60328 Federal Register / Vol. 65, No. 196 / Tuesday, October 10, 2000 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Office of Biotechnology Activities;

Recombinant DNA Research: Action

Under the Guidelines

AGENCY: National Institutes of Health

(NIH), PHS, DHHS.

ACTION: Notice of Actions Under the

NIH Guidelines for Research Involving

Recombinant DNA Molecules (NIH

Guidelines).

SUMMARY: This notice describes

amendments to the NIH Guidelines

regarding research participant

enrollment in human gene transfer

studies and the submission of study

protocols for NIH Recombinant DNA

Advisory Committee (RAC) review.

NIH’s goal in making these

modifications to the NIH Guidelines is

to ensure that no research participant is

enrolled in a human gene transfer study

until the RAC review process has been

completed, IBC and IRB approvals have

been obtained, and applicable

regulatory authorization(s) have been

obtained.

The NIH is modifying the

requirements for protocol submission to

the NIH Office of Biotechnology

Activities (OBA) for RAC review so that

clinical trial proposals: 1) may be

submitted for RAC review prior to local

Institutional Review Board (IRB)

approval; and 2) must be submitted to

the NIH OBA for RAC review and the

RAC review process completed prior to

local Institutional Biosafety Committee

(IBC) approval.

In the case of clinical trial proposals

that are reviewed publicly and lead to

specific recommendations from the RAC

with regard to the protocol, the NIH will

send written RAC recommendations to

the Principal Investigator and the IBC

and the IRB within 10 working days of

public RAC review and discussion.

Once the local IBC is in receipt of the

RAC recommendations, the IBC may

proceed with its protocol approval

process. Investigators may initiate

research participant enrollment when

they have obtained final IBC and IRB

approvals and all applicable regulatory

authorization(s).

No later than 20 working days after

enrollment of the first research

participant, the investigator must have

provided to NIH OBA: (1) the final

protocol, as approved by the local IRB

and IBC and as authorized by the FDA

along with the IND number; (2) the NIH

grant number(s), if applicable; (3) a copy

of the IRB and IBC approvals; (4) as

applicable, a written response

addressing each of the RAC

recommendations resulting from public

review and discussion of the protocol;

and (5) the date of the initiation of the

trial.

FOR FURTHER INFORMATION CONTACT:

Background documentation and

additional information can be obtained

from the Office of Biotechnology

Activities, National Institutes of Health,

MSC 7010, 6000 Executive Boulevard,

Suite 302, Bethesda, Maryland 20892–

7010, Phone 301–496–9838, FAX 301–

496–9839. The OBA web site is located

at http://www.nih.gov/od/oba/.

Background Information

Since the inception of both basic and

clinical recombinant DNA research, the

NIH RAC has publicly reviewed and

discussed the full range of scientific,

medical, ethical, legal, and social issues

attendant to this field of research. Prior

to the action described in this notice,

local IBC and IRB approval of human

gene transfer protocols were

prerequisites for submission of the

protocol to the NIH OBA for RAC

review.

The actions set forth here: (1) allow

all gene transfer protocols that meet the

requirements set forth in Appendix M of

the NIH Guidelines (Points to Consider

in the Design and Submission of

Protocols for the Transfer of

Recombinant DNA Molecules into One

or More Human Research Participants)

to be submitted for RAC review prior to

local IRB review and approval; (2)

require all gene transfer protocols that

meet the requirements set forth in

Appendix M of the NIH Guidelines to be

submitted for RAC review prior to local

IBC approval; (3) require, for protocols

selected for public discussion by the

RAC, that the discussion occur prior to

final IBC approval of those protocols;

and (4) ensure that no research

participant is enrolled on a clinical

study until the RAC review process is

completed, and IBC and IRB approvals

and applicable regulatory authorizations

are obtained. For the purposes of this

action, research participant enrollment

is defined as the process of obtaining

consent from a potential research

participant, or a designated legal

guardian of the participant, to undergo

any test or procedure associated with

the gene transfer experiment.

