[Federal Register Volume 59, Number 150 (Friday, August 5, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-19078]


[[Page Unknown]]

[Federal Register: August 5, 1994]


_______________________________________________________________________

Part IV





Department of Health and Human Services





_______________________________________________________________________



National Institutes of Health



_______________________________________________________________________




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

National Institutes of Health

 
Recombinant DNA Research: Actions Under the Guidelines

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice of Actions Under the NIH Guidelines for Research 
Involving Recombinant DNA Molecules.

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

SUMMARY: This notice sets forth three actions to be taken by the 
Director, National Institutes of Health (NIH), under the NIH Guidelines 
for Research Involving Recombinant DNA Molecules (Federal Register, 
July 5, 1994, Part IV).

FOR FURTHER INFORMATION CONTACT: Additional information can be obtained 
from Dr. Nelson A. Wivel, Director, Office of Recombinant DNA 
Activities (ORDA), Office of Science Policy and Technology Transfer, 
National Institutes of Health, Building 31, Room 4B11, Bethesda, 
Maryland 20892, (301) 496-9838.

SUPPLEMENTARY INFORMATION: Today three actions are being promulgated 
under the NIH Guidelines for Research Involving Recombinant DNA 
Molecules. These three proposed actions were published for comment in 
the Federal Register of May 11, 1994 (59 FR 24618), and reviewed and 
recommended for approval by the NIH Recombinant DNA Advisory Committee 
(RAC) at its meeting on June 9-10, 1994.

I. Background Information and Decisions on Actions Under the NIH 
Guidelines

A. Amendment to Appendix M-I-D of the NIH Guidelines Regarding Informed 
Consent for Human Gene Transfer Protocols

    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 the gene therapy aspects of 
the protocols are independent of an ongoing 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 translating its concern about 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 NIH Guidelines 
should be amended to introduce consistency in 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 Appendix M-I-
D, Informed Consent. Two versions of revised Appendix M-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 Appendix M-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 
Appendix M-I- D, Informed Consent, in response to the specific comments 
posed by the Recombinant DNA Advisory Committee at its March 3-4, 1994, 
meeting. The proposed amendments were reviewed by the Recombinant DNA 
Advisory Committee during the June 9-10, 1994, meeting. The Recombinant 
DNA Advisory Committee approved a motion to accept the proposed 
amendments with minor editorial changes to Appendix M-I-D, Informed 
Consent, by a vote of 13 in favor, 0 opposed, and no abstentions.
    The amended version of Appendix M-I-D, Informed Consent, reads:

Appendix M-I-D. Informed Consent

    In accordance with the requirements of DHHS regulations for the 
Protection of Human Subjects (45 CFR Part 46), investigators should 
indicate how subjects will be informed about the proposed study and 
the manner in which their consent will be solicited. They should 
also indicate how the Informed Consent document makes clear the 
special requirements of gene transfer research.

Appendix M-I-D-1. Communication About the Study to Potential 
Participants

    Appendix M-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 possible 
conflicts of interest if the investigator is also providing medical 
care to potential subjects?

Appendix M-I-D-1-b.

    How will the major points covered in Appendices M-I-A through M-
I-C be disclosed to potential participants and/or their parents or 
guardians in language that is understandable to them?

Appendix M-I-D-1-c.

    What is the length of time that potential participants will have 
to make a decision about their participation in the study?

Appendix M-I-D-1-d.

    If the study involves pediatric or mentally handicapped 
subjects, how will the assent of each person be obtained?

Appendix M-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 
Boards. 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.
    ``Because of the relative novelty of the procedures that are 
used, the potentially irreversible consequences of the procedures 
performed, and the fact that many of the potential risks remain 
undefined, the Informed Consent process should include the following 
specific information in addition to any requirements of the DHHS 
regulations for the Protection of Human Subjects (45 CFR 46). 
Indicate if each of the specified items appears in the Informed 
Consent document or, if not included in the Informed Consent 
document, how those items will be presented to potential subjects. 
Include an explanation if any of the following items are omitted 
from the consent process or the Informed Consent document.

