Review of Human Embryonic Stem Cell Research at Yale

I. Scope

This policy applies to the conduct of human embryonic stem cell (hESC) research and to all persons who conduct hESC research as Yale students, faculty or staff, using Yale facilities, or paid for with Yale funds (Yale hESC Research).

II. Purposes

The purposes of this policy are:

To ensure that any Yale hESC research is conducted only after full consideration is given to all relevant scientific, medical, regulatory, and ethical issues, including compliance with Connecticut statutes;
To ensure that the Federal government’s current prohibitions against direct or indirect use of Federal funds for research on Non-Registry hESC Lines are fully observed;
To establish an Embryonic Stem Cell Research Oversight Committee (ESCRO) to provide appropriate oversight of all Yale hESC Research;
To establish mechanisms to track and identify Yale hESC Research, including the sources or derivation of any hESCs planned for use or being used;
To develop mechanisms for appropriate training for all Yale hESC researchers; and
To develop appropriate operating procedures for laboratories where Yale hESC Research is conducted.

III. Definitions

Embryo-like Entities: Human entities that arise from mechanisms other than the joining of a human egg and sperm and which have the potential to yield Embryonic Stem Cells. Examples include entities produced using nuclear transfer, called nuclear transfer embryos, and entities produced by activation of an unfertilized ovum, called parthenogenetic embryos.

ESCRO: An institutionally-based Embryonic Stem Cell Research Oversight (ESCRO) Committee convened and operated in general accordance with the National Academy of Sciences’ Guidelines for Embryonic Human Stem Cell Research and the 2006 guidelines of the International Society for Stem Cell Research (ISSCR).

Germ Line Stem Cells: Pluripotent cells obtained from the fetal gonad or gonad-related tissues.

Human Embryo: The stage of human development from first cleavage after a fertilization event, by which a zygote has been formed, to 7-8 weeks after fertilization.

Human Embryonic Stem Cells (hESCs): Pluripotent cells created through the joining of a human egg and sperm, nuclear transfer, or other methods producing cells that are sufficiently undifferentiated that they cannot be identified as components of any specialized cell type, including Germ Line Stem Cells.

Human Embryonic Stem Cell (hESCs) Lines: Human Embryonic Stem Cells (hESCs), which have been cultured under in vitro conditions that allow proliferation without differentiation for months to years.

Human embryonic stem cell lines fall into two categories:

Registered Human Embryonic Stem Cell Lines: Registered hESC lines are those included on the National Institutes of Health (NIH) Human Embryonic Stem Cell Registry, which confirms that the stem cell lines are in compliance with the President’s criteria as stated on August 9, 2001. Federal funds may be used ONLY for research using registered hESC lines.
Non-registered Human Embryonic Stem Cell Lines: Non-registered hESC lines are excluded from the NIH registry because they do not meet the President’s criteria. Federal funds may not be used directly or indirectly for research using non-registered hESC lines (or their derivatives).

Human Embryonic Stem Cell (hESC) Research: All research involving hESCs including, but not limited to, the use and derivation of new stem cell lines derived from surplus blastocysts obtained from in-vitro fertilization clinics, from blastocysts produced with donated gametes, and from blastocysts produced using nuclear transfer.

Human Fetus: The stage of human development from the end of the embryonic period (7-8 weeks after fertilization) until birth.

Human Subjects Research: Research involving a living individual about whom an investigator conducting research obtains: (a) data through intervention or interaction with the individual or (b) identifiable private information.

Induced Pluripotent Stem Cells (iPS cells): Human pluripotent stem cells derived from non-embryonic sources

Pluripotent: Capable of supporting development of all tissue of an organism, but not alone capable of sustaining full organismal development in utero.

Stem Cell Research Resource Allocation Protocol Committee (SCRRAP): Yale’s committee responsible for ensuring compliance with restrictions on the use of federal funds for Non-registered Human Embryonic Stem Cell Lines.

Totipotent: Capable of supporting full organismal development in utero.

