61862 Federal Register / Vol. 62, No. 223 / Wednesday, November 19, 1997 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Recombinant DNA Research:

Proposed Actions Under the

Guidelines

AGENCY: National Institutes of Health

(NIH), PHS, DHHS.

ACTION: Notice of proposed actions

under the NIH Guidelines for Research

Involving Recombinant DNA Molecules

(NIH Guidelines).

SUMMARY: This notice sets forth

proposed actions to be taken under the

NIH Guidelines for Research Involving

Recombinant DNA Molecules (59 FR

34496, amended 59 FR 40170, 60 FR

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

4782, 62 FR 53335, 62 FR 56196, 62 FR

59032). Interested parties are invited to

submit comments concerning these

proposals. These proposals will be

considered by the Recombinant DNA

Advisory Committee (RAC) at its

meeting on December 15–16, 1997,

along with the proposed actions

published in the Federal Register on

October 16, 1997 (62 FR 53908). After

consideration of these proposals and

comments by the RAC, the NIH Director

will issue decisions in accordance with

the NIH Guidelines.

DATES: Interested parties are invited to

submit comments concerning the

proposed actions. Comments received

by December 8, 1997, will be

reproduced and distributed to the RAC

for consideration at its December 15–16,

1997, meeting. After consideration of

this proposal and comments by the

RAC, the NIH Director will issue

decisions in accordance with the NIH

Guidelines.

ADDRESSES: Written comments and

recommendations should be submitted

to Debra Knorr, Office of Recombinant

DNA Activities, National Institutes of

Health, MSC 7010, 6000 Executive

Boulevard, Suite 302, Bethesda,

Maryland 20892–7010, Phone 301–496–

9838, FAX 301–496–9839.

All comments received in response to

this notice will be considered and will

be available for public inspection in the

above office on weekdays between the

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

FOR FURTHER INFORMATION CONTACT:

Background documentation and

additional information can be obtained

from the Office of Recombinant DNA

Activities, National Institutes of Health,

MSC 7010, 6000 Executive Boulevard,

Suite 302, Bethesda, Maryland 20892–

7010, Phone 301–496–9838, FAX 301–

496–9839. The Office of Recombinant

DNA Activities web site is located at

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

information about the office.

I. Proposed Actions Regarding

Amendments to the NIH Guidelines

The NIH will consider the following

actions under the NIH Guidelines for

Research Involving Recombinant DNA

Molecules (NIH Guidelines):

I–A. Amendment to Appendix M–I,

Submission Requirements—Human

Gene Transfer Experiments, Under the

NIH Guidelines Regarding Deadline for

Submission for RAC Review

On November 12, 1997, Dr. Scott

McIvor, a member of the Recombinant

DNA Advisory Committee (RAC),

requested a proposed action regarding

the deadline for submission of human

gene transfer protocols that will require

public discussion at the RAC meetings.

To give the RAC sufficient time to

review the protocols and the

investigators to respond to primary

reviewer’s written comments, Appendix

M–I, Submission Requirements—

Human Gene Transfer Experiments, of

the NIH Guidelines, is proposed to be

amended to include a statement

regarding the submission deadline.

Submission material will be accepted by

NIH/ORDA at any time. However, if a

protocol is recommended for full RAC

review, the submission material must be

received in NIH/ORDA a minimum of

eight weeks prior to the next scheduled

RAC meeting.

Appendix M–I is proposed to read:

‘‘Appendix M–I. Submission Requirements—

Human Gene Transfer Experiments

‘‘Investigators must submit the following

material to the Office of Recombinant DNA

Activities, National Institutes of Health/MSC

7010, 6000 Executive Boulevard, Suite 302,

Bethesda, Maryland 20892–7010, (301) 496–

9838 (see exemption in Appendix M–VIII–A,

Footnotes of Appendix M). Proposals shall be

submitted to NIH/ORDA in the following

order: (1) Scientific abstract; (2) nontechnical abstract; (3) Institutional Biosafety

Committee and Institutional Review Board

approvals and their deliberations pertaining

to your protocol (Instutitional Biosafety

Committee approval must be obtained from

each institution at which recombinant DNA

material will be administered to human

subjects (as opposed to each institution

involved in the production of vectors for

human application and each institution at

which there is ex vivo transduction of

recombinant DNA material into target cells

for human application)); (4) Responses to

Appendix M–II through M–V. Description of

the Proposal, Informed Consent, Privacy and

Confidentiality, and Special Issues (the

pertinent responses can be provided in the

protocol or as an appendix to the protocol);

