Recombinant DNA Research: Proposed Actions Under the Guidelines

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

Recombinant DNA Research: Proposed Actions Under the Guidelines

Agency: National Institutes of Health (NIH), PHS, DHHS.

Action: Notice of Proposed Actions Under the NIH Guidelines for

Research Involving Recombinant DNA Molecules.

-----------------------------------------------------------------------

SUMMARY: This notice sets forth proposed actions to be taken under the

NIH Guidelines for Research Involving Recombinant DNA Molecules (59 FR

34496, amended 59 FR 40170, 60 FR 20726, 61 FR 1482, 61 FR 10004, 62 FR

4782). Interested parties are invited to submit comments concerning

these proposals. There proposals will be considered by the Recombinant

DNA Advisory Committee (RAC) at its meeting on March 6-7, 1997. After

consideration of these proposals and comments by the RAC, the NIH

Director will issue decisions in accordance with the NIH Guidelines.

Dates: Interested parties are invited to submit comments concerning

this proposal. Comments received by February 27, 1997, will be

reproduced and distributed to the RAC for consideration at its March 6-

7, 1997, meeting. After consideration of this proposal and comments by

the RAC, the NIH Director will issue decisions in accordance with the

NIH Guidelines.

Addresses: Written comments and recommendations should be submitted to

Debra Knorr, Office of Recombinant DNA Activities, National Institutes

of Health, MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,

Maryland 20892-7010, or by FAX to 301-496-9839.

All comments received in response to this notice will be considered

and will be available for public inspection in the above office on

weekdays between the hours of 8:30 a.m. and 5 p.m.

For Further Information Contact: Background documentation and

additional information can be obtained from the Office of Recombinant

DNA Activities, National Institutes of Health, MSC 7010, 6000 Executive

Boulevard, Suite 302, Bethesda, Maryland 20892-7010, Phone 301-496-

9838, FAX 301-496-9839.

Supplementary Information: The NIH will consider the following actions

under the NIH Guidelines for Research Involving Recombinant DNA

Molecules:

I. Amendment to the Overall Procedures for Human Gene Transfer

Protocols

I-A. Notice of Intent

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 NIH oversight of human gene transfer research.

Specifically, it was proposed that the 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 oversight 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

(GTPC). 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, the 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,

[[Page 7109]]

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 were submitted.

I-B. Proposed Actions--November 1996

On November 22, 1996, the NIH Director published Notice of Proposed

Actions Under the NIH Guidelines for Research Involving Recombinant DNA

Molecules (61 FR 59725). 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 discussion of gene

therapy.

In the Proposed Actions, the NIH Director proposed to: (1) Retain

the 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) reduce the membership of RAC from 25 members

to 15 members; (4) regularly convene GTPC; and (5) maintain public

access to human gene transfer clinical trial information. The following

summarizes the roles and responsibilities of the NIH Director, the RAC,

the ORDA, and the 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. The NIH Director

The roles and responsibilities of the NIH Director remain unchanged

except for relinquishing approval of human gene transfer experiments,

and establishing and convening Gene Therapy Policy Conferences. The NIH

Director is responsible for establishing the NIH Guidelines, overseeing

their implementation, and their final interpretation; promulgating

requirements as necessary to implement the NIH Guidelines; establishing

and maintaining the RAC; establishing and maintaining ORDA; 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; and establishing and convening Gene Therapy Policy

Conferences.

I-B-1-b. The Recombinant DNA Advisory Committee

The RAC will remain a chartered public advisory committee to the

NIH Director regarding recombinant DNA research conducted in compliance

with the NIH Guidelines. The RAC will conduct quarterly meetings. RAC

members will continue to be appointed by the DHHS Secretary or his/her

designee for 4-year terms. RAC membership will be reduced from 25 to 15

members. At least eight of these members shall be knowledgeable in the

fields of molecular genetics, molecular biology, recombinant DNA

research, or other related fields and at least four of these members

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

of Federal agencies shall continue to serve as non-voting members.

