BRIEF COMMUNICATION
Interpretive conundrum on the exclusion criterionof ‘‘transplantation with xenografts’’ for tissueand cell donation
Michael A. Cox • Scott A. Brubaker
Received: 13 March 2011 / Accepted: 1 June 2011 / Published online: 17 June 2011
� Springer Science+Business Media B.V. 2011
Abstract In the context of the EU Directives for
human tissues and cells (2004/23/EC, 2006/17/EC
and 2006/86/EC) further interest has arisen on the
practical application of a few clauses. One such
aspect, for the evaluation phase of a potential donor,
is the interpretation of the exclusion criterion ‘‘trans-
plantation with xenografts.’’ This article outlines the
consensus viewpoints regarding the earlier evaluation
of the risks related to xenotransplantation and
describes the current status of the terminology and
recommendations/laws in several healthcare sectors.
The application of uniform terminology is encour-
aged within the healthcare sectors at the international
level.
Keywords Xenografts � Xenotransplantation
recipient � Xenotransplantation � Xenotransplantation
product � Xenozoonosis � Non-viable animal tissues �Viable non-human animal cells
Introduction
Clarification based on further knowledge, develop-
ments and scientific evidence has inevitably followed
the implementation of the EU Directives for human
tissues and cells. The selection and exclusion criteria
for potential donors are clearly stated in Annex 1 of
Directive 2006/17/EC. Experience has shown that
different interpretations of the criterion ‘‘transplanta-
tion with xenografts’’ are possible.
As early as 2003 in Madrid the World Health
Organization (WHO) convened a global consultation
on ethical, access, and safety issues in organ and
tissue transplantation, and it included examination of
both human-to-human and animal-to-human trans-
plants (WHO Report 2003). It was resolved that one
of their roles should be ‘‘Encouraging nations to
support consensus on basic principles of xenotrans-
plantation safety and oversight.’’ To achieve this
consensus, it was described that terminology used
globally should be uniform.
Background
In October 1997 the Council of Europe set a legally
binding moratorium on xenotransplantation which
was adopted by the Parliamentary Assembly of the
Council of Europe (Resolution 1399 1999). Thereaf-
ter, in October 2001, an opinion on the state of the art
for xenotransplantation was adopted by the Scientific
This article expresses the views of the authors and does not
represent any formal regulatory position.
M. A. Cox (&)
Danish Medicines Agency, Axel Heides Gade 1,
2300 Copenhagen S, Denmark
e-mail: [email protected]
S. A. Brubaker
American Association of Tissue Banks, 1320 Old Chain
Bridge Road, Suite 450, McLean, VA, USA
e-mail: [email protected]
123
Cell Tissue Bank (2012) 13:225–229
DOI 10.1007/s10561-011-9264-2
Committee on Medicinal Products and Medical
Devices (Online document 1, 2001) and reported to
the European Commission (DG Sanco). The promis-
ing and innovative potential for proposed treatments
by xenotransplantation were counter balanced with
concerns related to the risk of transmitting infection
(i.e., non-human endogenous retroviruses) to the
transplanted patient, and the potential for these
patients to infect the wider population. For the
purpose of the opinion, xenotransplantation was
defined as: ‘‘Any procedure that involves the trans-
plantation or infusion into a human recipient of:
(a) living cells, tissues, or organs from a non-human
animal source, or (b) human body fluids, cells, tissues
or organs that have had ex vivo contact with living
non-human animal cells, tissues or organs (e.g.
extracorporeal perfusion).’’
A wide variety of healthcare products are used in
medical practice, some of which are manufactured
utilising material of animal origin: medical devices,
blood, organs, tissues, cells, medicinal products.
Medical devices
The focused reference in the opinion to living (non-
human) animal cells was particularly significant, thus
excluding the existing range of medical devices
utilising non-viable animal material, or their deriva-
tives, regulated by the Medical Device Directive (93/
42/EC). Illustrative healthcare products include
bovine bone for orthopaedic reconstruction, porcine
heart valves for cardiac replacement or collagen-
based wound dressings. Several of these starting
materials may originate from species susceptible to
transmissible spongiform encephalopathy (i.e.
bovine, ovine and caprine) and are further regulated
by a supplementary Directive (2003/32/EC), known
as the ‘‘TSE Directive.’’ Based on a risk management
process, several risk control options may be chosen,
as defined in the International Standard series EN ISO
22442 (Online document 2, 2007). The adopted
practices for sourcing, collection and handling are
important tools, as well as the control measures for
elimination/inactivation or removal. For certain ani-
mal tissues the inactivation processes are not com-
patible with the desired material properties for its
intended use, so the sourcing controls are of more
relevance. The TSE Directive contains specific
technical requirements to be achieved and seeks a
documented justification for the use of the medical
device; compared with its expected benefits to similar
alternatives (Cox and Geertsma 2006).