Appendix M-I-D-2-a. General Requirements of Human Subjects Research

    Appendix M-I-D-2-a-(1). Description/purpose of the study. ``The 
subjects should be provided with 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.
    Appendix M-I-D-2-a-(2). Alternatives. ``The Informed Consent 
document should indicate the availability of therapies and the 
possibility of other investigational interventions and approaches.
    Appendix M-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.
    Appendix M-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 studies that are 
not reasonably expected to provide a therapeutic benefit to 
subjects, the Informed Consent document should 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.
    Appendix M-I-D-2-a-(5). Possible risks, discomforts, and side 
effects. ``There should be clear itemization in the Informed Consent 
document of types of adverse experiences, their relative severity, 
and their expected frequencies. For consistency, the following 
definitions are suggested: side effects that are listed as mild 
should be ones which do not require a therapeutic intervention; 
moderate side effects require an intervention; and severe side 
effects are potentially fatal or life-threatening, disabling, or 
require prolonged hospitalization.
    ``If verbal descriptors (e.g., `rare,' `uncommon,' or 
`frequent') are used to express quantitative information regarding 
risk, these terms should be explained.
    ``The Informed Consent document should provide information 
regarding the approximate number of people who have previously 
received the genetic material under study. It is 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.
    ``The Informed Consent document should indicate any possible 
adverse medical consequences that may occur if the subjects withdraw 
from the study once the study has started.
    Appendix M-I-D-2-a-(6). Costs. ``The subjects should be provided 
with specific information about any financial costs associated with 
their participation in the protocol and in the long-term follow-up 
to the protocol that are not covered by the investigators or the 
institution involved.
    ``Subjects should be provided an explanation about the extent to 
which they will be responsible for any costs for medical treatment 
required as a result of research-related injury.

Appendix M-I-D-2-b. Specific Requirements of Gene Transfer Research

    Appendix M-I-D-2-b-(1). Reproductive considerations. ``To avoid 
the possibility that any of the reagents employed in the gene 
transfer research could cause harm to a fetus/child, subjects should 
be given information concerning possible risks and the need for 
contraception by males and females during the active phase of the 
study. The period of time for the use of contraception should be 
specified.
    ``The inclusion of pregnant or lactating women should be 
addressed.
    Appendix M-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. The Informed Consent document should include a 
list of persons who can be contacted in the event that questions 
arise during the follow-up period. The principal investigator should 
request that subjects continue to provide a current address and 
telephone number.
    ``The subjects should be informed that any significant findings 
resulting from the study will be made known in a timely manner to 
them and/or their parent or guardian including new information about 
the experimental procedure, the harms and benefits experienced by 
other individuals involved in the study, and any long-term effects 
that have been observed.
    Appendix M-I-D-2-b-(3). Request for autopsy. ``To obtain vital 
information about the safety and efficacy of gene transfer, 
autopsies are to be performed, if feasible. Subjects should be 
informed that at the time of death, no matter what the cause, 
permission for any autopsy will be requested of their families. 
Subjects should be asked to advise their families of the request and 
of its scientific and medical importance.
    Appendix M-I-D-2-b-(4). Interest of the media and others in the 
research. ``To alert subjects that others may have an interest in 
the innovative character of the protocol and in the status of the 
treated subjects, the subjects should be informed of the following: 
(i) that the institution and investigators will make efforts to 
provide protection from the media in an effort to protect the 
participants' privacy, and (ii) that representatives of applicable 
Federal agencies (e.g., the National Institutes of Health and the 
Food and Drug Administration), representatives of collaborating 
institutions, vector suppliers, etc., will have access to the 
subjects' medical records.''
    I accept this recommendation, and Appendix M-I-D, Informed 
Consent, of the NIH Guidelines will be added accordingly.

B. Amendment to Appendix M-VI of the NIH Guidelines Regarding 
Procedures to be Followed for Expedited Review of Single Patient Human 
Gene Transfer Experiments

    On April 29, 1994, Dr. Nelson Wivel of the Office of Recombinant 
DNA Activities, National Institutes of Health, Bethesda, Maryland, 
requested that Appendix M-VI, Procedures to be Followed for Expedited 
Review of Single Patient Human Gene Transfer Experiments, be amended to 
clarify submission requirements.
    The Procedures to be Followed for Expedited Review of Single 
Patient Human Gene Transfer Experiments currently reads:
    ``Appendix M-VI-D. Regardless of the method of review, the Points 
to Consider is the standard of review for all gene transfer 
protocols.''
    The proposed amendment reads:
    ``Appendix M-VI-D. Regardless of the method of review, the Points 
to Consider is the standard of review for all gene transfer protocols; 
therefore, submission of the response to the Points to Consider is 
required.''
    The proposed amendment was reviewed by the Recombinant DNA Advisory 
Committee during the June 9-10, 1994, meeting. The Recombinant DNA 
Advisory Committee approved a motion to accept the proposed amendment 
to Appendix M-VI, Procedures to be Followed for Expedited Review of 
Single Patient Human Gene Transfer Experiments, by a vote of 13 in 
favor, 0 opposed, and no abstentions.
    I accept this recommendation, and Appendix M-VI, Procedures to be 
Followed for Expedited Review of Single Patient Human Gene Transfer 
Experiments, of the NIH Guidelines will be amended accordingly.

