[Federal Register Volume 65, Number 166 (Friday, August 25, 2000)]
[Notices]
[Pages 51975-51981]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-21760]



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Part IV





Department of Health and Human Services





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National Institutes of Health



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National Institutes of Health Guidelines for Research Using Human 
Pluripotent Stem Cells and Notification of Request for Emergency 
Clearance; Modification of OMB No. 0925-0001/Exp. 2/01, ``PHS 398 
Research and Research Training Grant Applications and Related Forms''; 
Notices

Federal Register / Vol. 65, No. 166 / Friday, August 25, 2000 / 
Notices

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


National Institutes of Health Guidelines for Research Using Human 
Pluripotent Stem Cells

SUMMARY: The National Institutes of Health (NIH) is hereby publishing 
final ``National Institutes of Health Guidelines for Research Using 
Human Pluripotent Stem Cells.'' The Guidelines establish procedures to 
help ensure that NIH-funded research in this area is conducted in an 
ethical and legal manner.

EFFECTIVE DATE: These Guidelines are effective on August 25, 2000. The 
moratorium on research using human pluripotent stem cells derived from 
human embryos and fetal tissue put in place by the Director, NIH, in 
January 1999, will be lifted on August 25, 2000.

SUMMARY OF PUBLIC COMMENTS ON DRAFT GUIDELINES: On December 2, 1999 (64 
FR 67576), the NIH published Draft Guidelines for research involving 
human pluripotent stem cells (hPSCs) in the Federal Register for public 
comment. The comment period ended on February 22, 2000.
    The NIH received approximately 50,000 comments from members of 
Congress, patient advocacy groups, scientific societies, religious 
organizations, and private citizens. This Notice presents the final 
Guidelines together with NIH's response to the substantive public 
comments that addressed provisions of the Guidelines.

Scope of Guidelines and General Issues

    Respondents asked for clarification of terminology used in the 
Guidelines and some commented that the language was not appropriate or 
was too technical, particularly the informed consent sections. The NIH 
agrees that these Guidelines should be clear and understandable. 
Changes, including some reorganization of the sections, were made to 
this end. The Guidelines are written primarily for the purpose of 
informing investigators of the conditions that must be met in order to 
receive NIH funding for research using hPSCs and, therefore, some 
technical language is required. The Guidelines do not define the 
precise language that should appear in informed consent documents 
because these should be developed by the investigator/clinician 
specifically for a particular study protocol or procedure for which the 
consent is being sought. Existing regulatory provisions require (45 CFR 
46.116) that the language in informed consent documents be 
understandable to prospective participants in the study.

    Respondents suggested that NIH funding for research using hPSCs 
would be in violation of the DHHS appropriations law and that 
derivation of hPSCs cannot be distinguished from their use. For this 
reason, a number of respondents asked that the NIH withdraw the draft 
Guidelines. The NIH sought the opinion of the DHHS General Counsel, who 
determined that ``federally funded research that utilizes hPSCs would 
not be prohibited by the HHS appropriations law prohibiting human 
embryo research, because such cells are not human embryos.'' Comments 
questioning this conclusion did not present information or arguments 
that justify reconsideration of the conclusion.

    Respondents commented that the Guidelines are too restrictive or 
that there is no need for Federal Guidelines for this arena of 
research. Comments asserted that federally funded research using hPSCs 
should go forward without formal requirements, in the same manner as in 
the private sector. In order to help ensure that the NIH-funded 
research using hPSCs is conducted in an ethical and legal manner, the 
NIH felt it was advisable to develop and implement guidelines. To this 
end, the NIH Director convened a Working Group of the Advisory 
Committee to the Director, NIH (ACD), to advise the ACD on the 
development of guidelines and an oversight process for research 
involving hPSCs. The NIH Director charged the Working Group with 
developing appropriate guidelines to govern research involving the 
derivation and use of hPSCs from fetal tissue and research involving 
the use of hPSCs derived from human embryos that are in excess of 
clinical need.