The RAC will be responsible for: (1) Identifying novel human gene

transfer experiments deserving of public discussion by the full RAC and

transmitting comments/recommendations about specific human gene

transfer experiments or categories of human gene transfer experiments

to the NIH Director. (2) Identifying novel 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. (3)

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. (4)

Publicly reviewing human gene transfer clinical trial data captured by

NIH/ORDA in accordance with the annual data reporting requirements. (5)

Identifying broad scientific and ethical/social issues relevant to gene

therapy research as potential Gene Therapy Policy Conference topics.

The RAC will advise 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.

I-B-1-c. Gene Therapy Policy Conferences (GTPCs)

In order to enhance the depth and value of public discussion

relevant to scientific, safety, and ethical/societal implications of

gene therapy research, the NIH Director will convene GTPC at regular

intervals. As appropriate, the NIH Director may convene GTPC

immediately following scheduled RAC meetings. GTPC will be administered

by the 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 the RAC will serve as Co-chair of each GTPC and report the

findings of the GTPC to the full committee 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. GTPC will have representation

from other Federal agencies, including the FDA. GTPCs will focus on

broad over-arching policy and scientific issues related to gene therapy

research. Proposals for GTPC topics may be submitted by members of the

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 gene transfer. The findings of the GTPC 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

[[Page 7110]]

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. 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's

responsibilities include (but are not limited to) the following: (1)

Serving as the focal point for public access to summary information

pertaining to human gene transfer experiments. (2) Serving as the focal

point for data management of human gene transfer experiments. (3)

Administering the annual data reporting requirements (and subsequent

review) for human gene transfer experiments. (4) 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, sponsoring institution, and

other Department of Health and Human Services (DHHS) components, as

appropriate. (5) Collaborating with Principal Investigators,

Institutional Biosafety Committees, Institutional Review Boards, and

other DHHS components, to ensure human gene transfer experiment

registration compliance. (6) Administering Gene Therapy Policy

Conferences as deemed appropriate by the NIH Director. (7) 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 nanograms per

kilogram body weight in organisms other than Escherichia coli K-12. (8)

Serving as the executive secretary of the RAC. (9) Publishing in the

Federal Register the announcements of RAC meetings and tentative

agendas at least 15 days in advance, announcements of Gene Therapy

Policy Conferences and tentative agendas at least 15 days in advance,

proposed Major Actions at least 15 days prior to the RAC meeting; and

(10) Reviewing and approving the membership of an institution's

Institutional Biosafety Committee.

I-B-1-e. Local Institutions

The Notice of Proposed Actions would change the roles and

responsibilities of local institutions, Institutional Biosafety

Committees, Biosafety Officers, Principal Investigators, Animal

Facility Directors, Greenhouse Supervisors, and Human Gene Therapy

experts relevant to recombinant DNA research conducted in compliance

with the NIH Guidelines. These changes now include the following

requirements: (1) When the institution conducts recombinant DNA

research that requires Institutional Biosafety Committee approval, the

institution shall appoint at least one individual with expertise in

plant, plant pathogen, or plant pest containment principles (who is

also a member of the Institutional Biosafety Committee); (2) when the

institution conducts recombinant DNA research that requires

Institutional Biosafety Committee approval, the institution shall

appoint at least one individual with expertise in animal containment

principles (who is also a member of the Institutional Biosafety

Committee); and (3) when the institution participates in or sponsors

recombinant DNA research involving human subjects, the institution must

ensure that: (a) The Institutional Biosafety Committee has adequate

expertise and training (using ad hoc consultants as deemed necessary)

and (b) 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.

I-C. Recombinant DNA Advisory Committee Meeting--December 1996

During the December 9, 1996, Recombinant DNA Advisory Committee

meeting, the following motions were made:

I-C-1. Future RAC Membership--Committee Motion 1

A motion was made to invite former RAC members back to serve as ad

hoc consultants in order to ensure institutional continuity of the RAC.

The motion passed by a vote of 15 in favor, 0 opposed, and no

abstentions.

I-C-2. Triggering Mechanism for RAC Discussion--Committee Motion 2

A motion was made that: (1) The capacity for principal

investigators and institutional representatives to request public RAC

discussion of an individual gene transfer protocol should be deleted.

