Recombinant DNA Research: Proposed Actions Under the Guidelines

SUMMARY: On July 8, 1996, the NIH published a Notice of Intent to

modify NIH's oversight of gene therapy. Specifically, the NIH proposed

to: (1) Terminate the NIH Recombinant DNA Advisory Committee (RAC); (2)

relinquish all approval responsibilities for recombinant DNA

experiments involving human gene transfer to the Food and Drug

Administration (FDA), which holds statutory authority for such

approval; (3) establish the Office of Recombinant DNA Activities

Advisory Committee (OAC); (4) limit the membership of OAC to 6-10

individuals, as compared to the 25 members appointed to the RAC; (5)

regularly convene Gene Therapy Policy Conferences; and (6) continue the

publicly available, comprehensive NIH database of human gene transfer

clinical trials, including adverse events.

The NIH received 71 written comments in response to the Notice of

Intent, reflecting a broad range of opinions. After careful

consideration of these comments, the NIH Director revised the proposal

put forward in the July 8, Notice of Intent. This revised proposal,

described herein as the Notice of Proposed Actions, reflects both

public opinion and the NIH Director's intent to increase the

effectiveness and efficiency of public discussion of gene therapy.

Specifically, because of the historical importance of the RAC as a

public platform for discussion of the science, as well as the safe and

ethical conduct of gene therapy research, the NIH Director proposes 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 Gene

Therapy Policy Conferences; and (5) maintain public access to human

gene transfer clinical trial information.

This notice sets forth proposed actions to be taken by the

Director, National Institutes of Health (NIH), regarding enhanced

mechanisms for scientific and ethical/societal oversight of human gene

transfer research, under the NIH Guidelines for Research Involving

Recombinant DNA Molecules (NIH Guidelines) (59 FR 34496, amended 59 FR

40170, amended 60 FR 20726, amended 61 FR 1482, amended 61 FR 10004).

These proposed actions reflect a revision of the proposal set forth in

the July 8, 1996, Federal Register Notice of Intent. It is important to

note that the proposal outlined in the July 8, 1996, Notice of Intent

and the revised proposed actions described herein are applicable only

to recombinant DNA experiments involving human subjects. NIH oversight

of recombinant DNA research conducted in compliance with the NIH

Guidelines (with the exception of human gene transfer research) remains

unchanged.

DATES: Interested parties are invited to submit comments concerning

this proposal. Comments received by December 2, 1996, will be

reproduced and distributed to the Recombinant DNA Advisory Committee

for consideration at its December 9, 1996, meeting. After consideration

of this proposal and comments by the Recombinant DNA Advisory

Committee, the Director of the National Institutes of Health 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 5:00 p.m.

FOR FURTHER INFORMATION CONTACT: Background documentation and

additional information can be obtained from the Office of Recombinant

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

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

9838, FAX 301-496-9839.

SUPPLEMENTARY INFORMATION: In l990, the NIH reviewed and approved its

first gene therapy experiment. In the ensuing six years, knowledge

about and experience with somatic cell human gene therapy has grown

substantially. As the field has matured, the NIH has sought to preserve

both the effectiveness and efficiency of its oversight of human gene

therapy research by periodically modifying the functions of the

Recombinant DNA Advisory Committee (RAC).

When the NIH first published the Points to Consider in the Design

and Submission of Protocols for the Transfer of Recombinant DNA Into

the Genome of Human Subjects (Points to Consider) in the Federal

Register in 1990, each human gene therapy experiment was reviewed by

both the Human Gene Therapy Subcommittee (HGTS) and the RAC, and then

approved by the NIH Director. In 1992, when the HGTS was merged with

its parent committee (the Recombinant DNA Advisory Committee), the NIH

adopted a semiannual reporting process for human gene transfer

experiments. One year later, the NIH established an expedited review

process for single patient protocols by allowing written RAC review of

such protocols between the committee's quarterly meetings. In the

following year, the NIH adopted an accelerated review process for

certain categories of clinical trials that had been routinely reviewed

by the RAC and determined not to represent any significant risk to

human health and the environment. Under this mechanism, such protocols

were subject to written review by several RAC members outside of the

committee's quarterly meetings and NIH Office of Recombinant DNA

Activities (ORDA) approval. In l995, another change relevant to RAC

review occurred when the RAC approved consolidated review, in which all

protocols determined not to represent a novel gene therapy delivery

strategy or target disease were exempted from RAC review and approval

and were approved solely by the Food and Drug Administration (FDA).

