PHS Guideline on Infectious Disease Issues in Xenotransplantation
Several developments have fueled the renewed interest in xenotransplantation- the use of live animal cells, tissues and organs in the treatment or mitigation of human disease. The world-wide, critical shortage of human organs available for transplantation and advances in genetic engineering and in the immunology and biology of organ/tissue rejection have renewed scientists' interest in investigating xenotransplantation as a potentially promising means to treat a wide range of human disorders. This situation is highlighted by the fact that in the United States alone, 13 patients die each day waiting to receive a life-saving transplant to replace a diseased vital organ.
While animal organs are proposed as an investigational alternative to human organ transplantation, xenotransplantation is also being used in the effort to treat diseases for which human organ allotransplants are not traditional therapies (e.g., epilepsy, chronic intractable pain syndromes, insulin dependent diabetes mellitus and degenerative neurologic diseases such as Parkinson's disease and Huntington's disease). At present, the majority of clinical xenotransplantation procedures utilize avascular cells or tissues rather than solid organs in large part due to the immunologic barriers that the human host presents to vascularized xenotransplantation products. However, with recent scientific advances, xenotransplantation is viewed by many researchers as having the potential for treating not only end-organ failure but also chronic debilitating diseases that affect major segments of the world population.
Although the potential benefits may be considerable, the use of xenotransplantation also presents a number of significant challenges. These include (1) the potential risk of transmission of infectious agents from source animals to patients, their close contacts, and the general public;
(2) the complexities of informed consent; and (3) animal welfare issues.
On September 23, 1996, the Department of Health and Human Services (DHHS) published for public comment the Draft PHS Guideline on Infectious Disease Issues in Xenotransplantation to address the infectious disease concerns raised by xenotransplantation (61 Federal Register 49919). The Draft Guideline was jointly developed by five components within DHHS-the Centers for Disease Control and Prevention (CDC), Food and Drug Administration (FDA), Health Resources and Services Administration (HRSA), National Institutes of Health (NIH), all parts of the U.S. Public Health Service (PHS), plus the DHHS Office of the Assistant Secretary for Planning and Evaluation. This Draft Guideline discusses general principles for the prevention and control of infectious diseases that may be associated with xenotransplantation. Intended to minimize potential risks to public health, these general principles provide guidance on the development, design, and implementation of clinical protocols to sponsors of xenotransplantation clinical trials and local review bodies evaluating proposed xenotransplantation clinical protocols. The Draft Guideline emphasizes the need for appropriate clinical and scientific expertise on the xenotransplantation research team, adequate protocol review, thorough health surveillance plans, and comprehensive informed consent and education processes.
In response to the Draft Guideline, the DHHS received over 140 written comments reflecting a broad spectrum of public opinion (Federal Register docket No. 96M-0311). Comments were received from a variety of stakeholders, including representatives of academia; industry; patient, consumer, and animal welfare advocacy organizations; professional, scientific and medical societies; ethicists; researchers; other government agencies and private citizens.
In revising the Draft Guideline, careful consideration was given to recent scientific findings, each of the written comments, as well as to public comments received at several national, international, and DHHS-sponsored workshops. These meetings constituted critically important public forums for discussing the scientific, public health, and social issues attendant to xenotransplantation.
The DHHS sponsored two public workshops on xenotransplantation during 1997 and 1998. The first meeting, held in July 1997, focused on virology and documented evidence of cross species infections. Titled "Cross-Species Infectivity and Pathogenesis," the meeting addressed current knowledge about the mechanisms and consequences of infectious agent transmission across species barriers. Discussions also focused on the possibility that an infectious agent might cross from an animal donor organ or tissue to human xenotransplantation product recipients. The conference also highlighted gaps in knowledge about the emergence of new infections in humans, especially as a result of xenotransplantation. The basic consensus of the meeting was that while there were examples of animal infectious agents crossing species barriers to infect, and even cause diseases in humans, the actual likelihood of this in xenotransplantation product recipients cannot be ascertained at this time. Small adequate and well-controlled clinical trials designed to test the safety and efficacy of xenotransplantation were considered to be appropriate. One anticipated outcome of such trials would be to both minimize and better understand the risks of transmission of infectious agents. (The meeting summary can be accessed at:)
In January 1998, a second DHHS workshop titled "Developing U.S. Public Health Service Policy in Xenotransplantation," focused on the current and evolving U.S. public health policy in xenotransplantation. (The meeting transcripts can be accessed at http://www.fda.gov/ohrms/dockets/dockets/96m0311/96m0311.htm. Among other issues, the regulatory framework, a national xenotransplantation database, and a national advisory committee were discussed.