(5) clinical protocol (as approved by the local

Institutional Biosafety Committee and

Institutional Review Board); (6) Informed

Consent Document—approved by the

Institutional Review Board (see Appendix

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

(including tables, figures, and manuscripts);

and (8) curricula vitae—2 pages for each key

professional person in biographical sketch

format. Investigational New Drug (IND)

applications shall be submitted to FDA in the

format described in 21 CFR, Chapter I,

Subchapter D, Part 312, Subpart B, Section

23, IND Content and Format. Submissions to

FDA should be sent to the Division of

Congressional and Public Affairs, Document

Control Center, HFM–99, Center for Biologics

Evaluation and Research, 1401 Rockville

Pike, Rockville, Maryland 20852–1448.

‘‘Note: Submission material will be

accepted by NIH/ORDA at any time.

However, if a protocol is recommended for

full RAC review, the submission material

must be received in NIH/ORDA a minimum

of eight weeks prior to the next scheduled

RAC meeting.’’

I–B. Amendment to Appendix K,

Physical Containment for Large Scale

Uses of Organisms Containing

Recombinant DNA Molecules, of the

NIH Guidelines

In a letter dated November 5, 1997,

Gerard J. McGarrity, Ph.D., Senior Vice

President for Development, Genetic

Therapy, Inc., Gaithersburg, Maryland,

requested amendments to Appendix K,

Physical Containment for Large Scale of

Uses of Organisms Containing

Recombinant DNA Molecules, of the

NIH Guidelines to clarify the

containment requirements for large

scale production of viral vectors for

gene therapy. The letter states that:

‘‘The purpose of this correspondence is to

point out a section of Appendix K of the NIH

Guidelines (January 1997) that requires

clarification for large scale production of

viral vectors for gene therapy.

‘‘Appendix K specifies containment

guidelines for research or production

material that exceed 10 liters in volume. Each

of the large scale (LS) biosafety levels (BL):

Good Large Scale Production (GLSP), BL1/LS

(Appendix K–III–C), BL2/LS (Appendix K–

IV–C) and BL3/LS (Appendix K–V–C) specify

the requirements that:

‘Culture fluids (except as allowed by

Appendix K–III–D, K–IV–D, K–V–D) shall

not be removed from a closed system or other

primary containment equipment unless the

viable organisms containing recombinant

DNA molecules have been inactivated by a

validated inactivation procedure.’

‘‘Related language addresses the primary

containment equipment:

‘A closed system or other primary

containment equipment that has contained

viable organisms containing recombinant

DNA molecules shall not be opened for

maintenance or other purposes unless it has

been sterilized by a validated sterilization

procedure.’ (Sections K–III–F, K–IV–F and

K–V–F)

‘‘As its title (Physical Containment for

Large Scale Uses of Organisms Containing
Federal Register / Vol. 62, No. 223 / Wednesday, November 19, 1997 / Notices 61863

Recombinant DNA Molecules) indicates.

Appendix K was written to deal with

prokaryotic and eukaryotic cells that

elaborate proteins expressed by recombinant

DNA molecules. It was not intended for the

production of viral vectors used in gene

therapy. If fact, adherence to sections K–III–

C, K–IV–C, or K–V–C is incompatible with

the production and harvest of viral vectors in

volumes larger than 10 liters as active viral

vectors must be removed from the

equipment. Clearly, this was not the purpose

of Appendix K.

‘‘Several possible solutions exist. First,

Section III–D–6 of the Guidelines,

‘Experiments Involving More Than 10 Liters

Of Culture,’ states:

‘The appropriate containment will be

decided by the Institutional Biosafety

Committee. Where appropriate, Appendix K,

Physical Containment for Large Scale Uses of

Organisms Containing Recombinant DNA

Molecules, shall be used.’

‘‘We interpret this to mean that for

production of viral vectors, the IBC has the

authority to establish the specifics of large

scale containment, using the principles

described in Appendix K. For harvesting of

supernatant fluids that contain the viral

vector product, the IBC can establish

practices and facilities which are consistent

with the objectives and spirit of the NIH

Guidelines.