With this change, research

participants can be assured that, prior to

their participation in a gene transfer

clinical trial that is either novel and/or

raises significant ethical or safety

concerns, their local IRB and IBC, as

well as the principal investigator will be

apprised of the results of public RAC

review and discussion.

Public RAC discussion of selected

gene transfer protocols and issues of

general relevance to the field enhances

human subjects protection by informing

research participants, investigators, and

local and Federal oversight bodies about

the current state of knowledge of risks

and benefits, potential safety and ethical

concerns, and clinical trial design issues

associated with gene transfer research.

Local institutional review bodies, which

generally see only that subset of gene

transfer trials conducted at their

institution, benefit from the expertise,

broad perspective, and the experience of

the RAC.

In developing the actions set forth

here, the NIH consulted extensively

with the public, the RAC, and the

Advisory Committee to the Director,

NIH (ACD). A version of this proposed

action was initially published in the

Federal Register for public notice and

comment on August 11, 1999 (64 FR

43884). The draft proposal and public

comments were discussed by the RAC at

the September 2–3, 1999, meeting.

During this discussion, some RAC

members noted that optimizing the

effectiveness of the RAC review process

was a high priority, but expressed

concern that elimination of the

requirement for approval of gene

transfer protocols by IRBs and IBCs

before submission of protocols to NIH

might result in the submission of

incomplete or inadequately developed

clinical protocols. To address these

concerns, the NIH proposed that

protocols submitted to NIH OBA for

RAC review must address all the

elements set forth in Appendix M of the

NIH Guidelines. Other RAC members

expressed concern that RAC review

prior to local institutional review might

be perceived as diminishing the critical

role of IRBs and IBCs in protecting

human research participants and the

community. To address this concern,

NIH proposed that in evaluating gene

transfer protocols, the IBC should take

into consideration the issues raised and

recommendations made during public

RAC review and discussion, as well as

the Principal Investigator’s response to

those recommendations. The RAC voted

on September 3, 1999, to recommend

implementation of this revised proposal.

This proposal was not implemented

immediately due to events that occurred

shortly thereafter. For the first time in

the history of gene transfer research, a

research participant’s death was

attributed directly to participation in a

gene transfer study. This event raised

concerns about the safety of gene

transfer research. In response, the NIH

Federal Register / Vol. 65, No. 196 / Tuesday, October 10, 2000 / Notices 60329

Director established in December, 1999,

the ACD Working Group on NIH

Oversight of Clinical Gene Transfer

Research (the ACD Working Group) to

review the role of NIH and the RAC in

oversight of clinical gene transfer

research. The ACD Working Group

included scientists, clinicians,

bioethicists, and representatives of the

general public. The ACD Working

Group was asked to develop

recommendations on whether the

current NIH framework for oversight

and public discussion of clinical gene

transfer research is appropriate,

especially with regard to the role of the

RAC and the NIH Guidelines; whether

current NIH mechanisms are adequate

for coordination of the oversight of

clinical gene transfer research with the

FDA, the Office for Human Research

Protections, IRBs, and IBCs; whether

additional NIH measures are needed to

minimize risk associated with clinical

gene transfer research; and the

appropriate role of the NIH with regard

to reporting, analysis, and public

discussion of serious adverse events.

The ACD Working Group concurred

that participants must not be enrolled in

a gene transfer protocol until NIH OBA

and the RAC have determined whether

the protocol requires public RAC review

and, in the case of a protocol selected

for public review and discussion, until

that review has occurred. If the RAC

expresses concerns about the safety or

design of a protocol, there must be a

systematic and established mechanism

that allows RAC to communicate those

concerns to the investigators prior to

enrollment of participants.

The ACD Working Group specifically

recommended the following:

• Research participant safety would

be optimally enhanced if participants

are not enrolled in gene transfer

protocols selected for public RAC

review and discussion until that public

review has occurred and the investigator

has responded to the RAC

recommendations.

