Report by the Chief Inspector:

Imutran Ltd.: Compliance With Authorities Issued

Under the Animals (Scientific Procedures) Act 1986

2001

Preamble

In response to the Uncaged report ‘Diaries of Despair’ the Home
Secretary instructed the Chief Inspector of the Animals (Scientific
Procedures Inspectorate) to review the available evidence and
provide a brief report on Imutran LtdÂ’s compliance with authorities
issued under the Animals (Scientific Procedures) Act 1986 (ASPA)
for pig and non-human primate xenotransplantation research.

ASPA Compliance – Summary Findings

This review of ImutranÂ’s licensed work 1994-2000 confirms, with
the exceptions set out below, compliance with ASPA authorities.
Confirmation of three instances of non-compliance, previously selfreported
or reported by the Inspectorate, not deemed to have
caused unnecessary animal suffering, and dealt with as formal
infringements:

· Unauthorised re-use of three non-human primates (self-reported).

· Induction and maintenance of general anaesthesia without appropriate personal
licence authority (self-reported).

· Blood sampling without personal licence authority (reported by the Inspectorate).
Detection and verification of two previously undetected instances of
non-compliance not emerging from the Uncaged allegations and
concerns:

· The performance of surgical procedures technically at variance with the project licence
authority. It is not believed this resulted in any unnecessary animal suffering.

· Perceived failure to best implement a required humane endpoint.
Significant departures from best practice and errors of judgement:

· In one instance normal operating theatre working practices and safeguards were not
followed and a swab was left in the abdominal cavity of a non-human primate that
received a renal transplant.

· A renal transplant operation was performed using a kidney damaged during cold
storage, and the procedure was not terminated when the transplanted organ
malfunctioned.

· On two occasions the drug treatment regimens were compromised due to human
error, although it is not believed significant unnecessary animal suffering resulted.

1. Overview of ASPA Compliance Issues

All aspects of compliance with authorities issued under the 1986 Act were
reviewed, and the general findings were as follows:

1.1 Project licence authority was secured in all cases before studies were
undertaken.

1.2 Project licence authorities were not formally suspended under the
provision of Section 13(1) at any time. The suggestion that studies were
carried out while authorities were formally suspended is, therefore,
unfounded.

1.3 All protected animals used by Imutran were either bred at or obtained
from UK designated establishments, or obtained from overseas nondesignated
sources and used with the knowledge and consent of the Home
Office.

1.4 Journey times for imported non-human primates in some instances
exceeded the estimated journey times supplied prospectively to the Home
Office. The prospective estimates are considered only to represent indicative
times. The variation was due to factors beyond ImutranÂ’s control, within
tolerable limits, and all necessary information relating to the welfare of the
animals was provided to the Home Office after their arrival.

1.5 Licence conditions relating to the re-use of Animals were complied with in
all cases except one. This case was self-reported and dealt with as a formal
infringement in 1997.

1.6 There was no breach of ASPA authorities in respect of the time baboons
were held as stock.

1.7 All United Kingdom facilities used for the Imutran pig and non-human
primate xenotransplantation studies complied with the relevant provisions of
the Home Office Code of Practice.

1.8 Production of genetically modified animals complied with licence
authorities.

1.9 Appropriate general anaesthetic regimens were applied and the use of
analgesia was also timely and appropriate. The administration of anaesthesia
was compliant with one exception. This case was self-reported, did not result
in unnecessary animal suffering and was dealt with as a formal infringement
in 1997.

1.10 All operative surgery was performed by clinicians (who were also
personal licence holders) with experience in the relevant surgical disciplines.
One instance was identified of the performance of surgical procedures
technically at variance with the project licence authority. It is not believed
that this resulted in unnecessary animal suffering. Two instances of significant
departures from best practice and errors of judgement with respect to the
operative surgery were identified. In one instance normal operating theatre
working practices and safeguards were not followed and a swab was left in
the abdominal cavity of a non-human primate that received a renal
transplant. In the second instance a renal transplant was performed using a
kidney damaged during cold storage and the procedure was not terminated
when the transplanted organ malfunctioned.

