consistent with protection

of privacy and proprietary interests, the

institution is encouraged to open its

Institutional Biosafety Committee

meetings to the public.

‘‘Section IV–B–a–(7). Upon request,

the institution shall make available to

the public all Institutional Biosafety

Committee meeting minutes and any

documents submitted to or received

from funding agencies which the latter

are required to make available to the

public. If public comments are made on

Institutional Biosafety Committee

actions, the institution shall forward

both the public comments and the

Institutional Biosafety Committee’s

response 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.

‘‘Section IV–B–2–b. Functions

‘‘On behalf of the institution, the

Institutional Biosafety Committee is

responsible for:

‘‘Section IV–B–2–b–(1). Reviewing

recombinant DNA research conducted at

or sponsored by the institution for

compliance with the NIH Guidelines as

specified in Section III, Experiments

Covered by the NIH Guidelines, and

approving those research projects that

are found to conform with the NIH

Guidelines. This review shall include:

(i) Independent assessment of the

containment levels required by the NIH

Guidelines for the proposed research;

(ii) assessment of the facilities,

procedures, practices, and training and

expertise of personnel involved in

recombinant DNA research; and (iii)

ensuring compliance with all

surveillance, data reporting, and adverse

event reporting requirements required

by the NIH Guidelines.

‘‘Section IV–B–2–b–(2). Notifying the

Principal Investigator of the results of

the Institutional Biosafety Committee’s

review and approval.

‘‘Section IV–B–2–b–(3). Lowering

containment levels for certain

experiments as specified in Section III–

C–2–a, Experiments in which DNA from

Human or Animal Pathogens (Risk

Group 2, Risk Group 3, Risk Group 4, or

Restricted Agents is Cloned into

Nonpathogenic Prokaryotic or Lower

Eurkaryotic Host-Vector Systems.

‘‘Section IV–B–2–b–(4). Setting

containment levels as specified in

Sections III–C–4–b, Experiments

Involving Whole Animals, and III–C–5,

Experiments Involving Whole Plants.

‘‘Section IV–B–2–b–(5). Periodically

reviewing recombinant DNA research

conducted at the institution to ensure

compliance with the NIH Guidelines.

‘‘Section IV–B–2–b–(6). Adopting

emergency plans covering accidental

spills and personnel contamination

resulting from recombinant DNA

research.

‘‘Note: The Laboratory Safety Monograph

describes basic elements for developing

specific procedures dealing with major spills

of potentially hazardous materials in the

laboratory, including information and

references about decontamination and

emergency plans. The NIH and the Centers

for Disease Control and Prevention are

available to provide consultation and direct

assistance, if necessary, as posted in the

Laboratory Safety Monograph. The

institution shall cooperate with the state and

local public health departments by reporting

any significant research-related illness or

accident that may be hazardous to the public

health.

‘‘Section IV–B–2–b–(7). Reporting any

significant problems with or violations

of the NIH Guidelines and any

significant research-related accidents or

illnesses to the appropriate institutional

official and NIH/ORDA within 30 days,

unless the Institutional Biosafety

Committee determines that a report has

already been filed by the Principal

Investigator. Reports to NIH/ORDA shall

be sent 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.

‘‘Section IV–B–2–b–(8). The

Institutional Biosafety Committee may

not authorize initiation of experiments

which are not explicitly covered by the

NIH Guidelines until NIH (with the

advice of the RAC when required)

establishes the containment

requirement.

‘‘Section IV–B–2–b–(9). Performing

such other functions as may be

delegated to the Institutional Biosafety

Committee under Section IV–B–2,

Institutional Biosafety Committee.

‘‘Section IV–B–3. Biological Safety

Officer (BSO)

‘‘Section IV–B–3–a. The institution

shall appoint a Biological Safety Officer

if it engages in large scale research or

production activities involving viable

organisms containing recombinant DNA

molecules.

‘‘Section IV–B–3–b. The institution

shall appoint a Biological Safety Officer

if it engages in recombinant DNA

research at BL3 or BL4. The Biological

Safety Officer shall be a member of the

Institutional Biosafety Committee.

‘‘Section IV–B–3–c. The Biological

Safety Officer’s duties include, but are

not limited to:

‘‘Section IV–B–3–c–(1). Periodic

inspections to ensure that laboratory

standards are rigorously followed;

‘‘Section IV–B–3–c–(2). Reporting to

the Institutional Biosafety Committee

and the institution any significant

problems, violations of the NIH

Guidelines, and any significant

research-related accidents or illnesses of

which the Biological Safety Officer

becomes aware unless the Biological

Safety Officer determines that a report

has already been filed by the Principal

Investigator;

‘‘Section IV–B–3–c–(3). Developing

emergency plans for handling accidental

spills and personnel contamination and

investigating laboratory accidents

involving recombinant DNA research;

‘‘Section IV–B–3–c–(4). Providing

advice on laboratory security;

‘‘Section IV–B–3–c–(5). Providing

technical advice to Principal

Investigators and the Institutional

Biosafety Committee on research safety

procedures.

‘‘Note: See the Laboratory Safety

Monograph for additional information on the

duties of the Biological Safety Officer.

‘‘Section IV–B–4. Plant, Plant Pathogen,

or Plant Pest Containment Expert

‘‘When the institution conducts

recombinant DNA research that requires

Institutional Biosafety Committee

approval in accordance with Appendix

P, Physical and Biological Containment

for Recombinant DNA Research

Involving Plants, the institution shall

appoint at least one individual with

expertise in plant, plant pathogen, or

plant pest containment principles (who

is a member of the Institutional

Biosafety Committee).

