[Federal Register Volume 59, Number 90 (Wednesday, May 11, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-11466]


[[Page Unknown]]

[Federal Register: May 11, 1994]


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Part IX





Department of Health and Human Services





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National Institutes of Health



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Recombinant DNA Research: Proposed Actions Under the Guidelines; Notice
DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

 
Recombinant DNA Research: Proposed Actions Under the Guidelines

AGENCY: National Institutes of Health, PHS, HHS.

ACTION: Notice of proposed actions under the NIH guidelines for 
research involving recombinant DNA molecules (51 FR 16958).

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SUMMARY: This notice sets forth proposed actions to be taken under the 
National Institutes of Health (NIH) Guidelines for Research Involving 
Recombinant DNA Molecules (51 FR 16958). Interested parties are invited 
to submit comments concerning these proposals. These proposals will be 
considered by the Recombinant DNA Advisory Committee at its meeting on 
June 9-10, 1994. After consideration of these proposals 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.

DATES: Comments received by May 26, 1994, will be reproduced and 
distributed to the Recombinant DNA Advisory Committee for consideration 
at its June 9-10, 1994, meeting.

ADDRESSES: Written comments and recommendations should be submitted to 
Dr. Nelson A. Wivel, Director, Office of Recombinant DNA Activities 
(ORDA), building 31, room 4B11, National Institutes of Health, 
Bethesda, Maryland 20892, or sent by FAX to 301-496-9839.
    All comments received in timely response to this notice will be 
considered and will be available for public inspection in the above 
office on weekdays between the hours of 8:30 a.m. and 5 p.m.

FOR FURTHER INFORMATION CONTACT:
Background documentation and additional information can be obtained 
from the Office of Recombinant DNA Activities, building 31, room 4B11, 
National Institutes of Health, Bethesda, Maryland 20892, (301) 496-
9838.

SUPPLEMENTARY INFORMATION: The NIH will consider the following actions 
under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules:

I. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Drs. Sobol and Royston

    In a letter dated October 6, 1993, Drs. Robert Sobol and Ivor 
Royston of the San Diego Regional Cancer Center, San Diego, California, 
submitted the human gene transfer protocol entitled: Injection of 
Glioblastoma Patients with Tumor Cells Genetically Modified to Secrete 
Interleukin-2 (IL-2): A Phase I Study to the Recombinant DNA Advisory 
Committee for formal review and approval. At the December 2-3, 1993, 
meeting, the Recombinant DNA Advisory Committee disapproved the 
original protocol. The majority of the Recombinant DNA Advisory 
Committee members concluded that the preclinical data derived from a 
previous single patient protocol was inadequate to justify the 
experiment. The motion to disapprove the protocol passed by a vote of 
10 in favor, 5 opposed, and 1 abstention.
    In a letter dated April 8, 1994, Drs. Sobol and Royston submitted a 
revised protocol to the Recombinant DNA Advisory Committee for formal 
review and approval.

II. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Dr. Curiel

    In a letter dated April 13, 1994, Dr. David Curiel of the 
University of Alabama, Birmingham, Alabama, submitted the human gene 
transfer protocol entitled: Phase I Trial of a Polynucleotide Vaccine 
to Human Carcinoembryonic Antigen in Patients with Metastatic 
Colorectal Cancer to the Recombinant DNA Advisory Committee for formal 
review and approval.

III. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Drs. Evans and Robbins

    In a letter dated April 13, 1994, Drs. C. H. Evans and Paul Robbins 
of the University of Pittsburgh, Pittsburgh, Pennsylvania, submitted 
the human gene transfer protocol entitled: Clinical Trial to Assess the 
Safety, Feasibility, and Efficacy of Transferring a Potentially Anti-
arthritic Cytokine Gene to Human Joints with Rheumatoid Arthritis to 
the Recombinant DNA Advisory Committee for formal review and approval.

