3 Technology evaluation and the role
of the scientific gatekeeper
30. Given the risk posed by prion transmission and
the inability of existing measures to fully mitigate this risk,
efforts are continuing, both in the public and private sectors,
to develop new technologies for prion detection, inactivation
and removal. The primary customers for these technologies are
UK Blood Services and the NHS, access to both of which is typically
mediated by one of several scientific bodies responsible for assessing
the evidence to support technology adoption. Through the discussion
of three case studies, this chapter examines the Government's
approach to the evaluation of vCJD risk mitigation technologies,
with particular focus on the role played by these scientific gatekeepers.
Case study 1: decontamination
of surgical instruments
THE TECHNOLOGY: DUPONT'S RELY+ON
PRION INACTIVATOR
31. According to the Department of Health's Decontamination
Science Working Group, the risk to public health posed by surgical
prion transmission is "not thought to be great".[92]
However, "as it is known that a substantial number of people
in the UK are carrying the abnormal prion protein that is responsible
for the transmission of vCJD [
], it cannot be assumed that
there is no risk".[93]
In response to this threat, the Government has dedicated significant
funds to the field of decontamination science, valuing its current
programme of research into this area at approximately £3.4
million.[94] This includes
work focused on the development of new coatings for surgical instruments
and "novel decontamination processes such as plasma technology",
as well as "a substantial research project" looking
at "novel ways to detect protein on surgical instruments".[95]
32. According to Professor John Collinge, Director
of the MRC Prion Unit, this investment follows on from a similar
"directed programme" of decontamination research, worth
"I think [
] over £10 million", initiated
in the mid-2000s.[96]
This was intended to encourage research groups to develop novel
ways of removing prions from the surface of surgical instruments
and resulted in the creation of "several solutions and products",
one of which was based on a technology developed by the (publicly-funded)
MRC Prion Unit itself. This technology was later commercialised
by DuPont.[97] Dr Kelly
Board, a Technical Specialist at DuPont, explained how this partnership
came about:
Our former technical director at DuPont [Dr Crout]
approached Professor Collinge's group after seeing their research
demonstrating prion inactivation on surgical instruments using
surfactants and a blend of enzymes. Our company has marketed a
high-level disinfectant for surgical instruments called Rely+On
Perasafe since 1998, and Dr Crout saw an opportunity to incorporate
this disinfectant technology with that of the MRC Prion Unit.[98]
According to Dr Board, the resulting product, the
Rely+On Prion Inactivator, "rapidly reduces the potential
risk of prion transmission in biosurgical instruments through
use of a manual pre-soak product prior to the usual decontamination
methods".[99] Dr
Board added that the product's performance had been validated
multiple times and had been shown to reduce the risk of infection
"by greater than 1 million fold".[100]
Rely+On was launched in May 2007 and was subsequently evaluated
by the Government's Rapid Review Panel during 2008 and 2009.[101]
THE GATEKEEPER: THE RAPID REVIEW
PANEL
33. The Rapid Review Panel (RRP) is an "independent
arms-length" scientific advisory committee hosted by Public
Health England (PHE).[102]
It is responsible for providing "a prompt assessment of new
and novel equipment, materials and other products or protocols
that may be of value to the NHS in improving hospital infection
control and reducing hospital acquired infections", including
those caused by prions.[103]
According to Dr Paul Cosford, PHE Medical Director, the RRP was
set up "in the early 2000s at the specific request of UK
chief medical officers" as "a specific means of rapidly
reviewing new technologies and new ways of providing for hospital
infection control".[104]
The Government stressed that, despite its mandate to assess and
make recommendations about the potential value of new technologies,
it was not within the RRP's remit to "influence procurement
and the 'uptake' of products into the NHS".[105]
34. Following assessment by the RRP, a new technology
can receive one of eight recommendations. To obtain recommendation
1, the highest level of endorsement, the RRP must conclude that
scientific evaluation of the product has "shown benefits
that should be available to NHS bodies to include as appropriate
in their cleaning, hygiene or infection control protocols".[106]
In 2008, DuPont's Rely+On Prion Inactivator received the second
highest level of recommendation, recommendation 2, which recognised
that "basic research and development" had been completed
and that "the product may have potential value", but
recommended that further "in-use evaluations/trials"
take place "in an NHS clinical setting".[107]
35. Despite receiving this recommendation, DuPont
put further development of its product "on hold" in
2010.[108] It gave
two main reasons for this decision:
· Difficulties
trialling the product in an NHS setting:
DuPont stated that it experienced difficulty in fulfilling the
RRP's recommendation that it conduct further evaluation of its
product in an NHS setting, as arranging "meaningful NHS trials"
proved to be "incredibly challenging".[109]
According to Dr Board, "it was very difficult for us to obtain
approval to trial the product in healthcare settings" and,
although the company made "several attempts" to conduct
such trials, "only one materialised".[110]
(Dr Board stated that this trial was "successful".[111])
The obstacles involved in initiating a UK clinical trial were
well-documented in our own 2013 report on the subject.[112]
· Poor likelihood
of NHS uptake: According to DuPont, while
acknowledging that Rely+On "may have potential value",
the RRP nevertheless "indicated that a pre-soak decontamination
method would not obtain widespread use [in the NHS] while the
prevalence of vCJD in the population remained unclear".[113]
This was partly a result of the product's incompatibility with
existing processes: as a pre-soak product, use of Rely+On would
involve introduction of "an additional step to the decontamination
process".[114]
An Infection Prevention Product Specialist assigned by the Government
to work with RRP applicants advised DuPont that "unless a
much higher risk to the public" became apparent, such a change
in procedure was "unlikely to be recommended in authoritative