‘‘Section IV–B–5. Animal Containment

Expert

‘‘When the institution conducts

recombinant DNA research that requires

Institutional Biosafety Committee

approval in accordance with Appendix

Q, Physical and Biological Containment

for Recombinant DNA Research

Involving Animals, the institution shall

appoint at least one individual with

expertise in animal containment

principles (who is a member of the

Institutional Biosafety Committee).

‘‘Section IV–B–6. Human Gene Therapy

Expertise

‘‘When the institution participates in

or sponsors recombinant DNA research
59040 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

involving human subjects, the

institution must ensure that: (i) The

Institutional Biosafety Committee has

adequate expertise and training (using

ad hoc consultants as deemed

necessary) and (ii) all aspects of

Appendix M, Points to Consider in the

Design and Submission of Protocols for

the Transfer of Recombinant DNA

Molecules into One or More Human

Subjects (Points to Consider), have been

appropriately addressed by the

Principal Investigator prior to

submission to NIH/ORDA.

‘‘Section IV–B–7. Principal Investigator

(PI)

‘‘On behalf of the institution, the

Principal Investigator is responsible for

full compliance with the NIH

Guidelines in the conduct of

recombinant DNA research.

‘‘Section IV–B–7–a. General

Responsibilities

‘‘As part of this general responsibility,

the Principal Investigator shall:

‘‘Section IV–B–7–a–(1). Initiate or

modify no recombinant DNA research

which requires Institutional Biosafety

Committee approval prior to initiation

(see Sections III–A, III–B, III–C, and III–

D, Experiments Covered by the NIH

Guidelines) until that research or the

proposed modification thereof has been

approved by the Institutional Biosafety

Committee and has met all other

requirements of the NIH Guidelines;

‘‘Section IV–B–7–a–(2). Determine

whether experiments are covered by

Section III–D, Experiments that Require

Institutional Biosafety Committee

Notice Simultaneous with Initiation,

and ensure that the appropriate

procedures are followed;

‘‘Section IV–B–7–a–(3). Report any

significant problems, violations of the

NIH Guidelines, or any significant

research-related accidents and illnesses

to the Biological Safety Officer (where

applicable), Greenhouse/Animal

Facility Director (where applicable),

Institutional Biosafety Committee, NIH/

ORDA, and other appropriate

authorities (if applicable) within 30

days. Reports to NIH/ORDA shall be

sent 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;

‘‘Section IV–B–7–a–(4). Report any

new information bearing on the NIH

Guidelines to the Institutional Biosafety

Committee and to NIH/ORDA (reports to

NIH/ORDA shall be sent 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);

‘‘Section IV–B–7–a–(5). Be adequately

trained in good microbiological

techniques;

‘‘Section IV–B–7–a–(6). Adhere to

Institutional Biosafety Committee

approved emergency plans for handling

accidental spills and personnel

contamination; and

‘‘Section IV–B–7–a–(7). Comply with

shipping requirements for recombinant

DNA molecules (see Appendix H,

Shipment, for shipping requirements

and the Laboratory Safety Monograph

for technical recommendations).

‘‘Section IV–B–7–b. Submissions by the

Principal Investigator to NIH/ORDA

‘‘The Principal Investigator shall:

‘‘Section IV–B–7–b–(1). Submit

information to NIH/ORDA for

certification of new host-vector systems;

‘‘Section IV–B–7–b–(2). Petition NIH/

ORDA, with notice to the Institutional

Biosafety Committee, for proposed

exemptions to the NIH Guidelines;

‘‘Section IV–B–7–b–(3). Petition NIH/

ORDA, with concurrence of the

Institutional Biosafety Committee, for

approval to conduct experiments

specified in Sections III–A–1, Major

Actions Under the NIH Guidelines, and

III–B, Experiments that Require NIH/

ORDA and Institutional Biosafety

Committee Approval Before Initiation;

‘‘Section IV–B–7–b–(4). Petition NIH/

ORDA for determination of containment

for experiments requiring case-by-case

review; and

‘‘Section IV–B–7–b–(5). Petition NIH/

ORDA for determination of containment

for experiments not covered by the NIH

Guidelines.

‘‘Section IV–B–7–b–(6). Ensure that all

aspects of Appendix M, Points to

Consider in the Design and Submission

of Protocols for the Transfer of

Recombinant DNA Molecules into One

or More Human Subjects, have been

appropriately addressed prior to

submission of human gene therapy

experiments to NIH/ORDA.

‘‘Section IV–B–7–c. Submissions by the

Principal Investigator to the

Institutional Biosafety Committee

‘‘The Principal Investigator shall:

‘‘Section IV–B–7–c–(1). Make an

initial determination of the required

levels of physical and biological

containment in accordance with the

NIH Guidelines;

‘‘Section IV–B–7–c–(2). Select

appropriate microbiological practices

and laboratory techniques to be used for

the research;

‘‘Section IV–B–7–c–(3). Submit the

initial research protocol and any

subsequent changes (e.g., changes in the

source of DNA or host-vector system), if

covered under Sections III–A, III–B, III–

C, or III–D (Experiments Covered by the

NIH Guidelines), to the Institutional

Biosafety Committee for review and

approval or disapproval; and

‘‘Section IV–B–7–c–(4). Remain in

communication with the Institutional

Biosafety Committee throughout the

conduct of the project.

