Regulation and Oversight of Embryonic Stem Cell Research

R. Alta Charo

University of Wisconsin

December 2004

Overview: Federal Laws & Regulations Governing ES Cell Research

Protections for human subjects in research HIPAA Oversight of recombinant DNA research Protections for animals in research Good laboratory practices regulations Animal drug regulations Good tissue practices regulations Xenotransplantation regulations NIH funding restrictions Import regulations

Human Subjects Protections

Human subjects protections are triggered when there is:– An identifiable living individual who is the subject of

research– The research is funded by HHS or any other federal agency

that has signed on to the “Common Rule”– The research is regulated by the FDA as part of the process

for obtaining approval of a new human therapeutic drug, device or biologic.

– The research takes place at an institution that has pledged to apply federal human subjects protections even to research not funded or regulated by the federal government.

Human Subjects Protections: Basic Components

Voluntary informed consent of all subjects [unless the research meets the criteria for a waiver of consent (minimal risk, impractical to obtain consent, absence of consent does not violate the rights or welfare of the subjects)]

Minimization of risks and maximization of benefits of the research

Prior review by an IRB

Ongoing monitoring by the IRB during the course of the research

Derivation of New ES Cell Lines

Derivation from surplus IVF embryos (whether or not previously examined using preimplantation genetic diagnosis) requires, pursuant to state contract and property laws, permission from the embryo donors.

Where the embryo donors are not the progenitors (e.g. where donor gametes were used in the initial creation of the embryos), caution suggests examining the underlying agreement with the gamete donors.

Derivation from SCNT embryos requires attention to extant state laws governing the permissibility of SCNT research

Human Subjects Protections and ES Cell Derivation

Although not clearly falling within the definition of human subjects research (the ex vivo embryo cannot be a human subject of research and the donors may not be the subject of research, depending upon the protocol) most institutions have asked for IRB oversight of the donation process.

IRBs have experience looking at inducements, risks, and consent processes, all relevant to the recruitment of somatic cell, gamete and embryo donors.

Regulation of Use of Cell Lines in Laboratory Experiments

Laboratory work with cell lines may or may not be considered human subjects research covered by federal human subjects research protections:

Cell lines without identifiers:

HHS regulations: human subject means a living individual about whom an investigator obtains (1) data through interaction with the individual or (2) identifiable private information.

HHS-conducted or supported research that involves neither interactions with living individuals nor obtaining identifiable private information is not considered human subjects research.

In vitro research and research in animals using already established human cell lines, from which the identity of the donor(s) cannot readily be ascertained by the investigator, is not considered human subject research and is not governed by the HHS or FDA human subject protection regulations. IRB review is not required for such research.

Cell lines with Identifiers:

HHS-conducted or supported research that uses human cell lines where the donor(s) may be identified, including cells that retain links (such as a code) to identifying information is generally considered human subject research that is governed by 45 CFR Part 46 because the donors are human subjects. IRB review and approval is required for such research.

Exception to Rule Concerning Cell Lines with Identifiers:

In vitro research or research in animals using a human cell line that retains a link to identifying information will not be considered human subjects research if the identity of the donor(s) cannot be “readily ascertained” by the investigator or associated with the cell line because:

(1) the investigator and research institution do not have access to identifiable private information related to the cell line; and

(2) a written agreement is obtained from the holder of the identifiable private information related to the cell line providing that such information will not be released to the investigator under any circumstances.

In this case, an institution or an IRB could determine that IRB review of the research using the cell line was not needed.

Recombinant DNA research and ES cells

Each institution is responsible for ensuring that all recombinant DNA research conducted at or sponsored by that institution is conducted in compliance with the NIH guidelines. Institutional authority and responsibility place accountability for the safe conduct of the research at the local level.

Genetic Alteration of Embryonic Stem Cell Lines

An Institutional Biosafety Committee (IBC) is a review body appointed by an institution to review and approve potentially biohazardous lines of research. IBCs were originally established under the “NIH Guidelines for Research Involving Recombinant DNA Molecules” to provide local, institutional oversight of nearly all forms of research utilizing recombinant DNA.

IBC review

IBC review focuses on safety, not on compliance with human subjects protections or other aspects of state and federal law governing the ethical conduct of scientific research.

Human Gene Transfer Research

Human gene transfer research is also subject to oversight (mandatory for NIH funded work, voluntary for other work) by the Recombinant DNA Advisory Committee (“RAC”)

Genetic engineering of human ES cells is not human gene transfer research, however, because it does not involve the transfer of a gene into a person.

Creation of transgenic or chimeric animals using ES cells

ES cell research that involves the creation of transgenic or chimeric live-born animals is subject to animal welfare protections

USDA and the Animal Welfare Act

The Animal Welfare Act enacts congressional policy to ensure the most humane use of animals in research.

Animals covered by the act include any live or dead dog, cat, nonhuman primate mammal, guinea pig, hamster, rabbit, or such other warm-blooded animal, as the Secretary may determine

Animals not covered by the Animal Welfare Act

Birds

rats of the genus Rattus

mice of the genus Mus, bred for use in research

Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals.

The PHS Policy requires each institution receiving PHS support for an activity involving live, vertebrate animals to establish an appropriate institutional animal care and use program, including an Institutional Animal Care and Use Committee (IACUC) with specific responsibilities as described in the PHS Policy.

Adherence to the Policy and Guide are achieved primarily through voluntary compliance with an institutional animal care and use program described in an Animal Welfare Assurance (Assurance).