    Respondents commented regarding the sources of stem cells. Some 
respondents stated that research on hPSCs was unnecessary because stem 
cells from adults, umbilical cords, and placentas could be used 
instead. Other respondents asked the NIH to restrict Federal funding 
for hPSC research to those cells derived from fetal and adult tissue 
but not embryos. Other respondents asked that the Guidelines encompass 
research using stem cells from adult tissues.

    As stated under Section I. Scope of Guidelines, the Guidelines 
apply to the use of NIH funds for research using hPSCs derived from 
human embryos or human fetal tissue. The Guidelines do not impose 
requirements on Federal funding of research involving stem cells from 
human adults, umbilical cords, or placentas.
    Given the enormous potential of stem cells to the development of 
new therapies for the most devastating diseases, it is important to 
simultaneously pursue all lines of promising research. It is possible 
that no single source of stem cells is best or even suitable/usable for 
all therapies. Different types or sources of stem cells may be optimal 
for treatment of specific conditions. In order to determine the very 
best source of many of the specialized cells and tissues of the body 
for new treatments and even cures, it is vitally important to study the 
potential of adult stem cells for comparison to that of hPSCs derived 
from embryos and fetuses. Unless all stem cell types are studied, the 
differences between adult stem cells and embryo and fetal-derived hPSCs 
will not be known.
    Moreover, there is evidence that adult stem cells may have more 
limited potential than hPSCs. First, stem cells for all cell and tissue 
types have not yet been found in the adult human. Significantly, 
cardiac stem cells or pancreatic islet stem cells have not been 
identified in adult humans.
    Second, stem cells in adults are often present in only minute 
quantities, are difficult to isolate and purify, and their numbers may 
decrease with age. For example, brain cells from adults that may be 
neural stem cells have been obtained only by removing a portion of the 
brain of an adult with epilepsy, a complex and invasive procedure that 
carries the added risk of further neurological damage. Any attempt to 
use stem cells from a patient's own body for treatment would require 
that stem cells would first have to be isolated from the patient and 
then grown in culture in sufficient numbers to obtain adequate 
quantities for treatment. This would mean that for some rapidly 
progressing disorders, there may not be sufficient time to grow enough 
cells to use for treatment.
    Third, in disorders that are caused by a genetic defect, the 
genetic error likely would be present in the patient's stem cells, 
making cells from such a patient inappropriate for transplantation. In 
addition, adult stem cells may contain more DNA abnormalities caused by 
exposure to daily living, including sunlight, toxins, and errors made 
during DNA replication than will be found in fetal or embryonic hPSCs.
    Fourth, there is evidence that stem cells from adults may not have 
the same capacity to multiply as do younger cells. These potential 
weaknesses may limit the usefulness of adult stem cells.


[[Page 51977]]


    Respondents were concerned that these are guidelines and not 
requirements or regulations. Although these are guidelines and not 
regulations, they prescribe the documentation and assurances that must 
accompany requests for NIH funding for research utilizing hPSCs. If the 
funding requests do not contain the prescribed information, funding for 
hPSC research will not be provided. Compliance with the Guidelines will 
be imposed as a condition of grant award.

    Respondents commented that there had not been enough widespread 
public disclosure/discussion of this research or the Guidelines. Prior 
to the development of draft Guidelines, there were two Congressional 
hearings on hPSCs. In a further effort to ensure substantial discussion 
and comment, the NIH convened a Working Group of the Advisory Committee 
to the Director, NIH (ACD), to advise the ACD on the development of 
these Guidelines. The Working Group was composed of scientists, 
patients and patient advocates, ethicists, clinicians, and lawyers. The 
Working Group met in public session on April 8, 1999, and heard from 
members of the public, as well as professional associations and 
Congress. In developing the draft Guidelines, the NIH also considered 
advice from the National Bioethics Advisory Commission (NBAC). Draft 
Guidelines were published for public comment in the Federal Register on 
December 2, 1999, for 60 days, and, in response to public interest, the 
comment period was extended an additional 28 days. Approximately 50,000 
comments were received. NIH issued a national press release announcing 
the Federal Register notice and many of the Nation's newspapers carried 
articles on this area of research and on the Guidelines. Patient 
groups, scientific societies, and religious organizations convened 
meetings and discussion groups and disseminated materials about this 
area of research and about the Guidelines.