C. Deletion of Appendix L of the NIH Guidelines Regarding Release into 
the Environment

    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 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, as administered by the Environmental 
Protection Agency and the U.S. Department of Agriculture.
    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, 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* * *.''
    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 U.S. Department of 
Agriculture and the Environmental Protection Agency, 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 (Actions 
Under the Guidelines, Federal Register, July 5, Part III):
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 principles 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 Subcommittee, and specific approval by the NIH 
Director. Such experiments also require the approval of the 
Institutional Biosafety Committee before initiation.

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

    ``In consultation with the RAC Plant Subcommittee and without 
the requirement for full RAC review (Institutional Biosafety 
Committee review and approval is necessary), NIH/ORDA may approve 
the growing of plants containing recombinant DNA in the field under 
the following conditions: (i) the plant species is a cultivated crop 
of a genus that has no species known to be a noxious weed; (ii) the 
introduced DNA consists of well-characterized genes containing no 
sequences harmful to humans, animals, or plants; (iii) the vector 
consists of DNA from exempt host-vector systems (see Appendix C), 
from plants of the same or closely related species, from 
nonpathogenic prokaryotes or nonpathogenic lower eukaryotic plants, 
from plant pathogens only if sequences resulting in production of 
disease symptoms have been deleted, or chimeric vectors constructed 
from sequences of exempt host-vector systems (see Appendix C) or 
from sequences from plant pathogens in which the disease symptoms 
have been deleted. 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; (iv) 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 
Institutional Biosafety Committee 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 and approval by the Institutional Biosafety 
Committee. Copies of such results must be submitted to the Office of 
Recombinant DNA Activities, National Institutes of Health, Building 
31, Room 4B11, Bethesda, Maryland 20892, (301) 496-9838.''
    The proposed amendment was reviewed by the Recombinant DNA Advisory 
Committee during its June 9-10, 1994, meeting. The Recombinant DNA 
Advisory Committee approved a motion to accept the deletion of Appendix 
L, Regarding Release into the Environment, by a vote of 13 in favor, 0 
opposed, and no abstentions.
    I accept this recommendation, and Appendix L, Regarding Release 
into the Environment, of the NIH Guidelines will be deleted 
accordingly.

II. Summary of Actions

A. Amendment to Appendix M-I-D of the NIH Guidelines Regarding Informed 
Consent for Human Gene Transfer Protocols

    Appendix M-I-D will read as follows:

Appendix M-I-D. Informed Consent

    In accordance with the requirements of DHHS regulations for the 
Protection of Human Subjects (45 CFR Part 46), investigators should 
indicate how subjects will be informed about the proposed study and 
the manner in which their consent will be solicited. They should 
also indicate how the Informed Consent document makes clear the 
special requirements of gene transfer research.

Appendix M-I-D-1. Communication About the Study to Potential 
Participants

Appendix M-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 possible 
conflicts of interest if the investigator is also providing medical 
care to potential subjects?

Appendix M-I-D-1-b

    How will the major points covered in Appendices M-I-A through M-
I-C be disclosed to potential participants and/or their parents or 
guardians in language that is understandable to them?

Appendix M-I-D-1-c

    What is the length of time that potential participants will have 
to make a decision about their participation in the study?

Appendix M-I-D-1-d

    If the study involves pediatric or mentally handicapped 
subjects, how will the assent of each person be obtained?

Appendix M-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 
Boards. 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.
    ``Because of the relative novelty of the procedures that are 
used, the potentially irreversible consequences of the procedures 
performed, and the fact that many of the potential risks remain 
undefined, the Informed Consent document should include the 
following specific information in addition to any requirements of 
the DHHS regulations for the Protection of Human Subjects (45 CFR 
46). Indicate if each of the specified items appears in the Informed 
Consent document or, if not included in the Informed Consent 
document, how those items will be presented to potential subjects. 
Include an explanation if any of the following items are omitted 
from the consent process or the Informed Consent document.

Appendix M-I-D-2-a. General Requirements of Human Subjects Research

Appendix M-I-D-2-a-(1). Description/Purpose of the Study

    ``The subjects should be provided with 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.

Appendix M-I-D-2-a-(2). Alternatives

    ``The Informed Consent document should indicate the availability 
of therapies and the possibility of other investigational 
interventions and approaches.

Appendix M-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.

Appendix M-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 studies that are not reasonably expected to provide a 
therapeutic benefit to subjects, the Informed Consent document 
should 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.