guidance" and DuPont's product was "therefore unlikely
to be widely used".[115]
Dr Board stated that this lack of a regulatory driver for product
use was the "primary" barrier to further investment
and development.[116]
Professor Collinge stated that it was "perhaps
not surprising" that DuPont's product had not been adopted
by hospitals, as the NHS was "notoriously resistant to change".[117]
Nevertheless, he said that he considered it "quite extraordinary"
that a product which was the result of research directly funded
by the Government, and which successfully tackled a problem acknowledged
by the Department of Health, had not been put to use.[118]
DuPont stated that it had not received any return on the investment
that it made in this product and that there would need to be "significant
justification" for it to re-start development.[119]
36. The Minister stated that she was aware of Professor
Collinge's criticism of the Government's handling of this issue
but that there was "nothing to stop" DuPont from "taking
matters further [by] going back to the rapid review panel and
doing further development and further tests".[120]
She added:
As far as I can see, no barriers have been put
in the way of this product, but there is still some way to go
for the people behind it to prove that it can be effective and
cost-effective.[121]
Dame Sally repeated the RRP's view that "in-use
evaluation trials" were now needed "in an NHS clinical
setting" and stated that it was "for the company to
do that".[122]
37. Given the
NHS's resistance to change and the well-documented challenges
associated with initiating a UK clinical trial, the Minister's
assessment that "no barriers" were put in the way of
DuPont's prion inactivation product does not reflect the reality
of the situation. Where technologies are developed in direct response
to Government needand on the back of Government fundingthe
Government must be prepared to take steps to help companies overcome
barriers to adoption. We ask the Government
to set out how, in future, it will ensure that the directed research
that it funds is better supported through the technology readiness
pathway. In particular, we ask the Government to set out how it
will ensure that promising clinical technologies are promptly
trialled in an NHS setting, so that potential adoption challenges
can be quickly identified and resolved.
38. We also
question the value of a scientific review panel which has no mandate
or power to ensure that the products that it recommends can be
tested in, and eventually adopted by, the NHS. We see this as
further evidence of the Government's passive approach to technology
uptake. We propose that the Rapid Review
Panel (RRP) be given stronger powers to ensure that its recommendations
open the door to in-use evaluation and stimulate NHS uptake.
The Code of Practice for Scientific Advisory Committees
39. As a Scientific Advisory Committee (SAC), the
RRP falls within the scope of both the Government Office for Science's
2011 Code of Practice for Scientific Advisory Committees ("the
Code") and its 2010 Principles of scientific advice
to government ("the Principles").[123]
The Principles, which set out the "rules of engagement"
for the relationship between the Government and its scientific
advisers, highlight the need for "transparency and openness"
and state that "scientific advice to government should be
made publicly available unless there are over-riding reasons[124]
[
] for not doing so".[125]
The Code likewise states that "SACs should operate
from a presumption of openness" and sets out several measures
to achieve this.[126]
These include publishing, "as a minimum, programmes of work,
meeting agendas, minutes, final advice (where appropriate) and
an annual report".[127]
The Code also stipulates that "Chairs and members should
declare any interests they have that are relevant to the remit
of the SAC" and that these should be published as part of
the annual report.[128]
With the exception of brief statements communicating the results
of individual technology assessments, none of this information
currently appears to be available for the RRP.[129]
In particular, there was no evidence of any annual report having
been prepared or published and no declaration of interests from
the RRP's Chair or members. (We did not receive evidence from
the RRP as part of this inquiry.)
40. In our view,
all Scientific Advisory Committees should adhere to both the 2010
'Principles of Scientific Advice to Government' and the 2011 'Code
of Practice for Scientific Advisory Committees'. We were disappointed
to find that the Rapid Review Panel (RRP) failed to do so. We
recommend that the Chief Medical Officer takes action to rectify
current weaknesses. We request a progress report be sent to us
well before the dissolution of Parliament.
Case study 2: prion filtration
THE TECHNOLOGY: PROMETIC'S P-CAPT
PRION FILTER
41. Prion filtration is a process through which prions
are physically removed from blood through the use of highly specific
resin ligands, in order to "provide increased protection
against the transmission of vCJD via blood and blood-derived products".[130]
One group heavily involved in the development of this technology
is the UK-based company ProMetic BioSciences ("ProMetic").
In 2002, ProMetic established a joint venture with the American
Red Cross aimed at developing materials "with the ability
to capture and remove prion proteins from a wide variety of biological
source materials including blood, red cells, plasma and plasma
proteins".[131]
Four years later, following what ProMetic termed "extensive
performance and safety testing", the P-Capt prion filtration
device obtained its CE mark,[132]
making it "the world's first prion-filtration product acknowledged
to increase the safety of red blood cell concentrate".[133]
At this point, the product became subject to further scientific
evaluation, led by the Advisory Committee on the Safety of Blood,
Tissues and Organs (SaBTO).
THE GATEKEEPER: THE ADVISORY COMMITTEE
ON THE SAFETY OF BLOOD, TISSUES AND ORGANS
42. SaBTO is an independent scientific advisory committee
responsible for advising "UK ministers and health departments"
on "the most appropriate ways to ensure the safety of blood,
cells, tissues and organs for transfusion/transplantation".[134]
As part of its remit, SaBTO is specifically tasked with considering
the "cost-effectiveness of interventions, including the introduction
of new safety measures" such as prion filtration.[135]
43. In 2006, SaBTO initiated its evaluation of ProMetic's
P-Capt device.[136]
This consisted of three stages:
i) UK
Blood Service studies.