(2) A decision by the RAC to require full review of an individual

protocol should not have to be approved by the NIH Director. (3) The

NIH Director or an appropriate FDA representative may also request RAC

review of an individual protocol. (4) Rather than a majority vote, RAC

recommendations for full review of an individual protocol should be

changed to a minimum of three members. (5) 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-3. Feedback Mechanism--Committee Motion 3

A motion was made to request FDA to report back to the RAC how the

RAC recommendations on an individual protocol were implemented. The RAC

should require investigators to provide additional information if the

FDA information is not adequate. The motion failed by a vote of 3 in

favor, 7 opposed, and 4 abstentions.

I-C-4. Feedback Mechanism--Committee Motion 4

A motion was made to require investigators to report back to the

RAC in writing in a timely fashion. The report should include a

statement of how the investigators have responded to RAC's

recommendations and any modifications to the protocol following FDA

review. The motion passed by a vote of 12 in favor, 1 opposed, and 1

abstention.

I-C-5. Relationship of the RAC and GTPC--Committee Motion 5

A motion was made that the RAC, with the NIH Director's approval,

should have the primary responsibility for: (1) Planning the GTPC

agendas, and (2) summarizing GTPC recommendations in the form of a

report back to the NIH Director. The close GTPC/RAC relationship should

not preclude other parties from suggesting GTPC topics and GTPC should

be convened in consultation with FDA. The motion passed by a vote of 13

in favor, 0 opposed, and 2 abstentions.

I-C-6. Proposed Actions Concepts--Committee Motion 6

A motion was made to accept the overall concepts put forward in the

Proposed Actions as published in the November 22, 1996, Federal

Register (61 FR 59725). Specifically: (1) Retain the 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) reduce the membership of RAC from 25 members to 15

members; (4) regularly convene GTPC; and (5) maintain public access to

human

[[Page 7111]]

gene transfer clinical trial information. The members of the RAC noted

that several minor modifications still remained unresolved,

particularly with regard to the future discussion of gene therapy

protocols and defining the role of the RAC relative to the GTPCs. The

RAC recommended that final action on the Proposed Actions should be

postponed to the March 6-7, 1997, RAC meeting, in order to more fully

address these unresolved issues. The motion passed by a vote of 12 in

favor, 0 opposed, and 2 abstentions.

II. Meetings Between the NIH and FDA Regarding Simultaneous Submission

to Human Gene Transfer Protocols to the NIH and the 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 the

RAC and FDA. In her November 20, 1996, letter, Dr. Miller states:

`` * * * (1) Remove the requirement for submission of Appendix M to

the FDA. The FDA does not accept Appendix M in place of an IND

submission. The FDA is not proposed to be and need not be included in

the decision making process to identify protocols to undergo full RAC

review. Therefore, there is no reason for sponsors to submit Appendix M

materials to the FDA.

``(2) Explore the feasibility of a unified format for submission of

protocols to the 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 the 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 the

NIH and the FDA with regard to simultaneous submission of human gene

transfer protocols. The recommendations of NIH and FDA staff are

incorporated below in the Proposed Actions Regarding the Overall

Procedures for Human Gene Transfer Protocol.

III. Proposed Actions Regarding the Overall Procedures for Human Gene

Transfer Protocols

The NIH will consider the following proposed actions under the NIH

Guidelines for Research Involving Recombinant DNA Molecules:

[Note: Editorial changes and updating of references have been

incorporated to clarify the document.]

III-A. Proposed Amendments to Section I, Scope of the NIH Guidelines

Section I is proposed to be 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 the NIH, must be submitted to

the NIH or to another Federal agency that has jurisdiction for review

and approval. Once approvals, or other applicable clearances, have been

obtained from a Federal agency other than the NIH (whether the

experiment is referred to that agency by the NIH or sent directly there

by the submitter), the experiment may proceed without the necessity for

NIH review or approval. (See exception in Section I-A-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 the FDA of such information on the

proposed experiment as is prescribed by those agencies. Submission of

human gene transfer protocols to the NIH will be in the format

described in Appendix M-I, Submission Requirements--Human Gene Transfer

Experiments, of the NIH Guidelines. Submission to NIH shall be for

registration purposes and will ensure continued public access to

relevant human gene transfer information conducted in compliance with

the NIH Guidelines. Submission of human gene transfer protocols to the

FDA will be 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 thus deserving of full RAC discussion, reviewers will

examine the scientific rational, scientific content (relative to other

proposals reviewed by the RAC), whether the preliminary in vitro and in

vivo data were obtained in appropriate models and are sufficient, and

whether questions related to safety, efficacy, and social/ethical

contest 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 to other

Department of Health and Human Services (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 the NIH, including research performed directly by the 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

[[Page 7112]]

collaboration or contractual agreements, not mere provision 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.