During this workshop, several themes were raised repeatedly and echoed many of the written public comments on the Draft Guideline. First, there was a broad consensus that the Draft Guideline was important and should be implemented, albeit with some modifications. For example, it was expressed that there could be more public awareness and participation in the development of public health policies in the field of xenotransplantation. Second, there was strong support for the DHHS proposal to establish a national xenotransplantation advisory committee, not only to facilitate analysis and discussion of the scientific, medical, ethical, legal, and social issues raised by xenotransplantation, but also to review and make recommendations about proposed clinical trial protocols. There was broad support for proceeding cautiously with xenotransplantation trials; however, some participants held that a national moratorium on clinical trials in xenotransplantation might be advantageous until the national xenotransplantation advisory committee is established and operational. While there is no definitive scientific evidence that xenotransplantation would promote cross-species infectious agent transmission leading to disease, there are data providing a reasonable basis for caution [see revised guideline, section 6., references D.1.a; e.; f.; i.; l; o.; q.; r.& s.]. Some members of the scientific and medical community and concerned citizens expressed the opinion that there is a perceived greater risk from the use of xenotransplantation products procured from nonhuman primates (as opposed to other species) because of potential public health risks and animal welfare concerns.
The January 1998 workshop also included presentations by representatives of the World Health Organization (WHO), the Organization for Economic Cooperation and Development (OECD), and several nations engaged in developing policies on xenotransplantation. These presentations placed the U.S. policy in global context and enhanced international dialogue on important public health safeguards. Because of the potential for the secondary transmission of infectious agents, the public health risks posed by xenotransplantation transcend national boundaries. International communication and cooperation in the development of public health policies are critical elements in successfully addressing the global safety and ethical challenges inherent in xenotransplantation. To this end, several countries, including Canada, France, Germany, the Netherlands, Spain, Sweden, the United Kingdom, and the United States and several international organizations such as the WHO, OECD, and the Council of Europe are actively engaged in international workshops and consultations on xenotransplantation. [see revised guideline, section 6.C.7. for a partial bibliography of guidance documents and websites from national and international bodies].
Major Revisions and Clarifications to the Guideline
Major revisions and clarifications to the Draft Guideline are briefly summarized and discussed below. These revisions were prompted by public comments submitted to the Draft Guideline docket, concerns expressed at public workshops, evolving science, and developing international policies. PHS intends to address related issues that go beyond the scope of this Guideline in future guidance documents. In the future the Guideline may be amended as needed to appropriately reflect the accrual of new knowledge about cross-species infectivity and pathogenesis, new insights into the potential risks associated with xenotransplantation, policies currently under development (e.g., the Secretary's Advisory Committee on Xenotransplantation and the National Xenotransplantation Database), and other evolving public health policies in this arena.
Definition of Xenotransplantation and Xenotransplantation Product. The definition of "xenotransplantation" has been revised from that used in the Draft Guideline. For the purposes of this document and US PHS policy xenotransplantation is now defined to include 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. Furthermore, xenotransplantation products have been defined to include live cells, tissues or organs used in xenotransplantation. The term xenograft, used in previous PHS documents, will no longer be used to refer to all xenotransplantation products.
Clinical Protocol Review and Oversight. A variety of opinions were expressed regarding the appropriate level of protocol review and oversight of clinical trials in the U.S. For example, the American Society of Transplant Surgeons stated that the Draft Guideline represented an unnecessary intrusion of government regulation into the performance of transplant surgery. In contrast, some organizations with commercial interests in the development of xenotransplantation contended that an inappropriate share of the burden for oversight of clinical trials had been assigned to local review committees and that the responsibility for this oversight should reside at the national level with the FDA. Several academic veterinarians, a group of 44 virologists, and other concerned citizens asserted that strict regulations should accompany the Guideline and that the major responsibility for determining the suitability of any animals as sources of nonhuman animal live cells, tissues or organs used in xenotransplantation must reside with the FDA.