IV. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Drs. Heslop, Brenner, and Krance

    In a letter dated April 6, 1994, Drs. Helen Heslop, Malcolm 
Brenner, and Robert Krance of the St. Jude Children's Research 
Hospital, Memphis, Tennessee, submitted the human gene transfer 
protocol entitled: Use of Double Marking with Retroviral Vectors to 
Determine Rate of Reconstitution of Untreated and Cytokine Expanded 
CD34(+) Selected Marrow Cells in Patients Undergoing Autologous Bone 
Marrow Transplantation to the Recombinant DNA Advisory Committee for 
formal review and approval.

V. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Dr. Lyerly

    In a letter dated April 12, 1994, Dr. H. Kim Lyerly of Duke 
University Medical Center, Durham, North Carolina, submitted the human 
gene transfer protocol entitled: A Pilot Study of Autologous Human 
Interleukin-2 Gene Modified Tumor Cells in Patients with Refractory or 
Recurrent Metastatic Breast Cancer to the Recombinant DNA Advisory 
Committee for formal review and approval.

VI. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Drs. Economou, Glaspy, and McBride

    In a letter dated April 11, 1994, Drs. James Economou, John Glaspy, 
and William McBride of the University of California, Los Angeles, 
California, submitted a human gene transfer protocol entitled: A Phase 
I Testing of Genetically Engineered Interleukin-7 Melanoma Vaccines to 
the Recombinant DNA Advisory Committee for formal review and approval.

VII. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Dr. Freedman

    In a letter dated March 22, 1993, Dr. Ralph Freedman of M.D. 
Anderson Cancer Center, Houston, Texas, submitted the human gene 
transfer protocol entitled: Use of a Retroviral Vector to Study the 
Trafficking Patterns of Purified Ovarian Tumor Infiltrating Lymphocyte 
(TIL) Populations Used in Intraperitoneal Adoptive Immunotherapy of 
Ovarian Cancer Patients: A Pilot Study to the Recombinant DNA Advisory 
Committee for formal review and approval. At its June 7-8, 1993, 
meeting the Recombinant DNA Advisory Committee deferred the protocol 
until the investigators return to the full Recombinant DNA Advisory 
Committee with the following:
    (1) Data demonstrating efficient transduction of TIL,
    (2) Sufficient information regarding demonstration of selectivity, 
i.e., specific trafficking of TIL to tumor,
    (3) Complete statistical analysis,
    (4) Revised Informed Consent document in simplified language, and
    (5) Address concerns about patient responsibility for research-
related costs. The motion to defer the protocol pending full 
Recombinant DNA Advisory Committee review of additional information 
passed by a vote of 18 in favor, 0 opposed, and no abstentions.
    In a letter dated January 5, 1994, Dr. Freedman submitted a revised 
protocol to the Recombinant DNA Advisory Committee for formal review 
and approval. At its March 3-4, 1994, meeting, the Recombinant DNA 
Advisory Committee deferred the protocol until the investigator returns 
to the full Recombinant DNA Advisory Committee with:
    (1) A modified protocol, which includes a revised treatment schema 
that will provide statistically significant information, and
    (2) A revised Informed Consent document that adequately describes 
the procedures that will be performed in language understandable to lay 
persons. The motion to defer the protocol pending full Recombinant DNA 
Advisory Committee review of the additional information passed by a 
vote of 12 in favor, 1 opposed, and no abstentions.
    In a letter dated April 13, 1994, Dr. Freedman submitted a revised 
protocol to the Recombinant DNA Advisory Committee for formal review 
and approval.

VIII. Addition to Appendix D of the NIH Guidelines Regarding a Human 
Gene Transfer Protocol/Drs. Deisseroth, Hortobagyi, and Champlin

    In a letter dated April 12, 1994, Drs. Albert Deisseroth, Gabriel 
Hortobagyi, and Richard Champlin of the M.D. Anderson Cancer Center, 
Houston, Texas, submitted the human gene transfer protocol entitled: 
Use of Safety-Modified Retroviruses to Introduce Chemotherapy 
Resistance Sequences into Normal Hematopoietic Cells for 
Chemoprotection During the Therapy of Breast Cancer: A Pilot Trial to 
the Recombinant DNA Advisory Committee for formal review and approval.