‘‘Section IV–B–7–d. Responsibilities of

the Principal Investigator Prior To

Initiating Research

‘‘The Principal Investigator shall:

‘‘Section IV–B–7–d–(1). Make

available to all laboratory staff the

protocols that describe the potential

biohazards and the precautions to be

taken;

‘‘Section IV–B–7–d–(2). Instruct and

train laboratory staff in: (i) The practices

and techniques required to ensure

safety, and (ii) the procedures for

dealing with accidents; and

‘‘Section IV–B–7–d–(3). Inform the

laboratory staff of the reasons and

provisions for any precautionary

medical practices advised or requested

(e.g., vaccinations or serum collection).

‘‘Section IV–B–7–e. Responsibilities of

the Principal Investigator During the

Conduct of the Research

‘‘The Principal Investigator shall:

‘‘Section IV–B–7–e–(1). Supervise the

safety performance of the laboratory

staff to ensure that the required safety

practices and techniques are employed;

‘‘Section IV–B–7–e–(2). Investigate

and report any significant problems

pertaining to the operation and

implementation of containment

practices and procedures in writing to

the Biological Safety Officer (where

applicable), Greenhouse/Animal

Facility Director (where applicable),

Institutional Biosafety Committee, NIH/

ORDA, and other appropriate

authorities (if applicable) (reports to

NIH/ORDA shall be sent 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);

‘‘Section IV–B–7–e–(3). Correct work

errors and conditions that may result in

the release of recombinant DNA

materials; and

‘‘Section IV–B–7–e–(4). Ensure the

integrity of the physical containment

(e.g., biological safety cabinets) and the

biological containment (e.g., purity and

genotypic and phenotypic

characteristics).

‘‘Section IV–B–7–e–(5). Comply with

reporting requirements for human gene
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59041

transfer experiments conducted in

compliance with the NIH Guidelines

(see Appendix M–VII, Reporting

Requirements—Human Gene Transfer

Protocols).

‘‘Section IV–C. Responsibilities of the

National Institutes of Health (NIH)

‘‘Section IV–C–1. NIH Director

‘‘The NIH Director is responsible for:

(i) Establishing the NIH Guidelines, (ii)

overseeing their implementation, and

(iii) their final interpretation. The NIH

Director has responsibilities under the

NIH Guidelines that involve ORDA and

RAC. ORDA’s responsibilities under the

NIH Guidelines are administrative.

Advice from RAC is primarily scientific,

technical, and ethical. In certain

circumstances, there is specific

opportunity for public comment with

published response prior to final action.

‘‘Section IV–C–1–a. General

Responsibilities

‘‘The NIH Director is responsible for:

‘‘Section IV–C–1–a–(1). Promulgating

requirements as necessary to implement

the NIH Guidelines;

‘‘Section IV–C–1–a–(2). Establishing

and maintaining RAC to carry out the

responsibilities set forth in Section IV–

C–2, Recombinant DNA Advisory

Committee (RAC membership is

specified in its charter and in Section

IV–C–2);

‘‘Section IV–C–1–a–(3). Establishing

and maintaining NIH/ORDA to carry out

the responsibilities defined in Section

IV–C–3, Office of Recombinant DNA

Activities;

‘‘Section IV–C–1–a–(4). Conducting

and supporting training programs in

laboratory safety for Institutional

Biosafety Committee members,

Biological Safety Officers and other

institutional experts (if applicable),

Principal Investigators, and laboratory

staff.

‘‘Section IV–C–1–a–(5). Establishing

and convening Gene Therapy Policy

Conferences as described in Appendix

L, Gene Therapy Policy Conferences.

‘‘Section IV–C–1–b. Specific

Responsibilities

‘‘In carrying out the responsibilities

set forth in this section, the NIH

Director, or a designee shall weigh each

proposed action through appropriate

analysis and consultation to determine

whether it complies with the NIH

Guidelines and presents no significant

risk to health or the environment.

‘‘Section IV–C–1–b–(1). Major Actions

‘‘To execute Major Actions, the NIH

Director shall seek the advice of RAC

and provide an opportunity for public

and Federal agency comment.

Specifically, the Notice of Meeting and

Proposed Actions shall be published in

the Federal Register at least 15 days

before the RAC meeting. The NIH

Director’s decision/recommendation (at

his/her discretion) may be published in

the Federal Register for 15 days of

comment before final action is taken.

The NIH Director’s final decision/

recommendation, along with responses

to public comments, shall be published

in the Federal Register. The RAC and

Institutional Biosafety Committee Chairs

shall be notified of the following

decisions:

‘‘Section IV–C–1–b–(1)–(a). Changing

containment levels for types of

experiments that are specified in the

NIH Guidelines when a Major Action is

involved;

‘‘Section IV–C–1–b–(1)–(b). Assigning

containment levels for types of

experiments that are not explicitly

considered in the NIH Guidelines when

a Major Action is involved;

‘‘Section IV–C–1–b–(1)–(c).

Promulgating and amending a list of

classes of recombinant DNA molecules

to be exempt from the NIH Guidelines

because they consist entirely of DNA

segments from species that exchange

DNA by known physiological processes

or otherwise do not present a significant

risk to health or the environment;

‘‘Section IV–C–1–b–(1)–(d). Permitting

experiments specified by Section III–A,

Experiments that Require Institutional

Biosafety Committee Approval, RAC

Review, and NIH Director Approval

Before Initiation;

‘‘Section IV–C–1–b–(1)–(e). Certifying

new host-vector systems with the

exception of minor modifications of

already certified systems (the standards

and procedures for certification are

described in Appendix I–II, Certification

of Host-Vector Systems). Minor

modifications constitute (e.g., those of

minimal or no consequence to the

properties relevant to containment); and

‘‘Section IV–C–1–b–(1)–(f). Adopting

other changes in the NIH Guidelines.