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 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

[[Page 59727]]

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. 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.

I. Revised Proposal in Response to Public Comment

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, 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.

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, the NIH Director has revised the proposal

set forth in the July 8, 1996, Notice of Intent. In this amended

proposal, the NIH Director proposes to retain the RAC, while modifying

its responsibilities relevant to human gene therapy research. In doing

so, the NIH Director acknowledges the public's view that the RAC has

historical importance as a societal platform for discussion of the

science, as well as the safe and ethical conduct of gene therapy

research. The NIH Director recognizes that this tradition is lacking in

OAC and, therefore, decided to retain the RAC instead of replacing it

with OAC. The NIH Director's intent to increase the effectiveness and

efficiency of the RAC will be achieved by the continuing discussion of

novel human gene transfer experiments without RAC approval of

individual human gene transfer experiments. The membership of the RAC

will be reduced from 25 to 15 individuals to increase efficiency while

ensuring sufficient representation from scientific, ethical, and legal

communities. In order to stimulate public discussion of the safety,

scientific merit, and ethical nature of present and future

opportunities in gene therapy research, the NIH Director proposes to

regularly convene Gene Therapy Policy Conferences (GTPCs). Finally,

recognizing the importance of public access to human gene transfer

clinical trial information, the NIH will continue to maintain the gene

therapy clinical trial database.

II. Analysis of Written Comments in Response to the Notice of

Intent

The following analysis compares and contrasts, point by point, the

proposal set forth in the July 8, 1996, Notice of Intent, the public

response to each point, and the new proposal described herein as the

Notice of Proposed Actions.

II-A. Notice of Intent

Terminate the RAC and establish the Office of Recombinant DNA

Activities Advisory Committee (OAC).

Notice of Proposed Actions

Retain the RAC, while modifying its roles and responsibilities

relevant to human gene therapy research.

Of the 71 comments submitted in response to the Notice of Intent,

10 did not specifically address NIH's proposal to terminate the RAC. Of

the 61 responses which did address the proposal to terminate the RAC,

20 expressed support and 41 expressed opposition. Supporting and

opposing comments were submitted by representatives of: Academia (5

supported, 15 opposed), industry (8 supported, 4 opposed), private

citizens (4 supported, 6 opposed), current and previous RAC members (3

supported, 10 opposed), professional scientific societies (1 supported,

2 opposed), the ethics community (1 supported, 5 opposed), consumer

advocacy organizations (0 supported, 4 opposed), patient advocacy

organizations (0 supported, 6 opposed), and professional scientific

societies (0 supported, 2 opposed).

Comments in support of termination of the RAC reflected an interest

in making substantive changes in the role of the RAC. Most of these

comments supported the proposed restructuring of the functions of the

RAC and did not specifically endorse termination of RAC. Opposing

comments focused on the historical importance of retaining the RAC as

an internationally recognized forum for public discussion of the

science, safety, and ethics of human gene therapy research. These

authors articulated the critical role that the RAC plays in maintaining

public confidence in human gene therapy research.

The importance of the continuation of the RAC, per se, was

underscored by comments which specifically addressed the establishment

of the OAC. Of the 53 comments which addressed this issue, 12 expressed

support and 41 expressed opposition. The majority of comments submitted

in opposition to the OAC stated that the proposed functions of the OAC

could be accomplished by the RAC, or by a restructured version of the

RAC. Several authors emphasized that, absent the historic credibility

of the RAC, the OAC might suffer from an inability to attract and

motivate the type of expertise and judgement needed for this important

public forum.

II-B. Notice of Intent

Relinquish all approval responsibilities for recombinant DNA

experiments involving human gene transfer to the Food and Drug

Administration (FDA) which holds statutory authority for such approval.