In contrast to the aforementioned risk-mitigated
products, the therapeutic application of cultured
animal cells, or human cells in contact with animal
cells (e.g. fibroblasts and/or keratinocytes co-cultured
with attenuated murine feeder layer for the autolo-
gous treatment of burns—see Online Document 3)
represents different risks for a patient; in relation to
the potential for cross infection. Subsequently the
Working Group of the Scientific Committee
announced a series of recommendations for the
therapeutic application of ‘‘xenotransplants’’ to the
scientific and healthcare community.
Blood
A specific legislative Directive (2002/98/EC)
addresses the standards of quality and safety for
blood and blood components (e.g. erythrocytes,
plasma, etc.) and has been complemented further by
other technical Directives (e.g. 2004/33/EC). Within
this framework, blood establishments have the duty
to ensure accepted donors are in compliance with
eligibility criteria, which includes permanent deferral
if a prospective allogeneic donor is a ‘‘xenotransplant
recipient’’ (Annex III, 2004/33/EC). The universal
guide for blood prepared by the Committee for
Transfusion (Council of Europe 2010a) contains a
compendium of measures designed to ensure the
safety, efficacy and quality of blood components; and
is relevant to personnel working in the blood services.
As presented in the technical Directive, one of the
conditions leading to a permanent deferral of a
potential donor in the preparation, use and quality
assurance of blood components is any history of
being a ‘‘xenotransplant recipient.’’ The definition
listed in the guide defines xenotransplantation as;
‘‘Any procedure that involves the transplantation or
infusion into a human recipient of live animal cells,
tissues or organs, or human body fluids, cells, tissues
or organs that have ex vivo contact with live animal
cells, tissues or organs.’’ This approach mirrors the
principle of the opinion (Online document 1), which
places the emphasis on ‘‘living’’ (non-human) animal
materials. To date, a similar restrictive criterion for
226 Cell Tissue Bank (2012) 13:225–229
123
blood donors in the US, or in Canada, is not
mandated, but draft guidance has been published
(Online Document 4).
Organs, tissues, cells
The European regulations on the standards for the
safety and quality of human organs intended for
transplantation have been recently published in a
harmonised Directive (2010/45/EU). During its tran-
sitionary phase, to implement the national provisions
and regulations before August 2012, other delegated
measures and implementing acts will follow to assist
with its unification. It is common practice that an
organ donor is often a tissue donor, so it has been
recognised the technical requirements (e.g. donor
infection risk evaluation and biological testing)
should complement and be linked with pre-existing
control systems for tissues and cells, when indicated.
The forthcoming initiative for organ transplantation
is likely to reflect the recognised shortage of life
saving organs and the professional assessment of the
overall risk-benefits to the patient performed by
clinicians.
In the absence of a definition for ‘‘xenograft’’ in
the EU Directives for human tissues and cells, the
interpretive application of ‘‘transplantation with
xenografts’’ for the evaluation of a potential donor
is viewed to be ambiguous. By itself this phrase may
broadly be interpretated to include viable animal
organs, tissues or cells, as well as any non-viable
animal materials, such as tissues or derivatives (e.g.
collagen, gelatine). Alternatively, when reviewed in
the context of the earlier opinion; this supports a
more rational approach. With this fundamental
knowledge it is presumptive the exclusionary phrase
of ‘‘transplantation with xenografts’’ in reality per-
tains to the transplantation, infusion, implant, or
transfer of viable (living) organs, tissues or cells of
non-human animal origin to humans, or the receipt of
a product which had ex vivo contact with live, non-
human animal cells, tissues or organs during manu-
facture. This adoptive approach adequately addresses
the current state of the art and the scientific focus for
preventing the potential for transmitting infectious
agents from viable cells between species. In addition
this presumptive interpretation is in harmony with
other oversight bodies (Online Document 5).