IX. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Dr. Roth

    In a letter dated April 12, 1994, Dr. Jack Roth of M.D. Anderson 
Cancer Center, Houston, Texas, submitted the human gene transfer 
protocol entitled: Clinical Protocol for Modification of Tumor 
Suppressor Gene Expression and Induction of Apoptosis in Non-Small Cell 
Lung Cancer (NSCLC) with an Adenovirus Vector Expressing Wildtype p53 
and Cisplatin to the Recombinant DNA Advisory Committee for formal 
review and approval.

X. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Dr. Lotze

    In a letter dated April 13, 1994, Dr. Michael Lotze of the 
University of Pittsburgh, Pittsburgh, Pennsylvania submitted the human 
gene transfer protocol entitled: IL-12 Gene Therapy Using Direct 
Injection of Tumor with Genetically Engineered Autologous Fibroblasts 
to the Recombinant DNA Advisory Committee for formal review and 
approval.

XI. Addition to Appendix D of the NIH Guidelines Regarding a Human Gene 
Transfer Protocol/Drs. Liu and Young

    In a letter dated October 7, 1993, Drs. Johnson M. Liu and Neal S. 
Young of the National Institutes of Health, Bethesda, Maryland, 
submitted the human gene transfer protocol entitled: Retroviral 
Mediated Gene Transfer of the Fanconi Anemia Complementation Group C 
Gene to Hematopoietic Progenitors of Group C Patients to the 
Recombinant DNA Advisory Committee for formal review and approval. At 
the December 2-3, 1993, meeting, the Recombinant DNA Advisory Committee 
deferred the protocol until the investigators return to the full 
Recombinant DNA Advisory Committee with the following:
    (1) Murine data demonstrating in vivo expression of the FACC gene 
and safety data accumulated over a period of  4 months 
demonstrating that the FACC-transduced cells do not produce any 
untoward effects, i.e., malignant transformation:
    (2) Data (cited in Dr. Cynthia Dunbar's December 1993 data 
management report, Protocol #9206-025) regarding the possibility that 
``stem cell factor could favor the growth of leukemic versus normal 
progenitors during ex vivo culture periods;'' and
    (3) Revised eligibility criteria sections for both the protocol and 
Informed Consent document that describe the necessity for bone marrow 
examination following each infusion.
    The consensus of the Recombinant DNA Advisory Committee was that 
the investigators were not required to submit this additional data 
until 4 weeks prior to the Recombinant DNA Advisory Committee meeting 
at which the information is reviewed. Submission of previously reviewed 
information is not required. The motion to defer the protocol pending 
full Recombinant DNA Advisory Committee review of additional 
information passed by a vote of 14 in favor, 0 opposed, and 3 
abstentions.
    On May 2, 1994, Drs. Liu and Young submitted additional materials 
relating to the human gene transfer protocol to the Recombinant DNA 
Advisory Committee for formal review and approval.

XII. Amendment to Part I-D of the Points to Consider in the Design and 
Submission of Protocols for the Transfer of Recombinant DNA Into the 
Genome of Human Subjects, NIH Guidelines, Regarding Informed Consent/
Dr. Zallen