Notice of Proposed Actions

Relinquish all approval responsibilities of the RAC to the Food and

Drug Administration (FDA) which holds statutory authority for such

approval, while maintaining RAC discussion of novel human gene transfer

experiments.

Of the 71 comments submitted in response to the Notice of Intent,

24 respondents did not specifically address the proposal to eliminate

RAC approval of human gene transfer experiments; 23 respondents were in

support and 24 respondents were opposed to abolishing protocol

approval. Supporting and opposing comments were submitted by

representatives of academia (7 supported, 7 opposed), industry (11

supported, 0 opposed), private citizens (2 supported, 7 opposed),

previous or current RAC members (4 supported, 5 opposed), professional

scientific societies (4 supported, 1 opposed), the ethics community (2

supported, 4 opposed), patient advocacy organizations (0 supported, 2

opposed), and consumer advocacy organizations (0 supported, 4 opposed).

In discussing the responses to the proposal to eliminate RAC

approval of human gene therapy protocols, it is important to note that

the NIH Director's interest in relinquishing RAC approval recognizes

FDA authority to approve human gene therapy research under its

Investigational New Drug regulations. This proposal eliminates

duplication of this effort by the NIH, which does not have such

regulatory authority.

Respondents supporting elimination of RAC approval felt that the

current status of human gene transfer research is such that NIH

approval is no longer warranted and that it is appropriate that the FDA

exclusively manage the approval process. This point of view was

supported by authors who suggested that the efficient use of Federal

resources is optimized by

[[Page 59728]]

eliminating duplicate approval by the NIH. Opposing points of view

emphasized that the FDA does not routinely take moral and ethical

considerations into account in their review and approval process. Other

comments opposed to exclusive FDA approval expressed concern that

without NIH authority to approve individual human gene transfer

experiments, the FDA could ignore any recommendations coming from the

NIH.

After careful consideration of these letters, the NIH Director

proposes to retain this element of the Notice of Intent, i.e.,

eliminate NIH approval of individual protocols. Under this new proposal

the RAC will continue to emphasize the ethical, social, and scientific

issues arising from the public review and discussion of individual

novel protocols. The NIH Director recognizes that opinions on the

proposed elimination of NIH approval of human gene transfer experiments

were diverse. The majority of comments submitted in opposition to this

issue emphasized the critical role of the RAC in providing a forum for

the public discussion of ethical issues relevant to human gene therapy

research. The NIH Director maintains that the elimination of RAC

approval will not hamper critical public discussion, nor will it result

in any untoward effects on human health or the environment. NIH's

mission is to sponsor and conduct medical research of the highest

scientific merit to improve the health of the nation and the world.

Many of the submitted comments confirmed the NIH Director's concern

that NIH approval on the grounds of safety is often perceived as a

scientific endorsement of early-phase clinical trials, some of which

have inadequate study design and insufficient preclinical foundations.

II-C. Notice of Intent

Limit the membership of OAC to 6-10 individuals, as compared to the

25 members appointed to the RAC; membership would represent the

scientific, ethical and public advocacy communities.

Notice of Proposed Actions

Reduce the membership of RAC from 25 members to 15 members

representing the scientific, ethical, and public advocacy communities.

Of the 71 comments submitted in response to the Notice of Intent,

only 6 comments submitted specifically addressed the composition of

OAC; 2 expressed support and 4 expressed opposition. Supporting and

opposing comments were submitted by representatives of academia (1

supported, 0 opposed), current RAC members (1 supported, 2 opposed) and

private citizens (0 supported, 2 opposed). Although the vast majority

of responses to the Notice of Intent did not address the proposed

reduction in the size of the committee membership, those who were

opposed expressed concern that a standing committee membership of 6-10

individuals could not adequately represent the four fields of expertise

required under the committee charter. Other suggested that a minimum of

12-15 members would be sufficient.

In order to facilitate efficient review and discussion and in

response to comments questioning the extent of the reduction, the NIH

Director proposes to reduce the current RAC membership from 25 to 15

members, including the Chair. The appointment of the 15 member RAC will

adhere to the RAC Charter such that they will be appointed by the DHHS

Secretary or his/her designee. 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.