According to Professor Marc Turner, SaBTO, in 2006 UK Blood Services
were asked to "commission and carry out a number of independent
studies" to demonstrate the P-Capt filter's safety and efficacy
"in the real word".[137]
This included a series of laboratory studies and the PRISM A trial,
which was intended to detect any adverse effects from use of prion-filtered
red blood cells in a clinical setting.[138]
Professor Turner stated that these studies "broadly showed
that the filters were safe and were not causing any adverse impact
to patients".[139]
ii) First
set of efficacy evaluations. An initial
set of efficacy evaluations, conducted by the Health Protection
Agency (HPA, now Public Health England) and completed in 2009,
showed that the P-Capt filter "removed infectivity"
from test samples, "though not to the same extent as in the
studies reported by the manufacturer".[140]
Nevertheless, SaBTO concluded that the study supported the hypothesis
that "prion infectivity" could "be removed by the
filter" at levels high enough to confer protection on transfusion
recipients.[141]
iii) Second
set of efficacy evaluations. The second
set of efficacy evaluations consisted of two studies; one, in
hamsters, conducted by the HPA and one, in sheep, conducted by
the Roslin Institute. Interim results were reported to SaBTO in
March 2012;[142] to
our knowledge, final results have not yet been published in a
peer-reviewed journal.
Following completion of the first set of efficacy
evaluations in 2009, SaBTO concluded that there was "sufficient
evidence" to suggest that the P-Capt filter was effective
in reducing prion infectivity and recommended that "filtered
red cells be provided to those born since 1 January 1996, subject
to satisfactory completion of the PRISM clinical trial".[143]
The PRISM study was completed and reported positive results in
March 2012;[144] however,
at this time SaBTO received interim results from the second set
of efficacy evaluations and decided that "no final decision"
should be made until "further data on efficacy is available
with respect to both the ongoing hamster and sheep studies and
the final result of the current human appendix prevalence study".[145]
In its evaluation of ProMetic's P-Capt device, SaBTO also drew
on a cost-effectiveness analysis conducted on its behalf by the
Department of Health's Health Protection Analytical Team.[146]
In December 2012, having reviewed all of the available data, SaBTO
decided to rescind its initial recommendation.[147]
Prion filtration has therefore not been adopted by UK Blood Services
and ProMetic has, to date, received no return on its $50 million
(approximately £30 million) investment in this technology.[148]
According to the UK Blood Services Prion Working Group, research
conducted as part of this evaluation process cost upwards of £5.2
million.[149]
44. ProMetic criticised several aspects of this evaluation
process and stated that it "strongly believed" SaBTO's
2012 reversal of its provisional recommendation "to be motivated
by considerations other than filter efficacy".[150]
ProMetic was particularly critical of the length of time taken
to complete the PRISM A study (approximately 5 years), a technical
issue in one of the hamster studies which it claimed compromised
the filter's performance and the decision to test the filter in
sheep, which it had previously demonstrated was "not an appropriate
model" for determining the efficacy of the filter when used
on human blood.[151]
However, Dr Lorna Williamson, Medical and Research Director at
NHS Blood and Transplant (and also a member of SaBTO), stated
that these results had been "considered in the round"
alongside other evidence and that she was "happy" with
SaBTO's recommendation.[152]
45. We do not
wish to question the scientific decision-making of the Advisory
Committee on the Safety of Blood, Tissues and Organs (SaBTO) and
we respect its decision not to recommend adoption of prion filtration
at present. However, we feel that the time taken to reach this
decision was excessive and that the process, particularly in its
latter stages, entailed an unnecessary level of uncertainty for
the commercial developer. We have some sympathy for SaBTO's desire
to wait until more evidence was available before making a decision;
however, if industry is to continue to develop innovative blood
safety products for the UK market, SaBTO must introduce greater
speed and predictability into its evaluation process. We
recommend that, in future, when assessing a new technology, SaBTO
agree with stakeholders at the outset what the evaluation will
consist of, together with key dates, milestones and decision-points.
This 'evaluation roadmap', and any subsequent amendments, should
be made publicly available to ensure maximum transparency and
accountability.
46. We also
consider it important that the health technology appraisals conducted
by SaBTOand all other SACsuse the same methodology
and meet the same high standards as those undertaken by the UK's
centre of excellence for this activity: NICE. We
therefore recommend that the Government Office for Science work
with NICE over the next 12 months to develop and publish a standard
methodology for all SACs tasked with conducting health technology
appraisal. Until this guidance is published, we recommend that
a NICE representative review and, where necessary, provide input
to all such appraisals undertaken by, and on behalf of, SACs.