    During the December 2-3, 1993, Recombinant DNA Advisory Committee 
meeting, Dr. Gary Ellis, Director of the Office for Protection from 
Research Risks (OPRR), NIH, Bethesda, Maryland, responded to the 
written comments submitted by Dr. Zallen, Chair of the Working Group on 
Informed Consent Issues. Dr. Ellis noted the Recombinant DNA Advisory 
Committee's concern regarding specific issues that should be addressed 
in human gene transfer protocol Informed Consent documents, i.e., 
request for autopsy, recommendations for male/female contraception, 
separate Informed Consent documents when gene therapy is separate from 
a clinical protocol, commitment to long-term patient follow-up, and 
financial responsibility of the institution for all research-related 
costs. During his presentation, Dr. Ellis provided the Recombinant DNA 
Advisory Committee with background information regarding the roles of 
both OPRR and local Institutional Review Boards (IRB) in the review of 
research proposals involving human subjects. Dr. Ellis recommended that 
the Recombinant DNA Advisory Committee draft a letter outlining its 
specific recommendations to OPRR for distribution and consideration by 
the local IRBs.
    In a memorandum dated December 23, 1993, Dr. Ellis further 
clarified the avenues that should be pursued by the Recombinant DNA 
Advisory Committee with regard to the ``quality and content of informed 
consent documents into constructive changes in the informed consent 
process,'' specifically in relation to human gene transfer. Dr. Ellis 
recommended that the Points to Consider should be amended to introduce 
consistency in the Informed Consent document language.
    During the March 3-4, 1994, Recombinant DNA Advisory Committee 
meeting, Dr. Doris Zallen, Chair of the Working Group on Informed 
Consent, provided a summary of the proposed amendments to Part I-D, 
Informed Consent of the Points to Consider. Two versions of revised 
Part I-D were presented:
    (1) The version drafted by the working group, and
    (2) A modified version incorporating the modifications suggested by 
Mr. Alex Capron. The Recombinant DNA Advisory Committee recommended 
that the working group should develop a consolidated version of part I-
D which includes language from both proposed documents. The Recombinant 
DNA Advisory Committee suggested that questions should be prefaced with 
an explanation as to the necessity for the requested information.
    On April 27, 1994, Dr. Zallen submitted revised amendments to part 
I-D, Informed Consent, of the Points to Consider in response to the 
specific comments posed by the Recombinant DNA Advisory Committee at 
its March 3-4, 1994, meeting. The proposed amendments read:

Part I-D Informed Consent

    ``In accordance with the requirements of DHHS regulations for the 
protection of human subjects (45 CFR part 46), investigators shall 
indicate how subjects will be informed about the proposed study, the 
manner in which their consent will be solicited, and that the informed 
consent form makes clear the special requirements of gene transfer 
research.
Part 1-D-1. Communication of the Study to Potential Participants
    Part I-D-1-a. Which members of the research group and/or 
institution will be responsible for contacting potential participants 
and for describing the study to them? What procedures will be used to 
avoid potential conflicts of interest if the investigator is also 
providing medical care to potential subjects?
    Part I-D-1-b. Where will discussions or other means of informing 
individuals about the proposed study take place?
    Part I-D-1-c. How will the major points covered in Parts I-A 
through I-C of the Points to Consider be disclosed to potential 
participants and/or their parents or guardians in language that is 
understandable to them?
    Part I-D-1-d. What is the length of time that the potential 
participants will have to make a decision about their participation in 
the study?
    Part I-D-1-e. If the study involves pediatric or mentally 
handicapped subjects, how will the assent of each person be obtained?
Part I-D-2. Informed Consent Document
    ``Investigators submitting human gene transfer proposals for 
Recombinant DNA Advisory Committee review must include the Informed 
Consent document as approved by the local Institutional Review Board. A 
separate 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, such as when the gene is used as a `marker' 
or when it is used to enhance the power of immunotherapy for cancer.
    ``Because of the relative novelty of the procedures that are used, 
the potentially irreversible consequences of the procedures performed, 
and the possibility that many of the potential risks remain undefined, 
the Informed Consent document shall include the following specific 
information in addition to any requirements of the DHHS regulations for 
the protection of human subjects (45 CFR part 46). Indicate if each of 
the specified items appears in the consent form or, if not in the 
consent form, how those items will be presented to potential subjects. 
Include an explanation if any of the following items is omitted from 
the consent process or document.
Part I-D-2-a. General Requirements of Human Subjects Research
    Part I-D-2-a-(1). Description/purpose of study. ``The subjects 
should be provided a detailed explanation in non-technical language of 
the purpose of the study and the procedures associated with the conduct 
of the proposed study, including a description of the gene-transfer 
component.
    Part I-D-2-a-(2). Alternatives. ``The consent form should indicate 
the availability of other therapies, including the possibility of other 
investigational therapies and approaches.
    Part I-D-2-a-(3). Voluntary participation. ``The subjects should be 
informed that participation in the study is voluntary and that failure 
to participate in the study, or withdrawal of consent, will not result 
in any penalty or loss of benefits to which the subjects are otherwise 
entitled.
    Part I-D-2-a-(4). Benefits. ``The subjects should be provided with 
an accurate description of the possible benefits, if any, of 
participating in the proposed study. For experiments which are not 
reasonably expected to provide a therapeutic benefit to subjects, the 
consent form shall clearly state that no direct clinical benefit to 
subjects is expected to occur as a result of participation in the 
study, although knowledge may be gained that may benefit others.
    Part I-D-2-a-(5). Possible risks, discomforts, and side effects. 
``There should be a clear itemization in the consent form of types of 
adverse experiences, the relative severities, and the expected 
frequencies. For consistency of definition, side effects that are 
listed as mild should be ones which do not require a therapeutic 
intervention. Moderate side effects require an intervention. Severe 
side effects are potentially fatal or life-threatening, disabling, or 
require prolonged hospitalization. Rare side effects occur in less than 
one in one thousand subjects, uncommon side effects in less than 1% of 
subjects, common side effects in one to 10% of subjects, and frequent 
side effects are those which occur in more than 10% of subjects.
    ``The consent form should provide information regarding the 
approximate number of people who have received the genetic material 
under study. It is also necessary to warn potential subjects that for 
genetic materials previously used in relatively few or no humans, 
unforeseen risks are possible, including ones that could be severe.
    ``Any possible adverse medical consequences that may occur if the 
subjects withdraw from the study once the experiment has started should 
be indicated.
    ``Part I-D-2-a-(6). Costs. ``The subjects should be provided with 
information about any financial costs associated with their 
participation in the experiment and in the long-term follow-up to the 
experiment that are not covered by the investigators or the 
institutions involved. Comparable financial information for other 
available alternatives, including other investigational therapies, 
should also be provided.
    ``In the consent form, subjects should be informed about the extent 
to which they will be responsible for any costs for medical treatment 
required as a direct result of research-related injury.
Part I-D-2-b. Specific Requirements of Gene Transfer Research
    Part I-D-2-b-(1). Use of barrier contraception. ``To avoid the 
possibility that any of the reagents employed in gene transfer research 
could cause harm to a developing fetus, female subjects should be 
informed that they should not be pregnant during the course of their 
participation in the study. Both male and female subjects should be 
informed when barrier contraception is required during the active phase 
of their participation in the study.
    Part I-D-2-b-(2). Long-term follow-up. ``To permit evaluation of 
long-term safety and efficacy of gene transfer, the prospective 
subjects should be informed that they are expected to cooperate in 
long-term follow-up that extends beyond the active phase of the study. 
A list should be provided in the consent form of persons who can be 
contacted in the event that questions arise during the follow-up 
period. The principal investigator should request that subjects always 
keep the laboratory informed of a current address and telephone number.
    ``The subjects should also be informed that any significant 
findings resulting from the study will be made known to them and/or 
their parent or guardian including new information about the 
experimental procedure, the physical reactions experienced by other 
individuals involved in the study, and any long-term effects that have 
been noted.
    ``Part I-D-2-b-(3). Request for autopsy. ``To obtain vital 
information about the safety and efficacy of gene transfer, subjects 
should be informed that at the time of death, whenever that may occur, 
an autopsy will be requested and that they should advise their families 
of this request and of its scientific and medical importance.
    Part I-D-2-b-(4). Interest of media and others in the research. To 
alert the subjects that others may have an interest in the innovative 
character of the experiment and the status of treated subjects:
    ``The subjects should be informed that the institution and 
investigators will make every effort to provide protection from the 
media in an effort to protect participants' privacy;
    ``The subjects should be informed that representatives of 
applicable Federal agencies (e.g., NIH, Food and Drug Administration), 
representatives of collaborating institutions, vector suppliers, etc., 
will have access to medical records of the participants.''