‘‘Section IV–C–1–b–(2). Minor Actions

‘‘NIH/ORDA shall carry out certain

functions as delegated to it by the NIH

Director (see Section IV–C–3, Office of

Recombinant DNA Activities). Minor

Actions (as determined by NIH/ORDA

in consultation with the RAC Chair and

one or more RAC members, as

necessary) will be transmitted to RAC

and Institutional Biosafety Committee

Chairs:

‘‘Section IV–C–1–b–(2)–(a). Changing

containment levels for experiments that

are specified in Section III, Experiments

Covered by the NIH Guidelines (except

when a Major Action is involved);

‘‘Section IV–C–1–b–(2)–(b). Assigning

containment levels for experiments not

explicitly considered in the NIH

Guidelines;

‘‘Section IV–C–1–b–(2)–(c). Revising

the Classification of Etiologic Agents for

the purpose of these NIH Guidelines

(see Section V–A, Footnotes and

References of Sections I–IV).

‘‘Section IV–C–1–b–(2)–(d).

Interpreting the NIH Guidelines for

experiments to which the NIH

Guidelines do not specifically assign

containment levels;

‘‘Section IV–C–1–b–(2)–(e). Setting

containment under Sections III–C–1–d,

Experiments Using Risk Group 2, Risk

Group 3, Risk Group 4, or Restricted

Agents as Host-Vector Systems, and III–

C–2–b, Experiments in which DNA from

Risk Group 2, Risk Group 3, Risk Group

4, or Restricted Agents is Cloned into

Nonpathogenic Prokaryotic or Lower

Eukaryotic Host-Vector Systems;

‘‘Section IV–C–1–b–(2)–(f). Approving

minor modifications of already certified

host-vector systems (the standards and

procedures for such modifications are

described in Appendix I–II, Certification

of Host-Vector Systems);

‘‘Section IV–C–1–b–(2)–(g).

Decertifying already certified hostvector systems;

‘‘Section IV–C–1–b–(2)–(h). Adding

new entries to the list of molecules toxic

for vertebrates (see Appendix F,

Containment Conditions for Cloning of

Genes Coding for the Biosynthesis of

Molecules Toxic for Vertebrates); and

‘‘Section IV–C–1–b–(2)–(i).

Determining appropriate containment

conditions for experiments according to

case precedents developed under

Section IV–C–1–b–(2)–(c).

‘‘Section IV–C–2. Recombinant DNA

Advisory Committee (RAC)

‘‘RAC is responsible for carrying out

specified functions cited below as well

as others assigned under its charter or

by the DHHS Secretary and the NIH

Director. RAC consists of 15 voting

members including the Chair, appointed

by the DHHS Secretary or his/her

designee, at least 8 of whom are selected

from authorities knowledgeable in the

fields of molecular genetics, molecular

biology, recombinant DNA research, or

other scientific fields. At least 4

members of RAC shall be persons

knowledgeable in applicable law,

standards of professional conduct and

practice, public attitudes, the

environment, public health,

occupational health, or related fields.

Representatives from Federal agencies

shall serve as non-voting members.
59042 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

Nominations for RAC members may be

submitted 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.

‘‘All meetings of RAC shall be

announced in the Federal Register,

including tentative agenda items, 15

days before the meeting. Final agendas,

if modified, shall be available at least 72

hours before the meeting. No item

defined as a Major Action under Section

IV–C–1–b–(1) may be added to an

agenda following Federal Register

publication.

‘‘RAC shall be responsible for:

‘‘Section IV–C–2–a. Advising the NIH

Director on the following actions: (1)

Adopting changes in the NIH

Guidelines. (2) Assigning containment

levels, changing containment levels, and

approving experiments considered as

Major Actions under the NIH

Guidelines, i.e., the deliberate transfer

of a drug resistance trait to

microorganisms that are not known to

acquire the trait naturally, if such

acquisition could compromise the use of

the drug to control disease agents in

humans, veterinary medicine, or

agriculture. (3) Promulgating and

amending lists of classes of recombinant

DNA molecules to be exempt from the

NIH Guidelines because they consist

entirely of DNA segments from species

that exchange DNA by known

physiological processes or otherwise do

not present a significant risk to health

or the environment. (4) Certifying new

host-vector systems.

‘‘Section IV–C–2–b. Identifying novel

human gene transfer experiments

deserving of public discussion by the

full RAC;

‘‘Section IV–C–2–c. Transmitting to

the NIH Director specific comments/

recommendations about: (i) A specific

human gene transfer experiment, or (ii)

a category of human gene transfer

experiments;

‘‘Section IV–C–2–d. Publicly

reviewing human gene transfer clinical

trial data and relevant information

evaluated and summarized by NIH/

ORDA in accordance with the annual

data reporting requirements;

‘‘Section IV–C–2–e. Identifying broad

scientific, safety, social, and ethical

issues relevant to gene therapy research

as potential Gene Therapy Policy

Conference topics;

‘‘Section IV–C–2–f. Identifying novel

social and ethical issues relevant to

specific human applications of gene

transfer and recommending appropriate

modifications to the Points to Consider

that will provide guidance in the

preparation of relevant Informed

Consent documents; and

‘‘Section IV–C–2–g. Identifying novel

scientific and safety issues relevant to

specific human applications of gene

transfer and recommending appropriate

modifications to the Points to Consider

that will provide guidance in the design

and submission of human gene transfer

clinical trials.

‘‘Section IV–C–3. Office of Recombinant

DNA Activities (ORDA)

‘‘ORDA shall serve as a focal point for

information on recombinant DNA

activities and provide advice to all

within and outside NIH including

institutions, Biological Safety Officers,

Principal Investigators, Federal

agencies, state and local governments,

and institutions in the private sector.