• The timing of review of gene

transfer protocols by RAC, the IRB, the

IBC, and the FDA should be altered to

ensure that RAC functions as an

effective advisory committee to

investigators, local IRBs and IBCs, NIH,

and FDA.

• The requirement that the

investigator obtain IBC and IRB

approval prior to submission of a

protocol to OBA/RAC should be

eliminated. This change would allow

investigators to receive RAC input at an

earlier stage of protocol development.

• Final IBC approval should be

withheld until RAC review is complete.

In the case of protocols not selected for

public RAC review and discussion, IBC

approval can be granted as soon as the

IBC is notified that the protocol has not

been selected for further review. In the

case of protocols selected for public

RAC review and discussion, IBC

approval must be withheld until after

RAC discussion and the investigator has

responded to the review, thereby

preventing the initiation of a trial prior

to public RAC review.

The RAC unanimously endorsed the

ACD Working Group recommendations

on June 29, 2000. On July 15, 2000, the

ACD unanimously voted to accept the

ACD Working Group recommendations

regarding review of human gene transfer

protocols by the NIH RAC. Through this

notice of action, the NIH is amending

the NIH Guidelines in light of the

recommendations of the RAC and the

ACD.

The actions described in this notice

implement fundamental changes in the

NIH process for protocol submission

and review of gene transfer clinical

research protocols. These changes affect

multiple sections of the NIH Guidelines,

as set forth below. In addition,

Appendix M of the NIH Guidelines is

significantly modified. Specifically, the

text has been substantially changed and

reorganized in order to convey the

revised protocol review process in a

clear and logical manner. For the

convenience of the reader, those

portions of Appendix M that contain

amended language, as well as those

containing reorganized text, are

reprinted below. The revised NIH

Guidelines, in their entirety, can be

accessed at http://www4.od.nih.gov/

oba/guidelines.html. (Note: In the text

below, adverse event reporting

requirements remain unchanged;

however, a subsequent notice will

describe proposed changes for reporting

to NIH on serious adverse events that

occur during clinical gene transfer

research.)

Actions Amending the NIH Guidelines

Section I. Scope of the NIH Guidelines

Section I-A–1-a under Purpose is

amended to read:

‘‘Section I–A–1–a. For experiments

involving the deliberate transfer of

recombinant DNA, or DNA or RNA derived

from recombinant DNA, into human research

participants (human gene transfer), no

research participant shall be enrolled (see

definition of enrollment in Section I–E–7)

until the RAC review process has been

completed (see Appendix M–I–B, RAC

Review Requirements); Institutional

Biosafety Committee (IBC) approval (from the

clinical trial site) has been obtained;

Institutional Review Board approval has been

obtained; and all applicable regulatory

authorization(s) have been obtained.

‘‘For a clinical trial site that is added after

the RAC review process, no research

participant shall be enrolled (see definition

of enrollment in Section I-E–7) at the clinical

trial site until the following documentation

has been submitted to NIH OBA: (1) IBC

approval (from the clinical trial site); (2)

Institutional Review Board approval; (3)

Institutional Review Board-approved

informed consent document; and (4)

curriculum vitae of the principal

investigator(s) (no more than two pages in

biographical sketch format); and (5) NIH

grant number(s) if applicable.’’

A new Section I–E–7 is added to read:

‘‘Section I–E–7. ‘‘Enrollment’’ is the

process of obtaining informed consent from

a potential research participant, or a

designated legal guardian of the participant,

to undergo a test or procedure associated

with the gene transfer experiment.’’