‘‘In this regard, Genetic Therapy, Inc., has

adhered to Section III–D–6 in the

establishment of facilities and practices for

large scale production of retroviral vectors to

the extent that Sections can be applied to

viral vectors. These have included the

practices for the appropriate large scale

biosafety level except for the requirement to

inactivate the culture fluids and to sterilize

the primary containment equipment prior to

opening the primary containment equipment

and removing the culture fluids. These

practices have been approved by our IBC.

‘‘A second possible solution is to limit

volumes to less than 10 liters. However, this

will be impractical for commercial purposes.

Third, the Guidelines can be modified to

address the requirements for large scale

production of viral vectors for gene therapy.

‘‘For the longer term, we believe it is most

appropriate to revise the relevant portions of

Appendix K to enable application of large

scale to viral vectors. We request that RAC

address this issue and propose the following

language be added to the end of Section K–

III–C, K–IV–C and K–V–C of Appendix K:

‘Culture fluids that contain viable

organisms or viral vectors intended as final

product may be removed from the primary

containment equipment by way of closed

systems for sample analysis, further

processing or final fill.’

‘‘We propose the following language be

added to the end of the first sentence of

Sections K–III–F, K–IV–F and K–V–F:

‘* * * except when the culture fluids

contain viable organisms or vectors intended

as final product as described in Section K–

III–C (or K–IV–C or K–V–C respectively)

above.’

‘‘We believe these additions maintain the

original concept of Appendix K while

addressing the needs of specific product

types.’’

Appendix K–III–C is proposed to

read:

‘‘Appendix K–III. Biosafety Level (BL1)—

Large Scale

‘‘Appendix K–III–C. Culture fluids (except

as allowed in Appendix K–III–D) shall not be

removed from a closed system or other

primary containment equipment unless the

viable organisms containing recombinant

DNA molecules have been inactivated by a

validated inactivation procedure. A validated

inactivation procedure is one which has been

demonstrated to be effective using the

organism that will serve as the host for

propagating the recombinant DNA molecules.

Culture fluids that contain viable organisms

or viral vectors intended as final product may

be removed from the primary containment

equipment by way of closed systems for

sample analysis, further processing or final

fill.’’

Appendix K–III–F is proposed to read:

‘‘Appendix K–III–F. A closed system or

other primary containment equipment that

has contained viable organisms containing

recombinant DNA molecules shall not be

opened for maintenance or other purpose

unless it has been sterilized by a validated

sterilization procedure except when the

culture fluids contain viable organisms or

vectors intended as final product as

described in Section K–III–C above. A

validated sterilization procedure is one

which has been demonstrated to be effective

using the organism that will serve as the host

for propagating the recombinant DNA

molecules.’’

Appendix K–IV–C is proposed to

read:

‘‘Appendix K–IV. Biosafety Level 2 (BL2)—

Large Scale

‘‘Appendix K–IV–C. Culture fluids (except

as allowed in Appendix K–IV–D) shall not be

removed from a closed system or other

primary containment equipment unless the

viable organisms containing recombinant

DNA molecules have been inactivated by a

validated inactivation procedure. A validated

inactivation procedure is one which has been

demonstrated to be effective using the

organism that will serve as the host for

propagating the recombinant DNA molecules.

Culture fluids that contain viable organisms

or viral vectors intended as final product may

be removed from the primary containment

equipment by way of closed systems for

sample analysis, further processing or final

fill.’’

Appendix K–IV–F is proposed to

read:

‘‘Appendix K–IV–F. A closed system or

other primary containment equipment that

has contained viable organisms containing

recombinant DNA molecules shall not be

opened for maintenance or other purposes

unless it has been sterilized by a validated

sterilization procedure except when the

culture fluids contain viable organisms or

vectors intended as final product as

described in Section K–IV–C above. A

validated sterilization procedure is one

which has been demonstrated to be effective

using the organisms that will serve as the

host for propagating the recombinant DNA

molecules.’’