II-D. Notice of Intent

Convene regular Gene Therapy Policy Conferences.

Notice of Proposed Actions

Convene regular Gene Therapy Policy Conferences.

Of the 71 comments submitted in response to the Notice of Intent,

33 specifically addressed NIH's proposal to convene GTPCs. These

responses were equally divided, with 16 expressing support and 17

expressing opposition. Supporting and opposing comments were submitted

by representatives of academia (3 supported, 5 opposed), industry (7

supported, 3 opposed), private citizens (4 supported, 1 opposed),

current or previous RAC members (2 supported, 7 opposed), professional

scientific societies (0 supported, 2 opposed), consumer advocacy

organizations (0 supported, 2 opposed), patient advocacy organizations

(0 supported, 1 opposed), and the ethics community (0 supported, 4

opposed).

Opposing comments did not question the concept of holding GTPCs,

but rather suggested that the roles and responsibilities of the GTPCs

could be accomplished through the RAC. Supporting comments were

enthusiastic about a separate forum for public discussion of human gene

therapy issues which would expand its discussions beyond individual

protocols. Some responses put forth suggestions for future GTPCs,

including discussion of controversial issues that arise as a

consequence of human gene transfer clinical trials such as reproductive

decisions, susceptibility to workplace dangers, and privacy questions.

It was also suggested that GTPC topics should be actively solicited

from industry and academia to facilitate development of new

technologies.

After careful consideration of the comments submitted with regard

to the proposed establishment of GTPCs, the NIH Director proposes to

retain this element of the Notice of Intent and to establish GTPCs.

However, it is important to note several clarifications of the previous

proposal. GTPCs will focus on broad over-arching policy and scientific

issues related to gene therapy research. The RAC will advise the NIH

Director on GTPC topics. GTPC topics submitted by a member of the RAC,

representatives of academia, industry, patient and consumer advocacy

organizations, other Federal agencies, professional scientific

societies, and the general public will be considered by the NIH

Director. 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. A member of the RAC will co-chair each

GTPC. This member will be selected by the RAC. All RAC members will be

encouraged to attend these meetings. The NIH Director anticipates that

GTPCs will serve as a model for interagency communication and

collaboration, concentrated expert discussion of novel scientific

issues, and enhanced opportunity for public understanding of specific

gene therapy issues including ethical, legal, and social concerns.

II-E. Notice of Intent

Ensure public access to human gene transfer experiments information

by maintaining the publicly available, comprehensive NIH database of

human gene transfer clinical trials, including adverse events.

Notice of Proposed Actions

Ensure public access to human gene transfer experiments information

by maintaining the publicly available, comprehensive NIH database of

human

[[Page 59729]]

gene transfer clinical trials, including adverse events.

Of the 71 comments submitted in response to the Notice of Intent,

25 comments specifically addressed NIH's proposal to maintain its human

gene transfer database; 20 expressed support and 5 expressed

opposition. Supporting and opposing comments were submitted by

representatives of academia (8 supported, 1 opposed), industry (4

supported, 2 opposed), private citizens (1 supported, 0 opposed),

current or previous RAC members (5 supported, 2 opposed), the ethics

community (1 supported, 0 opposed), and the European community (France)

(1 supported, 0 opposed).

The overwhelming majority of comments expressed strong support for

the NIH Director's proposal to maintain the human gene transfer

database. Supporting comments emphasized the importance of maintaining

public understanding of human gene therapy research. The majority of

comments argued that the human gene transfer database is a vital tool

for ensuring public confidence in this novel area of research. Many

comments underscored the importance of capturing positive as well as

negative data derived from gene therapy clinical trials. Other

commentors felt that public access to such information avoids

unnecessary duplication of effort and clearly identifies gaps in

knowledge that are worthy of further preclinical and clinical

investigation.