The revised Guideline makes clear that, in addition to review by appropriate local review bodies (Institutional Review Boards, Institutional Animal Care and Use Committees, and the Institutional Biosafety Committees), the FDA has regulatory oversight for xenotransplantation clinical trials conducted in the U.S. Xenotransplantation products (i.e., live cells, tissues, or organs from a nonhuman animal source or human body fluids, cells, tissues, or organs that have had ex vivo contact with live cells, tissues, or organs from nonhuman animal sources and are used for xenotransplantation) are considered to be biological products, or combination products that contain a biological component, subject to regulation by FDA under section 351 of the Public Health Service Act (42 U.S.C. 262) and under the Federal Food, Drug and Cosmetic Act (21 U.S.C. 321 et seq.). In accordance with the applicable statutory provisions, xenotransplantation products are subject to the FDA regulations governing clinical investigations and product approvals (e.g., the Investigational new Drug [IND] regulations in 21 CFR Part 312, and the regulations governing licensing of biological products in 21 CFR Part 601). Investigators should submit an application for FDA review before proceeding with xenotransplantation clinical trials. Sponsors are strongly encouraged to meet with FDA staff in the pre-submission phase. In addition to the guidances referred to below, the FDA is considering further regulations and/or guidances regarding, for example, the development of xenotransplantation protocols and the technical and clinical development of xenotransplantation products.
Xenotransplantation clinical protocols may also be reviewed by the Secretary's Advisory Committee on Xenotransplantation. The scope and process for this review will be described in future publications. [see revised guideline, sections 2.3, 5.3]
Responsibility for Design and Conduct of Clinical Protocols. The Draft Guideline originally proposed that clinical centers, source animal facilities, and individual investigators share the responsibilities for various aspects of the clinical trial protocol, including pre-xenotransplantation screening programs, patient informed consent procedures, record keeping, and post-xenotransplantation surveillance activities. The revised Guideline clarifies that primary responsibility for designing and monitoring the conduct of xenotransplantation clinical trials rests with the sponsor(as provided under, e.g., 21 CFR 312.23(a)(6)(d) and 312.50).
Informed Consent and Patient Education. Virologists, infectious disease specialists, health care workers, and patient advocates emphasized the need for the sponsor to offer assistance to xenotransplantation product recipients in educating their close contacts about potential infectious disease risks and methods for reducing those risks. The Guideline has been revised to state that the sponsor should ensure that counseling regarding behavior modification and other issues associated with risk of infection is provided to the patient and made available to the patient's family and other close contacts prior to and at the time of consent, and that such counseling should continue to be available thereafter. The revised Guideline clarifies and strengthens the informed consent process for xenotransplantation product recipients and the education and counseling process for recipients and their close contacts, including associated health care professionals. It also emphasizes the need for xenotransplantation product recipients to comply with long-term or life-long surveillance regardless of the outcome of the clinical trial or the status of the graft or other xenotransplantation product. [see revised guideline, sections 2.5.3, 2.5.4, 2.5.7.]