Section III. Experiments Covered by the

NIH Guidelines

Section III–C is amended to read:

‘‘Section III–C. Experiments that Require

Institutional Biosafety Committee and

Institutional Review Board Approvals and

RAC Review Before Research Participant

Enrollment

‘‘Section III–C–1. Experiments Involving

the Deliberate Transfer of Recombinant DNA,

or DNA or RNA Derived from Recombinant

DNA, into One or More Human Research

Participants

‘‘For an experiment involving the

deliberate transfer of recombinant DNA, or

DNA or RNA derived from recombinant

DNA, into human research participants

(human gene transfer), no research

participant shall be enrolled (see definition

of enrollment in Section I–E–7) until the RAC

review process has been completed (see

Appendix M–I–B, RAC Review

Requirements).

‘‘In its evaluation of human gene transfer

proposals, the RAC will consider whether a

proposed human gene transfer experiment

presents characteristics that warrant public

RAC review and discussion (See Appendix

M-I-B–2). The process of public RAC review

and discussion is intended to foster the safe

and ethical conduct of human gene transfer

experiments. Public review and discussion of

a human gene transfer experiment (and

access to relevant information) also serves to

inform the public about the technical aspects

of the proposal, meaning and significance of

the research, and any significant safety,

social, and ethical implications of the

research.’’

‘‘Public RAC review and discussion of a

human gene transfer experiment may be: (1)

initiated by the NIH Director; or (2) initiated

by the NIH OBA Director following a

recommendation to NIH OBA by: (a) three or

more RAC members; or (b) a Federal agency

other than NIH. After a human gene transfer

experiment is reviewed by the RAC at a

regularly scheduled meeting, NIH OBA will

send a letter within 10 working days to the

NIH Director, the Principal Investigator, the

60330 Federal Register / Vol. 65, No. 196 / Tuesday, October 10, 2000 / Notices

sponsoring institution, and other DHHS

components, as appropriate, summarizing the

RAC recommendations.

‘‘For a clinical trial site that is added after

the RAC review process, no research

participant shall be enrolled (see definition

of enrollment in Section I–E–7) at the clinical

trial site until the following documentation

has been submitted to NIH OBA: (1)

Institutional Biosafety Committee approval

(from the clinical trial site); (2) Institutional

Review Board approval; (3) Institutional

Review Board-approved informed consent

document; and (4) curriculum vitae of the

principal investigator(s) (no more than two

pages in biographical sketch format).

‘‘In order to maintain public access to

information regarding human gene transfer

protocols (including protocols that are not

publicly reviewed by the RAC), NIH OBA

will maintain the documentation described

in Appendices M–I through M–V. The

information provided in response to

Appendix M should not contain any

confidential commercial information or trade

secrets, enabling all aspects of RAC review to

be open to the public.

‘‘Note: For specific directives concerning

the use of retroviral vectors for gene delivery,

consult Appendix B–V–1, Murine Retroviral

Vectors.’’

Section IV. Roles and Responsibilities

Section IV is amended to read in part:

Section IV–B. Responsibilities of the

Institution

Section IV–B–1. General Information. . .

Section IV–B–1–f. Ensure that . . . (ii) all

aspects of Appendix M have been

appropriately addressed by the Principal

Investigator; and (iii) no research participant

shall be enrolled (see definition of

enrollment in Section I–E–7) in a human

gene transfer experiment until the RAC

review process has been completed (see

Appendix M–I–B, RAC Review

Requirements). . . .’’

‘‘Section IV-B–2. Institutional Biosafety

Committee (IBC). . .

‘‘Section IV–B–2–a. Membership and

Procedures

Section IV–B–2–a–(1). . . . When the

institution participates in or sponsors

recombinant DNA research involving human

research participants, the institution must

ensure that: . . . (ii) all aspects of Appendix

M have been appropriately addressed by the

Principal Investigator; (iii) no research

participant shall be enrolled (see definition

of enrollment in Section I–E–7) in a human

gene transfer experiment until the RAC

review process has been completed (see

Appendix M–I–B, RAC Review

Requirements); and (iv) final IBC approval is

granted only after the RAC review process

has been completed (see Appendix M–I–B,

RAC Review Requirements). Institutional

Biosafety Committee approval must be

obtained from the institution at which

recombinant DNA material will be

administered to human research participants

(rather than the site involved in

manufacturing gene transfer products).’’