    Comment was received about whether the Guidelines apply to hPSC 
lines developed outside of the United States. The Guidelines make no 
distinction based upon the country in which an hPSC line is developed. 
All lines to be used in hPSC cell research funded by NIH must meet the 
same requirements.

Derivation and Use of hPSCs From Fetal Tissue

    Respondents made the point that the NIH has specified certain 
requirements for the use of human fetal tissue to derive hPSCs in 
addition to those imposed on other areas of human fetal tissue 
research. These respondents suggested that the section of the 
Guidelines pertaining to fetal tissue sources be omitted. In order to 
ensure uniformity in NIH's oversight of research using hPSCs, the 
Guidelines were extended to govern hPSCs derived from both human 
embryos and fetal tissue.

Use of hPSCs Derived From Human Embryos

    Respondents suggested that the Guidelines refer to ``fertility 
treatment'' rather than to ``infertility treatment'' in order to 
clarify that they allow the use of human embryos from treatments that 
employ assisted reproductive technologies to facilitate reproduction in 
fertile, as well as in infertile, individuals. The Guidelines have been 
changed accordingly.

    Respondents suggested dropping the word ``early'' throughout the 
document or more clearly defining ``early.'' The word ``early'' in 
reference to human embryos has been deleted; the Guidelines make it 
clear that NIH funding of research using hPSCs derived in the private 
sector from human embryos can involve only embryos that have not 
reached the stage at which the mesoderm is formed.

    Some respondents were concerned that embryos might be created for 
research purposes. Other respondents stated there should be no 
distinction between embryos created for research purposes and those 
created for fertility treatment. Investigators seeking NIH funds for 
research using hPSCs are required to provide documentation, prior to 
the award of any NIH funds, that embryos were created for the purposes 
of fertility treatment. President Clinton, many members of Congress, 
the NIH Human Embryo Research Panel, and the NBAC have all embraced the 
distinction between embryos created for research purposes and those 
created for reproductive purposes.

    Respondents were concerned about the creation of a ``black market'' 
for human embryos, and expressed concerns that individuals will be 
coerced into donating embryos. The Guidelines state that there can be 
no incentives for donation and that a decision to donate must be made 
free of coercion. In addition, the Guidelines set forth conditions that 
will help ensure all donations are voluntary. For example, with regard 
to hPSCs derived from embryos, research using Federal funds may only be 
conducted if the cells were derived from frozen embryos that were 
created for the purpose of fertility treatment and that were in excess 
of clinical need.

    Respondents commented on the requirement that human embryos be 
frozen in order to qualify for derivation of hPSCs to be used in NIH-
funded research. Respondents suggested that the freezing requirement 
would preclude the use of hPSCs derived from embryos that are 
genetically and chromosomally abnormal, since such embryos are usually 
not frozen for reproductive purposes. While the NIH acknowledges that 
research on hPSCs derived from such embryos could yield important 
scientific information, limiting research to hPSCs derived from frozen 
human embryos will help ensure that the decision to donate the embryo 
for hPSC research is distinct and separate from the fertility 
treatment.

Financial Issues

    Respondents expressed concern regarding the sale of fetal tissue 
for profit and whether hPSC research would encourage such activity. 
Respondents also were concerned about whether clinics or doctors would 
profit from the derivation of hPSCs and/or their sale. Section 498B of 
the Public Health Service Act prohibits any individual from knowingly 
acquiring or selling human fetal tissue for ``valuable consideration.'' 
In addition, the Guidelines prohibit any inducement for the donation of 
human embryos for research purposes. The Guidelines also call for an 
assurance that the hPSCs to be used in NIH-funded research were 
obtained through a donation or through a payment that does not exceed 
the reasonable costs associated with the transportation, processing, 
preservation, quality control and storage of the hPSCs. All grantees 
must sign an assurance that they are in compliance with all applicable 
Federal, State, and local laws. Each funded research institution is 
responsible for monitoring compliance by individual investigators with 
any such applicable laws.

    Respondents questioned the prohibition against embryo donors 
benefitting financially from their donation. This clause was retained 
in the final Guidelines to help ensure that the donating individuals 
are offered no inducements to donate and that all donations are 
voluntary.