Deferral of Allograft and Blood Donors. The 1996 Draft Guideline recommended that xenotransplantation product recipients refrain from donating body fluids and/or parts for use in humans. Some infectious disease specialists and an infectious disease control practitioner organization suggested that this be strengthened to active deferral of xenotransplantation product recipients, and that consideration also be given to the deferral of close contacts of xenotransplantation product recipients. This issue was addressed by the FDA Xenotransplantation Subcommittee of the Biological Response Modifiers Advisory Committee (December, 1997, for transcript: http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3365tl.rtf). The committee recommended that xenotransplantation product recipients and their close contacts be counseled and actively deferred from donation of body fluids and other parts. A proposed FDA policy was then later presented to FDA's Blood Products Advisory Committee for further discussion, (March, 1998, for transcript: http://www.fda.gov/ohrms/dockets/ac/98/transcpt/3391t2.rtf). Of note, at the time of both these advisory committee meetings the operative definition of xenotransplantation did not include, as it does now, the use of certain products involving limited ex vivo exposure to xenogeneic cell lines or tissues. FDA has published a draft guidance document ("Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and Their Contacts") for public comment, which was again discussed by the FDA Xenotransplantation Subcommittee of the Biological Response Modifiers Advisory Committee on January 13, 2000. FDA will further consult with its advisors to identify the range of xenotransplantation products for which recipients and/or their contacts should be recommended for deferral from blood donation. Additionally, the range of contacts who should be deferred from blood donation will be clarified after further public discussion. The Guideline has been revised to reflect comments made at the FDA advisory committee meetings [see revised guideline, sections 2.5.11].
Xenotransplantation Product Sources. Strong opposition to the use of nonhuman primates as xenotransplantation product sources was voiced by many individuals and groups, including 44 virologists, scientific and medical organizations such as the American Society of Transplant Physicians, the American College of Cardiology, private citizens, and commercial sponsors of xenotransplantation clinical trials. The concerns focused on the ethics of using animals so closely related to humans, as well as the risk of transmission of infectious diseases from nonhuman primates to humans. Many recommended that the Guideline state that clinical xenotransplantation trials using xenotransplantation products for which nonhuman primates served as source animals should not occur until a closer examination of infectious disease risks can be adequately carried out.
Scientific findings since the publication of the Draft Guideline have also resulted in revisions. For example, the ability of simian foamy virus (SFV) to persistently infect human hosts has been further characterized [see revised guideline, section 6., references D.2.m. & D.4.d.], the persistence of microchimerism with anatomically dispersed baboon cells containing SFV, baboon cytomegalovirus (CMV), and baboon endogenous retrovirus (BaEV) in human recipients of baboon liver xenotransplantation products has been documented [see revised guideline, section 6., references D.3.a. & D.4.h.], and new viruses capable of infecting humans have been identified in pigs [see revised guideline, section 6., references D.2.a., b., f., g., h., i., v., w., x., bb., cc., ee., & gg.]. The active expression of infectious porcine endogenous retrovirus from multiple porcine cell types, and the ability of porcine endogenous retrovirus variants A and B to infect human cell lines in vitro has been demonstrated [see revised guideline, section 6., references D.1.q., s.; D.2.jj.; D.3.i.; D.4.a., e., f., m., s. & t.], giving scientific plausibility to concerns that this retrovirus from porcine xenotransplantation products may be able to infect recipients in vivo.
Diagnostic tests for porcine endogenous retrovirus, BaEV, and other relevant infectious agents have been developed [see revised guideline, section 6., references D.4.a., b., d., g., h., l., n., p., q., t. & u.] and studies are currently underway to assess the presence or absence of infectious endogenous retroviruses and other relevant infectious agents in both porcine and baboon xenotransplantation products and in the recipients of these xenotransplantation products [see revised guideline, section 6., references D.3.a.; D.4.c., h., j., l. & n.]. The risk of endogenous retrovirus infection, however, is multi-factorial and it is not known whether results from these studies will be predictive of the potential infectious risks associated with future xenotransplantation products. One factor that impacts porcine endogenous retrovirus infectivity is its sensitivity to inactivation and lysis by human sera, yet the virus becomes resistant to inactivation after a single passage through human cells [see revised guideline, section 6., references D.2.jj. & D.4.m.]. It is hypothesized that pre-xenotransplantation removal of naturally occurring xenoreactive antibodies from the recipient and other modifications intended to facilitate xenotransplantation product survival, such as the procurement of xenotransplantation products or nonhuman animal live cells, tissues or organs used in the manufacture of xenotransplantation products from certain transgenic pigs, may also modulate the infectivity of endogenous retroviruses for xenotransplantation product recipients [see revised guideline, section 6., references D.1.d., o., q., s.; D.2.k., jj.; D.3.i.; D.4.e., k., m. & r.].