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:

. . . (iii) ensuring that all aspects of

Appendix M have been appropriately

addressed by the Principal Investigator; (iv)

ensuring that no research participant is

enrolled (see definition of enrollment in

Section I–E–7) in a human gene transfer

experiment until the RAC review process has

been completed (see Appendix M–I–B, RAC

Review Requirements); (v) for human gene

transfer protocols selected for public RAC

review and discussion, consideration of the

issues raised and recommendations made as

a result of this review and consideration of

the Principal Investigator’s response to the

RAC recommendations; (vi) ensuring that

final IBC approval is granted only after the

RAC review process has been completed (see

Appendix M–I–B, RAC Review

Requirements); and (vii) ensuring compliance

with all surveillance, data reporting, and

adverse reporting requirements set forth in

the NIH Guidelines.’’

‘‘Section IV–B–7. Principal Investigator

(PI). . .

‘‘Section IV–B–7–b. Information to Be

Submitted by the Principal Investigator to

NIH OBA

‘‘The Principal Investigator shall: ....

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

aspects of Appendix M have been

appropriately addressed prior to the

submission of a human gene transfer

experiment to NIH OBA, and provide a letter

signed by the Principal Investigator(s) on

institutional letterhead acknowledging that

the documentation being submitted to NIH

OBA complies with the requirements set

forth in Appendix M. No research participant

shall be enrolled (see definition of

enrollment in Section I–E–7) in a human

gene transfer experiment until the RAC

review process has been completed (see

Appendix M–I–B, RAC Review

Requirements); IBC approval (from the

clinical trial site) has been obtained;

Institutional Review Board (IRB) approval

has been obtained; and all applicable

regulatory authorization(s) have been

obtained.

‘‘For a clinical trial site that is added after

the RAC review process, no research

participant shall be enrolled (see definition

of enrollment in Section I–E–7) at the clinical

trial site until the following documentation

has been submitted to NIH OBA: (1) IBC

approval (from the clinical trial site); (2) IRB

approval; (3) IRB-approved informed consent

document; and (4) curriculum vitae of the

principal investigator(s) (no more than two

pages in biographical sketch format). . . .’’

Appendix M. Points To Consider in the

Design and Submission of Protocols for

the Transfer of Recombinant DNA

Molecules Into One or More Human

Research Participants (Points To

Consider)

Note: For the convenience of the reader,

those portions of Appendix M that contain

amended language, as well as those

containing reorganized text, are reprinted

below.

Appendix M is amended to read in

part:

‘‘Appendix M–I. Requirements for Protocol

Submission, Review, and Reporting—Human

Gene Transfer Experiments

‘‘Appendix M–I–A. Requirements for

Protocol Submission

‘‘The following documentation must be

submitted (see exemption in Appendix M–

VII–A, Footnotes of Appendix M) in printed

or electronic form to the: NIH Office of

Biotechnology Activities, National Institutes

of Health/MSC 7010, 6000 Executive

Boulevard, Suite 302, Bethesda, Maryland

20892–7010, Telephone: 301–496–9838,

Facsimile: 301–496–9839, E-mail:

rosenthg@od.nih.gov. NIH OBA will confirm

receipt within three working days after

receiving the submission.

‘‘1. A cover letter on institutional

letterhead, signed by the Principal

Investigator(s), that: (1) acknowledges that

the documentation submitted to NIH OBA

complies with the requirements set forth in

Appendix M–I–A, Requirements for Protocol

Submission; (2) identifies the Institutional

Biosafety Committee (IBC) and Institutional

Review Board (IRB) at the proposed clinical

trial site(s) responsible for local review and

approval of the protocol; and (3)

acknowledges that no research participant

will be enrolled (see definition of enrollment

in Section I–E–7) until the RAC review

process has been completed (see Appendix

M–I–B, RAC Review Requirements); IBC

approval (from the clinical trial site) has been

obtained; IRB approval has been obtained;

and all applicable regulatory authorizations

have been obtained.