[The remainder of Section I is proposed to be renumbered to reflect

above changes.]

III-B. Proposed Amendments to Section II, Safety Considerations

The second paragraph of Section II-A-3 is proposed to be 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 * * *

III-C. Proposed Amendments to Section III, Experiments Covered by the

NIH Guidelines

Section III is proposed to be amended to read:

Section III. Experiments Covered by the NIH Guidelines

This section describes six categories of experiments involving

recombinant DNA: (i) Those that require Institutional Biosafety

Committee (IBC) approval, RAC review, and NIH Director approval before

initiation (see Section III-A), (ii) those that require NIH/ORDA and

Institutional Biosafety Committee approval before initiation (see

Section III-B), (iii) those that require Institutional Biosafety

Committee 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

III-A, III-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

the RAC, and specific approval by the NIH. The containment conditions

or stipulation requirements for such experiments will be recommended by

the RAC and set by the NIH at the time of approval. Such experiments

require Institutional Biosafety Committee approval before initiation.

Specific experiments already approved are included in Appendix D, 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

[[Page 7113]]

control disease agents in humans, veterinary medicine, or agriculture,

will be reviewed by the 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, diphtheria toxin,

and Shigella dysenteriae neurotoxin). Specific approval has been given

for the cloning in Escherichia coli K-12 of DNA containing genes coding

for the biosynthesis of toxic molecules which are lethal to vertebrates

at 100 nanograms to 100 micrograms per kilogram body weight. Specific

experiments already approved under this section may be obtained from

the Office of Recombinant DNA Activities, National Institutes of

Health/MSC 7010, 6000 Executive Boulevard, Suite 302, Bethesda,

Maryland 20892-7010, (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 Human

Subjects

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 of

relevant information on the proposed experiment to both NIH/ORDA and

the FDA. Submission to NIH/ORDA shall be for registration purposes and

will ensure continued public access to relevant human gene transfer

information conducted in compliance with the NIH Guidelines. Submission

of human gene transfer protocols to the NIH will be in the format

described in Appendix M-I, Submission Requirements--Human Gene Transfer

Experiments, of the NIH Guidelines. Submission of human gene transfer

protocols to the FDA will be in the format described in 21 CFR, Chapter

I, Subchapter D, Part 312, Subpart B, Section 23, IND Content and

Format. Prior to submission of a human gene transfer experiment to NIH/

ORDA, the Principal Investigator must obtain Institutional Biosafety

Committee (IBC) approval from each institution that will handle

recombinant DNA material that is to be administered to human subjects

and Institutional Review Board approval from each institution in which

human subjects will undergo gene transfer. Specifically: (1) Any

institution involved in the production of the vectors for human

application, (2) any institution at which there is ex vivo transduction

of the recombinant DNA material into target cells for human

application, and (3) any institution at which the recombinant DNA

material will be directly administered to human subjects. These local

committee approvals and relevant protocol documentation shall be

submitted to NIH/ORDA for registration purposes and determination

regarding the necessity of full RAC review and approval/disapproval.

The RAC prefers that submission to NIH/ORDA in accordance with

Appendix M-I, Submission Requirements--Human Gene Transfer Experiments,

of the NIH Guidelines, 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. The 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.

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 Department of

Health and Human Services (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.

Section III-D. Experiments That Require Institutional Biosafety

Committee Approval Before Initiation

[This section remains unchanged except for renumbering and reference

changes due to renumbering.]

Section III-E. Experiments That Require Institutional Biosafety

Committee Notice Simultaneous With Initiation

[This section remains unchanged except for renumbering and reference

changes due to renumbering.]

Section III-F. Exempt Experiments

[This section remains unchanged except for renumbering and reference

changes due to renumbering.]