    Respondents suggested that the Guidelines be strengthened to 
include a waiver of intellectual property rights. This proposed change 
would be inconsistent with 45 CFR 46.116 of the regulation for the 
protection of human subjects of research, which provides that no 
informed consent may include

[[Page 51978]]

language through which the subject waives or appears to waive any of 
the subject's legal rights.

    Respondents questioned the reference in the requirements for 
informed consent related to the commercial potential of donated 
material. The paragraphs providing for disclosure in the informed 
consent of the possibility that the donated material could have 
commercial potential were modified. The reference in these paragraphs 
to ``donated material'' did not accurately reflect the intent of the 
provision. The Guidelines now make clear that the ``results of research 
on the human pluripotent stem cells may have commercial potential.''

Ineligible Research

    Respondents objected to the areas of research that the NIH has 
deemed ineligible, particularly research that is not restricted by 
statute or regulation, such as research utilizing hPSCs that were 
derived using somatic cell nuclear transfer, i.e., the transfer of a 
human somatic cell nucleus into a human egg. The NIH determined that, 
at this time, research using hPSCs derived from such sources has not 
received adequate discussion and consideration by the public and is, 
therefore, ineligible for NIH funding.

Separation of Fertility Treatment and Abortion From Research

    Respondents were concerned that hPSC research would encourage 
abortion. The law and the Guidelines guard against encouraging abortion 
by requiring that the decision to have an abortion be made apart from 
and prior to the decision to donate tissue.

    Respondents objected to the condition in the Guidelines that the 
fertility physician could not be the same person as the researcher 
deriving stem cells. Some respondents stated that the Institutional 
Review Board (IRB) or an independent physician would be able to guard 
against this conflict of interest. The restriction was designed so that 
the person treating the individuals seeking fertility treatment, who is 
involved in decisions such as how many embryos to produce, is not the 
person seeking to derive hPSCs. This separation will help ensure that 
embryos will not be created in numbers greater than necessary for 
fertility treatment.

    Respondents suggested that the clauses regarding donation of fetal 
tissue or human embryos for derivation of stem cells for eventual use 
in transplantation be changed explicitly to prevent directed donation. 
This change has been made.

Identifiers

    Respondents were concerned about removing identifiers. There was 
concern that the investigator would not be able to document compliance 
with the Guidelines requirements without identifiers, or that the 
removal of identifiers would make it impossible to conduct certain 
genetic studies or develop therapeutic materials. The Guidelines have 
been modified to clarify that the term ``identifier'' refers to any 
information from which the donor(s) can be identified, directly or 
through identifiers linked to the donors. However, since information 
identifying the donor(s) may be necessary if the tissue or cells are to 
be used in transplantation, the Guidelines have also been modified to 
state that the informed consent should notify donor(s) whether or not 
identifiers will be retained.

    Respondents commented that DNA is an identifier and that all donors 
of human embryos or fetal tissue should be told that identifiers such 
as DNA will be retained with the samples. Although DNA can be used to 
determine the individual from whom a tissue sample was taken, this can 
be done only when one has a sample from both the tissue in question and 
the putative donor; it cannot be used to identify an individual out of 
a population. Moreover, it is difficult to identify a donor using 
tissue derived from a fetus or embryo, since the tissue is not 
genetically identical to the donor.

Informed Consent and IRB Review

    Respondents asked why investigators were expected to provide 
documentation of IRB review of derivation from human embryos, but not 
for derivation from fetal tissue. Respondents suggested that the 
requirements be changed so that protocols for both sources of hPSCs 
must be approved by an IRB. The Guidelines have been changed to make 
clear that the IRB review requirements regarding the derivation of 
cells from fetal tissue and human embryos are the same.

    Comment was received expressing concern that the informed consent 
explicitly state that the donor will have no dispositional authority 
over derived pluripotent stem cells. The Guidelines state that donation 
of human embryos should have been made without any restriction 
regarding the individual(s) who may be the recipient of the cells 
derived from the hPSCs for transplantation. Such a statement is 
consistent with the statutory provision applicable to the donor 
informed consent for the use of fetal tissue for transplantation. The 
Guidelines now provide for the inclusion of a statement to this effect 
in the informed consent.