IV. Establishment of the Embryonic Stem Cell Research Oversight Committee (ESCRO)

In order to ensure adherence to ethical and legal principles of hESC Research, Yale University has established an Embryonic Stem Cell Research Oversight (ESCRO) Committee as recommended by the National Research Council and Institute of Medicine of the National Academies’ 2005 Guidelines for hESC Research. ESCRO members are appointed by and serve as advisors to the Office of the Provost. The membership of the ESCRO shall reflect the scientific, medical, and ethical expertise necessary to perform the aforementioned responsibilities, and may include members of the Yale community (faculty, staff and/or students), as well as outside members, at the election of the Provost.

The ESCRO is responsible for the following:

To provide scientific, medical and ethical review and approval of proposed hESC Research, regardless of whether the proposed research also requires consideration by an Institutional Review Board (IRB);
To provide a forum for campus consideration of all issues related to derivation and research use of hESC lines;
To facilitate education of investigators in the ethical, legal, and policy issues involved in hESC Research, including setting minimum educational requirements as prerequisites for conducting hESC Research;
To assist investigators in assessing which regulations apply to proposed hESC Research activities;
To ensure that the provenance of hESCs is documented, that there was IRB approval of the procurement process in order to ensure adherence to the basic ethical and legal principles of informed consent and protection of confidentiality, and that statutory requirements for informed consent were met;
To establish and maintain a registry of Yale hESC Research, including documentation of key personnel, descriptive information about the types of research being performed, and the hESCs in use;
To review evolving regulations and guidance and make recommendations to update University policy accordingly;
To ensure that all applicable hESC regulatory requirements are met and that hESC Research is conducted in accordance with the highest ethical standards; and
To review areas of ethically sensitive research involving the use of iPS cells.

V. ESCRO Review and Approval of hESC Research

Investigators who intend to engage in Yale hESC Research, whether using Registered Human Embryonic Stem Cell Lines or Non-registered Human Embryonic Stem Cell Lines, must secure certain institutional approvals prior to conducting such research or expending any funds on it.

More specifically, an investigator who plans to do hESC research must provide a description of the research, documentation of the provenance of the cell lines (including copies of the relevant informed consent templates and any available evidence of actual donor consent), and evidence of compliance with other mandated reviews to the Chair of the ESCRO. The Chair of the ESCRO (or his/her designee) will review the submission, assure that the provenance meets legal requirements, and assign the research proposal to one of the three categories described below, and either proceed with the relevant review and approval process or notify the researcher that the proposed research is not permitted. For Category 1 and Category 2 research, once ESCRO Committee approval is obtained, Connecticut General Statutes §19a-32d(d) require stem cell researchers to provide documentation to the Commissioner of the Department of Public Health verifying that any human embryos, embryonic stem cells, unfertilized human eggs or human sperm used in embryonic stem cell research have been donated voluntarily in accordance with the provisions of Connecticut General Statutes §19a-32d(c).

Research that is permissible only after review and approval of the Chair of the ESCRO and completion of other reviews mandated by current regulations and University policies:
- In vitro hESC Research with pre-existing coded or anonymous hESC lines.
- Introduction of hESC into nonhuman animals for the sole purpose of determining pluripotency (teratoma formation), provided the hESC is not introduced into the brain or gonads.
Research that is permissible only after review and approval by the ESCRO and completion of other reviews mandated by current regulations and University policies:
- Attempted derivation of new hESC lines from donated blastocysts, from in vitro fertilized oocytes, by nuclear transfer, or from other Embryo-Like Entities. The application to conduct the research shall set forth:
  - the scientific rationale for the need to generate new hESC lines;
  - the basis for the number of blastocysts or oocytes needed;
  - how privacy rights of the donors are respected; and
  - how donor rights to the biomaterials have been resolved.
- Introduction of hESCs into humans.
- Research in which the data relating to the donors of the blastocysts, gametes, or somatic cells from which hESCs are derived is not completely deidentified so that the identity of the donors might become known to the investigator.
- Introduction of hESCs into nonhuman animals at any stage of the animal’s embryonic, fetal, or postnatal development (except for teratoma formation as described in V.1 above).
- Introduction of cells derived from hESC into the brain of nonhuman animals at any stage of the animal’s embryonic, fetal or postnatal development.
- Forms of in vitro research in which human totipotent cells or pluripotent stem cells are mixed with pre-implantation human embryos. In no case shall such experiments be allowed to progress for more than 14 days of development in vitro, or past the point of the primitive streak formation, whichever is first.
Research and activities that are not permitted at this time:
- Research involving in vitro culture of any intact human embryo, regardless of derivation method, for longer than 14 days or until formation of the primitive streak begins, whichever occurs first.
- Research in which hESCs are introduced into nonhuman primate blastocysts or in which any embryonic stem cells are introduced into human blastocysts.
- Research in which any products of research involving human totipotent or pluripotent cells are implanted into a human or non-human primate uterus.
- Breeding of any animal into which hESCs have been introduced at any stage of development.