III-D. Proposed Amendments to Section IV, Roles and Responsibilities

Section IV is proposed to be 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 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

[[Page 7114]]

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 the 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

also 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 also 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. 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 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. Institutional Biosafety Committee approval must

be obtained from each institution that will handle recombinant DNA

material that is to be administered to human subjects.

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 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:

[[Page 7115]]

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 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. Institutional Biosafety Committee approval

must be obtained from each institution that will handle recombinant DNA

material that is to be administered to human subjects.

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-E-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), plant expert (if

applicable), and animal expert (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

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-2-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 Eukaryotic 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

[[Page 7116]]

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 also 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 also

a member of the Institutional Biosafety Committee).

Section IV-B-6. Human Gene Therapy Expert

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 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. Institutional Biosafety Committee approval must be obtained from

each institution that will handle recombinant DNA material that is to

be administered to human subjects.

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 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

[[Page 7117]]

and the Laboratory Safety Monograph for technical recommendations).

Section IV-B-7-b. Submissions by the Principal Investigator to the 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), the Institutional Biosafety Committee, NIH/ORDA, and other

appropriate authorities (if applicable) (reports to the 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 annual data reporting and adverse

event reporting requirements for human gene transfer experiments (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 the RAC. ORDA's responsibilities under

the NIH Guidelines are administrative. Advice from the 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 the 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 M, Points to Consider in

the Design and Submission of Protocols for the Transfer of Recombinant

DNA Molecules into One or More Human Subjects.

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

the 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

[[Page 7118]]

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 the 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 host-

vector 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)

The 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. The 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 the 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. Nominations for the RAC 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 the 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.

The 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 specific comments/recommendations

about: (i) a specific human gene transfer experiment, or (ii) a

category of human gene transfer experiments, to the NIH Director;

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; and

Section IV-C-2-e. Identifying broad scientific and ethical/social

issues relevant to gene therapy research as potential Gene Therapy

Policy Conference topics.

Section IV-C-2-f. Identifying novel 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;

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:

[[Page 7119]]

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

Department of Health and Human Services (DHHS) components, as

appropriate.

Section IV-C-3-e. Collaborating with Principal Investigators,

Institutional Biosafety Committees, Institutional Review Boards, and

other DHHS components (including the 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.

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 nanograms 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-I,

Containment Conditions for Cloning of Genes Coding for the Biosynthesis

of Molecules Toxic for Vertebrates--General Information, and Appendix

F-II, Cloning of Toxin Molecules Genes in Escherichia coli K-12);

Section IV-C-3-h. Serving as the executive secretary of the 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, an

individual intending to carry out research involving recombinant DNA is

encouraged to 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 Sections IV-E-2 through IV-E-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 Host-Vector 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-E-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-5-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

[[Page 7120]]

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 the 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 the 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, section 5.65 (d) and

(e).

Section IV-D-5-b. Presubmission Review

Any institution not otherwise covered by the NIH Guidelines, which

is considering submission of data or information voluntarily to NIH,

may request presubmission 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 presubmission 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 Code of Federal Regulations, 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 on 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.

V-E. Proposed Amendments to Appendix A, Exemptions Under Section III-E-

5--Sublists of Natural Exchanges

Appendix A, first paragraph, is proposed to be amended to reflect

renumbering of a previous section.

IV-F. Proposed Amendments to Appendix C, Exemptions Under Section III-

E-6

Appendix C is proposed to be amended to reflect renumbering of a

previous section.

IV-G. Proposed Amendments to Appendix I, Biological Containment

After the first paragraph in Section I-II-A, Responsibility, the

following Note is proposed to be 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 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 (see Section IV-D-3, Certification of Host-Vector

Systems--Voluntary Compliance).

III-H. Proposed 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 proposed to be amended to read:

Appendix M. 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)

Appendix M applies to research conducted at or sponsored by an

institution that receives any support for recombinant DNA research from

the NIH. Researchers not covered by the NIH Guidelines are encouraged

to use Appendix M (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: civic,

religious, scientific, and medical groups have all accepted, in

principle, the appropriateness of gene therapy of somatic cells in

humans for specific genetic diseases. Somatic cell gene therapy is seen

as an extension of present methods of therapy that might be preferable

to other technologies. In light of this public support, the Recombinant

DNA Advisory Committee (RAC) is prepared to consider proposals for

somatic cell gene transfer.