SaBTO's relationship with Government
47. The Government Office for Science's 2011 Code
of Practice for Scientific Advisory Committees ("the
Code") and its 2010 Principles of scientific advice
to government ("the Principles") both highlight
the importance of scientific advisors maintaining a level of independence
from Government.[153]
The Code, in particular, states that Scientific Advisory Committees
(SACs) such as SaBTO should "expect to operate free of influence
from the sponsor department officials" and that members should
be "professionally impartial in their activity" on behalf
of the SAC.[154]
48. Under its terms of reference, SaBTO is responsible
for providing advice to "Ministers of the UK Government and
the Devolved Administrations as well as UK Health Departments".[155]
It is not sponsored by, and its advice is not formally directed
at, any of the four UK Blood Services. However, SaBTO's Code of
Practice acknowledges that its advisory role extends to "UK
Blood Services [
] and to the NHS more widely" and many
of its recommendations are implemented by these organisations.[156]
At present, two members of SaBTO also hold senior management roles
in UK Blood Services: Dr Lorna Williamson, Medical and Research
Director of NHS Blood and Transplant (NHSBT), and Professor Marc
Turner, Medical Director of the Scottish National Blood Transfusion
Service (SNBTS). NHSBT is an NHS Special Health Authority and,
as such, "can be subject to ministerial direction".[157]
SNBTS is a division of NHS National Services Scotland, a non-departmental
public body of the Scottish Government.[158]
49. As well as being members of SaBTO, Dr Williamson
and Professor Turner are also members of UK Blood Services' Joint
Professional Advisory Committee (JPAC), which is responsible for
developing UK-wide operational policies, often drawing heavily
on SaBTO's advice.[159]
According to JPAC, this advisory relationship between SaBTO and
UK Blood Services also operates in reverse, as "much of the
detailed evidence on which SaBTO deliberates is the result of
work by Blood Services staff" and other Blood Service advisory
committees reporting in to JPAC.[160]
During the period in which ProMetic's prion filtration device
was being evaluated, Professor Turner was also Chair of both SaBTO's
prion sub-group and the UK Blood Services Prion Working Group.
50. Scientific
Advisory Committees should beand be seen to beindependent
of the bodies to which they are providing advice. At present,
the Advisory Committee on the Safety of Blood, Tissues and Organs
(SaBTO) comprises members who are both contributing to, and acting
on, the advice that it formulates. We consider that this could
be damaging to its perceived independence and a source of potential
conflicts of interest. We recommend that
SaBTO's terms of reference be amended to reflect the fact that
it does, in effect, provide advice to UK Blood Services as well
as the Government. We suggest that SaBTO's current membership
be reviewed and potentially revised in light of this change.
Case study 3: vCJD blood testing
THE NEED FOR A VCJD BLOOD TEST
51. A key strand in UK Blood Services' strategy for
preventing transfusion-transmitted infections is the use of blood
tests to enable those donations carrying known pathogens to be
identified and discarded.[161]
Unfortunately, this is not currently a viable strategy for mitigating
the risk of vCJD transmission because no suitable high-throughput
test currently exists. Witnesses were unanimous in their support
for the development of such a test. Professor Sheila Bird, MRC
Biostatistics Unit, expressed concern that the absence of a vCJD
blood test meant that we could not protect the blood supply from
prions in the same way that we can protect it from other pathogens,
such as hepatitis B and C and HIV, and stated that development
of a validated test should "undoubtedly" be a research
priority.[162] Professor
Richard Knight, Director of the National CJD Research and Surveillance
Unit ('the surveillance unit'), agreed that development of a test
was "extraordinarily important" and "would be a
great boon in all sorts of ways".[163]
In addition to its potential screening applications, witnesses
highlighted the role that a blood test could play in providing
certainty to patients thought to be at risk of vCJD. Joseph Peaty,
TaintedBlood, told us that, some years ago, it had "looked
very much" as though he was suffering from the early signs
of vCJD.[164] He explained:
It would have been incredibly helpful if we had
had access to [a test] at that point to identify, "Is this
the onset of variant CJD, or is it where these viruses overlap
and you've got HIV? Perhaps the medication, or perhaps hepatitis
C, is affecting the brain in some way." I had to go through
brain scans and vigilance for a number of months. I had insomnia,
where I hardly slept for three months. I was incredibly depressed
and anxious.[165]
The Government did not explicitly state its support
for the development of this technology but acknowledged that a
test "may be advantageous".[166]
52. The number of research groups working to develop
a vCJD blood test has fallen in recent years. According to Professor
Marc Turner, Advisory Committee on the Safety of Blood, Tissues
and Organs (SaBTO), "looking back a decade or so ago, there
were probably [
] a dozen or more different research groups
and commercial companies working" in this area. Now, however,
"there are really only two or three".[167]
Professor Turner stated that the "most advanced test by far"
was the one currently being developed by the MRC Prion Unit, a
publicly-funded research group led by Professor John Collinge.[168]
In addition, Prionics AG, a Swiss company, has continued to conduct
work in this area, as has the Scottish National Blood Transfusion
Service, working in partnership with the national surveillance
unit.[169]
THE TECHNOLOGY: THE PRIONICS BLOOD
TEST
53. Prionics AG is a developer of diagnostic tests
for major livestock diseases.[170]
In 2001, when surveillance programs for BSE became mandatory in
the European Union, Prionics "pioneered" the use of
in-situ rapid diagnostic tests and, today, the company continues
to develop diagnostic tools for prion diseases such as vCJD.[171]
According to Prionics, it has made a "significant investment"
in this area, spending "5 million to 10 million"
on the development of prototype vCJD blood tests since 2002.[172]
In 2009, NHS Blood and Transplant (NHSBT) issued a tender for
the development of a diagnostic test for use in vCJD blood screening.