‘‘2. The scientific abstract.

‘‘3. The non-technical abstract.

‘‘4. The proposed clinical protocol,

including tables, figures, and relevant

manuscripts.

‘‘5. Responses to Appendices M–II through

M–V, Description of the Proposal, Informed

Consent, Privacy and Confidentiality, and

Special Issues. Responses to Appendices M–

II through M–V may be provided either as an

appendix to the clinical protocol or

incorporated in the clinical protocol. If

responses to Appendices M–II through M–V

are incorporated in the clinical protocol, each

response must refer to the appropriate

Appendix M–II through M–V.

‘‘6. The proposed informed consent

document (see Appendix M–III, Informed

Consent).

‘‘7. Curricula vitae of the principal

investigator(s) (no more than two pages in

biographical sketch format).

Note: A human gene transfer experiment

submitted to NIH OBA should not contain

Federal Register / Vol. 65, No. 196 / Tuesday, October 10, 2000 / Notices 60331

confidential commercial information or trade

secrets, enabling all aspects of the review to

be open to the public.

‘‘Appendix M–I–B. RAC Review

Requirements

‘‘Appendix M–I–B–1. Initial RAC Review

‘‘The initial RAC review process shall

include a determination as to whether the

human gene transfer experiment presents

characteristics that warrant public RAC

review and discussion. During the RAC’s

initial review, individual committee

members may request additional information

relevant to the protocol. NIH OBA will

immediately notify the Principal

Investigator(s) of RAC requests for additional

information. In making a determination

whether an experiment presents

characteristics warranting public RAC review

and discussion, reviewers will examine the

scientific rationale, scientific content,

whether the preliminary in vitro and in vivo

safety data were obtained in appropriate

models and are sufficient, and whether

questions related to relevant social and

ethical issues have been resolved. Other

factors that may warrant public review and

discussion of a human gene transfer

experiment by the RAC include: (1) a new

vector/new gene delivery system; (2) a new

clinical application; (3) a unique application

of gene transfer; and/or (4) other issues

considered to require further public

discussion.

‘‘Initial RAC review shall be completed

within 15 working days of receipt of a

complete submission (see Appendix M–I–A,

Requirements for Protocol Submission). At

the end of the15-day review period, NIH

OBA will notify the Principal Investigator(s)

in writing about the results of the RAC’s

initial review. Two outcomes are possible: (1)

the experiment does not present

characteristics that warrant further review

and discussion and is therefore exempt from

public RAC review and discussion; or (2) the

experiment presents characteristics that

warrant public RAC review and discussion.

Completion of the RAC review process is

defined as: (1) receipt by the Principal

Investigator(s) of a letter from NIH OBA

indicating that the submission does not

present characteristics that warrant public

RAC review and discussion; or (2) receipt by

the Principal Investigator(s) of a letter from

NIH OBA after public RAC review that

summarizes the committee’s key comments

and recommendations (if any).

‘‘If a human gene transfer protocol is

submitted less than eight weeks before a

scheduled RAC meeting and is subsequently

recommended for public RAC review and

discussion, the review of the protocol by the

RAC will be deferred until the next

scheduled RAC meeting. This eight-week

period is needed to ensure adequate time for

public notice and comment and thorough

review by the committee members.

‘‘No research participant shall be enrolled

(see definition of enrollment in Section I–E–

7) in the human gene transfer experiment

until: (1) the RAC review process has been

completed; (2) Institutional Biosafety

Committee (IBC) approval (from the clinical

trial site) has been obtained; (3) Institutional

Review Board (IRB) approval has been

obtained; and (4) all applicable regulatory

authorization(s) have been obtained.