The RAC will not at present entertain proposals for germ line

alterations but will consider proposals involving somatic cell gene

transfer. The purpose of somatic cell gene therapy is to treat an

individual patient, e.g., by inserting a properly functioning gene into

the subject's somatic cells. Germ line alteration involves a specific

attempt to introduce genetic changes into the germ (reproductive) cells

of an individual, with the aim of changing the set of genes passed on

to the individual's offspring.

In the interest of maximizing the resources of both the NIH and the

Food and Drug Administration (FDA) and simplifying the method and

period for review, research proposals involving the deliberate transfer

of recombinant DNA or DNA or RNA derived from recombinant DNA into

human subjects

[[Page 7121]]

(human gene transfer) will be considered through a consolidated review

process involving both the NIH/ORDA and the FDA. Investigators shall

simultaneously submit their relevant information on the proposed human

gene transfer experiments to both the NIH/ORDA and the FDA. Submission

of human gene transfer protocols to the NIH will be in the format

described in Appendix M-I, Submission Requirements--Human Gene Transfer

Experiments, of the NIH Guidelines. Submission to NIH shall be for

registration purposes and will ensure continued public access to

relevant human gene transfer information conducted in compliance with

the NIH Guidelines. Submission of human gene transfer protocols to the

FDA will be in the format described in 21 CFR, Chapter I, Subchapter D,

Part 312, Subpart B, Section 23, IND Content and Format.

Factors that may contribute to public discussion of a human gene

transfer experiment by the 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 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 discussion, reviewers will examine the

scientific rationale, scientific context (relative to other proposals

reviewed by the RAC), whether the preliminary in vitro and in vivo data

were obtained in appropriate models and are sufficient, and whether

questions related to safety, efficacy, and social/ethical context 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 Department of

Health and Human Services (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). The 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 should 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) should: (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, the meaning and significance of the

research, significant safety issues, and ethical/societal 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.

RAC recommendations on a specific human gene transfer experiment

shall be forwarded to the NIH Director, the Principal Investigator, the

sponsoring institution, and other Department of Health and Human

Services (DHHS) components, as appropriate. In its evaluation of human

gene transfer proposals, the 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 the

RAC, NIH/ORDA, and the FDA, to assess the possibility that the proposed

experiment(s) will inadvertently affect reproductive cells or lead to

infection of other people (e.g., medical personnel or relatives).

In order to enhance the depth and value of public discussion

relevant to scientific, safety, and ethical/societal implications of

gene therapy research, the NIH Director will convene GTPC at regular

intervals. As appropriate, the NIH Director will convene GTPC

immediately following scheduled RAC meetings. GTPC will be administered

by the 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 the RAC will serve as Co-chair of each GTPC and report the

findings of the GTPC to the full committee 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. GTPC will have representation

from other Federal agencies, including the FDA. GTPCs will focus on

broad over-arching policy and scientific issues related to gene therapy

research. Proposals for GTPC topics may be submitted by members of the

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 gene transfer. The findings of the GTPC 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.

Appendix M will be considered for revisions as experience in

evaluating proposals accumulates and as new

[[Page 7122]]

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 to the NIH will be submitted 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; (4)

Responses to Appendix M-II through M-V, Description of the Proposal,

Informed Consent, Privacy and Confidentiality, and Special Issues; (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); (8) curricula vitae--2 pages for each key professional

person in biographical sketch format; and (9) two 3\1/2\-inch diskettes

with the complete vector nucleotide sequence in ASCII format.

Investigators must submit their human gene transfer protocols to the

FDA in the format described in 21 CFR, Chapter I, Subchapter D, Part

312, Subpart B, Section 23, IND Content and Format. Submissions 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 the RAC). The 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 discussion, reviewers will examine the

scientific rationale, scientific context (relative to other proposals

reviewed by the RAC), whether the preliminary in vitro and in vivo data

were obtained in appropriate models and are sufficient, and whether

questions related to safety, efficacy, and social/ethical context 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 Department of

Health and Human Services (DHHS) components, as appropriate.