As the science regarding porcine endogenous retroviruses summarized above began to emerge, the FDA placed all clinical trials using porcine xenotransplantation products on hold (October 16, 1997) pending development by sponsors of sensitive and specific assays for (1) preclinical detection of infectious porcine endogenous retrovirus in porcine xenotransplantation products, (2) post-xenotransplantation screening for porcine endogenous retrovirus and clinical follow-up of porcine xenotransplantation product recipients, and (3) the development of informed consent documents that indicate the potential clinical implications of the capacity of porcine endogenous retrovirus to infect human cells in vitro. These issues were discussed publicly by the FDA Xenotransplantation Subcommittee of the Biological Response Modifiers Advisory Committee (December, 1997, for transcript: http://www.fda.gov/ohrms/dockets/ac/97/transcpt/3365tl.rtf).
In response to concerns articulated by scientists and other members of the public regarding the use of nonhuman primate xenotransplantation products, the FDA, after consultation with other DHHS agencies, has issued a "Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans" containing the following conclusions:
While the document "Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans" specifically addresses the issue of nonhuman primates as sources for xenotransplantation products, the DHHS recognizes that other animal species have been used and/or are proposed as sources of xenotransplantation products and that all species pose infectious disease risks. Accordingly, the principles for source animal screening and health surveillance described in the revised Guideline apply to all candidate source animals regardless of species. These principles will need to be reassessed as new data become available.
Source Animal Screening and Qualification. Many groups and individuals expressed concern that the Draft Guideline did not set forth sufficiently stringent principles and criteria for source animal husbandry and screening, source animal facilities, and procurement and screening of xenotransplantation products. This view was expressed by virologists, veterinarians, infectious disease specialists, concerned citizens, commercial producers of laboratory animals, industrial sponsors of xenotransplantation trials, and a number of professional, scientific, medical, and advocacy organizations, such as the American Society of Transplant Surgeons, Doctors and Lawyers for Responsible Medicine, the American College of Cardiology, Biotechnology Industry Organization (BIO - representing 670 biotech companies), and the Association for Professionals in Infection Control and Epidemiology. Others expressed concern that the stringency of the Draft Guideline imposed high economic burdens on producers of xenotransplantation product source animals and/or on sponsors of xenotransplantation clinical trials. However, in order to reduce the potential public health risks posed by xenotransplantation, strict control of animal husbandry and health surveillance practices are needed during the course of development of this technology.
The Guideline has been revised to clarify the animal husbandry and pre-xenotransplantation infectious disease screening that should be performed before an animal can become a qualified source of xenotransplantation products. The revised Guideline now emphasizes that risk minimization precautions appropriate to each xenotransplantation product protocol should be employed during all steps of production and that screening, quarantine, and surveillance protocols should be tailored to the specific clinical protocol, xenotransplantation product, source animal and husbandry history. Breeding programs using cesarean derivation of animals should be used whenever possible. Source animals should be procured from closed herds or colonies raised in facilities that have appropriate barriers to effectively preclude the introduction or spread of infectious agents. These facilities should actively monitor the herds for infectious agents. The revised Guideline clarifies and strengthens the infectious disease screening and surveillance practices that should be in place before a clinical trial can begin.
Specimen Archives and Medical Records. A number of infectious disease specialists, veterinarians, epidemiologists, industry sponsors of xenotransplantation trials, biotechnology companies, professional organizations such as the American Society of Transplant Physicians, and consumer advocates requested clarification regarding the collection and usage of, and access to, biological specimens obtained from both source animals and xenotransplantation product recipients.
The revised Guideline clarifies the recommended types, volumes, and collection schedule for biological specimens from both source animals and xenotransplantation product recipients. It also clearly distinguishes between biological specimens archived for public health investigations [see revised guideline, sections 4.1.2. and 3.7.] and specimens archived for use by the sponsor in conducting surveillance of source animals and post-xenotransplantation laboratory surveillance of xenotransplantation product recipients. The revised Guideline also states that health records and biologic specimens should be maintained for 50 years, based on the latency periods of known human pathogenic persistent viruses and the precedents established by the US Occupational Safety and Health Administration with respect to record-keeping requirements.