FDA Good Laboratory Practice Regulations

These regulations establish standards for the proper conduct of nonclinical laboratory studies that include animals. Adherence to the regulations is achieved primarily through voluntary compliance.

The requirements apply to studies that support or are intended to support applications for research or marketing permits for products regulated by FDA, including human and animal drugs, medical devices for human use, and biological products.

Applicability of FDA Good Laboratory Practices Regulations

GLP applies to nonclinical laboratory studies

Nonclinical laboratory study means in vivo or in vitro experiments in which test articles are studied prospectively in test systems under laboratory conditions to determine their safety.

The term does not include basic exploratory studies carried out to determine whether a test article has any potential utility or to determine physical or chemical characteristics of a test article.

FDA Regulation of Animal Drugs and ES cell research

Because an “animal drug” is any article “intended to affect the structure or function of the body,” FDA regulates constructs inserted into animals.

If such constructs are intended for interstate commerce (e.g. as a new animal drug for sale) then a pre-approval process may be necessary.

If such constructs are intended only for laboratory research purposes, then a pre-approval should not be necessary.

Clinical Research Using Cell Lines and Differentiated Tissue – HHS/FDA Regulation:

All HHS-conducted or supported clinical research (and all research at institutions pledging to follow HHS rules even where not required) that involves interactions with living individuals, including the transplantation of human cells or test articles, such as differentiated cells derived from human embryos, into human recipients is human subjects research subject to HHS regulation because recipients are human subjects.

IRB review and approval is required for such research.

Clinical Research Using Cell Lines and Differentiated Tissue – HHS/FDA Regulation (cont):

In addition, all clinical research involving use of cells or test articles regulated by FDA as drugs, devices, and biological products is subject to regulation and oversight by FDA.

This clinical research must be conducted in compliance with FDA’s regulations governing investigational new drugs (INDs) or investigational device exemptions (IDEs) regardless of source of funding.

All human studies conducted under INDs and IDEs are subject to FDA’s IRB and informed consent regulations.

Cell-based therapies

Cell-based therapies are generally regulated as biologics.

Biologics can be regulated as devices or drugs (with the relevant pre-clearance or pre-market approvals based on safety and efficacy data) depending upon their primary mode of action, as per the FDCA and its subsequent amendments.

In addition, biologics are subject to additional precautions based on the PHS Act, primarily aimed at control of transmission of infectious disease.

The Tissue Action Plan

FDA announced "Reinventing the Regulation of Human Tissue" and "A Proposed Approach to the Regulation of Cellular and Tissue-Based Products" in February 1997. The agency will promulgate regulations to implement the Proposed Approach.

Components of the Tissue Action Plan for Manufacturers of Human Cell Therapy Products

Establishment Registration and Listing Donor Suitability Determination Good Tissue Practices Labeling Enforcement

Establishment Registration

Owners and operators of establishments or persons engaged in the recovery, screening, testing, processing, storage, or distribution of human cells, tissues, and cellular and tissue-based products must register and list those human cells, tissues, and cellular and tissue-based products with the Center for Biologics Evaluation and Research

Current Good Tissue Practice for HCT/P Establishments

CGTP requirements prevent the introduction, transmission, or spread of communicable diseases by human cell, tissue, and cellular and tissue-based products (HCT/Ps) (e.g., by ensuring that the HCT/Ps do not contain communicable disease agents, that they are not contaminated, and that they do not become contaminated during manufacturing).

CGTP requirements govern the methods used in, and the facilities and controls used for, the manufacture of HCT/Ps, including but not limited to all steps in recovery, donor screening, donor testing, processing, storage, labeling, packaging, and distribution.

Donor Suitability and Tracking

The good tissue practices will also include screening of donors to prevent the spread of communicable diseases, and a tracking system that will permit tracking from each human cell line or tissue back to the original donor(s).

Note the interplay between the tracking rules and the question of whether work on a cell line constitutes human subjects research: an agreement will need to be in place concerning the use of tracking information in order to avoid turning research on the cell lines into research on the original cell donors (thus triggering human subjects protections)

HIPAA

Donor suitability rules may require collection of medical record information about gamete and blastocyst donors whose biological materials were used to derive new embryonic stem cell lines

HIPAA may apply to the research uses of this medical record information

HIPAA and Research Uses of Medical Record Information

To use or disclose protected health information without authorization by the research participant, a covered entity must obtain documented Institutional Review Board (IRB) or Privacy Board Approval, based on finding that research is minimal risk and measures have been taken to protect confidentiality

In the alternative, consent for disclosure could be obtained from gamete and blastocyst donors at the time of donation

Clinical Research Involving Xenotransplantation:

Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either (a) live cells, tissues, or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs.

Tissue transplantation from cell lines grown on nonhuman feeder cells would be considered xenotransplantation, and require additional FDA review.

Importation of Cell-Lines for Clinical Use

FDA’s new tissue regulations also govern the importation of cell-lines and derived tissues for use in clinical transplantation.

Importation must be approved by FDA

FDA regulates the importation to prevent the transmission of communicable diseases.

Non-Federal Sources of Regulation or Oversight

State laws (e.g. CA & NJ) Patent owners’ licensing restrictions on use of licensed

products or methods Institutional oversight bodies other than IRBs, IBCs and animal

welfare committees (e.g. University of Wisconsin Bioethics Advisory Committee; conflict of interest committees)

Voluntary guidelines from professional societies and other NGOs (e.g. NAS guidelines; ASRM)

Rules imposed as condition of collaboration with foreign research center (e.g. HFEA)

International sources of guidance or regulation (e.g. W.H.O., UNESCO, Council of Europe, European Union)