Appendix M-VII. Reporting Requirements--Human Gene Transfer Protocols

Appendix M-VII-A. Annual Data Reporting

Investigators shall comply with the 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 the

RAC and NIH/ORDA, and reviewed at a future RAC meeting.

Appendix M-VII-B. Adverse Event Reporting

Investigators who have received approval from the FDA to initiate a

human gene transfer protocol must report any serious adverse event

immediately to the local Institutional Review Board, Institutional

Biosafety 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 M-VIII. Footnotes of Appendix M

Appendix M-VIII-A. Human studies in which the induction or

enhancement of an immune response to a vector-encoded microbial

immunogen 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-VIII, Reporting Requirements-

Human Gene Transfer Experiments.''

IV. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene

Transfer Protocol/Dr. Crystal

In a letter dated January 8, 1997, Dr. Ronald Crystal of New York-

Hospital-Cornell Medical Center, New York, New York, submitted a human

gene transfer protocol entitled: Immune Response to Intradermal

Administration of an Adenovirus Type 5 Gene Transfer Vector (ADGVCD.10)

in Normal Individuals (NIH Protocol #9701-171) to the RAC for

evaluation regarding the necessity for RAC review and approval.

V. Amendments to Appendix B of the NIH Guidelines Regarding

Classification of Human Etiologic Agents on the Basis of Hazard

In a letter dated January 21, 1997, Dr. Diane Fleming, Chair of the

Subcommittee on Laboratory Safety, American Society for Microbiology,

Washington, D.C., requested the following addition of certain select

agents not previously listed. The letter reads:

* * * Select agents were identified by the Centers for Disease

Control and Prevention as being subject to special

[[Page 7123]]

site registration and handling requirements under 42 CFR Part 72. Only

three of the special agents are not listed in Appendix B, but they

could now be added as follows:

Appendix B-III-D. Risk Group 3 viruses. Add

Arenaviruses: Flexal

Justification: Flexal is already covered by `other viruses listed

in the reference source' but now that it is on the list of select

agents, it should be listed here as well.

Appendix B-IV-D. Risk Group 4 viruses. Add

Arenaviruses: Sabia

Paramyxoviruses: Equine morbilli virus

Justification: As Chairman of the Subcommittee on Arboviral

Laboratory Safety (SALS), Dr. Michael P. Kiley told me that both Sabia

and equine morbilli virus are to be handled under Biosafety Level 4

containment. (Dr. Michael P. Kiley, of the Federal Laboratories for

Health Canada and Agriculture and Agri-Food, Winnipeg, Manitoba,

Canada, January 21, 1997, personal communication regarding the

classification of Sabia and equine morbilli virus).

* * * Recommendations for corrections and changes to errors in

Appendix B which may not require RAC review:

* * * Appendix B-II-A, pg 1487

Acinetobacter baumannii formerly Acinetobacter calcoaceticus var

anitratus is known as the Acinetobacter calcoaceticus-baumannii

complex. We can add var. anitratus to the A. calcoaceticus.

* * * Appendix II-B-IV-D. Remove erroneous reference to

Togaviruses, Group A now associated with the Arenaviruses.

* * * * *

OMB's ``Mandatory Information Requirements for Federal Assistance

Program Announcements'' (45 FR 39592) requires a statement concerning

the official government programs contained in the Catalog of Federal

Domestic Assistance. Normally NIH lists in its announcements the number

and title of affected individual programs for the guidance of the

public. Because the guidance in this notice covers not only virtually

every NIH program but also essentially every Federal research program

in which DNA recombinant molecule techniques could be used, it has been

determined to be not cost effective or in the public interest to

attempt to list these programs. Such a list would likely require

several additional pages. In addition, NIH could not be certain that

every Federal program would be included as many Federal agencies, as

well as private organizations, both national and international, have

elected to follow the NIH Guidelines. In lieu of the individual program

listing, NIH invites readers to direct questions to the information

address above about whether individual programs listed in the Catalog

of Federal Domestic Assistance are affected.

Dated: February 10, 1997.

Lana Skirboll,

Associate Director for Science Policy, National Institutes of Health

[FR Doc. 97-3735 Filed 2-13-97; 8:45 am]

BILLING CODE 4140-01-P