    Respondents urged that the Guidelines be revised to remove the 
prohibition on potential donors receiving information regarding 
subsequent testing of donated tissue in the situation when physicians 
deem disclosure to be in the donors' best interest. This change has 
been made.

    Respondents requested clarification regarding the persons from whom 
consent for donation of embryos for research must be obtained. The 
Guidelines call for informed consent from individual(s) who have sought 
fertility treatment. Only the individual(s) who were part of the 
decision to create the embryo for reproductive purposes should have 
been part of the decision to donate for the derivation of hPSCs.

    Respondents urged that fertility clinics should be able to discuss 
with patients the option of donating embryos for research at the 
beginning of the IVF process. The Guidelines do not delineate the 
timeframe during which the general option of donating embryos for 
research can be discussed. However, according to the Guidelines, 
obtaining consent for donation of embryos for the purpose of deriving 
hPSCs should not occur until after the embryos are determined to be in 
``excess of clinical need.''

Oversight

    Respondents stated that the NIH's oversight in this area of 
research was very important to the legal and ethical conduct of this 
research, and asked for more information regarding the oversight 
process. Information about the operations of the Human Pluripotent Stem 
Cell Review Group (HPSCRG) can be found in the final Guidelines and on 
the NIH Web page.

    Respondents were concerned about whether and how NIH would monitor 
research after a researcher receives NIH funds. Compliance with the 
Guidelines will be largely determined prior to the award of funds. 
Follow-up to ensure continued compliance with the Guidelines will be 
conducted in the same manner as for all other conditions of all other 
NIH grant awards. It is the responsibility of the investigator to file 
progress reports, and it is the responsibility of the funded 
institution to ensure compliance with the NIH Guidelines. NIH staff 
will also monitor the progress of these investigators as part of their 
regular duties.


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    Respondents asked about penalties for not following the Guidelines. 
The following actions may be taken by the NIH when there is a failure 
to comply with the terms and conditions of any award: (1) Under 45 CFR 
74.14, the NIH can impose special conditions on an award, including 
increased oversight/monitoring/reporting requirements for an 
institution, project or investigator; and (2) under 45 CFR 74.62, if a 
grantee materially fails to comply with the terms and conditions of the 
award, the NIH may withhold funds pending correction of the problem or, 
pending more severe enforcement action, disallow all or part of the 
costs of the activity that was not in compliance, withhold further 
awards for the project, or suspend or terminate all or part of the 
funding for the project. Individuals and institutions may be debarred 
from eligibility for all Federal financial assistance and contracts 
under 45 CFR Part 76 and 48 CFR Subpart 9.4, respectively. Because 
these sanctions pertain to all conditions of grant award, the NIH did 
not reiterate them in the Guidelines.

    Respondents suggested that the HPSCRG hold periodic Stem Cell 
Policy Conferences (similar to the Gene Therapy Policy Conferences 
conducted by the Recombinant DNA Advisory Committee (``RAC'')) in order 
to solicit and consider public comment from interested parties on the 
scientific, medical, legal, and ethical issues arising from stem cell 
research. Members of the HPSCRG will serve as a resource for 
recommending to the NIH any need for Human Pluripotent Stem Cell Policy 
Conferences.

Other Changes

    Because compliance materials may be made public prior to funding 
decisions, we have added a sentence requiring the principal 
investigator's written consent to the disclosure of such material 
necessary to carry out public review and other oversight procedures.
    The draft Guidelines required HPSCRG review of proposals from 
investigators planning to derive hPSCs from fetal tissue. Because the 
Guidelines address proposals for NIH funding for the use of hPSCs, this 
requirement has been removed from the Guidelines.
    The text of the final Guidelines follows.