Appendix M-I-D-2-a-(5). Possible Risks, Discomforts, and Side Effects

    ``There should be clear itemization in the Informed Consent 
document of types of adverse experiences, their relative severity, 
and their expected frequencies. For consistency, the following 
definitions are suggested: side effects that are listed as mild 
should be ones which do not require a therapeutic intervention; 
moderate side effects require an intervention; and severe side 
effects are potentially fatal or life-threatening, disabling, or 
require prolonged hospitalization.
    ``If verbal descriptors (e.g., `rare,' `uncommon,' or 
`frequent') are used to express quantitative information regarding 
risk, these terms should be explained.
    ``The Informed Consent document should provide information 
regarding the approximate number of people who have previously 
received the genetic material under study. It is 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.
    ``The Informed Consent document should indicate any possible 
adverse medical consequences that may occur if the subjects withdraw 
from the study once the study has started.

Appendix M-I-D-2-a-(6). Costs

    ``The subjects should be provided with specific information 
about any financial costs associated with their participation in the 
protocol and in the long-term follow-up to the protocol that are not 
covered by the investigators or the institution involved.
    ``Subjects should be provided an explanation about the extent to 
which they will be responsible for any costs for medical treatment 
required as a result of research-related injury.

Appendix M-I-D-2-b. Specific Requirements of Gene Transfer Research

Appendix M-I-D-2-b-(1). Reproductive Considerations

    ``To avoid the possibility that any of the reagents employed in 
the gene transfer research could cause harm to a fetus/child, 
subjects should be given information concerning possible risks and 
the need for contraception by males and females during the active 
phase of the study. The period of time for the use of contraception 
should be specified.
    ``The inclusion of pregnant or lactating women should be 
addressed.

Appendix M-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. The Informed Consent document should 
include a list of persons who can be contacted in the event that 
questions arise during the follow-up period. The principal 
investigator should request that subjects continue to provide a 
current address and telephone number.
    ``The subjects should be informed that any significant findings 
resulting from the study will be made known in a timely manner to 
them and/or their parent or guardian including new information about 
the experimental procedure, the harms and benefits experienced by 
other individuals involved in the study, and any long-term effects 
that have been observed.

Appendix M-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, no matter what the cause, permission for an autopsy will be 
requested of their families. Subjects should be asked to advise 
their families of the request and of its scientific and medical 
importance.

Appendix M-I-D-2-b-(4). Interest of the Media and Others in the 
Research

    ``To alert subjects that others may have an interest in the 
innovative character of the protocol and in the status of the 
treated subjects, the subjects should be informed of the following: 
(i) that the institution and investigators will make efforts to 
provide protection from the media in an effort to protect the 
participants' privacy, and (ii) that representatives of applicable 
Federal agencies (e.g., the National Institutes of Health and the 
Food and Drug Administration), representatives of collaborating 
institutions, vector suppliers, etc., will have access to the 
subjects' medical records.''

B. Amendment to Appendix M-VI of the NIH Guidelines Regarding 
Procedures to be Followed for Expedited Review of Single Patient Human 
Gene Transfer Experiments

    Appendix M-VI, Procedures to be Followed for Expedited Review of 
Single Patient Human Gene Transfer Experiments, will read as follows:
    ``Appendix M-VI-D. Regardless of the method of review, the Points 
to Consider is the standard of review for all gene transfer protocols; 
therefore, submission of the Points to Consider is required.''

C. Deletion of Appendix L of the NIH Guidelines Regarding Release into 
the Environment

    Appendix L, Release into the Environment of Certain Plants, be 
deleted in full: To see the full text of Appendix L, reference the 
background information and decisions on actions under the NIH 
Guidelines (Section I-C).
    OMB's ``Mandatory Information Requirements for Federal Assistance 
Program Announcements'' (45 FR 39592) requires a statement concerning 
the official government programs contained in the Catalog of Federal 
Domestic Assistance. Normally NIH lists in its announcements the number 
and title of affected individual programs for the guidance of the 
public. Because the guidance in this notice covers not only virtually 
every NIH program but also essentially every Federal research program 
in which DNA recombinant molecule techniques could be used, it has been 
determined to be not cost effective or in the public interest to 
attempt to list these programs. Such a list would likely require 
several additional pages. In addition, NIH could not be certain that 
every Federal program would be included as many Federal agencies, as 
well as private organizations, both national and international, have 
elected to follow the NIH Guidelines. In lieu of the individual program 
listing, NIH invites readers to direct questions to the information 
address above about whether individual programs listed in the Catalog 
of Federal Domestic Assistance are affected.

Effective Date: July 28, 1994.
Harold Varmus,
Director, National Institutes of Health.
[FR Doc. 94-19078 Filed 8-4-94; 8:45 am]
BILLING CODE 4140-01-P