1.11 Post-operative care monitoring schedules matched the perceived clinical
needs of the animals and were compliant.

1.12 Where professional judgement was required with respect to the
recognition and implementation of welfare-related endpoints it was generally
properly exercised. However, in several instances failure to implement the
endpoint earlier did result in unnecessary animal suffering. This finding is a
matter of clinical judgement – and I offer it as my opinion rather than an
undisputed fact. The decisions that were taken by the surgical team were
taken in good faith and based upon their clinical experience and judgement.

1.13 All blood sampling schedules undertaken for research purposes were as
authorised by the project licences. An infringement relating to the taking of
blood samples from pigs was identified and reported by the Inspectorate in
1997. This did not result in unnecessary animal suffering and was dealt with
as a formal infringement at the time.

1.14 With the exception of the unauthorised re-use of three non-human
primates all other regimens for the administration of pharmaceutical agents
for experimental or other scientific purposes were in compliance with the
licence authorities. However, on two occasions the drug treatment regimens
were compromised due to human error, although it is not believed significant
unnecessary animal suffering resulted.

1.15 Discharge of protected animals from the controls of the 1986 Act was
compliant.

1.16 Where required, submission of periodic summary progress reports was
generally timely, but further enquiries were at times necessary to elicit
supplementary information or to verify the accuracy of the information
supplied. In some cases the information supplied is now considered to have
been incomplete or inaccurate.

2. Introduction

2.1 In September 2000, Uncaged submitted to the Home Office a report
entitled ‘Diaries of Despair’. The Uncaged report makes a number of
allegations against all of the parties involved in the conduct and regulation of
xenotransplantation studies performed by Imutran Ltd – including allegations
that Imutran did not comply with the terms and conditions of licences issued
by the Home Office under the Animals (Scientific Procedures) Act 1986
(ASPA).

2.2 The Uncaged report is compiled largely from draft reports of, and other
documents relating to, ImutranÂ’s pig to non-human primate
xenotransplantation research conducted in the UK. Imutran did not authorise
the disclosure of these documents, and has obtained an injunction preventing
further unauthorised use or misuse of much of the material.

2.3 On 27 November 2000 the Home Secretary instructed the Chief Inspector
of the Animals (Scientific Procedures) Inspectorate to “…examine, as part of
the InspectorateÂ’s normal statutory inspection and reporting function, the
available evidence relating to compliance with authorities granted to Imutran
for its xenotransplantation work between 1995 and 2000.”.

2.4 The scope of the Chief InspectorÂ’s review and report, in line with the
Home SecretaryÂ’s instruction, is limited to ImutranÂ’s compliance with the
authorities issued to Imutran staff under the Animals (Scientific Procedures)
Act 1986 for pig and non-human primate xenotransplantation research.

2.5 This report sets out the Chief InspectorÂ’s findings.

3. Background

3.1 As part of Imutran LtdÂ’s research programme, project licences were
obtained under the Animals (Scientific Procedures) Act 1986 to produce
genetically modified pigs designed to control or eradicate xenograft
hyperacute rejection, and for the studies using pigs and non-human primates
with the intention of:

· Demonstrating proof of concept.

· Evaluating immunosuppressive regimens to tackle other forms of
xenograft rejection.

· Studying the biocompatibility and performance of solid-organ and tissue
xenografts.

3.2 In considering whether and on what terms to grant the project licence
applications the Home Office judgement of ‘potential benefit’ was based upon
the new scientific insights that might be gained. Imutran did not advance, and
the Home Office did not consider, claims of imminent clinical trials as a
realistic short-term potential benefit. The ‘cost’ was assessed on the basis that
there would be significant animal welfare problems as a direct consequence of
the regulated procedures applied (mainly the surgery and immunosuppressive
regimens), and additional contingent suffering experienced by wild-caught
non-human primates required for some of the studies. Such project licence
authorities were in place from 1994-2000.