ORDA shall carry out such other

functions as may be delegated to it by

the NIH Director. ORDA’s

responsibilities include (but are not

limited to) the following:

‘‘Section IV–C–3–a. Serving as the

focal point for public access to summary

information pertaining to human gene

transfer experiments;

‘‘Section IV–C–3–b. Serving as the

focal point for data management of

human gene transfer experiments;

‘‘Section IV–C–3–c. Administering the

annual data reporting requirements (and

subsequent review) for human gene

transfer experiments (see Appendix M–

VII, Reporting Requirements—Human

Gene Transfer Protocols);

‘‘Section IV–C–3–d. Transmitting

comments/recommendations arising

from public RAC discussion of a novel

human gene transfer experiment to the

NIH Director. RAC recommendations

shall be forwarded to the Principal

Investigator, the sponsoring institution,

and other DHHS components, as

appropriate.

‘‘Section IV–C–3–e. Collaborating

with Principal Investigators,

Institutional Biosafety Committees,

Institutional Review Boards, and other

DHHS components (including FDA and

Office for Protection from Research

Risks), to ensure human gene transfer

experiment registration compliance in

accordance with Appendix M–I,

Submission Requirements, Human Gene

Transfer Experiments of the NIH

Guidelines.

‘‘Section IV–C–3–f. Administering

Gene Therapy Policy Conferences as

deemed appropriate by the NIH Director

(see Appendix L, Gene Therapy Policy

Conference).

‘‘Section IV–C–3–g. Reviewing and

approving experiments in conjunction

with ad hoc experts involving the

cloning of genes encoding for toxin

molecules that are lethal for vertebrates

at an LD50 of less than or equal to 100

nanagrams per kilogram body weight in

organisms other than Escherichia coli

K–12 (see Section III–B–1, Experiments

Involving the Cloning of Toxin

Molecules with LD50 of Less than 100

Nanograms Per Kilogram Body Weight,

Appendix F, Containment Conditions

for Cloning of Genes Coding for the

Biosynthesis of Molecules Toxic for

Verebrates);

‘‘Section IV–C–3–h. Serving as the

executive secretary of RAC;

‘‘Section IV–C–3–i. Publishing in the

Federal Register:

‘‘Section IV–C–3–i–(1).

Announcements of RAC meetings and

tentative agendas at least 15 days in

advance (Note: If the agenda for a RAC

meeting is modified, ORDA shall make

the revised agenda available to anyone

upon request in advance of the

meeting);

‘‘Section IV–C–3–i–(2).

Announcements of Gene Therapy Policy

Conferences and tentative agendas at

least 15 days in advance;

‘‘Section IV–C–3–i–(3). Proposed

Major Actions (see Section IV–C–1–b–

(1), Major Actions) at least 15 days prior

to the RAC meeting; and

‘‘Section IV–C–3–j. Reviewing and

approving the membership of an

institution’s Institutional Biosafety

Committee, and where it finds the

Institutional Biosafety Committee meets

the requirements set forth in Section IV–

B–2, Institutional Biosafety Committee

(IBC), giving its approval to the

Institutional Biosafety Committee

membership.

‘‘Section IV–C–4. Other NIH

Components

‘‘Other NIH components shall be

responsible for certifying maximum

containment (BL4) facilities, inspecting

them periodically, and inspecting other

recombinant DNA facilities as deemed

necessary.

‘‘Section IV–D. Voluntary Compliance

‘‘Section IV–D–1. Basic Policy—

Voluntary Compliance

‘‘Individuals, corporations, and

institutions not otherwise covered by

the NIH Guidelines are encouraged to

follow the standards and procedures set

forth in Sections I through IV. In order

to simplify discussion, references

hereafter to ‘institutions’ are intended to

encompass corporations and individuals

who have no organizational affiliation.

For purposes of complying with the NIH

Guidelines, and individual intending to

carry out research involving

recombinant DNA is encouraged to
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59043

affiliate with an institution that has an

Institutional Biosafety Committee

approved under the NIH Guidelines.

‘‘Since commercial organizations have

special concerns, such as protection of

proprietary data, some modifications

and explanations of the procedures are

provided in Section IV–D–2 through IV–

D–5–b, Voluntary Compliance, in order

to address these concerns.

‘‘Section IV–D–2. Institutional Biosafety

Committee Approval—Voluntary

Compliance

‘‘It should be emphasized that

employment of an Institutional

Biosafety Committee member solely for

purposes of membership on the

Institutional Biosafety Committee does

not itself make the member an

institutionally affiliated member. Except

for the unaffiliated members, a member

of an Institutional Biosafety Committee

for an institution not otherwise covered

by the NIH Guidelines may participate

in the review and approval of a project

in which the member has a direct

financial interest so long as the member

has 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 purposes

of these institutions.

‘‘Section IV–D–3. Certification of HostVector Systems—Voluntary Compliance

‘‘A host-vector system may be

proposed for certification by the NIH

Director in accordance with the

procedures set forth in Appendix I–II,

Certification of Host-Vector Systems. In

order to ensure protection for

proprietary data, any public notice

regarding a host-vector system which is

designated by the institution as

proprietary under Section IV–D,

Voluntary Compliance, will be issued

only after consultation with the

institution as to the content of the

notice.

‘‘Section IV–D–4. Requests for

Exemptions and Approvals—Voluntary

Compliance

‘‘Requests for exemptions or other

approvals as required by the NIH

Guidelines should be submitted based

on the procedures set forth in Sections

I through IV. In order to ensure

protection for proprietary data, any

public notice regarding a request for an

exemption or other approval which is

designated by the institution as

proprietary under Section IV–D–5–a,

Voluntary Compliance, will be issued

only after consultation with the

institution as to the content of the

notice.