National Institutes of Health Guidelines for Research Using Human 
Pluripotent Stem Cells

I. Scope of Guidelines

    These Guidelines apply to the expenditure of National Institutes of 
Health (NIH) funds for research using human pluripotent stem cells 
derived from human embryos (technically known as human embryonic stem 
cells) or human fetal tissue (technically known as human embryonic germ 
cells). For purposes of these Guidelines, ``human pluripotent stem 
cells'' are cells that are self-replicating, are derived from human 
embryos or human fetal tissue, and are known to develop into cells and 
tissues of the three primary germ layers. Although human pluripotent 
stem cells may be derived from embryos or fetal tissue, such stem cells 
are not themselves embryos. NIH research funded under these Guidelines 
will involve human pluripotent stem cells derived: (1) From human fetal 
tissue; or (2) from human embryos that are the result of in vitro 
fertilization, are in excess of clinical need, and have not reached the 
stage at which the mesoderm is formed.
    In accordance with 42 Code of Federal Regulations (CFR) 52.4, these 
Guidelines prescribe the documentation and assurances that must 
accompany requests for NIH funding for research using human pluripotent 
stem cells from: (1) Awardees who want to use existing funds; (2) 
awardees requesting an administrative or competing supplement; and (3) 
applicants or intramural researchers submitting applications or 
proposals. NIH funds may be used to derive human pluripotent stem cells 
from fetal tissue. NIH funds may not be used to derive human 
pluripotent stem cells from human embryos. These Guidelines also 
designate certain areas of human pluripotent stem cell research as 
ineligible for NIH funding.

II. Guidelines for Research Using Human Pluripotent Stem Cells That 
Is Eligible for NIH Funding

A. Utilization of Human Pluripotent Stem Cells Derived From Human 
Embryos

1. Submission to NIH
    Intramural or extramural investigators who are intending to use 
existing funds, are requesting an administrative supplement, or are 
applying for new NIH funding for research using human pluripotent stem 
cells derived from human embryos must submit to NIH the following:
    a. An assurance signed by the responsible institutional official 
that the pluripotent stem cells were derived from human embryos in 
accordance with the conditions set forth in section II.A.2 of these 
Guidelines and that the institution will maintain documentation in 
support of the assurance;
    b. A sample informed consent document (with patient identifier 
information removed) and a description of the informed consent process 
that meet the criteria for informed consent set forth in section 
II.A.2.e of these Guidelines;
    c. An abstract of the scientific protocol used to derive human 
pluripotent stem cells from an embryo;
    d. Documentation of Institutional Review Board (IRB) approval of 
the derivation protocol;
    e. An assurance that the stem cells to be used in the research were 
or will be obtained through a donation or through a payment that does 
not exceed the reasonable costs associated with the transportation, 
processing, preservation, quality control and storage of the stem 
cells;
    f. The title of the research proposal or specific subproject that 
proposes the use of human pluripotent stem cells;
    g. An assurance that the proposed research using human pluripotent 
stem cells is not a class of research that is ineligible for NIH 
funding as set forth in section III of these Guidelines; and
    h. The Principal Investigator's written consent to the disclosure 
of all material submitted under Paragraph A.1 of this section, as 
necessary to carry out the public review and other oversight procedures 
set forth in section IV of these Guidelines.
2. Conditions for the Utilization of Human Pluripotent Stem Cells 
Derived From Human Embryos
    Studies utilizing pluripotent stem cells derived from human embryos 
may be conducted using NIH funds only if the cells were derived 
(without Federal funds) from human embryos that were created for the 
purposes of fertility treatment and were in excess of the clinical need 
of the individuals seeking such treatment.
    a. To ensure that the donation of human embryos in excess of the 
clinical need is voluntary, no inducements, monetary or otherwise, 
should have been offered for the donation of human embryos for research 
purposes. Fertility clinics and/or their affiliated laboratories should 
have implemented specific written policies and practices to ensure that 
no such inducements are made available.
    b. There should have been a clear separation between the decision 
to create embryos for fertility treatment and the decision to donate 
human embryos in excess of clinical need for research purposes to 
derive pluripotent stem cells. Decisions related to the creation of 
embryos for fertility treatment should have been made free