The expected safety and quality assurance stan-
dards for the transplantation of organs, tissues and
cells are comprehensively addressed by the Commit-
tee of Experts in their revised guide (Council of
Europe 2010b). The generic donor exclusion criteria,
including those for transmissible diseases and con-
cerning donor history of certain transplants (e.g.
human dura mater, cornea or scleral graft) are clearly
defined. In particular is the exclusionary text; ‘‘the
risk of transmitting prion disease, which includes a
definite diagnosis or high suspicion of any transmis-
sible spongiform encephalopathy’’ which is applica-
ble for the evaluation of the medical history. The
specific term of ‘‘xenotransplant recipient’’ is not
specified in the general exclusion criteria of donor
risk factors for transmissible diseases (Appendix 3,
Council of Europe 2010b), as its application, consis-
tent with existing practices, should not be misadver-
tently applied for the evaluation of life saving organ
donors.
Medicinal products
One of the many informative guidelines from the
European Medicines Agency (EMA) addresses the
technical expectations for xenogeneic cell-based
medicinal products for human use (Online Document
6, 2009). This cell-based therapy focuses on the
therapeutic use of viable animal somatic cell prepa-
rations, for implantation or infusion into a human
recipient or extracorporeal treatment by bringing
(non-human) animal cells into contact with human
organs, tissues or body fluids. The guideline, which
supports the Regulation for Advanced Therapy
Medicinal Products (Regulation 1394/2007), also
advises a recipient of a ‘‘xenogeneic medicinal
product’’ is to be excluded later as a potential donor
for blood, cells, tissues and organs. Since this is
applied to viable animal somatic cell preparations,
the criterion is comparable to the prescribed practices
for donor evaluation by tissue and blood
establishments.
Discussion
As a general comparison, risk screening for donors of
cells or tissues in the United States includes the
Cell Tissue Bank (2012) 13:225–229 227
123
description that the term ‘‘xenotransplantation’’ is
applicable to ‘‘any procedure that involves the
transplantation, implantation, or infusion into a
human recipient of either: (1) live cells, tissues, or
organs from a non-human animal source; or (2)
human body fluids, cells, tissues or organs which
have had ex vivo contact with live non-human animal
cells, tissues or organs.’’ (Online Document 7, 2007).
With the same equivalence to the opinion it continues
that xenotransplantation products include those which
utilise living non-human animal cells, tissues or
organs used for transplantation. Informatively, the US
Guidance for Industry clearly states any biological
products, drugs or medical devices sourced from non-
living cells, tissues or organs from non-human
animals are not considered xenotransplantation prod-
ucts (e.g. porcine insulin and biological heart valves).
The first principle of the earlier opinion (i.e. to
living non-human animal cells) has typically been
cited in regulations or guidance by the different
sectors; yet recognition of omitting other healthcare
products utilising non-viable materials from non-
human animal species is perhaps not as well known.
It is evident their medical application (e.g. in cardiac
and vascular surgery, dental procedures and wound
treatments) determined by the review of the donor
medical history might present some doubt or misin-
terpretation. Consequently this may inadvertently
lead to some donors of tissues, cells or blood being
ineligible or affect the availability of life-saving
organs. It is recognised that xenozoonotic disease is
not known to be caused by, and there is no suspicion
of any relationship to these healthcare products;
whereas this concern does apply to the use of
‘‘xenotransplantation products’’. With the clarifica-
tion of the scientific perspectives and the review of
existing statements these situations should be
avoidable.
Within different European frameworks for health-
care designed to safeguard the health of patients, this
exclusion criterion has been referenced by terms such
as ‘‘transplantation with xenografts’’, ‘‘xenotrans-
plant recipient’’, ‘‘xenogeneic cell based medicinal
product’’ and ‘‘xenotransplantation’’. With the over-
arching principle by the WHO promoting uniform
terminology there is an opportunity to clarify or
update the term of ‘‘transplantation with xenografts’’.
In the future the terms of ‘‘xenotransplant recipient’’
(with the caveat of the risk mitigated products) and/or
‘‘xenotransplantation products’’ may well appear in
different forums as prime candidates for the next step
towards a wider consensus. The global harmonisation
of cell and tissue donation criteria, especially their
interpretation, should be actively sought as the
protective guidelines that promote safety for tissue
and cell recipients (located anywhere) is a common
goal of this sector and its authoritative bodies. Public
confidence in governance can be diminished when
ambiguity or differences exist in minimum donor
requirements.
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