3.3 During the second quarter of 2000, prior to the publication of UncagedÂ’s
concerns and allegations, ImutranÂ’s parent company decided to close Imutran
and transfer the technology to a new company in North America. All extant
project licences, other than that authorising the conventional breeding and
keeping of established lines of genetically modified pigs, were voluntarily
surrendered for revocation at that time. All Imutran employees were made
redundant or transferred elsewhere in the parent company.

4. Methodology

4.1 The review was undertaken by the Chief Inspector of the Animals
(Scientific Procedures) Inspectorate. It has involved in excess of 250 manhours
of work and included seven visits to Imutran to view original study
documents and interview management and staff, and four visits to other
sites.

4.2 During the course of the review the Chief Inspector: -

· Considered all of the material contained in and appended to the
Uncaged report.

· Reviewed all of the original study documentation, including available
video footage of study animals.

· Reviewed all of the recorded information maintained by the Home
Office on the Imutran research programme.

· Interviewed Imutran management and staff, and other third parties,
thought to have essential information relevant to the review.

· Sought supplementary information, clarification and comment from the
Imutran management, and others, as required.

4.3 This review thus includes information not previously available to the Home
Office, and not available to Uncaged.

4.4 All of those contacted for information and comment co-operated promptly
and fully.

4.5 Where there are discrepancies between the draft study reports, the final
reports, and the original study documents the last are assumed to be the
definitive records.

4.6 Section 5 of this report reviews all aspects of formal ASPA compliance. It
also comments on several events, not strictly or necessarily representing
ASPA non-compliance, where I believe that proper judgement was not
exercised or where there were significant departures from best practice.

5. ASPA Compliance Issues

5.1 For convenience these are listed in the order they normally occur when
licensed studies are undertaken.

5.2 Project Licence Authority Secured Before Studies Undertaken:
compliance confirmed.

5.3 Allegation That Regulated Procedures Were Performed Whilst
Project Licence Authority Was Suspended: compliance confirmed.

5.3.1 The Uncaged report makes reference to regulated procedures
being performed whilst a project licence was ‘frozen’ pending an
infringement being dealt with by the Home Office.

5.3.2 The project licence had not been suspended under the provisions
of ASPA Section 13(1): the extant project licence authorities remained
in force whilst the Home Office dealt with the infringement.

5.3.3 ‘Frozen’ was the shorthand term used in the Imutran
documentation to indicate that the Home Office would not process
pending or proposed project licence amendments until the Secretary of
State had considered, and taken action with respect to, the
infringement.

5.4 Source of Animals – Provenance: compliance confirmed.

5.4.1 All protected animals used by Imutran were either bred at or
obtained from UK designated establishments, or obtained from
overseas non-designated sources and used with the knowledge and
consent of the Home Office.

5.5 Authority To Use Animals From Overseas Non-Designated
Sources – Journey Times: compliance confirmed.

5.5.1 The Uncaged report notes that the actual journey times for
imported non-human primates in some instances exceeded the
estimated journey times supplied prospectively to the Home Office.

5.5.2 The expected journey times supplied prospectively in support of
these requests are based upon reasonable estimates of likely transit
times and are used to judge the likely contingent welfare costs. They
are regarded as indicative times. Imutran supplied details of actual
journey times, and other information relating to the welfare of the
animals, to the Home Office after the arrival of each shipment of
animals.

5.6 Re-use of Animals: Compliant with one exception: a previously
self-reported instance of re-use of protected animals without the
permission of the Secretary of State, and dealt with at that time as a
formal infringement, was confirmed.

5.6.1 On one occasion three non-human primates that had previously
been used on, and had recovered from, an unrelated procedure were
re-used without the express consent of the Secretary of State. This
was due to human error, was self-reported, and was dealt with as a
formal infringement. It is not believed that any significant unnecessary
animal suffering resulted.