‘‘Section IV–D–5. Protection of

Proprietary Data—Voluntary

Compliance

‘‘Section IV–D–a. General

‘‘In general, the Freedom of

Information Act requires Federal

agencies to make their records available

to the public upon request. However,

this requirement does not apply to,

among other things, ‘trade secrets and

commercial or financial information

that is obtained from a person and that

is privileged or confidential.’ Under 18

U.S.C. 1905, it is a criminal offense for

an officer or employee of the U.S. or any

Federal department or agency to

publish, divulge, disclose, or make

known ‘in any manner or to any extent

not authorized by law any information

coming to him in the course of his

employment or official duties or by

reason of any examination or

investigation made by, or return, report

or record made to or filed with, such

department or agency or officer or

employee thereof, which information

concerns or relates to the trade secrets,

(or) processes * * * of any person, firm,

partnership, corporation, or association.’

This provision applies to all employees

of the Federal Government, including

special Government employees.

Members of RAC are ‘special

Government employees.’

‘‘In submitting to NIH for purposes of

voluntary compliance with the NIH

Guidelines, an institution may designate

those items of information which the

institution believes constitute trade

secrets, privileged, confidential,

commercial, or financial information. If

NIH receives a request under the

Freedom of Information Act for

information so designated, NIH will

promptly contact the institution to

secure its views as to whether the

information (or some portion) should be

released. If NIH decides to release this

information (or some portion) in

response to a Freedom of Information

request or otherwise, the institution will

be advised and the actual release will be

delayed in accordance with 45 Code of

Federal Regulations, § 5.65 (d) and (e).

‘‘Section IV–D–5–b. Pre-submission

Review

‘‘Any institution not otherwise

covered by the NIH Guidelines, which

is considering submission of data or

information voluntarily to NIH, may

request pre-submission review of the

records involved to determine if NIH

will make all or part of the records

available upon request under the

Freedom of Information Act.

‘‘A request for pre-submission review

should be submitted to NIH/ORDA

along with the records involved 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. These records shall be clearly

marked as being the property of the

institution on loan to NIH solely for the

purpose of making a determination

under the Freedom on Information Act.

NIH/ORDA will seek a determination

from the responsible official under

DHHS regulations (45 CFR part 5) as to

whether the records involved, (or some

portion) will be made available to

members of the public under the

Freedom of Information Act. Pending

such a determination, the records will

be kept separate from NIH/ORDA files,

will be considered records of the

institution and not NIH/ORDA, and will

not be received as part of NIH/ORDA

files. No copies will be made of such

records.

‘‘NIH/ORDA will inform the

institution of the DHHS Freedom of

Information Officer’s determination and

follow the institution’s instructions as to

whether some or all of the records

involved are to be returned to the

institution or to become a part of NIH/

ORDA files. If the institution instructs

NIH/ORDA to return the records, no

copies or summaries of the records will

be made or retained by DHHS, NIH, or

ORDA. The DHHS Freedom of

Information Officer’s determination will

represent that official’s judgment at the

time of the determination as to whether

the records involved (or some portion)

would be exempt from disclosure under

the Freedom of Information Act if at the

time of the determination the records

were in NIH/ORDA files and a request

was received for such files under the

Freedom of Information Act.’’

II–E. Amendments to Appendix A,

Exemptions Under Section III–E–5—

Sub-lists of Natural Exchanges

Appendix A, first paragraph, is

amended to reflect renumbering of a

previous section.

II–F. Amendments to Appendix C,

Exemptions Under Section III–E–6

Appendix C is amended to reflect

renumbering of a previous section.

II–G. Amendments to Appendix I,

Biological Containment

After the first paragraph in Section I–

II–A, Responsibility, the following Note

is added:

‘‘Note. A host-vector system may be

proposed for certification by the NIH Director

in accordance with the procedures set forth

in Appendix I–II, Certification of Host-Vector

Systems. In order to ensure protection for
59044 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

proprietary data, any public notice regarding

a host-vector system which is designated by

the institution as proprietary under Section

IV–D, Voluntary Compliance, will be issued

only after consultation with the institution as

as to the content of the notice (see Section

IV–D–3, Certification of Host-Vector SystemsVoluntary Compliance).’’

II–H. Addition of Appendix L, Gene

Therapy Policy Conferences, to the NIH

Guidelines

Appendix L is to read:

‘‘Appendix L. Gene Therapy Policy

Conferences (GTPCs)

‘‘In order to enhance the depth and

value of public discussion relevant to

scientific, safety, social, and ethical

implications of gene therapy research,

the NIH Director will convene GTPCs at

regular intervals. As appropriate, the

NIH Director may convene a GTPC in

conjunction with a RAC meeting. GTPCs

will be administered by NIH/ORDA.

Conference participation will not

involve a standing committee

membership but rather will offer the

unique advantage of assembling

numerous participants who possess

significant scientific, ethical, and legal

expertise and/or interest that is directly

applicable to a specific gene therapy

research issue. At least one member of

RAC will serve as Co-chair of each

GTPC and report the findings of each

GTPC to RAC at its next scheduled

meeting. The RAC representative for

each GTPC will be chosen based on the

participant’s area of expertise relative to

the specific gene therapy research issue

to be discussed. All RAC members will

be invited to attend GTPCs. GTPCs will

have representation from other Federal

agencies, including FDA and OPRR.