National Xenotransplantation Database. A number of infectious disease specialists, epidemiologists, transplant physicians, and a state health official emphasized the need for accurate and timely information on infectious disease surveillance and xenotransplantation protocols and their outcomes. They further supported the concept of a national xenotransplantation database as described in the Draft Guideline.
The revised Guideline describes the development of a pilot national xenotransplantation database to identify and implement routine data collection methods, system design, data reporting, and general start-up and to assess routine operational issues associated with a fully functional national database. The revisions also discuss plans to expand this pilot into a national xenotransplantation database intended to compile data from all clinical centers conducting trials in xenotransplantation and all animal facilities providing source animals for xenotransplantation.
Secretary's Advisory Committee on Xenotransplantation. Xenotransplantation research brings to the fore certain challenges in assessing the potential impact of science on society as a whole, including the role of the public in those assessments. The broad spectrum of public opinions expressed since the publication of the Draft Guideline indicates that there is neither uniform public endorsement nor rejection of xenotransplantation. The fields of research involved are rapidly moving ones, at the leading edge of medical science. Furthermore, in many instances the clinical trials are privately funded and the public may not even be aware of them. However, public awareness and understanding of xenotransplantation is vital because the potential infectious disease risks posed by xenotransplantation extend beyond the individual patient to the public at large. In addition to these safety issues, a variety of individuals and groups have identified and/or raised concerns about issues such as animal welfare, human rights, community interest and consent, social equity in access to novel biotechnologies, and allocation of human allografts versus xenotransplantation products. For all of these reasons, public discourse on xenotransplantation research is critical and necessary.
The revised Guideline acknowledges the complexity, importance, and relevance of these issues, but emphasizes that the scope of the Guideline is limited to infectious disease issues. The revised Guideline discusses the development of the Secretary's Advisory Committee on Xenotransplantation (SACX) as a mechanism for ensuring ongoing discussions of the scientific, medical, social, and ethical issues and the public health concerns raised by xenotransplantation, including ongoing and proposed protocols. The SACX will make recommendations to the Secretary on policy and procedures and, as needed, on changes to the Guideline.
PHS GUIDELINE ON INFECTIOUS DISEASE ISSUESIN XENOTRANSPLANTATION
TABLE OF CONTENTS
- Scope of theDocument
- Xenotransplantation Protocol Issues
- Xenotransplantation Team
- Clinical Xenotransplantation Site
- Clinical Protocol Review
- Health Screening and Surveillance Plans
- Informed Consent and Patient Education Processes
- Animal Sources for Xenotransplantation
- Animal Procurement Sources
- Source Animal Facilities
- Pre-xenotransplantation Screening for Known Infectious Agents
- Herd/Colony Health Maintenance and Surveillance
- Individual Source Animal Screening and Qualification
- Procurement and Screening of Nonhuman Animal Live Cells, Tissues or Organs Used for Xenotransplantation
- Archives of Source Animal Medical Records and Specimens
- Disposal of Animals and Animal By-products
- Clinical Issues
- Xenotransplantation Product Recipient
- Infection Control4.3. Health Care Records
- Public Health Needs
- National Xenotransplantation Database
- Biologic Specimen Archives
- Secretary's Advisory Committee on Xenotransplantation (SACX)
- Outlines the composition and function of the xenotransplantation team to ensure that appropriate technical expertise can be applied (section 2.1).
- Addresses aspects of the clinical protocol, clinical center, and the informed consent and patient education processes with respect to public health concerns raised by the potential for infections associated with xenotransplantation (sections 2.2-2.5).
- Provides a framework for pre-transplantation animal source screening to minimize the potential for transmission of xenogeneic infectious agents from the xenotransplantation product to the human recipient (section 3, particularly sections 3.3-3.6).
- Provides a framework for post-xenotransplantation surveillance to monitor transmission of infectious agents, including newly identified xenogeneic agents, to the recipient as well as health care workers and other individuals in close contact with the recipient (section 4, particularly sections 4.1.1. and 4.2.3.).
