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: mic@dkma.dk

S. A. Brubaker

American Association of Tissue Banks, 1320 Old Chain

Bridge Road, Suite 450, McLean, VA, USA

e-mail: brubakers@aatb.org

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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