[[Page 51980]]

from the influence of researchers or investigators proposing to derive 
or utilize human pluripotent stem cells in research. To this end, the 
attending physician responsible for the fertility treatment and the 
researcher or investigator deriving and/or proposing to utilize human 
pluripotent stem cells should not have been one and the same person.
    c. To ensure that human embryos donated for research were in excess 
of the clinical need of the individuals seeking fertility treatment and 
to allow potential donors time between the creation of the embryos for 
fertility treatment and the decision to donate for research purposes, 
only frozen human embryos should have been used to derive human 
pluripotent stem cells. In addition, individuals undergoing fertility 
treatment should have been approached about consent for donation of 
human embryos to derive pluripotent stem cells only at the time of 
deciding the disposition of embryos in excess of the clinical need.
    d. Donation of human embryos should have been made without any 
restriction or direction regarding the individual(s) who may be the 
recipients of transplantation of the cells derived from the human 
pluripotent stem cells.
    e. Informed Consent
    Informed consent should have been obtained from individuals who 
have sought fertility treatment and who elect to donate human embryos 
in excess of clinical need for human pluripotent stem cell research 
purposes. The informed consent process should have included discussion 
of the following information with potential donors, pertinent to making 
the decision whether or not to donate their embryos for research 
purposes.
    Informed consent should have included:
    (i) A statement that the embryos will be used to derive human 
pluripotent stem cells for research that may include human 
transplantation research;
    (ii) A statement that the donation is made without any restriction 
or direction regarding the individual(s) who may be the recipient(s) of 
transplantation of the cells derived from the embryo;
    (iii) A statement as to whether or not information that could 
identify the donors of the embryos, directly or through identifiers 
linked to the donors, will be removed prior to the derivation or the 
use of human pluripotent stem cells;
    (iv) A statement that derived cells and/or cell lines may be kept 
for many years;
    (v) Disclosure of the possibility that the results of research on 
the human pluripotent stem cells may have commercial potential, and a 
statement that the donor will not receive financial or any other 
benefits from any such future commercial development;
    (vi) A statement that the research is not intended to provide 
direct medical benefit to the donor; and
    (vii) A statement that embryos donated will not be transferred to a 
woman's uterus and will not survive the human pluripotent stem cell 
derivation process.
    f. Derivation protocols should have been approved by an IRB 
established in accord with 45 CFR 46.107 and 46.108 or FDA regulations 
at 21 CFR 56.107 and 56.108.

B. Utilization of Human Pluripotent Stem Cells Derived From Human Fetal 
Tissue

1. Submission to NIH
    Intramural or extramural investigators who are intending to use 
existing funds, are requesting an administrative supplement, or are 
applying for new NIH funding for research using human pluripotent stem 
cells derived from fetal tissue must submit to NIH the following:
    a. An assurance signed by the responsible institutional official 
that the pluripotent stem cells were derived from human fetal tissue in 
accordance with the conditions set forth in section II.A.2 of these 
Guidelines and that the institution will maintain documentation in 
support of the assurance;
    b. A sample informed consent document (with patient identifier 
information removed) and a description of the informed consent process 
that meet the criteria for informed consent set forth in section 
II.B.2.b of these Guidelines;
    c. An abstract of the scientific protocol used to derive human 
pluripotent stem cells from fetal tissue;
    d. Documentation of IRB approval of the derivation protocol;
    e. An assurance that the stem cells to be used in the research were 
or will be obtained through a donation or through a payment that does 
not exceed the reasonable costs associated with the transportation, 
processing, preservation, quality control and storage of the stem 
cells;
    f. The title of the research proposal or specific subproject that 
proposes the use of human pluripotent stem cells;
    g. An assurance that the proposed research using human pluripotent 
stem cells is not a class of research that is ineligible for NIH 
funding as set forth in section III of these Guidelines; and
    h. The Principal Investigator's written consent to the disclosure 
of all material submitted under Paragraph B.1 of this section, as 
necessary to carry out the public review and other oversight procedures 
set forth in section IV of these Guidelines.
2. Conditions for the Utilization of Human Pluripotent Stem Cells 
Derived From Fetal Tissue.
    a. Unlike pluripotent stem cells derived from human embryos, DHHS 
funds may be used to support research to derive pluripotent stem cells 
from fetal tissue, as well as for research utilizing such cells. Such 
research is governed by Federal statutory restrictions regarding fetal 
tissue research at 42 U.S.C. 289g-2(a) and the Federal regulations at 
45 CFR 46.210. In addition, because cells derived from fetal tissue at 
the early stages of investigation may, at a later date, be used in 
human fetal tissue transplantation research, it is the policy of NIH to 
require that all NIH-funded research involving the derivation or 
utilization of pluripotent stem cells from human fetal tissue also 
comply with the fetal tissue transplantation research statute at 42 
U.S.C. 289g-1.
    b. Informed Consent
    As a policy matter, NIH-funded research deriving or utilizing human 
pluripotent stem cells from fetal tissue should comply with the 
informed consent law applicable to fetal tissue transplantation 
research (42 U.S.C. 289g-1) and the following conditions. The informed 
consent process should have included discussion of the following 
information with potential donors, pertinent to making the decision 
whether to donate fetal tissue for research purposes.
    Informed consent should have included:
    (i) A statement that fetal tissue will be used to derive human 
pluripotent stem cells for research that may include human 
transplantation research;
    (ii) A statement that the donation is made without any restriction 
or direction regarding the individual(s) who may be the recipient(s) of 
transplantation of the cells derived from the fetal tissue;
    (iii) A statement as to whether or not information that could 
identify the donors of the fetal tissue, directly or through 
identifiers linked to the donors, will be removed prior to the 
derivation or the use of human pluripotent stem cells;
    (iv) A statement that derived cells and/or cell lines may be kept 
for many years;