In response to these comments, the NIH Director will maintain

public accountability for human gene therapy research through the

publicly available, comprehensive database for human gene transfer

clinical trials. Information entered into the database will be derived

from the documentation submitted to NIH/ORDA in compliance with: (i)

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

and (ii) Appendix M-VII--Reporting Requirements--Human Gene Transfer

Experiments, of 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) of the NIH Guidelines. In

compliance with the NIH Guidelines, investigators will continue to be

required to register human gene transfer experiments with NIH/ORDA to

ensure continued public access to protocol information, ongoing data

(including adverse and significant clinical events), and long-term

follow-up data.

III. Proposed Roles and Responsibilities in Accordance With the NIH

Guidelines

III-A. The NIH Director

The roles and responsibilities of the NIH Director remain unchanged

except for relinquishing approval of human gene transfer experiments.

The NIH Director is responsible for: (1) Establishing the NIH

Guidelines and overseeing their implementation. (2) Promulgating

requirements as necessary to implement the NIH Guidelines. (3)

Establishing and maintaining the RAC. (4) Establishing and maintaining

ORDA.

III-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.

III-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 Gene Therapy

Policy Conferences (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 also 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

[[Page 59730]]

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

communications 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.

III-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 the safe conduct of recombinant DNA

research. (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) Reviewing and approving the

membership of Institutional Biosafety Committees. (10) Changing

containment levels for experiments that are specified in Section III,

Experiments Covered by the NIH Guidelines (except when a Major Action

is involved). (11) Assigning containment levels for experiments not

explicitly considered in the NIH Guidelines. (12) Interpreting the NIH

Guidelines for experiments to which the NIH Guidelines do not

specifically assign containment levels. (13) Approving minor

modifications and decertifying host-vector systems. (14) Preparing

minutes of RAC meetings and gene therapy policy conferences.

III-E. Local Institutions

The roles and responsibilities of local institutions, Institutional

Biosafety Committees, Biosafety Officers, Principal Investigators,

Animal Facility Directors, and Greenhouse Supervisors relevant to

recombinant DNA research conducted in compliance with the NIH

Guidelines, remains unchanged.

IV. Proposed Actions

The NIH will consider the following actions under the NIH

Guidelines for Research Involving Recombinant DNA Molecules:

[Note: Editorial changes and updating of references are proposed

to clarify the document in addition to the Proposed Actions

regarding the Notice of Intent.]

IV-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. In the interest of maximizing the resources of

both the NIH and the Food and Drug Administration (FDA) and simplifying

the method and period for review, research proposals involving the

deliberate transfer of recombinant DNA or DNA or RNA derived from

recombinant DNA into human subjects (human gene transfer) will be

considered through a consolidated submission process involving both the

NIH and the FDA. An investigator shall simultaneously submit a human

gene transfer experiment to both the NIH and the FDA in a single

submission format. This format shall include (but is not limited to)

the documentation described in Appendices M-I through M-V, of 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). Submission to the NIH Office of Recombinant DNA

Activities (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. The RAC will receive

periodic updates regarding recent submissions to NIH/ORDA. 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 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 will be

forwarded to the NIH Director, the Principal Investigator, the

sponsoring institution, and, as appropriate, to other Department of

Health and Human Services (DHHS) components.

``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

[[Page 59731]]

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 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. The policies on noncompliance 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.

``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 remainder of Section I is proposed to be renumbered to reflect

above changes.]

IV-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 * * *.''

IV-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

expressed 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

[[Page 59732]]

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 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

``Experiments in this category cannot be initiated without

simultaneous submission of relevant information on the proposed

experiment to both NIH/ORDA and the FDA in a single submission format.

This format shall include (but is not limited to) the documentation

described in Appendices M-I through M-V, of 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).

Prior to initiation of a human gene transfer experiment, the Principal

Investigator must obtain both Institutional Biosafety Committee and

Institutional Review Board approvals. 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 discussion. 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 review to be open to the public.

Full RAC review of an individual human gene transfer experiment can be

recommended by: (i) A majority of the RAC, (ii) other Federal agencies,

(iii) the Principal Investigator, or (iv) the sponsoring institution.