‘‘For a clinical trial site that is added after

the RAC review process, no research

participant shall be enrolled (see definition

of enrollment in Section I–E–7) at the clinical

trial site until the following documentation

has been submitted to NIH OBA: (1) IBC

approval (from the clinical trial site); (2) IRB

approval; (3) IRB-approved informed consent

document; and (4) curriculum vitae of the

principal investigator(s) (no more than two

pages in biographical sketch format).’’

‘‘Appendix M–I–B–2. Public RAC Review

and Discussion

‘‘Public RAC review and discussion of a

human gene transfer experiment may be: (1)

initiated by the NIH Director; or (2) initiated

by the NIH OBA Director following a

recommendation to NIH OBA by: (a) three or

more RAC members; or (b) a Federal agency

other than NIH. In making a determination

whether an experiment presents

characteristics warranting public RAC review

and discussion, reviewers will examine the

scientific rationale, scientific content,

whether the preliminary in vitro and in vivo

safety data were obtained in appropriate

models and are sufficient, and whether

questions related to relevant social and

ethical issues have been resolved. Other

factors that may warrant public review and

discussion of a human gene transfer

experiment by the RAC include: (1) a new

vector/new gene delivery system; (2) a new

clinical application; (3) a unique application

of gene transfer; and/or (4) other issues

considered to require further public

discussion.

‘‘After a human gene transfer experiment is

reviewed by the full RAC at a regularly

scheduled meeting, NIH OBA will send a

letter summarizing the RAC key comments

and recommendations (if any) regarding the

protocol to the NIH Director, the Principal

Investigator, the sponsoring institution, and

other DHHS components, as appropriate.

Completion of RAC review is defined as

receipt by the Principal Investigator(s) of a

letter from NIH OBA that summarizes the

committee’s findings. Unless NIH OBA

determines that there are exceptional

circumstances, the RAC summary letter will

be sent to the Principal Investigator(s) within

10 working days after the completion of the

RAC meeting at which the experiment was

reviewed.

‘‘RAC meetings will be open to the public

except where trade secrets or confidential

commercial information are reviewed. To

enable all aspects of the protocol review

process to be open to the public, information

provided in response to Appendix M should

not contain trade secrets or confidential

commercial information. No application

submitted to NIH OBA shall be designated as

‘confidential’ in its entirety. In the event that

an investigator determines that specific

responses to one or more of the items

described in Appendix M should be

considered as confidential commercial

information or a trade secret, each item must

be clearly identified as such. The cover letter

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

clearly designate the information that is

considered as confidential commercial

information or a trade secret; and (2) explain

and justify each designation.’’

‘‘Appendix M–I–C. Reporting Requirements

‘‘Appendix M–I–C–1. Initiation of the

Clinical Investigation

‘‘No later than 20 working days after

enrollment (see definition of enrollment in

Section I–E–7) of the first research

participant on a human gene transfer

experiment, the Principal Investigator(s) shall

submit the following documentation to NIH

OBA: (1) a copy of the informed consent

document approved by the Institutional

Review Board (IRB); (2) a copy of the

protocol approved by the Institutional

Biosafety Committee (IBC) and IRB; (3) a

copy of the final IBC approval from the

clinical trial site; (4) a copy of the final IRB

approval; (5) a brief written report that

includes the following information: (a) how

the investigator(s) responded to each of the

RAC’s recommendations on the protocol (if

applicable); and (b) any modifications to the

protocol as required by FDA; (6) applicable

NIH grant number(s); (7) the FDA

Investigational New Drug Application (IND)

number; and (8) the date of the initiation of

the trial. The purpose of requesting the FDA

IND number is for facilitating interagency

collaboration in the Federal oversight of

human gene transfer research.’’