[[Page 51981]]

    (v) Disclosure of the possibility that the results of research on 
the human pluripotent stem cells may have commercial potential, and a 
statement that the donor will not receive financial or any other 
benefits from any such future commercial development; and
    (vi) A statement that the research is not intended to provide 
direct medical benefit to the donor.
    c. Derivation protocols should have been approved by an IRB 
established in accord with 45 CFR 46.107 and 46.108 or FDA regulations 
at 21 CFR 56.107 and 56.108.

III. Areas of Research Involving Human Pluripotent Stem Cells That 
Are Ineligible for NIH Funding

    Areas of research ineligible for NIH funding include:
    A. The derivation of pluripotent stem cells from human embryos;
    B. Research in which human pluripotent stem cells are utilized to 
create or contribute to a human embryo;
    C. Research utilizing pluripotent stem cells that were derived from 
human embryos created for research purposes, rather than for fertility 
treatment;
    D. Research in which human pluripotent stem cells are derived using 
somatic cell nuclear transfer, i.e., the transfer of a human somatic 
cell nucleus into a human or animal egg;
    E. Research utilizing human pluripotent stem cells that were 
derived using somatic cell nuclear transfer, i.e., the transfer of a 
human somatic cell nucleus into a human or animal egg;
    F. Research in which human pluripotent stem cells are combined with 
an animal embryo; and
    G. Research in which human pluripotent stem cells are used in 
combination with somatic cell nuclear transfer for the purposes of 
reproductive cloning of a human.

IV. Oversight

    A. The NIH Human Pluripotent Stem Cell Review Group (HPSCRG) will 
review documentation of compliance with the Guidelines for funding 
requests that propose the use of human pluripotent stem cells. This 
working group will hold public meetings when a funding request proposes 
the use of a line of human pluripotent stem cells that has not been 
previously reviewed and approved by the HPSCRG.
    B. In the case of new or competing continuation (renewal) or 
competing supplement applications, all applications shall be reviewed 
by HPSCRG and for scientific merit by a Scientific Review Group. In the 
case of requests to use existing funds or applications for an 
administrative supplement or in the case of intramural proposals, 
Institute or Center staff should forward material to the HPSCRG for 
review and determination of compliance with the Guidelines prior to 
allowing the research to proceed.
    C. The NIH will compile a yearly report that will include the 
number of applications and proposals reviewed and the titles of all 
awarded applications, supplements or administrative approvals for the 
use of existing funds, and intramural projects.
    D. Members of the HPSCRG will also serve as a resource for 
recommendations to the NIH with regard to any revisions to the NIH 
Guidelines for Research Using Human Pluripotent Stem Cells and any need 
for human pluripotent stem cell policy conferences.

    Dated: August 17, 2000.
Ruth L. Kirschstein,
Principal Deputy Director, NIH.
[FR Doc. 00-21760 Filed 8-23-00; 8:45 am]
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