VI. Research Involving iPS cells

Investigators who intend to engage in research using iPS cells must secure ESCRO approvals to the extent specified below prior to conducting such research or expending any funds on it. Derivation of new human iPS lines does not require ESCRO review, but may require IRB approval. To apply for review, submit a completed ESCRO application form along with any related IRB, IACUC and IBC approvals.

The process of review for iPS cell research is analogous to the process outlined for hESCs above.

Research that is permissible without ESCRO review.
- Derivation of new human iPS lines.
- Purely in vitro research that does not involve the generation of human gametes, embryos, or other types of totipotent cells.
- Introduction of iPS cells into nonhuman animals for the sole purpose of determining pluripotency (teratoma formation), provided the cells are not introduced into the brain or gonads
Research that is permissible only after review and approval of the Chair of the ESCRO and completion of other reviews mandated by current regulations and University policies. Submit a completed ESCRO application form along with any related IRB, IACUC and IBC approvals.
- Purely in vitro research that involves the generation of human gametes.
- In vivo research that implants human iPS cells into animals into nonhuman animals except as limited below in VI.3 or as allowed above in VI.1.
Research that is permissible only after review and approval by the ESCRO and completion of other reviews mandated by current regulations and University policies. Submit a completed ESCRO application form along with any related IRB, IACUC and IBC approvals.
- In vitro research that involves the generation of embryos or other types of totipotent cells.
- In vivo research that injects human iPS cells into prenatal nonhuman animals or into the brain of postnatal nonhuman animals.
- Introduction of cells derived from iPS cells into the brain of nonhuman animals at any stage of the animal’s embryonic, fetal or postnatal development.
Research that is not permitted at this time:
- Research that is prohibited for hESCs under Section V.3 is also prohibited for human iPS cells.

VII. Establishment of the Stem Cell Research Resource Allocation Protocol Committee

In order to ensure adherence to federal requirements that federal funding not be used to support hESC research on Non-registered Lines, Yale University has established a Stem Cell Research Resource Allocation Protocol Committee (SCRRAP Committee). SCRRAP Committee members are appointed by and serve as advisors to the Office of the Provost. The membership of the SCRRAP Committee shall reflect the financial, accounting, legal, business, and management expertise necessary for the SCRRAP Committee to perform the aforementioned function.

The SCRRAP Committee is responsible for the following:

To develop standards, guidelines, and checklists for the use of physical, financial and human resources to conduct hESC research on Non-registered Lines;
To define SCRRAP Committee standards and procedures for review and approval of hESC research protocols using Non-registered Lines; to review all proposed protocols to use physical, financial and human resources to conduct hESC research on Non-registered Lines, and approve only those protocols that would satisfy federal requirements;
To develop and implement detailed procedures specifying how investigators will submit to the SCRRAP Committee proposed protocols for allocating effort, equipment, supplies, and facilities to hESC research on Non-registered Lines;
To assist investigators and university staff in understanding federal resource allocation requirements for hESC research, through formal training programs, web-based information, consultations, and other means as appropriate;
To establish and implement, as appropriate, mechanisms to identify resources used for hESC research involving Registered and Non-registered Lines, in order to provide appropriate documentation of the separation of Federal funds and resources from use for research on Non-registered Lines; and
To track all relevant information regarding hESC research on Non-registered Lines, including the locations of the research, equipment being used for the research, and funding sources for facilities, equipment, and other infrastructure.