‘‘Appendix M–I–C–2. Additional Clinical

Trial Sites

‘‘No research participant shall be enrolled

(see definition of enrollment in Section I–E–

7) at a clinical trial site until the following

documentation has been submitted to NIH

OBA: (1) Institutional Biosafety Committee

approval (from the clinical trial site); (2)

Institutional Review Board approval; (3)

Institutional Review Board-approved

informed consent document; (4) curriculum

vitae of the principal investigator(s) (no more

than two pages in biographical sketch

format); and (5) NIH grant number(s) if

applicable.’’

‘‘Appendix M–I–C–3. Annual Reporting

‘‘Investigators shall comply with annual

data reporting requirements. Annual data

report forms will be forwarded by NIH OBA

to investigators. Information submitted in

these annual reports will be evaluated by

NIH OBA and the RAC, and possibly

considered at a future RAC meeting.

Information obtained through the annual data

reporting process will be included in the NIH

Human Gene Transfer Information System to:

(1) provide clinical trial information; (2)

provide administrative details of protocol

registration; (3) provide annual status reports

of protocols; (4) facilitate risk assessment of

individual applications of human gene

transfer; and (5) enhance public awareness of

relevant scientific, safety, social, and ethical

issues.’’

‘‘Appendix M–I–C–4. Serious Adverse Event

Reporting

‘‘Investigators who have received

authorization from FDA to initiate a human

gene transfer protocol must report any

60332 Federal Register / Vol. 65, No. 196 / Tuesday, October 10, 2000 / Notices

serious adverse event immediately to the

local Institutional Review Board,

Institutional Biosafety Committee, Office for

Human Research Protections (if applicable),

and NIH OBA, followed by the submission of

a written report filed with each group.

Reports submitted to NIH OBA shall be sent

to the Office of Biotechnology Activities,

National Institutes of Health/MSC 7010, 6000

Executive Boulevard, Suite 302, Bethesda,

Maryland 20892–7010, (301) 496–9838.’’

‘‘Appendix M–II. Description of Proposal

. . .’’

‘‘Appendix M–III. Informed Consent . . .

‘‘M–III–B. Informed Consent Document

‘‘Submission of a human gene transfer

experiment to NIH OBA must include a copy

of the proposed informed consent document.

A separate informed consent document

should be used for the gene transfer portion

of a research project when gene transfer is

used as an adjunct in the study of another

technique, e.g., when a gene is used as a

‘‘marker’’ or to enhance the power of

immunotherapy for cancer. . . .’’

‘‘Appendix M–IV. Privacy and

Confidentiality . . .’’

‘‘Appendix M–V. Special Issues . . .’’

Appendix M–VI, RAC Review—Human

Gene Transfer Experiments has been

incorporated into new Appendix M–I–B,

RAC Review Requirements.

Appendix M–VII, Reporting Requirements,

has been incorporated into new Appendix

M–I–C, Reporting Requirements.

Appendix VIII, Footnotes of Appendix M,

will be renumbered to Appendix VI.

* * * * *

OMB’s ‘‘Mandatory Information

Requirements for Federal Assistance Program

Announcements’’ (45 FR 39592) requires a

statement concerning the official government

programs contained in the Catalog of Federal

Domestic Assistance. Normally, NIH lists in

its announcements the number and title of

affected individual programs for the guidance

of the public. Because the guidance in this

notice covers virtually every NIH and Federal

research program in which recombinant DNA

techniques could be used, it has been

determined not to be cost effective or in the

public interest to attempt to list these

programs. In addition, NIH could not be

certain that every Federal program would be

included as many Federal agencies, as well

as private organizations, both national and

international, have elected to follow the NIH

Guidelines. In lieu of the individual program

listing, NIH invites readers to direct

questions to the information address above

about whether individual programs listed in

the Catalog of Federal Domestic Assistance

are affected.

Dated: September 30, 2000.

Ruth L. Kirschstein,

Principal Deputy Director, National Institutes

of Health.

[FR Doc. 00–25891 Filed 10–6–00; 8:45 am]

BILLING CODE 4140–01–P