GTPCs will focus on broad overarching

policy and scientific issues related to

gene therapy research. Proposals for

GTPC topics may be submitted by

members of RAC, representatives of

academia, industry, patient and

consumer advocacy organizations, other

Federal agencies, professional scientific

societies, and the general public. GTPC

topics will not be limited to discussion

of human applications of gene therapy

research, i.e., they may include basic

research on the use of novel gene

delivery vehicles, or novel applications

of human gene transfer. The RAC, with

the Director’s approval, will have the

primary responsibility for planning

GTPC agendas. GTPC findings will be

transmitted to the NIH Director and will

be made publicly available. The NIH

Director anticipates that this public

policy forum will serve as a model for

interagency communication and

collaboration, concentrated expert

discussion of novel scientific issues and

their potential societal implications, and

enhanced opportunity for public

discussion of specific issues and

potential impact of such applications on

human health and the environment.’’

II–I. Amendments to Appendix M,

Points To Consider in the Design and

Submission of Protocols for the

Transfer of Recombinant DNA

Molecules Into One or More Human

Subjects

Appendix M is amended to read:

‘‘Appendix M. Points To Consider in

the Design and Submission of Protocols

for the Transfer of Recombinant DNA

Molecules Into One or More Human

Subjects (Points to Consider)

‘‘Appendix M applies to research

conducted at or sponsored by an

institution that receives any support for

recombinant DNA research from NIH.

Researchers not covered by the NIH

Guidelines are encouraged to use

Appendix M (see Section I–C, General

Applicability).

‘‘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 that 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, RAC is

prepared to consider proposals for

somatic cell gene transfer.

‘‘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 NIH/ORDA and RAC.

Investigators shall submit their relevant

information on the proposed human

gene transfer experiments to NIH/

ORDA. Submission of human gene

transfer protocols to NIH will be in the

format described in Appendix M–I,

Submission Requirements—Human

Gene Transfer Experiments. Submission

to NIH shall be for registration purposes

and will ensure continue public access

to relevant human gene transfer

information conducted in compliance

with the NIH Guidelines. Investigational

New Drug (IND) applications should be

submitted to FDA in the format

described in 21 CFR, Chapter I,

Subchapter D, Part 312, Subpart B,

Section 23, IND Content and Format.

‘‘Institutional Biosafety Committee

approval must be obtained from each

institution at which recombinant DNA

material will be administered to human

subjects (as opposed to each institution

involved in the production of vectors for

human application and each institution

at which there is ex vivo transduction

of recombinant DNA material into target

cells for human application).

‘‘Factors that may contribute to public

discussion of a human gene transfer

experiment by RAC 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

discussion are those determined not to

represent possible risk to human health

or the environment. Full RAC review of

an individual human gene transfer

experiment can be initiated by the NIH

Director or recommended to the NIH

Director by: (i) Three or more RAC

members, or (ii) other Federal agencies.

An individual human gene transfer

experiment that is recommended for full

RAC review should represent novel

characteristics deserving of public

discussion. If the Director, NIH,

determines that an experiment will

undergo full RAC discussions, NIH/

ORDA will immediately notify the

Principal Investigator. RAC members

may forward individual requests for

additional information relevant to a

specific protocol through NIH/ORDA to

the Principal Investigator. In making a
Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices 59045

determination whether an experiment is

novel, and thus deserving of full RAC

discussion, reviewers will examine the

scientific rationale, scientific context

(relative to other proposals reviewed by

RAC), whether the preliminary in vitro

and in vivo safety data were obtained in

appropriate models and are sufficient,

and whether questions related to

relevant social and ethical issues have

been resolved. RAC recommendations

on a specific human gene transfer

experiment shall be forwarded to the

NIH Director, the Principal Investigator,

the sponsoring institution, and other

DHHS components, as appropriate.

Relevant documentation will be

included in the material for the RAC

meeting at which the experiment is

scheduled to be discussed. RAC

meetings will be open to the public

except where trade secrets and

proprietary information are reviewed

(see Section IV–D–5, Protection of

Proprietary Data). RAC prefers 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.

‘‘Note: Any application submitted to NIH/

ORDA shall not be designated as

‘confidential’ in its entirety. In the event that

a sponsor determines that specific responses

to one or more of the items described in

Appendix M should be considered as

proprietary or trade secret, each item should

be clearly identified as such. The cover letter

(attached to the submitted material) shall: (1)

Clearly indicate that select portions of the

application contain information considered

as proprietary or trade secret, (2) a brief

explanation as to the reason that each of

these items is determined proprietary or

trade secret.

‘‘Public discussion of human gene

transfer experiments (and access to

relevant information) shall serve to

inform the public about the technical

aspects of the proposals, meaning and

significance of the research, and

significant safety, social, and ethical

implications of the research. RAC

discussion is intended to ensure safe

and ethical conduct of gene therapy

experiments and facilitate public

understanding of this novel area of

biomedical research.

In its evaluation of human gene

transfer proposals, RAC 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 request information that will

enable 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).

‘‘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. 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–VIII–A, Footnotes of Appendix M).

Proposals shall be submitted to NIH/

ORDA in the following order: (1)

Scientific abstract; (2) non-technical

abstract; (3) Institutional Biosafety

Committee and Institutional Review

Board approvals and their deliberations

pertaining to your protocol (Institutional

Biosafety Committee approval must be

obtained from each institution at which

recombinant DNA material will be

administered to human subjects (as

opposed to each institution involved in

the production of vectors for human

application and each institution at

which there is ex vivo transduction of

recombinant DNA material into target

cells for human application)); (4)

Responses to Appendix M–II through

M–V, Description of the Proposal,

Informed Consent, Privacy and

Confidentiality, and Special Issues (the

pertinent responses can be provided in

the protocol or as an appendix to the

protocol); (5) clinical protocol (as

approved by the local Institutional

Biosafety Committee and Institutional

Review Board); (6) Informed Consent

document—approved by the

Institutional Review Board (see

Appendix M–III, Informed Consent); (7)

appendices (including tables, figures,

and manuscripts); and (8) curricula

vitae—2 pages for each key professional

person in biographical sketch format.