Appendix K–V–C is proposed to read:

‘‘Appendix K–V. Biosafety Level 3 (BL3)—

Large Scale

‘‘Appendix K–V–C. Culture fluids (except

as allowed in Appendix K–V–D) shall not be

removed from a closed system or other

primary containment equipment unless the

viable organisms containing recombinant

DNA molecules have been inactivated by a

validated inactivation procedure. A validated

inactivation procedure is one which has been

demonstrated to be effective using the

organisms that will serve as the host for

propagating the recombinant DNA molecules.

Culture fluids that contain viable organisms

or viral vectors intended as final product may

be removed from the primary containment

equipment by way of closed systems for

sample analysis, further processing or final

fill.’’

Appendix K–V–F is proposed to read:

‘‘Appendix K–V–F. A closed system or

other primary containment equipment that

has contained viable organisms containing

recombinant DNA molecules shall not be

opened for maintenance or other purposes

unless it has been sterilized by a validated

sterilization procedure except when the

culture fluids contain viable organisms or

vectors intended as final product as

described in Section K–V–C above. A

validated sterilization procedure is one

which has been demonstrated to be effective

using the organisms that will serve as the

host for propagating the recombinant DNA

molecules.’’

I–C. Amendment to Section III–D–6,

Experiments Involving More Than 10

Liters of Culture, of the NIH Guidelines

In a letter dated November 6, 1997,

Richard A. Knazek, Medical Officer,

Clinical Research, National Center for

Research Resources, NIH, requested an

amendment to Section III–D–6,

Experiments Involving More Than 10

Liters of Culture, of the NIH Guidelines.

Dr. Knazek proposed an addition of a

statement, ‘‘When more than 10 Liters of

culture media is to be produced within

a GMP-accredited facility for subsequent

clinical use, the level of appropriate

containment shall be determined by the

Institutional Biosafety Committee (IBC)

affiliated with the institution where the

investigator will perform the clinical

manipulation of the vector.’’ Dr. Knazek

stated the rationale of his request as

follows:

‘‘The purpose of this amendment is to

prevent an additional layer of bureaucracy

from impeding the implementation of an

appropriately reviewed and approved gene

therapy protocol.

‘‘The risks due to exposure to a gene vector

will be greatest at the time when the final

media product is either incubated with the

target cells (ex vivo transduction) and/or
61864 Federal Register / Vol. 62, No. 223 / Wednesday, November 19, 1997 / Notices

infused into the recipient (in vivo

transduction). The IBC at that clinical

institution bears the responsibility of being

knowledgeable about attendant risks to the

investigator, laboratory and medical

personnel, patient and the environment.

‘‘While being produced within a qualified

GMP facility, the vector is, by definition,

both protected from the environment and

prevented from escaping into the

environment.

‘‘Clearly, the vector and its proposed use

must be scrutinized by an IBC. However, the

IBC review of the vector and its protocol is

most appropriately performed at the clinical

site rather than at the GMP facility. Review

by more than one IBC would be redundant.’’

Section III–D–6 is proposed to read:

‘‘Section III–D. Experiments That Require

Institutional Biosafety Committee Approval

Before Initiation

‘‘Section III–D–6. Experiments Involving

More than 10 Liters of Culture. The

appropriate containment will be decided by

the Institutional Biosafety Committee. Where

appropriate, Appendix K, Physical

Containment for Large Scale Uses of

Organisms Containing Recombinant DNA

Molecules, shall be used. Appendix K

describes containment conditions Good Large

Scale Practice through BL3–Large Scale.

When more than 10 Liters of culture media

is to be produced within a GMP-accredited

facility for subsequent clinical use, the level

of appropriate containment shall be

determined by the IBC affiliated with the

institution where the investigator will

perform the clinical manipulation of the

vector.’’

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 DNA recombinant molecule

techniques could be used, it has been

determined not to be cost effective or in

the public interest to attempt to list

these programs. Such a list would likely

require several additional pages. In

addition, NIH could not be certain that

every Federal program would be

included as many Federal agencies, as

well as private organizations, both

national and international, have elected

to follow the NIH Guidelines. In lieu of

the individual program listing, NIH

invites readers to direct questions to the

information address above about

whether individual programs listed in

the Catalog of Federal Domestic

Assistance are affected.

Dated: November 12, 1997.

Lana R. Skirboll,

Associate Director for Science Policy,

National Institutes of Health.

[FR Doc. 97–30321 Filed 11–18–97; 8:45 am]

BILLING CODE 4140–01–M