- Provides a framework for hospital infection control practices to reduce the risk of nosocomial transmission of zoonotic and xenogeneic infectious agents (section 4.2.).
- Provides a framework for maintaining appropriate records, including human and veterinary health care records (section 4.3. and 3.7), standard operating procedures of facilities and centers (sections 3.2, 3.4), and occupational health service program records (section 4.3).
- Provides a framework for archiving biologic samples from the source animal and the xenotransplantation product recipient. These records and samples will be essential in the event that public health investigations are necessitated by infectious diseases and other adverse events arising from xenotransplantation that could affect the public health (sections 3.7, 4.1.2., and 5.2).
- Discusses the creation of a national database that will enable population based public health surveillance and investigation(s). (section 5.1).
Discusses the creation of a Secretary's Advisory Committee on Xenotransplantation (SACX) that will consider the full range of complex and interrelated issues raised by xenotransplantation, including ongoing and proposed protocols (sections 2.3. and 5.3. ).
2. Xenotransplantation Protocol Issues.
3. Animal Sources for Xenotransplantation
4. Clinical Issues
5. Public Health Needs
- Food and Drug Administration
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- Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals; (August 12, 1993; 58 FR 42974)*
- Application of Current Statutory Authorities to Human Somatic Cell Therapy Products and Gene Therapy Products; (October 14, 1993; 58 FR 53248)*
- Bovine Derived Materials; Agency Letters to Manufacturers of FDA Regulated Products; (August 29, 1994; 59 FR 44591)
- Points to Consider in the Manufacture and Testing of Therapeutic Products for Human Use Derived from Transgenic Animals; (August 24, 1995; 60 FR 44036)** (http://www.fda.gov/cber/guidelines.htm)
- Q5D Quality of Biotechnological/Biological Products: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products (September 21, 1998; 63 FR 50244). **(http://www.ifpma.org/ich5q.html)
- Q5A Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin; (September 24, 1998; 63 FR 51074) **(http://www.ifpma.org/ich5q.html)
- Guidance for Industry: Public Health Issues Posed by the Use of Nonhuman Primate Xenografts in Humans; (Notice of Availability: April 6, 1999; 64 FR 16743-16744). **(http://www.fda.gov/cber/guidelines.htm)
- Guidance for Industry: Precautionary Measures to Reduce the Possible Risk of Transmission of Zoonoses by Blood and Blood Products from Xenotransplantation Product Recipients and Their Close Contacts; (Notice of Availability: December 30, 1999; 64 FR 73562 - 73563). **(http://www.fda.gov/cber/guidelines.htm)[Please note that the documents identified with an asterisk "*" can be obtained from FDA/CBER/Office of Communication, Training and Manufacturers Assistance via FAX by calling 1-800-835-4709 or via mail by calling 301-827-1800. In addition, documents marked with two asterisks "**" can be found on the internet at the indicated websites.]
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National Research Council
- Barbeito et al. Recommended biocontainment features for research and diagnostic facilities where animal pathogens are used. Rev. sci. Tech. Off. Int. Epiz., 1995;14:873-887.
National and International Bodies
- NRC. Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council, 2101 Constitution Avenue NW, Washington, DC 20418. National Academy Press, Washington DC, 1996. (http://www.nap.edu/readingroom/books/labrats/)]
- Advisory Group on the Ethics of Xenotransplantation. Animal tissue into humans. United Kingdom Department of Health, London, UK: Stationery Office, 1996.
- Council of Europe. Recommendation on xenotransplantation, September 1997.
- Health. Proposed Canadian Standard for Xenotransplantation. The Expert Working Group on Xenotransplantation. July 1999. (Available at: http://www.hc-sc.gc.ca/hpb-dgps/therapeut/zfiles/english/bgtd/xeno_std_e.html)].
- Health Council of the Netherlands: Committee on Xenotransplantation. Xenotransplantation. Rijswijk: Health Council of the Netherlands, 1998; publication no. 1998/01E.
- Institute of Medicine. Xenotransplantation: Science, Ethics, and Public Policy. Washington, D.C.: National Academy Press, 1996.