Following a successful bid, Prionics was awarded a framework contract
pending further evaluation of its test by the National Institute
of Biological Standards and Controls (NIBSC), the body tasked
with maintaining and managing the distribution of rare vCJD blood
samples.[173]
THE GATEKEEPER: THE NATIONAL INSTITUTE
OF BIOLOGICAL STANDARDS AND CONTROLS
54. The National Institute of Biological Standards
and Controls (NIBSC) is a body of the Medicines and Healthcare
Products Regulatory Agency, an Executive Agency of the Department
of Health.[174] It
hosts the CJD Resource Centre, which exists to "help research
scientists obtain characterised materials for studying and developing
diagnostic tests" for all forms of CJD.[175]
55. In order to develop a diagnostic blood test,
it is necessary for researchers to have access to blood samples
from people who have suffered from the target infection. In the
case of common blood-borne pathogens such as hepatitis B and HIV,
such samples can be easily obtained. However, because vCJD is
such a rare disease, patient samples are extremely scarce.[176]
In the UK, the majority of samples from confirmed vCJD cases are
initially collected and stored at either the surveillance unit
or the MRC Prion Unit.[177]
According to the NIBSC, following requests for access to these
samples from several test developers in the mid-2000s, the Government
concluded that access should be "controlled" and only
granted to those developers whose tests were most likely to be
successful.[178] In
2007, an Oversight Committee was established within the CJD Resource
Centre to "perform evaluations" of prototype tests and
"manage the distribution of samples" according to a
standard protocol.[179]
According to Dame Sally Davies, Chief Medical Officer, the NIBSC
currently holds samples from 16 individual vCJD patients: equivalent
to approximately "one and a half tablespoons" of blood.[180]
56. In order to gain access to these samples, test
developers require NIBSC approval. However, according to the NIBSC,
"it was agreed at the start of the [CJD Resource] Centre's
existence" that the two primary centres of UK prion researchthe
national surveillance unit and the MRC Prion Unitshould
be exempt from this process in order to avoid "unreasonably"
restricting their research work.[181]
Additional samples are therefore currently held and used by these
units and, on occasion, are provided directly to other test developers
without recourse to the NIBSC evaluation process.[182]
57. Several witnesses expressed concern about the
way in which access to vCJD samples was controlled in the UK.
Christine Lord, mother of vCJD victim Andrew Black, pointed out
that the Government held "all the keys" to vCJD test
development and claimed that a "few select scientists and
Government officials" held "a monopoly" over this
research area.[183]
Mrs Lord added that relatives of victims had been "thwarted
and blocked" in their attempts to share blood samples with
foreign research groups.[184]
Dr Alex Raeber, Head of Research and Development at Prionics AG,
agreed that, "as a foreign company", Prionics was "not
treated in the same way as other stakeholders" and had faced
"big challenges" in obtaining access to samples.[185]
According to Dr Raeber, while the NIBSC had done "an excellent
job" in setting up the test validation process, the number
of samples made available through this process was "very
limited".[186]
Prionics' test was evaluated on the basis of two samples from
known vCJD patients and, on the basis of this evaluation, was
deemed "not sufficiently fit for purpose".[187]
The test was never used by UK Blood Services.
58. Dr Raeber criticised this evaluation process,
stating that it was "really not adequate" for the NIBSC
to validate the efficacy of his company's test on the basis of
only two samples[188],
particularly given that there was no guarantee that prions were
present in these particular samples.[189]
Professor Sheila Bird, MRC Biostatistics Unit, agreed that the
statistical significance of this evaluation was questionable and
pointed out that "provision of fewer than five or six vCJD
samples within a blind panel of 500" was an "inadequateor
very harsh" statistical assessment to which to submit a prototype
test.[190] In contrast,
the test developed by the MRC Prion Unit (discussed below) has
so far been validated on the basis of 21 samples from known vCJD
cases, all sourced directly from its own collection of patient
samples.[191] In response
to these criticisms, the NIBSC stated that its process was "open
to all" and that, in fact, "most interactions"
had been with non-UK developers rather than UK companies.[192]
It acknowledged that it was "not ideal that only two samples
were made available" to Prionics, but stressed that this
decision was made only after "substantial discussion in the
Oversight Committee".[193]
59. We understand
the need to carefully control access to rare vCJD samples and
commend the National Institute of Biological Standards and Controls
(NIBSC) for putting in place a standard protocol for test validation.
However, we are disappointed that so few samples are currently
held by the NIBSC and consider its process to be undermined by
the fact that the two major centres of UK prion researchthe
National CJD Research and Surveillance Unit and the MRC Prion
Unitcan each use and distribute samples independent of
NIBSC evaluation. All test developers
should be given equal opportunity to gain access to the available
samples and these should be distributed on the basis of merit
alone. We recommend that access to all vCJD patient samplesincluding
those currently held elsewhere in the UKbe managed through
the NIBSC, according to a consistent set of test validation protocols.
60. We were
also concerned by the apparent statistical weakness of past NIBSC
evaluations. We recommend that the CJD
Resource Centre Oversight Committee add to its membership an individual
with expertise in biostatistics, who can provide it with expert
advice on this matter during future deliberations.