An individual human gene transfer experiment that is recommended for

full RAC review should represent novel characteristics deserving of

public discussion. Recommendations for full RAC review of individual

human gene transfer experiments will be transmitted to the NIH

Director, who will determine whether an individual human gene transfer

experiment shall be discussed by the full RAC and determine the

priority of the discussions if more than one experiment is awaiting

discussion. RAC recommendations on a specific human gene transfer

experiment shall be forwarded to the NIH Director, the Principal

Investigator, the sponsoring institution, and, as appropriate, other

Department of Health and Human Services (DHHS) components.

``Institutional Biosafety Committee approval must be obtained from

any institution responsible for constructing or handling the

recombinant DNA material to be used in the experiments. 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.

``Section III-C-1. Experiments Involving the Deliberate Transfer of

Recombinant DNA or DNA or RNA Derived From Recombinant DNA Into Human

Subjects

``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. 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 recommended by: (i) a majority of

the RAC, (ii) other Federal agencies, (iii) the Principal Investigator,

or (iv) the sponsoring institution. An individual human gene transfer

experiment that is recommended for full RAC review should represent

novel characteristics deserving of public discussion. Recommendations

for full RAC review of individual human gene transfer experiments will

be transmitted to the NIH Director, who will determine whether an

individual human gene transfer experiment shall be discussed by the

full RAC and determine the priority of the discussions if more than one

experiment is awaiting discussion.

[[Page 59733]]

If a determination is made that an experiment shall undergo discussion

by the full RAC, 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. Relevant documentation will be included

in the material for the RAC meeting at which the experiment is

scheduled to be discussed. RAC recommendations on a specific human gene

transfer experiment shall be forwarded to the NIH Director, the

Principal Investigator, the sponsoring institution, and, as

appropriate, other Department of Health and Human Services (DHHS)

components.

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.]

IV-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 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. 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-g. 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.

``Note: 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-h. Determine the necessity for health surveillance

of personnel involved in connection with individual recombinant DNA

projects;

[[Page 59734]]

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-i. Report any significant problems, violations of

the NIH Guidelines, or any significant research-related accidents and

illnesses to NIH/ORDA within thirty days, unless the institution

determines that a report has already been filed by the Principal

Investigator or Institutional Biosafety Committee. Reports shall be

sent to the Office of Recombinant DNA Activities, National Institutes

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

Maryland 20892-7010, (301) 496-9838.

``Section IV-B-2. Institutional Biosafety Committee (IBC)

``The institution shall establish an Institutional Biosafety

Committee whose responsibilities need not be restricted to recombinant

DNA. The Institutional Biosafety Committee shall meet the following

requirements:

``Section IV-B-2-a. Membership and Procedures

``Section IV-B-2-a-(1). The Institutional Biosafety Committee must

be comprised of no fewer than five members so selected that they

collectively have experience and expertise in recombinant DNA

technology and the capability to assess the safety of recombinant DNA

research and to identify any potential risk to public health or the

environment. At least two members shall not be affiliated with the

institution (apart from their membership on the Institutional Biosafety

Committee) and who represent the interest of the surrounding community

with respect to health and protection of the environment (e.g.,

officials of state or local public health or environmental protection

agencies, members of other local governmental bodies, or persons active

in medical, occupational health, or environmental concerns in the

community). The Institutional Biosafety Committee shall include at

least one individual with expertise in plant, plant pathogen, or plant

pest containment principles when experiments utilizing Appendix P,

Physical and Biological Containment for Recombinant DNA Research

Involving Plants, require prior approval by the Institutional Biosafety

Committee. The Institutional Biosafety Committee shall include at least

one scientist with expertise in animal containment principles when

experiments utilizing Appendix Q, Physical and Biological Containment

for Recombinant DNA Research Involving Animals, require Institutional

Biosafety Committee prior approval. When the institution conducts

recombinant DNA research at BL3, BL4, or Large Scale (greater than 10

liters), a Biological Safety Officer is mandatory and shall be a member

of the Institutional Biosafety Committee (see Section IV-B-3,

Biological Safety Officer).

``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.

``Note: 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 will be administered

to human subjects.

``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

[[Page 59735]]

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 (Class 2, Class 3, Class 4, or Class 5

Agents is Cloned into Nonpathogenic Prokaryotic or Low er 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 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 be 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 Expertise

``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.