5.6.2 The unauthorised ‘re-use’ consisted of the administration of
prophylactic drugs to reduce the risk of anaemia following surgery: the
error was discovered and reported before any surgical procedures had
been performed.

5.6.3 Re-use under similar circumstances had previously been allowed
with the consent of the Secretary of State.

5.7 Allegation That Baboons Were Held As Stock Beyond The Time
Scale Prescribed By The Home Office: no compliance issue.

5.7.1 Although the Home Office expected that the animals would not
remain as stock for longer than necessary, the Home Office did not
prescribe the length of time they might be held before use, and thus
no breach of ASPA authorities occurred.

5.8 Animal Accommodation: compliance confirmed.

5.8.1 All UK facilities used for the Imutran pig and non-human primate
xenotransplantation studies complied with the provisions of the
relevant Home Office Code of Practice.

5.8.2 Concerns in the Uncaged report that the facilities were
understaffed are unfounded. The documents obtained by Uncaged
relate primarily to an inability to increase the amount of
xenotransplantation research being conducted without a concomitant
increase in support staff.

5.9 Production of Genetically Modified Animals: compliance with
licence authorities confirmed.

5.10 Anaesthesia And Analgesia (Regimens): compliance confirmed.

5.10.1 Appropriate general anaesthetic regimens were applied. There
was active veterinary input.

5.10.2 The Uncaged report (and the Imutran documents upon which it
is based) makes reference to the anaesthetic complications caused by
the administration of ‘very high doses’ of diazepam. In fact the doses
administered were within the normal clinical range, and post mortem
findings established that the main clinical findings and outcomes were
due to other processes and pathologies.

5.10.3 The use of analgesia was timely and appropriate. There was
active veterinary involvement and oversight.

5.11 Anaesthesia (Administration): Compliant with one exception: a
previously self-reported instance of non-compliance, not resulting in
unnecessary animal suffering, dealt with as a formal infringement at
the time, and not mentioned in the Uncaged document.

5.11.1 Two personal licensees induced and maintained general
anaesthesia in pigs – a species not listed on their personal licences.
The omission of this species was an administrative error when the
licence applications were prepared. The issue was legal competence
rather than technical competence (both licensees were trained and
technically proficient). The procedures were competently performed
and no unnecessary animal suffering resulted.

5.11.2 The lapse was detected by the in-house controls, was selfreported
to the Home Office, and was dealt with as a formal
infringement.

5.12 Operative Surgery: One instance of technical non-compliance,
not referenced in the Uncaged report and not resulting in
unnecessary animal suffering, was established.

5.12.1 All operative surgery was performed by clinicians (who were
also personal licence holders) with experience in the relevant surgical
disciplines.

5.12.2 The number of operative ‘technical failures’ (early graft failures
not related to rejection) for the programme of a whole was of the
order of 20% – consistent (and directly comparable) with reported
rates in human paediatric practice. The incidence of technical failures
varied from study to study, but the available evidence does not
indicate that the technical competence of any individual surgeon was
substandard.

5.12.3 Nevertheless in 1999, as the result of one study with an
unexpectedly high technical failure rate, ImutranÂ’s operative surgery
programme was halted whilst protocols and practice were reviewed
and revised to ensure that the likelihood of problems had been
minimised. This moratorium was voluntarily proposed and implemented
by Imutran management to address its own, and the Home OfficeÂ’s,
concerns. Work did not restart until Imutran and the Home Office were
of the view that all reasonable steps had been taken to ensure that the
likelihood of technical failures had been minimised.

5.12.4 The one instance of technical non-compliance with operative
procedures detailed on a project licence related to a study involving the
transplantation of pig meniscal cartilage into the knees of non-human
primates. The project licence specified that the xenograft would be
placed in the right knee of the recipient animal: in some cases it was
placed in the left knee instead. It is not considered that additional
animal suffering was caused. It is not clear why the technical authority
was drafted in this way, or why the variation on the prescribed
procedure was performed.

5.12.5 There are two other events where I believe the judgement of
those performing surgical procedures is called into question.