THE TECHNOLOGY: THE MRC PRION UNIT
BLOOD TEST
61. The MRC Prion Unit was established in 1998 and
is located at the UCL Institute of Neurology.[194]
It was formed "to provide a national centre of excellence
with all necessary facilities to pursue a major long-term research
strategy in prion and related diseases".[195]
The Unit undertakes research across a wide-range of topics and
aims to "seamlessly combine basic (laboratory) and clinical
(patient-based) research" in order to enable "better
early diagnosis, prevention, and effective treatment" of
prion disease.[196]
It receives approximately £6 million per year from the Medical
Research Council and is led by John Collinge, Professor of Neurology
and Head of the Department of Neurodegenerative Disease at the
UCL Institute of Neurology.[197]
62. In February 2011, the Unit announced that it
had developed a prototype blood test capable of detecting "blood
spiked with a dilution of vCJD to within one part per ten billion100,000
times more sensitive than any other method developed so far".[198]
In this study, the prototype test returned no false positives
from 100 control samples and accurately identified 15 of 21 samples
taken from known vCJD patients as positive, indicating that the
test was 100% specific and approximately 70% sensitive.[199]
In a larger follow-up study published in early 2014, the prototype
was tested on 5,000 control samples (from US citizens considered
not to have been exposed to BSE) and a subset of the vCJD samples
previously used in the 2011 study. It again demonstrated 100%
specificity and 70% sensitivity.[200]
63. Professor Collinge stated that the next logical
step in the test's development would be to carry out a larger
'population prevalence' study in which the prototype would be
used to test 20,000 UK blood samples and 20,000 US blood samples,
at an estimated cost of £750,000.[201]
According to Professor Collinge, if, during this study, the test
returned positive results only from UK samples, two things could
be concluded:
One is that our test is capable of detecting
[vCJD] carriers, which we don't formally know yet: we have simply
looked at [vCJD] patients. Secondly, we would have confirmed that
there is, indeed, a problem in the British donor core. In our
view, that piece of research is required to make the case to progress
that test further.[202]
A proposal for this study was considered by the MRC
in March 2013, but was rejected, in part because of the test's
"low level of sensitivity".[203]
According to the MRC:
the Unit was advised to consider ways to improve
the test sensitivity to provide greater confidence of identification
of infected people, in order to make the test more accurate for
prevalence studies and more attractive for development into a
screening test.[204]
Professor Collinge disputed the MRC's decision, claiming
that the recommended steps constituted "test development
work" which lay outside of his unit's area of expertise.[205]
He added that, in the view of his Unit's "statistical advisers",
the test's sensitivity was "perfectly adequate to do the
study that we propose to do" and that it may not be possible
to further increase sensitivity because "it could be that
only 70% of people with vCJD have prions in their blood".[206]
Professor Collinge also highlighted that feedback from diagnostics
companies was "very much" that they wanted to see the
results of a larger study "before thinking about whether
they would help us to take [the test] any further"a
view confirmed by several industry representatives.[207]
64. Expert witnesses strongly supported Professor
Collinge's proposal for a UK blood prevalence study; indeed, Dr
Simon Mead, Association of British Neurologists, stated that there
now appeared to be "scientific consensus" on this matter.[208]
Professor Marc Turner, SaBTO, agreed with Professor Collinge that
the test's sensitivity was "pretty good" and considered
a blood prevalence study to be "the next logical step"
in its development, while Dr Roland Salmon, Acting Chair of the
Advisory Committee on Dangerous Pathogens, considered there to
be "a great deal of scope" for the test to be used for
research purposes in its current state.[209]
Dr Lorna Williamson, NHS Blood and Transplant (NHSBT), took a
similar view:
I think we are all in agreement that the next
step, if there were a medium throughput test available, would
be to conduct a study of the UK population using blood samples
to understand what the frequency of prion infection in the blood
actually is.[210]
The Government, however, stated that there were "currently
no tests suitable" for this purpose and was non-committal
in its support for further test development work.[211]
Dame Sally Davies, Chief Medical Officer, stressed that the
Government had "limited budgets for healthcare, public health
and research" and that it had previously "given a lot
of money to this area of prion research, particularly to Professor
Collinge".[212]
The Minister said that she was "open-minded to receiving
advice" on this matter, but added that she was "pretty
satisfied that, proportionate particularly to the number of cases
and deaths over the last 10 years or so, there is a good body
of work going on at the moment".[213]
65. The
incubation period of prion diseases such as vCJD can extend to
several decades and it is therefore possible that individuals
infected in the 1990s might not yet have developed symptoms. We
do not follow the Minister's logic that there should be a link
between the number of cases seen in the last ten years and the
level of resource dedicated to prion research. We simply do not
know, at present, how many people have been exposed to prions
and what the implications of this might be for the blood donor
pool. There is an urgent need to reduce this uncertainty.
66. Based on
the testimony that we have heard, we consider that a vCJD blood
prevalence study utilising a version of the prototype test developed
by the MRC Prion Unit would be of considerable value, both for
test development and research purposes. We recognise that significant
public funds have already been directed towards the development
of this test; we view this as even more reason to ensure that
a return on this investment is realised. To cut off support now
would be a false economy. We recommend
that the Government ensures that a large-scale vCJD blood prevalence
study be initiated in the UK within the next 12 months.
92 BTO20 para 3 [DH DSWG] Back
93
BTO20 para 3 [DH DSWG] Back
94
BTO55 [Government supplementary] Back
95
BTO20 paras 7-9 [DH DSWG]. See also BTO55 [Government supplementary] Back
96
Oral evidence taken on 27 November 2013, HC (2013-14) 846, Q43 Back
97
Oral evidence taken on 27 November 2013, HC (2013-14) 846, Q43 Back
98
Q67 Back
99
Q67 Back
100
Q67 Back
101
Q67 Back
102
Public Health England, 'Rapid Review Panel', hpa.org.uk, accessed
30 June 2014 Back
103
Public Health England, 'About the Rapid Review Panel', hpa.org.uk,
accessed 30 June 2014; BTO31 para 53 [Government] Back
104
Q263 Back
105
BTO31 para 52 [Government] Back
106
Public Health England, 'Recommendation statements by the Rapid Review Panel',
hpa.org.uk, accessed 30 June 2014 Back
107
Q73 [Dr Kelly Board]; Public Health England, 'Recommendation statements by the Rapid Review Panel',
hpa.org.uk, accessed 30 June 2014 Back
108
Q67 [Dr Kelly Board] Back
109
BTO44 [DuPont] Back
110
Q117 Back
111
Q117 Back
112
Science and Technology Committee, Third Report of Session 2012-13,
'Clinical Trials', HC104 Back
113
BTO44 [DuPont] Back
114
Q117 [Dr Kelly Board] Back
115
BTO44 [DuPont] Back
116
Q117 Back
117
Oral evidence taken on 27 November 2013, HC (2013-14) 846, Q43.