XIII. Deletion of Appendix L of the NIH Guidelines Regarding Release 
Into the Environment/Dr. Wivel

    On April 29, 1994, Dr. Nelson Wivel of the Office of Recombinant 
DNA Activities, National Institutes of Health, Bethesda, Maryland, 
requested that Appendix L, Release into the Environment of Certain 
Plants, be deleted from the NIH Guidelines.
    The Office of Recombinant DNA Activities (ORDA) requests that 
Appendix L, Release into the Environment of Certain Plants, be deleted 
from the NIH Guidelines based on the following:
    (1) Section I of the NIH Guidelines allows experiments to proceed 
that are reviewed and approved by another Federal agency that has 
jurisdiction for review and approval without the necessity for NIH 
review or approval (52 FR 31849);
    (2) The Recombinant DNA Advisory Committee has not reviewed any 
deliberate release experiment involving recombinant DNA since 1984;
    (3) At its May 30-31, 1991, meeting, the Recombinant DNA Advisory 
Committee recommended that Section III-A-2 be deleted from the NIH 
Guidelines; and
    (4) Experiments involving deliberate release into the environment 
are currently reviewed within the framework of existing Federal 
regulations, i.e., the Environmental Protection Agency (EPA) and the 
United States Department of Agriculture (USDA).
    Section I of the NIH Guidelines was amended on August 24, 1987, 
such that any recombinant DNA experiment (other than human gene 
transfer) may proceed without Recombinant DNA Advisory Committee and 
NIH approval if it has been reviewed and approved by another Federal 
agency that has jurisdiction over such a proposal. The amended version 
(52 FR 31849) of Section I reads as follows:

Section I-A. Purpose

    ``* * * 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 approval, or other applicable clearances, has 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 * * *.''
    On December 6, 1990, the Recombinant DNA Advisory Committee 
Planning Subcommittee recommended that the requirement for Recombinant 
DNA Advisory Committee review of experiments involving deliberate 
environmental release of organisms containing recombinant DNA be 
eliminated from the NIH Guidelines. This recommendation reflected the 
fact that the Federal regulatory agencies, the USDA and EPA, are 
responsible for the review and approval of environmental release 
experiments. The Recombinant DNA Advisory Committee reviewed the 
request and recommended that the following sections be deleted from the 
NIH Guidelines:
Section III-A-2
    Deliberate release into the environment of any organism containing 
recombinant DNA except those listed below. The term ``deliberate 
release'' is defined as a planned introduction of recombinant DNA-
containing microorganisms, plants, or animals into the environment.
    Section III-A-2-a. Introductions conducted under conditions 
considered to be accepted scientific practices in which there is 
adequate evidence of biological and/or physical control of the 
recombinant DNA-containing organisms. The nature of such evidence is 
described in appendix L.
    Section III-A-2-b. Deletion derivatives and single base changes not 
otherwise covered by the NIH Guidelines.
    Section III-A-2-c. For extrachromosomal elements and microorganisms 
(including viruses), rearrangements and amplifications within a single 
genome. Rearrangements involving the introduction of DNA from different 
strains of the same species would not be covered by this exemption.
    Based on these amendments to the NIH Guidelines, that have 
previously been recommended by the Recombinant DNA Advisory Committee, 
and the fact that the principals of planned introduction are now in 
place which provide a risk-assessment method by other Federal 
regulatory agencies, the Office of Recombinant DNA Activities requests 
that Appendix L be deleted from the NIH Guidelines.
    Appendix L will be deleted as follows:

Appendix L. Release Into the Environment of Certain Plants

Appendix L-I. General Information

    ``Appendix L specifies conditions under which certain plants as 
specified below, may be approved for release into the environment. 
Experiments in this category cannot be initiated without submission 
of relevant information on the proposed experiment to NIH, review by 
the RAC Plant Working Group, and specific approval by the NIH 
Director. Such experiments also require the approval of the IBC 
before initiation. Information on specific experiments which have 
been approved will be available in ORDA and will be listed in 
appendix L-III when the Guidelines are republished.
    ``Experiments which do not meet the specifications of appendix 
L-II fall under section III-A and require RAC review and NIH and IBC 
approval before initiation.

Appendix L-II. Criteria Allowing Review by the RAC Plant Working 
Group Without the Requirement for Full RAC Review

    ``Approval may be granted by ORDA in consultation with the Plant 
Working Group without the requirement for full RAC review (IBC 
review is also necessary) for growing plants containing recombinant 
DNA in the field under the following conditions:
    Appendix L-II-A. The plant species is a cultivated crop of a 
genus that has no species known to be a noxious weed.
    Appendix L-II-B. The introduced DNA consists of well/
characterized genes containing no sequences harmful to humans, 
animals, or plants.
    Appendix L-II-C. The vector consists of DNA:
    (i) From exempt host-vector systems (see Appendix C);
    (ii) From plants of the same or closely related species;
    (iii) From nonpathogenic prokaryotes or nonpathogenic lower 
eukaryotic plants;
    (iv) From plant pathogens only if sequences resulting in 
production of disease symptoms have been deleted; or
    (v) Chimeric vectors constructed from sequences defined in (i) 
or (iv) above. The DNA may be introduced by any suitable method. If 
sequences resulting in production of disease symptoms are retained 
for purposes of introducing the DNA into the plant, greenhouse-grown 
plants must be shown to be free of such sequences before such 
plants, their derivatives, or seed can be used in field tests.
    Appendix L-II-D. Plants are grown in controlled access fields 
under specified conditions appropriate for the plant under study and 
the geographical location. Such conditions should include provisions 
for using good cultural and pest control practices, for physical 
isolation from plants of the same species outside of the 
experimental plot in accordance with pollination characteristics of 
the species, and the prevention of plants containing recombinant DNA 
from becoming established in the environment. Review by the IBC 
should include an appraisal by scientists knowledgeable of the crop, 
its production practices, and the local geographical conditions. 
Procedures for assessing alterations in and the spread of organisms 
containing recombinant DNA must be developed. The results of the 
outlined tests must be submitted for review by the IBC. Copies must 
also be submitted to the Plant Working Group of the RAC.

XIV. Amendment to Part VI of the Points To Consider, NIH Guidelines, 
Regarding Expedite Review/Dr. Wivel

    On April 29, 1994, Dr. Nelson Wivel of the Office of Recombinant 
DNA Activities, National Institutes of Health, Bethesda, Maryland, 
requested that part VI, Procedures to be Followed for Expedited Review, 
of the Points to Consider be amended to clarify submission requirements 
for Expedited Review.
    The Procedures to be Followed for Expedited Review currently reads:
    ``4. Regardless of the method of review, the Points to Consider 
must be the standard review for all gene transfer protocols.''
    The proposed amendment reads:
    ``4. Regardless of the method of review, the Points to Consider 
must be the standard review for all gene transfer protocols; therefore, 
submission of the Points to Consider is required.''
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592, June 11, 1980) 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 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: May 4, 1994.
Suzanne Medgyesi-Mitschang,
Acting Deputy Director for Science Policy and Technology Transfer.
[FR Doc. 94-11466 Filed 5-10-94; 8:45 am]
BILLING CODE 4140-01-P