5.12.6 In one instance a swab was unintentionally left inside the
abdomen of an animal that had received a renal transplant: this was
not disclosed to the Home Office in a progress report submitted shortly
thereafter. The operation was performed without the normal
complement of theatre staff. This background information emerged
during the course of this review. The decision to operate in the
absence of a trained theatre nurse was, in my opinion, both a
significant error of judgement and the causal factor. It is my opinion
that in clinical practice this decision would not have been defensible.

5.12.7 The Uncaged report (and some Imutran documentation) makes
reference to a kidney destined for transplantation being ‘frozen solid’
during a period of cold storage. The kidney was not ‘frozen solid’ – but
did show evidence of surface frosting. This was caused by human
error and was the result of contact between the kidney and other
material held in cold storage at the same time. Contrary to the
Uncaged report the damaged kidney was transplanted into a recipient
animal: the decision to proceed was taken by the surgical team aware
of the problem during storage. The kidney, when re-perfused, did not
show immediate normal function or appearance. The surgeon did not
terminate the procedure at that point, and the animal died before
recovering from the general anaesthesia. The fact that the kidney had
been damaged in storage was notified to the Home Office in a progress
report supplied shortly after thereafter. However the summary report
did not supply details of the intra-operative problems. The damage in
cold storage was due to human error. It is my opinion that, in
retrospect, it is not possible from the information available to offer an
informed opinion about the judgement exercised by the surgical team
to transplant the damaged organ. However, I believe the decision not
to immediately terminate the procedure when abnormalities were
apparent after the organ was re-perfused was an error of judgement.

5.13 Post-operative Care: compliance confirmed.

5.13.1 The records of the clinical condition of animals reproduced,
interpreted and commented on in the Uncaged document are not
informed by, and therefore do not take into account, the active clinical
management of, and the specific, supportive and symptomatic
treatments provided to, the animals.

5.13.2 Monitoring schedules matched the perceived clinical needs of
the animals. The records available to Uncaged record only the first and
last observation of each day. Normally of the order of six observations
a day were made and recorded, in some cases the frequency was three
times this, and when appropriate animals were continuously monitored.

5.13.3 Records confirm that both veterinary and medical staff provided
24-hour-a-day clinical cover.

5.14 Implementation of Endpoints: perceived non-compliance with
respect to the implementation of a humane endpoint.

5.14.1 Detailed endpoints were specified on the project licences for
each of the authorised protocols. Some required the exercise of
professional judgement in determining whether the endpoint had been
reached and on what action should be taken, others did not.

5.14.2 A thorough review of all of the available documentation for all of
the animals subjected to surgical procedures and/or drug treatment
suggests that where professional judgement was required with respect
to the recognition and implementation of welfare-related endpoints it
was generally properly exercised. When there were differences of
opinion amongst those exercising these professional judgements, due
weight was given to the opinion of the attending, independent
veterinary surgeon.

5.14.3 One endpoint prescribed the action to be taken when renal
transplant recipients developed irreversible renal failure. This endpoint
was to be implemented if the findings were thought to be caused by
irreversible renal failure; if a specific biochemical abnormality was
confirmed (in a number of instances the biochemical finding was
transitory, not due to irreversible renal failure, and normal renal
function was rapidly restored); and the general health of the animal
was failing as a result (in a number of instances the biochemical
endpoint was reached whilst the animals appeared in good general
health). Experience and clinical judgement were required to determine,
based upon knowledge of the clinical condition of the animal and
access to the laboratory findings, if the endpoint had been reached.

5.14.4 In every instance where irreversible renal failure was diagnosed
by the surgical team animals were humanely killed when, or before,
these criteria were fulfilled.

5.14.5 However, I am of the opinion that in a several instances there
is, in retrospect, sufficient evidence (as recorded in the original study
documents) for irreversible renal failure to have been diagnosed up to
24 hours before the endpoint was applied. I conclude that, in these
cases, failure to implement the endpoint earlier did result in some
unnecessary animal suffering.