Note: the NHS's slow uptake of new technologies has also been
documented in several other reports, including: Science and Technology
Committee, Eighth report of session 2012-13, 'Bridging the valley of death: improving the commercialisation of research',
HC348; The King's Fund, 'Technology in the NHS: Transforming the patient's experience of care',
2008; The Medical Technology Group. 'Medical technology: can we afford to miss out?',
2009. See also: 'NHS is "resistant to change" and "difficult
to work with", says survey', PF Discovery, 19 November
2011 and 'Resistance to change in NHS "has cost thousands
of lives", The Times, 1 July 2014. Back
118
Oral evidence taken on 27 November 2013, HC (2013-14) 846, Qq43-44.
See also Q125 [Professor John Collinge] Back
119
Q73; Q123 [Dr Kelly Board] Back
120
Q303 Back
121
Q303 Back
122
Q302 Back
123
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011; Government Office for Science, Principles of scientific advice to Government,
2010 Back
124
"Such as national security of the facilitation of a crime". Back
125
Government Office for Science, Principles of scientific advice to Government,
2010 Back
126
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011, para 72 Back
127
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011, para 116 Back
128
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011, para 49 Back
129
Based on a review of Public Health England, 'Rapid Review Panel'
(and associated pages), hpa.org.uk, accessed 30 June 2014 Back
130
BTO12 [ProMetic]; A biological ligand is a molecule that bind
to a protein with a high degree of specificity. Examples are the
substrate of an enzyme and a hormone binding to a cell receptor. Back
131
BTO12 para 3 [ProMetic] Back
132
CE marking is required for many products traded across the European
Economic Area and "attests the verification by a manufacturer
that these products meet EU safety, health or environmental requirements".
See 'CE marking', gov.uk for more information. Back
133
BTO12 para 6 [ProMetic] Back
134
Advisory Committee on the Safety of Blood, Tissues and Organs,
'Homepage', Government.uk, accessed 30 June 2014 Back
135
Advisory Committee on the Safety of Blood, Tissues and Organs,
'Terms of Reference', Government.uk, accessed 30 June 2014 Back
136
According to NHSBT, ProMetic, alongside another prion filtration
developer, was also invited to meet regularly with the UK Blood
Services Prion Removal Working Group, a group set up in 2005 to
evaluate new commercial filters (BTO14 para 26 [UKBS PWG]). Back
137
Q49 Back
138
Q124 [Dr Steven Burton]; BTO53 [ProMetic supplementary] Back
139
Q49 Back
140
Advisory Committee on the Safety of Blood, Tissues and Organs,
Minutes of the eighth meeting, 27 October 2009, para 6.9 Back
141
Advisory Committee on the Safety of Blood, Tissues and Organs,
Minutes of the eighth meeting, 27 October 2009, para 6.10 Back
142
Advisory Committee on the Safety of Blood, Tissues and Organs,
Final minutes of the sixteenth meeting, 9 March 2012, para 4.19-21 Back
143
Advisory Committee on the Safety of Blood, Tissues and Organs,
Summary of the eighth meeting, 27 October 2009, para 3 Back
144
See: Elebute et al, 'Transfusion of prion-filtered red cells
does not increase the rate of alloimmunization or transfusion
reactions in patients: results of the UK trial of prion-filtered
versus standard red cells in surgical patients (PRISM A)',
British Journal of Haematology, Volume 160, Issue 5, pp.701-708,
March 2013. DOI: 10.1111/bjh.12188 Back
145
Advisory Committee on the Safety of Blood, Tissues and Organs,
Final minutes of the sixteenth meeting, 9 March 2012, para 4.22.