[[Page 59736]]

``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 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

[[Page 59737]]

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 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 containment 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 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 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

[[Page 59738]]

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 actions listed

in Sections IV-C-1-b, NIH Director--Specific Responsibility;

``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-3. Office of Recombinant DNA Activities (ORDA)

``ORDA shall serve as a focal point for information on recombinant

DNA activities and provide advice to all within and outside NIH

including institutions, Biological Safety Officers, Principal

Investigators, Federal agencies, state and local governments, and

institutions in the private sector. ORDA shall carry out such other

functions as may be delegated to it by the NIH Director. ORDA's

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

``Section IV-C-3-a. Serving as the focal point for public access to

summary information pertaining to human gene transfer experiments;

``Section IV-C-3-b. Serving as the focal point for data management

of human gene transfer experiments;

``Section IV-C-3-c. Administering the annual data reporting

requirements (and subsequent review) for human gene transfer

experiments (see Appendix M-VII, Reporting Requirements--Human Gene

Transfer Protocols);

``Section IV-C-3-d. Transmitting comments/recommendations arising

from public RAC discussion of a novel human gene transfer experiment to

the NIH Director. RAC recommendations shall be forwarded to the

Principal Investigator, the sponsoring institution, and, as

appropriate, other Department of Health and Human Services (DHHS)

components.

``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;

``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 do so by following 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

[[Page 59739]]

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 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.''

IV-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).''

IV-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

[[Page 59740]]

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 (human gene transfer) will be considered through a

consolidated review process involving both the NIH and the FDA.

Investigators shall simultaneously submit their human gene transfer

proposal to both the NIH and the FDA. Submissions shall include (but

are not limited to) the documentation described in Appendices M-I

through M-V of the Points to Consider.

``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 recommended by: (i) A majority of the

RAC, (ii) other Federal agencies, (iii) the Principal Investigator, or

(iv) the sponsoring institution. An individual human gene transfer

experiment that is recommended for full RAC review should represent

novel characteristics deserving of public discussion. Recommendations

for full RAC review of individual human gene transfer experiments will

be transmitted to the NIH Director. The NIH Director will determine

whether an individual human gene transfer experiment shall be discussed

by the full RAC and will determine the priority of the discussions if

more that one experiment is awaiting discussion. 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, as appropriate, other Department of Health

and Human Services (DHHS) components. 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 requests 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 recognition of the social concern that surrounds the subject

of human gene transfer, the RAC, NIH/ORDA, and the FDA, will cooperate

with other groups in assessing the possible long-term consequences of

the proposal and related laboratory and animal experiments in order to

define appropriate human applications of this emerging technology.

``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 Gene Therapy

Policy Conferences (GTPC) as deemed appropriate. GTPC will be

administered by the NIH/ORDA. These conferences 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. GTPC

topics for discussion may be submitted by a member of the RAC, other

Federal agencies, Principal Investigators, industry representatives,

patient advocacy groups, or individuals who represent the general

public interest through NIH/ORDA to the NIH Director. GTPC topics may

include areas such as basic research on the use of novel gene delivery

vehicles, novel applications of gene transfer, and relevant ethical/

societal implications of a particular application of gene transfer

technology. 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 communications and collaboration, concentrated expert

discussion of novel scientific issues and their potential societal

implications, and enhanced opportunity for public discussion of

specific issues and

[[Page 59741]]

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 scientific developments

occur. This review will be carried out periodically as needed.

``Appendix M-I. Submission Requirements--Human Gene Transfer

Experiments

``Investigators must simultaneously submit the following material

to both: (1) 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); and (2) 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. Proposals 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.

``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 recommended by: (i) A majority of

the RAC, (ii) other Federal agencies, (iii) the Principal Investigator,

or (iv) the sponsoring institution. 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, as appropriate, other

Department of Health and Human Services (DHHS) components.

``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.''

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

[[Page 59742]]

the Catalog of Federal Domestic Assistance are affected.

Dated: November 15, 1996.

Harold Varmus,

Director National Institutes of Health.

[FR Doc. 96-29891 Filed 11-21-96; 8:45 am]

BILLING CODE 4140-01-P