5.14.6 This finding is a matter of clinical judgement – and I offer it as
my opinion rather than an undisputed fact. The decisions that were
taken by the surgical team were taken in good faith and based upon
their clinical experience and judgement. In addition to access to the
recorded information available to me for the purposes of this review,
they were present and examined the animals at the time. Nevertheless,
with the benefit of hindsight, I believe that in some instances the
available evidence was, on balance, indicative of irreversible renal
failure up to 24-hours before the endpoint was applied.

5.15 Blood Sampling (Regimens): compliance confirmed.

5.15.1 All sampling schedules undertaken for research purposes were
as authorised by the project licences.

5.16 Blood Sampling (Performance): one instance of previously
detected non-compliance confirmed. This did not result in
unnecessary animal suffering and was dealt with as a formal
infringement at the time. It is not referenced in the Uncaged report.

5.16.1 An infringement relating to the taking of blood samples from
pigs was identified and reported by the Inspectorate in 1997. On one
occasion blood samples were taken by a person without appropriate
personal licence authority: the technique was competently applied and
no unnecessary animal suffering resulted. It was dealt with as a formal
infringement.

5.17 Drug Administration (Regimens and Performance): other than
the unauthorised re-use reported above, compliance confirmed.

5.17.1 The issue of the unauthorised re-use of three non-human
primates is dealt with separately above. All other regimens for the
administration of pharmaceutical agents for experimental or other
scientific purposes were in compliance with the licence authorities.
Expert judgement was generally properly exercised in matching the
day-to-day dosing schedules to the clinical condition and laboratory
findings of individual animals.

5.17.2 The Uncaged document does however identify, and this review
confirms, two unrelated events where, due to human error, the drug
administration regimens were compromised.

5.17.3 In the first instance an error in calculating the dose to be
administered resulted in an animal receiving four-times the prescribed
dose of an immuno-suppressant. This was detected shortly after the
drug had been administered, the subsequent dosing regimen was
adjusted, and normal therapeutic blood levels were re-established
within 24 hours. Although the animal was killed on welfare grounds the
day after the mis-dosing, the clinical records and post-mortem findings
strongly suggest that the animalÂ’s failing health was not due to drug
toxicity.

5.17.4 In the second instance a blood sample to establish the ‘trough’
level of a drug was taken after rather than before the animal was
dosed: the purpose of the procedure was to inform the dosing regimen
for the following day. This mistake was recognised the same day. As a
result the dosing regimen for the following day was determined on the
basis of the animalÂ’s clinical condition and standard laboratory test
results rather than also being informed by knowledge of the circulating
trough level of the drug. It is not believed that any unnecessary animal
suffering resulted.

5.18 Discharge Of Protected Animals From The Controls Of The 1986
Act: compliance confirmed.

5.19 Submission Of Special Reports: general compliance confirmed.

5.19.1 A number of the Imutran project licences were subject to a
condition of issue requiring the periodic submission of summary
progress reports. These were generally timely and informative. Further
enquiries were at times necessary to elicit supplementary information
or to verify the accuracy of the information supplied. As indicated
above, there were times when the material disclosed to the Home
Office by Imutran was incomplete.

6. Conclusions

6.1 This report reviews a seven-year programme of work involving many
thousands of animals and regulated procedures.

6.2 Imutran supplied the Home Office with large amounts of summary
information relating to the studies, and the Home Office inspection
programme specifically targeted the operative procedures and post-operative
care of the animals. Nevertheless the complete picture of events only became
clear when substantial additional resource was found for all of the original
study documentation, not previously available to the Home Office or Uncaged,
to be scrutinised in detail.

6.3 Although compliance on most fronts was confirmed, several instances of
non-compliance (most previously detected/reported and dealt with as formal
infringements) are described. In one instance, the apparent delays in
diagnosing irreversible renal failure, I believe some unnecessary animal
suffering did result.

Chief Inspector

ASPI

2001