Note: the appendix study referred to was reported to SaBTO in
September 2012 and was published in October 2013. See O Noel Gill
et al, Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey,
British Medical Journal, Volume 349, Issue 7929. BMJ2013;347:f5675 Back
146
SaBTO, Prion reduction filters for red cell concentrates,
Eighteenth meeting, Agenda item 4, 10 December 2012 Back
147
Q49; Q56; Advisory Committee on the Safety of Blood, Tissues
and Organs, Final minutes of the eighteenth meeting, 10 December
2012, para 4.1-3 Back
148
Q69-72 [Dr Steven Burton] Back
149
BTO14 pars 23 [UKBK Prion Working Group] Back
150
BTO53 [ProMetic supplementary] Back
151
BTO53 [ProMetic supplementary] Back
152
Q252-254 Back
153
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011; Government Office for Science, Principles of scientific advice to Government,
2010 Back
154
Government Office for Science, Code of Practice for Scientific Advisory Committees,
2011, paras 31-32 Back
155
Advisory Committee on the Safety of Blood, Tissues and Organs,
Terms of Reference, Government.uk, accessed 30 June 2014 Back
156
Advisory Committee on the Safety of Blood, Tissues and Organs,
Code of Practice, para 7, Government.uk, accessed 30 June 2014 Back
157
NHSBT. 'Home', nhsbt.nhs.uk. NHS Choices, 'The NHS in England',
nhs.uk. Both accessed 1 July 2014 Back
158
SNBTS, 'About us', scotblood.co.uk. NHS National Services Scotland,
'About us', nhsnss.org. Both accessed 1 July 2014 Back
159
See, for example: JPAC/Health Protection Agency, Position Statement: Blood donor selection to minimise risk of transfusion transmissible infectious agents entering the blood supply,
14 November 2012 and Position Statement: Creutzfeldt-Jakob Disease,
12 November 2012, transfusionguidelines.org.uk, accessed 30 June
2014 Back
160
JPAC. 'About JPAC', transfusionguidelines.org.uk, accessed 30
June 2014 Back
161
BTO30 para 8 and para 11 [JPAC] Back
162
Q147; Q175 Back
163
Q178 Back
164
Q16 Back
165
Q16 Back
166
BTO31 para 33 [Government] Back
167
Q62 Back
168
Q62; MRC Prion Unit, 'About the Unit', prion.ucl.ac.uk, accessed
30 June 2014 Back
169
BTO14 para 28 [UKBS Prion Working Group] Back
170
BTO39 [Prionics] Back
171
BTO39 [Prionics] Back
172
BTO39 [Prionics]; Q73 [Dr Alex Raeber] Back
173
BTO39 [Prionics] Back
174
National Institute for Biological Standards and Control, 'About us',
nibsc.org, accessed 30 June 2014; Medicines and Healthcare Products
Regulatory Agency, 'About us', mhra.Government.uk, accessed 30
June 2014 Back
175
National Institute for Biological Standards and Control, 'CJD Resource Centre',
nibsc.org, accessed 30 June 2014 Back
176
BTO05 para 3 [NIBSC] Back
177
Q103 [Professor John Collinge] Back
178
BTO05 para 3 [NIBSC] Back
179
BTO05 para 12; annex 4 [NIBSC] Back
180
Q292 Back
181
BTO05 para 5 [NIBSC supplementary] Back
182
Q292 [Dame Sally Davies]; Q103 [Professor John Collinge] Back
183
Q3 Back
184
Q15 Back
185
Q102; Q97 Back
186
Q102; Q96 Back
187
Q96 Back
188
These two vCJD samples were contained within a blind panel of
200 samples. Back
189
Q96. See also Mead et al., Variant Creutzfeldt-Jakob Disease
With Extremely Low Lymphoreticular Deposition of Prion Protein,
JAMA Neurology, Volume 71, Issue 3, March 2014. doi:10.1001/jamaneurol.2013.5378 Back
190
BTO51 [Professor Sheila Bird]. Note: while the Prionics test
was evaluated on the basis of two vCJD samples contained within
a blind panel of 200, another company that similarly underwent
evaluation by NIBSC were provided with two vCJD samples in a blind
panel of 500. Back
191
Jackson et al., A highly specific blood test for vCJD,
Blood, Volume 123, pp.452-453, January 2014. doi:10.1182/blood-2013-11-539239 Back
192
BTO50 para 4 [NIBSC supplementary] Back
193
BTO50 para 4 [NIBSC supplementary] Back
194
MRC Prion Unit, 'About the Unit', prion.ucl.ac.uk, accessed 30
June 2014 Back
195
MRC Prion Unit, 'About the Unit', prion.ucl.ac.uk, accessed 30
June 2014 Back
196
MRC Prion Unit, 'About the Unit', prion.ucl.ac.uk, accessed 30
June 2014 Back
197
BTO31 para 20 [Government] Back
198
BTO27 para 21 [MRC]. See also Edgeworth et al., Detection
of prion infection in variant Creutzfeldt-Jakob disease: a blood-based
assay, The Lancet, Volume 377, Issue 9764, pp.487-493, 5 February
2011. doi:10.1016/S0140-6736(10)62308-2 Back
199
Edgeworth et al., Detection of prion infection in variant
Creutzfeldt-Jakob disease: a blood-based assay, The Lancet,
Volume 377, Issue 9764, pp.487-493, 5 February 2011. doi:10.1016/S0140-6736(10)62308-2.
Note: sensitivity refers to the ability of a test to detect an
agent when present. A low level of sensitivity could lead to "false
negatives"-that is, people who receive a negative result
but do actually carry the agent. Specificity refers to the ability
of a test to detect the absence of an agent. A low level of specificity
could lead to "false positives"-that is, people who
receive a positive result who do not in fact carry the agent. Back
200
Jackson et al., A highly specific blood test for vCJD,
Blood, Volume 123, pp.452-453, January 2014. doi:10.1182/blood-2013-11-539239 Back
201
Q87; Oral evidence taken on 27 November 2013, HC (2013-14) 846,
Q14 Back
202
Q87 Back
203
BTO27 para 22 [MRC] Back
204
BTO27 para 22 [MRC] Back
205
Q90 Back
206
Q90. See Mead et al., Variant Creutzfeldt-Jakob Disease With
Extremely Low Lymphoreticular Deposition of Prion Protein,
JAMA Neurology, Volume 71, Issue 3, March 2014. doi:10.1001/jamaneurol.2013.5378 Back
207
Q87 [Professor John Collinge]; Q93-95 [Dr Alex Raeber; Dr Steven
Burton; Nigel Talboys] Back
208
Q161 [Dr Simon Mead] Back
209
Q62 [Professor Marc Turner]; Q63 [Dr Roland Salmon] Back
210
Q244 Back
211
BTO31 para 33 [Government] Back
212
Q288 Back
213
Q287 Back
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