- Nuffield Council on Bioethics. Animals-to-human transplants. The ethics of xenotransplantation. London, Nuffield Council on Bioethics, 1996.
- Organization for Economic Cooperation and Development. Xenotransplantation: International Policy Issues. OECD Proceedings prepared by Elettra Ronchi, OECD Secretariat. OECD Publications, Paris, France, 1999. (OECD website for xenotransplantation international policy issues: Internet: http://www.oecd.org/dsti/sti/s_t/biotech/prod/xeno.htm).
- Subcommission of Xenotransplantation of the Permanent Commission of Transplants of the Interterritorial Council of the National Health System. Xenotransplantation: Recommendations for the Regulation of these Activities in Spain. Available in Spanish or English translation from: Organizacion Nacional de Trasplantes, C/ Sinesio Delgado, 8, 28029 Madrid, Tel: (44) 91 314 24 06; Fax: (44) 91 314 29 69; E-mail: firstname.lastname@example.org
- Swedish Committee on Xenotransplantation. From one species to another - transplantation from animals to humans. A report by the Swedish Committee on Xenotransplantation, Stockholm 1999. Swedish Government Official Report No. 1999:120. Ministry of Health and Social Affairs. The complete report in Swedish or a short version (Summary and Statutory Proposals) in English are available upon request from: Stefan Reimer, Secretary, The Swedish Committee on Xenotransplantation, P.O. Box 187,S-201 21 MALMO, Sweden. E-mail: email@example.com
- World Health Organization. Xenotransplantation: Guidance on infectious disease prevention and management. World Health Organization, Geneva, Switzerland, November 1998 (document WHO/EMC/ZOO/98.1; available from Division of Emerging and Other Communicable Diseases Surveillance and Control, World Health Organization, 1211 Geneva 27, Switzerland) (Internet: http://www.who.int/emc-documents/zoonoses/whoemczoo981c.html)].
- Xenotransplantation: Scientific Frontiers and Public Policy. Proceedings of an OECD/NY Academy of Sciences Workshop on Xenotransplantation. Edited by J Fishman, D Sachs, and R Shaikh. Annals of the New York Academy of Science 1998; volume 862.
NOTE: As you can see under National and International Bodies there is no word about Germany and USSR, two countries where cell therapy was born in 1920’s where the regulations about cell therapy were issued first by the governments in 1984 (USSR) and Germany (after WW2).
D. Scientific Articles and Other Reports – the rest of bibliography is omitted.
The above regulation, the best in the world when it comes to the prevention of the transmission of xenoses, unfortunately declared cell, tissue or organ xenotransplants ‘products’, and thereby made the whole regulatory situation illogical. How can a baboon heart be classified a ‘product’ is hard to conceive.
Likewise lumping together cell, tissue and organ xeno-transplantation, and thereby giving an impression that cell (or tissue) xeno-transplantation belongs in the same group as organ xeno-transplantation, has been misleading. Fetal cell (or tissue) xenotransplantation have been officially around since 1931, and used for treatment of a huge number of patients, but that has not applied to organ xeno-transplantation, and will not so for many years to come. Immunological issues of cell (or tissue) xeno-transplantation have been solved for the daily use of such therapeutic method in clinical practice, definitely so in two countries: USSR, and Germany, as you can learn from this text, but with organ xeno-transplantation it has been just the opposite, and it will take a long time before organ xeno-transplantation becomes a standard treatment the way cell (or tissue) xeno-transplantation is already today.
But the largest problem is that the above U.S. FDA regulation is the only one about cell (or tissue) xeno-transplantation that U.S. FDA has ever issued. In all other aspects of application for a license the usual drug regulations have to be used and it is against all logic to have to refer to the regulations applicable to drugs of chemical origin when submitting the documentation dealing with live cells for fetal cell transplantation.Fetal precursor cell transplantation is, as its name states, a transplantation, a surgical procedure, and not a therapy by mass produced drugs. All surgical operations are ‘individualized therapeutic procedures’. Double blind studies have never been used for evaluation of results of surgical procedures. Fetal precursor cell xeno-transplants are not, and will not, become ‘mass-produced’ therapeutica, because they simply are not.