VIII. SCRRAP Committee Review and Approval of hESC Research

Investigators who intend to engage in Yale hESC research using Non-registered Lines must develop physical, financial, and human resource allocation protocols, and obtain SCRRAP approval of the protocols prior to commencing the research or expending funds.

IX. Other Reviews and Approvals of hESC Research

This policy supplements, but does not replace, existing law and other Yale University policies. Accordingly, research that is subject to ESCRO and/or SCRRAP review may also be subject to additional Yale compliance committee reviews. For example:

Research involving hESCs where the donor may be identified by the Yale investigator, including cell lines that retain links (such as code) to identifiable information, is considered to be Human Subjects Research that requires IRB review.
Research involving hESCs where there is interaction or intervention with a living individual and information about such individual, or tissue from such individual, is obtained, is considered Human Subjects Research that requires IRB review.
Research involving access to Protected Health Information is subject to Health Insurance Portability and Accountability Act (HIPAA) review.
All hESC research involving the use of live vertebrate animals is subject to the approval of the Institutional Animal Care and Use Committee (IACUC).

Review and approval by other Yale compliance committees prior to or concurrently with ESCRO, IRB, IACUC and HIPAA review may be required depending upon the nature of the proposed research.

X. Tracking of All hESC Research Undertaken at Yale or by University Investigators

It is necessary for Yale University officials to know at all times what hESC Research has been proposed by and is being conducted by Yale investigators and/or at Yale University. Investigators who are using or plan to use hESCs are required to provide the following detailed information to the ESCRO on the designated tracking form for all hESC research, regardless of the source of funding:

Sources of the hESCs, including the original sources of derived cell lines,
Sources of funding for the research work, and
Locations, on or off campus, at which the work will be or is being performed.

XI. Identification and Training for All Involved Researchers

All Yale University individuals, including faculty, staff, postdoctoral scholars, students, visiting scholars and other researchers who plan to engage in hESC Research or iPS research that requires ESCRO oversight are required to receive training regarding the ethical considerations and the policies and regulations pertaining to hESC Research or covered iPS research before they begin work on any project involving hESCs or iPS cells . All aforementioned persons must complete the requisite training courses satisfactorily as a prerequisite to beginning preparatory work associated with such research.

XII. Compliance, Monitoring, and Reporting to Ensure that Established Requirements and Procedures are Implemented as Intended

Faculty investigators will be expected to participate in periodic reviews by the Yale University Audit Department to assure that all applicable regulations are being followed, and to evaluate the effectiveness of Yale policies and procedures related to the conduct of hESC Research.

XIII. Questions and Comments Regarding hESC Policy

Questions and comments regarding this policy may be directed to the Office of the Deputy Provost for Health Affairs and Academic Integrity, 1 Hillhouse Avenue, New Haven, CT 06520; telephone 203-432-4446.

Researchers are also directed to the ESCRO Committee website for useful links and contact information.

International Society for Stem Cell Research (ISSCR): Guidelines for the Conduct of Human Embryonic Stem Cell Research, Version 1, December 21, 2006.

On August 9, 2001, President George W. Bush announced that federal funds may not be used for research using human embryonic stem cell (hESC) lines unless (1) the stem cells were derived from an embryo that was created for reproductive purposes and was no longer needed; (2) informed consent was obtained for the donation of the embryo, and the donation did not involve financial inducements; and (3) the process of derivation was begun prior to 9 pm EDT on August 9, 2001. Although the August 9, 2001 policy bars the use of federal funds for Non-registered hESC Research, it does not prevent researchers from conducting such research with non-federal funds.

45 CFR 46.102(f)

NAS Guidelines For Embryonic Human Stem Cell Research (2005), as amended (2007 and 2008), http://www.nap.edu/books/0309096537/html/.

http://www.isscr.org/guidelines/ ISSCRhESCguidelines2006.pdf

45 CFR 46.102(f).

Last updated: March, 2012