Investigational New Drug (IND)

applications shall be submitted to FDA

in the format described in 21 CFR,

chapter I, subchapter D, part 312,

subpart B, section 23, IND Content and

Format. Submissions to FDA should be

sent to the Division of Congressional

and Public Affairs, Document Control

Center, HFM–99, Center for Biologics

Evaluation and Research, 1401

Rockville Pike, Rockville, Maryland

20852–1448.

‘‘Appendix M–II. Description of the

Proposal’’

[This section remains unchanged]

‘‘Appendix M–III. Informed Consent’’

[This section remains unchanged]

‘‘Appendix M–IV. Privacy and

Confidentiality’’

[This section remains unchanged]

‘‘Appendix M–V. Special Issues’’

[This section remains unchanged]

‘‘Appendix M–VI. RAC Review—

Human Gene Transfer Experiments

‘‘In order to maintain public access to

information regarding human gene

transfer protocols, NIH/ORDA will

maintain the documentation described

in Appendices M–I through M–V

(including protocols that are not

reviewed by RAC). RAC prefers that

information provided in response to

Appendix M, Points to Consider,

contain no proprietary data or trade

secrets, enabling all aspects of the

discussion to be open to the public.

‘‘Appendix M–VI–A. RAC Members’

Written Comments

‘‘Following receipt by NIH/ORDA,

summary information on each human

gene transfer protocol will be forwarded

to RAC members. Each RAC member

shall notify NIH/ORDA within 15

working days regarding the necessity for

full RAC discussion. Full RAC review of

an individual human gene transfer

experiment can be initiated by the NIH

Director or recommended to the NIH

Director by: (i) Three or more RAC

members, or (ii) other Federal agencies.

An individual human gene transfer

experiment that is recommended for full

RAC review should represent novel

characteristics deserving of public

discussion. If the Director, NIH,

determines that an experiment will

undergo full RAC discussion, NIH/

ORDA will immediately notify the

Principal Investigator. RAC members

may forward individual requests for

additional information relevant to a

specific protocol through NIH/ORDA to

the Principal Investigator. In making a

determination whether an experiment is

novel, and thus deserving of full RAC
59046 Federal Register / Vol. 62, No. 211 / Friday, October 31, 1997 / Notices

discussion, reviewers shall examine the

scientific rationale, scientific context

(relative to other proposals reviewed by

RAC), whether the preliminary in vitro

and in vitro safety data were obtained in

appropriate models and are sufficient,

and whether questions related to

relevant social and ethical issues have

been resolved. RAC recommendations

on a specific human gene transfer

experiment shall be forwarded to the

NIH Director, the Principal Investigator,

the sponsoring insititution, and other

DHHS components, as appropriate.

‘‘Appendix M–VII. Reporting

Requirements—Human Gene Transfer

Protocols

‘‘Appendix M–VII–A. Investigational

New Drug Application Reporting

‘‘Upon receipt of notification of

permission to proceed with an

Investigational New Drug application

for a human gene transfer protocol, the

Principal Investigator(s) shall submit a

written report that includes the

following information: (1) How the

investigator(s) responded to RAC’s

recommendations on the protocol (if

applicable), and (2) any modifications to

the protocol as required by FDA.

‘‘Appendix M–VII–B. Annual Data

Reporting and Gene Therapy Database

‘‘Investigators shall comply with

annual data reporting requirements.

Annual Data Report forms will be

forwarded by NIH/ORDA to

investigators. Data submitted in these

reports will be evaluated by RAC and

NIH/ORDA, and reviewed at a future

RAC meeting. Information obtained

through annual data reporting will be

included in a human gene transfer

database that will be administered by

NIH/ORDA. The purpose of this human

gene transfer database is to: (1) Maintain

an institutional memory, (2) provide

administrative details of protocol

registration, (3) provide annual status

reports of protocols, (4) facilitate risk

assessment of individual applications of

human gene transfer, and (5) enhance

public awareness of relevant scientific,

safety, social, and ethical issues.

‘‘Appendix M–VII–C. Adverse Event

Reporting

‘‘Investigators who have received

approval for FDA to initiate a human

gene transfer protocol must report any

serious adverse event immediately to

the local Institutional Review Board,

Institutional Boisafety Committee,

Office for Protection from Research

Risks (if applicable), NIH/ORDA, and

FDA, followed by the submission of a

written report filed with each group.

Reports submitted to NIH/ORDA shall

be sent 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.

‘‘Appendix VIII. Footnotes of Appendix

M

‘‘Appendix VIII–A. Human studies in

which induction or enhancement of an

immune response to a vector-encoded

microbialimmunogen is the major goal,

such an immune response has been

demonstrated in model systems, and the

persistence of the vector-encoded

immunogen is not expected, are exempt

from Appendix M–I, Submission

Requirements, and Appendix M–VII,

Reporting Requirements—Human Gene

Transfer Experiments.’’

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 virtually

every NIH and Federal research program

in which recombinant DNA molecule

techniques could be used, it has been

determined not to be cost effective or in

the public interst 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.

Effective Date: October 22, 1997.

Harold Varmus,

Director, National Institutes of Health.

[FR Doc. 97–28921 Filed 10–30–97; 8:45 am]

BILLING CODE 4140–01–M